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Arabzadeh E, Sarshin A, Feizolahi F, Mohabbat M, Soleiman-Fallah MA, Rahimi A, Petridou A, Emami Z, Tajik H, Bozorg Omid R, Maleki A, Ekrami Ogholbag H, Khademi A, Zargani M. Synergistic salvation: HIIT and herbal allies reverse NAFLD damage in rats. J Mol Histol 2025; 56:131. [PMID: 40186827 DOI: 10.1007/s10735-025-10413-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
Fatty liver disease is a build-up of fats in the liver that can damage the organ and lead to serious complications. This study aimed to investigate the effects of exercise training and supplementation (milk thistle, chicory and cumin) on liver metabolites related to its function and health in rats with non-alcoholic fatty liver disease (NAFLD). Forty adult male Wistar rats with an average weight of 215 ± 10 g were divided into a control group fed on the basal diet and four experimental groups fed with high-fat diet (HFD) for 6 weeks to induce non-alcoholic fatty liver disease (NAFLD). The 4 NAFLD groups were subdivided and treated with (a) plain HFD, (b) high-intensity interval training (HIIT), (c) supplement (milk thistle, chicory, and cumin), and (d) combined HIIT and supplementation for 4 weeks. The induction of NAFLD through HFD yielded dyslipidemia, liver tissue damage, increased malondialdehyde, uncoupling protein 2 (UCP2), and phosphatidylinositol-3 kinase (PI3K), as well as decreased superoxide dismutase (SOD) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) in liver tissue (p < 0.05). The 4 weeks intervention with either HIIT, supplement or especially the combined application of both, reversed these factors (p < 0.05) through changes in their concentrations in a direction indicative of enhanced liver health and function. HIIT beside supplementation (milk thistle, chicory, and cumin) improved indices related to oxidative stress, lipid profile, and the expression of PI3K, UCP2, PGC-1α genes expression and PGC-1α protein content, making it potentially promising in the treatment of liver damage caused by HFD.
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Affiliation(s)
- Ehsan Arabzadeh
- Exercise Physiology Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Sarshin
- Clinical Care and Health Promotion Research Center, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Foad Feizolahi
- Clinical Care and Health Promotion Research Center, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Majid Mohabbat
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Guilan, Rasht, Iran
| | | | - Alireza Rahimi
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Anatoli Petridou
- Laboratory of Evaluation of Human Biological Performance, School of Physical Education and Sport Science at Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Zahra Emami
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Helena Tajik
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Reza Bozorg Omid
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Amir Maleki
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | | | - Ali Khademi
- PhD in Sport Management, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Mehdi Zargani
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran.
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Mao S. Emerging role and the signaling pathways of uncoupling protein 2 in kidney diseases. Ren Fail 2024; 46:2381604. [PMID: 39090967 PMCID: PMC11299446 DOI: 10.1080/0886022x.2024.2381604] [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: 08/15/2023] [Revised: 06/18/2024] [Accepted: 07/13/2024] [Indexed: 08/04/2024] Open
Abstract
OBJECTIVES Uncoupling protein 2 (UCP2) was involved in the pathogenesis and development of kidney diseases. Many signaling pathways and factors regulate the expression of UCP2. We aimed to investigate the precise role of UCP2 and its signaling pathways in kidney diseases. METHODS We summarized the available evidence to yield a more detailed conclusion of the signal transduction pathways of UCP2 and its role in the development and progression of kidney diseases. RESULTS UCP2 could interact with 14.3.3 family proteins, mitochondrial phospholipase iPLA2γ, NMDAR, glucokinase, PPARγ2. There existed a signaling pathway between UCP2 and NMDAR, PPARγ. UCP2 can inhibit the ROS production, inflammatory response, and apoptosis, which may protect against renal injury, particularly AKI. Meanwhile UCP2 can decrease ATP production and inhibit the secretion of insulin, which may alleviate chronic renal damages, such as diabetic nephropathy and kidney fibrosis. CONCLUSIONS Homeostasis of UCP2 is helpful for kidney health. UCP2 may play different roles in different kinds of renal injury.
