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AL-Noshokaty TM, Abdelhamid R, Abdelmaksoud NM, Khaled A, Hossam M, Ahmed R, Saber T, Khaled S, Elshaer SS, Abulsoud AI. Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential. Toxicol Rep 2025; 14:101895. [PMID: 39911322 PMCID: PMC11795145 DOI: 10.1016/j.toxrep.2025.101895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 02/07/2025] Open
Abstract
Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.
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Affiliation(s)
- Tohada M. AL-Noshokaty
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Rehab Abdelhamid
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | | | - Aya Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mariam Hossam
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Razan Ahmed
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Toka Saber
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shahd Khaled
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Ahmed I. Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt
- Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
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2
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Cai Z, Sun F, Wang Q, Li S, Wang L, Li H, Su Y, Yang H, Dong B. Icariin alleviates cardiomyocyte pyroptosis through AMPK-NLRP3 pathway to ameliorates diabetic cardiomyopathy. Int Immunopharmacol 2025; 156:114690. [PMID: 40262250 DOI: 10.1016/j.intimp.2025.114690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/28/2025] [Accepted: 04/15/2025] [Indexed: 04/24/2025]
Abstract
Among the multitude of pressing global health concerns, diabetes mellitus stands out as a significant issue. An alarming consequence of this condition is diabetic cardiomyopathy (DCM), which represents a critical contributor to mortality in individuals with diabetes. Recently, research has unveiled the pivotal role that pyroptosis plays in the progression of myocardial fibrosis associated with DCM. An epimedial flavonoid monomer, Icariin (ICA), primarily sourced from Epimedium genus plants, has shown a safeguarding influence on cardiac health through various means, encompassing anti-inflammatory actions and its capacity against oxidative stress. Our research endeavor focuses on elucidating the beneficial impacts alongside the underlying physiological processes triggered by ICA within the context of DCM. An animal model representative of DCM was developed through intraperitoneal administration of streptozotocin (STZ). In parallel, in vitro experiments utilized H9C2 cardiomyocytes to mimic hyperglycemic environments relevant to disease states. In vivo experiments found that ICA improved cardiac function, alleviated myocardial fibrosis, and reduced NLRP3-mediated pyroptosis in heart tissue of DCM mice. Under in vitro settings characterized by elevated glucose concentrations, there was a notable elevation in both NLRP3 pyroptosis-associated proteins and oxidative stress markers within the heart muscle cells. ICA treatment attenuated pyroptosis and oxidative stress caused by high glucose in cardiomyocytes. Further studies revealed that when treated with an AMPK inhibitor, the shielding benefits conferred by ICA on cardiomyocytes were negated, suggesting that the regulatory effects of ICA on cardiomyocyte pyroptosis may be achieved through the AMPK-NLRP3 pathway. In conclusion, ICA exerts protective effects in DCM by inhibiting cardiomyocyte pyroptosis, alleviating myocardial fibrosis, and improving cardiac function via the AMPK-NLRP3 pathway.
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Affiliation(s)
- Zhenhao Cai
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China; Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fengxiao Sun
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qingyan Wang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shengnan Li
- Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lanlan Wang
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Huixin Li
- Binhai New Area Hospital of TCM, Tianjin, China
| | - Yudong Su
- Tongnan District Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Hongbo Yang
- Weifang Rehabilitation Hospital, Weifang, China
| | - Bo Dong
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China; Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China; Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
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An Y, Zhao H, He C, Shi L, Su X, Zhang H, Huang Y, Shan Z, Wang M, Du Y, Xie J, Zhao Y, Yang Y, Huang Z, Wan A, Zhao Y, Zhao B. Xiasangju alleviates hepatic insulin resistance in db/db mice via AMPK pathway: Mechanisms and active components study. Int Immunopharmacol 2025; 156:114675. [PMID: 40286785 DOI: 10.1016/j.intimp.2025.114675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/30/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025]
Abstract
Type 2 diabetes mellitus (T2DM), one of the prevalent chronic diseases, significantly impacts individuals and society. Xiasangju (XSJ), a herbal tea formulation, has been commonly used in traditional Chinese medicine. Accumulating evidence suggests that XSJ can alleviate metabolic syndrome by regulating glucose and lipid metabolism, lowering liver index and improving glucose tolerance. In the present study, db/db mice were used to examine the effect of XSJ on treating T2DM, and Western blotting was performed to explore the underlying anti-T2DM pharmacological mechanisms. With AMP-activated protein kinase (AMPK) chosen as the target protein, surface plasmon resonance (SPR)-LC-MS technology was used to identify potential active ingredients of XSJ. To further explore the role of potential active ingredients of XSJ, their effects were investigated in insulin resistance (IR)-HepG2 cells. Our results demonstrate that in diabetic db/db mice, XSJ activated the AMPK pathway, which regulated hepatic glucose metabolism and inhibited oxidative stress caused by hepatic NADPH oxidase 4 (NOX4), thereby ameliorating hepatic IR. By means of SPR-LC-MS experiments, 4-Methylesculetin was identified as an important active ingredient in XSJ. Subsequently, to further elucidate the effects of this ingredient, in IR-HepG2 cells, 4-Methylesculetin was found to mitigate oxidative stress, enhance glucose consumption, and promote glycogen synthesis. This study demonstrated that XSJ improved T2DM and mitigated oxidative stress by activating the AMPK pathway. Specifically, 4-Methylesculetin emerged as a promising therapeutic agent for T2DM.
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Affiliation(s)
- Yongcheng An
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Hongbin Zhao
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Changhao He
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Lu Shi
- Central Laboratories, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao 266001, China
| | - Xiaohua Su
- Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou 510288, China
| | - Huilin Zhang
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yan Huang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Ziyi Shan
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Menglu Wang
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yuhang Du
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jiamei Xie
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yige Zhao
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yang Yang
- Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhiyun Huang
- Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou 510288, China
| | - Anfeng Wan
- Guangzhou Baiyunshan Xingqun Pharmaceutical Co., Ltd., Guangzhou 510288, China
| | - Ying Zhao
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Baosheng Zhao
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
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Foudah AI, Alqarni MH, Balaha MF, Devi S, Alam A. Neuroprotective effect of Bergenin in diabetic neuropathy: modulation of AMPK and NF-κB signaling. Neurol Res 2025:1-18. [PMID: 40377493 DOI: 10.1080/01616412.2025.2504716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Accepted: 05/04/2025] [Indexed: 05/18/2025]
Abstract
AIM AND OBJECTIVES This study explores the therapeutic potential of Bergenin (BER), a plant-derived bioactive compound, in treating diabetic neuropathy, with a focus on its effects on activated protein kinase (AMPK) signaling pathways. METHODOLOGY Diabetic rats were randomly divided into several groups: a control group, an STZ-only group, control groups treated with varying doses of BER (10, 20, and 40 mg/kg), and a group treated with pregabalin (PRE) at 10 mg/kg. After the treatment period, blood samples and sciatic nerve tissues were collected for analysis. RESULTS The results showed that BER, particularly at the highest dose, produced a sustained reduction in blood glucose levels, indicating a potential dose-dependent effect. BER also significantly alleviated cold allodynia, mechanical allodynia, and mechanical hyperalgesia, supporting its promise as a pain management option for diabetic neuropathy. Treatment with 40 mg/kg BER notably reduced oxidative stress markers and boosted antioxidant levels. Additionally, BER inhibited NF-kβ activity, reduced neuroinflammation, and suppressed the production of inflammatory cytokines such as TNF-α and NF-kβ. Activation of AMPK, confirmed by elevated P-AMPK levels, suggests that BER may help restore damaged cellular pathways associated with diabetic neuropathy. CONCLUSION In conclusion, BER demonstrates strong potential as a therapeutic agent, reducing inflammation and oxidative stress while enhancing nerve function, likely through modulation of AMPK signaling pathways.
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Affiliation(s)
- Ahmed I Foudah
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Mohammed H Alqarni
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Mohamed F Balaha
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
- Pharmacology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Sushma Devi
- Chitkara College of Pharmacy, Chitkara University, Rajpura, India
| | - Aftab Alam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
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Zhao YF, Lv JH, Chen DF, Wang ZH, Teng Y, Ntim M, Xia M, Li S, Wang B. Triglyceride-glucose index in predicting gastric cancer prognosis: A need for caution. World J Gastroenterol 2025; 31:104525. [DOI: 10.3748/wjg.v31.i18.104525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/02/2025] [Accepted: 03/27/2025] [Indexed: 05/13/2025] Open
Abstract
Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide. Accurate prognostic assessment, which is essential for enhancing overall survival (OS), currently depends on pathologic and clinical staging. This underscores the urgent need for reliable and real-time prognostic biomarkers. The triglyceride-glucose (TyG) index, a readily available marker of insulin resistance, has recently emerged as a potential prognostic tool in GC. Numerous studies have consistently shown a significant association between elevated TyG levels and inferior OS as well as progression-free survival. Despite these promising findings, several challenges must be addressed before the TyG index can be widely adopted in clinical practice. Firstly, the TyG index lacks cancer-specificity, reflecting broader metabolic disturbances commonly observed in conditions such as obesity, diabetes, and cardiovascular disease. This lack of specificity complicates its interpretation in oncological settings. Additionally, the cutoff values for TyG index vary across studies, hindering the establishment of a standardized threshold for clinical application. While the TyG index provides valuable insights into a patient's metabolic health, its limited cancer specificity necessitates cautious use when evaluating the prognosis of GC treatment.
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Affiliation(s)
- Yi-Fan Zhao
- Liaoning Provincial Key Laboratory of Cerebral Diseases, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Jia-Hui Lv
- Liaoning Provincial Key Laboratory of Cerebral Diseases, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - De-Fang Chen
- Department of Emergency Medicine, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China
| | - Zhi-Hui Wang
- Liaoning Provincial Key Laboratory of Cerebral Diseases, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Yun Teng
- Liaoning Provincial Key Laboratory of Cerebral Diseases, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Michael Ntim
- Liaoning Provincial Key Laboratory of Cerebral Diseases, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research, Dalian Medical University, Dalian 116000, Liaoning Province, China
- Department of Physiology, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi 00233, Ashanti, Ghana
| | - Min Xia
- Liaoning Provincial Key Laboratory of Cerebral Diseases, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Shao Li
- Liaoning Provincial Key Laboratory of Cerebral Diseases, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research, Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Bin Wang
- Liaoning Provincial Key Laboratory of Cerebral Diseases, College of Basic Medical Sciences, National-Local Joint Engineering Research Center for Drug Research, Dalian Medical University, Dalian 116000, Liaoning Province, China
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6
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Song G, Liu N, He J, Tang S, Yu Y, Song L. Exploring the role of Myo-inositol in alleviating insulin resistance in polycystic ovary syndrome through the AMPK/GLUT4 pathway. Mol Biol Rep 2025; 52:454. [PMID: 40358794 DOI: 10.1007/s11033-025-10553-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is a multifactorial disorder associated with insulin resistance, hyperandrogenism, and metabolic dysfunction. Myo-inositol, a promising therapeutic alternative, may improve glucose and lipid metabolism through the 5'-adenosine monophosphate-activated protein kinase (AMPK)-glucose transporter type 4 (GLUT4) pathway. This study aimed to investigate the molecular and metabolic effects of Myo-inositol in a letrozole-induced rat model of PCOS. METHODS AND RESULTS We divided rats into six groups: controls, PCOS, and different doses of Myo-inositol- or metformin-treated groups. We examined the rat blood glucose, insulin, lipid profiles, and hormone levels alongside ovarian histology and AMPK/GLUT4 expression via polymerase chain reaction and western blotting assays. Myo-inositol treatment demonstrated dose-dependent improvements in glucose homeostasis, lipid profiles, and GLUT4 expression, with high-dose treatment reducing glucose by 0.85-fold and improving lipid metabolism compared to metformin treatment. Ovarian histology revealed partial restoration of follicular development, and AMPK activation supported enhanced glucose uptake. CONCLUSIONS Myo-inositol effectively alleviated insulin resistance and metabolic dysfunction, offering a promising alternative to conventional PCOS treatments.
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Affiliation(s)
- Guihong Song
- Department of Medicine, Shandong College of Traditional Chinese Medicine, Yantai, 264199, China
| | - Nannan Liu
- Department of Medicine, Shandong College of Traditional Chinese Medicine, Yantai, 264199, China
| | - Jiajin He
- Department of Medicine, Shandong College of Traditional Chinese Medicine, Yantai, 264199, China
| | - Saisai Tang
- Department of Medicine, Shandong College of Traditional Chinese Medicine, Yantai, 264199, China
| | - Yiping Yu
- Department of Medicine, Shandong College of Traditional Chinese Medicine, Yantai, 264199, China
| | - Lihua Song
- Department of Obstetrics and Gynecology, Yantai Municipal Laiyang Central Hospital, No. 111 Changshan Road, Laiyang, 265200, China.
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Wang J, Zhang Y, Cao C, Hua J, Xing L, Wu C. The anti-atherosclerosis effect and molecular mechanism of AMPKα1 by polarizing monocytes to an M2 phenotype via cell-intrinsic lysosomal lipolysis. Cardiovasc Pathol 2025:107742. [PMID: 40354887 DOI: 10.1016/j.carpath.2025.107742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 05/09/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025] Open
Abstract
Regulating the differentiation of monocytes into M2 macrophages can promote the regression of Atherosclerosis (AS) plaque. However, the key molecules regulating the differentiation of monocytes to M2 are unknown. In this study, we reported that adenosine-activated protein kinase α1 (AMPKα1) plays an anti-AS role by polarizing monocytes to an M2 phenotype via promoting fatty acid oxidation (FAO). AMPKα1 enhances the decomposition of cholesterol esters by increasing lysosomal acid lipase expression to provide fatty acids for FAO. Furthermore, AMPKα1 can induce lysosomal biogenesis and enhance lipolysis by promoting the transcription factor EB (TFEB) expression and facilitating TFEB nuclear translocation. In conclusion, AMPKα1 enhances the decomposition of cholesterol esters by increasing lysosomal acid lipase expression to produce fatty acids, which may represent a mechanism to promote FAO and inflammatory monocytes differentiation towards M2 phenotype.
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Affiliation(s)
- Jing Wang
- Institutes of Biomedical Sciences, Shanxi University, 92 Wucheng Road, Taiyuan, 030006, Shanxi province, China.
| | - Yahui Zhang
- School of Life Science, Shanxi University, Taiyuan, 030006, China
| | - Caixing Cao
- Institutes of Biomedical Sciences, Shanxi University, 92 Wucheng Road, Taiyuan, 030006, Shanxi province, China
| | - Jiale Hua
- Institutes of Biomedical Sciences, Shanxi University, 92 Wucheng Road, Taiyuan, 030006, Shanxi province, China
| | - Li Xing
- Institutes of Biomedical Sciences, Shanxi University, 92 Wucheng Road, Taiyuan, 030006, Shanxi province, China
| | - Changxin Wu
- Institutes of Biomedical Sciences, Shanxi University, 92 Wucheng Road, Taiyuan, 030006, Shanxi province, China.
