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Xu C, Wang S, Meng D, Wang M, Yan R, Dai Y. Neuregulin1 ameliorates metabolic dysfunction-associated fatty liver disease via the ERK/SIRT1 signaling pathways. BMC Gastroenterol 2025; 25:47. [PMID: 39885382 PMCID: PMC11783944 DOI: 10.1186/s12876-025-03632-5] [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: 06/08/2024] [Accepted: 01/20/2025] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND Neuregulin (NRG) family is involved in energy metabolism, among which NRG1 is a neuregulin proved to play a protective role in MAFLD cells. But the presice echanism has not been fully illustrated. This study aimed to investigate the role of NRG1 via the ERK/SIRT1 signaling in the pathogenesis of MAFLD. METHODS C57BL/6 mice were fed with high-fat diet for 8 weeks, and then injected with NRG1 (0.3 mg/kg/d) and PD98059 (0.3 mg/kg/d) via tail vein for 5 weeks. HepG2 cells induced by oleic acid and palmitic acid were treated with 20ng/mL NRG1 and 10µmol/L PD98059. The changes of histopathological, biochemical indexes, inflammatory factors, lipid metabolism, apoptosis and autophagy parameters were measured. RESULTS The expressions of NRG1 in MAFLD cell and animal models were significantly lower than that in the control group. After the intervention of ERK inhibitor PD98059, the expression of NRG1 decreased significantly in vivo, but no significant change was observed in vitro. Moreover, NRG1 ameliorated hepatic steatosis, enhanced cell viability, reduced cell apoptosis, and attenuated liver injury both in vitro and in vivo. After NRG1 intervention, the expressions of ERBB2, ERBB3, p-ERK1/2, SIRT1 and p-FOXO1 as well as the LC3II/I ratio in MAFLD cells and liver tissues of MAFLD mice were significantly increased, while the expression of SREBP1c was decreased. The aforementioned therapeutic effect of NRG1 was lost after the intervention of PD98059. CONCLUSION NRG1 might play a protective role in the pathogenesis of MAFLD by activating the downstream ERK1/2 through ErbB2-ErbB3, which promotes the expression of SIRT1 and autophagy markers. This study might indicate a new therapeutic strategy for MAFLD.
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Affiliation(s)
- Chengan Xu
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Shouhao Wang
- Hepatology Diagnosis and Treatment Center, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, Zhejiang, 325035, China
| | - Di Meng
- Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China
| | - Mingshan Wang
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Rong Yan
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Yining Dai
- Center for General Practice Medicine, Department of Infectious Diseases, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China.
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Zhang M, Traspov A, Yang J, Zheng M, Kharzinova VR, Ai H, Zinovieva NA, Huang L. Genomic and transcriptomic insights into vitamin A-induced thermogenesis and gene reuse as a cold adaptation strategy in wild boars. Commun Biol 2025; 8:116. [PMID: 39856249 PMCID: PMC11759952 DOI: 10.1038/s42003-025-07536-8] [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: 09/08/2024] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
Wild boars inhabit diverse climates, including frigid regions like Siberia, but their migration history and cold adaptation mechanisms into high latitudes remain poorly understood. We constructed the most comprehensive wild boar whole-genome variant dataset to date, comprising 124 samples from tropical to frigid zones, among which 47 Russian, 8 South Chinese and 3 Vietnamese wild boars were newly supplemented. We also gathered 75 high-quality RNA-seq datasets from 10 tissues of 6 wild boars from Russia and 6 from southern China. Demographic analysis revealed the appearance of Russian wild boars in Far East of Asia (RUA) and Europe (RUE) after the last glacial maximum till ~ 10 thousand years ago. Recent gene flow (<100 years) from RUA to RUE reflects human-mediated introductions. Cold-region wild boars exhibit strong selection signatures indicative of genetic adaptation to cold climates. Further pathway and transcriptomic analyses reveal a novel cold resistance mechanism centered on enhanced vitamin A metabolism and catalysis, involving the reuse of UGT2B31 and rhythm regulation by ANGPTL8, RLN3 and ZBTB20. This may compensate for the pig's lack of brown fat/UCP1 thermogenesis. These findings provide new insights into the molecular basis of cold adaptation and improve our understanding of Eurasian wild boar migration history.
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Affiliation(s)
- Mingpeng Zhang
- National Key Laboratory for Swine genetic improvement and production technology, Ministry of Science and Technology of China, Jiangxi Agricultural University, Nanchang, Jiangxi Province, P.R. China
- Key Laboratory of Biodiversity Conservation and Bioresource Utilization of Jiangxi Province, College of Life Sciences, Jiangxi Normal University, Nanchang, Jiangxi Province, P.R. China
| | - Aleksei Traspov
- L.K. Ernst Federal Research Center for Animal Husbandry, Dubrovitsy, Podolsk Municipal District, Moscow Region, Podolsk, Russia
| | - Jiawen Yang
- National Key Laboratory for Swine genetic improvement and production technology, Ministry of Science and Technology of China, Jiangxi Agricultural University, Nanchang, Jiangxi Province, P.R. China
| | - Min Zheng
- National Key Laboratory for Swine genetic improvement and production technology, Ministry of Science and Technology of China, Jiangxi Agricultural University, Nanchang, Jiangxi Province, P.R. China
| | - Veronika R Kharzinova
- L.K. Ernst Federal Research Center for Animal Husbandry, Dubrovitsy, Podolsk Municipal District, Moscow Region, Podolsk, Russia
| | - Huashui Ai
- National Key Laboratory for Swine genetic improvement and production technology, Ministry of Science and Technology of China, Jiangxi Agricultural University, Nanchang, Jiangxi Province, P.R. China.
| | - Natalia A Zinovieva
- L.K. Ernst Federal Research Center for Animal Husbandry, Dubrovitsy, Podolsk Municipal District, Moscow Region, Podolsk, Russia.
| | - Lusheng Huang
- National Key Laboratory for Swine genetic improvement and production technology, Ministry of Science and Technology of China, Jiangxi Agricultural University, Nanchang, Jiangxi Province, P.R. China.
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Wu S, Guo N, Xu H, Li Y, Sun T, Jiang X, Fu D, You T, Diao S, Huang Y, Hu C. Caveolin-1 ameliorates hepatic injury in non-alcoholic fatty liver disease by inhibiting ferroptosis via the NOX4/ROS/GPX4 pathway. Biochem Pharmacol 2024; 230:116594. [PMID: 39490677 DOI: 10.1016/j.bcp.2024.116594] [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: 05/04/2024] [Revised: 10/17/2024] [Accepted: 10/22/2024] [Indexed: 11/05/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally, with a complex and contentious pathogenesis. Caveolin-1 (CAV1) is an important regulator of liver function and can mitigate liver injury by scavenging reactive oxygen species (ROS). Evidence suggests that NOX4 is a source of ROS production, that oxidative stress and ferroptosis are closely related, and that both are involved in the onset and progression of NAFLD. However, whether CAV1 attenuates liver injury in NAFLD caused by high-fat diet via the NOX4/ROS/GPX4 pathway remains unclear. An in vivo fatty liver model was established by feeding mice with a high-fat diet for 16 weeks. In addition, an in vitro fatty liver model was established by incubating AML-12 cells with free fatty acids for 24 h using an in vitro culture method. In our study, it was observed that a high-fat diet induces mitochondrial damage and worsens oxidative stress in NAFLD. This diet also hinders GPX4 expression, leading to an escalation of ferroptosis and lipid accumulation. To counteract these effects, intraperitoneal administration of CSD peptide in mice attenuated the high-fat diet-induced liver mitochondrial damage and ferroptosis. Likewise, overexpression of CAV1 resulted in an increase in GPX4 expression and a reduction in levels of ROS-mediated iron metamorphosis, thus mitigating the progression of the disease. However, the effects of CAV1 on GPX4-mediated ferroptosis and lipid deposition could be reversed by CAV1 small interfering RNA (SiRNA). Finally, NOX4 inhibitor (GLX351322) treatment increased CAV1 siRNA-mediated GPX4 expression and decreased the level of ROS-mediated ferroptosis. These findings suggest a potential mechanism underlying the protective role of CAV1 against high-fat diet-induced hepatotoxicity in NAFLD, shedding new light on the interplay between CAV1, GPX4, and ferroptosis in liver pathology.
