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Moayedfard Z, Bagheri Lankarani K, Alizadeh AA, Nekooeian AA, Dara M, Koohpeyma F, Parsa S, Nikeghbalian S, Hosseinpouri A, Azarpira N. The Ameliorative Effect of Adipose-Derived Mesenchymal Stem Cells and Their Exosomes in Non-alcoholic Steatohepatitis by Simultaneously Enhancing Autophagic Flux and Suppressing Endoplasmic Reticulum Stress. IRANIAN JOURNAL OF MEDICAL SCIENCES 2025; 50:334-350. [PMID: 40438157 PMCID: PMC12116527 DOI: 10.30476/ijms.2024.103376.3660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 09/01/2024] [Accepted: 09/22/2024] [Indexed: 06/01/2025]
Abstract
Background Due to the scarcity of treatment options, managing the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to cirrhosis necessitates innovative approaches. This study focused on endoplasmic reticulum (ER) stress, apoptosis, and autophagy as key mechanisms in NAFLD pathogenesis. It also highlighted the potential of adipose-derived mesenchymal stem cells (AD-MSCs) and their exosomes as promising therapeutic options. Methods The study was conducted at the Department of Regenerative Medicine, Shiraz University of Medical Sciences, (Shiraz, Iran) from November 2021 to December 2023. The mice (n=32) were divided into four groups: control, high-fat diet (HFD) without treatment, HFD with AD-MSCs treatment, and HFD with AD-MSCs-derived exosomes groups. The mice were fed HFD for 8 weeks. They received MSC and exosomes for the last 3 weeks. One week after the final injection, mice were tested for serum testing, stereological analysis, and real-time polymerase chain reaction (RT-PCR). The data were analyzed using the Graph-Pad Prism software by one-way analysis of variance (ANOVA) with Tukey analysis as a post hoc comparison between groups. P<0.05 indicated a significant difference. Results AD-MSCs-exosomes significantly reduced ER stress indicators (IRE1α [P=0.0001], PERK [P=0.0006], ATF6 [P=0.0001], and GRP78 [P=0.0001]), apoptosis markers (Bax [P=0.005] and Cas3 [P=0.001]), and autophagic flux markers (P62 [P=0.0001] and LC3B/A [P=0.003]). Conclusion In this investigation, AD-MSCs-exosomes significantly restored autophagy and suppressed unfolded protein response (UPR) pathways in the early stages of NAFLD.
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Affiliation(s)
- Zahra Moayedfard
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Ali Akbar Alizadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Akbar Nekooeian
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahintaj Dara
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farhad Koohpeyma
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Endocrine and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shima Parsa
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Abu Ali Sina Hospital for Medicine and Organ Transplant, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arghavan Hosseinpouri
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Zhang L, Zheng Y, Shao M, Chen A, Liu M, Sun W, Li T, Fang Y, Dong Y, Zhao S, Luo H, Feng J, Wang Q, Li L, Zheng Y. AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease. Pharmacol Res 2025; 212:107617. [PMID: 39832686 DOI: 10.1016/j.phrs.2025.107617] [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: 12/04/2024] [Revised: 01/12/2025] [Accepted: 01/17/2025] [Indexed: 01/22/2025]
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF's effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. In vivo, QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF's mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5'-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. In vitro, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.
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Affiliation(s)
- Lulu Zhang
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, China
| | - Yi Zheng
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Mingyan Shao
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Aiping Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Meiyi Liu
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China; School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wenlong Sun
- Institute of Biomedical Research, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255000, China
| | - Tianxing Li
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yini Fang
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yang Dong
- Monitoning and Statistical Research Center, National Administration of Traditional Chinese Medicine, Beijing 100600, China
| | - Shipeng Zhao
- Graduate School of China Academy of Chinese Medical Sciences, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Hui Luo
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Juan Feng
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen 518118, China.
| | - Qi Wang
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Lingru Li
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Yanfei Zheng
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
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Wang C, Li M, Zhang J, Li H, Li Y, Huang S, Zhu H, Liu Z. Associations of the Intake of Individual and Multiple Flavonoids with Metabolic Dysfunction Associated Steatotic Liver Disease in the United States. Nutrients 2025; 17:205. [PMID: 39861335 PMCID: PMC11768006 DOI: 10.3390/nu17020205] [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: 12/09/2024] [Revised: 12/29/2024] [Accepted: 01/05/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Evidence regarding the individual and combined impact of dietary flavonoids on the risk of metabolic dysfunction associated with steatotic liver disease (MASLD) remains scarce. Our objective is to evaluate the association between individual and multiple dietary flavonoids with MASLD in adults. METHODS Data sets were obtained from the National Health and Nutrition Examination Survey (NHANES), 2017-2018. In total, 2581 participants aged over 18 years, with complete information on dietary flavonoid intake, MASLD, and covariates, were included. Flavonoid intake was energy-adjusted using the residual method. Logistic regression analysis was employed to examine the impact of total flavonoid intake on MASLD. Weighted quantile sum (WQS) analyses were used to evaluate the combined and individual effects of flavonoids on MASLD and to identify the predominant types with the most significant contribution to MASLD prevention. RESULTS The highest tertile of total flavonoid intake was associated with a 29% reduction in the risk of MASLD compared to the lowest tertile after multivariable adjustments (OR: 0.71, 95% CI: 0.51-0.97). The WQS analysis revealed that anthocyanidins, flavones, and flavanones were the most critical contributors among six subclasses (weights = 0.317, 0.279, and 0.227, respectively) and naringenin, apigenin, and delphinidin were the most critical contributors among 29 monomers. (weights = 0.240, 0.231, and 0.114, respectively). Also, a higher intake of anthocyanidins, flavones, naringenin, apigenin, and delphinidin was linked to a reduced risk of MASLD (p < 0.05). CONCLUSIONS Our findings suggested that a higher flavonoid intake is associated with a lower risk of MASLD, with anthocyanidins, flavones, flavanones, naringenin, apigenin, delphinidin, and myricetin contributing most to the protective effects of flavonoids.
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Affiliation(s)
- Chen Wang
- Department of Nutrition, School of Public Health, Sun Yat-sen University, 74 Zhong Shan Road 2, Guangzhou 510080, China; (C.W.); (M.L.); (J.Z.); (S.H.); (H.Z.)
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Mengchu Li
- Department of Nutrition, School of Public Health, Sun Yat-sen University, 74 Zhong Shan Road 2, Guangzhou 510080, China; (C.W.); (M.L.); (J.Z.); (S.H.); (H.Z.)
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Jiali Zhang
- Department of Nutrition, School of Public Health, Sun Yat-sen University, 74 Zhong Shan Road 2, Guangzhou 510080, China; (C.W.); (M.L.); (J.Z.); (S.H.); (H.Z.)
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Hongguang Li
- Department of Clinical Nutrition, Zhongshan City People’s Hospital, Zhongshan 528400, China; (H.L.); (Y.L.)
| | - Yue Li
- Department of Clinical Nutrition, Zhongshan City People’s Hospital, Zhongshan 528400, China; (H.L.); (Y.L.)
| | - Siyu Huang
- Department of Nutrition, School of Public Health, Sun Yat-sen University, 74 Zhong Shan Road 2, Guangzhou 510080, China; (C.W.); (M.L.); (J.Z.); (S.H.); (H.Z.)
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Huilian Zhu
- Department of Nutrition, School of Public Health, Sun Yat-sen University, 74 Zhong Shan Road 2, Guangzhou 510080, China; (C.W.); (M.L.); (J.Z.); (S.H.); (H.Z.)
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Zhaoyan Liu
- Department of Nutrition, School of Public Health, Sun Yat-sen University, 74 Zhong Shan Road 2, Guangzhou 510080, China; (C.W.); (M.L.); (J.Z.); (S.H.); (H.Z.)
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
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Li Z, Li J, He S, Chen J, Deng C, Duan J. Ellagic Acid Modulates Necroptosis, Autophagy, Inflammations, and Stress to Ameliorate Nonalcoholic Liver Fatty Disease in a Rat Model. Food Sci Nutr 2025; 13:e4694. [PMID: 39830906 PMCID: PMC11742184 DOI: 10.1002/fsn3.4694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/25/2024] [Accepted: 12/03/2024] [Indexed: 01/22/2025] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered one of the most common metabolic disorders worldwide. Although the pathoetiology of NAFLD is not fully elucidated, recent evidence suggests the involvement of stress, inflammation, and programmed death in the onset and progression of the disease. This investigation aimed to evaluate the effects of ellagic acid (EA), a known herbal antioxidant, on a high-fat diet (HFD)-induced animal model of NAFLD by evaluating the status of lipid profile, necroptosis (RIPK1, RIPK3, and MLKL), autophagy (LC3, ATG5, and BECN1), inflammation (TNF-α, IL-6, IL-4, and IL-10), and stress (SOD, CAT, GR, GPx, and MDA). In this regard, rats were randomly divided into 6 groups as follows: normal diet controls, HFD (supplemented with high caloric diet model), EA low dose (HFD and 10 mg/kg/day EA), EA middle dose (HFD and 25 mg/kg/day EA), EA high dose (HFD and 50 mg/kg/day EA), and Rosiglitazone (HFD and 10 mg/kg/day Rosi). After the treatment, the levels of markers related to necroptosis and autophagy in the liver tissue as well as the lipid profiles, inflammation, and oxidative stress status were analyzed. It was shown that the dose of EA was able to improve the weight gain and lipid profile when compared to NAFLD animals (p-value < 0.001). Moreover, EA increased the level of LC3 and ATG5 while decreasing BECN 1, RIPK1, RIPK3, and MLKL compared to the HFD-induced NAFLD rats (p-value < 0.05). TNF-α and IL-6 were decreased after EA administration, whereas IL-4 and IL-10 levels were increased (p-value < 0.001). Furthermore, the increase in the activity of SOD, CAT, GR, and GPx along with the decrease in MDA levels indicated the suppression of oxidative stress by EA treatment compared to the NAFLD rats (p-value < 0.0001). The current findings may suggest that EA improves NAFLD via modulation of necroptosis, autophagy, inflammation, and stress.