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Guo Y, Xu N, Meng Q, Zhong M, Yang M, Xu F, Zhang L, Jiang M, Wu J, Ma Z, Xu Y, Li Y. Mechanisms of Inonotus obliquus (Fr.) Pilát Polysaccharides in Ameliorating Lipid-Induced Skeletal Muscle Insulin Resistance via PI3K/AKT and AMPK/ACC1/CPT1 Signaling Pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025:119938. [PMID: 40348308 DOI: 10.1016/j.jep.2025.119938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/14/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Inonotus obliquus (Fr.) Pilát, a traditional medicinal fungi, has been used to treat diabetes in China and Russia since the 16th century. Recent studies show Inonotus obliquus (Fr.) Pilát polysaccharides (IOP) have hypoglycemic and lipid-lowering effects in type 2 diabetes mellitus (T2DM) mice and can recover liver insulin resistance. AIM OF THE STUDY This study aims to assess the effect of IOP and its mechanisms in ameliorating insulin resistance and lipid metabolism disorders in T2DM. MATERIALS AND METHODS The potential targets of IOP for T2DM were identified by network pharmacology and molecular docking. In vitro, an insulin resistance model in C2C12 cells was induced, and IOP's effects on glucose uptake, glycogen, lipid content, and lipid metabolism-related mRNAs were assessed. In vivo, a T2DM mice model was established. Blood glucose, lipids, glucose tolerance, and insulin sensitivity were evaluated. Histopathology was used to assess morphological changes in mice skeletal muscle. Western blotting was utilized to evaluate the expression levels of PI3K/AKT and AMPK/ACC1/CPT1 signaling pathway proteins both in vivo and in vitro. RESULTS Network pharmacology results showed IOP and T2DM targets were enriched in PI3K/AKT, insulin resistance, and lipid metabolism pathways. Cell experiments showed IOP enhanced glucose uptake and glycogen content, reduced lipid content, and improved lipid deposition in insulin-resistant C2C12 cells. Animal experiments showed IOP improved hyperglycemia and hyperlipidemia, enhanced glucose tolerance and insulin sensitivity, and reduced insulin resistance in T2DM mice. Western blot showed IOP activated PI3K/AKT and AMPK/ACC1/CPT1 pathways, promoting GLUT4 expression and translocation, and GSK3β phosphorylation. CONCLUSIONS In summary, the results indicated that IOP was able to ameliorate lipid-induced skeletal muscle insulin resistance in T2DM. The mechanism may be related to the PI3K/AKT and AMPK/ACC1/CPT1 signaling pathways.
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Affiliation(s)
- Yiming Guo
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China
| | - Nuo Xu
- Department of Intensive Care Medicine, The Second School of Clinical Medical, Binzhou Medical University, Yantai, Shandong Province, China
| | - Qinyu Meng
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China
| | - Mengru Zhong
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China
| | - Meizi Yang
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China
| | - Fang Xu
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China
| | - Lei Zhang
- Department of Intensive Care Medicine, The Second School of Clinical Medical, Binzhou Medical University, Yantai, Shandong Province, China
| | - Muchen Jiang
- Department of Pharmacy, School of Pharmacy, Binzhou Medical University, Yantai, Shandong Province, China
| | - Junze Wu
- Department of Clinical Medicine, The First School of Clinical Medical, Binzhou Medical University, Yantai, Shandong Province, China
| | - Zihan Ma
- Department of Clinical Medicine, The First School of Clinical Medical, Binzhou Medical University, Yantai, Shandong Province, China
| | - Yingjiang Xu
- Department of Clinical Medicine, The First School of Clinical Medical, Binzhou Medical University, Yantai, Shandong Province, China.
| | - Yana Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai, Shandong Province, China.
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Sharma AK, Mukherjee M, Akhtar MS, Orayj K, Farooqui S, Khan A. Genetic-epigenetic targets for PCOS-associated diabesity. Drug Discov Today 2025; 30:104373. [PMID: 40345613 DOI: 10.1016/j.drudis.2025.104373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 04/08/2025] [Accepted: 05/01/2025] [Indexed: 05/11/2025]
Abstract
Polycystic ovary syndrome (PCOS) and diabesity are interconnected endocrine disorders driven by a complex interplay of genetic, epigenetic and environmental factors. This review examines the molecular crosstalk between PCOS and diabesity, focusing on shared pathophysiological pathways and their regulatory mechanisms. Key genetic predispositions (such as polymorphisms) associated with insulin resistance, androgen biosynthesis and inflammation have been conferred that could significantly contribute to their overlapping phenotypes. Additionally, epigenetic modifications, including DNA methylation, histone modifications and non-coding RNAs, have been discussed that further participate in regulation of gene expression and metabolic dysfunction. Understanding these molecular interconnections highlights crucial signaling nodes that can serve as potential therapeutic targets. This review underscores emerging avenues for drug development, aiming to mitigate disease progression and improve patient outcomes.
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Affiliation(s)
- Arun K Sharma
- Department of Pharmacology, Amity Institute of Pharmacy, Amity University Haryana, Gurugram, Haryana 122413, India.
| | - Monalisa Mukherjee
- Molecular Sciences and Engineering Laboratory, Amity Institute of Click Chemistry Research and Studies, Amity University, Noida, Uttar Pradesh 201303, India.
| | - Md Sayeed Akhtar
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Alfara, Abha 62223, Saudi Arabia
| | - Khalid Orayj
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Alfara, Abha 62223, Saudi Arabia
| | - Sadaf Farooqui
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Abida Khan
- Center for Health Research, Northern Border University, Arar 73213, Saudi Arabia
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Xie L, Peng YQ, Shen X. Identifying therapeutic target genes for diabetic retinopathy using systematic druggable genome-wide Mendelian randomization. Diabetol Metab Syndr 2025; 17:145. [PMID: 40301928 PMCID: PMC12039192 DOI: 10.1186/s13098-025-01710-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 04/22/2025] [Indexed: 05/01/2025] Open
Abstract
INTRODUCTION The treatment and prevention of diabetic retinopathy (DR) remain significant challenges. Mendelian randomization (MR) has been widely used to explore novel therapeutic targets. In this study, we conducted a systematic druggable genome-wide MR analysis to explore potential therapeutic targets for DR. METHODS We obtained data on druggable genes and screened for genes within blood expression quantitative trait loci (eQTL), which were then subjected to MR analysis and colocalization analysis with DR genome-wide association studies data to identify genes strongly associated with DR. Additionally, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction (PPI) network construction, drug candidate prediction, and molecular docking were performed to provide valuable insights for the development of more effective and targeted therapeutic drugs. RESULTS MR analysis of blood eQTLs revealed 30 significant DR-associated druggable genes, with PRKAB1 (OR = 0.935, 95% CI: 0.892 to 0.980) and CNR1 (OR = 0.814, 95% CI: 0.696 to 0.951) being protective genes, whereas CACNA1E (OR = 1.282, 95% CI: 1.050 to 1.565), NME1 (OR = 1.198, 95% CI: 1.028 to 1.397), and CHRNA2 (OR = 1.192, 95% CI: 1.025 to 1.386) were associated with increased risk. KEGG analysis highlighted significant pathways, including adrenergic signaling in cardiomyocytes (hsa04261), the oxytocin signaling pathway (hsa04921), and arrhythmogenic right ventricular cardiomyopathy (hsa05412). PPI network analysis identified two key modules: one comprising BIN1, CDH2, ACTN1, EPAS1, CEBPA, and CTSD nodes, and the other consisting of CACNG6, CACNA1E, CACNA2D3, and RASGRP3 nodes. Drug candidate prediction suggested ethanol and isoflupredone as potential therapeutic interventions, and molecular docking revealed C5's strong protein binding affinity. CONCLUSIONS This study utilized MR and colocalization analysis to identify potential drug targets for DR. The findings provide promising leads for the treatments of DR, potentially reducing drug development costs.
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Affiliation(s)
- Long Xie
- Department of Orthopedics, The Fourth Hospital of Changsha (Integrated Traditional Chinese and Western Medicine Hospital of Changsha), Hunan Normal University, Changsha, Hunan Province, 410006, China.
| | - Yu Qin Peng
- Department of Ophthalmology, The Fourth Hospital of Changsha (Integrated Traditional Chinese and Western Medicine Hospital of Changsha), Hunan Normal University, Changsha, Hunan Province, 410006, China
| | - Xiang Shen
- Department of Orthopedics, The Fourth Hospital of Changsha (Integrated Traditional Chinese and Western Medicine Hospital of Changsha), Hunan Normal University, Changsha, Hunan Province, 410006, China
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11
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Mourmans SGJ, Achten A, Hermans R, Scheepers MJE, D'Alessandro E, Swennen G, Woudstra J, Appelman Y, Goor HV, Schalkwijk C, Knackstedt C, Weerts J, Eringa EC, van Empel VPM. The effect of empagliflozin on peripheral microvascular dysfunction in patients with heart failure with preserved ejection fraction. Cardiovasc Diabetol 2025; 24:182. [PMID: 40281528 PMCID: PMC12023568 DOI: 10.1186/s12933-025-02679-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 03/10/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Empagliflozin is an effective treatment for heart failure with preserved ejection fraction (HFpEF), but its definite mechanism of action is unclear. Systemic microvascular dysfunction strongly relates to HFpEF aetiology, and we hypothesised that empagliflozin improves microvascular function in HFpEF. OBJECTIVE To investigate the effect of the sodium-glucose cotransporter-2 inhibitor empagliflozin on peripheral microvascular function in HFpEF. METHODS This is a pre-post intervention study in patients diagnosed with HFpEF who are eligible for treatment with empagliflozin. Microvascular function assessment using laser speckle contrast analysis of the dorsal forearm during iontophoresis of vasoactive stimuli (acetylcholine, insulin sodium nitroprusside) was performed at baseline and after 3 months of empagliflozin treatment (10 mg daily). The primary outcome was the difference in blood flow measured in the forearm microvasculature between baseline and at follow-up (cutaneous vascular conductance, CVC). Secondarily we investigated quality-of-life based on the EQ-5D-5 L questionnaire at baseline and follow-up. RESULTS Twenty six patients finished the study according to protocol (mean age of 74 ± 7 years, 62% female). We observed a decreased blood flow response to acetylcholine after 3 months of empagliflozin (CVC: 0.77 ± 0.24 vs. 0.64 ± 0.20, p < 0.001). In contrast, the response to insulin improved (CVC: 0.61 ± 0.43 vs. 0.81 ± 0.32, p = 0.03), and the response to sodium nitroprusside remained stable after 3 months. No significant correlations were found between the changes in blood flow and quality of life. CONCLUSION This study shows that three months treatment with empagliflozin changed peripheral microvascular function in patients with HFpEF. Empagliflozin may enhance microvascular blood flow specifically via vascular actions of insulin, rather than a general effect on endothelial vasoregulation or smooth muscle cell function. As such, systemic microvascular dysfunction can be a modifiable factor in patients with HFpEF, while the clinical implications thereof warrant further investigations. TRIAL REGISTRATION The trial was preregistered at clinicaltrials.gov (NCT06046612).
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Affiliation(s)
- Sanne G J Mourmans
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
| | - Anouk Achten
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
| | - Raquel Hermans
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
| | - Marijne J E Scheepers
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
| | - Elisa D'Alessandro
- Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
| | - Geertje Swennen
- Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
| | - Janneke Woudstra
- Department of Cardiology, Amsterdam UMC Heart Centre, Amsterdam, The Netherlands
| | - Yolande Appelman
- Department of Cardiology, Amsterdam UMC Heart Centre, Amsterdam, The Netherlands
| | - Harry van Goor
- Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Casper Schalkwijk
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
| | - Christian Knackstedt
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
| | - Jerremy Weerts
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands
| | - Etto C Eringa
- Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, The Netherlands
| | - Vanessa P M van Empel
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands.
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12
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Li L, Zou J, Zhou T, Liu X, Tan D, Xiang Q, Yu R. mTOR-mediated nutrient sensing and oxidative stress pathways regulate autophagy: a key mechanism for traditional Chinese medicine to improve diabetic kidney disease. Front Pharmacol 2025; 16:1578400. [PMID: 40337513 PMCID: PMC12055823 DOI: 10.3389/fphar.2025.1578400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 04/08/2025] [Indexed: 05/09/2025] Open
Abstract
Context Autophagy plays a pivotal role in the pathogenesis of DKD, and the mechanistic target of rapamycin (mTOR) pathway, which regulates nutrient sensing and oxidative stress responses, is a key regulator of autophagy. Traditional Chinese Medicine (TCM) has garnered attention for its potential to treat DKD by modulating the mTOR signaling pathway, reducing oxidative stress, and restoring autophagic function. Objective The objective of this study is to examine how mTOR-mediated regulation of nutrient sensing and oxidative stress impacts autophagy in DKD, and to explore how TCM modulates these pathways to improve the condition. Methods A systematic review was conducted using PubMed, Web of Science, Wanfang Data, and China National Knowledge Infrastructure (CNKI), with the search extended to December 2024. The search subject terms included 'diabetic kidney disease,' 'Traditional Chinese Medicine,' 'mTOR,' 'nutrient sensing,' and 'oxidative stress.' Studies were rigorously screened by two investigators. Results This review systematically examines the pathogenesis of mTOR-mediated nutrient sensing dysfunction and oxidative stress in DKD, highlighting their impact on autophagy. It further clarifies how these mechanisms are targeted by Chinese medicine in the treatment of DKD. The review summarizes the potential mechanisms by which TCM, including monomers (e.g., Astragaloside IV), individual botanical drugs (e.g., Dendrobium nobile Lindl.), and compound formulations (e.g., Tongluo Digui Decoction), regulate autophagy in DKD through pathways such as AMP-activated protein kinase (AMPK), mTOR, sirtuins (Sirt), and the phosphatidylinositol three kinase (PI3K)/Akt/mTOR signaling pathway. TCM compound formulas share a common foundational framework, with the majority being formulated based on therapeutic principles such as 'Yiqi', 'Yangyin', 'Tongluo', and 'Huashi'. Conclusion TCM shows promise in treating DKD, with unique advantages in modulating key signaling pathways. However, the underlying mechanisms remain complex and warrant further investigation.
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Affiliation(s)
- Liu Li
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Junju Zou
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Tongyi Zhou
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Xiu Liu
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Danni Tan
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Qin Xiang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Rong Yu
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Key Laboratory of Traditional Chinese Medicine Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, China
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13
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Kaushik AS, Agarwal V, Kumar N, Rehman M, Chaudhary R, Srivastava S, Srivastava S, Mishra V. Stimulation of auricular vagus nerve ameliorates chronic stress induced metabolic syndrome via activation of Sirtuin-6. Biochem Biophys Res Commun 2025; 756:151567. [PMID: 40056501 DOI: 10.1016/j.bbrc.2025.151567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/18/2025] [Accepted: 02/28/2025] [Indexed: 03/10/2025]
Abstract
Chronic stress is one of the potential causes of the progression of metabolic syndrome (MS). Chronic stress decreases the release of Sirtuin-6 (SIRT6), which regulates MS by controlling glucose, insulin, lipids, and hypertension. Vagus nerve stimulation (VNS) activates SIRT6 via the cholinergic anti-inflammatory pathway (CAP). However, the effectiveness of VNS therapy for treating MS induced by chronic stress has not yet been studied. In this study, we first validated a rat model of chronic unpredictable stress (CUS) and assessed the characteristic features of MS. The CUS rats were exposed to random stressors daily for 8 weeks. The stress response was then confirmed by behavioral alteration and elevated serum corticosterone levels in rats, as measured by various behavioral tests and an ELISA kit, respectively. The MS characteristics in CUS rats were assessed using measurements of fasting blood glucose (FBG), systolic blood pressure (SBP), lipid indices, insulin levels, and HOMA-IR. The stressed animals demonstrated a rise in FBG, SBP, and insulin along with altered lipid indices. After CUS, the rats were treated with VNS (6 Hz, 1.0 ms, 6 V, for 40 min × 14 days, alternatively), and their metabolic activity and vagal flow were assessed. Moreover, SIRT6 and AMP-activated protein kinase (AMPK) expression in rats was also assessed by immunohistochemistry and mRNA expression of liver and pancreatic tissue. SIRT6 and AMPK expression was decreased in CUS animals. Interestingly, VNS treatment attenuated CUS induced MS-associated parameters. These results indicate that VNS may be a beneficial complementary and non-pharmacological method for managing CUS-associated MS.