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Affiliation(s)
- Song Mao
- Department of Pediatrics, Shanghai Sixth People’s Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Wang X, Zhang C, Bao N. Molecular mechanism of palmitic acid and its derivatives in tumor progression. Front Oncol 2023; 13:1224125. [PMID: 37637038 PMCID: PMC10447256 DOI: 10.3389/fonc.2023.1224125] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/24/2023] [Indexed: 08/29/2023] Open
Abstract
Palmitic acid (PA) is a saturated fatty acid commonly found in coconut oil and palm oil. It serves as an energy source for the body and plays a role in the structure and function of cell membranes. Beyond its industrial applications, PA has gained attention for its potential therapeutic properties. Modern pharmacological studies have demonstrated that PA exhibits anti-inflammatory, antioxidant, and immune-enhancing effects. In recent years, PA has emerged as a promising anti-tumor agent with demonstrated efficacy against various malignancies including gastric cancer, liver cancer, cervical cancer, breast cancer, and colorectal cancer. Its anti-tumor effects encompass inducing apoptosis in tumor cells, inhibiting tumor cell proliferation, suppressing metastasis and invasion, enhancing sensitivity to chemotherapy, and improving immune function. The main anticancer mechanism of palmitic acid (PA) involves the induction of cell apoptosis through the mitochondrial pathway, facilitated by the promotion of intracellular reactive oxygen species (ROS) generation. PA also exhibits interference with the cancer cell cycle, leading to cell cycle arrest predominantly in the G1 phase. Moreover, PA induces programmed cell autophagy death, inhibits cell migration, invasion, and angiogenesis, and synergistically enhances the efficacy of chemotherapy drugs while reducing adverse reactions. PA acts on various intracellular and extracellular targets, modulating tumor cell signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), endoplasmic reticulum (ER), B Cell Lymphoma-2 (Bcl-2), P53, and other signaling pathways. Furthermore, derivatives of PA play a significant regulatory role in tumor resistance processes. This paper provides a comprehensive review of recent studies investigating the anti-tumor effects of PA. It summarizes the underlying mechanisms through which PA exerts its anti-tumor effects, aiming to inspire new perspectives for the treatment of malignant tumors in clinical settings and the development of novel anti-cancer drugs.
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Affiliation(s)
- Xitan Wang
- Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Chaonan Zhang
- Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, China
- Weifang Medical University, Weifang, Shandong, China
| | - Na Bao
- Jining First People’s Hospital, Jining, Shandong, China
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Shatta MA, El-Derany MO, Gibriel AA, El-Mesallamy HO. Rhamnetin ameliorates non-alcoholic steatosis and hepatocellular carcinoma in vitro. Mol Cell Biochem 2023; 478:1689-1704. [PMID: 36495373 PMCID: PMC10267014 DOI: 10.1007/s11010-022-04619-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022]
Abstract
Non-alcoholic fatty liver (NAFLD) is a widespread disease with various complications including Non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis and ultimately hepatocellular carcinoma (HCC). Up till now there is no FDA approved drug for treatment of NAFLD. Flavonoids such as Rhamnetin (Rhm) have been ascribed effective anti-inflammatory and anti-oxidative properties. Thus, Rhm as a potent flavonoid could target multiple pathological cascades causing NAFLD to prevent its progression into HCC. NAFLD is a multifactorial disease and its pathophysiology is complex and is currently challenged by the 'Multiple-hit hypothesis' that includes wider range of comorbidities rather than previously established theory of 'Two-hit hypothesis'. Herein, we aimed at establishing reliable in vitro NASH models using different mixtures of variable ratios and concentrations of oleic acid (OA) and palmitic acid (PA) combinations using HepG2 cell lines. Moreover, we compared those models in the context of oil red staining, triglyceride levels and their altered downstream molecular signatures for genes involved in de novo lipogenesis, inflammation, oxidative stress and apoptotic machineries as well. Lastly, the effect of Rhm on NASH and HCC models was deeply investigated. Over the 10 NASH models tested, PA 500 µM concentration was the best model to mimic the molecular events of steatosis induced NAFLD. Rhm successfully ameliorated the dysregulated molecular events caused by the PA-induced NASH. Additionally, Rhm regulated inflammatory and oxidative machinery in the HepG2 cancerous cell lines. In conclusion, PA 500 µM concentration is considered an effective in vitro model to mimic NASH. Rhm could be used as a promising therapeutic modality against both NASH and HCC pathogenesis.