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Affiliation(s)
- Zhuoheng Li
- Gastroenterology DepartmentKunming Children's HospitalKunmingChina
| | - Juan Li
- Gastroenterology DepartmentKunming Children's HospitalKunmingChina
| | - Shuli He
- Gastroenterology DepartmentKunming Children's HospitalKunmingChina
| | - Jun Chen
- Gastroenterology DepartmentKunming Children's HospitalKunmingChina
| | - Chengjun Deng
- Gastroenterology DepartmentKunming Children's HospitalKunmingChina
| | - Jintao Duan
- Gastroenterology DepartmentKunming Children's HospitalKunmingChina
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Chu X, Liu S, Qu B, Xin Y, Lu L. Salidroside may target PPARα to exert preventive and therapeutic activities on NASH. Front Pharmacol 2024; 15:1433076. [PMID: 39415834 PMCID: PMC11479876 DOI: 10.3389/fphar.2024.1433076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024] Open
Abstract
Background Salidroside (SDS), a phenylpropanoid glycoside, is an antioxidant component isolated from the traditional Chinese medicine Rhodiola rosea and has multifunctional bioactivities, particularly possessing potent hepatoprotective function. Non-alcoholic steatohepatitis (NASH) is one of the most prevalent chronic liver diseases worldwide, but it still lacks efficient drugs. This study aimed to assess the preventive and therapeutic effects of SDS on NASH and its underlying mechanisms in a mouse model subjected to a methionine- and choline-deficient (MCD) diet. Methods C57BL/6J mice were fed an MCD diet to induce NASH. During or after the formation of the MCD-induced NASH model, SDS (24 mg/kg/day) was supplied as a form of diet for 4 weeks. The histopathological changes were evaluated by H&E staining. Oil Red O staining and Sirius Red staining were used to quantitatively determine the lipid accumulation and collagen fibers in the liver. Serum lipid and liver enzyme levels were measured. The morphology of autophagic vesicles and autophagosomes was observed by transmission electron microscopy (TEM), and qRT-PCR and Western blotting were used to detect autophagy-related factor levels. Immunohistochemistry and TUNEL staining were used to evaluate the apoptosis of liver tissues. Flow cytometry was used to detect the composition of immune cells. ELISA was used to evaluate the expression of serum inflammatory factors. Transcript-proteome sequencing, molecular docking, qRT-PCR, and Western blotting were performed to explore the mechanism and target of SDS in NASH. Results The oral administration of SDS demonstrated comprehensive efficacy in NASH. SDS showed both promising preventive and therapeutic effects on NASH in vivo. SDS could upregulate autophagy, downregulate apoptosis, rebalance immunity, and alleviate inflammation to exert anti-NASH properties. Finally, the results of transcript-proteome sequencing, molecular docking evaluation, and experimental validation showed that SDS might exert its multiple effects through targeting PPARα. Conclusion Our findings revealed that SDS could regulate liver autophagy and apoptosis, regulating both innate immunity and adaptive immunity and alleviating inflammation in NASH prevention and therapy via the PPAR pathway, suggesting that SDS could be a potential anti-NASH drug in the future.
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Affiliation(s)
- Xueru Chu
- Department of Infectious Disease, Qingdao Municipal Hospital, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao, China
| | - Shousheng Liu
- Clinical Research Center, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Baozhen Qu
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Yongning Xin
- Department of Infectious Disease, Qingdao Municipal Hospital, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao, China
| | - Linlin Lu
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
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Huang X, You D, An T, Zhao X, Jiang T, Huang Z. Glycyrrhizic acid attenuates the malignant biological properties of nonalcoholic fatty liver disease-related hepatocellular carcinoma. ENVIRONMENTAL TOXICOLOGY 2024; 39:4677-4688. [PMID: 38700384 DOI: 10.1002/tox.24295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/27/2024] [Accepted: 04/01/2024] [Indexed: 05/05/2024]
Abstract
Glycyrrhizic acid (GA) has effects on anti-hepatic fibrosis, anti-tumor and prevention from hepatocellular carcinoma (HCC) progression. Yet, the capacity of GA to ameliorate the advance of HCC pertinent to nonalcoholic fatty liver disease (NAFLD) remains to be clarified. We used the CCK-8 method to detect the optimal treatment concentration and time for L-02 cells, palmitic acid (PA)-induced L-02 cells and HepG2 cells, and selected 40 μM and 48 h to treat PA-induced L-02 cells and 60 μM for 24 h to treat HepG2 cells. Moreover, functional associations of HepG2 cells were elucidated through various assays. The results showed that GA demonstrated enhances lipid deposition and alleviates the inflammatory response in L-02 cells induced by palmitic acid. Simultaneously, we found that GA inhibits the proliferation, migration, and invasion while promoting apoptosis in HepG2 cells. In pursuit of constructing of HCC model rats, a combination of high-fat diets and diethylnitrosamine was utilized. The results showed that GA significantly decreased the liver index, body weight, liver weight, and the number of nodules in HCC model rats. Moreover, GA mitigated infiltration and heightened apoptosis in these rats. Mechanistically, GA notably attenuated the KKβ/NF-κB pathway in both HepG2 cells and the HCC model rats. In conclusion, GA functions as an inhibitor in the progression of NAFLD-related HCC cells, which might be relevant to the KKβ/NF-κB pathway. Therefore, GA is a potential drug for NAFLD-related HCC treatment.
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Affiliation(s)
- Xueqing Huang
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Dengwei You
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Tianzhi An
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xuya Zhao
- Department of Interventional Radiology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, China
| | - Tianpeng Jiang
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Zhi Huang
- Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
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Wang Y, Chen Y, Xiao X, Deng S, Kuang J, Li Y. HRD1-mediated ubiquitination of HDAC2 regulates PPARα-mediated autophagy and alleviates metabolic-associated fatty liver disease. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119765. [PMID: 38815686 DOI: 10.1016/j.bbamcr.2024.119765] [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: 11/01/2023] [Revised: 04/30/2024] [Accepted: 05/23/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Metabolic-associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease worldwide. Autophagy plays a pivotal role in lipid metabolism; however, the mechanism underlying the reduced autophagic activity in MAFLD remains elusive. METHODS Autophagy was monitored by TUNEL assay and immunofluorescence staining of LC3. The expression of autophagy-related proteins, PPARα, HDAC2, and HRD1 was detected by Western blot. The association between HDAC2 and PPARα promoter was assessed by chromatin immunoprecipitation (ChIP) and dual-luciferase assays, and the HRD1-mediated ubiquitin-proteasomal degradation of HDAC2 was detected by co-immunoprecipitation (co-IP). The in vitro findings were validated in a hypoxia-induced MAFLD mouse model. Histological changes, fibrosis, and apoptosis in liver tissues were detected by hematoxylin and eosin staining, Masson's trichrome staining, and TUNEL assay. The immunoreactivities of key molecules were examined by IHC analysis. RESULTS Hypoxia-suppressed autophagy in hepatocytes. Hypoxic exposure downregulated HRD1 and PPARα, while upregulating HDAC2 in hepatocytes. Overexpression of PPARα promoted hepatic autophagy, while knocking down HDAC2 or overexpressing HRD1 reduced hypoxia-suppressed autophagy in hepatocytes. Mechanistically, HDAC2 acted as a transcriptional repressor of PPARα, and HRD1 mediated the degradation of HDAC2 through the ubiquitin-proteasome pathway. Functional studies further showed that hypoxia-suppressed hepatic autophagy via the HRD1/HDAC2/PPARα axis in vitro and in vivo. CONCLUSION HRD1-mediated ubiquitination of HDAC2 regulates PPARα-mediated autophagy and ameliorates hypoxia-induced MAFLD.
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Affiliation(s)
- Yina Wang
- Department of Geriatrics, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yuanguo Chen
- Department of Emergency, the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China
| | - Xiao Xiao
- Department of Geriatrics, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Silei Deng
- Department of Geriatrics, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jingjie Kuang
- Department of Geriatrics, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yayong Li
- Department of Emergency, the Third Xiangya Hospital of Central South University, Changsha 410013, Hunan, China.
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Pan M, Deng Y, Qiu Y, Pi D, Zheng C, Liang Z, Zhen J, Fan W, Song Q, Pan J, Li Y, Yan H, Yang Q, Zhang Y. Shenling Baizhu powder alleviates non-alcoholic fatty liver disease by modulating autophagy and energy metabolism in high-fat diet-induced rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155712. [PMID: 38763008 DOI: 10.1016/j.phymed.2024.155712] [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: 12/04/2023] [Revised: 04/18/2024] [Accepted: 05/03/2024] [Indexed: 05/21/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has emerged as a burgeoning health problem worldwide, but no specific drug has been approved for its treatment. Shenling Baizhu powder (SL) is extensively used to treat NAFLD in Chinese clinical practice. However, the therapeutic components and pharmacological mechanisms of SL against NAFLD have not been thoroughly investigated. PURPOSE This study aimed to investigate the pharmacological impact and molecular mechanism of SL on NAFLD. METHODS First, we established an animal model of NAFLD by high-fat diet (HFD) feeding, and evaluated the therapeutic efficacy of SL on NAFLD by physiological, biochemical, pathological, and body composition analysis. Next, the effect of SL on autophagic flow in NAFLD rats was evaluated by ultrastructure, immunofluorescence staining, and western blotting. Moreover, an integrated strategy of targeted energy metabolomics and network pharmacology was performed to characterize autophagy-related genes and explore the synergistic effects of SL active compounds. UPLC-MS/MS, molecular docking combined with in vivo and in vitro experiments were conducted to verify the key compounds and genes. Finally, a network was established among SL-herb-compound-genes-energy metabolites-NAFLD, which explains the complicated regulating mechanism of SL on NAFLD. RESULTS We discovered that SL decreased hepatic lipid accumulation, hepatic steatosis, and insulin resistance, and improved systemic metabolic disorders and pathological abnormalities. Subsequently, an integrated strategy of targeted energy metabolomics and network pharmacology identified quercetin, ellagic acid, kaempferol, formononetin, stigmasterol, isorhamnetin and luteolin as key compounds; catalase (CAT), AKT serine/threonine kinase 1 (AKT), nitric oxide synthase 3 (eNOS), NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase 1 (HO-1) and hypoxia-inducible factor 1 subunit alpha (HIF-1α) were identified as key genes; while nicotinamide adenine dinucleotide phosphate (NADP) and succinate emerged as key energy metabolites. Mechanistically, we revealed that SL may exert its anti-NAFLD effect by inducing autophagy activation and forming a comprehensive regulatory network involving key compounds, key genes, and key energy metabolites, ultimately alleviating oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction. CONCLUSION Our study demonstrated the therapeutic effect of SL in NAFLD models, and establishes a basis for the development of potential products from SL plant materials for the treatment of NAFLD.
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Affiliation(s)
- Maoxing Pan
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Yuanjun Deng
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China; Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Yebei Qiu
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Dajin Pi
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Chuiyang Zheng
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Zheng Liang
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Jianwei Zhen
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Wen Fan
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Qingliang Song
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Jinyue Pan
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Yuanyou Li
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Haizhen Yan
- Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510240, Guangdong Province, China.
| | - Qinhe Yang
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China.
| | - Yupei Zhang
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, Guangdong Province, China.
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9
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Aggeletopoulou I, Tsounis EP, Triantos C. Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights. Int J Mol Sci 2024; 25:4901. [PMID: 38732118 PMCID: PMC11084591 DOI: 10.3390/ijms25094901] [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: 03/15/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.
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Affiliation(s)
| | | | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (I.A.); (E.P.T.)