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Affiliation(s)
- Arjun Singh Kaushik
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India
| | - Vipul Agarwal
- MIT College of Pharmacy, Ram Ganga Vihar Phase-II, Moradabad, 244001, (U.P.), India
| | - Neeraj Kumar
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India
| | - Mujeeba Rehman
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India
| | - Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India
| | - Siddhi Srivastava
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India
| | - Sukriti Srivastava
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India
| | - Vikas Mishra
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India.
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14
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Abou-El-Naga AM, Mansour HAELH, El-Sawi MR, El-Dein MA, Tag YM, Ghanem RA, Shawki MA. Restorative effects of Momordica charantia extract on cerebellar GFAP and NGF expression in pregnant diabetic rats and their offspring. PLoS One 2025; 20:e0321022. [PMID: 40184394 PMCID: PMC11970674 DOI: 10.1371/journal.pone.0321022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/27/2025] [Indexed: 04/06/2025] Open
Abstract
Maternal diabetes mellitus is linked to neurobiological and cognitive impairments, increasing the risk of brain and cerebellar defects in diabetic pregnant rats and their offspring. Momordica charantia (bitter melon) possesses antidiabetic properties due to its bioactive compounds, including phenolics, alkaloids, proteins, steroids, inorganic compounds, and lipids. Forty pregnant rats were randomly assigned to four groups: control; M charantia (BM); diabetic (DM); and diabetic treated with M charantia (BM+DM). Diabetic maternal rats showed significantly elevated serum glucose, insulin, leptin, and homeostasis model assessment of insulin resistance (HOMA-IR) levels, with a concomitant decrease in insulin sensitivity check index (QUICKI), glucose transporter 4 (GLUT4), adenosine monophosphate-activated protein kinase (AMPK), acetylcholine (ACh), and dopamine. Oxidative stress markers in cerebellar tissue indicated increased malondialdehyde (MDA) and decreased glutathione (GSH) levels. Cerebellar tissue analysis revealed significantly reduced superoxide dismutase (SOD), catalase (CAT), B-cell lymphoma 2 (Bcl-2), and nerve growth factor (NGF), while Bcl-2-associated X protein (BAX) and glial fibrillary acidic protein (GFAP) were elevated. Histological and ultrastructural analysis of the diabetic maternal cerebellum showed moderate vacuolation of the neuropil in all cerebellar cortical layers, along with Purkinje cell degeneration and necrosis, including Nissl substance loss. Offspring of diabetic mothers exhibited multifocal Purkinje cell loss, empty baskets, and cerebellar cortical dysplasia with abnormal tissue development and organization. In conclusion, M. charantia supports central nervous system health in diabetic pregnant rats and their offspring by enhancing antioxidant markers, regulating GFAP and NGF, and mitigating apoptosis, ultimately improving cerebellar pathology and neural development.
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Affiliation(s)
| | | | - Mamdouh R. El-Sawi
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Mai Alaa El-Dein
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Yasmin M. Tag
- Oral BiologyDepartment, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Gamsa, Egypt
| | - Reham A. Ghanem
- Oral BiologyDepartment, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Gamsa, Egypt
| | - Manar A. Shawki
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
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15
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Han G, Hu K, Luo T, Wang W, Zhang D, Ouyang L, Liu X, Liu J, Wu Y, Liang J, Ling J, Chen Y, Xuan R, Zhang J, Yu P. Research progress of non-coding RNA regulating the role of PANoptosis in diabetes mellitus and its complications. Apoptosis 2025; 30:516-536. [PMID: 39755822 DOI: 10.1007/s10495-024-02066-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2024] [Indexed: 01/06/2025]
Abstract
Diabetes is a chronic metabolic disease that is endemic worldwide and is characterized by persistent hyperglycemia accompanied by multiple severe complications, including cardiovascular disease, kidney dysfunction, neuropathy, and retinopathy. The pathogenesis of diabetes mellitus and its complications is multifactorial, involving various molecular and cellular pathways. In recent years, research has indicated that mechanisms of cell death play a significant role in the advancement of diabetes and its complications. PANoptosis is a complex phenomenon caused by three cell death pathways: programmed apoptosis, necroptosis and pyroptosis. The contribution of PANoptosis to diabetes and its complications remains incompletely understood. Non-coding RNA, an important molecule in gene expression regulation, has shown significant regulatory functions in a variety of diseases. This paper reviews the underlying mechanisms of diverse types of non-coding RNAs (including lncRNA, miRNA and circRNA) in regulating PANoptosis and their specific contributions in diabetes, aiming to explore how non-coding RNAs influence PANoptosis and their effects in diabetes.
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Affiliation(s)
- Guangyu Han
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- The Second Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Kaibo Hu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- The Second Clinical Medical College, Nanchang University, Nanchang, 330006, China
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Tianfeng Luo
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- The Second Clinical Medical College, Nanchang University, Nanchang, 330006, China
| | - Wenting Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Hainan Medical University, Haikou, 571199, China
| | - Deju Zhang
- Ood and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong, China
| | - Liu Ouyang
- Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA, 30303, USA
| | - Xiao Liu
- Department of Cardiology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jianping Liu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yuting Wu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Jianqi Liang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Jitao Ling
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yixuan Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Rui Xuan
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
| | - Peng Yu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
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De Leo M, Ciccone L, Menicagli V, Balestri E, Braca A, Nieri P, Testai L. Cymodocea nodosa, a Promising Seagrass of Nutraceutical Interest: Overview of Phytochemical Constituents and Potential Therapeutic Uses. Nutrients 2025; 17:1236. [PMID: 40218994 PMCID: PMC11990611 DOI: 10.3390/nu17071236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 03/25/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND/OBJECTIVES Seagrasses are marine angiosperms capable of completing their life cycle in water; they have been used as food source and biomass for producing fertilizer, but their potential nutritional and health-promoting properties have been largely overlooked. Cymodocea nodosa (Ucria) Ascherson (family Cymodoceaceae) is emerging as one of the most interesting seagrass species due to its content in health promoting substances. METHODS In this review article, a revision of the literature on phytochemical constituents and the main potential therapeutic uses of C. nodosa was carried out. RESULTS Despite the growing interest in C. nodosa for its key ecological role and for being a potential source of bioactive compounds, comprehensive chemical studies about its composition are still limited. Compounds reported as C. nodosa constituents include fatty acids, phytosterols, polysaccharides, phenolic acids, hydroxycinnamic acids, flavonoid glycosides, terpenoids, and diarylheptanoids. As concerns potential therapeutic uses, C. nodosa extract, both polyphenolic and polysaccharidic, might be useful for the management of metabolic disorders, which is currently the most documented in addition to the antioxidant action. CONCLUSIONS Cymodocea nodosa emerges as one of the most promising seagrass species as a source of bioactive compounds and for its potential in maintaining health status.
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Affiliation(s)
- Marinella De Leo
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (M.D.L.); (L.C.); (A.B.); (P.N.)
- Marine Pharmacology Interdepartmental Center, University of Pisa, 56126 Pisa, Italy;
- Interdepartmental Center Nutrafood “Nutraceuticals and Food for Health”, Interdepartmental Center, University of Pisa, 56124 Pisa, Italy
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, 56126 Pisa, Italy
| | - Lidia Ciccone
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (M.D.L.); (L.C.); (A.B.); (P.N.)
- Marine Pharmacology Interdepartmental Center, University of Pisa, 56126 Pisa, Italy;
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, 56126 Pisa, Italy
| | | | - Elena Balestri
- Marine Pharmacology Interdepartmental Center, University of Pisa, 56126 Pisa, Italy;
- Interdepartmental Center Nutrafood “Nutraceuticals and Food for Health”, Interdepartmental Center, University of Pisa, 56124 Pisa, Italy
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, 56126 Pisa, Italy
- Department of Biology, University of Pisa, 56126 Pisa, Italy;
| | - Alessandra Braca
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (M.D.L.); (L.C.); (A.B.); (P.N.)
- Marine Pharmacology Interdepartmental Center, University of Pisa, 56126 Pisa, Italy;
- Interdepartmental Center Nutrafood “Nutraceuticals and Food for Health”, Interdepartmental Center, University of Pisa, 56124 Pisa, Italy
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, 56126 Pisa, Italy
| | - Paola Nieri
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (M.D.L.); (L.C.); (A.B.); (P.N.)
- Marine Pharmacology Interdepartmental Center, University of Pisa, 56126 Pisa, Italy;
- Interdepartmental Center Nutrafood “Nutraceuticals and Food for Health”, Interdepartmental Center, University of Pisa, 56124 Pisa, Italy
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, 56126 Pisa, Italy
| | - Lara Testai
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (M.D.L.); (L.C.); (A.B.); (P.N.)
- Marine Pharmacology Interdepartmental Center, University of Pisa, 56126 Pisa, Italy;
- Interdepartmental Center Nutrafood “Nutraceuticals and Food for Health”, Interdepartmental Center, University of Pisa, 56124 Pisa, Italy
- Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, 56126 Pisa, Italy
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17
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Huang Y, Chen K, Xiao X, Zhong S. Identification of FLVCR1 as the iron metabolism-related gene of statin-associated diabetes. Acta Diabetol 2025:10.1007/s00592-025-02491-6. [PMID: 40146399 DOI: 10.1007/s00592-025-02491-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 03/14/2025] [Indexed: 03/28/2025]
Abstract
AIMS Long-term statin use has been linked to increased diabetes risk. Iron metabolism disruption may explain this association. The objective of this study was to identify the co-expression gene modules and the iron metabolism-related gene (IMG) linking statin administration and diabetes, making the hunt for novel therapeutic targets necessary. METHODS Weighted gene co-expression network analysis (WGCNA) was applied to the GSE130991 dataset to detect co-expressed gene modules. Enrichment analysis and single sample gene set enrichment analysis (ssGSEA) were conducted to characterize the biological processes and iron metabolism differences, respectively. Candidate IMGs were identified by intersecting WGCNA hub genes, differentially expressed genes (DEGs) from the statin-using and non-using obese individuals within the GSE130991 liver tissue dataset, and IMGs from Molecular Signatures Database Molecular Signatures Database (MisgDB). Mediation analysis was utilized to identify the definitive IMG. Expression validation was conducted through reverse transcription quantitative PCR (RT-qPCR) experiments and cross-referencing with additional datasets. RESULTS A shared gene module was identified between statin-users and diabetes patients, with functional enrichment analysis indicating involvement in iron ion binding. ssGSEA revealed differentially expressed iron metabolism in both statin-users and diabetes patients. Five IMG genes (CYP51A1, SC5D, MSMO1, SCD, and FLVCR1) were shortlisted, with FLVCR1 emerging as the key intermediary biomarker. FLVCR1 was positively correlated with insulin resistance and demonstrated robust predictive capabilities for diabetes. An increase in FLVCR1 mRNA levels was observed following statin treatment, as confirmed by RT-qPCR experiments and the GSE24188 dataset. Elevated FLVCR1 mRNA was also noted in diabetes patients across datasets GSE130991, GSE23343, and GSE95849. CONCLUSION In this study, bioinformatics evidence supporting the association between statin use and diabetes was presented. FLVCR1 was identified as the iron metabolism-related mediator gene implicated in this relationship. Overall, our findings provide a theoretical foundation for new directions for future research exploring the complex interplay between statin treatment, iron metabolism regulation, and diabetes pathogenesis.
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Affiliation(s)
- YiJia Huang
- South China University of Technology School of Medicine, Guangzhou, 510006, China
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China
| | - Kai Chen
- South China University of Technology School of Medicine, Guangzhou, 510006, China
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China
| | - Xiao Xiao
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China.
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.
| | - Shilong Zhong
- South China University of Technology School of Medicine, Guangzhou, 510006, China.
- Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Road, Guangzhou, 510080, China.
- Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.
- Laboratory of Phase I Clinical Trials, Guangzhou, China.
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18
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Tashkandi AJ, Gorman A, McGoldrick Mathers E, Carney G, Yacoub A, Setyaningsih WAW, Kuburas R, Margariti A. Metabolic and Mitochondrial Dysregulations in Diabetic Cardiac Complications. Int J Mol Sci 2025; 26:3016. [PMID: 40243689 PMCID: PMC11988959 DOI: 10.3390/ijms26073016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/16/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
The growing prevalence of diabetes highlights the urgent need to study diabetic cardiovascular complications, specifically diabetic cardiomyopathy, which is a diabetes-induced myocardial dysfunction independent of hypertension or coronary artery disease. This review examines the role of mitochondrial dysfunction in promoting diabetic cardiac dysfunction and highlights metabolic mechanisms such as hyperglycaemia-induced oxidative stress. Chronic hyperglycaemia and insulin resistance can activate harmful pathways, including advanced glycation end-products (AGEs), protein kinase C (PKC) and hexosamine signalling, uncontrolled reactive oxygen species (ROS) production and mishandling of Ca2+ transient. These processes lead to cardiomyocyte apoptosis, fibrosis and contractile dysfunction. Moreover, endoplasmic reticulum (ER) stress and dysregulated RNA-binding proteins (RBPs) and extracellular vesicles (EVs) contribute to tissue damage, which drives cardiac function towards heart failure (HF). Advanced patient-derived induced pluripotent stem cell (iPSC) cardiac organoids (iPS-COs) are transformative tools for modelling diabetic cardiomyopathy and capturing human disease's genetic, epigenetic and metabolic hallmarks. iPS-COs may facilitate the precise examination of molecular pathways and therapeutic interventions. Future research directions encourage the integration of advanced models with mechanistic techniques to promote novel therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | - Refik Kuburas
- Wellcome Wolfson Institute of Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; (A.J.T.); (A.G.); (E.M.M.); (G.C.); (A.Y.); (W.A.W.S.)
| | - Andriana Margariti
- Wellcome Wolfson Institute of Experimental Medicine, Queens University Belfast, Belfast BT9 7BL, Northern Ireland, UK; (A.J.T.); (A.G.); (E.M.M.); (G.C.); (A.Y.); (W.A.W.S.)
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19
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Park YI, Park R, Lee S, Lee C, Yoo I, Ka H, Huh YH, Hong J, Park J. AMPK Knockout Impairs the Formation of Three-Dimensional Spheroids. Life (Basel) 2025; 15:525. [PMID: 40283080 PMCID: PMC12028351 DOI: 10.3390/life15040525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/29/2025] Open
Abstract
AMP-activated protein kinase (AMPK) is an important regulator of cellular energy homeostasis, and AMPK contributes to cell growth, apoptosis, and autophagy. Although most cell studies have been performed using two-dimensional (2D) cell culture, recent studies have demonstrated that the three-dimensional (3D) spheroid technique is helpful in various cell research fields, such as tumor biology, due to its resemblance to the 3D tissue structure. However, the role of AMPK in 3D spheroid formation has not been characterized clearly. This study used the AMPK knockout cell line to examine the role of AMPK in 3D spheroid formation and is the first report describing the generation of 3D spheroids using AMPK knockout cells. While control cells produced round spheroids with a similar length-to-width ratio, AMPK knockout produced an oval shape with a more significant length-to-width ratio. We demonstrate that AMPK knockout spheroids contain significantly more prominent lysosomes in each cell, indicating that autophagic flux is impaired in 3D spheroids. Finally, flow cytometry analysis showed that AMPK knockout spheroids contain more apoptotic cells than control cells. These results indicate that AMPK is required for efficient 3D spheroid formation.