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Affiliation(s)
- Mahmoud A Shatta
- Department of Biochemistry, Faculty of Pharmacy, The British University in Egypt, Cairo, 11837, Egypt
| | - Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
| | - Abdullah A Gibriel
- Department of Biochemistry, Faculty of Pharmacy, The British University in Egypt, Cairo, 11837, Egypt
| | - Hala O El-Mesallamy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
- Dean of Faculty of Pharmacy, Sinai University, North Sinai, 45518, Egypt
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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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Li C, Sun S, Tu Y, Zhang H, Yao F, Liao S, Sun S, Li Z, Wang Z. High Glucose Accelerates Tumor Progression by Regulating MEDAG-Mediated Autophagy Levels in Breast Cancer. Int J Biol Sci 2022; 18:4289-4300. [PMID: 35864962 PMCID: PMC9295059 DOI: 10.7150/ijbs.70002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 06/23/2022] [Indexed: 12/11/2022] Open
Abstract
Recent studies have shown that diabetes is a major risk factor for breast cancer (BC), but the mechanism is incompletely understood. Mesenteric estrogen-dependent adipogenesis (MEDAG) plays a significant role in both glucose uptake and BC development. However, the relationship between MEDAG and BC under high glucose (HG) conditions remains unclear. In our study, MEDAG expression was higher in BC tissue from diabetic patients than in BC tissue from nondiabetic patients. HG promoted BC progression in vitro and in vivo by upregulating MEDAG expression. Furthermore, MEDAG deficiency increased the autophagosome number and autophagic flux. Moreover, inhibition of autophagy partially reversed MEDAG knockdown (MEDAGKD)-induced suppression of tumorigenic biological behaviors and epithelial-mesenchymal transition (EMT) progression. Finally, MEDAG significantly suppressed AMPK phosphorylation. Additionally, the AMPK inhibitor Compound C markedly reduced autophagosome accumulation and antitumor effects in MEDAGKD cells. Treatment with the AMPK activator AICAR exhibited similar effects in MEDAG-overexpressing (MEDAGOE) cells. In conclusion, the MEDAG-AMPK-autophagy axis is vital to BC progression in diabetic patients. Our findings provide a novel treatment target for BC in patients with diabetes.
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Affiliation(s)
- Chenyuan Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Si Sun
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Yi Tu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Hanpu Zhang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Feng Yao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Shichong Liao
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Zhiyu Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Zhong Wang
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
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Lipke K, Kubis-Kubiak A, Piwowar A. Molecular Mechanism of Lipotoxicity as an Interesting Aspect in the Development of Pathological States-Current View of Knowledge. Cells 2022; 11:cells11050844. [PMID: 35269467 PMCID: PMC8909283 DOI: 10.3390/cells11050844] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 02/06/2023] Open
Abstract
Free fatty acids (FFAs) play numerous vital roles in the organism, such as contribution to energy generation and reserve, serving as an essential component of the cell membrane, or as ligands for nuclear receptors. However, the disturbance in fatty acid homeostasis, such as inefficient metabolism or intensified release from the site of storage, may result in increased serum FFA levels and eventually result in ectopic fat deposition, which is unfavorable for the organism. The cells are adjusted for the accumulation of FFA to a limited extent and so prolonged exposure to elevated FFA levels results in deleterious effects referred to as lipotoxicity. Lipotoxicity contributes to the development of diseases such as insulin resistance, diabetes, cardiovascular diseases, metabolic syndrome, and inflammation. The nonobvious organs recognized as the main lipotoxic goal of action are the pancreas, liver, skeletal muscles, cardiac muscle, and kidneys. However, lipotoxic effects to a significant extent are not organ-specific but affect fundamental cellular processes occurring in most cells. Therefore, the wider perception of cellular lipotoxic mechanisms and their interrelation may be beneficial for a better understanding of various diseases’ pathogenesis and seeking new pharmacological treatment approaches.