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10
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Hazrati A, Malekpour K, Khorramdelazad H, Rajaei S, Hashemi SM. Therapeutic and immunomodulatory potentials of mesenchymal stromal/stem cells and immune checkpoints related molecules. Biomark Res 2024; 12:35. [PMID: 38515166 PMCID: PMC10958918 DOI: 10.1186/s40364-024-00580-2] [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: 01/05/2024] [Accepted: 03/07/2024] [Indexed: 03/23/2024] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) are used in many studies due to their therapeutic potential, including their differentiative ability and immunomodulatory properties. These cells perform their therapeutic functions by using various mechanisms, such as the production of anti-inflammatory cytokines, growth factors, direct cell-to-cell contact, extracellular vesicles (EVs) production, and mitochondrial transfer. However, mechanisms related to immune checkpoints (ICPs) and their effect on the immunomodulatory ability of MSCs are less discussed. The main function of ICPs is to prevent the initiation of unwanted responses and to regulate the immune system responses to maintain the homeostasis of these responses. ICPs are produced by various types of immune system regulatory cells, and defects in their expression and function may be associated with excessive responses that can ultimately lead to autoimmunity. Also, by expressing different types of ICPs and their ligands (ICPLs), tumor cells prevent the formation and durability of immune responses, which leads to tumors' immune escape. ICPs and ICPLs can be produced by MSCs and affect immune cell responses both through their secretion into the microenvironment or direct cell-to-cell interaction. Pre-treatment of MSCs in inflammatory conditions leads to an increase in their therapeutic potential. In addition to the effect that inflammatory environments have on the production of anti-inflammatory cytokines by MSCs, they can increase the expression of various types of ICPLs. In this review, we discuss different types of ICPLs and ICPs expressed by MSCs and their effect on their immunomodulatory and therapeutic potential.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Samira Rajaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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11
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Chen P, Li Y, Dai Y, Wang Z, Zhou Y, Wang Y, Li G. Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepatocellular Carcinoma. J Hepatocell Carcinoma 2024; 11:581-594. [PMID: 38525158 PMCID: PMC10960512 DOI: 10.2147/jhc.s450460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 03/13/2024] [Indexed: 03/26/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the primary cause of death in cancer cases, with significant public health concern worldwide. Despite the overall decline in the incidence and mortality rates of HCC in recent years in recent years, the emergence of metabolic liver disease-related HCC is causing heightened concern, especially in countries like the United States, the United Kingdom, and P.R. China. The escalation of metabolic liver disease-related HCC is attributed to a combination of factors, including genetic predisposition, lifestyle choices, and changes in the living environment. However, the pathogenesis of metabolic liver disease-associated HCC remains imperfect. In this review, we encapsulate the latest advances and essential aspects of the pathogenesis of metabolic liver disease-associated HCC, including alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and inherited metabolic liver diseases.
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Affiliation(s)
- Pinggui Chen
- Department of Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China
| | - Yaoxuan Li
- Department of School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China
| | - Yunyan Dai
- Department of Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China
| | - Zhiming Wang
- Department of Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China
| | - Yunpeng Zhou
- Department of Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China
| | - Yi Wang
- Department of Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China
| | - Gaopeng Li
- Department of Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, People’s Republic of China
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12
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Ren Q, Sun Q, Fu J. Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease. Autophagy 2024; 20:221-241. [PMID: 37700498 PMCID: PMC10813589 DOI: 10.1080/15548627.2023.2254191] [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: 05/01/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
ABBREVIATIONS ACOX1: acyl-CoA oxidase 1; ADH5: alcohol dehydrogenase 5 (class III), chi polypeptide; ADIPOQ: adiponectin, C1Q and collagen domain containing; ATG: autophagy related; BECN1: beclin 1; CRTC2: CREB regulated transcription coactivator 2; ER: endoplasmic reticulum; F2RL1: F2R like trypsin receptor 1; FA: fatty acid; FOXO1: forkhead box O1; GLP1R: glucagon like peptide 1 receptor; GRK2: G protein-coupled receptor kinase 2; GTPase: guanosine triphosphatase; HFD: high-fat diet; HSCs: hepatic stellate cells; HTRA2: HtrA serine peptidase 2; IRGM: immunity related GTPase M; KD: knockdown; KDM6B: lysine demethylase 6B; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LAP: LC3-associated phagocytosis; LDs: lipid droplets; Li KO: liver-specific knockout; LSECs: liver sinusoidal endothelial cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MED1: mediator complex subunit 1; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NFE2L2: NFE2 like bZIP transcription factor 2; NOS3: nitric oxide synthase 3; NR1H3: nuclear receptor subfamily 1 group H member 3; OA: oleic acid; OE: overexpression; OSBPL8: oxysterol binding protein like 8; PA: palmitic acid; RUBCNL: rubicon like autophagy enhancer; PLIN2: perilipin 2; PLIN3: perilipin 3; PPARA: peroxisome proliferator activated receptor alpha; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; RAB: member RAS oncogene family; RPTOR: regulatory associated protein of MTOR complex 1; SCD: stearoyl-CoA desaturase; SIRT1: sirtuin 1; SIRT3: sirtuin 3; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1;SREBF2: sterol regulatory element binding transcription factor 2; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; TAGs: triacylglycerols; TFEB: transcription factor EB; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VMP1: vacuole membrane protein 1.
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Affiliation(s)
- Qiannan Ren
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Qiming Sun
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junfen Fu
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
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13
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Zhang D, Ma Y, Liu J, Wang D, Geng Z, Wen D, Chen H, Wang H, Li L, Zhu X, Wang X, Huang M, Zou C, Chen Y, Ma L. Fenofibrate improves hepatic steatosis, insulin resistance, and shapes the gut microbiome via TFEB-autophagy in NAFLD mice. Eur J Pharmacol 2023; 960:176159. [PMID: 37898287 DOI: 10.1016/j.ejphar.2023.176159] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/23/2023] [Accepted: 10/24/2023] [Indexed: 10/30/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major liver disease subtype worldwide, is commonly associated with insulin resistance and obesity. NAFLD is characterized by an excessive hepatic lipid accumulation, as well as hepatic steatosis. Fenofibrate is a peroxisome proliferator-activated receptor α agonist widely used in clinical therapy to effectively ameliorate the development of NAFLD, but its mechanism of action is incompletely understood. Here, we found that fenofibrate dramatically modulate the gut microbiota composition of high-fat diet (HFD)-induced NAFLD mouse model, and the change of gut microbiota composition is dependent on TFEB-autophagy axis. Furthermore, we also found that fenofibrate improved hepatic steatosis, and increased the activation of TFEB, which severed as a regulator of autophagy, thus, the protective effects of fenofibrate against NAFLD are depended on TFEB-autophagy axis. Our study demonstrates the host gene may influence the gut microbiota and highlights the role of TFEB and autophagy in the protective effect of NAFLD. This work expands our understanding of the regulatory interactions between the host and gut microbiota and provides novel strategies for alleviating obesity.
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Affiliation(s)
- Dan Zhang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Yicheng Ma
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, 650091, PR China
| | - Jianjun Liu
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Biomedical Engineering, Kunming Medical University, Kunming, 650500, PR China
| | - Da Wang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Zuotao Geng
- Department of Pediatrics, Women and Children's Hospital of Lijiang, Lijiang, 674100, PR China
| | - Daiyan Wen
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Hang Chen
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Hui Wang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Lanyi Li
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Xiaotong Zhu
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Xuemin Wang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Minshan Huang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China
| | - Chenggang Zou
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, 650091, PR China.
| | - Yuanli Chen
- Faculty of Basic Medicine, Kunming Medical University, Kunming, 650500, PR China.
| | - Lanqing Ma
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, 650032, PR China.
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14
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Panneerselvam S, Wilson C, Kumar P, Abirami D, Pamarthi J, Reddy MS, Varghese J. Overview of hepatocellular carcinoma: from molecular aspects to future therapeutic options. Cell Adh Migr 2023; 17:1-21. [PMID: 37726886 PMCID: PMC10512929 DOI: 10.1080/19336918.2023.2258539] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the seventh most highly prevalent malignant tumor globally and the second most common cause of mortality. HCC develops with complex pathways that occur through multistage biological processes. Non-alcoholic fatty liver disease, metabolic-associated fatty liver disease, alcoholic liver disease, autoimmune hepatitis, hepatitis B, and hepatitis C are the causative etiologies of HCC. HCC develops as a result of epigenetic changes, protein-coding gene mutations, and altered signaling pathways. Biomarkers and potential therapeutic targets for HCC open up new possibilities for treating the disease. Immune checkpoint inhibitors are included in the treatment options in combination with molecular targeted therapy.
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Affiliation(s)
- Sugan Panneerselvam
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Cornelia Wilson
- Natural and Applied Sciences, School of Psychology and Life Sciences, Canterbury Christ Church University, Discovery Park, Sandwich, UK
| | - Prem Kumar
- Department of Hepatology and Transplant Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Dinu Abirami
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Jayakrishna Pamarthi
- Multi-Disciplinary Research Unit, Madras Medical College, Chennai, Tamil Nadu, India
| | - Mettu Srinivas Reddy
- The Director and Head, Liver Transplant and HPB surgery, Gleneagles Global Health City, Chennai, Tamil Nadu, India
| | - Joy Varghese
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, Tamil Nadu, India
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15
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Kaur M, Murugesan S, Singh S, Uy KN, Kaur J, Mann N, Sekhon RK. The Influence of Coffee on Reducing Metabolic Dysfunction-Associated Steatotic Liver Disease in Patients With Type 2 Diabetes: A Review. Cureus 2023; 15:e50118. [PMID: 38192918 PMCID: PMC10772480 DOI: 10.7759/cureus.50118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2023] [Indexed: 01/10/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a liver disease characterized by hepatic fat accumulation associated with various severities of inflammation and scarring. As studies explore specialized treatments, emerging evidence suggests a potential protective effect of coffee consumption. Consumption of coffee or its components, such as caffeine and/or chlorogenic acid (CA), can reduce markers of liver injury and induce a myriad of other health benefits. However, there is limited research on patients with both MASLD and type 2 diabetes (T2D). Current research suggests that patients with MASLD are at greater risk of developing T2D and future liver-related complications and vice versa. Given that both MASLD and T2D are global burdens, the present literature review analyzes current research to identify trends and determine if coffee can be a viable treatment for MASLD patients with T2D. Results indicate that coffee consumption may protect against MASLD in T2D patients who are overweight/obese through a declined rate of weight gain, inhibition of the mammalian target of rapamycin (mTOR) gene, and insignificant changes to the gut microbiome. More longitudinal research on human subjects is needed to establish a causal relationship between coffee consumption and MASLD alleviation.
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Affiliation(s)
- Manpreet Kaur
- Medicine, University of California, Davis, Davis, USA
| | | | | | | | - Jasjeet Kaur
- Medicine, University of California, Davis, Davis, USA
| | - Navina Mann
- Medicine, University of California, Davis, Davis, USA
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16
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Abstract
Studies have found that intermittent fasting (IF) can prevent diabetes, cancer, heart disease, and neuropathy, while in humans it has helped to alleviate metabolic syndrome, asthma, rheumatoid arthritis, Alzheimer's disease, and many other disorders. IF involves a series of coordinated metabolic and hormonal changes to maintain the organism's metabolic balance and cellular homeostasis. More importantly, IF can activate hepatic autophagy, which is important for maintaining cellular homeostasis and energy balance, quality control, cell and tissue remodeling, and defense against extracellular damage and pathogens. IF affects hepatic autophagy through multiple interacting pathways and molecular mechanisms, including adenosine monophosphate (AMP)-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), silent mating-type information regulatory 2 homolog-1 (SIRT1), peroxisomal proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR), as well as signaling pathways and molecular mechanisms such as glucagon and fibroblast growth factor 21 (FGF21). These pathways can stimulate the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), play a cytoprotective role, downregulate the expression of aging-related molecules, and prevent the development of steatosis-associated liver tumors. By influencing the metabolism of energy and oxygen radicals as well as cellular stress response systems, IF protects hepatocytes from genetic and environmental factors. By activating hepatic autophagy, IF has a potential role in treating a variety of liver diseases, including non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis, hepatic fibrosis, and hepatocellular carcinoma. A better understanding of the effects of IF on liver autophagy may lead to new approaches for the prevention and treatment of liver disease.