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Affiliation(s)
- Yea-In Park
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Rackhyun Park
- Department of Life Science, Yong-In University, Yongin 17092, Republic of Korea
| | - Siyun Lee
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Chunghyeon Lee
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Inkyu Yoo
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Hakhyun Ka
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Yang Hoon Huh
- Electron Microscopy Research Center, Korea Basic Science Institute (KBSI), Cheongju 28119, Republic of Korea
| | - Jongkwang Hong
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
| | - Junsoo Park
- Division of Biological Science and Technology, Yonsei University, Wonju 26493, Republic of Korea
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20
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Wang YT, Wu H, Wu JJ, Yu YS, Wen J, Zou B, Li L, Peng J, Cheng LN, Bu ZB, Xu YJ, Hu TG. The hypoglycemic effect of mulberry ( Morus atropurpurea) fruit lacking fructose and glucose by regulation of the gut microbiota. Food Funct 2025; 16:2444-2460. [PMID: 40017446 DOI: 10.1039/d4fo02781g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Mulberries are known to be rich in hypoglycemic active substances such as anthocyanins and dietary fiber, which primarily aid in regulating gut microbiota. However, their high sugar content, such as fructose, hinders their application in hypoglycemic functional foods. This research utilized microbial fermentation technology to remove the fructose and glucose in mulberries (FM), subsequently evaluating their hypoglycemic properties and balancing gut microbiota. Results indicated that administering varying doses of FM to type 2 diabetic mice for five weeks notably decreased blood sugar and insulin levels, improved dyslipidemia and insulin resistance, enhanced antioxidant capacity, repaired organ damage, and regulated hypoglycemic activity by influencing mRNA expression of key signaling factors in the PI3K/Akt and AMPK pathways. Analysis of the intestinal microbiota composition revealed that FM can modulate specific bacterial populations, increasing beneficial bacteria like Lactobacillus, Bifidobacterium and Akkermansia while inhibiting harmful bacteria like Escherichia-Shigella and Helicobacter. This restoration of the intestinal microecological balance helped regulate host sugar metabolism homeostasis and affect the secretion of short chain fatty acid (SCFA) synthase in the gut microbiota to increase the production of SCFAs. These findings offer significant support for the potential use of FM in the treatment of diabetes.
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Affiliation(s)
- Ya-Ting Wang
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
- School of Food Science and Engineering, South China University of Technology, China
| | - Hong Wu
- School of Food Science and Engineering, South China University of Technology, China
| | - Ji-Jun Wu
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
| | - Yuan-Shan Yu
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, China
- Heyuan Branch, Guangdong Laboratory for Lingnan Modern Agriculture, China
| | - Jing Wen
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
| | - Bo Zou
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
- Heyuan Branch, Guangdong Laboratory for Lingnan Modern Agriculture, China
| | - Lu Li
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
| | - Jian Peng
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
| | - Li-Na Cheng
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
| | - Zhi-Bin Bu
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
| | - Yu-Juan Xu
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
- Heyuan Branch, Guangdong Laboratory for Lingnan Modern Agriculture, China
| | - Teng-Gen Hu
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences/Key Laboratory of Functional Foods, Ministry of Agriculture and Rural Affairs/Guangdong Key Laboratory of Agricultural Products Processing, China.
- Heyuan Branch, Guangdong Laboratory for Lingnan Modern Agriculture, China
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21
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Zhao J, Najm AA, Mahmood I, Ming ZY, Dutta PP, Talib WH, Law D, Fazry S. In Vitro and In Silico Antidiabetic Efficacy of Solanum lasiocarpum Dunal Fruit Extract. PLoS One 2025; 20:e0312600. [PMID: 40063647 PMCID: PMC11892833 DOI: 10.1371/journal.pone.0312600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 10/08/2024] [Indexed: 05/13/2025] Open
Abstract
Exploring the possibility of familiar dietary sources as additional diabetes treatments is crucial, especially considering the financial difficulties related to diabetes mellitus. Using both in vitro and in silico techniques, this work aims to assess the antidiabetic benefits of extract from Solanum lasiocarpum Dunal. The evaluations encompass the ability to scavenge DPPH radicals, inhibition of α-amylase, α-glucosidase, inhibition of DPP-4, cytotoxicity, and glucose absorption kinetics. With an IC50 value of 0.69 ± 0.14 mg/ml, S. lasiocarpum showed encouraging DPPH inhibition. IC50 values of 2.123 ± 0.14 mg/ml inhibited the enzymes α-amylase, α-glucosidase, and DPP-4. Furthermore, a notable increase (P < 0.05) in glucose uptake by L6 myoblasts was observed with the administration of various combinations. In silico analysis, including XP docking and MM-GBSA, revealed that 10 and 21 compounds within the combination exhibited substantial interactions and stable binding capabilities with α-amylase and DPP-4 proteins, indicating their potential as enzyme inhibitors. Therefore, it can be inferred that S. lasiocarpum represents a promising therapeutic approach for diabetes management.
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Affiliation(s)
- Jing Zhao
- Department of Food Science, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia
| | - Ahmed Abdulkareem Najm
- Department of Food Science, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia
| | - Ibrahim Mahmood
- Dentistry Department, Al-Rafidain University College, Baghdad, Iraq
| | - Zhang Yu Ming
- Faculty of Health and Life Sciences, Inti International University, Nilai, Negeri Sembilan, Malaysia
| | - Partha Pratim Dutta
- Faculty of Pharmaceutical Science, Assam down town University, Panikhaiti, Guwahati, Assam, India
| | - Wamidh H. Talib
- Faculty of Allied Medical Sciences, Applied Science Private University, Amman, Jordan
| | - Douglas Law
- Faculty of Health and Life Sciences, Inti International University, Nilai, Negeri Sembilan, Malaysia
- ENIAC, Centro Universitario de Excelencia. R. Força Pública, 89, Centro Guarulhos-S.P., Brazil
| | - Shazrul Fazry
- Department of Food Science, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia
- Tasik Chini Research Center, The Centre for Natural and Physical Laboratory Management, Universiti Kebangsaan Malaysia, Bangi, Selangor, Malaysia
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22
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Botezatu IC, Martu MA, Stoica L, Botez AE, Onofrei P, Dimitriu CD, Grecu BV, Grigoriu IDG, Ciurcanu O, Solcan C, Sin AI, Cotrutz EC. Expression of MMP-14 and CD147 in Gingival Tissue of Patients With and Without Diabetes Mellitus Type II. Diagnostics (Basel) 2025; 15:609. [PMID: 40075856 PMCID: PMC11899478 DOI: 10.3390/diagnostics15050609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 02/13/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Background: Diabetes mellitus (DM) is a major risk factor for the development of periodontal disease and aggravates the severity of periodontal conditions. Matrix metalloproteinases (MMPs) are known to degrade periodontal ligament attachment and bone matrix proteins. Increased expression of CD147 is associated with increased synthesis of several MMPs, being a modulator of MMP expression, including that of MMP-14. The purpose of this study was to quantify and compare the expressions of MMP-14 and CD147 in gingival tissues of patients with and without type 2 diabetes mellitus. Material and Methods: In this histological study, we included 33 subjects with periodontal disease: 16 patients with type 2 DM (test group) and 17 systemically healthy patients (control group). Tissue fragments were processed using an immunohistochemistry technique to determine immunoreactivity (IR) intensity of MMP-14 and CD147. Results: In the group of diabetes patients with periodontitis, 56.2% showed weak positive expressions (+), while 43.8% had intensely positive expressions (+++) of MMP-14. Statistically significant differences between test and control groups (p = 0.004, p = 0.883, and p = 0.002) were found for the membranous IR intensity of MMP-14. In the group of diabetes patients with periodontitis, 56.2% had moderate positive expressions (++) of CD 147, while 43.8% showed intensely positive expressions (+++). Statistically significant differences between the test and control groups were found (p = 0.001, p = 0.002, and p = 0.003) for the membranous IR intensity of CD147. Conclusions: The significantly higher membranous IR intensity for MMP-14 and CD 147 demonstrates the role of these biomarkers in the development of periodontal pathology in diabetes patients. It can be assumed that MMP-14 and CD147 could be further investigated as potential predictive biomarkers.
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Affiliation(s)
- Ionut Catalin Botezatu
- Department of Cell and Molecular Biology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania; (I.C.B.); (L.S.); (A.E.B.); (P.O.); (B.V.G.); (I.D.G.G.); (A.I.S.); (E.-C.C.)
| | - Maria-Alexandra Martu
- Department of Periodontology, Faculty of Dental Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
| | - Laura Stoica
- Department of Cell and Molecular Biology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania; (I.C.B.); (L.S.); (A.E.B.); (P.O.); (B.V.G.); (I.D.G.G.); (A.I.S.); (E.-C.C.)
| | - Ana Emanuela Botez
- Department of Cell and Molecular Biology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania; (I.C.B.); (L.S.); (A.E.B.); (P.O.); (B.V.G.); (I.D.G.G.); (A.I.S.); (E.-C.C.)
| | - Pavel Onofrei
- Department of Cell and Molecular Biology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania; (I.C.B.); (L.S.); (A.E.B.); (P.O.); (B.V.G.); (I.D.G.G.); (A.I.S.); (E.-C.C.)
| | - Cristina Daniela Dimitriu
- Department of Biochemistry, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania;
| | - Bogdan Vasile Grecu
- Department of Cell and Molecular Biology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania; (I.C.B.); (L.S.); (A.E.B.); (P.O.); (B.V.G.); (I.D.G.G.); (A.I.S.); (E.-C.C.)
| | - Ionut Daniel Gafincu Grigoriu
- Department of Cell and Molecular Biology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania; (I.C.B.); (L.S.); (A.E.B.); (P.O.); (B.V.G.); (I.D.G.G.); (A.I.S.); (E.-C.C.)
| | - Oana Ciurcanu
- Department of Dento-Alveolar Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania;
| | - Carmen Solcan
- Department of Cell and Molecular Biology, University of Agricultural Science and Veterinary Medicine “Ion Ionescu de la Brad”, 700490 Iași, Romania;
| | - Anca Ileana Sin
- Department of Cell and Molecular Biology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania; (I.C.B.); (L.S.); (A.E.B.); (P.O.); (B.V.G.); (I.D.G.G.); (A.I.S.); (E.-C.C.)
| | - Elena-Carmen Cotrutz
- Department of Cell and Molecular Biology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania; (I.C.B.); (L.S.); (A.E.B.); (P.O.); (B.V.G.); (I.D.G.G.); (A.I.S.); (E.-C.C.)
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23
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Ji L, Ma J, Ma Y, Cheng Z, Gan S, Yuan G, Liu D, Li S, Liu Y, Xue X, Bai J, Wang K, Cai H, Li S, Liu K, Yu M, Liu L. Berberine Ursodeoxycholate for the Treatment of Type 2 Diabetes: A Randomized Clinical Trial. JAMA Netw Open 2025; 8:e2462185. [PMID: 40029660 PMCID: PMC11877176 DOI: 10.1001/jamanetworkopen.2024.62185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 12/20/2024] [Indexed: 03/05/2025] Open
Abstract
Importance Few of the available therapies for type 2 diabetes (T2D) comprehensively address disease burden beyond glycemic control. Examining whether berberine ursodeoxycholate (HTD1801), a first-in-class gut-liver anti-inflammatory metabolic modulator, has the potential to treat the core aspects of metabolic disease is important. Objective To assess the safety and efficacy of HTD1801 in patients with T2D that is inadequately controlled with diet and exercise. Design, Setting, and Participants This phase 2 double-blind, placebo-controlled, 12-week randomized clinical trial, conducted in China between March 2022 and January 2023, included patients with T2D who underwent 8 or more weeks of diet and exercise, had a hemoglobin A1c (HbA1c) level of 7.0% to 10.5%, and had a fasting plasma glucose (FPG) level less than 250.5 mg/dL. Interventions Patients were randomized 1:1:1 to placebo (n = 38), HTD1801 500 mg twice daily (n = 37), and HTD1801 1000 mg twice daily (n = 38). Main Outcomes and Measures The primary end point was the HbA1c level change from baseline to week 12. Secondary end points included glycemic, hepatic, and cardiometabolic parameters. The primary end point was analyzed using a mixed-effects model for repeated measures, with the HbA1c level change from baseline as the dependent variable. Treatment group, measurement time point, and interaction between treatment group and measurement time point were independent variables. Results The study included 113 patients with T2D (mean [SD] age, 54.3 [10.6] years; 72 male [63.7%]) who were randomized. Among these patients, the mean (SD) HbA1c level was 8.2% (0.8%); body mass index, 25.5 (3.7), calculated as weight in kilograms divided by height in meters squared; and FPG level, 160.7 (38.3) mg/dL. Baseline disease severity was balanced across treatment groups. The primary end point was achieved with significant dose-dependent reductions in the HbA1c level in both HTD1801 groups compared with the placebo group. The least-squares mean difference in the HbA1c level at week 12 was -0.4% (95% CI, -0.79% to -0.03%; P = .04) for the 500-mg group and -0.7% (95% CI, -1.10% to -0.35%; P < .001) for the 1000-mg group compared with the placebo group. HbA1c level reductions were paralleled with mean (SD) improvements in the FPG level in both the 500-mg group (-13.0 [38.2] mg/dL) and the 1000-mg group (-18.4 [21.8] mg/dL) groups. Reductions were observed in lipids and markers of liver injury in the 1000-mg group. HTD1801 was safe and well tolerated, with 110 patients (97.3%) completing the study. Treatment-emergent adverse events, generally mild, occurred in 59 patients (52.2%) overall. One patient (in the 500-mg group) experienced a serious adverse event of retinal hemorrhage, which was unlikely related to treatment. No patients discontinued due to an adverse event. Conclusions and Relevance In this placebo-controlled randomized clinical trial, treatment with HTD1801 resulted in significant reductions in the HbA1c level and improvements in key cardiometabolic and liver parameters. HTD1801 was safe and well tolerated. These findings are being confirmed in ongoing phase 3 studies. The effects demonstrated by HTD1801 support an oral treatment option for T2D and its comorbidities. Trial Registration ClinicalTrials.gov Identifier: NCT06411275.