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Affiliation(s)
- Shuai Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Ning Guo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Hanlin Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Yu Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Tianyin Sun
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Xiangfu Jiang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Dongdong Fu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Tingyu You
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Shaoxi Diao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Yan Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
| | - Chengmu Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei 230032, China; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei 230032, China.
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Maiese K. Cardiovascular and nonalcoholic fatty liver disease: Sharing common ground through SIRT1 pathways. World J Cardiol 2024; 16:632-643. [PMID: 39600987 PMCID: PMC11586725 DOI: 10.4330/wjc.v16.i11.632] [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: 07/13/2024] [Revised: 08/27/2024] [Accepted: 10/10/2024] [Indexed: 10/30/2024] Open
Abstract
As a non-communicable disease, cardiovascular disorders have become the leading cause of death for men and women. Of additional concern is that cardiovascular disease is linked to chronic comorbidity disorders that include nonalcoholic fatty liver disease (NAFLD). NAFLD, also termed metabolic-dysfunction-associated steatotic liver disease, is the greatest cause of liver disease throughout the world, increasing in prevalence concurrently with diabetes mellitus (DM), and can progress to nonalcoholic steatohepatitis that leads to cirrhosis and liver fibrosis. Individuals with metabolic disorders, such as DM, are more than two times likely to experience cardiac disease, stroke, and liver disease that includes NAFLD when compared individuals without metabolic disorders. Interestingly, cardiovascular disorders and NAFLD share a common underlying cellular mechanism for disease pathology, namely the silent mating type information regulation 2 homolog 1 (SIRT1; Saccharomyces cerevisiae). SIRT1, a histone deacetylase, is linked to metabolic pathways through nicotinamide adenine dinucleotide and can offer cellular protection though multiple avenues, including trophic factors such as erythropoietin, stem cells, and AMP-activated protein kinase. Translating SIRT1 pathways into clinical care for cardiovascular and hepatic disease can offer significant hope for patients, but further insights into the complexity of SIRT1 pathways are necessary for effective treatment regimens.
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Affiliation(s)
- Kenneth Maiese
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20810, United States.
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Fei B, Zhao Y, Wang J, Wen P, Li J, Tanaka M, Wang Z, Li S. Leveraging adrenergic receptor blockade for enhanced nonalcoholic fatty liver disease treatment via a biomimetic nanoplatform. J Nanobiotechnology 2024; 22:591. [PMID: 39342261 PMCID: PMC11438098 DOI: 10.1186/s12951-024-02864-z] [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: 04/25/2024] [Accepted: 09/16/2024] [Indexed: 10/01/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, steatosis and fibrosis. Sympathetic nerves play a critical role in maintaining hepatic lipid homeostasis and regulating fibrotic progression through adrenergic receptors expressed by hepatocytes and hepatic stellate cells; however, the use of sympathetic nerve-focused strategies for the treatment of NAFLD is still in the infancy. Herein, a biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was developed for the codelivery of retinoic acid (RA) and the adrenoceptor antagonist labetalol (LA). The nanoplatform exhibited improved accumulation and sufficient drug release in the fibrotic liver, thereby achieving precise codelivery of drugs. Integration of adrenergic blockade effectively interrupted the vicious cycle of sympathetic nerves with hepatic stellate cells (HSCs) and hepatocytes, which not only combined with RA to restore HSCs to a quiescent state but also helped to reduce hepatic lipid accumulation. We demonstrated the excellent ability of the biomimetic nanoplatform to ameliorate liver inflammation, fibrosis and steatosis. Our work highlights the tremendous potential of a sympathetic nerve-focused strategy for the management of NAFLD and provides a promising nanoplatform for the treatment of NAFLD.
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Affiliation(s)
- Bingyuan Fei
- Department of Gastrointestinal Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China
| | - Yuewu Zhao
- CAS Key Laboratory of Nano-Bio Interface Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, Jiangsu, 215123, China
| | - Jine Wang
- CAS Key Laboratory of Nano-Bio Interface Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, Jiangsu, 215123, China
| | - Panyue Wen
- Institute for Materials Chemistry and Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Junjie Li
- Institute for Materials Chemistry and Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Masaru Tanaka
- Institute for Materials Chemistry and Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan
| | - Zheng Wang
- CAS Key Laboratory of Nano-Bio Interface Suzhou Institute of Nano-Tech and Nano-Bionics Chinese Academy of Sciences, Suzhou, Jiangsu, 215123, China.
| | - Shuo Li
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, 130033, China.
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Chen J, Rao H, Zheng X. Identification of novel targets associated with cholesterol metabolism in nonalcoholic fatty liver disease: a comprehensive study using Mendelian randomization combined with transcriptome analysis. Front Genet 2024; 15:1464865. [PMID: 39359475 PMCID: PMC11445148 DOI: 10.3389/fgene.2024.1464865] [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: 07/18/2024] [Accepted: 09/06/2024] [Indexed: 10/04/2024] Open
Abstract
Background There is limited research on cholesterol metabolism-related genes (CM-RGs) in non-alcoholic fatty liver disease (NAFLD), despite hypercholesterolemia being a recognized risk factor. The role of CM-RGs in NAFLD remains unclear. Methods The differentially expressed genes (DEGs) between NAFLD and control were acquired by differential expression analysis. The differentially expressed genes associated with cholesterol metabolism (DE-CM-RGs) were identified and functional enrichment analyses were performed. Protein-protein interaction network analysis and a two-sample Mendelian randomization study were utilized for identifying hub genes. Nomogram model, competing endogenous RNA and messenger RNA-drug networks were established. In addition, immunoinfiltration analysis was performed. Results We identified four hub genes (MVK, HMGCS1, TM7SF2, and FDPS) linked to NAFLD risk. MVK and TM7SF2 were protective factors, HMGCS1 and FDPS were risk factors for NAFLD. The area under the curve values of nomograms in GSE135251 and GSE126848 were 0.79 and 0.848, respectively. The gene set enrichment analysis indicated that hub genes participated in calcium signaling pathways and biosynthesis of unsaturated fatty acids. NAFLD patients showed increased CD56dim NK cells and Th17. Tretinoin, alendronate, zoledronic acid, and quercetin are potential target agents in NAFLD. Conclusion Our study has linked cholesterol metabolism genes (MVK, HMGCS1, TM7SF2, and FDPS) to NAFLD, providing a promising diagnostic framework, identifying treatment targets, and offering novel perspectives into its mechanisms.