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Affiliation(s)
- Ya-Nan Ma
- Department of Gastroenterology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Xuemei Jiang
- Department of Gastroenterology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Wei Tang
- International Health Care Center, National Center for Global Health and Medicine, Tokyo, Japan
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Peipei Song
- Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
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17
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Nguyen TH, Nguyen TM, Ngoc DTM, You T, Park MK, Lee CH. Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions. Int J Mol Sci 2023; 24:16255. [PMID: 38003445 PMCID: PMC10671265 DOI: 10.3390/ijms242216255] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
This review aims to provide a comprehensive understanding of the molecular mechanisms underlying autophagy and mitophagy in hepatocellular carcinoma (HCC). Autophagy is an essential cellular process in maintaining cell homeostasis. Still, its dysregulation is associated with the development of liver diseases, including HCC, which is one of leading causes of cancer-related death worldwide. We focus on elucidating the dual role of autophagy in HCC, both in tumor initiation and progression, and highlighting the complex nature involved in the disease. In addition, we present a detailed analysis of a small subset of autophagy- and mitophagy-related molecules, revealing their specific functions during tumorigenesis and the progression of HCC cells. By understanding these mechanisms, we aim to provide valuable insights into potential therapeutic strategies to manipulate autophagy effectively. The goal is to improve the therapeutic response of liver cancer cells and overcome drug resistance, providing new avenues for improved treatment options for HCC patients. Overall, this review serves as a valuable resource for researchers and clinicians interested in the complex role of autophagy in HCC and its potential as a target for innovative therapies aimed to combat this devastating disease.
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Affiliation(s)
- Thi Ha Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | | | - Taesik You
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Mi Kyung Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cance Center, Goyang 10408, Republic of Korea
- Department of Bio-Healthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
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18
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Mastoridou EM, Goussia AC, Kanavaros P, Charchanti AV. Involvement of Lipophagy and Chaperone-Mediated Autophagy in the Pathogenesis of Non-Alcoholic Fatty Liver Disease by Regulation of Lipid Droplets. Int J Mol Sci 2023; 24:15891. [PMID: 37958873 PMCID: PMC10649352 DOI: 10.3390/ijms242115891] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 10/30/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of lipids in the form of lipid droplets in more than 5% of hepatocytes. It is regarded as a range of diverse pathologies, including simple steatosis and steatohepatitis. The structural characteristics of lipid droplets, along with their protein composition, mainly including perilipins, have been implicated in the etiology of the disease. These proteins have garnered increasing attention as a pivotal regulator since their levels and distinct expression appear to be associated with the progression from simple steatosis to steatohepatitis. Perilipins are target proteins of chaperone-mediated autophagy, and their degradation is a prerequisite for lipolysis and lipophagy to access the lipid core. Both lipophagy and chaperone-mediated autophagy have significant implications on the development of the disease, as evidenced by their upregulation during the initial phases of simple steatosis and their subsequent downregulation once steatosis is established. On the contrary, during steatohepatitis, the process of chaperone-mediated autophagy is enhanced, although lipophagy remains suppressed. Evidently, the reduced levels of autophagic pathways observed in simple steatosis serve as a defensive mechanism against lipotoxicity. Conversely, in steatohepatitis, chaperone-mediated autophagy fails to compensate for the continuous generation of small lipid droplets and thus cannot protect hepatocytes from lipotoxicity.
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Affiliation(s)
- Eleftheria M. Mastoridou
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; (E.M.M.); (P.K.)
| | - Anna C. Goussia
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; (E.M.M.); (P.K.)
| | - Antonia V. Charchanti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; (E.M.M.); (P.K.)
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19
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Zhuang S, Zhou X, Yang X, Chang D, Chen T, Sun Y, Wang C, Zhang C, Jiang J, Chen Y, Lin X, Wang X, Yu W, Lin X, He C, Zheng Y, Zhang J, Shi H. Dendrobium mixture ameliorates hepatic injury induced by insulin resistance in vitro and in vivo through the downregulation of AGE/RAGE/Akt signaling pathway. Heliyon 2023; 9:e22007. [PMID: 38034607 PMCID: PMC10685200 DOI: 10.1016/j.heliyon.2023.e22007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 12/02/2023] Open
Abstract
Dendrobium mixture (DM) is a patented Chinese herbal medicine which has been shown to ameliorate type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD) in vivo and in vitro. We aimed to investigate the underlying mechanism of DM as a therapeutic agent in attenuating liver steatosis in relation to type 2 diabetes mellitus (T2DM). DM (16.2 g/kg/d) was administered to db/db mice for 4 weeks. The db/m mice and db/db mice in the control and model groups were given normal saline. Additionally, DM (11.25 g/kg/d) was administered to Sprague-Dawley (SD) rats, and the serum was collected and used in an experiment involving palmitic acid (PA)-induced human liver HepG2 cells with abnormal lipid and glucose metabolism. In db/db mice, the administration of DM significantly alleviated liver steatosis, including histological damage and cell apoptosis. DM was found to prevent the upregulation of the RAGE and AKT1 proteins in liver tissues. The underlying mechanism of DM was further studied in PA-induced HepG2 cells. Post-DM administration serum from SD rats reduced lipid accumulation and regulated glucose metabolism in HepG2 cells. Consequently, it inhibited RAGE/AKT signaling and restored autophagy activity. The upregulated autophagy was associated with the mTOR-AMPK signaling pathway. Furthermore, post-DM administration serum reduced apoptosis of hepatocytes in PA-induced HepG2 cells. Our study supports the potential use of DM as a therapeutic agent for the treatment of NAFLD in T2DM. The mechanism underlying this therapeutic potential is associated with the downregulation of the AGE/RAGE/Akt signaling pathway.
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Affiliation(s)
- Shuting Zhuang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Xian Zhou
- NICM Health Research Institute, Western Sydney University, Westmead, NSW, 2006, Australia
| | - Xiaowen Yang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Westmead, NSW, 2006, Australia
| | - Tao Chen
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350100, China
| | - Yibin Sun
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350100, China
| | - Chenxiang Wang
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350100, China
| | - Chutian Zhang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Jichao Jiang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Yong Chen
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Xiaohui Lin
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Xiaoning Wang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Wenzhen Yu
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Xinjun Lin
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Caigu He
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Yanfang Zheng
- College of Pharmacy, Fujian Key Laboratory of Chinese Materia Medica, Fujian University of Traditional Chinese Medicine, Fuzhou, 350100, China
| | - Jieping Zhang
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
| | - Hong Shi
- College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fu Zhou, 350100, China
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20
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Abdelrahman BA, El-Khatib AS, Attia YM. Insights into the role of vitamin D in targeting the culprits of non-alcoholic fatty liver disease. Life Sci 2023; 332:122124. [PMID: 37742738 DOI: 10.1016/j.lfs.2023.122124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 09/12/2023] [Accepted: 09/21/2023] [Indexed: 09/26/2023]
Abstract
Vitamin D (VD) is a secosteroid hormone that is renowned for its crucial role in phospho-calcium homeostasis upon binding to the nuclear vitamin D receptor (VDR). Over and above, the pleiotropic immunomodulatory, anti-inflammatory, and metabolic roles VD plays in different disease settings started to surface in the past few decades. On the other hand, a growing body of evidence suggests a correlation between non-alcoholic fatty liver disease (NAFLD) and its progressive inflammatory form non-alcoholic steatohepatitis (NASH) with vitamin D deficiency (VDD) owing to the former's ingrained link with obesity and metabolic syndrome. Accordingly, a better understanding of the contribution of disrupted VDR signalling to NAFLD incidence and progression would provide further insights into its diagnosis, treatment modalities, and prognosis. This is especially significant as, hitherto, no drug for NAFLD has been approved. This review, therefore, sought to set forth the likely contribution of VDR signalling in NAFLD and how it might influence its multiple drivers.
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Affiliation(s)
- Basma A Abdelrahman
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Aiman S El-Khatib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Yasmeen M Attia
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
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21
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Afshari H, Noori S, Zarghi A. A novel combination of metformin and resveratrol alleviates hepatic steatosis by activating autophagy through the cAMP/AMPK/SIRT1 signaling pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:3135-3148. [PMID: 37209153 DOI: 10.1007/s00210-023-02520-7] [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: 02/08/2023] [Accepted: 05/03/2023] [Indexed: 05/22/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver disorder that is associated with the accumulation of triglycerides (TG) in hepatocytes. Resveratrol (RSV), as a natural product, and metformin have been reported to have potential lipid-lowering effects for the treatment of NAFLD via autophagy, but the combined effects of both have not yet been studied. The current study aimed to investigate the role of autophagy in the lipid-lowering effects of RSV, alone and in combination with metformin, on the hepatic steatosis model of HepG2 cells and elucidate the mechanism of action. Triglyceride measurement and real-time PCR showed that RSV-metformin reduced lipid accumulation and the expression of lipogenic genes in palmitic acid (PA)-induced HepG2 cells. Additionally, the LDH release assay indicated that this combination protected HepG2 cells against PA-induced cell death through autophagy. The western blotting analysis revealed that RSV-metformin induced autophagy by reducing the expression of p62 and increasing LC3-I and LC3-II proteins. This combination also enhanced cAMP, phosphorylated AMP-activated protein kinase (p-AMPK), and Beclin-1 levels in HepG2 cells. Furthermore, SIRT1 inhibitor treatment inhibited autophagy induced by RSV-metformin, which indicated the autophagy induction is SIRT1-dependent. This study demonstrated for the first time that RSV-metformin reduced hepatic steatosis by triggering autophagy via the cAMP/AMPK/SIRT1 signaling pathway.
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Affiliation(s)
- Havva Afshari
- Department of Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shokoofe Noori
- Department of Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Afshin Zarghi
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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22
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Liu R, Qian MP, Cui YY. Protein kinases: The key contributors in pathogenesis and treatment of nonalcoholic fatty liver disease-derived hepatocellular carcinoma. Metabolism 2023; 147:155665. [PMID: 37517794 DOI: 10.1016/j.metabol.2023.155665] [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: 05/24/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 08/01/2023]
Abstract
Protein kinases (PKs), one of the largest protein families, can be further divided into different groups based on their substrate or structure and function. PKs are important signaling messengers in numerous life activities, including cell metabolism, proliferation, division, differentiation, senescence, death, and disease. Among PK-related diseases, nonalcoholic fatty liver disease (NAFLD) has been recognized as a major contributor to hepatocellular carcinoma (HCC) and liver transplantation. Unfortunately, NAFLD-derived HCC (NAFLD-HCC) has poor prognosis because it is typically accompanied by older age, multiple metabolic syndromes, obstacles in early-stage diagnosis, and limited licensed drugs for treatment. Accumulating evidence suggests that PKs are implicated in the pathogenic process of NAFLD-HCC, via aberrant metabolism, hypoxia, autophagy, hypoxia, gut microbiota dysbiosis, and/or immune cell rearrangement. The present review aims to summarize the latest research advances and emphasize the feasibility and effectiveness of therapeutic strategies that regulate the expression and activities of PKs. This might yield clinically significant effects and lead to the design of novel PK-targeting therapies. Furthermore, we discuss emerging PK-based strategies for the treatment of other malignant diseases similar to NAFLD-HCC.