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Affiliation(s)
- Linong Ji
- Department of Endocrinology, Peking University People’s Hospital, Beijing, China
| | - Jianhua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing, Jiangsu, China
| | - Yujin Ma
- Department of Endocrinology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China
| | - Zhifeng Cheng
- Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shenglian Gan
- Department of Endocrinology, Changde First People’s Hospital, Changde, Hunan, China
| | - Guoyue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Dexue Liu
- Department of Endocrinology, The First Affiliated Hospital of Nanyang Medical College, Nanyang, Henan, China
| | - Sheli Li
- Department of Endocrinology, Affiliated Hospital of Yan’an University, Yan’an, Shangxi, China
| | - Yu Liu
- Department of Endocrinology, Nanjing Medical University Hospital, Nanjing, Jiangsu, China
| | - Xia Xue
- Department of Endocrinology, Jinan Central Hospital, Jinan, Shandong, China
| | - Jie Bai
- Department of Endocrinology, Liaocheng People’s Hospital, Liaocheng, Shandong, China
| | - Kun Wang
- Department of Endocrinology, Nanjing Jiangning Hospital, Nanjing, Jiangsu, China
| | - Hanqing Cai
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Shu Li
- Department of Endocrinology, Huizhou Central People’s Hospital, Huizhou, Guangdong, China
| | - Kui Liu
- Shenzhen HighTide Biopharmaceutical Ltd, Shenzhen, Guangdong, China
| | - Meng Yu
- Shenzhen HighTide Biopharmaceutical Ltd, Shenzhen, Guangdong, China
| | - Liping Liu
- Shenzhen HighTide Biopharmaceutical Ltd, Shenzhen, Guangdong, China
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24
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Waseem T, Zargaham MK, Ahmed M, Rajput TA, Amin A, Nadeem H. Computational investigation to identify multi-targeted anti-hyperglycemic potential of substituted 2-Mercaptobenzimidazole derivatives and synthesis of new α-glucosidase inhibitors. J Comput Aided Mol Des 2025; 39:9. [PMID: 39992499 DOI: 10.1007/s10822-025-00587-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 02/14/2025] [Indexed: 02/25/2025]
Abstract
One of the most widespread diseases recognized all over the world is diabetes, accounting for 1.5 million deaths each year. Recent studies have demonstrated benzimidazole derivatives as potential antidiabetic agents. Hence, the present study is focused on designing new derivatives of 2-mercaptobenzimidazole by C-S cross-coupling reaction and are subjected to computational screening to identify the most promising candidate. Molecular docking and MM-GBSA calculations were performed to ascertain the binding potential with different antidiabetic targets, including α-glucosidase, PPaR-γ, DPP-4, and AMPK. We observed somewhat moderate binding interactions of the synthesized compound against the α-glucosidase. Since binding affinities can be improved using synthetic chemistry approaches, synthesis of analogues (A-18a-c) by designing hybrids at sites such as the acidic functionality of A-18 was done. The analogue A-18a, with p-fluorobenzyl substitution, exhibited enhanced binding affinity (-4.339 Kcal/mol) with the α-glucosidase compared to the parent compound (-3.827 Kcal/mol). The synthesized analogues were also subjected to an in-vitro α-glucosidase inhibitory assay. Among them, A-18a exhibited the most significant inhibitory potential, with an IC50 value of 0.521 ± 0.01 µM as compared to the standard drug Acarbose (IC50 21.0 ± 0.5 µM). This aligns with the computational study findings, where A-18a exhibited stronger binding interactions within the active site of the enzyme. Hence, a promising analogue of the designed compound was synthesized through a computationally guided approach as an anti-hyperglycaemic agent. Additionally, most of the designed compounds showed significantly greater binding affinity with PPaR-γ as compared to the standard pioglitazone. A-18 was successfully synthesized by S-arylation reaction using CuI in 89% yield and was subjected to MD-simulation against PPaR-γ, which revealed stable binding throughout the 200 ns run. Future studies will focus on exploring the activity of the designed drugs against PPaR-γ through in-vitro and in-vivo assays.
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Affiliation(s)
- Tanya Waseem
- Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Muhammad Kazim Zargaham
- Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Madiha Ahmed
- Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan.
| | - Tausif Ahmed Rajput
- Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Adnan Amin
- NPRL Department of Pharmacognosy, Faculty of Pharmacy, Gomal University, Dera Ismail Khan, Pakistan
| | - Humaira Nadeem
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
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25
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Lee YG, Kim D. Tomatine Improves Glucose Metabolism and Mitochondrial Respiration in Insulin-Resistant Hepatocyte Cell Lines AML12 and HepG2 via an AMP-Activated Protein Kinase-Dependent Pathway. Cells 2025; 14:329. [PMID: 40072058 PMCID: PMC11898437 DOI: 10.3390/cells14050329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/19/2025] [Accepted: 02/22/2025] [Indexed: 03/15/2025] Open
Abstract
Insulin resistance (IR) disrupts hepatic glucose metabolism and mitochondrial function, which contributes to metabolic disorders. The present study examined the effects of tomatine on glucose metabolism in high-glucose-induced IR hepatocytes and explored its underlying mechanisms using AML12 and HepG2 cell models. The results showed that tomatine did not exhibit cytotoxic effects. Under IR conditions, tomatine dose-dependently improved glucose metabolism by enhancing glucose consumption and restoring the mRNA expression of the glucose transporter Glut2 and gluconeogenesis-related genes (Pepck and G6pase). Mechanistically, tomatine activated the phosphorylation of AMP-activated protein kinase (AMPK) and upregulated the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), reversing the IR-induced suppression of the AMPK/PGC1α pathway. In addition, tomatine enhanced mitochondrial oxidative function by restoring the oxygen consumption rate, increasing ATP production, and upregulating mitochondrial oxidative phosphorylation complex proteins. Both genetic and pharmacological inhibition of AMPK abolished these beneficial effects, confirming its central role in mediating tomatine's actions. Overall, our findings suggest that tomatine is a promising therapeutic candidate for enhancing hepatic glucose metabolism and mitochondrial function in IR-associated metabolic disorders through AMPK activation.
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Affiliation(s)
| | - Donghwan Kim
- Food Functionality Research Division, Korea Food Research Institute (KFRI), Wanju-gun 55365, Jeonbuk-do, Republic of Korea;
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26
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Irisarri A, Corral A, Perez-Salvador N, Bellver-Sanchis A, Ribalta-Vilella M, Bentanachs R, Alegret M, Laguna JC, Barroso E, Palomer X, Ortuño-Sahagún D, Vázquez-Carrera M, Pallàs M, Herrero L, Griñán-Ferré C. FTO inhibition mitigates high-fat diet-induced metabolic disturbances and cognitive decline in SAMP8 mice. Mol Med 2025; 31:73. [PMID: 39984825 PMCID: PMC11843768 DOI: 10.1186/s10020-025-01126-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 02/12/2025] [Indexed: 02/23/2025] Open
Abstract
This study investigated the effects of fat mass and obesity-associated (FTO) inhibition on cognitive function and metabolic parameters of senescence-accelerated mouse prone 8 (SAMP8) mice fed a high-fat diet (HFD). SAMP8 mice fed an HFD exhibited increased body weight, impaired glucose tolerance, and elevated serum leptin levels. In epididymal white adipose tissue (eWAT), pharmacological treatment with FB23, a well-established FTO inhibitor, increased leptin production and modulated genes involved in lipid metabolism (Cpt1a, Atgl, Hsl, Fas), oxidative stress (OS) (Bip, Edem), and inflammation (Mcp1, Tnfα). Expression of hepatic genes related to lipid metabolism (Cpt1a, Atgl, Mgl, Dgat2, Srebp, Plin2) and OS (catalase, Edem) were modulated by FB23, although hepatic steatosis remained unchanged. Remarkably, FB23 treatment increased m6A RNA methylation in the brain, accompanied by changes in N6-methyladenosine (m6A)-regulatory enzymes and modulation of neuroinflammatory markers (Il6, Mcp1, iNOS). FTO inhibition reduced the activity of matrix metalloproteases (Mmp2, Mmp9) and altered IGF1 signaling (Igf1, Pten). Notably, enhanced leptin signaling was observed through increased expression of immediate early genes (Arc, Fos) and the transcription factor Stat3. Improved synaptic plasticity was evident, as shown by increased levels of neurotrophic factors (Bdnf, Ngf) and restored neurite length and spine density. Consistent with these findings, behavioral tests demonstrated that FB23 treatment effectively rescued cognitive impairments in SAMP8 HFD mice. The novel object recognition test (NORT) and object location test (OLT) revealed that treated mice exhibited enhanced short- and long-term memory and spatial memory compared to the HFD control group. Additionally, the open field test showed a reduction in anxiety-like behavior after treatment with FB23. In conclusion, pharmacological FTO inhibition ameliorated HFD-induced metabolic disturbances and cognitive decline in SAMP8 mice. These results suggest that targeting FTO may be a promising therapeutic approach to counteract obesity-induced cognitive impairment and age-related neurodegeneration.
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Grants
- PID2021-122116OB-100 Ministerio de Economía, Industria Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI) and European Union NextGenerationEU/PRTR
- PDC2022-133441-I00 Ministerio de Economía, Industria Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI) and European Union NextGenerationEU/PRTR
- PID2020-114953RB-C21 Ministerio de Economía, Industria Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI) and European Union NextGenerationEU/PRTR
- PID2022-139016OA-I00 Ministerio de Economía, Industria Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI) and European Union NextGenerationEU/PRTR
- CIBERDEM CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)
- 2021 SGR 00357 the Government of Catalonia
- CB06/03/0001 CIBEROBN
- 2021SGR00367 Carlos III Health Institute project and the Government of Catalonia
- Producte 0092 Departament d'Empresa i Coneixement de la Generalitat de Catalunya 2023
- Llavor 005 and 007 Departament d'Empresa i Coneixement de la Generalitat de Catalunya 2023
- Departament d’Empresa i Coneixement de la Generalitat de Catalunya 2023
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Affiliation(s)
- Alba Irisarri
- pHD Program in Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035, Barcelona, Spain
| | - Ana Corral
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
| | - Núria Perez-Salvador
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
| | - Aina Bellver-Sanchis
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035, Barcelona, Spain
| | - Marta Ribalta-Vilella
- pHD Program in Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035, Barcelona, Spain
| | - Roger Bentanachs
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
| | - Marta Alegret
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Juan Carlos Laguna
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Emma Barroso
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM) - National Institute of Health Carlos III, 28029, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, 08950, Esplugues de Llobregat, Barcelona, Spain
| | - Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM) - National Institute of Health Carlos III, 28029, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, 08950, Esplugues de Llobregat, Barcelona, Spain
| | - Daniel Ortuño-Sahagún
- Laboratorio de Neuroinmunología Molecular, Instituto de Investigación de Ciencias Biomédicas (IICB) CUCS, Universidad de Guadalajara, 44340, Guadalajara, Jalisco, Mexico
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM) - National Institute of Health Carlos III, 28029, Madrid, Spain
- Pediatric Research Institute-Hospital Sant Joan de Déu, 08950, Esplugues de Llobregat, Barcelona, Spain
| | - Mercè Pallàs
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035, Barcelona, Spain
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Herrero
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Christian Griñán-Ferré
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028, Barcelona, Spain.
- Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035, Barcelona, Spain.
- Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
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Zhang CY, Liu S, Sui YX, Yang M. Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 inflammasome: From action mechanism to therapeutic target in clinical trials. World J Gastrointest Oncol 2025; 17:100094. [PMID: 39958558 PMCID: PMC11756006 DOI: 10.4251/wjgo.v17.i2.100094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 01/18/2025] Open
Abstract
The nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a critical modulator in inflammatory disease. Activation and mutation of NLRP3 can cause severe inflammation in diseases such as chronic infantile neurologic cutaneous and articular syndrome, Muckle-Wells syndrome, and familial cold autoinflammatory syndrome 1. To date, a great effort has been made to decode the underlying mechanisms of NLRP3 activation. The priming and activation of NLRP3 drive the maturation and release of active interleukin (IL)-18 and IL-1β to cause inflammation and pyroptosis, which can significantly trigger many diseases including inflammatory diseases, immune disorders, metabolic diseases, and neurodegenerative diseases. The investigation of NLRP3 as a therapeutic target for disease treatment is a hot topic in both preclinical studies and clinical trials. Developing potent NLRP3 inhibitors and downstream IL-1 inhibitors attracts wide-spectrum attention in both research and pharmaceutical fields. In this minireview, we first updated the molecular mechanisms involved in NLRP3 inflammasome activation and the associated downstream signaling pathways. We then reviewed the molecular and cellular pathways of NLRP3 in many diseases, including obesity, diabetes, and other metabolic diseases. In addition, we briefly reviewed the roles of NLRP3 in cancer growth and relative immune checkpoint therapy. Finally, clinical trials with treatments targeting NLRP3 and its downstream signaling pathways were summarized.
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Affiliation(s)
- Chun-Ye Zhang
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Yu-Xiang Sui
- School of Life Science, Shanxi Normal University, Linfen 041004, Shanxi Province, China
| | - Ming Yang
- Department of Surgery, University of Connecticut, School of Medicine, Farmington, CT 06030, United States
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28
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Jiao Q, Huang Y, He J, Xu Y. Advances in Oral Biomacromolecule Therapies for Metabolic Diseases. Pharmaceutics 2025; 17:238. [PMID: 40006605 PMCID: PMC11859201 DOI: 10.3390/pharmaceutics17020238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 02/08/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Metabolic diseases like obesity and diabetes are on the rise, and therapies with biomacromolecules (such as proteins, peptides, antibodies, and oligonucleotides) play a crucial role in their treatment. However, these drugs are traditionally injected. For patients with chronic diseases (e.g., metabolic diseases), long-term injections are accompanied by inconvenience and low compliance. Oral administration is preferred, but the delivery of biomacromolecules is challenging due to gastrointestinal barriers. In this article, we introduce the available biomacromolecule drugs for the treatment of metabolic diseases. The gastrointestinal barriers to oral drug delivery and strategies to overcome these barriers are also explored. We then discuss strategies for alleviating metabolic defects, including glucose metabolism, lipid metabolism, and energy metabolism, with oral biomacromolecules such as insulin, glucagon-like peptide-1 receptor agonists, proprotein convertase subtilisin/kexin type 9 inhibitors, fibroblast growth factor 21 analogues, and peptide YY analogues.
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Affiliation(s)
- Qiuxia Jiao
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuan Huang
- Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Jinhan He
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yining Xu
- Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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29
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Li C, Yuan Y, Jia Y, Zhou Q, Wang Q, Jiang X. Cellular senescence: from homeostasis to pathological implications and therapeutic strategies. Front Immunol 2025; 16:1534263. [PMID: 39963130 PMCID: PMC11830604 DOI: 10.3389/fimmu.2025.1534263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 01/15/2025] [Indexed: 02/20/2025] Open
Abstract
Cellular aging is a multifactorial and intricately regulated physiological process with profound implications. The interaction between cellular senescence and cancer is complex and multifaceted, senescence can both promote and inhibit tumor progression through various mechanisms. M6A methylation modification regulates the aging process of cells and tissues by modulating senescence-related genes. In this review, we comprehensively discuss the characteristics of cellular senescence, the signaling pathways regulating senescence, the biomarkers of senescence, and the mechanisms of anti-senescence drugs. Notably, this review also delves into the complex interactions between senescence and cancer, emphasizing the dual role of the senescent microenvironment in tumor initiation, progression, and treatment. Finally, we thoroughly explore the function and mechanism of m6A methylation modification in cellular senescence, revealing its critical role in regulating gene expression and maintaining cellular homeostasis. In conclusion, this review provides a comprehensive perspective on the molecular mechanisms and biological significance of cellular senescence and offers new insights for the development of anti-senescence strategies.