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Mao JY, Su LX, Li DK, Zhang HM, Wang XT, Liu DW. The effects of UCP2 on autophagy through the AMPK signaling pathway in septic cardiomyopathy and the underlying mechanism. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:259. [PMID: 33708886 PMCID: PMC7940903 DOI: 10.21037/atm-20-4819] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Background Mitochondrial dysfunction plays an important role in the development of septic cardiomyopathy. This study aimed to reveal the protective role of uncoupling protein 2 (UCP2) in mitochondria through AMP-activated protein kinase (AMPK) on autophagy during septic cardiomyopathy. Methods UCP2 knockout mice via a cecal ligation and puncture (CLP) model and the H9C2 cardiomyocyte cell line in response to lipopolysaccharide (LPS) in vitro were used to study the effect. The myocardial morphological alterations, indicators of mitochondrial injury and levels of autophagy-associated proteins (pAMPK, pmTOR, pULK1, pTSC2, Beclin-1, and LC3-I/II) were assessed. In addition, the mechanism of the interaction between UCP2 and AMPK was further studied through gain- and loss-of-function studies. Results Compared with the wild-type mice, the UCP2 knockout mice exhibited more severe cardiomyocyte injury after CLP, and the AMPK agonist AICAR protected against such injury. Consistent with this result, silencing UCP2 augmented the LPS-induced pathological damage and mitochondrial injury in the H9C2 cells, limited the upregulation of autophagy proteins and reduced AMPK phosphorylation. AICAR protected the cells from morphological changes and mitochondrial membrane potential loss and promoted autophagy. The silencing and overexpression of UCP2 led to correlated changes in the AMPK upstream kinases pLKB1 and CAMKK2. Conclusions UCP2 exerts cardioprotective effects on mitochondrial dysfunction during sepsis via the action of AMPK on autophagy.
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Affiliation(s)
- Jia-Yu Mao
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Long-Xiang Su
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Dong-Kai Li
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Hong-Min Zhang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Xiao-Ting Wang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
| | - Da-Wei Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
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Fan X, Lin L, Cui B, Zhao T, Mao L, Song Y, Wang X, Feng H, Qingxiang Y, Zhang J, Jiang K, Cao X, Wang B, Sun C. Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe. Pharmacol Res 2020; 159:104945. [PMID: 32454225 DOI: 10.1016/j.phrs.2020.104945] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/04/2020] [Accepted: 05/19/2020] [Indexed: 12/14/2022]
Abstract
Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.
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Affiliation(s)
- Xiaofei Fan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Lin Lin
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Binxin Cui
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Tianming Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Lihong Mao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Yan Song
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Xiaoyu Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Hongjuan Feng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Department of Nutriology, Tianjin Third Central Hospital, Jintang Road 83, Hedong District, Tianjin 300170, China
| | - Yu Qingxiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Kui Jiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Xiaocang Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China.
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China.