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Affiliation(s)
- Rong Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ming-Ping Qian
- Department of General Surgery, Suzhou First People's Hospital, Anhui 234099, China; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Ying-Yu Cui
- Department of Cell Biology, Tongji University School of Medicine, Shanghai 200331, China; Institute of Medical Genetics, Tongji University School of Medicine, Shanghai 200331, China; Key Laboratory of Arrhythmias of the Ministry of Education of China (Tongji University), Tongji University School of Medicine, Shanghai 200331, China.
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23
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Cao P, Wang Y, Zhang C, Sullivan MA, Chen W, Jing X, Yu H, Li F, Wang Q, Zhou Z, Wang Q, Tian W, Qiu Z, Luo L. Quercetin ameliorates nonalcoholic fatty liver disease (NAFLD) via the promotion of AMPK-mediated hepatic mitophagy. J Nutr Biochem 2023; 120:109414. [PMID: 37423322 DOI: 10.1016/j.jnutbio.2023.109414] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/12/2023] [Accepted: 07/05/2023] [Indexed: 07/11/2023]
Abstract
The global incidence of nonalcoholic fatty liver disease (NAFLD) has been surging in recent years, however, no drug is currently approved to treat this disease. Quercetin, a natural flavonoid abundant in plants and fruits, has been reported to alleviate NAFLD, however, the exact molecular mechanism remains unclear. This study aims to further elucidate its potential mechanism of action. The beneficial effects and the underlying mechanism of quercetin in alleviating NAFLD were explored both in vitro and in vivo, by employing chemical inhibitors of autophagosomes (3-methyladenine, 3-MA), autolysosomes (chloroquine, CQ), AMPK (Compound C, CC) and SIRT1 (selisistat, EX-527). The levels of intracellular lipids, reactive oxygen species, mitochondria function, autophagy, and mitophagy were assessed by fluorescent labeling and examined using flow cytometry or confocal microscopy. Key protein expressions of autophagy, mitophagy, and inflammation were also determined. In vivo, quercetin was shown to dose-dependently effectively alleviate NAFLD, but intraperitoneal injection of 3-MA could block the beneficial effects of quercetin on body weight, liver weight, serum ALT/AST, hepatic ROS and inflammation. In vitro, quercetin could reduce intracellular lipids (Nile Red staining) and ROS/DHE accumulation, which could be also blocked by 3-MA or CQ. Furthermore, we found that CC could abrogate the protective effects of quercetin on lipid and ROS accumulation in vitro. Also, CC abolished the proautophagic and anti-inflammatory effects of quercetin, as shown by western blot determination and Lyso-Tracker labeling. Importantly, mitophagy, a specific form of mitochondria-targeted autophagy, was enhanced by quercetin, as demonstrated by PINK1/Parkin protein variation and immunofluorescence colocalization of autophagosomes and mitochondria, which could also be blocked by the intervention of CC. This study demonstrates that quercetin prevents NAFLD through AMPK-mediated mitophagy and suggests that promoting mitophagy via an upregulation of AMPK may be a promising therapeutic strategy against NAFLD.
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Affiliation(s)
- Peng Cao
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China
| | - Cong Zhang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Mitchell A Sullivan
- Translational Research Institute, Glycation and Diabetes, Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Wen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang Jing
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong, China
| | - Huifan Yu
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, China
| | - Fei Li
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, China
| | - Qu Wang
- The First Clinical College, Guangdong Medical University, Zhanjiang, China
| | - Zhongshi Zhou
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Qi Wang
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Wen Tian
- The First Clinical College, Guangdong Medical University, Zhanjiang, China
| | - Zhenpeng Qiu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China.
| | - Lianxiang Luo
- The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong, China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong, China.
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24
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Schwertheim S, Alhardan M, Manka PP, Sowa JP, Canbay A, Schmidt HHJ, Baba HA, Kälsch J. Higher pNRF2, SOCS3, IRF3, and RIG1 Tissue Protein Expression in NASH Patients versus NAFL Patients: pNRF2 Expression Is Concomitantly Associated with Elevated Fasting Glucose Levels. J Pers Med 2023; 13:1152. [PMID: 37511764 PMCID: PMC10381647 DOI: 10.3390/jpm13071152] [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: 04/17/2023] [Revised: 07/05/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) embraces simple steatosis in non-alcoholic fatty liver (NAFL) to advanced non-alcoholic steatohepatitis (NASH) associated with inflammation, fibrosis, and cirrhosis. NAFLD patients often have metabolic syndrome and high risks of cardiovascular and liver-related mortality. Our aim was to clarify which proteins play a role in the progression of NAFL to NASH. The study investigates paraffin-embedded samples of 22 NAFL and 33 NASH patients. To detect potential candidates, samples were analyzed by immunohistochemistry for the proteins involved in innate immune regulation, autophagy, apoptosis, and antioxidant defense: IRF3, RIG-1, SOCS3, pSTAT3, STX17, SGLT2, Ki67, M30, Caspase 3, and pNRF2. The expression of pNRF2 immunopositive nuclei and SOCS3 cytoplasmic staining were higher in NASH than in NAFL (p = 0.001); pNRF2 was associated with elevated fasting glucose levels. SOCS3 immunopositivity correlated positively with RIG1 (r = 0.765; p = 0.001). Further, in NASH bile ducts showed stronger IRF3 immunostaining than in NAFL (p = 0.002); immunopositive RIG1 tissue was higher in NASH than in NAFL (p = 0.01). Our results indicate that pNRF2, SOCS3, IRF3, and RIG1 are involved in hepatic lipid metabolism. We suggest that they may be suitable for further studies to assess their potential as therapeutics.
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Affiliation(s)
- Suzan Schwertheim
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Malek Alhardan
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Paul P Manka
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Jan-Peter Sowa
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Ali Canbay
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
| | - Hartmut H-J Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Hideo A Baba
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Julia Kälsch
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University of Duisburg-Essen, 45147 Essen, Germany
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25
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Jiang X, Wu S, Hu C. A narrative review of the role of exosomes and caveolin-1 in liver diseases and cancer. Int Immunopharmacol 2023; 120:110284. [PMID: 37196562 DOI: 10.1016/j.intimp.2023.110284] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/16/2023] [Accepted: 05/02/2023] [Indexed: 05/19/2023]
Abstract
Exosomes are nanoscale (40-100 nm) vesicles secreted by different types of cells and have attracted extensive interest in recent years because of their unique role in disease development. It can carry related goods, such as lipids, proteins, and nucleic acids, to mediate intercellular communication. This review summarizes exosome biogenesis, release, uptake, and their role in mediating the development of liver diseases and cancer, such as viral hepatitis, drug-induced liver injury, alcohol-related liver disease, non-alcoholic fatty liver disease, hepatocellular carcinoma, and other tumors. Meanwhile, a fossa structural protein, caveolin-1(CAV-1), has also been proposed to be involved in the development of various diseases, especially liver diseases and tumors. In this review, we discuss the role of CAV-1 in liver diseases and different tumor stages (inhibition of early growth and promotion of late metastasis) and the underlying mechanisms by which CAV-1 regulates the process. In addition, CAV-1 has also been found to be a secreted protein that can be released directly through the exosome pathway or change the cargo composition of the exosomes, thus contributing to enhancing the metastasis and invasion of cancer cells during the late stage of tumor development. In conclusion, the role of CAV-1 and exosomes in disease development and the association between them remains to be one challenging uncharted area.
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Affiliation(s)
- Xiangfu Jiang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui medical university, Hefei 230032, China; Key Laboratory of anti-inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China
| | - Shuai Wu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui medical university, Hefei 230032, China; Key Laboratory of anti-inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China
| | - Chengmu Hu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui medical university, Hefei 230032, China; Key Laboratory of anti-inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
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26
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Yang M, Liu C, Jiang N, Liu Y, Luo S, Li C, Zhao H, Han Y, Chen W, Li L, Xiao L, Sun L. Myostatin: a potential therapeutic target for metabolic syndrome. Front Endocrinol (Lausanne) 2023; 14:1181913. [PMID: 37288303 PMCID: PMC10242177 DOI: 10.3389/fendo.2023.1181913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/04/2023] [Indexed: 06/09/2023] Open
Abstract
Metabolic syndrome is a complex metabolic disorder, its main clinical manifestations are obesity, hyperglycemia, hypertension and hyperlipidemia. Although metabolic syndrome has been the focus of research in recent decades, it has been proposed that the occurrence and development of metabolic syndrome is related to pathophysiological processes such as insulin resistance, adipose tissue dysfunction and chronic inflammation, but there is still a lack of favorable clinical prevention and treatment measures for metabolic syndrome. Multiple studies have shown that myostatin (MSTN), a member of the TGF-β family, is involved in the development and development of obesity, hyperlipidemia, diabetes, and hypertension (clinical manifestations of metabolic syndrome), and thus may be a potential therapeutic target for metabolic syndrome. In this review, we describe the transcriptional regulation and receptor binding pathway of MSTN, then introduce the role of MSTN in regulating mitochondrial function and autophagy, review the research progress of MSTN in metabolic syndrome. Finally summarize some MSTN inhibitors under clinical trial and proposed the use of MSTN inhibitor as a potential target for the treatment of metabolic syndrome.
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Affiliation(s)
- Ming Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Chongbin Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Na Jiang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Yan Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Chenrui Li
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Hao Zhao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Yachun Han
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Wei Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Li Li
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Li Xiao
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
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27
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Naiel MAE, Negm SS, Ghazanfar S, Shukry M, Abdelnour SA. The risk assessment of high-fat diet in farmed fish and its mitigation approaches: A review. J Anim Physiol Anim Nutr (Berl) 2023; 107:948-969. [PMID: 35934925 DOI: 10.1111/jpn.13759] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/10/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022]
Abstract
In the era of intensification of fish farms, the high-fat diet (HFD) has been applied to promote growth and productivity, provide additional energy and substitute partial protein in fish feeds. Certainly, HFD within specific concentrations was found to be beneficial in boosting fish performance throughout a short-term feeding. However, excessive dietary fat levels displayed vast undesirable impacts on growth, feed efficiency, liver function, antioxidant capacity and immune function and finally reduced the economic revenue of cultured fish. Moreover, studies have shown that fish diets containing a high level of fats resulted in increasing lipid accumulation, stimulated endoplasmic reticulum stress and suppressed autophagy in fish liver. Investigations showed that HFD could impair the intestinal barrier of fish via triggering inflammation, metabolic disorders, oxidative stress and microbiota imbalance. Several approaches have been widely used for reducing the undesirable influences of HFD in fish. Dietary manipulation could mitigate the adverse impacts triggered by HFD, and boost growth and productivity via reducing blood lipids profile, attenuating oxidative stress and hepatic lipid deposition and improving mitochondrial activity, immune function and antioxidant activity in fish. As well, dietary feed additives have been shown to decrease hepatic lipogenesis and modulate the inflammatory response in fish. Based on the literature, previous studies indicated that phytochemicals could reduce apoptosis and enhance the immunity of fish fed with HFD. Thus, the present review will explore the potential hazards of HFD on fish species. It will also provide light on the possibility of employing some safe feed additives to mitigate HFD risks in farmed fish.
