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Zhang Y, Han L, Ning Q, Zhang X, Zhang M, Peng J, Chen H, Zhao Z, Wang D. Gastrodin attenuates hypercholesterolaemia through regulating the PCSK9/LDLR signalling pathway by suppressing HNF-1α and activating FoxO3a. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156778. [PMID: 40279963 DOI: 10.1016/j.phymed.2025.156778] [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: 11/23/2024] [Revised: 03/24/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Hypercholesterolaemia is a prevalent etiological factor of cardiovascular diseases (CVDs). Gastrodin (Gas), the paramount active constituent in Gastrodia elata Bl., has lipid-lowering and anti-inflammatory properties for the treatment of CVDs. Nevertheless, the underlying mechanism responsible for hypolipidemic efficacy remains to be elucidated. The signalling pathwayof PCSK9/LDLR is a key signalling pathway that regulates cholesterol metabolism. PURPOSE This investigation elucidated whether Gas has an inhibitory effect on hypercholesterolaemia and whether this effect is associated with the regulation of the PCSK9/LDLR signalling pathway. METHODS We induced hypercholesterolaemia of mice by feeding them a high-fat diet (HFD) for 12 weeks to analyse the therapeutic effects and related pathways of Gas in vivo. In vitro, western blotting, qRT-PCR, molecular docking, and transfection were employed to verify the molecular mechanism of action of Gas in the treatment of hypercholesterolaemia. RESULTS Gas exhibited potent therapeutic effects against hypercholesterolaemia in HFD mice. Moreover, the HFD-induced hepatic lipid accumulation and liver damage were attenuated by Gas. Mechanistically, Gas decreased the expression of PCSK9 via inhibiting the JAK2/STAT3 signalling pathway to suppress HNF-1α and promote FoxO3a. In addition, Gas increased LDLR transcription via SREBP2 activation. CONCLUSION Collectively, our data provide new insights into the prevention and treatment of hyperlipidaemia by Gas.
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Affiliation(s)
- Yaowen Zhang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230011, China
| | - Lan Han
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230011, China; Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui, 230012, China
| | - Qiyuan Ning
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230011, China
| | - Xixi Zhang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230011, China
| | - Menglian Zhang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230011, China
| | - Jinyong Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230011, China
| | - Hao Chen
- First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Zhiwei Zhao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, China.
| | - Dandan Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230011, China; Anhui Provincial Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui, 230012, China; Institute for the Evaluation of the Efficacy and Safety of Chinese Medicines, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230011, China.
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Walker EM, Pearson GL, Lawlor N, Stendahl AM, Lietzke A, Sidarala V, Zhu J, Stromer T, Reck EC, Li J, Levi-D’Ancona E, Pasmooij MB, Hubers DL, Renberg A, Mohamed K, Parekh VS, Zhang IX, Thompson B, Zhang D, Ware SA, Haataja L, Qi N, Parker SCJ, Arvan P, Yin L, Kaufman BA, Satin LS, Sussel L, Stitzel ML, Soleimanpour SA. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues. Science 2025; 388:eadf2034. [PMID: 39913641 PMCID: PMC11985298 DOI: 10.1126/science.adf2034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 09/13/2024] [Accepted: 01/07/2025] [Indexed: 02/13/2025]
Abstract
Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. In this work, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Pharmacologic blockade of the integrated stress response in vivo restored β cell identity after the loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.
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Affiliation(s)
- Emily M. Walker
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Gemma L. Pearson
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Nathan Lawlor
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA
| | - Ava M. Stendahl
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Anne Lietzke
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Vaibhav Sidarala
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jie Zhu
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Tracy Stromer
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Emma C. Reck
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Jin Li
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Elena Levi-D’Ancona
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mabelle B. Pasmooij
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Dre L. Hubers
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Aaron Renberg
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Kawthar Mohamed
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Vishal S. Parekh
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
| | - Irina X. Zhang
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
| | - Benjamin Thompson
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
| | - Deqiang Zhang
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Sarah A. Ware
- Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Leena Haataja
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Nathan Qi
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Stephen C. J. Parker
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Peter Arvan
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Lei Yin
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Brett A. Kaufman
- Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Leslie S. Satin
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
| | - Lori Sussel
- Barbara Davis Center for Diabetes, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Michael L. Stitzel
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA
| | - Scott A. Soleimanpour
- Division of Metabolism, Endocrinology & Diabetes and Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
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Ding S, Banerjee A, Burke SN, Hernandez AR. Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats. GeroScience 2025:10.1007/s11357-025-01632-7. [PMID: 40153191 DOI: 10.1007/s11357-025-01632-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 03/20/2025] [Indexed: 03/30/2025] Open
Abstract
Many of the "hallmarks of aging" involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation, and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver, and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8 to 25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. Within the brain, SIRT1 and MAPK8 were reduced in CA3 of kTRF-fed rats. Additionally, IGF1 expression was significantly upregulated in the CA1 of cTRF-fed rats, but this effect was ameliorated in the kTRF fed group. AKT and FOXO1 expression were significantly reduced in kTRF-fed rats within liver. Interestingly, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance, and FOXO1 expression was higher in the CA3 of AL-fed rats correlated with the poorest cognitive performance. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.
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Affiliation(s)
- Sarah Ding
- Division of Gerontology, Geriatrics and Palliative Care, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Anisha Banerjee
- Division of Gerontology, Geriatrics and Palliative Care, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sara N Burke
- Department of Neuroscience, University of Florida, Gainesville, FL, USA
| | - Abbi R Hernandez
- Division of Gerontology, Geriatrics and Palliative Care, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
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Ülger Y, Delik A. Gene expression profile in ulcerative colitis patients: FOXO4, ALDOB, SLC26A3, SOD2 genes as potential biomarkers. Genes Genomics 2025:10.1007/s13258-025-01625-y. [PMID: 40153227 DOI: 10.1007/s13258-025-01625-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/14/2025] [Indexed: 03/30/2025]
Abstract
BACKGROUND Ulcerative colitis (UC) is a complex, chronic inflammatory disease that primarily impacts the colon mucosa. One of the key pathological contributors to the development and progression of inflammatory bowel disease (IBD) is oxidative stress, which results in reactive oxygen species (ROS)-induced mucosal damage. This stress leads to dysfunction of the intestinal barrier. OBJECTIVES The purpose of this study is to examine the expression levels of genes involved in various inflammatory pathways, including autophagy, unfolded protein response (UPR), ubiquitination, metabolic pathways, and immune responses in the colon mucosa of patients with UC. MATERIAL AND METHODS Patients diagnosed with UC at Çukurova University, Balcalı Hospital, Gastroenterology Department between December 2023 and January 2024 were included in this prospective study. A total of 40 participants were included in the study: 27 ulcerative colitis patients and 13 controls. To isolate high-quality RNA, colon biopsy material obtained during colonoscopy was immediately placed in stabilization solution and stored at - 80 degrees Celsius. The relative quantification of target gene mRNA was determined using a Light Cycler. Subsequently, differences in gene expression between patients and the control group were evaluated using the Mann-Whitney U and Kruskal-Wallis tests. RESULTS In our study, FOXO4 gene expression increased in UC patients during both active and remission phases compared to the control group. The high expression of this gene is associated with its role in inflammation and cell death processes. Additionally, the high expression of ALDOB and SLC26A genes is linked to increased inflammation and energy demand. Lastly, the elevated expression of the SOD2 gene can be considered a response to oxidative stress-related inflammatory processes in the disease. CONCLUSION These findings propose that these genes could serve as potential biomarkers for genomic identification and understanding the pathogenesis of UC.
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Affiliation(s)
- Yakup Ülger
- Division of Gastroenterology, Faculty of Medicine, Cukurova University, 01330, Adana, Turkey.
- Balcalı Hospital, Sarıcam, Adana, Turkey.
| | - Anıl Delik
- Division of Gastroenterology, Faculty of Medicine, Cukurova University, 01330, Adana, Turkey
- Balcalı Hospital, Sarıcam, Adana, Turkey
- Division of Biology, Faculty of Science and Literature, Cukurova University, 01330, Adana, Turkey
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Chen H, Cao T, Lin C, Jiao S, He Y, Zhu Z, Guo Q, Wu R, Cai H, Zhang B. Akkermansia muciniphila ameliorates olanzapine-induced metabolic dysfunction-associated steatotic liver disease via PGRMC1/SIRT1/FOXO1 signaling pathway. Front Pharmacol 2025; 16:1550015. [PMID: 40176900 PMCID: PMC11961884 DOI: 10.3389/fphar.2025.1550015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 02/26/2025] [Indexed: 04/05/2025] Open
Abstract
Akkermansia muciniphila (AKK), classified as "lean bacteria," has emerged as a promising candidate for ameliorating metabolic disorders, including obesity, diabetes, and liver disease. In this study, we investigated the therapeutic potential of AKK to counteract metabolic dysfunctions induced by Olanzapine (OLZ), a first-class antipsychotic known for its high therapeutic efficacy but also its association with metabolic disturbances, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Previous studies have implicated progesterone receptor membrane component 1 (PGRMC1) as a key player in antipsychotic-induced metabolic side effects. Using male C57BL/6J mice fed a high-fat diet, we assessed the effects of AKK supplementation on OLZ-induced metabolic disturbances. Key parameters such as body weight, hepatic injury markers, glucose tolerance, insulin resistance, and lipid metabolism were analyzed. The study revealed that AKK supplementation reduced hepatic lipid accumulation, oxidative stress, and insulin resistance, while normalizing lipid and glucose metabolism. These effects are likely mediated through the restoration of PGRMC1/SIRT1/FOXO1 signaling pathway by AKK. Additionally, changes in gut microbiota composition, including a reduction in pathogenic bacteria such as Lactococcus and enrichment of beneficial bacteria, were observed. Overall, the study suggests that AKK has therapeutic potential to counteract OLZ-induced MASLD by modulating gut microbiota and key metabolic pathways, making it a promising strategy for managing metabolic side effects in patients receiving antipsychotic treatment.
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Affiliation(s)
- Hui Chen
- Department of Pharmacy, Changsha Stomatological Hospital, Changsha, Hunan, China
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - Ting Cao
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - ChenQuan Lin
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - ShiMeng Jiao
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - YiFang He
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - ZhenYu Zhu
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - QiuJin Guo
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - RenRong Wu
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - HuaLin Cai
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
| | - BiKui Zhang
- Department of pharmacy, Institute of Clinical Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China
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Yang J, Li L, An Z, Lv Y, Li R, Li J, Guo M, Sun H, Yang H, Wang L, Liu Y, Guo H. Role of hepatocyte-specific FOXO1 in hepatic glucolipid metabolic disorders induced by perfluorooctane sulfonate. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 367:125632. [PMID: 39755352 DOI: 10.1016/j.envpol.2025.125632] [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: 10/14/2024] [Revised: 12/25/2024] [Accepted: 01/01/2025] [Indexed: 01/06/2025]
Abstract
Perfluorooctane sulfonate (PFOS), a prevalent perfluoroalkyl substance (PFAS), is widely present in various environmental media, animals, and even human bodies. It primarily accumulates in the liver, contributing to the disruption of hepatic metabolic homeostasis. However, the precise mechanism underlying PFOS-induced hepatic glucolipid metabolic disorders remains elusive. The transcription factor forkhead box protein O 1 (FOXO1) plays a crucial role in regulating hepatic glucolipid metabolism; however, its involvement in PFOS-induced hepatic glucolipid metabolic disorders has not been thoroughly explored. Molecular docking revealed high binding affinity between PFOS and FOXO1. Male C57BL/6 mice were exposed to PFOS at doses of 0.3, 1.0, and 3.0 mg/kg body weight for 12 weeks to assess its subchronic effects on hepatic glucolipid metabolism in this work. The results indicate that PFOS exposure increases hepatic acetylated FOXO1 expression, promotes liver lipid accumulation, suppresses gluconeogenesis, whereas fasting blood glucose levels remain unaffected but this dysregulation results in insulin resistance. Furthermore, hepatic deletion of FOXO1 in PFOS-exposed mice ameliorates liver injury and reduces lipid accumulation by suppressing hepatic autophagy without significantly affecting gluconeogenesis. In conclusion, FOXO1 may play a pivotal role in the development of PFOS-induced hepatic glucolipid metabolic disorder.
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Affiliation(s)
- Jing Yang
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China; Ningxia Hui Autonomous Region Center for Disease Control and Prevention, Yinchuan, 750001, PR China
| | - Longfei Li
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Ziwen An
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Yi Lv
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Ran Li
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Jing Li
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Mingmei Guo
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Heming Sun
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Huiling Yang
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Lei Wang
- Department of Medicinal Chemistry, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Yi Liu
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China.
| | - Huicai Guo
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, 050017, PR China; Hebei Key Laboratory of Environment and Human Health, Hebei Province, Shijiazhuang, 050017, PR China.