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Ethnopharmacology of Fruit Plants: A Literature Review on the Toxicological, Phytochemical, Cultural Aspects, and a Mechanistic Approach to the Pharmacological Effects of Four Widely Used Species. Molecules 2020; 25:molecules25173879. [PMID: 32858815 PMCID: PMC7504726 DOI: 10.3390/molecules25173879] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 07/31/2020] [Accepted: 07/31/2020] [Indexed: 02/07/2023] Open
Abstract
Fruit plants have been widely used by the population as a source of food, income and in the treatment of various diseases due to their nutritional and pharmacological properties. The aim of this study was to review information from the most current research about the phytochemical composition, biological and toxicological properties of four fruit species widely used by the world population in order to support the safe medicinal use of these species and encourage further studies on their therapeutic properties. The reviewed species are: Talisia esculenta, Brosimum gaudichaudii, Genipa americana, and Bromelia antiacantha. The review presents the botanical description of these species, their geographical distribution, forms of use in popular medicine, phytochemical studies and molecules isolated from different plant organs. The description of the pharmacological mechanism of action of secondary metabolites isolated from these species was detailed and toxicity studies related to them were reviewed. The present study demonstrates the significant concentration of phenolic compounds in these species and their anti-inflammatory, anti-tumor, photosensitizing properties, among others. Such species provide important molecules with pharmacological activity that serve as raw materials for the development of new drugs, making further studies necessary to elucidate mechanisms of action not yet understood and prove the safety for use in humans.
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Acaz-Fonseca E, Castelló-Ruiz M, Burguete MC, Aliena-Valero A, Salom JB, Torregrosa G, García-Segura LM. Insight into the molecular sex dimorphism of ischaemic stroke in rat cerebral cortex: Focus on neuroglobin, sex steroids and autophagy. Eur J Neurosci 2020; 52:2756-2770. [PMID: 32243028 DOI: 10.1111/ejn.14731] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 02/12/2020] [Accepted: 03/22/2020] [Indexed: 12/12/2022]
Abstract
Including sex is of paramount importance in preclinical and clinical stroke researches, and molecular studies dealing in depth with sex differences in stroke pathophysiology are needed. To gain insight into the molecular sex dimorphism of ischaemic stroke in rat cerebral cortex, male and female adult rats were subjected to transient middle cerebral artery occlusion. The expression of neuroglobin (Ngb) and other functionally related molecules involved in sex steroid signalling (oestrogen and androgen receptors), steroidogenesis (StAR, TSPO and aromatase) and autophagic activity (LC3B-II/LC3B-I ratio, UCP2 and HIF-1α) was assessed in the ipsilateral ischaemic and contralateral non-ischaemic hemispheres. An increased expression of Ngb was detected in the injured female cerebral cortex. In contrast, increased expression of oestrogen receptor α, GPER, StAR, TSPO and UCP2, and decreased androgen receptor expression were detected in the injured male cortex. In both sexes, the ischaemic insult induced an upregulation of LC3B-II/-I ratio, indicative of increased autophagy. Therefore, the cerebral cortex activates both sex-specific and common molecular responses with neuroprotective potential after ischaemia-reperfusion, which globally results in similar stroke outcome in both sexes. Nonetheless, these different potential molecular targets should be taken into account when neuroprotective drugs aiming to reduce brain damage in ischaemic stroke are investigated.
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Affiliation(s)
- Estefanía Acaz-Fonseca
- Instituto Cajal - CSIC, Madrid, Spain.,Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - María Castelló-Ruiz
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universidad de Valencia, Valencia, Spain.,Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Valencia, Spain
| | - María C Burguete
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universidad de Valencia, Valencia, Spain.,Departamento de Fisiología, Universidad de Valencia, Valencia, Spain
| | - Alicia Aliena-Valero
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universidad de Valencia, Valencia, Spain
| | - Juan B Salom
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universidad de Valencia, Valencia, Spain.,Departamento de Fisiología, Universidad de Valencia, Valencia, Spain
| | - Germán Torregrosa
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe - Universidad de Valencia, Valencia, Spain
| | - Luis M García-Segura
- Instituto Cajal - CSIC, Madrid, Spain.,Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
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Korbecki J, Bajdak-Rusinek K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflamm Res 2019; 68:915-932. [PMID: 31363792 PMCID: PMC6813288 DOI: 10.1007/s00011-019-01273-5] [Citation(s) in RCA: 299] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1β and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.