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Affiliation(s)
- Chunhong Li
- Department of Oncology, Suining Central Hospital, Suining, Sichuan, China
| | - Yixiao Yuan
- Department of Medicine, Health Cancer Center, University of Florida, Gainesville, FL, United States
| | - YingDong Jia
- Gastrointestinal Surgical Unit, Suining Central Hospital, Suining, Sichuan, China
| | - Qiang Zhou
- Department of Oncology, Suining Central Hospital, Suining, Sichuan, China
| | - Qiang Wang
- Gastrointestinal Surgical Unit, Suining Central Hospital, Suining, Sichuan, China
| | - Xiulin Jiang
- Department of Medicine, Health Cancer Center, University of Florida, Gainesville, FL, United States
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30
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Jiang Y, He H, Jia X. Protective Role of Oxycodone in Myocardial Oxidative Stress and Mitochondrial Dysfunction Induced by Ischemia-Reperfusion. J Biochem Mol Toxicol 2025; 39:e70151. [PMID: 39865943 PMCID: PMC11837462 DOI: 10.1002/jbt.70151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/24/2024] [Accepted: 01/16/2025] [Indexed: 01/28/2025]
Abstract
Ischemia-reperfusion (I/R) injury is a significant clinical problem impacting the heart and other organs, such as the kidneys and liver. This study explores the protective effects of oxycodone on myocardial I/R injury and its underlying mechanisms. Using a myocardial I/R model in Sprague-Dawley (SD) rats and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in H9c2 cells, we administered oxycodone and inhibited AMP-activated protein kinase (AMPK) with Compound C (C.C). Our results showed that oxycodone significantly reduced lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) production while stabilizing mitochondrial membrane potential (MMP). Western blot and RT-qPCR analyzes confirmed that oxycodone enhances AMPK phosphorylation and upregulates the expression of Silent Information Regulator 1 (SIRT1) and Peroxisome Proliferator-Activated Receptor γ Coactivator 1α (PGC-1α), thereby protecting myocardial cells. These findings suggest that oxycodone exerts significant protective effects against I/R injury by activating the AMPK pathway, offering new potential therapeutic targets for myocardial protection.
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Affiliation(s)
- Yongzheng Jiang
- The People's Hospital of Jiawang District of Xuzhou CityXuzhouChina
| | - Hua He
- Department of CardiologyAffiliated Hospital of Hebei UniversityBaodingChina
| | - Xinwei Jia
- Department of CardiologyAffiliated Hospital of Hebei UniversityBaodingChina
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31
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Ou Y, Zhao YL, Su H. Pancreatic β-Cells, Diabetes and Autophagy. Endocr Res 2025; 50:12-27. [PMID: 39429147 DOI: 10.1080/07435800.2024.2413064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/23/2024] [Accepted: 08/18/2024] [Indexed: 10/22/2024]
Abstract
PURPOSE Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. METHODS We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. RESULTS Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. CONCLUSION Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function.
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Affiliation(s)
- Yang Ou
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, P.R. China
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, P.R. China
| | - Yan-Li Zhao
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
| | - Heng Su
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, P.R. China
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32
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Meng F, Wang J, Wang L, Zou W. Glucose metabolism impairment in major depressive disorder. Brain Res Bull 2025; 221:111191. [PMID: 39788458 DOI: 10.1016/j.brainresbull.2025.111191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/26/2024] [Accepted: 01/02/2025] [Indexed: 01/12/2025]
Abstract
Major depressive disorder (MDD) is a common mental disorder with chronic tendencies that seriously affect regular work, life, and study. However, its exact pathogenesis remains unclear. Patients with MDD experience systemic and localized impairments in glucose metabolism throughout the disease course, disrupting various processes such as glucose uptake, glycoprotein transport, glycolysis, the tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). These impairments may result from mechanisms including insulin resistance, hyperglycemia-induced damage, oxidative stress, astrocyte abnormalities, and mitochondrial dysfunction, leading to insufficient energy supply, altered synaptic plasticity, neuronal cell death, and functional and structural damage to reward networks. These mechanical changes contribute to the pathogenesis of MDD and severely interfere with the prognosis. Herein, we summarized the impairment of glucose metabolism and its pathophysiological mechanisms in patients with MDD. In addition, we briefly discussed potential pharmacological interventions for glucose metabolism to alleviate MDD, including glucagon-like peptide-1 receptor agonists, metformin, topical insulin, liraglutide, and pioglitazone, to encourage the development of new therapeutics.
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Affiliation(s)
- Fanhao Meng
- The Graduate School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China
| | - Jing Wang
- The Graduate School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China
| | - Long Wang
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
| | - Wei Zou
- First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
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33
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Li Y, Tian YY, Yang Q, Yang X, Wang J, Zhang MM, Xie YH, Li J, Wang XF, Wang SW. Integrated HPLC, pharmacodynamics, and immunoprofiling to explore active components and mechanism of Zhi Bai Heye Fang on glycolipid metabolic disorders in mice. J Chromatogr B Analyt Technol Biomed Life Sci 2025; 1252:124446. [PMID: 39754817 DOI: 10.1016/j.jchromb.2024.124446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 11/13/2024] [Accepted: 12/26/2024] [Indexed: 01/06/2025]
Abstract
Zhi Bai Heye Fang (AR-PCC-NF) exerts a positive effect on glycolipid metabolic disorders in the clinical setting; however, its efficacy components and mechanisms of action remain unclear. Glycolipid metabolic disorders in mice were used to evaluate the therapeutic effects of AR-PCC-NF and its individual components, and the chemical components of AR-PCC-NF were detected by HPLC. An insulin-resistant cell model was then treated with 12 biological components in vitro, and seven candidate active components were administered to mice with glycolipid metabolic disorders to investigate the efficacy and mechanism of AR-PCC-NF. AR-PCC-NF improved glucolipid metabolism more effectively than did the individual components. The protein expression of INSR and GLUT4 was elevated, and FOXO1 expression and impaired mitochondrial debris in the liver were reduced by AR-PCC-NF. Furthermore, neomangiferin, chlorogenic acid, isomangiferin, 2-hydroxy-1-methoxyaporphine, hyperoside, nuciferine, and berberine improved glucose consumption or T-CHO in vitro. Interestingly, in vivo, neomangiferin, chlorogenic acid, isomangiferin, 2-hydroxy-1-methoxyaporphine, hyperoside, nuciferine, and berberine partially improved abnormal glucolipid metabolism in mice when used separately, but the effects were equivalent to those of AR-PCC-NF when the seven active components were used in combination. Moreover, AR-PCC-NF and its efficacy components upregulated the protein expression of p-AMPK/AMPK and PGC-1α, decreased the levels PPARα, and reduced mitochondrial debris in the liver. In conclusion, neomangiferin, chlorogenic acid, isomangiferin, 2-hydroxy-1-methoxyaporphine, hyperoside, nuciferine, and berberine are the main active components of AR-PCC-NF in the treatment of glycolipid metabolic diseases, and the mechanism is related to the regulation of the AMPK/PGC-1α.
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Affiliation(s)
- Yao Li
- The College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Yun-Yuan Tian
- The College of Life Sciences, Northwest University, Xi'an, China
| | - Qian Yang
- Department of Chinese Materia Medica and Natural Medicines, Air Force Medical University, Xi'an, China
| | - Xu Yang
- The College of Life Sciences, Northwest University, Xi'an, China
| | - Juan Wang
- The College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Meng-Meng Zhang
- The College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Yan-Hua Xie
- The College of Life Sciences, Northwest University, Xi'an, China
| | - Jie Li
- Department of Chinese Materia Medica and Natural Medicines, Air Force Medical University, Xi'an, China.
| | - Xu-Fang Wang
- Department of Pharmacy, Taiyuan Third People's Hospital, Taiyuan, China.
| | - Si-Wang Wang
- The College of Life Sciences, Northwest University, Xi'an, China.
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Ye C, Li Y, Shi J, He L, Shi X, Yang W, Lei W, Quan S, Lan X, Liu S. Network pharmacology analysis revealed the mechanism and active compounds of jiao tai wan in the treatment of type 2 diabetes mellitus via SRC/PI3K/AKT signaling. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118898. [PMID: 39374878 DOI: 10.1016/j.jep.2024.118898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/01/2024] [Accepted: 10/03/2024] [Indexed: 10/09/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Jiao-tai-wan (JTW) is a traditional Chinese herbal prescription, exerts its therapeutic effects on type 2 diabetes mellitus (T2DM). However, its mechanisms and active components remain unclear. AIM OF THE STUDY To investigate the therapeutic mechanisms of JTW in treating type 2 diabetes mellitus (T2DM), focusing on identifying active components, their targets, and validating efficacy through SRC/PI3K/AKT signaling pathway modulation in vitro and in vivo. MATERIALS AND METHODS Active ingredients were retrieved from the Traditional Chinese Medicine System Pharmacology (TCMSP) and Comprehensive Traditional Chinese Medicine Database (TCMID). Targets for these components were identified using the ChemMapper database based on 3D structural similarity. T2DM-related genes were sourced from the DisGeNET and Gene Expression Omnibus (GEO) databases. Protein-protein interaction (PPI) analysis and functional enrichment analysis were conducted to construct a pathway network of "herbs-active ingredients-candidate targets", identifying core molecular mechanisms and key active ingredients. SwissDock was used for molecular docking to predict ligands for candidate targets. The diabetic models were established using C57BL/6 mice and human liver HepG2 cell lines. Their Effectiveness and key molecules were verified through biochemical detection and immunoblotting. RESULTS Total 30 active compounds, 597 active ingredient targets, 9631 T2DM-related genes, and 521 overlapping candidate targets were found for JTW on T2DM. Go enrichment indicated the core pathways enriched on insulin and glucose metabolism. The auto-docking demonstrated SRC has potential binds to ingredients of JTW. In vivo, JTW can reduce blood glucose, and blood lipid levels, and HOMA-IR, and increase HOMA-ISI levels in T2DM mice with reduced ALT, AST, MDA levels and increased SOD levels. Meanwhile, decreased phosphorylation of SRC, along with increased levels of phosphorylated PI3K, PI3K, and phosphorylated AKT, were observed. HE staining of liver tissues further confirmed that JTW administration improved liver morphology, reducing inflammation and necrosis. In vitro, JTW significantly ameliorates upstream dysregulation by reducing SRC phosphorylation while enhancing phosphorylated PI3K, PI3K, and AKT phosphorylation levels. CONCLUSION JTW may alleviate glucose, insulin resistance, and lipid metabolism disorders by the SRC/PI3K/AKT signaling pathway, that provide a novel view of potential active compounds and essential targets in treating T2DM.
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Affiliation(s)
- Cunsi Ye
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China
| | - Yumeng Li
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China
| | - Jiayin Shi
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China
| | - Liena He
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China
| | - Xinyan Shi
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China
| | - Wei Yang
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China
| | - Wenbo Lei
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China
| | - Shijian Quan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaopeng Lan
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China.
| | - Shuangquan Liu
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, China.
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Schröder K. Sodium-Glucose-Cotransporter-2 Inhibitor Therapy and Intermitted Fasting in Cardiorenal Syndrome: The Role of Glucose-Mediated Oxidative Stress. J Clin Med 2025; 14:746. [PMID: 39941418 PMCID: PMC11818847 DOI: 10.3390/jcm14030746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/16/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Cardiorenal syndrome (CRS) is a complex clinical disorder characterized by the interplay between heart and kidney dysfunction. This condition is exacerbated by comorbidities such as diabetes mellitus, which contribute to glucose-mediated oxidative stress, further complicating the management of CRS. The management of CRS has evolved with the discovery of sodium-glucose-cotransporter-2 (SGLT2) inhibitors, which have been established as effective agents in reducing hyperglycemia and demonstrated cardiorenal protective effects. Concurrently, intermittent fasting has gained attention as an intervention without pharmacological treatment for its metabolic benefits, including improved glucose metabolism and insulin regulation and sensitivity, both with a potential reduction in oxidative stress. This review provides a summary of current findings on the roles of SGLT2 inhibitors and intermittent fasting in managing CRS, with a particular focus on glucose-mediated oxidative stress. We evaluate the mechanisms by which these interventions exert their effects, identify gaps in current research, and offer recommendations for future studies. While both SGLT2 inhibitors and intermittent fasting demonstrate potential in managing CRS, more research is needed to elucidate their long-term efficacy, safety, and potential synergistic effects.
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Affiliation(s)
- Katrin Schröder
- Institute of Cardiovascular Physiology, Medical Faculty, Goethe University, 60590 Frankfurt, Germany; ; Tel.: +49-(0)69-6301-83660; Fax: +49-(0)69-6301-7668
- German Center of Cardiovascular Research (DZHK), Partner Site Rhein-Main, 60590 Frankfurt, Germany
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Shi XF, He X, Sun ZR, Duo J, Yang H. Different expression of circulating microRNA profile in tibetan OSAHS with metabolic syndrome patients. Sci Rep 2025; 15:3013. [PMID: 39849122 PMCID: PMC11758385 DOI: 10.1038/s41598-025-87662-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 01/21/2025] [Indexed: 01/25/2025] Open
Abstract
Recent empirical investigations reinforce the understanding of a profound interconnection between metabolic functions and Obstructive Sleep Apnea-hypopnea Syndrome (OSAHS). This study identifies distinctive miRNA signatures in OSAHS with Metabolic Syndrome (Mets) patients from healthy subjects, that could serve as diagnostic biomarkers or describe differential molecular mechanisms with potential therapeutic implications. In this study, OSAHS with MetS patients showed significantly higher Apnea Hyponea Index(AHI), but lower oxygen desaturation index(ODI 4/h) and minimum pulse oxygen saturation(SpO2). A total of 33 differentially expressed miRNAs by Limma method, and 31 differentially expressed miRNAs by DEseq2 method were screened. In addition, GO enrichment analysis of target genes associated with differentially expressed miRNAs revealed significant enrichment in metabolic processes, suggesting that the differential expression of OSAHS-induced miRNAs may contribute to the progression of metabolic disorders through the regulation of metabolic pathways. Furthermore, KEGG pathway enrichment analysis revealed significant enrichment in the p53 signaling pathway and several other pathways. Notably, the Wnt signaling pathway, PI3K-Akt signaling pathway, cAMP signaling pathway, and AMPK signaling pathway are implicated in the metabolic processes of glucose dysregulation and lipid homeostasis, as well as the pathogenesis of hypertension associated with OSAHS. We identified IKBKB, PIK3R1, and MAP2K1 as the target genes most associated with Mets pathogenesis in OSAHS, regulated by miR-503-5p, miR-497-5p, and miR-497-5p, respectively. Additionally, the target genes of differentially expressed miRNAs between Tibetan OSAHS patients with MetS and healthy individuals are regulated by transcription factors such as NR2C1, STAT3, STAT5a, HIF1a, ETV4, NANOG, RELA, SP1, E2F1, NFKB1, AR, and MYC. In conlusion, we found differentially expressed miRNAs in Tibetan OSAHS patients with Metabolic Syndrome for the first time. Enrichment analysis results suggest that differentially expressed miRNAs may involved in the development of OSAHS-related metabolic disorders by regulating metabolic pathways. We also revealed that IKBKB, PIK3R1, and MAP2K1 are mostly associated with metabolic disorder in OSAHS, and miR-503-5p and miR-497-5p may regulate the development of MetS associated with OSAHS by modulating IKBKB, PIK3R1, and MAP2K1.
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Affiliation(s)
- Xue-Feng Shi
- Department of Respiratory Medicine, Qinghai Provincial People's Hospital, Xining, 810007, Qinghai, People's Republic of China
| | - Xiang He
- Department of Respiratory Medicine, Qinghai Provincial People's Hospital, Xining, 810007, Qinghai, People's Republic of China
- Department of Infectious Diseases, No.988 Hospital of Joint Logistic Support Force, Zhengzhou, People's Republic of China
| | - Ze-Rui Sun
- Department of Respiratory Medicine, Qinghai Provincial People's Hospital, Xining, 810007, Qinghai, People's Republic of China
- Department of Respiratory Medicine, Henan Huanghe Science and Technology College Affiliated Hospital, Zhengzhou, 450061, People's Republic of China
| | - Jie Duo
- Department of Respiratory Medicine, Qinghai Provincial People's Hospital, Xining, 810007, Qinghai, People's Republic of China.
| | - Hao Yang
- Department of Respiratory medicine, Taian 88 Hospital, Taian, 271000, People's Republic of China.