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7
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Samizu M, Iida K. Glucosamine Inhibits the Proliferation of Hepatocellular Carcinoma Cells by Eliciting Apoptosis, Autophagy, and the Anti-Warburg Effect. SCIENTIFICA 2025; 2025:5685884. [PMID: 39816727 PMCID: PMC11735062 DOI: 10.1155/sci5/5685884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 12/09/2024] [Indexed: 01/18/2025]
Abstract
Although glucosamine (GlcN) exhibits antitumor effects, its mechanism of action remains controversial. Additionally, its impact on hepatocellular carcinoma (HCC) is not well understood. This study aimed to investigate the antitumor effects of GlcN and its underlying mechanism in a mouse HCC cell line, Hepa1-6. GlcN treatment significantly inhibited Hepa1-6 cell proliferation. Gene expression analysis revealed that GlcN upregulated Chop and Bax while downregulating Bcl2, indicating the involvement of endoplasmic reticulum (ER) stress-induced apoptosis in the antiproliferative effects of GlcN. GlcN also increased the expression of FoxO1 and FoxO3, known tumor suppressors in various cancers. Furthermore, GlcN treatment elevated the levels of LC3II (an autophagy marker) and AMP-activated protein kinase activity, suggesting intracellular energy shortage. Indeed, GlcN treatment significantly suppressed glycolytic flux, lactate, and ATP production. Supplementing GlcN treatment with a high glucose concentration (20 mM) significantly attenuated its effect. We postulate that GlcN inhibits Hepa1-6 cell growth by inducing ER stress-induced apoptosis and autophagy and by inhibiting aerobic glycolysis (the Warburg effect), a key hallmark of cancer metabolism. Given that glucose transporter 2 (GLUT2), which is abundantly expressed in hepatocytes, has a high affinity for GlcN, these effects may result from GlcN competing with glucose for hepatocyte uptake by GLUT2. Our novel findings have potential implications for HCC treatment.
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Affiliation(s)
- Misako Samizu
- Department of Food and Nutritional Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo 1128610, Japan
| | - Kaoruko Iida
- Department of Food and Nutritional Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo 1128610, Japan
- Division of Nutritional Science, Institute of Human Life Science, Ochanomizu University, Tokyo 1128610, Japan
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8
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Wu H, Yang ASP, Stelloo S, Roos FJM, te Morsche RHM, Verkerk AH, Luna-Velez MV, Wingens L, de Wilt JHW, Sauerwein RW, Mulder KW, van Heeringen SJ, Verstegen MMA, van der Laan LJW, Marks H, Bártfai R. Multi-omics analysis reveals distinct gene regulatory mechanisms between primary and organoid-derived human hepatocytes. Dis Model Mech 2025; 18:dmm050883. [PMID: 39878507 PMCID: PMC11810045 DOI: 10.1242/dmm.050883] [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: 05/07/2024] [Accepted: 11/25/2024] [Indexed: 01/31/2025] Open
Abstract
Hepatic organoid cultures are a powerful model to study liver development and diseases in vitro. However, hepatocyte-like cells differentiated from these organoids remain immature compared to primary human hepatocytes (PHHs), which are the benchmark in the field. Here, we applied integrative single-cell transcriptome and chromatin accessibility analysis to reveal gene regulatory mechanisms underlying these differences. We found that, in mature human hepatocytes, activator protein 1 (AP-1) factors co-occupy regulatory regions with hepatocyte-specific transcription factors, including HNF4A, suggesting their potential cooperation in governing hepatic gene expression. Comparative analysis identified distinct transcription factor sets that are specifically active in either PHHs or intrahepatic cholangiocyte organoid (ICO)-derived human hepatocytes. ELF3 was one of the factors uniquely expressed in ICO-derived hepatocytes, and its expression negatively correlated with hepatic marker gene expression. Functional analysis further revealed that ELF3 depletion increased the expression of key hepatic markers in ICO-derived hepatocytes. Our integrative analysis provides insights into the transcriptional regulatory networks of PHHs and hepatic organoids, thereby informing future strategies for developing improved hepatic models.
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Affiliation(s)
- Haoyu Wu
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Annie S. P. Yang
- Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands
| | - Suzan Stelloo
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Oncode Institute, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Floris J. M. Roos
- Department of Surgery, Erasmus University Medical Center Transplant Institute, University Medical Center Rotterdam,Rotterdam 3000CA, TheNetherlands
| | - René H. M. te Morsche
- Department of Gastroenterology and Hepatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands
| | - Anne H. Verkerk
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Maria V. Luna-Velez
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Oncode Institute, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Laura Wingens
- Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Johannes H. W. de Wilt
- Department of Surgery, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands
| | - Robert W. Sauerwein
- Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen 6500HB, The Netherlands
| | - Klaas W. Mulder
- Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Simon J. van Heeringen
- Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Monique M. A. Verstegen
- Department of Surgery, Erasmus University Medical Center Transplant Institute, University Medical Center Rotterdam,Rotterdam 3000CA, TheNetherlands
| | - Luc J. W. van der Laan
- Department of Surgery, Erasmus University Medical Center Transplant Institute, University Medical Center Rotterdam,Rotterdam 3000CA, TheNetherlands
| | - Hendrik Marks
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
| | - Richárd Bártfai
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Science, Radboud University, Nijmegen 6525GA, The Netherlands
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Al Amaz S, Shahid MAH, Jha R, Mishra B. Prehatch thermal manipulation of embryos and posthatch baicalein supplementation increased liver metabolism, and muscle proliferation in broiler chickens. Poult Sci 2024; 103:104155. [PMID: 39216265 PMCID: PMC11402044 DOI: 10.1016/j.psj.2024.104155] [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: 05/24/2024] [Revised: 07/28/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
The exposure of broiler chickens to high ambient temperatures causes heat stress (HS), negatively affecting their health and production performance. To mitigate heat stress in broilers, various strategies, including dietary, managerial, and genetic interventions, have been extensively tested with varying degrees of efficacy. For sustainable broiler production, it is imperative to develop an innovative approach that effectively mitigates the adverse effects of HS. Our previous studies have provided valuable insights into the effects of prehatch embryonic thermal manipulation (TM) and posthatch baicalein supplementation on embryonic thermotolerance, metabolism, and posthatch growth performance. This follow-up study investigated the effect of these interventions on gluconeogenesis and lipid metabolism in the liver, as well as muscle proliferation and regeneration capacity in heat-stressed broiler chickens. A total of six-hundred fertile Cobb 500 eggs were incubated for 21 d. After candling, 238 eggs were subjected to TM at 38.5°C with 55% relative humidity (RH) from embryonic day (ED) 12 to 18. These eggs were transferred to the hatcher and kept at a standard temperature (37.5°C) from ED 19 to 21, while 236 eggs were incubated at a controlled temperature (37.5°C) till hatch. After hatching, 180 day-old chicks from both groups were raised in 36 pens treatment (n = 10 birds/pen, 6 replicates per treatment). The treatments were: 1) Control, 2) TM, 3) Control heat stress (CHS), 4) Thermal manipulation heat stress (TMHS), 5) Control heat stress supplement (CHSS), and 6) Thermal manipulation heat stress supplement (TMHSS). Baicalein was added to the treatment group diets starting from d 1. All birds were raised under the standard environment for 21 d, followed by chronic heat stress from d 22 to 35 (32-33 ⁰C for 8 h) in the CHS, TMHS, CHSS, and TMHSS groups. A thermoneutral (22-24⁰C) environment was maintained in the Control and TM groups. RH was constant (50 ± 5%) throughout the trial. In the liver, TM significantly increased (P < 0.05) IGF2 expression. Baicalein supplementation significantly increased (P < 0.05) HSF3, HSP70, SOD1, SOD2, TXN, PRARα, and GHR expression. Moreover, the combination of TM and baicalein supplementation significantly increased (P < 0.05) the expression of HSPH1, HSPB1, HSP90, LPL, and GHR. In the muscle, TM significantly increased (P < 0.05) HSF3 and Myf5 gene expression. TM and baicalein supplementation significantly increased (P < 0.05) the expression of MyoG and significantly (P < 0.05) decreased mTOR and PAX7. In conclusion, the prehatch TM of embryos and posthatch baicalein supplementation mitigated the deleterious effects of HS on broiler chickens by upregulating genes related to liver gluconeogenesis, lipid metabolism, and muscle proliferation.
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Affiliation(s)
- Sadid Al Amaz
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawai'i at Manoa, Honolulu, HI 96822
| | - Md Ahosanul Haque Shahid
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawai'i at Manoa, Honolulu, HI 96822
| | - Rajesh Jha
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawai'i at Manoa, Honolulu, HI 96822
| | - Birendra Mishra
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawai'i at Manoa, Honolulu, HI 96822.
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10
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Bhandari S, Kyrrestad I, Simón-Santamaría J, Li R, Szafranska KJ, Dumitriu G, Sánchez Romano J, Smedsrød B, Sørensen KK. Mouse liver sinusoidal endothelial cell responses to the glucocorticoid receptor agonist dexamethasone. Front Pharmacol 2024; 15:1377136. [PMID: 39439887 PMCID: PMC11494038 DOI: 10.3389/fphar.2024.1377136] [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: 01/26/2024] [Accepted: 09/13/2024] [Indexed: 10/25/2024] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) which make up the fenestrated wall of the hepatic sinusoids, are active scavenger cells involved in blood waste clearance and liver immune functions. Dexamethasone is a synthetic glucocorticoid commonly used in the clinic and as cell culture supplement. However, the response is dependent on tissue, cell type, and cell state. The aim of this study was to investigate the effect of dexamethasone on primary mouse LSECs (C57BL/6J); their viability (live-dead, LDH release, caspase 3/7 assays), morphology (scanning electron microscopy), release of inflammatory markers (ELISA), and scavenging functions (endocytosis assays), and associated biological processes and pathways. We have characterized and catalogued the proteome of LSECs cultured for 1, 10, or 48 h to elucidate time-dependent and dexamethasone-specific cell responses. More than 6,000 protein IDs were quantified using tandem mass tag technology and advanced mass spectrometry (synchronous precursor selection multi-notch MS3). Enrichment analysis showed a culture-induced upregulation of stress and inflammatory markers, and a significant shift in cell metabolism already at 10 h, with enhancement of glycolysis and concomitant repression of oxidative phosphorylation. At 48 h, changes in metabolic pathways were more pronounced with dexamethasone compared to time-matched controls. Dexamethasone repressed the activation of inflammatory pathways (IFN-gamma response, TNF-alpha signaling via NF-kB, Cell adhesion molecules), and culture-induced release of interleukin-6, VCAM-1, and ICAM-1, and improved cell viability partly through inhibition of apoptosis. The mouse LSECs did not proliferate in culture. Dexamethasone treated cells showed upregulation of xanthine dehydrogenase/oxidase (Xdh), and the transcription regulator Foxo1. The drug further delayed but did not block the culture-induced loss of LSEC fenestration. The LSEC capacity for endocytosis was significantly reduced at 48 h, independent of dexamethasone, which correlated with diminished expression of several scavenger receptors and C-type lectins and altered expression of proteins in the endocytic machinery. The glucocorticoid receptor (NR3C1) was suppressed by dexamethasone at 48 h, suggesting limited effect of the drug in prolonged LSEC culture. Conclusion: The study presents a detailed overview of biological processes and pathways affected by dexamethasone in mouse LSECs in vitro.
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11
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Lin HY, Lin CH, Kuo YH, Shih CC. Antidiabetic and Antihyperlipidemic Activities and Molecular Mechanisms of Phyllanthus emblica L. Extract in Mice on a High-Fat Diet. Curr Issues Mol Biol 2024; 46:10492-10529. [PMID: 39329975 PMCID: PMC11430370 DOI: 10.3390/cimb46090623] [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: 08/05/2024] [Revised: 09/09/2024] [Accepted: 09/11/2024] [Indexed: 09/28/2024] Open
Abstract
We planned to explore the protective activities of extract of Phyllanthus emblica L. (EPE) on insulin resistance and metabolic disorders including hyperlipidemia, visceral obesity, and renal dysfunction in high-fat diet (HFD)-progressed T2DM mice. Mice treatments included 7 weeks of HFD induction followed by EPE, fenofibrate (Feno), or metformin (Metf) treatment daily for another 4-week HFD in HFD-fed mice. Finally, we harvested blood to analyze some tests on circulating glycemia and blood lipid levels. Western blotting analysis was performed on target gene expressions in peripheral tissues. The present findings indicated that EPE treatment reversed the HFD-induced increases in blood glucose, glycosylated HbA1C, and insulin levels. Our findings proved that treatment with EPE in HFD mice effectively controls hyperglycemia and hyperinsulinemia. Our results showed that EPE reduced blood lipid levels, including a reduction in blood triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA); moreover, EPE reduced blood leptin levels and enhanced adiponectin concentrations. EPE treatment in HFD mice reduced BUN and creatinine in both blood and urine and lowered albumin levels in urine; moreover, EPE decreased circulating concentrations of inflammatory NLR family pyrin domain containing 3 (NLRP3) and kidney injury molecule-1 (KIM-1). These results indicated that EPE displayed antihyperglycemic and antihyperlipidemic activities but alleviated renal dysfunction in HFD mice. The histology examinations indicated that EPE treatment decreased adipose hypertrophy and hepatic ballooning, thus contributing to amelioration of lipid accumulation. EPE treatment decreased visceral fat amounts and led to improved systemic insulin resistance. For target gene expression levels, EPE enhanced AMP-activated protein kinase (AMPK) phosphorylation expressions both in livers and skeletal muscles and elevated the muscular membrane glucose transporter 4 (GLUT4) expressions. Treatment with EPE reduced hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expressions to suppress glucose production in the livers and decreased phosphorylation of glycogen synthase kinase 3β (GSK3β) expressions to affect hepatic glycogen synthesis, thus convergently contributing to an antidiabetic effect and improving insulin resistance. The mechanism of the antihyperlipidemic activity of EPE involved a decrease in the hepatic phosphorylation of mammalian target of rapamycin complex C1 (mTORC1) and p70 S6 kinase 1 (S6K1) expressions to improve insulin resistance but also a reduction in hepatic sterol regulatory element binding protein (SREBP)-1c expressions, and suppression of ACC activity, thus resulting in the decreased fatty acid synthesis but elevated hepatic peroxisome proliferator-activated receptor (PPAR) α and SREBP-2 expressions, resulting in lowering TG and TC concentrations. Our results demonstrated that EPE improves insulin resistance and ameliorates hyperlipidemia in HFD mice.