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Affiliation(s)
- Mohammed A E Naiel
- Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Samar S Negm
- Fish Biology and Ecology Department, Central Lab for Aquaculture Research (CLAR), Abassa, Agriculture Research Center, Giza, Egypt
| | - Shakira Ghazanfar
- National Institute for Genomics Advanced and Biotechnology (NIGAB), National Agricultural Research Centre, Islamabad, Pakistan
| | - Mustafa Shukry
- Physiology Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Sameh A Abdelnour
- Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
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Tu W, Zhang Y, Jiang K, Jiang S. Osteocalcin and Its Potential Functions for Preventing Fatty Liver Hemorrhagic Syndrome in Poultry. Animals (Basel) 2023; 13:ani13081380. [PMID: 37106943 PMCID: PMC10135196 DOI: 10.3390/ani13081380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/20/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Osteocalcin (OCN) is synthesized and secreted by differentiating osteoblasts. In addition to its role in bone, OCN acts as a hormone in the pancreas, liver, muscle, fat, and other organs to regulate multiple pathophysiological processes including glucose homeostasis and adipic acid metabolism. Fat metabolic disorder, such as excessive fat buildup, is related to non-alcoholic fatty liver disease (NAFLD) in humans. Similarly, fatty liver hemorrhage syndrome (FLHS) is a metabolic disease in laying hens, resulting from lipid accumulation in hepatocytes. FLHS affects hen health with significant impact on poultry egg production. Many studies have proposed that OCN has protective function in mammalian NAFLD, but its function in chicken FLHS and related mechanism have not been completely clarified. Recently, we have revealed that OCN prevents laying hens from FLHS through regulating the JNK pathway, and some pathways related to the disease progression have been identified through both in vivo and vitro investigations. In this view, we discussed the current findings for predicting the strategy for using OCN to prevent or reduce FLHS impact on poultry production.
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Affiliation(s)
- Wenjun Tu
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Yuhan Zhang
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Kunyu Jiang
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China
| | - Sha Jiang
- Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China
- Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 402460, China
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Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
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Wang D, Ji DC, Yu CY, Wu DN, Qi L. Research progress on the mitochondrial mechanism of age-related non-alcoholic fatty liver. World J Gastroenterol 2023; 29:1982-1993. [PMID: 37155524 PMCID: PMC10122792 DOI: 10.3748/wjg.v29.i13.1982] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/20/2023] [Accepted: 03/13/2023] [Indexed: 04/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. Reduced activity and slower metabolism in the elderly affect the balance of lipid metabolism in the liver leading to the accumulation of lipids. This affects the mitochondrial respiratory chain and the efficiency of β-oxidation and induces the overproduction of reactive oxygen species. In addition, the dynamic balance of the mitochondria is disrupted during the ageing process, which inhibits its phagocytic function and further aggravates liver injury, leading to a higher incidence of NAFLD in the elderly population. The present study reviewed the manifestations, role and mechanism of mitochondrial dysfunction in the progression of NAFLD in the elderly. Based on the understanding of mitochondrial dysfunction and abnormal lipid metabolism, this study discusses the treatment strategies and the potential therapeutic targets for NAFLD, including lipid accumulation, antioxidation, mitophagy and liver-protecting drugs. The purpose is to provide new ideas for the development of innovative drugs for the prevention and treatment of NAFLD.
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Affiliation(s)
- Dan Wang
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Duo-Chun Ji
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Chun-Yan Yu
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Dan-Ni Wu
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Ling Qi
- Central Laboratory, Qingyuan People's Hospital, Qingyuan 511518, Guangdong Province, China
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31
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Xie J, Chen Q, Zhao Y, Luo M, Zeng X, Qin L, Tan D, He Y. Transcriptome Sequencing Reveals Autophagy Networks in Rat Livers during the Development of NAFLD and Identifies Autophagy Hub Genes. Int J Mol Sci 2023; 24:ijms24076437. [PMID: 37047411 PMCID: PMC10094595 DOI: 10.3390/ijms24076437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/21/2023] [Accepted: 03/28/2023] [Indexed: 04/14/2023] Open
Abstract
(1) Autophagy is an important biological process in cells and is closely associated with the development and progression of non-alcoholic fatty liver disease (NAFLD). Therefore, this study aims to investigate the biological function of the autophagy hub genes, which could be used as a potential therapeutic target and diagnostic markers for NAFLD. (2) Male C57BL/6J mice were sacrificed after 16 and 38 weeks of a high-fat diet, serum biochemical indexes were detected, and liver lobules were collected for pathological observation and transcriptome sequencing. The R software was used to identify differentially expressed autophagy genes (DEGs) from the transcriptome sequencing data of mice fed with a normal diet for 38 weeks (ND38) and a high-fat diet for 38 weeks (HFD38). Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed on the DEGs, a protein-protein interaction (PPI) network of the DEGs was established using the STRING data website, and the results were visualized through Cytoscape. (3) After 16 weeks and 38 weeks of a high-fat diet, there was a significant increase in body weight, serum total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and triglycerides (TG) in mice, along with lipid accumulation in the liver, which was more severe at 38 weeks than at 16 weeks. The transcriptome data showed significant changes in the expression profile of autophagy genes in the livers of NAFLD mice following a long-term high-fat diet. Among the 31 differentially expressed autophagy-related genes, 13 were upregulated and 18 were downregulated. GO and KEGG pathway analysis revealed that these DEGs were primarily involved in autophagy, cholesterol transport, triglyceride metabolism, apoptosis, the FoxO signaling pathway, the p53 signaling pathway and the IL-17 signaling pathway. Four hub genes were identified by the PPI network analysis, of which Irs2, Pnpla2 and Plin2 were significantly downregulated, while Srebf2 was significantly upregulated by the 38-week high-fat diet. (4) The hub genes Irs2, Pnpla2, Srebf2 and Plin2 may serve as key therapeutic targets and early diagnostic markers in the progression of NAFLD.
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Affiliation(s)
- Jian Xie
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- 2011 Cooperative Inovational Center for Guizhou Traditional Chinese Medicine and Ethnic Medicine, Zunyi Medical University, Zunyi 563000, China
- Department of Medical Genetics, Zunyi Medical University, Zunyi 563000, China
| | - Qiuyi Chen
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- 2011 Cooperative Inovational Center for Guizhou Traditional Chinese Medicine and Ethnic Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Yongxia Zhao
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- 2011 Cooperative Inovational Center for Guizhou Traditional Chinese Medicine and Ethnic Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Mingxia Luo
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- 2011 Cooperative Inovational Center for Guizhou Traditional Chinese Medicine and Ethnic Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Xin Zeng
- Department of Medical Genetics, Zunyi Medical University, Zunyi 563000, China
| | - Lin Qin
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- 2011 Cooperative Inovational Center for Guizhou Traditional Chinese Medicine and Ethnic Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Daopeng Tan
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- 2011 Cooperative Inovational Center for Guizhou Traditional Chinese Medicine and Ethnic Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Yuqi He
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
- 2011 Cooperative Inovational Center for Guizhou Traditional Chinese Medicine and Ethnic Medicine, Zunyi Medical University, Zunyi 563000, China
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Wu Y, Tan HWS, Lin JY, Shen HM, Wang H, Lu G. Molecular mechanisms of autophagy and implications in liver diseases. LIVER RESEARCH 2023; 7:56-70. [PMID: 39959698 PMCID: PMC11792062 DOI: 10.1016/j.livres.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/03/2022] [Accepted: 02/15/2023] [Indexed: 02/22/2023]
Abstract
Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome, which plays an important role in energy and nutrient balance, and protein or organelle quality control. The liver is the most important organ for metabolism. Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions, and the impairment of autophagy has been closely linked to various liver diseases. Therefore, a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy. In this review, we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, viral hepatitis, hepatocellular carcinoma, and acetaminophen-induced liver injury.
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Affiliation(s)
- Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hayden Weng Siong Tan
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jin-Yi Lin
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Han-Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guang Lu
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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Dihydromyricetin inhibits Hepatitis B virus replication by activating NF-κB, MAPKs, and autophagy in HepG2.2.15 cells. Mol Biol Rep 2023; 50:1403-1414. [PMID: 36474061 DOI: 10.1007/s11033-022-07971-4] [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: 06/11/2022] [Accepted: 09/21/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a severe global health problem, and there has been no effective method to eliminate HBV. This study was designed to explore the pharmacological mechanism of Dihydromyricetin (DHM) treatment on HBV replication in vitro. METHODS AND RESULTS DHM is a flavonoid compound from Ampelopsis grossedentata. Using HepG2.2.15 cells, which can stably express HBV in vitro, we demonstrated that DHM treatment dramatically reduced HBV replication and secretions of HBsAg and HBeAg. Meanwhile, DHM inhibited mRNA expression of HBV RNAs in HepG2.2.15 cells, including Total HBV RNA, HBV pregenomic RNA (pgRNA), and HBV precore mRNA (pcRNA). Also, DHM elevated the mRNA expressions of inflammatory cytokines and antiviral effectors. In contrast, DHM decreased the mRNA level of HNF4α, which positively correlated with HBV replication. Further studies show that the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway played a critical role in DHM-initiated inhibition of HBV replication in HepG2.2.15 cells. Besides, activated autophagy was another contributor that may accelerate the clearance of HBV components. CONCLUSION In summary, DHM could suppress HBV replication by activating NF-κB, MAPKs, and autophagy in HepG2.2.15 cells. Our studies shed light on the future application of DHM for the clinical treatment of HBV infection.
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Qu B, Liu X, Liang Y, Zheng K, Zhang C, Lu L. Salidroside in the Treatment of NAFLD/NASH. Chem Biodivers 2022; 19:e202200401. [PMID: 36210339 DOI: 10.1002/cbdv.202200401] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 10/03/2022] [Indexed: 12/27/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the commonest reason for chronic liver diseases in the world and is commonly related to the hepatic manifestation of the metabolic syndrome. Non-alcoholic steatohepatitis (NASH) is a deteriorating form of NAFLD, which can eventually develop into fibrosis, cirrhosis, and liver cancer. The reason for NAFLD/NASH development is complicated, such as liver lipid metabolism, oxidative stress, inflammatory response, apoptosis and autophagy, liver fibrosis and gut microbiota. Apart from bariatric surgery and lifestyle changes, officially approved drug therapy for NAFLD/NASH treatment is lacking. Salidroside (SDS) is a phenolic compound extensively distributed in the tubers of Rhodiola plants, which possesses many significant biological activities. This review summarized the related targets regulated by SDS in treating NAFLD/NASH. It is indicated that SDS could improve the status of NAFLD/NASH by ameliorating abnormal lipid metabolism, inhibiting oxidative stress, regulating apoptosis and autophagy, reducing inflammatory response, alleviating fibrosis and regulating gut microbiota. In conclusion, although the multiple bioactivities of SDS have been confirmed, the clinical data are inadequate and need to become the focus of attention in the later study.
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Affiliation(s)
- Baozhen Qu
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, 127 Siliunan Road, Qingdao, 266042, China
| | - Xuemao Liu
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, 127 Siliunan Road, Qingdao, 266042, China
| | - Yanjiao Liang
- Department of Oncology Center, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, Qingdao, 266042, China
| | - Keke Zheng
- Department of Oncology Center, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, Qingdao, 266042, China
| | - Chunling Zhang
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, 127 Siliunan Road, Qingdao, 266042, China
| | - Linlin Lu
- Qingdao Cancer Prevention and Treatment Research Institute, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, 127 Siliunan Road, Qingdao, 266042, China
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Rusu I, Pirlog R, Chiroi P, Nutu A, Puia VR, Fetti AC, Rusu DR, Berindan-Neagoe I, Al Hajjar N. The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC. Int J Mol Sci 2022; 23:12370. [PMID: 36293225 PMCID: PMC9603983 DOI: 10.3390/ijms232012370] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.