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Abdou HM, Elmageed GMA, Hussein HK, Yamari I, Chtita S, El-Samad LM, Hassan MA. Antidiabetic Effects of Quercetin and Silk Sericin in Attenuating Dysregulation of Hepatic Gluconeogenesis in Diabetic Rats Through Potential Modulation of PI3K/Akt/FOXO1 Signaling: In Vivo and In Silico Studies. J Xenobiot 2025; 15:16. [PMID: 39846548 PMCID: PMC11755466 DOI: 10.3390/jox15010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/31/2024] [Accepted: 01/14/2025] [Indexed: 01/24/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) is an intricate disease correlated with many metabolic deregulations, including disordered glucose metabolism, oxidative stress, inflammation, and cellular apoptosis due to hepatic gluconeogenesis aberrations. However, there is no radical therapy to inhibit hepatic gluconeogenesis disturbances yet. We thus sought to probe the effectiveness and uncover the potential mechanism of quercetin (QCT) and silk sericin (SS) in mitigating hyperglycemia-induced hepatic gluconeogenesis disorder, which remains obscure. Administration of QCT and SS to diabetic male albino rats markedly restored the levels of glucose, insulin, advanced glycation end-products (AGEs), liver function enzymes, alpha-fetoprotein (AFP), globulin, and glycogen, in addition to hepatic carbohydrate metabolizing enzymes and gluconeogenesis in comparison with diabetic rats. Furthermore, treatment with QCT and SS modulated hepatic malondialdehyde (MD), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), nitric oxide, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β), in addition to serum interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), implying their effectiveness in safeguarding cells against oxidative impairment and inflammation. Remarkably, QCT and SS treatments led to the upregulation of expression of phosphatidylinositol 3-kinases (PI3K), phospho-Akt (p-Akt), and forkhead box-O1 (FOXO1) genes in hepatic tissues compared to diabetic rats, orchestrating these singling pathways for curtailing hyperglycemia and pernicious consequences in hepatic tissues. Importantly, immunohistochemical investigations exhibited downregulation of caspase-3 expression in rats treated with QCT and SS compared to diabetic animals. Beyond that, the histopathological results of hepatic tissues demonstrated notable correlations with biochemical findings. Interestingly, the in silico results supported the in vivo findings, showing notable binding affinities of QCT and SS to PI3K, GPx, and TNF-α proteins. These results imply that QCT and SS could mitigate oxidative stress and inflammation and regulate hepatic gluconeogenesis in diabetic rats. However, QCT revealed greater molecular interactions with the studied proteins than SS. Overall, our results emphasize that QCT and SS have significant therapeutic effects on attenuating hyperglycemia-induced hepatic gluconeogenesis, with QCT showing superior effectiveness.
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Affiliation(s)
- Heba M. Abdou
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; (H.M.A.); (G.M.A.E.); (H.K.H.); (L.M.E.-S.)
| | - Ghada M. Abd Elmageed
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; (H.M.A.); (G.M.A.E.); (H.K.H.); (L.M.E.-S.)
| | - Hussein K. Hussein
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; (H.M.A.); (G.M.A.E.); (H.K.H.); (L.M.E.-S.)
| | - Imane Yamari
- Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P. O. Box 7955, Morocco; (I.Y.); (S.C.)
| | - Samir Chtita
- Laboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of Casablanca, Casablanca P. O. Box 7955, Morocco; (I.Y.); (S.C.)
| | - Lamia M. El-Samad
- Department of Zoology, Faculty of Science, Alexandria University, Alexandria 21321, Egypt; (H.M.A.); (G.M.A.E.); (H.K.H.); (L.M.E.-S.)
| | - Mohamed A. Hassan
- Protein Research Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt
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Luo J, Wu T, Zhang J, Liang Z, Shao W, Wang D, Li L, Zuo D, Zhou J. D-mannose promotes diabetic wound healing through inhibiting advanced glycation end products formation in keratinocytes. Mol Med 2025; 31:15. [PMID: 39827347 PMCID: PMC11748336 DOI: 10.1186/s10020-025-01070-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 01/05/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Diabetic chronic foot ulcers pose a significant therapeutic challenge around the world, resulting in adverse effects and complications in patients. D-mannose is enriched in cirtus peel and exerts beneficial effects among various diseases, especially against inflammation-related disorders. METHODS Here, we examined the potential effect of D-mannose during wound healing process in streptozotocin (STZ)-induced diabetes mice in vivo and by culturing keratinocytes under high glucose condition in vitro. The skin lesion healing was recorded in photos and evaluated by histochemical staining. What's more, the advanced glycation end products (AGEs) concentration in blood and mice skin was quantified. Apoptotic cells were assessed by flow cytometry and Western blotting. Inflammatory cytokines and cellular differential gene expression levels were measured by real-time PCR. The expression of the AMPK/Nrf2/HO-1 signaling-related molecules was determined by Western blotting. RESULTS We first found that topical supplementation of D-mannose remarkably improved skin wound healing in diabetes mice. Furthermore, both in vivo and in vitro experiments demonstrated that D-mannose reduced the AGEs generation. Mechanistically, D-mannose inhibited AGEs, then upregulated AMPK/Nrf2/HO-1 signaling in the context of high glucose to maintain keratinocyte normal functions, which positively influenced macrophage and fibroblast to accelerate diabetic wound healing. Noteworthily, these protective effects of D-mannose were abolished by the pretreatment with inhibitors of AGEs or AMPK. CONCLUSION As far as we know, this is the first study exploring the protective role of D-mannose on diabetic wound healing via topical supplementation. We find that D-mannose protects keratinocytes from high glucose stimulation via inhibition of AGEs formation as well as orchestrates inflammatory microenvironment in diabetic wounded skin, suggesting its supplementation as a potential therapy to promote refractory wound healing in diabetic patients.
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Affiliation(s)
- Jialiang Luo
- Institute of Molecular Immunology, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Department of Dermatology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tianxing Wu
- The Second School of Clinical Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jing Zhang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Zhicheng Liang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Weijie Shao
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Di Wang
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Southern Medical University, Guangzhou, China
| | - Lei Li
- Institute of Molecular Immunology, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Daming Zuo
- Institute of Molecular Immunology, Key Laboratory of Infectious Diseases Research in South China, Ministry of Education, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China.
| | - Jia Zhou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
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Kakoti BB, Zothantluanga JH, Deka K, Halder RK, Roy D. In silico design and computational screening of berberine derivatives for potential antidiabetic activity through allosteric activation of the AMPK pathway. In Silico Pharmacol 2025; 13:12. [PMID: 39780772 PMCID: PMC11704122 DOI: 10.1007/s40203-024-00295-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Globally, there is an increase in the prevalence of metabolic illnesses, including diabetes mellitus. However, current therapies for diabetes and other metabolic illnesses are not well understood. Pharmacological treatment of type 2 diabetes is challenging, moreover, the majority of antidiabetic medications are incompatible with individuals who have cardiac disease, renal illness, or liver damage. Despite the ongoing development of innovative medicines, the quest for an optimal treatment that serves both as a hypoglycaemic agent and mitigates diabetes-related problems remains unattained. Recent research demonstrates that berberine has significant promise in the treatment of diabetes. Berberine influences glucose metabolism by enhancing insulin secretion, promoting glycolysis, decreasing adipogenesis, disrupting the function of the mitochondria, stimulating the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway, thereby augmenting glucokinase activity. In this study, we virtually designed and synthesized 5 berberine derivatives (data not yet published) to study their impact on the AMP-activated protein kinase (AMPK) pathway through molecular docking and dynamic simulation study. Activation of AMPK plays an important role by enhancing glucose uptake in cells. Berberine and its derivatives showed potential for allosteric activation of the AMPK pathway. The allosteric activation of AMPK α- & β-subunit involves complex interactions with standard activators like A-769662. Berberine and its derivatives showed potential binding affinity at the allosteric site of AMPK α- & β-subunit, forming similar interactions to A-769662. Molecular dynamic simulations indicated stability of these complexes. However, interactions of these derivatives with the AMPK γ-subunit were less stable, suggesting limited potential for allosteric activation at this site. Further studies are required to assess the long-term stability and efficacy of berberine and its derivatives as allosteric AMPK activators. Additionally, ADMET predictions suggest these derivatives to be safe, warranting further experimental and preclinical investigations as potential antidiabetic agents. Supplementary Information The online version contains supplementary material available at 10.1007/s40203-024-00295-0.
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Affiliation(s)
- Bibhuti Bhusan Kakoti
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
| | - James H. Zothantluanga
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
| | - Kangkan Deka
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
- NETES Institute of Pharmaceutical Science, NEMCARE Group of Institutions, Mirza, Kamrup, Guwahati, Assam 781125 India
| | - Raj Kumar Halder
- Ruhvenile Biomedical, Plot-8 OCF Pocket Institution, Sarita Vihar, Delhi, 110076 India
| | - Dhritiman Roy
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
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Zhang Q, Liu H, Zhang J, Ouyang Y, Fu X, Xie C. The efficacy and safety of qiwei baizhu san in the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis. Front Pharmacol 2025; 15:1501990. [PMID: 39845797 PMCID: PMC11752898 DOI: 10.3389/fphar.2024.1501990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 12/16/2024] [Indexed: 01/24/2025] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, mostly resulting from impaired insulin production and diminished glucose metabolism regulation. Qiwei Baizhu San (QWBZS) is a classic formula used in traditional Chinese medicine for the treatment of T2DM. A comprehensive analysis of the efficacy and safety of QWBZS in the treatment of T2DM is essential. Methods This study's protocol was registered with PROSPERO (CRD42024576129). As of August 2024, we searched eight databases to screen and include randomized controlled trials of QWBZS for T2DM. Heterogeneity sources were examined via subgroup analyses, the robustness of the results was determined by sensitivity analyses, publication bias was evaluated using funnel plots and Egger's test, evidence quality was appraised with GRADEpro, and possible mechanisms of QWBZS for T2DM were categorized and summarized. Results This analysis encompassed 14 qualifying trials with a total of 1,169 subjects. The analytical results suggested that QWBZS, when combined with conventional treatment, was more effective than conventional treatment alone in improving FBG, 2hPG, HbA1c, HOMA-IR, TC, TG, LDL-C, and HDL-C. When QWBZS was used alone, it was more effective than conventional therapy in FBG, 2hPG, and HbA1c. And QWBZS could improve the overall effectiveness of clinical treatment in T2DM patients. The impact of QWBZS therapy alone on HOMA-IR and lipid metabolism remained unclear due to the limited number of trials included. Analysis of adverse events suggested that QWBZS was relatively safe. Conclusion This study suggested that QWBZS, when combined with conventional treatment, was more effective in improving glucose metabolism, insulin resistance, and lipid metabolism compared to conventional treatment alone in individuals with T2DM. QWBZS alone also contributed to the regulation of blood glucose levels. Meanwhile, QWBZS could improve the overall effective rate of clinical treatment with a relatively high safety profile. Nevertheless, owing to the inferior quality and significant heterogeneity of the existing evidence, additional high-quality studies are requisite to furnish more dependable evidence for the future clinical application of QWBZS. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=576129, identifier [CRD42024576129].
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Affiliation(s)
- Quan Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongyan Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiahong Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yujie Ouyang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoxu Fu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chunguang Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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An H, Jang Y, Choi J, Hur J, Kim S, Kwon Y. New Insights into AMPK, as a Potential Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease and Hepatic Fibrosis. Biomol Ther (Seoul) 2025; 33:18-38. [PMID: 39702310 PMCID: PMC11704404 DOI: 10.4062/biomolther.2024.188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/21/2024] Open
Abstract
AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.
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Affiliation(s)
- Haeun An
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yerin Jang
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jungin Choi
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Juhee Hur
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Seojeong Kim
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Youngjoo Kwon
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
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Aydin S, Tekinalp SG, Tuzcu B, Cam F, Sevik MO, Tatar E, Kalaskar D, Cam ME. The role of AMP-activated protein kinase activators on energy balance and cellular metabolism in type 2 diabetes mellitus. OBESITY MEDICINE 2025; 53:100577. [DOI: 10.1016/j.obmed.2024.100577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Peng L, Tian Y, Wu X, Liu F, Zhou M, Wu Z, Xia Y, Liu X, Cheng C. Suppression of TRIM72-mediated endoplasmic reticulum stress facilitates FOXM1 promotion of diabetic ulcer healing. Wound Repair Regen 2025; 33:e13247. [PMID: 39721954 PMCID: PMC11669624 DOI: 10.1111/wrr.13247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/09/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
Foot ulcers are amongst the most prevalent complications of diabetes, known for their delayed healing process. Recent research indicates that the transcription factor forkhead box M1 (FOXM1) plays a role in promoting diabetic ulcer repair. However, the precise mechanisms underlying FOXM1 functions in this context remain unclear. This study aimed to clarify the role of tripartite motif-containing protein 72 (TRIM72)-mediated endoplasmic reticulum stress in FOXM1 promotive effects. Immunohistochemistry revealed that FOXM1 expression was significantly reduced in the lesion tissues of diabetic foot ulcer patients. In vitro experiments revealed a decrease in FOXM1 expression in cultured dermal fibroblasts under high glucose conditions. Activating FOXM1 with a plasmid accelerated the proliferation, migration, and differentiation of dermal fibroblasts and mitigated endoplasmic reticulum stress under high glucose conditions. Additionally, ChIP and luciferase reporter gene assays confirmed that FOXM1 suppressed TRIM72 expression transcriptionally by binding to its promoter. Furthermore, high glucose induced ubiquitination of adenosine 5'-monophosphate-activated protein kinase alpha (AMPKα), whilst inactivation of AMPKα signalling reversed the aforementioned effects of FOXM1 on cells. Finally, the FOXM1-overexpressing plasmid was transfected in vivo, which promoted wound healing in a murine diabetic ulcer model. In conclusion, FOXM1 reduces endoplasmic reticulum stress by inhibiting TRIM72-mediated AMPKα ubiquitination, thereby accelerating the healing of diabetic ulcers.
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Affiliation(s)
- Lingling Peng
- Department of DermatologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Yaning Tian
- Department of DermatologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Xiangkai Wu
- Department of HorticultureXinjiang Agricultural UniversityUrumqiChina
| | - Fengqi Liu
- Department of DermatologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Mingzhu Zhou
- Department of DermatologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Zixi Wu
- Wuhan Britain‐China International SchoolWuhanChina
| | - Yumin Xia
- Department of DermatologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
| | - Xiaoming Liu
- Department of DermatologySouthern University of Science and Technology HospitalShenzhenChina
| | - Chuantao Cheng
- Department of DermatologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anChina
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Guo W, Wang X, Wang B, Zhang Y, Zhao F, Qu Y, Yao L, Yun J. In vitro digestion and fecal fermentation behaviors of exopolysaccharide from Morchella esculenta and its impacts on hypoglycemic activity via PI3K/Akt signaling and gut microbiota modulation. Food Chem X 2024; 24:101870. [PMID: 39431209 PMCID: PMC11490802 DOI: 10.1016/j.fochx.2024.101870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/28/2024] [Accepted: 09/30/2024] [Indexed: 10/22/2024] Open
Abstract
This study aimed to evaluate the effects of gastrointestinal digestion on the physicochemical properties and hypoglycemic activity of extracellular polysaccharides from Morchella esculenta (MEPS). The results showed that the MEPS digestibility was 22.57 % after saliva-gastrointestinal digestion and only partial degradation had occurred. Contrarily, after 48 h of fecal fermentation, its molecular weight and molar ratios of the monosaccharide composition varied significantly due to being utilized by human gut microbiota, and the final fermentation rate was 76.89 %. Furthermore, the MEPS-I, the final product of saliva-gastrointestinal digestion still retained significant hypoglycemic activity, it alleviated insulin resistance and increased the IR cells glucose consumption by activating PI3K/AKT signaling pathway. MEPS-I treatment reduced the proportion of Firmicutes to Bacteroidetes, and the relative abundance of beneficial bacteria that enhanced insulin sensitivity and glucose uptake was promoted. This research can provide a theoretical basis for the further development of Morchella esculenta as a health functional food.