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Affiliation(s)
- Hsing-Yi Lin
- Department of Internal Medicine, Cheng Ching Hospital, No. 139, Pingdeng St., Central District, Taichung City 40045, Taiwan
| | - Cheng-Hsiu Lin
- Department of Internal Medicine, Fengyuan Hospital, Ministry of Health and Welfare, Fengyuan District, Taichung City 42055, Taiwan
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung City 40402, Taiwan
| | - Chun-Ching Shih
- Department of Nursing, College of Nursing, Central Taiwan University of Science and Technology, No. 666 Buzih Road, Beitun District, Taichung City 40601, Taiwan
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12
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Friedline RH, Noh HL, Suk S, Albusharif M, Dagdeviren S, Saengnipanthkul S, Kim B, Kim AM, Kim LH, Tauer LA, Baez Torres NM, Choi S, Kim BY, Rao SD, Kasina K, Sun C, Toles BJ, Zhou C, Li Z, Benoit VM, Patel PR, Zheng DXT, Inashima K, Beaverson A, Hu X, Tran DA, Muller W, Greiner DL, Mullen AC, Lee KW, Kim JK. IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease. Nat Commun 2024; 15:5506. [PMID: 38951527 PMCID: PMC11217362 DOI: 10.1038/s41467-024-49633-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 06/13/2024] [Indexed: 07/03/2024] Open
Abstract
Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.
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Affiliation(s)
- Randall H Friedline
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Hye Lim Noh
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Sujin Suk
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- WCU Biomodulation Major, Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea
| | - Mahaa Albusharif
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Sezin Dagdeviren
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Suchaorn Saengnipanthkul
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Division of Nutrition, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Bukyung Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kosin University College of Medicine, Busan, Republic of Korea
| | - Allison M Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Lauren H Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Lauren A Tauer
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Natalie M Baez Torres
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Stephanie Choi
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Bo-Yeon Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
| | - Suryateja D Rao
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Kaushal Kasina
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Cheng Sun
- Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Benjamin J Toles
- Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Chan Zhou
- Division of Biostatistics and Health Services Research, Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Zixiu Li
- Division of Biostatistics and Health Services Research, Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Vivian M Benoit
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Payal R Patel
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Doris X T Zheng
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Kunikazu Inashima
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Annika Beaverson
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Xiaodi Hu
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Duy A Tran
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Werner Muller
- Division of Infection, Immunity & Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
| | - Dale L Greiner
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Alan C Mullen
- Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Ki Won Lee
- WCU Biomodulation Major, Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea
- XO Center, Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea
| | - Jason K Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
- WCU Biomodulation Major, Department of Agricultural Biotechnology, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea.
- Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA.
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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13
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Mesmar F, Muhsen M, Farooq I, Maxey G, Tourigny JP, Tennessen J, Bondesson M. Exposure to the pesticide tefluthrin causes developmental neurotoxicity in zebrafish. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.28.596249. [PMID: 38854095 PMCID: PMC11160659 DOI: 10.1101/2024.05.28.596249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
BACKGROUND The insecticide tefluthrin is widely used in agriculture, resulting in widespread pollution. Tefluthrin is a type I pyrethroid characterized by its high persistence in the environment. Understanding the mechanisms of toxicity of tefluthrin will improve its risk assessment. OBJECTIVES We aimed to decipher the molecular modes of action of tefluthrin. METHODS Phenotypic developmental toxicity was assessed by exposing zebrafish embryos and larvae to increasing concentrations of tefluthrin. Tg(mnx:mGFP) line was used to assess neurotoxicity. Multi-omics approaches including transcriptomics and lipidomics were applied to analyze RNA and lipid contents, respectively. Finally, an in-silico ligand-protein docking computational method was used to study a possible interaction between tefluthrin and a protein target. RESULTS Tefluthrin exposure caused severe morphological malformations in zebrafish larvae, including motor neuron abnormalities. The differentially expressed genes were associated with neurotoxicity and metabolic disruption. Lipidomics analysis revealed a disruption in fatty acid, phospholipid, and lysophospholipid recycling. Protein docking modeling suggested that the LPCAT3 enzyme, which recycles lysophospholipids in the Land's cycle, directly interacts with tefluthrin. CONCLUSIONS Tefluthrin exposure causes morphological and neuronal malformations in zebrafish larvae at nanomolar concentrations. Multi-omics results revealed a potential molecular initiating event i.e., inhibition of LPCAT3, and key events i.e., an altered lysophospholipid to phospholipid ratio, leading to the adverse outcomes of neurotoxicity and metabolic disruption.
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14
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Habtemariam S. Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane. Biomedicines 2024; 12:1169. [PMID: 38927376 PMCID: PMC11200786 DOI: 10.3390/biomedicines12061169] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Isothiocyanates (ITCs) belong to a group of natural products that possess a highly reactive electrophilic -N=C=S functional group. They are stored in plants as precursor molecules, glucosinolates, which are processed by the tyrosinase enzyme upon plant tissue damage to release ITCs, along with other products. Isolated from broccoli, sulforaphane is by far the most studied antioxidant ITC, acting primarily through the induction of a transcription factor, the nuclear factor erythroid 2-related factor 2 (Nrf2), which upregulates downstream antioxidant genes/proteins. Paradoxically, sulforaphane, as a pro-oxidant compound, can also increase the levels of reactive oxygen species, a mechanism which is attributed to its anticancer effect. Beyond highlighting the common pro-oxidant and antioxidant effects of sulforaphane, the present paper was designed to assess the diverse anti-inflammatory mechanisms reported to date using a variety of in vitro and in vivo experimental models. Sulforaphane downregulates the expression of pro-inflammatory cytokines, chemokines, adhesion molecules, cycloxyhenase-2, and inducible nitric oxide synthase. The signalling pathways of nuclear factor κB, activator protein 1, sirtuins 1, silent information regulator sirtuin 1 and 3, and microRNAs are among those affected by sulforaphane. These anti-inflammatory actions are sometimes due to direct action via interaction with the sulfhydryl structural moiety of cysteine residues in enzymes/proteins. The following are among the topics discussed in this paper: paradoxical signalling pathways such as the immunosuppressant or immunostimulant mechanisms; crosstalk between the oxidative and inflammatory pathways; and effects dependent on health and disease states.
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Affiliation(s)
- Solomon Habtemariam
- Pharmacognosy Research & Herbal Analysis Services UK, University of Greenwich, Central Avenue, Chatham-Maritime, Kent ME4 4TB, UK
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15
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Amaz SA, Shahid MAH, Chaudhary A, Jha R, Mishra B. Embryonic thermal manipulation reduces hatch time, increases hatchability, thermotolerance, and liver metabolism in broiler embryos. Poult Sci 2024; 103:103527. [PMID: 38412748 PMCID: PMC10907853 DOI: 10.1016/j.psj.2024.103527] [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: 08/28/2023] [Revised: 01/26/2024] [Accepted: 01/28/2024] [Indexed: 02/29/2024] Open
Abstract
The broilers' health and growth performance are affected by egg quality, incubation conditions, and posthatch management. Broilers are more susceptible to heat stress because they have poor thermoregulatory capacity. So, it is crucial to develop a strategy to make chicks thermotolerant and cope with heat stress in post-hatch life. This study investigated the effects of embryonic thermal manipulation (TM) on different hatching parameters (hatch time, hatchability, and hatch weight), brain thermotolerance, and liver metabolism. Six hundred fertile Cobb 500 eggs were incubated for 21 d. After candling on embryonic day (ED) 10, 238 eggs were thermally manipulated at 38.5°C with 55% relative humidity (RH) from ED 12 to 18, then transferred to the hatcher (ED 19-21, standard temperature, 37.5°C) and 236 eggs were incubated at a standard temperature (37.5°C) till hatch. The samples were collected from the Control and TM groups on ED 15 and 18 of the embryonic periods. Hatchability was significantly higher (P < 0.05) in the TM group (94.50%) than in the control group (91.0%). Hatch weight did not differ significantly between the TM group (50.54 g) and the Control group (50.39 g). Most importantly, hatch time was significantly lower (P < 0.05) in the TM group than in the Control. In the D15 embryo brain, the mRNA expression of TRPV1,TRPV2, TRPV3, and the epigenetic marker H3K27 were significantly lower (P < 0.05) in the TM group compared to the Control group. However, in the D18 brain, the expression of TRPV1, TRPV2, and CRHR1 was significantly higher (P < 0.05) in the TM group than in the Control group. In the liver, the mRNA expression of SLC6A14 was significantly lower (P < 0.05) in the D15 TM group than in the D15 Control group. Conversely, the DIO3 mRNA expression was significantly higher (P < 0.05) in the D15 TM group than in the D15 Control group. The expression of GPX3, FOXO1, IGF2, and GHR in the liver was significantly higher in the D18 TM group compared to the D18 Control group (P < 0.05). In conclusion, increased expression of the aforementioned markers during the later embryonic period has been linked to reduced hatch time by increasing liver metabolism and thermotolerance capacity in the brain.
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Affiliation(s)
- Sadid Al Amaz
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, Hawaii, 96822
| | - Md Ahosanul Haque Shahid
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, Hawaii, 96822
| | - Ajay Chaudhary
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, Hawaii, 96822
| | - Rajesh Jha
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, Hawaii, 96822
| | - Birendra Mishra
- Department of Human Nutrition, Food and Animal Sciences, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, Hawaii, 96822.
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16
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Manoharan S, Prajapati K, Perumal E. Natural bioactive compounds and FOXO3a in cancer therapeutics: An update. Fitoterapia 2024; 173:105807. [PMID: 38168566 DOI: 10.1016/j.fitote.2023.105807] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 12/14/2023] [Accepted: 12/29/2023] [Indexed: 01/05/2024]
Abstract
Forkhead box protein 3a (FOXO3a) is a transcription factor that regulates various downstream targets upon its activation, leading to the upregulation of tumor suppressor and apoptotic pathways. Hence, targeting FOXO3a is an emerging strategy for cancer prevention and treatment. Recently, Natural Bioactive Compounds (NBCs) have been used in drug discovery for treating various disorders including cancer. Notably, several NBCs have been shown as potent FOXO3a activators. NBCs upregulate FOXO3a expressions through PI3K/Akt, MEK/ERK, AMPK, and IκB signaling pathways. FOXO3a promotes its anticancer effects by upregulating the levels of its downstream targets, including Bim, FasL, and Bax, leading to apoptosis. This review focuses on the dysregulation of FOXO3a in carcinogenesis and explores the potent FOXO3a activating NBCs for cancer prevention and treatment. Additionally, the review evaluates the safety and efficacy of NBCs. Looking ahead, NBCs are anticipated to become a cost-effective, potent, and safer therapeutic option for cancer, making them a focal point of research in the field of cancer prevention and treatment.
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Affiliation(s)
- Suryaa Manoharan
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, India
| | - Kunjkumar Prajapati
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, India
| | - Ekambaram Perumal
- Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, India.
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Abdelhady R, Mohammed OA, Doghish AS, Hamad RS, Abdel-Reheim MA, Alamri MMS, Alharthi MH, Alfaifi J, Adam MIE, Alhalafi AH, Mohammed NA, Isa AI, Abdel-Ghany S, Attia MA, Elmorsy EA, Al-Noshokaty TM, Nomier Y, El-Dakroury WA, Saber S. Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights. FASEB J 2024; 38:e23480. [PMID: 38354025 DOI: 10.1096/fj.202302461rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/17/2024] [Accepted: 01/26/2024] [Indexed: 02/16/2024]
Abstract
Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.