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Affiliation(s)
- Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
| | - Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Paul Chiroi
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Andreea Nutu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Vlad Radu Puia
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Alin Cornel Fetti
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Daniel Radu Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
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Hydrogen Sulfide and Its Donors: Keys to Unlock the Chains of Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms232012202. [PMID: 36293058 PMCID: PMC9603526 DOI: 10.3390/ijms232012202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/30/2022] [Accepted: 10/09/2022] [Indexed: 11/17/2022] Open
Abstract
Hydrogen sulfide (H2S) has emerged as the third “gasotransmitters” and has a crucial function in the diversity of physiological functions in mammals. In particular, H2S is considered indispensable in preventing the development of liver inflammation in the case of excessive caloric ingestion. Note that the concentration of endogenous H2S was usually low, making it difficult to discern the precise biological functions. Therefore, exogenous delivery of H2S is conducive to probe the physiological and pathological roles of this gas in cellular and animal studies. In this review, the production and metabolic pathways of H2S in vivo, the types of donors currently used for H2S release, and study evidence of H2S improvement effects on nonalcoholic fatty liver disease are systematically introduced.
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HS1BP3, transcriptionally regulated by ESR1, promotes hepatocellular carcinoma progression. Biochem Biophys Res Commun 2022; 623:111-119. [DOI: 10.1016/j.bbrc.2022.07.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/08/2022] [Accepted: 07/13/2022] [Indexed: 11/23/2022]
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Zhang Y, Chen Y. Roles of organelle-specific autophagy in hepatocytes in the development and treatment of non-alcoholic fatty liver disease. Chin Med J (Engl) 2022; 135:1673-1681. [PMID: 35950774 PMCID: PMC9509094 DOI: 10.1097/cm9.0000000000002263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Indexed: 02/04/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disorder of lipid metabolism. The lipotoxic intermediates of lipid metabolism cause mitochondrial dysfunction and endoplasmic reticulum stress. Organelle-specific autophagy is responsible for the removal of dysfunctional organelles to maintain intracellular homeostasis. Lipophagy contributes to lipid turnover by degrading lipid droplets. The level of autophagy changes during the course of NAFLD, and the activation of hepatocyte autophagy might represent a method of treating NAFLD.
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Affiliation(s)
- Yizhi Zhang
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You’an Hospital Affiliated to Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing 100069, China
| | - Yu Chen
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You’an Hospital Affiliated to Capital Medical University, Beijing 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing 100069, China
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39
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Cell Autophagy in NASH and NASH-Related Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23147734. [PMID: 35887082 PMCID: PMC9322157 DOI: 10.3390/ijms23147734] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/10/2022] [Accepted: 07/11/2022] [Indexed: 12/21/2022] Open
Abstract
Autophagy, a cellular self-digestion process, involves the degradation of targeted cell components such as damaged organelles, unfolded proteins, and intracellular pathogens by lysosomes. It is a major quality control system of the cell and plays an important role in cell differentiation, survival, development, and homeostasis. Alterations in the cell autophagic machinery have been implicated in several disease conditions, including neurodegeneration, autoimmunity, cancer, infection, inflammatory diseases, and aging. In non-alcoholic fatty liver disease, including its inflammatory form, non-alcoholic steatohepatitis (NASH), a decrease in cell autophagic activity, has been implicated in the initial development and progression of steatosis to NASH and hepatocellular carcinoma (HCC). We present an overview of autophagy as it occurs in mammalian cells with an insight into the emerging understanding of the role of autophagy in NASH and NASH-related HCC.
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40
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Duwaerts CC, Maiers JL. ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets. Front Mol Biosci 2022; 8:804097. [PMID: 35174209 PMCID: PMC8841999 DOI: 10.3389/fmolb.2021.804097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/18/2021] [Indexed: 11/13/2022] Open
Abstract
The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.
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Affiliation(s)
- Caroline C. Duwaerts
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Jessica L. Maiers
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
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Ma C, Wang C, Zhang Y, Zhou H, Li Y. Potential Natural Compounds for the Prevention and Treatment of Nonalcoholic Fatty Liver Disease: A Review on Molecular Mechanisms. Curr Mol Pharmacol 2021; 15:846-861. [PMID: 34923950 DOI: 10.2174/1874467215666211217120448] [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: 07/14/2021] [Revised: 09/27/2021] [Accepted: 10/08/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, and there is no specific drug for its clinical treatment currently. In recent years, a large amount of literature has reported that many natural compounds extracted from traditional Chinese medicine (TCM) can improve NAFLD through various mechanisms. According to the latest reports, some emerging natural compounds have shown great potential to improve NAFLD but are seldom used clinically due to the lacking special research. PURPOSE This paper aims to summarize the molecular mechanisms of the potential natural compounds on improving NAFLD, thus providing a direction and basis for further research on the pathogenesis of NAFLD and the development of effective drugs for the prevention and treatment of NAFLD. METHODS By searching various online databases, such as Web of Science, SciFinder, PubMed, and CNKI, NAFLD and these natural compounds were used as the keywords for detailed literature retrieval. RESULTS The pathogenesis of NAFLD and the molecular mechanisms of the potential natural compounds on improving NAFLD have been reviewed. CONCLUSION Many natural compounds from traditional Chinese medicine have a good prospect in the treatment of NAFLD, which can serve as a direction for the development of anti-NAFLD drugs in the future.
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Affiliation(s)
- Cheng Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Cheng Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yafang Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Honglin Zhou
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
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Chen X, Xiao J, Pang J, Chen S, Wang Q, Ling W. Pancreatic β-Cell Dysfunction Is Associated with Nonalcoholic Fatty Liver Disease. Nutrients 2021; 13:nu13093139. [PMID: 34579016 PMCID: PMC8468093 DOI: 10.3390/nu13093139] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/03/2021] [Accepted: 09/08/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is associated with decreased insulin sensitivity. However, the association between NAFLD and pancreatic β-cell function is still ambiguous. Here, we assessed whether pancreatic β-cell function is associated with NAFLD. Method: The data of NHANES III from 1988 to 1994 were used. NAFLD was diagnosed when subjects had ultrasonographically hepatic steatosis without other liver diseases. Disposition index (DI) was employed to assess pancreatic β-cell function. A total of 6168 participants were included in this study. Results: NAFLD participants had much higher HOMA2-%B (weighted mean, 124.1; standard error, 1.8) than the non-NAFLD participants (weighted mean, 100.7; standard error, 0.9). However, when evaluating the β-cell function in the context of insulin resistance by using DI index, DI levels were much lower in NAFLD subjects (weighted mean, 79.5; standard error, 1.0) compared to non-NAFLD (weighted mean, 95.0; standard error, 0.8). Multivariate logistic regression analyses showed that DI was inversely associated with NAFLD prevalence. The adjusted OR (95% CI) for quartile 1 versus quartile 4 was 1.81 (1.31–2.50) (p < 0.001 for trend). Moreover, DI was also inversely associated with the presence of moderate to severe hepatic steatosis. The multivariable-adjusted ORs across quartiles of DI were 2.47, 1.44, 0.96 and 1.00 for the presence of moderate to severe hepatic steatosis (p < 0.001 for trend). Conclusions: Pancreatic β-cell function might be a new predictor for the presence of NAFLD, and insufficient compensatory β-cell function is associated with NAFLD.
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Affiliation(s)
- Xu Chen
- Department of Nutrition, School of Public Health, Ningxia Medical University, Yinchuan 750004, China
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Jinghe Xiao
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Juan Pang
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Shen Chen
- Department of Toxicology, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qing Wang
- Department of Toxicology, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Wenhua Ling
- Department of Nutrition, School of Public Health, Ningxia Medical University, Yinchuan 750004, China
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
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Dolicka D, Foti M, Sobolewski C. The Emerging Role of Stress Granules in Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22179428. [PMID: 34502337 PMCID: PMC8430939 DOI: 10.3390/ijms22179428] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Stress granules (SGs) are small membrane-free cytosolic liquid-phase ordered entities in which mRNAs are protected and translationally silenced during cellular adaptation to harmful conditions (e.g., hypoxia, oxidative stress). This function is achieved by structural and functional SG components such as scaffold proteins and RNA-binding proteins controlling the fate of mRNAs. Increasing evidence indicates that the capacity of cells to assemble/disassemble functional SGs may significantly impact the onset and the development of metabolic and inflammatory diseases, as well as cancers. In the liver, the abnormal expression of SG components and formation of SG occur with chronic liver diseases, hepatocellular carcinoma (HCC), and selective hepatic resistance to anti-cancer drugs. Although, the role of SG in these diseases is still debated, the modulation of SG assembly/disassembly or targeting the expression/activity of specific SG components may represent appealing strategies to treat hepatic disorders and potentially cancer. In this review, we discuss our current knowledge about pathophysiological functions of SGs in HCC as well as available molecular tools and drugs capable of modulating SG formation and functions for therapeutic purposes.
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Zhang D, Ma Y, Liu J, Deng Y, Zhou B, Wen Y, Li M, Wen D, Ying Y, Luo S, Shi C, Pu G, Miao Y, Zou C, Chen Y, Ma L. Metformin Alleviates Hepatic Steatosis and Insulin Resistance in a Mouse Model of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Promoting Transcription Factor EB-Dependent Autophagy. Front Pharmacol 2021; 12:689111. [PMID: 34366846 PMCID: PMC8346235 DOI: 10.3389/fphar.2021.689111] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/13/2021] [Indexed: 12/31/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) results from an abnormal accumulation of lipids within hepatocytes, and is commonly associated with obesity, insulin resistance, and hyperlipidemia. Metformin is commonly used to treat type 2 diabetes mellitus and, in recent years, it was found to play a potential role in the amelioration of NAFLD. However, the mechanisms underlying the protective effect of metformin against NAFLD remain largely unknown. Transcription factor EB (TFEB) is a master transcriptional regulator of lysosomal biogenesis and autophagy and, when activated, is effective against disorders of lipid metabolism. However, the role of TFEB in hepatic steatosis is not well understood. In this report, we demonstrate that the activity of TFEB is reduced in the liver of mice fed a high-fat diet. Metformin treatment significantly reverses the activity of TFEB, and the protective effect of metformin against hepatic steatosis and insulin resistance is dependent on TFEB. We show that metformin-induced autophagy is regulated by TFEB, and our findings reveal that TFEB acts as a mediator, linking metformin with autophagy to reverse NAFLD, and highlight that TFEB may be a promising molecular target for the treatment of NAFLD.