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Affiliation(s)
- Juan Chen
- Department of Gastroenterology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian, China
| | - Huajing Rao
- Emergency Internal Medicine, Affiliated Fuzhou First Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Xiaoling Zheng
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian, China
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Wu X, Yuan C, Pan J, Zhou Y, Pan X, Kang J, Ren L, Gong L, Li Y. CXCL9, IL2RB, and SPP1, potential diagnostic biomarkers in the co-morbidity pattern of atherosclerosis and non-alcoholic steatohepatitis. Sci Rep 2024; 14:16364. [PMID: 39013959 PMCID: PMC11252365 DOI: 10.1038/s41598-024-66287-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/01/2024] [Indexed: 07/18/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a hepatocyte inflammation based on hepatocellular steatosis, yet there is no effective drug treatment. Atherosclerosis (AS) is caused by lipid deposition in the endothelium, which can lead to various cardiovascular diseases. NASH and AS share common risk factors, and NASH can also elevate the risk of AS, causing a higher morbidity and mortality rate for atherosclerotic heart disease. Therefore, timely detection and diagnosis of NASH and AS are particularly important. In this study, differential gene expression analysis and weighted gene co-expression network analysis were performed on the AS (GSE100927) and NASH (GSE89632) datasets to obtain common crosstalk genes, respectively. Then, candidate Hub genes were screened using four topological algorithms and externally validated in the GSE43292 and GSE63067 datasets to obtain Hub genes. Furthermore, immune infiltration analysis and gene set variation analysis were performed on the Hub genes to explore the underlying mechanisms. The DGIbd database was used to screen candidate drugs for AS and NASH. Finally, a NASH model was constructed using free fatty acid-induced human L02 cells, an AS model was constructed using lipopolysaccharide-induced HUVECs, and a co-morbidity model was constructed using L02 cells and HUVECs to verify Hub gene expression. The result showed that a total of 113 genes common to both AS and NASH were identified as crosstalk genes, and enrichment analysis indicated that these genes were mainly involved in the regulation of immune and metabolism-related pathways. 28 candidate Hub genes were screened according to four topological algorithms, and CXCL9, IL2RB, and SPP1 were identified as Hub genes after in vitro experiments and external dataset validation. The ROC curves and SVM modeling demonstrated the good diagnostic efficacy of these three Hub genes. In addition, the Hub genes are strongly associated with immune cell infiltration, especially macrophages and γ-δ T cell infiltration. Finally, five potential therapeutic drugs were identified. has-miR-185 and hsa-miR-335 were closely related to AS and NASH. This study demonstrates that CXCL9, IL2RB, and SPP1 may serve as potential biomarkers for the diagnosis of the co-morbidity patterns of AS and NASH and as potential targets for drug therapy.
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Affiliation(s)
- Xize Wu
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
- Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, Nantong, 226000, Jiangsu, China
| | - Changbin Yuan
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
| | - Jiaxiang Pan
- The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, Liaoning, China
| | - Yi Zhou
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
| | - Xue Pan
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
- Dazhou Vocational College of Chinese Medicine, Dazhou, 635000, Sichuan, China
| | - Jian Kang
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China
| | - Lihong Ren
- Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, Nantong, 226000, Jiangsu, China.
| | - Lihong Gong
- Liaoning University of Traditional Chinese Medicine, No. 79 Chongshan East Road, Huanggu District, Shenyang, 110847, Liaoning, China.
- The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, Liaoning, China.
- Liaoning Provincial Key Laboratory of TCM Geriatric Cardio-Cerebrovascular Diseases, Shenyang, 110847, Liaoning, China.
| | - Yue Li
- The Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, 110032, Liaoning, China.
- Liaoning Provincial Key Laboratory of TCM Geriatric Cardio-Cerebrovascular Diseases, Shenyang, 110847, Liaoning, China.
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Mohammadian K, Fakhar F, Keramat S, Stanek A. The Role of Antioxidants in the Treatment of Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review. Antioxidants (Basel) 2024; 13:797. [PMID: 39061866 PMCID: PMC11273623 DOI: 10.3390/antiox13070797] [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: 05/18/2024] [Revised: 06/19/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global public health problem that causes liver-related morbidity and mortality. It is also an independent risk factor for non-communicable diseases. In 2020, a proposal was made to refer to it as "metabolic dysfunction-associated fatty liver disease (MAFLD)", with concise diagnostic criteria. Given its widespread occurrence, its treatment is crucial. Increased levels of oxidative stress cause this disease. This review aims to evaluate various studies on antioxidant therapies for patients with MAFLD. A comprehensive search for relevant research was conducted on the PubMed, SCOPUS, and ScienceDirect databases, resulting in the identification of 87 studies that met the inclusion criteria. In total, 31.1% of human studies used natural antioxidants, 53.3% used synthetic antioxidants, and 15.5% used both natural and synthetic antioxidants. In human-based studies, natural antioxidants showed 100% efficacy in the treatment of MAFLD, while synthetic antioxidants showed effective results in only 91% of the investigations. In animal-based research, natural antioxidants were fully effective in the treatment of MAFLD, while synthetic antioxidants demonstrated effectiveness in only 87.8% of the evaluations. In conclusion, antioxidants in their natural form are more helpful for patients with MAFLD, and preserving the correct balance of pro-oxidants and antioxidants is a useful way to monitor antioxidant treatment.
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Affiliation(s)
- Kiana Mohammadian
- Division of Hematology and Blood Banking, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz 71348, Iran; (K.M.); (F.F.)
| | - Fatemeh Fakhar
- Division of Hematology and Blood Banking, Department of Medical Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz 71348, Iran; (K.M.); (F.F.)
| | - Shayan Keramat
- VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy;
- Support Association of Patients of Buerger’s Disease, Buerger’s Disease NGO, Mashhad 9183785195, Iran
| | - Agata Stanek
- VAS-European Independent Foundation in Angiology/Vascular Medicine, Via GB Grassi 74, 20157 Milan, Italy;
- Department and Clinic of Internal Medicine, Angiology, and Physical Medicine, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 41-902 Bytom, Poland
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Tian C, Huang R, Xiang M. SIRT1: Harnessing multiple pathways to hinder NAFLD. Pharmacol Res 2024; 203:107155. [PMID: 38527697 DOI: 10.1016/j.phrs.2024.107155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/04/2024] [Accepted: 03/21/2024] [Indexed: 03/27/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. It is the primary cause of chronic liver disorders, with a high prevalence but no approved treatment. Therefore, it is indispensable to find a trustworthy therapy for NAFLD. Recently, mounting evidence illustrates that Sirtuin 1 (SIRT1) is strongly associated with NAFLD. SIRT1 activation or overexpression attenuate NAFLD, while SIRT1 deficiency aggravates NAFLD. Besides, an array of therapeutic agents, including natural compounds, synthetic compounds, traditional Chinese medicine formula, and stem cell transplantation, alleviates NALFD via SIRT1 activation or upregulation. Mechanically, SIRT1 alleviates NAFLD by reestablishing autophagy, enhancing mitochondrial function, suppressing oxidative stress, and coordinating lipid metabolism, as well as reducing hepatocyte apoptosis and inflammation. In this review, we introduced the structure and function of SIRT1 briefly, and summarized the effect of SIRT1 on NAFLD and its mechanism, along with the application of SIRT1 agonists in treating NAFLD.
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Affiliation(s)
- Cheng Tian
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rongrong Huang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ming Xiang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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10
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Liu Y, Qin X, Chen T, Chen M, Wu L, He B. Exploring the interactions between metabolic dysfunction-associated fatty liver disease and micronutrients: from molecular mechanisms to clinical applications. Front Nutr 2024; 11:1344924. [PMID: 38549744 PMCID: PMC10973017 DOI: 10.3389/fnut.2024.1344924] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/05/2024] [Indexed: 01/06/2025] Open
Abstract
Metabolic (dysfunction)-associated fatty liver disease (MAFLD) has emerged as a significant global health concern, representing a major cause of liver disease worldwide. This condition spans a spectrum of histopathologic stages, beginning with simple fatty liver (MAFL), characterized by over 5% fat accumulation, and advancing to metabolic (dysfunction)-associated steatohepatitis, potentially leading to hepatocellular carcinoma. Despite extensive research, there remains a substantial gap in effective therapeutic interventions. This condition's progression is closely tied to micronutrient levels, crucial for biological functions like antioxidant activities and immune efficiency. The levels of these micronutrients exhibit considerable variability among individuals with MAFLD. Moreover, the extent of deficiency in these nutrients can vary significantly throughout the different stages of MAFLD, with disease progression potentially exacerbating these deficiencies. This review focuses on the role of micronutrients, particularly vitamins A, D, E, and minerals like iron, copper, selenium, and zinc, in MAFLD's pathophysiology. It highlights how alterations in the homeostasis of these micronutrients are intricately linked to the pathophysiological processes of MAFLD. Concurrently, this review endeavors to harness the existing evidence to propose novel therapeutic strategies targeting these vitamins and minerals in MAFLD management and offers new insights into disease mechanisms and treatment opportunities in MAFLD.