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Affiliation(s)
- Rasha Abdelhady
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Egypt
| | - Rabab S Hamad
- Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, Saudi Arabia
- Central Laboratory, Theodor Bilharz Research Institute, Giza, Egypt
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Aldawadmi, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt
| | - Mohannad Mohammad S Alamri
- Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Muffarah Hamid Alharthi
- Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Jaber Alfaifi
- Department of Child Health, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Masoud I E Adam
- Department of Medical Education and Internal Medicine, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Abdullah Hassan Alhalafi
- Department of Family and Community Medicine, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Nahid A Mohammed
- Department of Physiology Unit, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Adamu Imam Isa
- Department of Physiology Unit, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Sameh Abdel-Ghany
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohammed A Attia
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia
| | - Elsayed A Elmorsy
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | | | - Yousra Nomier
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Al-khod, Sultanate of Oman
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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18
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Lee J, Hong SW, Kim MJ, Lim YM, Moon SJ, Kwon H, Park SE, Rhee EJ, Lee WY. Inhibition of Sodium-Glucose Cotransporter-2 during Serum Deprivation Increases Hepatic Gluconeogenesis via the AMPK/AKT/FOXO Signaling Pathway. Endocrinol Metab (Seoul) 2024; 39:98-108. [PMID: 38171209 PMCID: PMC10901661 DOI: 10.3803/enm.2023.1786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/25/2023] [Accepted: 10/17/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGRUOUND Sodium-dependent glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in the renal proximal tubules, and SGLT2 inhibitors are used as therapeutic agents for treating type 2 diabetes mellitus. This study aimed to elucidate the effects and mechanisms of SGLT2 inhibition on hepatic glucose metabolism in both serum deprivation and serum supplementation states. METHODS Huh7 cells were treated with the SGLT2 inhibitors empagliflozin and dapagliflozin to examine the effect of SGLT2 on hepatic glucose uptake. To examine the modulation of glucose metabolism by SGLT2 inhibition under serum deprivation and serum supplementation conditions, HepG2 cells were transfected with SGLT2 small interfering RNA (siRNA), cultured in serum-free Dulbecco's modified Eagle's medium for 16 hours, and then cultured in media supplemented with or without 10% fetal bovine serum for 8 hours. RESULTS SGLT2 inhibitors dose-dependently decreased hepatic glucose uptake. Serum deprivation increased the expression levels of the gluconeogenesis genes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), glucose 6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (PEPCK), and their expression levels during serum deprivation were further increased in cells transfected with SGLT2 siRNA. SGLT2 inhibition by siRNA during serum deprivation induces nuclear localization of the transcription factor forkhead box class O 1 (FOXO1), decreases nuclear phosphorylated-AKT (p-AKT), and p-FOXO1 protein expression, and increases phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK) protein expression. However, treatment with the AMPK inhibitor, compound C, reversed the reduction in the protein expression levels of nuclear p- AKT and p-FOXO1 and decreased the protein expression levels of p-AMPK and PEPCK in cells transfected with SGLT2 siRNA during serum deprivation. CONCLUSION These data show that SGLT2 mediates glucose uptake in hepatocytes and that SGLT2 inhibition during serum deprivation increases gluconeogenesis via the AMPK/AKT/FOXO1 signaling pathway.
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Affiliation(s)
- Jinmi Lee
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seok-Woo Hong
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min-Jeong Kim
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yu-Mi Lim
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sun Joon Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyemi Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Eun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun-Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won-Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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19
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Ebrahimnezhad M, Natami M, Bakhtiari GH, Tabnak P, Ebrahimnezhad N, Yousefi B, Majidinia M. FOXO1, a tiny protein with intricate interactions: Promising therapeutic candidate in lung cancer. Biomed Pharmacother 2023; 169:115900. [PMID: 37981461 DOI: 10.1016/j.biopha.2023.115900] [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: 07/24/2023] [Revised: 11/08/2023] [Accepted: 11/14/2023] [Indexed: 11/21/2023] Open
Abstract
Nowadays, lung cancer is the most common cause of cancer-related deaths in both men and women globally. Despite the development of extremely efficient targeted agents, lung cancer progression and drug resistance remain serious clinical issues. Increasing knowledge of the molecular mechanisms underlying progression and drug resistance will enable the development of novel therapeutic methods. It has been revealed that transcription factors (TF) dysregulation, which results in considerable expression modifications of genes, is a generally prevalent phenomenon regarding human malignancies. The forkhead box O1 (FOXO1), a member of the forkhead transcription factor family with crucial roles in cell fate decisions, is suggested to play a pivotal role as a tumor suppressor in a variety of malignancies, especially in lung cancer. FOXO1 is involved in diverse cellular processes and also has clinical significance consisting of cell cycle arrest, apoptosis, DNA repair, oxidative stress, cancer prevention, treatment, and chemo/radioresistance. Based on the critical role of FOXO1, this transcription factor appears to be an appropriate target for future drug discovery in lung cancers. This review focused on the signaling pathways, and molecular mechanisms involved in FOXO1 regulation in lung cancer. We also discuss pharmacological compounds that are currently being administered for lung cancer treatment by affecting FOXO1 and also point out the essential role of FOXO1 in drug resistance. Future preclinical research should assess combination drug strategies to stimulate FOXO1 and its upstream regulators as potential strategies to treat resistant or advanced lung cancers.
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Affiliation(s)
- Mohammad Ebrahimnezhad
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Natami
- Department of Urology,Shahid Mohammadi Hospital, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | | | - Peyman Tabnak
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Ebrahimnezhad
- Department of Microbiology, Faculty of Basic Science, Urmia Branch, Islamic Azad University, Urmia, Iran
| | - Bahman Yousefi
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran.
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20
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Bellanti F, Mangieri D, Vendemiale G. Redox Biology and Liver Fibrosis. Int J Mol Sci 2023; 25:410. [PMID: 38203581 PMCID: PMC10778611 DOI: 10.3390/ijms25010410] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatic fibrosis is a complex process that develops in chronic liver diseases. Even though the initiation and progression of fibrosis rely on the underlying etiology, mutual mechanisms can be recognized and targeted for therapeutic purposes. Irrespective of the primary cause of liver disease, persistent damage to parenchymal cells triggers the overproduction of reactive species, with the consequent disruption of redox balance. Reactive species are important mediators for the homeostasis of both hepatocytes and non-parenchymal liver cells. Indeed, other than acting as cytotoxic agents, reactive species are able to modulate specific signaling pathways that may be relevant to hepatic fibrogenesis. After a brief introduction to redox biology and the mechanisms of fibrogenesis, this review aims to summarize the current evidence of the involvement of redox-dependent pathways in liver fibrosis and focuses on possible therapeutic targets.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Domenica Mangieri
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
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21
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Yan H, Ding M, Peng T, Zhang P, Tian R, Zheng L. Regular Exercise Modulates the dfoxo/ dsrebp Pathway to Alleviate High-Fat-Diet-Induced Obesity and Cardiac Dysfunction in Drosophila. Int J Mol Sci 2023; 24:15562. [PMID: 37958546 PMCID: PMC10650635 DOI: 10.3390/ijms242115562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/22/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Obesity is a prevalent metabolic disorder associated with various diseases, including cardiovascular conditions. While exercise is recognized as an effective approach for preventing and treating obesity, its underlying molecular mechanisms remain unclear. This study aimed to explore the impact of regular exercise on high-fat-diet-induced obesity and cardiac dysfunction in Drosophila, shedding light on its molecular mechanisms by identifying its regulation of the dfoxo and dsrebp signaling pathways. Our findings demonstrated that a high-fat diet leads to weight gain, fat accumulation, reduced climbing performance, and elevated triglyceride levels in Drosophila. Additionally, cardiac microfilaments in these flies exhibited irregularities, breakages, and shortening. M-mode analysis revealed that high-fat-diet-fed Drosophila displayed increased heart rates, shortened cardiac cycles, decreased systolic intervals, heightened arrhythmia indices, reduced diastolic diameters, and diminished fractional shortening. Remarkably, regular exercise effectively ameliorated these adverse outcomes. Further analysis showed that regular exercise reduced fat synthesis, promoted lipolysis, and mitigated high-fat-diet-induced cardiac dysfunction in Drosophila. These results suggest that regular exercise may mitigate high-fat-diet-induced obesity and cardiac dysfunction in Drosophila by regulating the dfoxo and dsrebp signaling pathways, offering valuable insights into the mechanisms underlying the beneficial effects of exercise on obesity and cardiac dysfunction induced by a high-fat diet.
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Affiliation(s)
| | | | | | | | | | - Lan Zheng
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, College of Physical Education, Hunan Normal University, Changsha 410012, China; (H.Y.); (M.D.); (T.P.); (P.Z.); (R.T.)
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22
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Miao G, Wang Y, Wang B, Yu H, Liu J, Pan R, Zhou C, Ning J, Zheng Y, Zhang R, Jin X. Multi-omics analysis reveals hepatic lipid metabolism profiles and serum lipid biomarkers upon indoor relevant VOC exposure. ENVIRONMENT INTERNATIONAL 2023; 180:108221. [PMID: 37742460 DOI: 10.1016/j.envint.2023.108221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/01/2023] [Accepted: 09/18/2023] [Indexed: 09/26/2023]
Abstract
As a widespread indoor air pollutant, volatile organic compound (VOC) caused various adverse health effects, especial the damage to liver, which has become a growing public concern. However, the current toxic data are intrinsically restricted in the single or major VOC species. Limited knowledge is available regarding toxic effects, biomarkers and underlying mechanisms of real indoor VOC-caused liver damage. Herein, an indoor relevant VOC exposure model was established to evaluate the hepatic adverse outcomes. Machine learning and multi-omics approaches, including liver lipidomic, serum lipidomic and liver transcriptomic, were utilized to uncover the characteristics of liver damage, serum lipid biomarkers, and involved mechanism stimulated by VOC exposure. The result showed that indoor relevant VOC led to the abnormal hepatic lipid metabolism, mainly manifested as a decrease in triacylglycerol (TG) and its precursor substance diacylglycerol (DG), which could be contributed to the occurrence of hepatic adverse outcomes. In terms of serum lipid biomarkers, five lipid biomarkers in serum were uncovered using machine learning to reflect the hepatic lipid disorders induced by VOC. Multi-omics approaches revealed that the upregulated Dgkq disturbed the interconversion of DG and phosphatidic acid (PA), leading to a TG downregulation. The in-depth analysis revealed that VOC down-regulated FoxO transcription factor, contributing to the upregulation of Dgkq. Hence, this study can provide valuable insights into the understanding of liver damage caused by indoor relevant VOC exposure model VOC exposure, from the perspective of multi-omics analysis.
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Affiliation(s)
- Gan Miao
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China
| | - Yu Wang
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China
| | - Baoqiang Wang
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China
| | - Hongyan Yu
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China
| | - Jing Liu
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China
| | - Ruonan Pan
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China
| | - Chengying Zhou
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China
| | - Jie Ning
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China
| | - Yuxin Zheng
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China
| | - Rong Zhang
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang, China.
| | - Xiaoting Jin
- Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University, Qingdao, China.
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23
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Chen Y, Pan Q, Liao W, Ai W, Yang S, Guo S. Transcription Factor Forkhead Box O1 Mediates Transforming Growth Factor-β1-Induced Apoptosis in Hepatocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1143-1155. [PMID: 37263346 PMCID: PMC10477955 DOI: 10.1016/j.ajpath.2023.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/27/2023] [Accepted: 05/18/2023] [Indexed: 06/03/2023]
Abstract
Dysregulation of hepatocyte apoptosis is associated with several types of chronic liver diseases. Transforming growth factor-β1 (TGF-β1) is a well-known pro-apoptotic factor in the liver, which constitutes a receptor complex composed of TGF-β receptor I and II, along with transcription factor Smad proteins. As a member of the forkhead box O (Foxo) class of transcription factors, Foxo1 is a predominant regulator of hepatic glucose production and apoptosis. This study investigated the potential relationship between TGF-β1 signaling and Foxo1 in control of apoptosis in hepatocytes. TGF-β1 induced hepatocyte apoptosis in a Foxo1-dependent manner in hepatocytes isolated from both wild-type and liver-specific Foxo1 knockout mice. TGF-β1 activated protein kinase A through TGF-β receptor I-Smad3, followed by phosphorylation of Foxo1 at Ser273 in promotion of apoptosis in hepatocytes. Moreover, Smad3 overexpression in the liver of mice promoted the levels of phosphorylated Foxo1-S273, total Foxo1, and a Foxo1-target pro-apoptotic gene Bim, which eventually resulted in hepatocyte apoptosis. The study further demonstrated a crucial role of Foxo1-S273 phosphorylation in the pro-apoptotic effect of TGF-β1 by using hepatocytes isolated from Foxo1-S273A/A knock-in mice, in which the phosphorylation of Foxo1-S273 was disrupted. Taken together, this study established a novel role of TGF-β1→protein kinase A→Foxo1 signaling cascades in control of hepatocyte survival.
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Affiliation(s)
- Yunmei Chen
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Quan Pan
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Wang Liao
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Weiqi Ai
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Sijun Yang
- Institute of Animal Model for Human Disease, Wuhan University, Wuhan, China
| | - Shaodong Guo
- Department of Nutrition, Texas A&M University, College Station, Texas.