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Affiliation(s)
- Jan Korbecki
- Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland.
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland
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Khakisahneh S, Zhang XY, Nouri Z, Hao SY, Chi QS, Wang DH. Thyroid hormones mediate metabolic rate and oxidative, anti-oxidative balance at different temperatures in Mongolian gerbils (Meriones unguiculatus). Comp Biochem Physiol C Toxicol Pharmacol 2019; 216:101-109. [PMID: 30476595 DOI: 10.1016/j.cbpc.2018.11.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 11/19/2018] [Accepted: 11/21/2018] [Indexed: 02/07/2023]
Abstract
Oxidative damage is a potential physiological cost of thermoregulation during seasonal adjustments to air temperature (Ta) in small mammals. Here, we hypothesized that Ta affects serum thyroid hormone levels and these hormones can mediate the changes in metabolic rate and oxidative damage. Mongolian gerbils (Meriones unguiculatus) were acclimated at different Tas (5 °C, 23 °C and 37 °C) for 3 weeks. Serum tri-iodothyronine (T3) levels increased at 5 °C but decreased at 37 °C compared to the control (23 °C). Protein carbonyls increased in liver at 37 °C compared with control, however, lipid damage (malonaldehyde, MDA) in both serum and liver was unrelated to Ta. After the effects of different Tas on thyroid hormone levels and oxidative damage markers were determined, we further investigate whether thyroid hormones mediated metabolic rate and oxidative damage. Another set of gerbils received 0.0036% L-thyroxin (hyperthyroid), 0.04% Methylimazol (hypothyroid) or water (control). Hypothyroid group showed a 34% reduction in resting metabolic rate (RMR) also 42% and 26% increases in MDA and liver protein carbonyl respectively, whereas hyperthyroid group had higher RMR, liver mass and superoxide dismutase (SOD) compared to control. Serum T3 or T3/T4 levels were correlated positively with RMR, liver mass, and SOD, but negatively with MDA and uncoupling protein 2 (UCP2). We concluded that high Ta induced hypothyroidism, decreased RMR and increased oxidative damage, whereas low Ta induced hyperthyroidism, increased RMR and unchanged oxidative damage. These data supported our hypothesis that thyroid hormones can be a cue to mediate metabolic rate and different aspects of oxidative and antioxidant activities at different Tas.
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Affiliation(s)
- Saeid Khakisahneh
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xue-Ying Zhang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Zahra Nouri
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shao-Yan Hao
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Qing-Sheng Chi
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - De-Hua Wang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Ježek P, Holendová B, Garlid KD, Jabůrek M. Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling. Antioxid Redox Signal 2018; 29:667-714. [PMID: 29351723 PMCID: PMC6071544 DOI: 10.1089/ars.2017.7225] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1-5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. CRITICAL ISSUES A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling. FUTURE DIRECTIONS Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667-714.