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Affiliation(s)
- Yuan Liu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Xiang Qin
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Tianzhu Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Mengyao Chen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Liyan Wu
- Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Beihui He
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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11
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Okrit F, Chayanupatkul M, Wanpiyarat N, Siriviriyakul P, Werawatganon D. Genistein and sex hormone treatment alleviated hepatic fat accumulation and inflammation in orchidectomized rats with nonalcoholic steatohepatitis. Heliyon 2024; 10:e26055. [PMID: 38380011 PMCID: PMC10877361 DOI: 10.1016/j.heliyon.2024.e26055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 01/25/2024] [Accepted: 02/07/2024] [Indexed: 02/22/2024] Open
Abstract
Testosterone deficiency has been reported to accelerate nonalcoholic fatty liver disease (NAFLD). However, there are minimal data on the risk of NAFLD in transgender women and the treatment of NAFLD in this population. This study aimed to investigate the treatment effects and the mechanisms of action of genistein and sex hormones in orchiectomized (ORX) rats with nonalcoholic steatohepatitis (NASH) induced by a high fat high fructose diet (HFHF). Seven-week old male Sprague-Dawley rats were randomly divided into 7 groups (n = 6 each group); 1) control group, 2) ORX + standard diet group, 3) HFHF group, 4) ORX + HFHF group, 5) ORX + HFHF diet + testosterone group (50 mg/kg body weight (BW) once weekly), 6) ORX + HFHF diet + estradiol group (1.6 mg/kg BW daily), and 7) ORX + HFHF diet + genistein group (16 mg/kg BW daily). The duration of treatment was 6 weeks. Liver tissue was used for histological examination by hematoxylin and eosin staining and hepatic fat measurement by Oil Red O staining. Protein expression levels of histone deacetylase3 (HDAC3) and peroxisome proliferator-activated receptor delta (PPARδ) were analyzed by immunoblotting. Hepatic nuclear factor (NF)-ĸB expression was evaluated by immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, hepatocyte ballooning and the highest percentage of positive Oil Red O staining area among all groups. The expression of HDAC3 and PPARδ was downregulated, while NF-ĸB expression was upregulated in the ORX + HFHF group when compared with control and ORX + standard diet groups. Testosterone, estradiol and genistein treatment improved histological features of NASH together with the reversal of HDAC3, PPARδ and NF-ĸB protein expression comparing with the ORX + HFHF group. In summary, genistein and sex hormone treatment could alleviate NASH through the up-regulation of HDAC3 and PPARδ, and the suppression of NF-ĸB expression.
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Affiliation(s)
- Fatist Okrit
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Maneerat Chayanupatkul
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natcha Wanpiyarat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Prasong Siriviriyakul
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Duangporn Werawatganon
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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12
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Maiese K. The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk. Front Immunol 2023; 14:1273570. [PMID: 38022638 PMCID: PMC10663950 DOI: 10.3389/fimmu.2023.1273570] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.
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Affiliation(s)
- Kenneth Maiese
- Innovation and Commercialization, National Institutes of Health, Bethesda, MD, United States
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13
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Abstract
Retinoic acid (RA) is a metabolite of vitamin A and is essential for development and growth as well as cellular metabolism. Through genomic and nongenomic actions, RA regulates a variety of physiological functions. Dysregulation of RA signaling is associated with many diseases. Targeting RA signaling has been proven valuable to human health. All-trans retinoic acid (AtRA) and anthracycline-based chemotherapy are the standard treatment of acute promyelocytic leukemia (APL). Both human and animal studies have shown a significant relationship between RA signaling and the development and progression of nonalcoholic fatty liver disease (NAFLD). In this review article, we will first summarize vitamin A metabolism and then focus on the role of RA signaling in NAFLD. AtRA inhibits the development and progression of NAFLD via regulating lipid metabolism, inflammation, thermogenesis, etc.
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Affiliation(s)
- Fathima N Cassim Bawa
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA 44272
| | - Yanqiao Zhang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA 44272
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14
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Munteanu C, Schwartz B. The Effect of Bioactive Aliment Compounds and Micronutrients on Non-Alcoholic Fatty Liver Disease. Antioxidants (Basel) 2023; 12:antiox12040903. [PMID: 37107278 PMCID: PMC10136128 DOI: 10.3390/antiox12040903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 03/28/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
In the current review, we focused on identifying aliment compounds and micronutrients, as well as addressed promising bioactive nutrients that may interfere with NAFLD advance and ultimately affect this disease progress. In this regard, we targeted: 1. Potential bioactive nutrients that may interfere with NAFLD, specifically dark chocolate, cocoa butter, and peanut butter which may be involved in decreasing cholesterol concentrations. 2. The role of sweeteners used in coffee and other frequent beverages; in this sense, stevia has proven to be adequate for improving carbohydrate metabolism, liver steatosis, and liver fibrosis. 3. Additional compounds were shown to exert a beneficial action on NAFLD, namely glutathione, soy lecithin, silymarin, Aquamin, and cannabinoids which were shown to lower the serum concentration of triglycerides. 4. The effects of micronutrients, especially vitamins, on NAFLD. Even if most studies demonstrate the beneficial role of vitamins in this pathology, there are exceptions. 5. We provide information regarding the modulation of the activity of some enzymes related to NAFLD and their effect on this disease. We conclude that NAFLD can be prevented or improved by different factors through their involvement in the signaling, genetic, and biochemical pathways that underlie NAFLD. Therefore, exposing this vast knowledge to the public is particularly important.
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Affiliation(s)
- Camelia Munteanu
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
| | - Betty Schwartz
- The Institute of Biochemistry, Food Science and Nutrition, The School of Nutritional Sciences, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel
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15
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Yao JM, Ying HZ, Zhang HH, Qiu FS, Wu JQ, Yu CH. Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells. Free Radic Biol Med 2023; 195:58-73. [PMID: 36572267 DOI: 10.1016/j.freeradbiomed.2022.12.085] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/13/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022]
Abstract
Exosomes containing various biological cargoes have potential to be novel diagnostic biomarkers for metabolic diseases. In this study, retinol-binding protein 4 (RBP4) was found to be enriched in serum exosomes, and its increased levels could be considered as an independent risk factor for the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Exosomal RBP4 (exo-RBP4), primarily derived from hepatocytes, significantly enhanced the M1-like polarization of Kupffer cells (KCs) via promoting the activation of NOX2 and NF-κB and reactive oxygen species (ROS) accumulation, resulting in the over-production of inflammatory cytokines including TNF-α. Subsequently, those excess cytokines remarkably increased the levels of intracellular free fatty acid uptake and lipogenesis-related genes (FAS and SREBP-1c) but decreased fatty acid degradation-related genes (CPT-1 and PPARα) in palmitic acid-treated LO2 cells. More notably, TNF-α significantly elevated RBP4 transcription by activating STAT3 in hepatocytes, playing a positive role in NAFLD development. Intravenous injection with RBP4 (50 μg/kg) potentiated hepatic lipid accumulation, M1-type KC proportion, and serum pro-inflammatory cytokine levels in the hepatic tissues of high-fat-diet-fed mice. Collectively, these data indicated that exo-RBP4 converted KCs to M1 subtype by mediating the NOX2/ROS/NF-κB pathway, subsequently promoting de novo lipogenesis in hepatocytes by TNF-α secretion to activate the JAK2/STAT3 signaling pathway. Therefore, this study uncovered a novel intercellular communication between the inflammatory microenvironment and lipid metabolism for fostering NAFLD progression and found the potential of exo-RBP4 as a novel diagnostic biomarker and therapeutic target for NAFLD.