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24
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Barreda-Sánchez M, Guillén-Navarro E. [From basic research to clinical practice: RNA interference]. Med Clin (Barc) 2023; 159 Suppl 1:S33-S37. [PMID: 37827889 DOI: 10.1016/j.medcli.2023.05.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 10/14/2023]
Affiliation(s)
- María Barreda-Sánchez
- Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), Murcia, España; Universidad Católica San Antonio de Murcia (UCAM), Murcia, España
| | - Encarna Guillén-Navarro
- Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), Murcia, España; Sección de Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, España; Departamento de Pediatría, Facultad de Medicina, Universidad de Murcia, Campus de Ciencias de la Salud, Murcia, España; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, España.
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25
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Peluso T, Nittoli V, Reale C, Porreca I, Russo F, Roberto L, Giacco A, Silvestri E, Mallardo M, De Felice M, Ambrosino C. Chronic Exposure to Chlorpyrifos Damages Thyroid Activity and Imbalances Hepatic Thyroid Hormones Signaling and Glucose Metabolism: Dependency of T3-FOXO1 Axis by Hyperglycemia. Int J Mol Sci 2023; 24:ijms24119582. [PMID: 37298533 DOI: 10.3390/ijms24119582] [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: 03/02/2023] [Revised: 05/08/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Early life exposure to Endocrine Disruptor Chemicals (EDCs), such as the organophosphate pesticide Chlorpyrifos (CPF), affects the thyroid activity and dependent process, including the glucose metabolism. The damage of thyroid hormones (THs) as a mechanism of action of CPF is underestimated because the studies rarely consider that TH levels and signaling are customized peripherally. Here, we investigated the impairment of metabolism/signaling of THs and lipid/glucose metabolism in the livers of 6-month-old mice, developmentally and lifelong exposed to 0.1, 1, and 10 mg/kg/die CPF (F1) and their offspring similarly exposed (F2), analyzing the levels of transcripts of the enzymes involved in the metabolism of T3 (Dio1), lipids (Fasn, Acc1), and glucose (G6pase, Pck1). Both processes were altered only in F2 males, affected by hypothyroidism and by a systemic hyperglycemia linked to the activation of gluconeogenesis in mice exposed to 1 and 10 mg/kg/die CPF. Interestingly, we observed an increase in active FOXO1 protein due to a decrease in AKT phosphorylation, despite insulin signaling activation. Experiments in vitro revealed that chronic exposure to CPF affected glucose metabolism via the direct modulation of FOXO1 activity and T3 levels in hepatic cells. In conclusion, we described different sex and intergenerational effects of CPF exposure on the hepatic homeostasis of THs, their signaling, and, finally, glucose metabolism. The data points to FOXO1-T3-glucose signaling as a target of CPF in liver.
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Affiliation(s)
- Teresa Peluso
- Department of Science and Technology, University of Sannio, Via de Sanctis, 82100 Benevento, Italy
- Biogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Valeria Nittoli
- Biogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Carla Reale
- Biogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Immacolata Porreca
- Biogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Filomena Russo
- Biogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Luca Roberto
- Biogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Antonia Giacco
- Department of Science and Technology, University of Sannio, Via de Sanctis, 82100 Benevento, Italy
| | - Elena Silvestri
- Department of Science and Technology, University of Sannio, Via de Sanctis, 82100 Benevento, Italy
| | - Massimo Mallardo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy
| | - Mario De Felice
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Via Pansini 6, 80131 Naples, Italy
| | - Concetta Ambrosino
- Department of Science and Technology, University of Sannio, Via de Sanctis, 82100 Benevento, Italy
- Biogem Scarl, Institute of Molecular Biology and Genetics Research, Via Camporeale, 83031 Ariano Irpino, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), CNR, Via Pansini 6, 80131 Naples, Italy
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26
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Moore XTR, Gheghiani L, Fu Z. The Role of Polo-Like Kinase 1 in Regulating the Forkhead Box Family Transcription Factors. Cells 2023; 12:cells12091344. [PMID: 37174744 PMCID: PMC10177174 DOI: 10.3390/cells12091344] [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: 03/28/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Polo-like kinase 1 (PLK1) is a serine/threonine kinase with more than 600 phosphorylation substrates through which it regulates many biological processes, including mitosis, apoptosis, metabolism, RNA processing, vesicle transport, and G2 DNA-damage checkpoint recovery, among others. Among the many PLK1 targets are members of the FOX family of transcription factors (FOX TFs), including FOXM1, FOXO1, FOXO3, and FOXK1. FOXM1 and FOXK1 have critical oncogenic roles in cancer through their antagonism of apoptotic signals and their promotion of cell proliferation, metastasis, angiogenesis, and therapeutic resistance. In contrast, FOXO1 and FOXO3 have been identified to have broad functions in maintaining cellular homeostasis. In this review, we discuss PLK1-mediated regulation of FOX TFs, highlighting the effects of PLK1 on the activity and stability of these proteins. In addition, we review the prognostic and clinical significance of these proteins in human cancers and, more importantly, the different approaches that have been used to disrupt PLK1 and FOX TF-mediated signaling networks. Furthermore, we discuss the therapeutic potential of targeting PLK1-regulated FOX TFs in human cancers.
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Affiliation(s)
- Xavier T R Moore
- Department of Biology, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Lilia Gheghiani
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Zheng Fu
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
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Kumar V, Sethi B, Staller DW, Xin X, Ma J, Dong Y, Talmon GA, Mahato RI. Anti-miR-96 and Hh pathway inhibitor MDB5 synergistically ameliorate alcohol-associated liver injury in mice. Biomaterials 2023; 295:122049. [PMID: 36827892 PMCID: PMC9998370 DOI: 10.1016/j.biomaterials.2023.122049] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 02/06/2023] [Accepted: 02/11/2023] [Indexed: 02/19/2023]
Abstract
Alcohol-associated liver disease (ALD) and its complications are significant health problems worldwide. Several pathways in ALD are influenced by alcohol that drives inflammation, fatty acid metabolism, and fibrosis. Although miR-96 has become a key regulator in several liver diseases, its function in ALD remains unclear. In contrast, sonic hedgehog (SHH) signaling has a well-defined role in liver disease through influencing the activation of hepatic stellate cells (HSCs) and the inducement of liver fibrosis. In this study, we investigated the expression patterns of miR-96 and Hh molecules in mouse and human liver samples. We showed that miR-96 and Shh were upregulated in ethanol-fed mice. Furthermore, alcoholic hepatitis (AH) patient specimens also showed upregulated FOXO3a, TGF-β1, SHH, and GLI2 proteins. We then examined the effects of Hh inhibitor MDB5 and anti-miR-96 on inflammatory and extracellular matrix (ECM)-related genes. We identified FOXO3 and SMAD7 as direct target genes of miR-96. Inhibition of miR-96 decreased the expression of these genes in vitro in AML12 cells, HSC-T6 cells, and in vivo in ALD mice. Furthermore, MDB5 decreased HSCs activation and the expression of ECM-related genes, such as Gli1, Tgf-β1, and collagen. Lipid nanoparticles (LNPs) loaded with the combination of MDB5, and anti-miR-96 ameliorated ALD in mice. Our study demonstrated that this combination therapy could serve as a new therapeutic target for ALD.
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Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Bharti Sethi
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Dalton W Staller
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Xiaofei Xin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jingyi Ma
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yuxiang Dong
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Geoffrey A Talmon
- Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA; Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.
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Obukhova L, Kopytova T, Murach E, Shchelchkova N, Kontorshchikova C, Medyanik I, Orlinskaya N, Grishin A, Kontorshchikov M, Badanina D. Glutathione and Its Metabolic Enzymes in Gliomal Tumor Tissue and the Peritumoral Zone at Different Degrees of Anaplasia. Curr Issues Mol Biol 2022; 44:6439-6449. [PMID: 36547100 PMCID: PMC9777065 DOI: 10.3390/cimb44120439] [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: 11/07/2022] [Revised: 12/10/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
This research was aimed at investigating the features of free radical activity and the parameters of glutathione metabolism in tumor tissues and the peritumoral zone at different degrees of glial tumor anaplasia. We analyzed postoperative material from 20 patients with gliomas of different degrees of anaplasia. The greatest differences compared to adjacent noncancerous tissues were found in the tumor tissue: an increased amount of glutathione and glutathione-related enzymes at Grades I and II, and a decrease of these parameters at Grades III and IV. For the peritumoral zone of Grades I and II, the indices changed in different directions, while for Grades III and IV, they occurred synchronously with the tumor tissue changes. For Low Grade and High Grade gliomas, opposite trends were revealed regarding changes in the level of glutathione and the enzymes involved in its metabolism and in the free radical activity in the peritumoral zone. The content of glutathione and the enzymes involved in its metabolism decreased with the increasing degree of glioma anaplasia. In contrast, free radical activity increased. The glutathione system is an active participant in the antioxidant defense of the body and can be used to characterize the cell condition of gliomas at different stages of tumor development.
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Role of FOXO3a Transcription Factor in the Regulation of Liver Oxidative Injury. Antioxidants (Basel) 2022; 11:antiox11122478. [PMID: 36552685 PMCID: PMC9774119 DOI: 10.3390/antiox11122478] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Oxidative stress has been identified as a key mechanism in liver damage caused by various chemicals. The transcription factor FOXO3a has emerged as a critical regulator of redox imbalance. Multiple post-translational changes and epigenetic processes closely regulate the activity of FOXO3a, resulting in synergistic or competing impacts on its subcellular localization, stability, protein-protein interactions, DNA binding affinity, and transcriptional programs. Depending on the chemical nature and subcellular context, the oxidative-stress-mediated activation of FOXO3a can induce multiple transcriptional programs that play crucial roles in oxidative injury to the liver by chemicals. Here, we mainly review the role of FOXO3a in coordinating programs of genes that are essential for cellular homeostasis, with an emphasis on exploring the regulatory mechanisms and potential application of FOXO3a as a therapeutic target to prevent and treat liver oxidative injury.
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Obukhova L, Kopytova T, Murach E, Shchelchkova N, Kontorshchikova C, Medyanik I, Orlinskaya N, Grishin A, Kontorshchikov M, Badanina D. Relationship between Glutathione-Dependent Enzymes and the Immunohistochemical Profile of Glial Neoplasms. Biomedicines 2022; 10:biomedicines10102393. [PMID: 36289655 PMCID: PMC9598304 DOI: 10.3390/biomedicines10102393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/25/2022] Open
Abstract
This research aimed to investigate the relationships between the parameters of glutathione metabolism and the immunohistochemical characteristics of glial tumors. Postoperative material from 20 patients with gliomas of different grades of anaplasia was analyzed. Bioinformatic analysis of the interactions between the gliomas’ immunohistochemical markers and their glutathione-dependent enzymes was carried out using the STRING, BioGrid, while Signor databases revealed interactions between such glioma markers as IDH and p53 and the glutathione exchange enzymes (glutathione peroxidase, glutathione reductase, glutathione S-transferase). The most pronounced relationship with glutathione metabolism was demonstrated by the level of the nuclear protein Ki67 as a marker of proliferative activity, and the presence of the IDH1 mutation as one of the key genetic events of gliomagenesis. The glutathione system is an active participant in the body’s antioxidant defense, involving the p53 markers and MGMT promoter methylation. It allows characterization of the gliomal cells’ status at different stages of tumor development.
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31
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Aljabban J, Rohr M, Syed S, Cohen E, Hashi N, Syed S, Khorfan K, Aljabban H, Borkowski V, Segal M, Mukhtar M, Mohammed M, Boateng E, Nemer M, Panahiazar M, Hadley D, Jalil S, Mumtaz K. Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data. World J Gastrointest Oncol 2022; 14:1856-1873. [PMID: 36187396 PMCID: PMC9516659 DOI: 10.4251/wjgo.v14.i9.1856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 04/26/2022] [Accepted: 08/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.
AIM To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.
METHODS We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis.
RESULTS Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.
CONCLUSION This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.