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Affiliation(s)
- Weihong Guo
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Xuerui Wang
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Biao Wang
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Yajie Zhang
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Fengyun Zhao
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Yuling Qu
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
| | - Liang Yao
- Gannong Moli (Qingyang) Agricultural Development Co., Ltd, Qingyang 745000, Gansu, China
| | - Jianmin Yun
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, Gansu, China
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Mekonnen Z, Petito G, Shitaye G, D’Abrosca G, Legesse BA, Addisu S, Ragni M, Lanni A, Fattorusso R, Isernia C, Comune L, Piccolella S, Pacifico S, Senese R, Malgieri G, Gizaw ST. Insulin-Sensitizing Properties of Decoctions from Leaves, Stems, and Roots of Cucumis prophetarum L. Molecules 2024; 30:98. [PMID: 39795155 PMCID: PMC11722063 DOI: 10.3390/molecules30010098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/25/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by insulin resistance and impaired beta-cell secretory function. Since existing treatments often present side effects based on different mechanisms, alternative therapeutic options are needed. In this scenario, the present study first evaluates the cytotoxicity of decoctions from the leaves, stems, and roots of Cucumis prophetarum L. on HepG2 and L6C5 cells. The extracts were chemically investigated by UV-Vis and ATR-FTIR spectroscopic techniques and by ultra high-performance chromatographic techniques, coupled with high-resolution mass spectrometry. Briefly, decoctions from the leaves and stems were mainly composed of apigenin C-glycosides, while the root decoction was rich in raffinose and cucumegastigmane II. To evaluate the insulin-sensitizing properties of the extracts in insulin-resistant L6 myoblasts, an evaluation by Western blot analysis of the proteins in the insulin signaling pathway was then performed. Particularly, key proteins of insulin signaling were investigated, i.e., insulin receptor substrate (IRS-1), protein kinase B (PKB/AKT), and glycogen synthase kinase-3 (GSK-3β), which have gained considerable attention from scientists for the treatment of diabetes. Under all conditions tested, the three decoctions showed low cytotoxicity. The stem and root decoction (300 μg/mL) resulted in a significant increase in the levels of p-IRS-1 (Tyr612), GSK3β (Ser9), and p-AMPK (Thr172) compared to those of the palmitic acid-treated group, and the leaf decoction resulted an increase in the level of p-IRS-1 (Tyr612) and p-AMPK (Thr172) and a decrease in p-GSK3β (Ser9) compared to the levels for the palmitic acid-treated group. The root decoction also reduced the level of p-mToR (Ser2448). Overall, the acquired data demonstrate the effect of reducing insulin resistance induced by the investigated decoctions, opening new scenarios for the evaluation of these effects aimed at counteracting diabetes and related diseases in animal models.
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Affiliation(s)
- Zewdie Mekonnen
- Department of Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa P. O. Box 9086, Ethiopia; (Z.M.); (S.T.G.)
- Department of Biomedical Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar P. O. Box 79, Ethiopia;
| | - Giuseppe Petito
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Getasew Shitaye
- Department of Biomedical Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar P. O. Box 79, Ethiopia;
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Gianluca D’Abrosca
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71100 Foggia, Italy
| | - Belete Adefris Legesse
- Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), College of Health Sciences, Addis Ababa University, Addis Ababa P. O. Box 9086, Ethiopia
| | - Sisay Addisu
- Department of Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa P. O. Box 9086, Ethiopia; (Z.M.); (S.T.G.)
| | - Maurizio Ragni
- Center for Study and Research on Obesity, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy;
| | - Antonia Lanni
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Roberto Fattorusso
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Carla Isernia
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Lara Comune
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Simona Piccolella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Severina Pacifico
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Rosalba Senese
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Gaetano Malgieri
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy; (G.P.); (A.L.)
| | - Solomon Tebeje Gizaw
- Department of Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa P. O. Box 9086, Ethiopia; (Z.M.); (S.T.G.)
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Liu P, Zhang Z, Chen Q. [Roles of ferroptosis in the development of diabetic nephropathy]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 53:708-714. [PMID: 39757741 PMCID: PMC11736350 DOI: 10.3724/zdxbyxb-2024-0114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 10/28/2024] [Indexed: 01/07/2025]
Abstract
Diabetic nephropathy is a common microvascular complication of diabetes mellitus and one of the main causes of death in patients with diabetes mellitus. Ferroptosis is a newly discovered iron-dependent regulated cell death, which may contribute to the pathogenesis and development of diabetic nephropathy. Adenosine monophosphate-activated protein kinase (AMPK)-mediated ferroptosis-related signaling pathways can slow down the progression of diabetic nephropathy, but excessive activation of AMPK signaling pathway may induce cells to undergo autophagic death. Activation of the signaling pathway mediated by nuclear factor-erythroid 2-related factor (Nrf) 2 and heme oxygenase (HO)-1 can inhibit ferroptosis of cells and alleviate diabetic nephropathy. However, the regulatory effect of HO-1 on ferroptosis is bidirectional, and activation of HIF-1α/HO-1 pathway may lead to intracellular iron overload and ultimately promote ferroptosis. Transforming growth factor (TGF)-β1 mediated signaling pathways can accelerate lipid peroxidation by down-regulating the levels of SLC7A11/GSH/GPX4. The ferroptosis-related signaling pathways mediated by exosome lncRNAs/circRNAs/miRNAs are also involved in the pathogenesis and development of diabetic nephropathy. In addition, signaling pathways mediated by stimulator of interferon gene (STING) and the novel ferroptosis promoter acyl-CoA synthetase long-chain family (ACSL) 1 can induce ferroptosis to promote the progression of diabetic nephropathy. In this review, we focus on the roles of ferroptosis in diabetic nephropathy through the signaling pathways mediated by AMPK, Nrf2/HO-1, TGF-β and exosomes, to elaborate the pathogenesis and development of diabetic nephropathy, and the potential therapeutic target for diabetic nephropathy.
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Affiliation(s)
- Pan Liu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
| | - Zhengdong Zhang
- Department of Orthopedics, School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China.
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
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Aboushouk AA, Saad HM, Rohiem AH, Gad El-Karim DRS. New Insights on the potential therapeutic effects of glibenclamide and Obeticholic acid against Alloxan-Induced diabetes mellitus in rat model. Int Immunopharmacol 2024; 143:113469. [PMID: 39461241 DOI: 10.1016/j.intimp.2024.113469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 10/19/2024] [Accepted: 10/20/2024] [Indexed: 10/29/2024]
Abstract
Diabetes mellitus (DM) represents a highly prevalent metabolic disorder across the globe. This study aimed to determine the ameliorative efficacy of glibenclamide (Gli) and obeticholic acid (OCA) against biochemical and pathological changes related to alloxan-induced diabetes. Twenty male Wistar rats were allocated into four groups; Control group, Diabetic group: received intraperitoneal injection of alloxan (120 mg/kg) for induction of diabetes, Diabetic + Gli group: Diabetic rats treated daily with oral Gli (5 mg/kg) and Diabetic + OCA group: Diabetic rats treated daily with oral OCA (10 mg/kg). All rats were subjected to 30 days treatments. Our results indicated that Gli successfully ameliorated hyperglycemia and dyslipidemia with a significant decline in serum pancreatic lipase activity and increased insulin level, while OCA had the same effect but without any enhancement in serum insulin levels. Additionally, the disturbances in liver function-related parameters and the evoked oxidative stress, interleukin(IL)-6 and IL-10 in the liver and pancreas were abrogated upon treatment with Gli and OCA. Furthermore, Gli and OCA increased AMP-activated protein kinase (P-AMPK), insulin receptor substrate 1 (IRS1), farnesoid X receptor (FXR), and glucagon-like peptide-1 receptor (GLP-1R) expressions and downregulated sterol regulatory element binding protein-1c mRNA expression. Besides, Gli and OCA have alleviated diabetes-induced histopathological distortions in hepatic and pancreatic tissues and enhanced the immunoexpression of insulin, and proliferating cell nuclear antigen with decreased immune reactivity of glucagon within pancreatic tissues. Gli and OCA decreased the immune reactivity of nuclear factor kappa B and increased the glycogen content of hepatic tissues. In conclusion, OCA is efficacious in the management of dyslipidemia and hyperglycemia of DM and its related oxidative stress.
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Affiliation(s)
- Asmaa A Aboushouk
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Alexandria University, Egypt.
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh 51744, Egypt.
| | - Aya H Rohiem
- Department of Physiology, Faculty of Veterinary Medicine, Alexandria University, Egypt.
| | - Dina R S Gad El-Karim
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Alexandria University, Egypt.
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Wang K, Zhang L, Deng B, Zhao K, Chen C, Wang W. Mitochondrial uncoupling protein 2: a central player in pancreatic disease pathophysiology. Mol Med 2024; 30:259. [PMID: 39707176 DOI: 10.1186/s10020-024-01027-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
Pancreatic diseases pose considerable health challenges due to their complex etiology and limited therapeutic options. Mitochondrial uncoupling protein 2 (UCP2), highly expressed in pancreatic tissue, participates in numerous physiological processes and signaling pathways, indicating its potential relevance in these diseases. Despite this, UCP2's role in acute pancreatitis (AP) remains underexplored, and its functions in chronic pancreatitis (CP) and pancreatic steatosis are largely unknown. Additionally, the mechanisms connecting various pancreatic diseases are intricate and not yet fully elucidated. Given UCP2's diverse functionality, broad expression in pancreatic tissue, and the distinct pathophysiological features of pancreatic diseases, this review offers a comprehensive analysis of current findings on UCP2's involvement in these conditions. We discuss recent insights into UCP2's complex regulatory mechanisms, propose that UCP2 may serve as a central regulatory factor in pancreatic disease progression, and hypothesize that UCP2 dysfunction could significantly contribute to disease pathogenesis. Understanding UCP2's role and mechanisms in pancreatic diseases may pave the way for innovative therapeutic and diagnostic approaches.
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Affiliation(s)
- Kunpeng Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lilong Zhang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Beiying Deng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kailiang Zhao
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chen Chen
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
- General Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
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Ashraf MS, Tuli K, Moiz S, Sharma SK, Sharma D, Adnan M. AMP kinase: A promising therapeutic drug target for post-COVID-19 complications. Life Sci 2024; 359:123202. [PMID: 39489398 DOI: 10.1016/j.lfs.2024.123202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 10/27/2024] [Accepted: 10/29/2024] [Indexed: 11/05/2024]
Abstract
The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in severe respiratory issues and persistent complications, particularly affecting glucose metabolism. Patients with or without pre-existing diabetes often experience worsened symptoms, highlighting the need for innovative therapeutic approaches. AMPK, a crucial regulator of cellular energy balance, plays a pivotal role in glucose metabolism, insulin sensitivity, and inflammatory responses. AMPK activation, through allosteric or kinase-dependent mechanisms, impacts cellular processes like glucose uptake, fatty acid oxidation, and autophagy. The tissue-specific distribution of AMPK emphasizes its role in maintaining metabolic homeostasis throughout the body. Intriguingly, SARS-CoV-2 infection inhibits AMPK, contributing to metabolic dysregulation and post-COVID-19 complications. AMPK activators like capsaicinoids, curcumin, phytoestrogens, cilostazol, and momordicosides have demonstrated the potential to regulate AMPK activity. Compounds from various sources improve fatty acid oxidation and insulin sensitivity, with metformin showing opposing effects on AMPK activation compared to the virus, suggesting potential therapeutic options. The diverse effects of AMPK activation extend to its role in countering viral infections, further highlighting its significance in COVID-19. This review explores AMPK activation mechanisms, its role in metabolic disorders, and the potential use of natural compounds to target AMPK for post-COVID-19 complications. Also, it aims to review the possible methods of activating AMPK to prevent post-COVID-19 diabetes and cardiovascular complications. It also explores the use of natural compounds for their therapeutic effects in targeting the AMPK pathways. Targeting AMPK activation emerges as a promising avenue to mitigate the long-term effects of COVID-19, offering hope for improved patient outcomes and a better quality of life.
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Affiliation(s)
- Mohammad Saquib Ashraf
- Department of Medical Laboratory Science College of Pharmacy, Nursing and Medical Science Riyadh ELM University, Riyadh, P.O. Box 12734, Saudi Arabia.
| | - Kanika Tuli
- Guru Nanak Institute of Pharmacy, Dalewal, Hoshiarpur 144208, Punjab, India
| | - Shadman Moiz
- Department of Biotechnology, Lalit Narayan Mithila University, Darbhanga 846004, Bihar, India
| | - Satish Kumar Sharma
- Department of Pharmacology, Glocal School of Pharmacy, The Glocal University, Saharanpur, India
| | - Deepa Sharma
- UMM Matrix Innovations Private Limited, Delhi 110044, India
| | - Mohd Adnan
- Department of Biology, College of Science, University of Ha'il, Ha'il, P.O. Box 2440, Saudi Arabia; Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 602105, India
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50
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El-Marasy SA, Farouk H, Khattab MS, Moustafa PE. Beta-carotene ameliorates diabetic nephropathy in rats: involvement of AMPK/SIRT1/autophagy pathway. Immunopharmacol Immunotoxicol 2024; 46:763-772. [PMID: 39308310 DOI: 10.1080/08923973.2024.2402347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 09/03/2024] [Indexed: 11/19/2024]
Abstract
OBJECTIVE This study aimed to demonstrate the protective effect of beta-carotene against STZ-induced DN in rats and explore the possible underlying mechanisms that may have mediated such condition. MATERIAL AND METHODS Wistar rats were allocated into four groups. Normal group received distilled water for 3 weeks. The other three groups were rendered diabetic by an intraperitoneal dose of STZ (50 mg/kg), 48 h later, group 2: received the vehicle and served as control, groups (3 &4) received orally beta-carotene in doses of 10 and 20 mg/kg, respectively for 3 weeks. Then serum and renal tissue were collected for biochemical, molecular, immunohistopathological, and histopathological examination. RESULTS Beta-carotene ameliorated the reduction in body weight, reduced blood glucose, elevated serum insulin, reduced blood urea nitrogen, and serum creatinine levels. Beta-carotene elevated phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK)/AMPK, alleviated phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR, reduced interleukin 1 beta (IL-1β), increased Beclin 1, LC3II/LC3I, and reduced p62 renal contents. Moreover, it elevated renal SIRT1 gene expression and reduced renal tumor necrosis factor-alpha (TNF-α) and caspase-3 protein expressions. CONCLUSION Beta-carotene exerted renoprotective effect against STZ-induced DN and histopathological alterations through alleviating hyperglycemia, attenuating inflammation, activating AMPK/SIRT1/autophagy pathway, and combating apoptosis.
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Affiliation(s)
- Salma A El-Marasy
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Hadir Farouk
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
| | - Marwa S Khattab
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Passant E Moustafa
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt
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