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Affiliation(s)
- Dan Zhang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Yicheng Ma
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, China
| | - Jianjun Liu
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Research Center of Biomedical Engineering, Kunming Medical University, Kunming, China
| | - Yi Deng
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Bo Zhou
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Yu Wen
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Mingke Li
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Daiyan Wen
- Faculty of Basic Medicine, Kunming Medical University, Kunming, China
| | - Yunyan Ying
- Faculty of Basic Medicine, Kunming Medical University, Kunming, China
| | - Sufeng Luo
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Chunjing Shi
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Guangyu Pu
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Yinglei Miao
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
| | - Chenggang Zou
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, China
| | - Yuanli Chen
- Faculty of Basic Medicine, Kunming Medical University, Kunming, China
| | - Lanqing Ma
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, China
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Sobolewski C, Legrand N. Celecoxib Analogues for Cancer Treatment: An Update on OSU-03012 and 2,5-Dimethyl-Celecoxib. Biomolecules 2021; 11:biom11071049. [PMID: 34356673 PMCID: PMC8302000 DOI: 10.3390/biom11071049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 12/20/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) is an important enzyme involved in prostaglandins biosynthesis from arachidonic acid. COX-2 is frequently overexpressed in human cancers and plays a major tumor promoting function. Accordingly, many efforts have been devoted to efficiently target the catalytic site of this enzyme in cancer cells, by using COX-2 specific inhibitors such as celecoxib. However, despite their potent anti-tumor properties, the myriad of detrimental effects associated to the chronic inhibition of COX-2 in healthy tissues, has considerably limited their use in clinic. In addition, increasing evidence indicate that these anti-cancerous properties are not strictly dependent on the inhibition of the catalytic site. These findings have led to the development of non-active COX-2 inhibitors analogues aiming at preserving the antitumor effects of COX-2 inhibitors without their side effects. Among them, two celecoxib derivatives, 2,5-Dimethyl-Celecoxib and OSU-03012, have been developed and suggested for the treatment of viral (e.g., recently SARS-CoV-2), inflammatory, metabolic diseases and cancers. These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches.
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Affiliation(s)
- Cyril Sobolewski
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland
- Correspondence: ; Tel.: +41-22-379-5421
| | - Noémie Legrand
- Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland;
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Ma M, Xie W, Li X. Identification of Autophagy-Related Genes in the Progression from Non-Alcoholic Fatty Liver to Non-Alcoholic Steatohepatitis. Int J Gen Med 2021; 14:3163-3176. [PMID: 34262330 PMCID: PMC8275104 DOI: 10.2147/ijgm.s317785] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 06/18/2021] [Indexed: 12/30/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Autophagy plays a vital role in NAFLD development and progression. We aimed to establish a novel autophagy-related gene (ARG) signature as a therapeutic target in NAFLD patients based on high-throughput sequencing data. Methods ARGs obtained from the HAMdb and high-sequencing data obtained from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed ARGs (DEARGs) between normal and NASH tissues. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore potential biological and pathological functions of DEARGs. The protein-protein interaction (PPI) network of the DEARGs was established through the STRING website, and visualized by Cytoscape. In addition, hub genes were validated by an independent dataset GSE89632. Finally, we performed Gene Set Variation Analysis (GSVA) pathway-related analysis to identify the pivotal signaling pathways and genes for the progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). Results A total of 76 DEARGs were identified in the GSE126848 dataset, of which 45 genes were upregulated and 31 genes were downregulated. GO analysis showed that the biological functions of DEARGs focused primarily on autophagy, cellular response to external stimulus, fibroblast proliferation, late endosome, and ubiquitin protein ligase binding. KEGG pathway analysis showed that these DEARGs were mainly involved in the apoptosis, PI3K-Akt signaling pathway, and estrogen signaling pathway. Among DEGs, 9 most closely related genes were identified from the PPI network. Furthermore, NOS3, IGF1, VAMP8, FOS, and HMOX1 were verified in the GSE89632 dataset. At last, the MAPK signal pathway was identified as important pathway, and JUN was identified as a key gene involved in the progression from NAFL to NASH. Conclusion This study may provide credible molecular biomarkers in terms of screening and diagnosis for NAFLD. Meanwhile, it also serves as a basis for exploring the molecular mechanisms underlying the progression of NAFL to NASH.
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Affiliation(s)
- Mengyao Ma
- Department of Laboratory Medicine, Biology Science Institutes, Chongqing Medical University, Chongqing, 400032, People's Republic of China
| | - Wenhua Xie
- Department of Laboratory Medicine, Biology Science Institutes, Chongqing Medical University, Chongqing, 400032, People's Republic of China
| | - Xi Li
- Department of Laboratory Medicine, Biology Science Institutes, Chongqing Medical University, Chongqing, 400032, People's Republic of China
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Flessa CM, Kyrou I, Nasiri-Ansari N, Kaltsas G, Papavassiliou AG, Kassi E, Randeva HS. Endoplasmic Reticulum Stress and Autophagy in the Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD): Current Evidence and Perspectives. Curr Obes Rep 2021; 10:134-161. [PMID: 33751456 DOI: 10.1007/s13679-021-00431-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease with rising prevalence worldwide. Herein, we provide a comprehensive overview of the current knowledge supporting the role of ER stress and autophagy processes in NAFLD pathogenesis and progression. We also highlight the interrelation between these two pathways and the impact of ER stress and autophagy modulators on NAFLD treatment. RECENT FINDINGS The pathophysiological mechanisms involved in NAFLD progression are currently under investigation. The endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR) seem to contribute to its pathogenesis mainly due to high ER content in the liver which exerts significant metabolic functions and can be dysregulated. Furthermore, disruption of autophagy processes has also been identified in NAFLD. The crucial role of these two pathways in NAFLD is underlined by the fact that they have recently emerged as promising targets of therapeutic interventions. There is a greater need for finding the natural/chemical compounds and drugs which can modulate the ER stress pathway and autophagy for the treatment of NAFLD. Clarifying the inter-relation between these two pathways and their interaction with inflammatory and apoptotic mechanisms will allow the development of additional therapeutic options which can better target and reprogram the underlying pathophysiological pathways, aiming to attenuate NAFLD progression.
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Affiliation(s)
- Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, B4 7ET, Birmingham, UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece.
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
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Raza S, Tewari A, Rajak S, Sinha RA. Vitamins and non-alcoholic fatty liver disease: A Molecular Insight ⋆. LIVER RESEARCH (BEIJING, CHINA) 2021; 5:62-71. [PMID: 34221537 PMCID: PMC7611112 DOI: 10.1016/j.livres.2021.03.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/23/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is rising rapidly across the globe. NAFLD pathogenesis is largely driven by an imbalance in hepatic energy metabolism and at present, there is no approved drug for its treatment. The liver plays a crucial role in micronutrient metabolism and deregulation of this micronutrient metabolism may contribute to the pathogenesis of NAFLD. Vitamins regulate several enzymatic processes in the liver, and derangement in vitamin metabolism is believed to play a critical role in NAFLD progression. The anti-oxidant activities of vitamin C and E have been attributed to mitigate hepatocyte injury, and alterations in the serum levels of vitamin D, vitamin B12 and folate have shown a strong correlation with NAFLD severity. This review aims to highlight the role of these vitamins, which represent promising therapeutic targets for the management of NAFLD.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Archana Tewari
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Zhang L, Zhang Y, Jiang Y, Dou X, Li S, Chai H, Qian Q, Wang M. Upregulated SOCC and IP3R calcium channels and subsequent elevated cytoplasmic calcium signaling promote nonalcoholic fatty liver disease by inhibiting autophagy. Mol Cell Biochem 2021; 476:3163-3175. [PMID: 33864571 DOI: 10.1007/s11010-021-04150-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/01/2021] [Indexed: 12/22/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is related to elevated cytoplasmic calcium signaling in hepatocytes, which may be mediated by store-operated calcium channel (SOCC) and inositol triphosphate receptor (IP3R). However, the regulatory effect of calcium signaling on lipid accumulation and degeneration in hepatocytes and the underlying molecular mechanism remain unknown. Autophagy inhibition promotes lipid accumulation and steatosis in hepatocytes. However, the association between elevated calcium signaling and autophagy inhibition in hepatocytes and its effect on hepatocyte fatty lesions remain unclear. Here, we established a mouse hepatocyte fatty gradient model using oleic acid. SOCC and IP3R channel opening and cytoplasmic calcium levels gradually increased with the hepatocyte pimelosis degree, whereas autophagy gradually decreased. We also established an optimal oleic acid (OOA) hepatocyte model, observing significantly increased SOCC and IP3R channel opening and calcium influx alongside significantly decreased autophagy and aggravated cellular fatty lesion. Calcium channel blockers (CCBs) and calcium channel gene silencing reagents (CCGSRs), respectively, reversed these effects, indicating that elevated cytoplasmic calcium signaling promotes NAFLD occurrence and the development by inhibiting hepatocyte autophagy. In the OOA model, upregulated extracellular regulated protein kinases 1/2 (ERK1/2), which can be regulated by SOCC and IP3R proteins transient receptor potential canonical 1 (TRPC1)/IP3R with elevated cytoplasmic calcium signaling, over-inhibited forkhead/winged helix O (FOXO) signaling and over-activated mammalian target of rapamycin complex 1 (mTORC1) signaling. Over-inhibited FOXO signaling significantly downregulated autophagy-related gene 12, which inhibits autophagosome maturation, while over-activated mTORC1 signaling over-inactivated Unc-51 like autophagy activating kinase 1, which inhibits preautophagosome formation. CCBs and CCGSRs recovered autophagy by significantly downregulating ERK1/2 to block abnormal changes in FOXO and mTORC1 signaling. Our findings indicate that upregulated SOCC and IP3R channels and subsequent elevated cytoplasmic calcium signaling in hepatocyte fatty lesions inhibits hepatocyte autophagy through (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling pathways, causes lipid accumulation and degeneration in hepatocytes, and promotes NAFLD occurrence and development.
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Affiliation(s)
- Lin Zhang
- College of Life Science/Institute of Molecular Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Yifan Zhang
- College of Life Science/Institute of Molecular Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Yuanqing Jiang
- College of Life Science, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Xiaobing Dou
- College of Life Science/Institute of Molecular Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Songtao Li
- Institute of Molecular Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Hui Chai
- College of Life Science/Institute of Molecular Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Qianyu Qian
- College of Life Science/Institute of Molecular Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Miaojuan Wang
- Department of General Practice, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
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Ramos VDM, Kowaltowski AJ, Kakimoto PA. Autophagy in Hepatic Steatosis: A Structured Review. Front Cell Dev Biol 2021; 9:657389. [PMID: 33937257 PMCID: PMC8081956 DOI: 10.3389/fcell.2021.657389] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/16/2021] [Indexed: 01/18/2023] Open
Abstract
Steatosis is the accumulation of neutral lipids in the cytoplasm. In the liver, it is associated with overeating and a sedentary lifestyle, but may also be a result of xenobiotic toxicity and genetics. Non-alcoholic fatty liver disease (NAFLD) defines an array of liver conditions varying from simple steatosis to inflammation and fibrosis. Over the last years, autophagic processes have been shown to be directly associated with the development and progression of these conditions. However, the precise role of autophagy in steatosis development is still unclear. Specifically, autophagy is necessary for the regulation of basic metabolism in hepatocytes, such as glycogenolysis and gluconeogenesis, response to insulin and glucagon signaling, and cellular responses to free amino acid contents. Also, genetic knockout models for autophagy-related proteins suggest a critical relationship between autophagy and hepatic lipid metabolism, but some results are still ambiguous. While autophagy may seem necessary to support lipid oxidation in some contexts, other evidence suggests that autophagic activity can lead to lipid accumulation instead. This structured literature review aims to critically discuss, compare, and organize results over the last 10 years regarding rodent steatosis models that measured several autophagy markers, with genetic and pharmacological interventions that may help elucidate the molecular mechanisms involved.
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Affiliation(s)
| | | | - Pamela A. Kakimoto
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
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