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Affiliation(s)
- Jihad Aljabban
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Rohr
- Department of Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Saad Syed
- Department of Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, United States
| | - Eli Cohen
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Naima Hashi
- Department of Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Sharjeel Syed
- Department of Medicine, University of Chicago Hospitals, Chicago, IL 60637, United States
| | - Kamal Khorfan
- Department of Gastroenterology and Hepatology, University of California San Francisco-Fresno, Fresno, CA 93701, United States
| | - Hisham Aljabban
- Department of Medicine, Barry University, Miami, FL 33161, United States
| | - Vincent Borkowski
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Michael Segal
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Mohamed Mukhtar
- Department of Medicine, Michigan State University College of Human Medicine, Lansing, MI 49503, United States
| | - Mohammed Mohammed
- Department of Medicine, Windsor University School of Medicine, Frankfort, IL 60423, United States
| | - Emmanuel Boateng
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN 37232, United States
| | - Mary Nemer
- Department of Medicine, University of Wisconsin Hospital and Clinics, Madison, WI 53792, United States
| | - Maryam Panahiazar
- Department of Surgery, University of California San Francisco, San Francisco, CA 94143, United States
| | - Dexter Hadley
- Department of Pathology, University of Central Florida College of Medicine, Orlando, FL 32827, United States
| | - Sajid Jalil
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Khalid Mumtaz
- Department of Gastroenterology and Hepatology, Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
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Asong-Fontem N, Panisello-Rosello A, Beghdadi N, Lopez A, Rosello-Catafau J, Adam R. Pre-Ischemic Hypothermic Oxygenated Perfusion Alleviates Protective Molecular Markers of Ischemia-Reperfusion Injury in Rat Liver. Transplant Proc 2022; 54:1954-1969. [PMID: 35961798 DOI: 10.1016/j.transproceed.2022.05.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 04/26/2022] [Accepted: 05/22/2022] [Indexed: 11/16/2022]
Abstract
To expand the pool of organs, hypothermic oxygenated perfusion (HOPE), one of the most promising perfusion protocols, is currently performed after cold storage (CS) at transplant centers (HOPE-END). We investigated a new timing for HOPE, hypothesizing that performing HOPE before CS (HOPE-PRE) could boost mitochondrial protection allowing the graft to better cope with the accumulation of oxidative stress during CS. We analyzed liver injuries at 3 different levels. Histologic analysis demonstrated that, compared to classical CS (CTRL), the HOPE-PRE group showed significantly less ischemic necrosis compared to CTRL vs HOPE-END. From a biochemical standpoint, transaminases were lower after 2 hours of reperfusion in the CTRL vs HOPE-PRE group, which marked decreased liver injury. qPCR analysis on 37 genes involved in ischemia-reperfusion injury revealed protection in HOPE-PRE and HOPE-END compared to CTRL mediated through similar pathways. However, the CTRL vs HOPE-PRE group demonstrated an increased transcriptional level for protective genes compared to the CTRL vs HOPE-END group. This study provides insights on novel biomarkers that could be used in the clinic to better characterize graft quality improving transplantation outcomes.
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Affiliation(s)
- Njikem Asong-Fontem
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France.
| | - Arnau Panisello-Rosello
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Catalonia, Spain
| | - Nassiba Beghdadi
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France; Center Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Villejuif, France
| | - Alexandre Lopez
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France
| | - Joan Rosello-Catafau
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Catalonia, Spain
| | - René Adam
- Université Paris-Saclay, Faculté de Médecine, Unité Chronothérapie, Cancers et Transplantation, Kremlin-Bicêtre, France; Center Hépato-Biliaire, APHP Hôpital Universitaire Paul Brousse, Villejuif, France
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Taylor RS, Ruiz Daniels R, Dobie R, Naseer S, Clark TC, Henderson NC, Boudinot P, Martin SA, Macqueen DJ. Single cell transcriptomics of Atlantic salmon ( Salmo salar L.) liver reveals cellular heterogeneity and immunological responses to challenge by Aeromonas salmonicida. Front Immunol 2022; 13:984799. [PMID: 36091005 PMCID: PMC9450062 DOI: 10.3389/fimmu.2022.984799] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/03/2022] [Indexed: 11/13/2022] Open
Abstract
The liver is a multitasking organ with essential functions for vertebrate health spanning metabolism and immunity. In contrast to mammals, our understanding of liver cellular heterogeneity and its role in regulating immunological status remains poorly defined in fishes. Addressing this knowledge gap, we generated a transcriptomic atlas of 47,432 nuclei isolated from the liver of Atlantic salmon (Salmo salar L.) contrasting control fish with those challenged with a pathogenic strain of Aeromonas salmonicida, a problematic bacterial pathogen in global aquaculture. We identified the major liver cell types and their sub-populations, revealing poor conservation of many hepatic cell marker genes utilized in mammals, while identifying novel heterogeneity within the hepatocyte, lymphoid, and myeloid lineages. This included polyploid hepatocytes, multiple T cell populations including γδ T cells, and candidate populations of monocytes/macrophages and dendritic cells. A dominant hepatocyte population radically remodeled its transcriptome following infection to activate the acute phase response and other defense functions, while repressing routine functions such as metabolism. These defense-specialized hepatocytes showed strong activation of genes controlling protein synthesis and secretion, presumably to support the release of acute phase proteins into circulation. The infection response further involved up-regulation of numerous genes in an immune-cell specific manner, reflecting functions in pathogen recognition and killing, antigen presentation, phagocytosis, regulation of inflammation, B cell differentiation and T cell activation. Overall, this study greatly enhances our understanding of the multifaceted role played by liver immune and non-immune cells in host defense and metabolic remodeling following infection and provides many novel cell-specific marker genes to empower future studies of this organ in fishes.
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Affiliation(s)
- Richard S. Taylor
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom
| | - Rose Ruiz Daniels
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom
| | - Ross Dobie
- Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, United Kingdom
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Shahmir Naseer
- School of Biological Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Thomas C. Clark
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France
| | - Neil C. Henderson
- Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, United Kingdom
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Pierre Boudinot
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, France
| | - Samuel A.M. Martin
- School of Biological Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Daniel J. Macqueen
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom
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Alzahrani N. Hepatitis C Virus, Insulin Resistance, and Diabetes: A Review. Microbiol Immunol 2022; 66:453-459. [PMID: 35941761 DOI: 10.1111/1348-0421.13023] [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: 01/25/2022] [Revised: 07/19/2022] [Accepted: 08/03/2022] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) infection and diabetes mellitus (DM) are two chronic diseases that are a cause of significant health and economic burdens worldwide. HCV is associated with the development of insulin resistance (IR) and diabetes mellitus (DM). The mechanisms through which HCV induces IR and DM include direct viral effects, pro-inflammatory cytokines and other immune-mediated processes. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are both chronic diseases that involve impaired glucose homeostasis, albeit through different mechanisms. T1DM is an autoimmune disease that leads to the destruction of pancreatic beta cells resulting in insulin deficiency. In T2DM, a combination of peripheral insulin resistance and irregular production of insulin eventually lead to beta cell destruction and insulin insufficiency. Both type 1 and type 2 DM etiologies involve a combination of genetic and environmental factors. The data on HCV and T1DM association is limited, unlike T2DM, where a large body of evidence linking HCV to T2DM is available. Here, we intend to outline the current state of knowledge on HCV, IR, and DM. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Nabeel Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, Riyadh, 14611, Saudi Arabia
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Sabir U, Irfan HM, Alamgeer, Umer I, Niazi ZR, Asjad HMM. Phytochemicals targeting NAFLD through modulating the dual function of forkhead box O1 (FOXO1) transcription factor signaling pathways. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:741-755. [PMID: 35357518 DOI: 10.1007/s00210-022-02234-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/18/2022] [Indexed: 02/06/2023]
Abstract
Literature evidence reveals that natural compounds are potential candidates for ameliorating obesity-associated non-alcoholic fatty liver disease (NAFLD) by targeting forkhead box O1 (FOXO1) transcription factor. FOXO1 has a dual and complex role in regulating both increase and decrease in lipid accumulation in hepatocytes and adipose tissues (AT) at different stages of NAFLD. In insulin resistance (IR), it is constitutively expressed, resulting in increased hepatic glucose output and lipid metabolism irregularity. The studies on different phytochemicals indicate that dysregulation of FOXO1 causes disturbance in cellular nutrients homeostasis, and the natural entities have an enduring impact on the mitigation of these abnormalities. The current review communicates and evaluates certain phytochemicals through different search engines, targeting FOXO1 and its downstream cellular pathways to find lead compounds as potential therapeutic agents for treating NAFLD and related metabolic disorders. The findings of this review confirm that polyphenols, flavonoids, alkaloids, terpenoids, and anthocyanins are capable of modulating FOXO1 and associated signaling pathways, and they are potential therapeutic agents for NAFLD and related complications. HIGHLIGHTS: • FOXO1 has the potential to be targeted by novel drugs from natural sources for the treatment of NAFLD and obesity. • FOXO1 regulates cellular autophagy, inflammation, oxidative stress, and lipogenesis through alternative mechanisms. • Phytochemicals treat NAFLD by acting on FOXO1 or SREBP1c and PPARγ transcription factor signaling pathways.
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Affiliation(s)
- Usman Sabir
- Department of Pharmacology, College of Pharmacy, University of Sargodha, Sargodha, Pakistan
| | - Hafiz Muhammad Irfan
- Department of Pharmacology, College of Pharmacy, University of Sargodha, Sargodha, Pakistan.
| | - Alamgeer
- Punjab University College of Pharmacy, University of the Punjab Lahore, Lahore, Pakistan
| | - Ihtisham Umer
- Pharmacy Department, Comsat International University Lahore Campus, Lahore, Pakistan
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36
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Rudnick DA, Huang J, Hidvegi T, Chu AS, Hale P, Munanairi A, Dietzen DJ, Cliften PF, Tycksen E, Lutkewitte AJ, Finck BN, Pak SC, Silverman GA, Perlmutter DH. Regulation of PGC1α Downstream of the Insulin Signaling Pathway Plays a Role in the Hepatic Proteotoxicity of Mutant α1-Antitrypsin Deficiency Variant Z. Gastroenterology 2022; 163:270-284. [PMID: 35301011 PMCID: PMC9232923 DOI: 10.1053/j.gastro.2022.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Insulin signaling is known to regulate essential proteostasis mechanisms. METHODS The analyses here examined effects of insulin signaling in the PiZ mouse model of α1-antitrypsin deficiency in which hepatocellular accumulation and proteotoxicity of the misfolded α1-antitrypsin Z variant (ATZ) causes liver fibrosis and cancer. RESULTS We first studied the effects of breeding PiZ mice to liver-insulin-receptor knockout (LIRKO) mice (with hepatocyte-specific insulin-receptor gene disruption). The results showed decreased hepatic ATZ accumulation and liver fibrosis in PiZ x LIRKO vs PiZ mice, with reversal of those effects when we bred PiZ x LIRKO mice onto a FOXO1-deficient background. Increased intracellular degradation of ATZ mediated by autophagy was identified as the likely mechanism for diminished hepatic proteotoxicity in PiZ x LIRKO mice and the converse was responsible for enhanced toxicity in PiZ x LIRKO x FOXO1-KO animals. Transcriptomic studies showed major effects on oxidative phosphorylation and autophagy genes, and significant induction of peroxisome proliferator-activated-receptor-γ-coactivator-1α (PGC1α) expression in PiZ-LIRKO mice. Because PGC1α plays a key role in oxidative phosphorylation, we further investigated its effects on ATZ proteostasis in our ATZ-expressing mammalian cell model. The results showed PGC1α overexpression or activation enhances autophagic ATZ degradation. CONCLUSIONS These data implicate suppression of autophagic ATZ degradation by down-regulation of PGC1α as one mechanism by which insulin signaling exacerbates hepatic proteotoxicity in PiZ mice, and identify PGC1α as a novel target for development of new human α1-antitrypsin deficiency liver disease therapies.
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Affiliation(s)
- David A. Rudnick
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.,Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110
| | - Jiansheng Huang
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
| | - Tunda Hidvegi
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
| | - Andrew S. Chu
- Department of Pediatrics, Baylor College of Medicine
| | - Pamela Hale
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
| | - Admire Munanairi
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
| | - Dennis J. Dietzen
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
| | - Paul F. Cliften
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.,The Genome Technology Access Center, Washington University School of Medicine, St. Louis, MO 63110
| | - Eric Tycksen
- The Genome Technology Access Center, Washington University School of Medicine, St. Louis, MO 63110
| | - Andrew J. Lutkewitte
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Brian N. Finck
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Stephen C. Pak
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
| | - Gary A. Silverman
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
| | - David H. Perlmutter
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.,Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110
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37
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McGinnis CD, Jennings EQ, Harris PS, Galligan JJ, Fritz KS. Biochemical Mechanisms of Sirtuin-Directed Protein Acylation in Hepatic Pathologies of Mitochondrial Dysfunction. Cells 2022; 11:cells11132045. [PMID: 35805129 PMCID: PMC9266223 DOI: 10.3390/cells11132045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/06/2022] [Accepted: 06/10/2022] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial protein acetylation is associated with a host of diseases including cancer, Alzheimer’s, and metabolic syndrome. Deciphering the mechanisms regarding how protein acetylation contributes to disease pathologies remains difficult due to the complex diversity of pathways targeted by lysine acetylation. Specifically, protein acetylation is thought to direct feedback from metabolism, whereby nutritional status influences mitochondrial pathways including beta-oxidation, the citric acid cycle, and the electron transport chain. Acetylation provides a crucial connection between hepatic metabolism and mitochondrial function. Dysregulation of protein acetylation throughout the cell can alter mitochondrial function and is associated with numerous liver diseases, including non-alcoholic and alcoholic fatty liver disease, steatohepatitis, and hepatocellular carcinoma. This review introduces biochemical mechanisms of protein acetylation in the regulation of mitochondrial function and hepatic diseases and offers a viewpoint on the potential for targeted therapies.