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Affiliation(s)
- Petr Ježek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Blanka Holendová
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Keith D Garlid
- 2 UCLA Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA , Los Angeles, California
| | - Martin Jabůrek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
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Kanda T, Matsuoka S, Yamazaki M, Shibata T, Nirei K, Takahashi H, Kaneko T, Fujisawa M, Higuchi T, Nakamura H, Matsumoto N, Yamagami H, Ogawa M, Imazu H, Kuroda K, Moriyama M. Apoptosis and non-alcoholic fatty liver diseases. World J Gastroenterol 2018; 24:2661-2672. [PMID: 29991872 PMCID: PMC6034146 DOI: 10.3748/wjg.v24.i25.2661] [Citation(s) in RCA: 208] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/04/2018] [Accepted: 06/21/2018] [Indexed: 02/06/2023] Open
Abstract
The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Motomi Yamazaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Toshikatsu Shibata
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazushige Nirei
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroshi Takahashi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Tomohiro Kaneko
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mariko Fujisawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Teruhisa Higuchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hitomi Nakamura
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroaki Yamagami
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Hiroo Imazu
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Kazumichi Kuroda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
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Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin. Biomedicines 2018; 6:biomedicines6020039. [PMID: 29587429 PMCID: PMC6027249 DOI: 10.3390/biomedicines6020039] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 03/21/2018] [Accepted: 03/22/2018] [Indexed: 12/24/2022] Open
Abstract
For centuries, plants have been exploited by mankind as sources of numerous cancer chemotherapeutic agents. Good examples of anticancer compounds of clinical significance today include the taxanes (e.g., taxol), vincristine, vinblastine, and the podophyllotoxin analogues that all trace their origin to higher plants. While all these drugs, along with the various other available therapeutic options, brought some relief in cancer management, a real breakthrough or cure has not yet been achieved. This critical review is a reflection on the lessons learnt from decades of research on the iridoid glycoside geniposide and its aglycone, genipin, which are currently used as gold standard reference compounds in cancer studies. Their effects on tumour development (carcinogenesis), cancer cell survival, and death, with particular emphasis on their mechanisms of actions, are discussed. Particular attention is also given to mechanisms related to the dual pro-oxidant and antioxidant effects of these compounds, the mitochondrial mechanism of cancer cell killing through reactive oxygen species (ROS), including that generated through the uncoupling protein-2 (UCP-2), the inflammatory mechanism, and cell cycle regulation. The implications of various studies for the evaluation of glycosidic and aglycone forms of natural products in vitro and in vivo through pharmacokinetic scrutiny are also addressed.
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Melatonin Balance the Autophagy and Apoptosis by Regulating UCP2 in the LPS-Induced Cardiomyopathy. Molecules 2018; 23:molecules23030675. [PMID: 29547569 PMCID: PMC6017117 DOI: 10.3390/molecules23030675] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 02/28/2018] [Accepted: 03/01/2018] [Indexed: 12/30/2022] Open
Abstract
To explore the mechanism of mitochondrial uncoupling protein 2 (UCP2) mediating the protective of melatonin when septic cardiomyopathy. UCP2 knocked out mice and cardiomyocytes were used to study the effect of melatonin in response to LPS. Indicators of myocardial and mitochondria injury including mitochondrial membrane potential, mitochondrial permeability transition pore, calcium loading, ROS, and ATP detection were assessed. In addition cell viability and apoptosis as well as autophagy-associated proteins were evaluated. Melatonin was able to protect heart function from LPS, which weakened in the UCP2-knockout mice. Consistently, genipin, a pharmacologic inhibitor of UCP2, augmented LPS-induced damage of AC16 cells. In contrast, melatonin upregulated UCP2 expression and protected the cells from the changes in morphology, mitochondrial membrane potential loss, mitochondrial Ca2+ overload, the opening of mitochondrial permeability transition pore, and subsequent increased ROS generation as well as ATP reduction. Mitophagy proteins (Beclin-1 and LC-3β) were increased while apoptosis-associated proteins (cytochrome C and caspase-3) were decreased when UCP2 was up-regulated. In conclusion, UCP2 may play a protecting role against LPS by regulating the balance between autophagy and apoptosis of cardiomyocytes, and by which mechanisms, it may contribute to homeostasis of cardiac function and cardiomyocytes activity. Melatonin may protect cardiomyocytes through modulating UCP2.