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Affiliation(s)
- Jin-Mei Yao
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Hua-Zhong Ying
- Zhejiang Provincial Laboratory of Experimental Animal's & Nonclinical Laboratory Studies, Hangzhou Medical College, Hangzhou, 310013, China
| | - Huan-Huan Zhang
- Zhejiang Provincial Laboratory of Experimental Animal's & Nonclinical Laboratory Studies, Hangzhou Medical College, Hangzhou, 310013, China
| | - Fen-Sheng Qiu
- Zhejiang Provincial Laboratory of Experimental Animal's & Nonclinical Laboratory Studies, Hangzhou Medical College, Hangzhou, 310013, China; Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310018, China; Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China
| | - Jun-Qi Wu
- Clinical Laboratory, Jinhua Municipal Central Hospital Medical Group, Jinhua, 321000, China
| | - Chen-Huan Yu
- Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, 310018, China; Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China; Institute of Rheumatology and Immunology, Zhejiang Provincial People's Hospital (Hangzhou Medical College), Hangzhou, 310014, China.
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16
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Zhu S, Zhang J, Zhu D, Jiang X, Wei L, Wang W, Chen YQ. Adipose tissue plays a major role in retinoic acid-mediated metabolic homoeostasis. Adipocyte 2022; 11:47-55. [PMID: 34957917 PMCID: PMC8726720 DOI: 10.1080/21623945.2021.2015864] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Retinoic acid (RA), a bioactive metabolite of vitamin A, has shown therapeutic effects in liver disease, and its effect in improving non-alcoholic fatty liver disease (NAFLD) is associated with the inhibition of adipogenesis in the white adipose tissue (WAT) and fatty acid oxidation induction in the liver. However, the major target organ of RA is unknown. We performed chronic administration of RA in high-fat diet (HFD)-induced NAFLD mice. Further, hepatic and adipose cells were used to study the direct effect of RA on lipid metabolism. In addition, qRT-PCR was performed to examine differential gene expression in mouse adipose tissue. RA administration ameliorated NAFLD in HFD-induced obese mice and increased mouse energy expenditure. Although RA had therapeutic effects on liver histology and lipid accumulation, it did not directly affect lipid metabolism in HepG2 cells. In contrast, RA reduced the weight of several adipose tissues and improved lipid accumulation in OP9 cells. In addition, RA upregulated genes responsible for fatty acid oxidation and thermogenesis in three different WATs. Our work suggests that the liver may not be the main target organ of RA during NAFLD treatment. WAT browning induced by RA may be the primary contributor towards the amelioration of NAFLD in HFD-induced obese mice.
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Affiliation(s)
- Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, China
| | - Jingwei Zhang
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Doudou Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Xuan Jiang
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Lengyun Wei
- School of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Wei Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Yong Q. Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
- Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, China
- School of Food Science and Technology, Jiangnan University, Wuxi, China
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17
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Steinhoff JS, Wagner C, Taschler U, Wulff S, Kiefer MF, Petricek KM, Wowro SJ, Oster M, Flores RE, Yang N, Li C, Meng Y, Sommerfeld M, Weger S, Henze A, Raila J, Lass A, Schupp M. Acute retinol mobilization by retinol-binding protein 4 in mouse liver induces fibroblast growth factor 21 expression. J Lipid Res 2022; 63:100268. [PMID: 36030930 PMCID: PMC9493389 DOI: 10.1016/j.jlr.2022.100268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/19/2022] [Accepted: 08/20/2022] [Indexed: 11/22/2022] Open
Abstract
Hepatocytes secrete retinol-binding protein 4 (RBP4) into circulation, thereby mobilizing vitamin A from the liver to provide retinol for extrahepatic tissues. Obesity and insulin resistance are associated with elevated RBP4 levels in the blood. However, in a previous study, we observed that chronically increased RBP4 by forced Rbp4 expression in the liver does not impair glucose homeostasis in mice. Here, we investigated the effects of an acute mobilization of hepatic vitamin A stores by hepatic overexpression of RBP4 in mice. We show that hepatic retinol mobilization decreases body fat content and enhances fat turnover. Mechanistically, we found that acute retinol mobilization increases hepatic expression and serum levels of fibroblast growth factor 21 (FGF21), which is regulated by retinol mobilization and retinoic acid in primary hepatocytes. Moreover, we provide evidence that the insulin-sensitizing effect of FGF21 is associated with organ-specific adaptations in retinoid homeostasis. Taken together, our findings identify a novel crosstalk between retinoid homeostasis and FGF21 in mice with acute RBP4-mediated retinol mobilization from the liver.
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Affiliation(s)
- Julia S Steinhoff
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Carina Wagner
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Ulrike Taschler
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Sascha Wulff
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Marie F Kiefer
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Konstantin M Petricek
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Sylvia J Wowro
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Moritz Oster
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Roberto E Flores
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Na Yang
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Chen Li
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Yueming Meng
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Manuela Sommerfeld
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany
| | - Stefan Weger
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Campus Benjamin Franklin, Berlin, Germany
| | - Andrea Henze
- Martin Luther University Halle-Wittenberg, Institute of Agricultural and Nutritional Sciences, Halle, Germany; Junior Research Group ProAID, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Jens Raila
- Department of Physiology and Pathophysiology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Achim Lass
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
| | - Michael Schupp
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany.
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18
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Whey protein protects liver mitochondrial function against oxidative stress in rats exposed to acrolein. Arh Hig Rada Toksikol 2022; 73:200-206. [PMID: 36226819 PMCID: PMC9837534 DOI: 10.2478/aiht-2022-73-3640] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 08/01/2022] [Indexed: 12/13/2022] Open
Abstract
Acrolein (AC) is one of the most toxic environmental pollutants, often associated with incomplete combustion of petrol, wood, and plastic, oil frying, and tobacco smoking, that causes oxidative damage to DNA and mitochondria. Considering that little is known about the protective effects of whey protein (WP) against AC-induced liver toxicity, the aim of our study was to learn more about them in respect to liver mitochondrial oxidative stress, respiratory enzymes, Krebs cycle enzymes, and adenosine triphosphate (ATP). To do that, we treated Sprague Dawley rats with daily doses of AC alone (5 mg/kg bw in 0.9 % NaCl solution), WP alone (200 mg/kg bw, in 0.9 % NaCl solution), or their combination by oral gavage for six days a week over 30 days. As expected, the AC group showed a drop in glutathione levels and antioxidant, transport chain, and tricarboxylic acid cycle enzyme activities and a significant rise in mitochondrial lipid peroxidation and protein carbonyl levels. Co-treatment with WP mitigated oxidative stress and improved enzyme activities. Judging by the measured parameters, WP reduced AC toxicity by improving bioenergetic mechanisms and eliminating oxidative stress.
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19
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A Molecular Insight into the Role of Antioxidants in Nonalcoholic Fatty Liver Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9233650. [PMID: 35602098 PMCID: PMC9117022 DOI: 10.1155/2022/9233650] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines fat accumulation in the liver, and it is commonly associated with metabolic syndromes like diabetes and obesity. Progressive NAFLD leads to nonalcoholic steatohepatitis (NASH) and ultimately causes cirrhosis and hepatocellular carcinoma, and NASH is currently a frequent cause of liver transplantation. Oxidative stress is often contributed to the progression of NAFLD, and hence, antioxidants such as silymarin, silybin, or silibinin, pentoxifylline, resveratrol, and vitamins A, C, and E are used in clinical trials against NAFLD. Silymarin induces the peroxisome proliferator-activated receptor α (PPARα), a fatty acid sensor, which promotes the transcription of genes that are required for the enzymes involved in lipid oxidation in hepatocytes. Silybin inhibits sterol regulatory element-binding protein 1 and carbohydrate response element-binding protein to downregulate the expression of genes responsible for de novo lipogenesis by activating AMP-activated protein kinase phosphorylation. Pentoxifylline inhibits TNF-α expression and endoplasmic reticulum stress-mediated inflammatory nuclear factor kappa B (NF-κB) activation. Thus, it prevents NAFLD to NASH progression. Resveratrol inhibits methylation at Nrf-2 promoters and NF-κB activity via SIRT1 activation in NAFLD conditions. However, clinically, resveratrol has not shown promising beneficial effects. Vitamin C is beneficial in NAFLD patients. Vitamin E is not effectively regressing hepatic fibrosis. Hence, its combination with antifibrotic agents is used as an adjuvant to produce a synergistic antifibrotic effect. However, to date, none of these antioxidants have been used as a definite therapeutic agent in NAFLD patients. Further, these antioxidants should be studied in NAFLD patients with larger populations and multiple endpoints in the future.