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Affiliation(s)
- Courtney D. McGinnis
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
| | - Erin Q. Jennings
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; (E.Q.J.); (J.J.G.)
| | - Peter S. Harris
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
| | - James J. Galligan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; (E.Q.J.); (J.J.G.)
| | - Kristofer S. Fritz
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
- Correspondence:
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Behl T, Wadhwa M, Sehgal A, Singh S, Sharma N, Bhatia S, Al-Harrasi A, Aleya L, Bungau S. Mechanistic insights into the role of FOXO in diabetic retinopathy. Am J Transl Res 2022; 14:3584-3602. [PMID: 35836845 PMCID: PMC9274583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 04/28/2022] [Indexed: 06/15/2023]
Abstract
Diabetes mellitus (DM), a metabolic disorder characterized by insulin-deficiency or insulin-resistant conditions. The foremost microvascular complication of diabetes is diabetic retinopathy (DR). This is a multifaceted ailment mainly caused by the enduring adverse effects of hyperglycaemia. Inflammation, oxidative stress, and advanced glycation products (AGES) are part and parcel of DR pathogenesis. In regulating many cellular and biological processes, the family of fork-head transcription factors plays a key role. The current review highlights that FOXO is a requisite regulator of pathways intricate in diabetic retinopathy on account of its effect on microvascular cells inflammatory and apoptotic gene expression, and FOXO also has the foremost province in regulating cell cycle, proliferation, apoptosis, and metabolism. Blockage of insulin turns into an exaggerated level of glucose in the bloodstream and can upshot into the exaggerated triggering of FOXO1, which can ultimately uplift the production of several factors of apoptosis and inflammation, such as TNF-α, NF-kB, and various others, as well as reactive oxygen species, which can also come up with diabetic retinopathy. The current review also focuses on various therapies which can be used in the future, like SIRT1 signalling, resveratrol, retinal VEGF, etc., which can be used to suppress FOXO over activation and can prevent the progression of diabetic complications viz. diabetic retinopathy.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara UniversityPunjab 140401, India
| | - Muskan Wadhwa
- Chitkara College of Pharmacy, Chitkara UniversityPunjab 140401, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara UniversityPunjab 140401, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara UniversityPunjab 140401, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara UniversityPunjab 140401, India
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Centre, University of NizwaNizwa 342001, Oman
- School of Health Science, University of Petroleum and Energy StudiesDehradun-248007, Uttarakhand, India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of NizwaNizwa 342001, Oman
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté UniversityFrance
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of OradeaOradea 410028, Romania
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Forkhead O Transcription Factor 4 Restricts HBV Covalently Closed Circular DNA Transcription and HBV Replication through Genetic Downregulation of Hepatocyte Nuclear Factor 4 Alpha and Epigenetic Suppression of Covalently Closed Circular DNA via Interacting with Promyelocytic Leukemia Protein. J Virol 2022; 96:e0054622. [PMID: 35695580 PMCID: PMC9278149 DOI: 10.1128/jvi.00546-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Nuclear located hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) remains the key obstacle to cure chronic hepatitis B (CHB). In our previous investigation, it was found that FoxO4 could inhibit HBV core promoter activity through downregulating the expression of HNF4α. However, the exact mechanisms whereby FoxO4 inhibits HBV replication, especially its effect on cccDNA, remain unclear. Here, our data further revealed that FoxO4 could effectively inhibit cccDNA mediated transcription and HBV replication without affecting cccDNA level. Mechanistic study showed that FoxO4 could cause epigenetic suppression of cccDNA. Although FoxO4-mediated downregulation of HNF4α contributed to inhibiting HBV core promoter activity, it had little effect on cccDNA epigenetic regulation. Further, it was found that FoxO4 could colocalize within promyelocytic leukemia protein (PML) nuclear bodies and interact with PML. Of note, PML was revealed to be critical for FoxO4-mediated inhibition of cccDNA epigenetic modification and of the following cccDNA transcription and HBV replication. Furthermore, FoxO4 was found to be downregulated in HBV-infected hepatocytes and human liver tissues, and it was negatively correlated with cccDNA transcriptional activity in CHB patients. Together, these findings highlight the role of FoxO4 in suppressing cccDNA transcription and HBV replication via genetic downregulation of HNF4α and epigenetic suppression of cccDNA through interacting with PML. Targeting FoxO4 may present as a new therapeutic strategy against chronic HBV infection. IMPORTANCE HBV cccDNA is a determining factor for viral persistence and the main obstacle for a cure of chronic hepatitis B. Strategies that target cccDNA directly are therefore of great importance in controlling persistent HBV infection. In present investigation, we found that FoxO4 could efficiently suppress cccDNA transcription and HBV replication without affecting the level of cccDNA itself. Further, our data revealed that FoxO4 might inhibit cccDNA function via a two-part mechanism: one is to epigenetically suppress cccDNA transcription via interacting with PML, and the other is to inhibit HBV core promoter activity via the genetic downregulation of HNF4α. Of note, HBV might dampen the expression of FoxO4 for its own persistent infection. We propose that manipulation of FoxO4 may present as a potential therapeutic strategy against chronic HBV infection.
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Guo S, Mangal R, Dandu C, Geng X, Ding Y. Role of Forkhead Box Protein O1 (FoxO1) in Stroke: A Literature Review. Aging Dis 2022; 13:521-533. [PMID: 35371601 PMCID: PMC8947839 DOI: 10.14336/ad.2021.0826] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
Stroke is one of the most prevalent causes of death around the world. When a stroke occurs, many cellular signaling cascades and regulators are activated, which results in severe cellular dysfunction and debilitating long-term disability. One crucial regulator of cell fate and function is mammalian Forkhead box protein O1 (FoxO1). Many studies have found FoxO1 to be implicated in many cellular processes, including regulating gluconeogenesis and glycogenolysis. During a stroke, modifications of FoxO1 have been linked to a variety of functions, such as inducing cell death and inflammation, inhibiting oxidative injury, affecting the blood brain barrier (BBB), and regulating hepatic gluconeogenesis. For these functions of FoxO1, different measures and treatments were applied to FoxO1 after ischemia. However, the subtle mechanisms of post-transcriptional modification and the role of FoxO1 are still elusive and even contradictory in the development of stroke. The determination of these mechanisms will lead to further enlightenment for FoxO1 signal transduction and the identification of targeted drugs. The regulation and function of FoxO1 may provide an important way for the prevention and treatment of diseases. Overall, the functions of FoxO1 are multifactorial, and this paper will summarize all of the significant pathways in which FoxO1 plays an important role during stroke damage and recovery.
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Affiliation(s)
- Sichao Guo
- 1Luhe Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China.,3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Ruchi Mangal
- 3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Chaitu Dandu
- 3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Xiaokun Geng
- 1Luhe Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China.,2Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China.,3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Yuchuan Ding
- 3Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
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Linton MF, Yancey PG, Leuthner ZM, Brown JD. The FoxOs are in the ApoM house. J Clin Invest 2022; 132:158471. [PMID: 35362476 PMCID: PMC8970665 DOI: 10.1172/jci158471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The prevalence of metabolic syndrome continues to increase globally and heightens the risk for cardiovascular disease (CVD). Insulin resistance is a core pathophysiologic mechanism that causes abnormal carbohydrate metabolism and atherogenic changes in circulating lipoprotein quantity and function. In particular, dysfunctional HDL is postulated to contribute to CVD risk in part via loss of HDL-associated sphingosine-1-phosphate (S1P). In this issue of the JCI, Izquierdo et al. demonstrate that HDL from humans with insulin resistance contained lower levels of S1P. Apolipoprotein M (ApoM), a protein constituent of HDL that binds S1P and controls bioavailability was decreased in insulin-resistant db/db mice. Gain- and loss-of-function mouse models implicated the forkhead box O transcription factors (FoxO1,3,4) in the regulation of both ApoM and HDL-associated S1P. These data have important implications for potential FoxO-based therapies designed to treat lipid and carbohydrate abnormalities associated with human metabolic disease and CVD.
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Affiliation(s)
- MacRae F Linton
- Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine and.,Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Patricia G Yancey
- Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine and
| | - Zoe M Leuthner
- Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine and
| | - Jonathan D Brown
- Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine and
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A REVIEW ON POTENTIAL ANTI-DIABETIC MECHANISMS OF CHITOSAN AND ITS DERIVATIVES. CARBOHYDRATE POLYMER TECHNOLOGIES AND APPLICATIONS 2022. [DOI: 10.1016/j.carpta.2022.100188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Vohra MS, Benchoula K, Serpell CJ, Hwa WE. AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity. Eur J Pharmacol 2022; 915:174611. [PMID: 34798121 DOI: 10.1016/j.ejphar.2021.174611] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 10/27/2021] [Accepted: 10/27/2021] [Indexed: 02/08/2023]
Abstract
Obesity is a major health crisis affecting over a third of the global population. This multifactorial disease is regulated via interoceptive neural circuits in the brain, whose alteration results in excessive body weight. Certain central neuronal populations in the brain are recognised as crucial nodes in energy homeostasis; in particular, the hypothalamic arcuate nucleus (ARC) region contains two peptide microcircuits that control energy balance with antagonistic functions: agouti-related peptide/neuropeptide-Y (AgRP/NPY) signals hunger and stimulates food intake; and pro-opiomelanocortin (POMC) signals satiety and reduces food intake. These neuronal peptides levels react to energy status and integrate signals from peripheral ghrelin, leptin, and insulin to regulate feeding and energy expenditure. To manage obesity comprehensively, it is crucial to understand cellular and molecular mechanisms of information processing in ARC neurons, since these regulate energy homeostasis. Importantly, a specific strategy focusing on ARC circuits needs to be devised to assist in treating obese patients and maintaining weight loss with minimal or no side effects. The aim of this review is to elucidate the recent developments in the study of AgRP-, NPY- and POMC-producing neurons, specific to their role in controlling metabolism. The impact of ghrelin, leptin, and insulin signalling via action of these neurons is also surveyed, since they also impact energy balance through this route. Lastly, we present key proteins, targeted genes, compounds, drugs, and therapies that actively work via these neurons and could potentially be used as therapeutic targets for treating obesity conditions.
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Affiliation(s)
- Muhammad Sufyan Vohra
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Khaled Benchoula
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Christopher J Serpell
- School of Physical Sciences, Ingram Building, University of Kent, Canterbury, Kent, CT2 7NH, United Kingdom
| | - Wong Eng Hwa
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia.
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Zuo Z, Li Y, Zeng C, Xi Y, Tao H, Guo Y. Integrated Analyses Identify Key Molecules and Reveal the Potential Mechanism of miR-182-5p/FOXO1 Axis in Alcoholic Liver Disease. Front Med (Lausanne) 2021; 8:767584. [PMID: 34950682 PMCID: PMC8688759 DOI: 10.3389/fmed.2021.767584] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/15/2021] [Indexed: 12/20/2022] Open
Abstract
Background: Alcoholic liver disease (ALD) is one of the most common chronic liver diseases worldwide. However, the potential molecular mechanism in ALD development remains unclear. The objective of this work was to identify key molecules and demonstrate the underlying regulatory mechanisms. Methods: RNA-seq datasets were obtained from Gene Expression Omnibus (GEO), and key molecules in ALD development were identified with bioinformatics analysis. Alcoholic liver disease mouse and cell models were constructed using Lieber-DeCarli diets and alcohol medium, respectively. Quantitative real-time PCR and Western blotting were conducted to confirm the differential expression level. Dual-luciferase reporter assays were performed to explore the targeting regulatory relationship. Overexpression and knockdown experiments were applied to reveal the potential molecular mechanism in ALD development. Results: Between ALD patients and healthy controls, a total of 416 genes and 21 microRNAs (miRNAs) with significantly differential expression were screened. A comprehensive miRNA-mRNA network was established; within this network, the miR-182-5p/FOXO1 axis was considered a significant pathway in ALD lipid metabolism. Mouse and cell experiments validated that miR-182-5p was substantially higher in ALD than in normal livers, whereas the expression of FOXO1 was dramatically decreased by alcohol consumption (P < 0.05). Next, dual-luciferase reporter assays demonstrated that miR-182-5p directly targets the binding site of the FOXO1 3′UTR and inhibits its mRNA and protein expression. In addition, miR-182-5p was found to promote hepatic lipid accumulation via targeting the FOXO1 signaling pathway, and inhibition of the miR-182-5p/FOXO1 axis improved hepatic triglyceride (TG) deposition in ALD by regulating downstream genes involved in lipid metabolism. Conclusion: In summary, key molecules were identified in ALD development and a comprehensive miRNA–mRNA network was established. Meanwhile, our results suggested that miR-182-5p significantly increases lipid accumulation in ALD by targeting FOXO1, thereby providing novel scientific insights and potential therapeutic targets for ALD.