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Zhang Q, Wang SP, Li LL, Zhang Y. Effects of mitochondrial uncoupling protein 2 inhibition by Genipin on rat bone marrow mesenchymal stem cells under hypoxia and serum deprivation (H/SD) conditions. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:10047-10055. [PMID: 31966895 PMCID: PMC6965974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 03/20/2017] [Indexed: 06/10/2023]
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) have shown great promise for ischemic tissue repair. However, poor viability of transplanted BMSCs within ischemic tissues has limited their therapeutic potential. Numerous evidences suggested that reactive oxygen species (ROS) generated and apoptosis play an important role in regulation BMSCs loss at the ischemic site. Uncoupling protein 2 (UCP2), a member of the anion carrier superfamily of mitochondrial inner membrane and high expression in stem cells, has been reported to influence mitochondrial ROS production and regulate the energy metabolism. However the exact roles of UCP2 in regulation the BMSCs apoptosis are still not clear. In our study, we determined the functions of UCP2 in BMSCs from SD rats. Genipin, a special UCP2 inhibitor, was added into the cultural medium to reduce the UCP2 expression in BMSCs. Apoptosis was induced by the specific apoptotic insult hypoxia and serum deprivation (SD). There was no significant differences in ATP level in BMSCs from Genipin treatment group as compared with other treatment groups. But, the levels of Reactive oxygen species (ROS) and malondialdehyde (MDA) content in BMSCs treated with Genipin were significant higher than other groups (P<0.05). Furthermore, the level of BMSCs apoptosis was much higher in H/SD and 50 μM Genipin treatment group (31.93% ± 0.16) than H/SD treatment (17.59 ± 0.69) or control group (5.79 ± 0.04) (P<0.05). In addition, Bax and caspase3 activation were elevated after treatment with Genipin (P<0.05). However, the level of anti-apoptotic protein Bcl2 was significantly declined after treatment with Genipin (P<0.05). Taken together, our findings indicate that inhibitionof UCP2 by Genipin enhanced the BMSCs apoptosis under H/SD conditions.
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Affiliation(s)
- Qi Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityHeilongjiang Province, China
- First Department of Cardiology, Central Hospital of Jiamusi CityHeilongjiang Province, China
| | - Shi-Peng Wang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityHeilongjiang Province, China
| | - Li-Li Li
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityHeilongjiang Province, China
| | - Yao Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityHeilongjiang Province, China
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Yan H, Gao Y, Zhang Y. Inhibition of JNK suppresses autophagy and attenuates insulin resistance in a rat model of nonalcoholic fatty liver disease. Mol Med Rep 2016; 15:180-186. [PMID: 27909723 PMCID: PMC5355648 DOI: 10.3892/mmr.2016.5966] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 10/03/2016] [Indexed: 12/29/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease, the pathological process of which is complex. Activation of the c‑Jun N‑terminal kinase (JNK) signaling pathway is associated with the mechanism underlying obesity-induced insulin resistance. Furthermore, the JNK signaling pathway and dysfunctional autophagy serve important roles in hepatic lipid metabolism. However, the exact role of JNK in autophagy and obesity‑induced insulin resistance is not fully understood. Therefore, the present study aimed to investigate the underlying mechanisms by which the JNK signaling pathway regulates autophagy and insulin resistance in fatty liver. A rat model of NAFLD was established using a high‑fat diet (HFD), and insulin resistance in the livers of HFD rats was determined by peritoneal glucose tolerance testing. The results indicated that a HFD induced impaired glucose tolerance, liver function injury, insulin resistance and increased autophagy in rats. Treatment with SP600125, an inhibitor of JNK, relieved NAFLD in rats. Furthermore, SP600125 decreased the expression levels of autophagy-associated genes, including Beclin-1, microtubule-associated protein 1A/1B light chain 3, autophagy related gene (Atg)3 and Atg5, and the phosphorylation of insulin receptor (IR) β-subunit, IR substrate-1 and protein kinase B in vivo. In conclusion, JNK inhibition may suppress autophagy and attenuate insulin resistance. Therefore, JNK inhibition may provide a novel therapeutic strategy for the treatment of NAFLD.
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Affiliation(s)
- Hua Yan
- Department of Gerontology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Yanqiong Gao
- Department of Functional Examination, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Ying Zhang
- Department of Gerontology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
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