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20
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Melis M, Tang XH, Trasino SE, Gudas LJ. Retinoids in the Pathogenesis and Treatment of Liver Diseases. Nutrients 2022; 14:1456. [PMID: 35406069 PMCID: PMC9002467 DOI: 10.3390/nu14071456] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/24/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023] Open
Abstract
Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARβ, and RARγ, all-trans-retinoic acid, an active metabolite of VA, is a potent regulator of numerous biological pathways, including embryonic and somatic cellular differentiation, immune functions, and energy metabolism. The liver is the primary organ for retinoid storage and metabolism in humans. For reasons that remain incompletely understood, a body of evidence shows that reductions in liver retinoids, aberrant retinoid metabolism, and reductions in RAR signaling are implicated in numerous diseases of the liver, including hepatocellular carcinoma, non-alcohol-associated fatty liver diseases, and alcohol-associated liver diseases. Conversely, restoration of retinoid signaling, pharmacological treatments with natural and synthetic retinoids, and newer agonists for specific RARs show promising benefits for treatment of a number of these liver diseases. Here we provide a comprehensive review of the literature demonstrating a role for retinoids in limiting the pathogenesis of these diseases and in the treatment of liver diseases.
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Affiliation(s)
- Marta Melis
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA; (M.M.); (X.-H.T.)
| | - Xiao-Han Tang
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA; (M.M.); (X.-H.T.)
| | - Steven E. Trasino
- Nutrition Program, Hunter College, City University of New York, New York, NY 10065, USA;
| | - Lorraine J. Gudas
- Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA; (M.M.); (X.-H.T.)
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21
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Garcinia cambogia Ameliorates Non-Alcoholic Fatty Liver Disease by Inhibiting Oxidative Stress-Mediated Steatosis and Apoptosis through NRF2-ARE Activation. Antioxidants (Basel) 2021; 10:antiox10081226. [PMID: 34439474 PMCID: PMC8388869 DOI: 10.3390/antiox10081226] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 07/28/2021] [Indexed: 12/14/2022] Open
Abstract
Excessive free fatty acids (FFAs) causes reactive oxygen species (ROS) generation and non-alcoholic fatty liver disease (NAFLD) development. Garcinia cambogia (G. cambogia) is used as an anti-obesity supplement, and its protective potential against NAFLD has been investigated. This study aims to present the therapeutic effects of G. cambogia on NAFLD and reveal underlying mechanisms. High-fat diet (HFD)-fed mice were administered G. cambogia for eight weeks, and steatosis, apoptosis, and biochemical parameters were examined in vivo. FFA-induced HepG2 cells were treated with G. cambogia, and lipid accumulation, apoptosis, ROS level, and signal alterations were examined. The results showed that G. cambogia inhibited HFD-induced steatosis and apoptosis and abrogated abnormalities in serum chemistry. G. cambogia increased in NRF2 nuclear expression and activated antioxidant responsive element (ARE), causing induction of antioxidant gene expression. NRF2 activation inhibited FFA-induced ROS production, which suppressed lipogenic transcription factors, C/EBPα and PPARγ. Moreover, the ability of G. cambogia to inhibit ROS production suppressed apoptosis by normalizing the Bcl-2/BAX ratio and PARP cleavage. Lastly, these therapeutic effects of G. cambogia were due to hydroxycitric acid (HCA). These findings provide new insight into the mechanism by which G. cambogia regulates NAFLD progression.
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22
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Maiese K. Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways. Biomolecules 2021; 11:1002. [PMID: 34356626 PMCID: PMC8301848 DOI: 10.3390/biom11071002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 01/18/2023] Open
Abstract
Neurodegenerative disorders affect fifteen percent of the world's population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer's disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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23
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Yang FC, Xu F, Wang TN, Chen GX. Roles of vitamin A in the regulation of fatty acid synthesis. World J Clin Cases 2021; 9:4506-4519. [PMID: 34222419 PMCID: PMC8223857 DOI: 10.12998/wjcc.v9.i18.4506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/25/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Dietary macronutrients and micronutrients play important roles in human health. On the other hand, the excessive energy derived from food is stored in the form of triacylglycerol. A variety of dietary and hormonal factors affect this process through the regulation of the activities and expression levels of those key player enzymes involved in fatty acid biosynthesis such as acetyl-CoA carboxylase, fatty acid synthase, fatty acid elongases, and desaturases. As a micronutrient, vitamin A is essential for the health of humans. Recently, vitamin A has been shown to play a role in the regulation of glucose and lipid metabolism. This review summarizes recent research progresses about the roles of vitamin A in fatty acid synthesis. It focuses on the effects of vitamin A on the activities and expression levels of mRNA and proteins of key enzymes for fatty acid synthesis in vitro and in vivo. It appears that vitamin A status and its signaling pathway regulate the expression levels of enzymes involved in fatty acid synthesis. Future research directions are also discussed.
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Affiliation(s)
- Fu-Chen Yang
- Food College, Jiangsu Food and Pharmaceutical College, Huaian 223003, Jiangsu Province, China
| | - Feng Xu
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Tian-Nan Wang
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37909, United States
| | - Guo-Xun Chen
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37909, United States
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24
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Nan W, Si H, Zhang H, Mu L, Li G, Lou Y. Effect of dietary vitamin A supplementation on growth performance, nutrient digestibility, serum parameters and liver histology of growing-furring male mink kits (Neovison vison). Anim Feed Sci Technol 2021. [DOI: 10.1016/j.anifeedsci.2021.114898] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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Maiese K. Nicotinamide as a Foundation for Treating Neurodegenerative Disease and Metabolic Disorders. Curr Neurovasc Res 2021; 18:134-149. [PMID: 33397266 PMCID: PMC8254823 DOI: 10.2174/1567202617999210104220334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023]
Abstract
Neurodegenerative disorders impact more than one billion individuals worldwide and are intimately tied to metabolic disease that can affect another nine hundred individuals throughout the globe. Nicotinamide is a critical agent that may offer fruitful prospects for neurodegenerative diseases and metabolic disorders, such as diabetes mellitus. Nicotinamide protects against multiple toxic environments that include reactive oxygen species exposure, anoxia, excitotoxicity, ethanolinduced neuronal injury, amyloid (Aß) toxicity, age-related vascular disease, mitochondrial dysfunction, insulin resistance, excess lactate production, and loss of glucose homeostasis with pancreatic β-cell dysfunction. However, nicotinamide offers cellular protection in a specific concentration range, with dosing outside of this range leading to detrimental effects. The underlying biological pathways of nicotinamide that involve the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and mammalian forkhead transcription factors (FoxOs) may offer insight for the clinical translation of nicotinamide into a safe and efficacious therapy through the modulation of oxidative stress, apoptosis, and autophagy. Nicotinamide is a highly promising target for the development of innovative strategies for neurodegenerative disorders and metabolic disease, but the benefits of this foundation depend greatly on gaining a further understanding of nicotinamide's complex biology.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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26
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Ilić I, Oršolić N, Rođak E, Odeh D, Lovrić M, Mujkić R, Delaš Aždajić M, Grgić A, Tolušić Levak M, Vargek M, Dmitrović B, Belovari T. The effect of high-fat diet and 13-cis retinoic acid application on lipid profile, glycemic response and oxidative stress in female Lewis rats. PLoS One 2020; 15:e0238600. [PMID: 32947606 PMCID: PMC7500970 DOI: 10.1371/journal.pone.0238600] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 08/19/2020] [Indexed: 01/24/2023] Open
Abstract
Vitamin A and its metabolites are key regulators of the development of adipose tissue and associated metabolic complications. The aim of this study was to determine the effect of high fat diet and 13-cis retinoic acid (13 cRA) application on metabolic parameters, adipogenic and inflammatory indicators in female Lewis rats. Female rats of Lewis strain were fed standard laboratory diet (STD) and high fat diet (HFD, 45% of saturated fatty acids) during 30 days. The groups were divided into additional 3 groups (6 rats each): two experimental groups that received 13 cRA orally on a daily basis during 30 days (7.5 mg/kg and 15 mg/kg, respectively) and the control group that was given sunflower oil. Animals were sacrificed after 60 days. Feeding of Lewis rats with chronic HFD diet with 13 cRA supplementation increased weight gain, adiposity index, dyslipidaemia, hyperleptinaemia, insulin resistance, VLDL concentrations, oxidative stress and atherogenic indices. Administration of 13 cRA in Lewis rats fed STD did not change the weight of the animals, but it slightly increased the atherogenic parameters. 13 cRA and HFD affect metabolic parameters, glucose and lipid metabolism in Lewis rats and its administration has a completely different effect on metabolism in rats fed STD, highlighting the complex role of vitamin A supplementation in obesity. Other factors, such as genetics, age, sex, adipose tissue distribution, also must be taken into consideration.