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Affiliation(s)
- Zhihua Zuo
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yiqin Li
- Department of Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Chuyi Zeng
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yuge Xi
- Department of Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Hualin Tao
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yongcan Guo
- Department of Clinical Laboratory, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
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Shi B, Tao X, Betancor MB, Lu J, Tocher DR, Meng F, Figueiredo-Silva C, Zhou Q, Jiao L, Jin M. Dietary chromium modulates glucose homeostasis and induces oxidative stress in Pacific white shrimp (Litopenaeus vannamei). AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2021; 240:105967. [PMID: 34555743 DOI: 10.1016/j.aquatox.2021.105967] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 06/13/2023]
Abstract
While chromium (Cr) has been recognized as an essential nutrient for all animals, and dietary supplementation can be beneficial, it can also be toxic. The present study aimed to investigate the contrasting effects of dietary chromium in Pacific white shrimp Litopenaeus vannamei. Five experimental diets were formulated to contain Cr at levels of 0.82 (Cr0.82, unsupplemented diet), 1.01 (Cr1.01), 1.22 (Cu1.22), 1.43 (Cr1.43) and 1.63 (Cr1.63) mg/kg and were fed to shrimp for 8 weeks. Highest weight gain was recorded in shrimp fed the diet containing 1.22 mg/kg Cr. Shrimp fed the diet containing the highest level of Cr (1.63 mg/kg) showed the lowest weight gain and clear signs of oxidative stress and apoptosis as evidenced by higher levels of H2O2, malondialdehyde and 8-hydroxydeoxyguanosine, and expression of caspase 2, 3, 5, and lower contents of total and oxidized glutathione, and expression of Cu/Zn sod, cat, gpx, mt, bcl2. Chromium supplementation promoted glycolysis and inhibited gluconeogenesis as shown by increased activities of hexokinase, phosphofructokinase and pyruvate kinase, and reduced activity of phosphoenolpyruvate carboxykinase in shrimp fed the diet containing 1.43 mg/kg Cr. Shrimp fed the diet with 1.63 mg/kg Cr had lowest contents of crustacean hyperglycemic hormone and insulin like peptide in hemolymph. Expression of genes involved in insulin signaling pathway and glycose metabolism including insr, irs1, pik3ca, pdpk1, akt, acc1, gys, glut1, pk, hk were up-regulated, and foxO1, gsk-3β, g6pc, pepck were down-regulated in shrimp fed the diets supplemented with Cr. This study demonstrated that optimum dietary supplementation of Cr had beneficial effects on glucose homeostasis and growth, whereas excess caused oxidative damage and impaired growth. The results contribute to our understanding of the biological functions of chromium in shrimp.
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Affiliation(s)
- Bo Shi
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Xinyue Tao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Mónica B Betancor
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, Scotland, UK
| | - Jingjing Lu
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Douglas R Tocher
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China
| | - Fanyi Meng
- Zinpro Corporation, Eden Prairie, Minnesota, USA
| | | | - Qicun Zhou
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Lefei Jiao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Min Jin
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
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Wang S, Tao J, Chen H, Kandadi MR, Sun M, Xu H, Lopaschuk GD, Lu Y, Zheng J, Peng H, Ren J. Ablation of Akt2 and AMPK α2 rescues high fat diet-induced obesity and hepatic steatosis through Parkin-mediated mitophagy. Acta Pharm Sin B 2021; 11:3508-3526. [PMID: 34900533 PMCID: PMC8642450 DOI: 10.1016/j.apsb.2021.07.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 06/04/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023] Open
Abstract
Given the opposing effects of Akt and AMP-activated protein kinase (AMPK) on metabolic homeostasis, this study examined the effects of deletion of Akt2 and AMPKα2 on fat diet-induced hepatic steatosis. Akt2-Ampkα2 double knockout (DKO) mice were placed on high fat diet for 5 months. Glucose metabolism, energy homeostasis, cardiac function, lipid accumulation, and hepatic steatosis were examined. DKO mice were lean without anthropometric defects. High fat intake led to adiposity and decreased respiratory exchange ratio (RER) in wild-type (WT) mice, which were ablated in DKO but not Akt2 -/- and Ampkα2 -/- mice. High fat intake increased blood and hepatic triglycerides and cholesterol, promoted hepatic steatosis and injury in WT mice. These effects were eliminated in DKO but not Akt2 -/- and Ampkα2 -/- mice. Fat diet promoted fat accumulation, and enlarged adipocyte size, the effect was negated in DKO mice. Fat intake elevated fatty acid synthase (FAS), carbohydrate-responsive element-binding protein (CHREBP), sterol regulatory element-binding protein 1 (SREBP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), peroxisome proliferator-activated receptor-α (PPARα), PPARγ, stearoyl-CoA desaturase 1 (SCD-1), phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and diglyceride O-acyltransferase 1 (DGAT1), the effect was absent in DKO but not Akt2 -/- and Ampkα2 -/- mice. Fat diet dampened mitophagy, promoted inflammation and phosphorylation of forkhead box protein O1 (FoxO1) and AMPKα1 (Ser485), the effects were eradicated by DKO. Deletion of Parkin effectively nullified DKO-induced metabolic benefits against high fat intake. Liver samples from obese humans displayed lowered microtubule-associated proteins 1A/1B light chain 3B (LC3B), Pink1, Parkin, as well as enhanced phosphorylation of Akt, AMPK (Ser485), and FoxO1, which were consolidated by RNA sequencing (RNAseq) and mass spectrometry analyses from rodent and human livers. These data suggest that concurrent deletion of Akt2 and AMPKα2 offers resilience to fat diet-induced obesity and hepatic steatosis, possibly through preservation of Parkin-mediated mitophagy and lipid metabolism.
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Affiliation(s)
- Shuyi Wang
- Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China
- Shanghai University School of Medicine, Shanghai 200044, China
- University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
| | - Jun Tao
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510000, China
| | - Huaguo Chen
- Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China
| | - Machender R. Kandadi
- University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
- Medprime Health Services LLC, Paris, TX 75460, USA
| | - Mingming Sun
- University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Haixia Xu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China
- Department of Cardiology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Gary D. Lopaschuk
- Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
| | - Yan Lu
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Junmeng Zheng
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510000, China
| | - Hu Peng
- Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China
| | - Jun Ren
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA
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Abstract
Significance: During aging, excessive production of reactive species in the liver leads to redox imbalance with consequent oxidative damage and impaired organ homeostasis. Nevertheless, slight amounts of reactive species may modulate several transcription factors, acting as second messengers and regulating specific signaling pathways. These redox-dependent alterations may impact the age-associated decline in liver regeneration. Recent Advances: In the last few decades, relevant findings related to redox alterations in the aging liver were investigated. Consistently, recent research broadened understanding of redox modifications and signaling related to liver regeneration. Other than reporting the effect of oxidative stress, epigenetic and post-translational modifications, as well as modulation of specific redox-sensitive cellular signaling, were described. Among them, the present review focuses on Wnt/β-catenin, the nuclear factor (erythroid-derived 2)-like 2 (NRF2), members of the Forkhead box O (FoxO) family, and the p53 tumor suppressor. Critical Issues: Even though alteration in redox homeostasis occurs both in aging and in impaired liver regeneration, the associative mechanisms are not clearly defined. Of note, antioxidants are not effective in slowing hepatic senescence, and do not clearly improve liver repopulation after hepatectomy or transplant in humans. Future Directions: Further investigations are needed to define mutual redox-dependent molecular pathways involved both in aging and in the decline of liver regeneration. Preclinical studies aimed at the characterization of these pathways would define possible therapeutic targets for human trials. Antioxid. Redox Signal. 35, 832-847.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Yudhani RD, Nugrahaningsih DAA, Sholikhah EN, Mustofa M. The Molecular Mechanisms of Hypoglycemic Properties and Safety Profiles of Swietenia Macrophylla Seeds Extract: A Review. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2022] Open
Abstract
BACKGROUND: Insulin resistance (IR) is known as the root cause of type 2 diabetes; hence, it is a substantial therapeutic target. Nowadays, studies have shifted the focus to natural ingredients that have been utilized as a traditional diabetes treatment, including Swietenia macrophylla. Accumulating evidence supports the hypoglycemic activities of S. macrophylla seeds extract, although its molecular mechanisms have yet to be well-established.
AIM: This review focuses on the hypoglycemic molecular mechanisms of S. macrophylla seeds extract and its safety profiles.
METHODS: An extensive search of the latest literature was conducted from four main databases (PubMed, Scopus, Science Direct, and Google Scholar) using several keywords: “swietenia macrophylla, seeds, and diabetes;” “swietenia macrophylla, seeds, and oxidative stress;” “swietenia macrophylla, seeds, and inflammation;” “swietenia macrophylla, seeds, and GLUT4;” and “swietenia macrophylla, seeds, and toxicities.”
RESULTS: The hypoglycemic activities occur through modulating several pathways associated with IR and T2D pathogenesis. The seeds extract of S. macrophylla modulates oxidative stress by decreasing malondialdehyde (MDA), oxidized low-density lipoprotein, and thiobarbituric acid-reactive substances while increasing antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase). Another propose mechanism is the modulating of the inflammatory pathway by attenuating nuclear factor kappa β, tumor necrosis factor α, inducible nitric oxide synthase, and cyclooxygenase 2. Some studies have shown that the extract can also control phosphatidylinositol-3-kinase/ Akt (PI3K/Akt) pathway by inducing glucose transporter 4, while suppressing phosphoenolpyruvate carboxykinase. Moreover, in vitro cytotoxicity and in vivo toxicity studies supported the safety profile of S. macrophylla seeds extract with the LD50 higher than 2000 mg/kg.
CONCLUSION: The potential of S. macrophylla seeds as antidiabetic candidate is supported by many studies that have documented their non-toxic and hypoglycemic effects, which involve several molecular pathways.
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Yang Z, Roth K, Agarwal M, Liu W, Petriello MC. The transcription factors CREBH, PPARa, and FOXO1 as critical hepatic mediators of diet-induced metabolic dysregulation. J Nutr Biochem 2021; 95:108633. [PMID: 33789150 PMCID: PMC8355060 DOI: 10.1016/j.jnutbio.2021.108633] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 01/31/2021] [Accepted: 03/09/2021] [Indexed: 02/06/2023]
Abstract
The liver is a critical mediator of lipid and/or glucose homeostasis and is a primary organ involved in dynamic changes during feeding and fasting. Additionally, hepatic-centric pathways are prone to dysregulation during pathophysiological states including metabolic syndrome (MetS) and non-alcoholic fatty liver disease. Omics platforms and GWAS have elucidated genes related to increased risk of developing MetS and related disorders, but mutations in these metabolism-related genes are rare and cannot fully explain the increasing prevalence of MetS-related pathologies worldwide. Complex interactions between diet, lifestyle, environmental factors, and genetic predisposition jointly determine inter-individual variability of disease risk. Given the complexity of these interactions, researchers have focused on master regulators of metabolic responses incorporating and mediating the impact of multiple environmental cues. Transcription factors are DNA binding, terminal executors of signaling pathways that modulate the cellular responses to complex metabolic stimuli and are related to the control of hepatic lipid and glucose homeostasis. Among numerous hepatic transcription factors involved in regulating metabolism, three emerge as key players in transducing nutrient sensing, which are dysregulated in MetS-related perturbations in both clinical and preclinical studies: cAMP Responsive Element Binding Protein 3 Like 3 (CREB3L3), Peroxisome Proliferator Activated Receptor Alpha (PPAR), and Forkhead Box O1 (FOXO1). Additionally, these three transcription factors appear to be amenable to dietary and/or nutrient-based therapies, being potential targets of nutritional therapy. In this review we aim to describe the activation, regulation, and impact of these transcription factors in the context of metabolic homeostasis. We also summarize their perspectives in MetS and nutritional therapies.
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Affiliation(s)
- Zhao Yang
- Institute of Environmental Health Sciences (IEHS), Wayne State University, Detroit, MI, USA
| | - Katherine Roth
- Institute of Environmental Health Sciences (IEHS), Wayne State University, Detroit, MI, USA
| | - Manisha Agarwal
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Wanqing Liu
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI, USA
| | - Michael C Petriello
- Institute of Environmental Health Sciences (IEHS), Wayne State University, Detroit, MI, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA.
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Moon KM, Lee MK, Hwang T, Choi CW, Kim MS, Kim HR, Lee B. The multi-functional roles of forkhead box protein O in skin aging and diseases. Redox Biol 2021; 46:102101. [PMID: 34418600 PMCID: PMC8385202 DOI: 10.1016/j.redox.2021.102101] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 12/11/2022] Open
Abstract
Forkhead box, class O (FoxO) family members are multifunctional transcription factors that are involved in several metabolic processes, including energy metabolism, apoptosis, DNA repair, and oxidative stress. However, their roles in skin health have not been well-documented. Recent studies have indicated that FoxOs are important factors to control skin homeostasis and health. The activation or deactivation of some FoxO family members is closely related to melanogenesis, wound healing, acne, and melanoma. In this review, we have discussed the recent findings that demonstrate the relationship between FoxOs and skin health as well as the underlying mechanisms associated with their functions.
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Affiliation(s)
- Kyoung Mi Moon
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Min-Kyeong Lee
- Department of Food Science and Nutrition, Pukyong National University, Nam-Gu, Busan, Republic of Korea
| | - Taehyeok Hwang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea
| | - Chun Whan Choi
- Natural Product Research Team, Biocenter, Gyeonggido Business and Science Accelerator, Gyeonggi-Do, Republic of Korea
| | - Min Soo Kim
- Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul, 02792, Republic of Korea
| | - Hyeung-Rak Kim
- Department of Food Science and Nutrition, Pukyong National University, Nam-Gu, Busan, Republic of Korea
| | - Bonggi Lee
- Department of Food Science and Nutrition, Pukyong National University, Nam-Gu, Busan, Republic of Korea.
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