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Affiliation(s)
- Ivana Ilić
- Department of Anatomy, Histology, Embryology, Pathological Anatomy and Pathological Histology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Department of Histology and Embryology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Nada Oršolić
- Department of Animal Physiology, Faculty of Science Zagreb, University of Zagreb, Zagreb, Croatia
| | - Edi Rođak
- Department of Histology and Embryology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Dyana Odeh
- Department of Animal Physiology, Faculty of Science Zagreb, University of Zagreb, Zagreb, Croatia
| | - Marko Lovrić
- Department of Histology and Embryology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Robert Mujkić
- Department of Anatomy, Histology, Embryology, Pathological Anatomy and Pathological Histology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Marija Delaš Aždajić
- Department of Dermatology and Venereology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Anđela Grgić
- Department of Anatomy, Histology, Embryology, Pathological Anatomy and Pathological Histology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Maja Tolušić Levak
- Department of Histology and Embryology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Department of Dermatology and Venereology, University Hospital Osijek, Osijek, Croatia
| | - Martin Vargek
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Branko Dmitrović
- Department of Anatomy, Histology, Embryology, Pathological Anatomy and Pathological Histology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
- Clinical Institute of Pathology and Forensic Medicine, University Hospital Osijek, Osijek, Croatia
| | - Tatjana Belovari
- Department of Histology and Embryology, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
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27
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Patruno I, Thompson D, Dall'Angelo S, Windhorst AD, Vugts DJ, Poot AJ, Mody N, Zanda M. Design, Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome-Preventive Agents. ChemMedChem 2020; 15:1579-1590. [PMID: 32497314 DOI: 10.1002/cmdc.202000143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/21/2020] [Indexed: 12/31/2022]
Abstract
Fenretinide (4-HPR) is a synthetic derivative of all-trans-retinoic acid (ATRA) characterised by improved therapeutic properties and toxicological profile relative to ATRA. 4-HPR has been mostly investigated as an anti-cancer agent, but recent studies showed its promising therapeutic potential for preventing metabolic syndrome. Several biological targets are involved in 4-HPR's activity, leading to the potential use of this molecule for treating different pathologies. However, although 4-HPR displays quite well-understood multitarget promiscuity with regards to pharmacology, interpreting its precise physiological role remains challenging. In addition, despite promising results in vitro, the clinical efficacy of 4-HPR as a chemotherapeutic agent has not been satisfactory so far. Herein, we describe the preparation of a library of 4-HPR analogues, followed by the biological evaluation of their anti-cancer and anti-obesity/diabetic properties. The click-type analogue 3 b showed good capacity to reduce the amount of lipid accumulation in 3T3-L1 adipocytes during differentiation. Furthermore, it showed an IC50 of 0.53±0.8 μM in cell viability tests on breast cancer cell line MCF-7, together with a good selectivity (SI=121) over noncancerous HEK293 cells. Thus, 3 b was selected as a potential PET tracer to study retinoids in vivo, and the radiosynthesis of [18 F]3b was successfully developed. Unfortunately, the stability of [18 F]3b turned out to be insufficient to pursue imaging studies.
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Affiliation(s)
- Ilaria Patruno
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK
| | - Dawn Thompson
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK
| | - Sergio Dall'Angelo
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK
| | - Albert D Windhorst
- Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Danielle J Vugts
- Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Alex J Poot
- Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Nimesh Mody
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK
| | - Matteo Zanda
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.,C.N.R.-SCITEC, via Mancinelli 7, 20131, Milan, Italy.,Current address: Loughborough University School of Science, Centre for Sensing and Imaging Science Sir David Davies Building, Loughborough, LE11 3TU, UK
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28
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Bonet ML, Ribot J, Galmés S, Serra F, Palou A. Carotenoids and carotenoid conversion products in adipose tissue biology and obesity: Pre-clinical and human studies. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158676. [PMID: 32120014 DOI: 10.1016/j.bbalip.2020.158676] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 02/07/2023]
Abstract
Antiobesity activities of carotenoids and carotenoid conversion products (CCPs) have been demonstrated in pre-clinical studies, and mechanisms behind have begun to be unveiled, thus suggesting these compounds may help obesity prevention and management. The antiobesity action of carotenoids and CCPs can be traced to effects in multiple tissues, notably the adipose tissues. Key aspects of the biology of adipose tissues appear to be affected by carotenoid and CCPs, including adipogenesis, metabolic capacities for energy storage, release and inefficient oxidation, secretory function, and modulation of oxidative stress and inflammatory pathways. Here, we review the connections of carotenoids and CCPs with adipose tissue biology and obesity as revealed by cell and animal intervention studies, studies addressing the role of endogenous retinoid metabolism, and human epidemiological and intervention studies. We also consider human genetic variability influencing carotenoid and vitamin A metabolism, particularly in adipose tissues, as a potentially relevant aspect towards personalization of dietary recommendations to prevent or manage obesity and optimize metabolic health. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.
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Affiliation(s)
- M Luisa Bonet
- Grup de Recerca Nutrigenòmica i Obesitat, Laboratori de Biologia Molecular, Nutrició i Biotecnologia (LBNB), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain.
| | - Joan Ribot
- Grup de Recerca Nutrigenòmica i Obesitat, Laboratori de Biologia Molecular, Nutrició i Biotecnologia (LBNB), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain
| | | | - Francisca Serra
- Grup de Recerca Nutrigenòmica i Obesitat, Laboratori de Biologia Molecular, Nutrició i Biotecnologia (LBNB), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain
| | - Andreu Palou
- Grup de Recerca Nutrigenòmica i Obesitat, Laboratori de Biologia Molecular, Nutrició i Biotecnologia (LBNB), Universitat de les Illes Balears, Palma de Mallorca, Spain; Institut d'Investigació Sanitària Illes Balears (IdISBa), Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Spain
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Maiese K. Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes. Curr Neurovasc Res 2020; 17:765-783. [PMID: 33183203 PMCID: PMC7914159 DOI: 10.2174/1567202617999201111195232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022]
Abstract
Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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30
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Ye TJ, Lu YL, Yan XF, Hu XD, Wang XL. High mobility group box-1 release from H 2O 2-injured hepatocytes due to sirt1 functional inhibition. World J Gastroenterol 2019; 25:5434-5450. [PMID: 31576091 PMCID: PMC6767985 DOI: 10.3748/wjg.v25.i36.5434] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 08/07/2019] [Accepted: 08/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND High mobility group box-1 (HMGB1), recognized as a representative of damage-associated molecular patterns, is released during cell injury/death, triggering the inflammatory response and ultimately resulting in tissue damage. Dozens of studies have shown that HMGB1 is involved in certain diseases, but the details on how injured hepatocytes release HMGB1 need to be elicited.
AIM To reveal HMGB1 release mechanism in hepatocytes undergoing oxidative stress.
METHODS C57BL6/J male mice were fed a high-fat diet for 12 wk plus a single binge of ethanol to induce severe steatohepatitis. Hepatocytes treated with H2O2 were used to establish an in vitro model. Serum alanine aminotransferase, liver H2O2 content and catalase activity, lactate dehydrogenase and 8-hydroxy-2-deoxyguanosine content, nicotinamide adenine dinucleotide (NAD+) levels, and Sirtuin 1 (Sirt1) activity were detected by spectrophotometry. HMGB1 release was measured by enzyme linked immunosorbent assay. HMGB1 translocation was observed by immunohistochemistry/immunofluorescence or Western blot. Relative mRNA levels were assayed by qPCR and protein expression was detected by Western blot. Acetylated HMGB1 and poly(ADP-ribose)polymerase 1 (Parp1) were analyzed by Immunoprecipitation.
RESULTS When hepatocytes were damaged, HMGB1 translocated from the nucleus to the cytoplasm because of its hyperacetylation and was passively released outside both in vivo and in vitro. After treatment with Sirt1-siRNA or Sirt1 inhibitor (EX527), the hyperacetylated HMGB1 in hepatocytes increased, and Sirt1 activity inhibited by H2O2 could be reversed by Parp1 inhibitor (DIQ). Parp1 and Sirt1 are two NAD+-dependent enzymes which play major roles in the decision of a cell to live or die in the context of stress . We showed that NAD+ depletion attributed to Parp1 activation after DNA damage was caused by oxidative stress in hepatocytes and resulted in Sirt1 activity inhibition. On the contrary, Sirt1 suppressed Parp1 by negatively regulating its gene expression and deacetylation.
CONCLUSION The functional inhibition between Parp1 and Sirt1 leads to HMGB1 hyperacetylation, which leads to its translocation from the nucleus to the cytoplasm and finally outside the cell.
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Affiliation(s)
- Ting-Jie Ye
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan-Lin Lu
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Oncology and Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xiao-Feng Yan
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xu-Dong Hu
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiao-Ling Wang
- Department of Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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31
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Peroxiredoxin 5 ameliorates obesity-induced non-alcoholic fatty liver disease through the regulation of oxidative stress and AMP-activated protein kinase signaling. Redox Biol 2019; 28:101315. [PMID: 31505325 PMCID: PMC6736789 DOI: 10.1016/j.redox.2019.101315] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/23/2019] [Accepted: 09/01/2019] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally. NAFLD—which can develop into liver fibrosis, nonalcoholic steatohepatosis, cirrhosis, and hepatocellular carcinoma—is defined as an excess accumulation of fat caused by abnormal lipid metabolism and excessive reactive oxygen species (ROS) generation in hepatocytes. Recently, we reported that Peroxiredoxin 5 (Prx5) plays an essential role in regulating adipogenesis and suggested the need to further investigation on the potential curative effects of Prx5 on obesity-induced fatty liver disease. In the present study, we focused on the role of Prx5 in fatty liver disease. We found that Prx5 overexpression significantly suppressed cytosolic and mitochondrial ROS generation. Additionally, Prx5 regulated the AMP-activated protein kinase pathway and lipogenic gene (sterol regulatory element binding protein-1 and FAS) expression; it also inhibited lipid accumulation, resulting in the amelioration of free fatty acid-induced hepatic steatosis. Silence of Prx5 triggered de novo lipogenesis and abnormal lipid accumulation in HepG2 cells. Concordantly, Prx5 knockout mice exhibited a high susceptibility to obesity-induced hepatic steatosis. Liver sections of Prx5-deletion mice fed on a high-fat diet displayed Oil Red O-stained dots and small leaky shapes due to immoderate fat deposition. Collectively, our findings suggest that Prx5 functions as a protective regulator in fatty liver disease and that it may be a valuable therapeutic target for the management of obesity-related metabolic diseases.
Prx5 decreased the FFA-induced intracellular and mitochondrial ROS generation. Prx5 improved hepatic steatosis via regulation of AMP-activated protein kinase. Knockout of Prx5 aggravated obesity related fatty liver disease. Prx5 has a crucial role in hepatic lipid metabolism.
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Maiese K. Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer. Curr Neurovasc Res 2018; 14:299-304. [PMID: 28721811 DOI: 10.2174/1567202614666170718092010] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 06/22/2017] [Accepted: 07/06/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease. METHODS In light of the significant role circadian rhythm can hold over the body's normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis. RESULTS In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer's disease and Parkinson's disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury and block tumor cell growth. CONCLUSION Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, NY. United States
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The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders. Biochem Soc Trans 2018. [PMID: 29523769 DOI: 10.1042/bst20170121] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
As a result of the advancing age of the global population and the progressive increase in lifespan, neurodegenerative disorders continue to increase in incidence throughout the world. New strategies for neurodegenerative disorders involve the novel pathways of the mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) that can modulate pathways of apoptosis and autophagy. The pathways of mTOR and SIRT1 are closely integrated. mTOR forms the complexes mTOR Complex 1 and mTOR Complex 2 and can impact multiple neurodegenerative disorders that include Alzheimer's disease, Huntington's disease, and Parkinson's disease. SIRT1 can control stem cell proliferation, block neuronal injury through limiting programmed cell death, drive vascular cell survival, and control clinical disorders that include dementia and retinopathy. It is important to recognize that oversight of programmed cell death by mTOR and SIRT1 requires a fine degree of precision to prevent the progression of neurodegenerative disorders. Additional investigations and insights into these pathways should offer effective and safe treatments for neurodegenerative disorders.
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Maiese K. Sirtuins: Developing Innovative Treatments for Aged-Related Memory Loss and Alzheimer's Disease. Curr Neurovasc Res 2018; 15:367-371. [PMID: 30484407 PMCID: PMC6538488 DOI: 10.2174/1567202616666181128120003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/14/2018] [Accepted: 10/20/2018] [Indexed: 02/07/2023]
Abstract
The world's population continues to age at a rapid pace. By the year 2050, individuals over the age of 65 will account for sixteen percent of the world's population and life expectancy will increase well over eighty years of age. Accompanied by the aging of the global population is a significant rise in Non-Communicable Diseases (NCDs). Neurodegenerative disorders will form a significant component for NCDs. Currently, dementia is the 7th leading cause of death and can be the result of multiple causes that include diabetes mellitus, vascular disease, and Alzheimer's Disease (AD). AD may represent at least sixty percent of these cases. Current treatment for these disorders is extremely limited to provide only some symptomatic relief at present. Sirtuins and in particular, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), represent innovative strategies for the treatment of cognitive loss. New work has revealed that SIRT1 provides protection against memory loss through mechanisms that involve oxidative stress, Aβ toxicity, neurofibrillary degeneration, vascular injury, mitochondrial dysfunction, and neuronal loss. In addition, SIRT1 relies upon other avenues that can include trophic factors, such as erythropoietin, and signaling pathways, such as Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). Yet, SIRT1 can have detrimental effects as well that involve tumorigenesis and blockade of stem cell differentiation and maturation that can limit reparative processes for cognitive loss. Further investigations with sirtuins and SIRT1 should be able to capitalize upon these novel targets for dementia and cognitive loss.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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Maiese K. Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors. Curr Neurovasc Res 2018; 15:81-91. [PMID: 29557749 PMCID: PMC6021214 DOI: 10.2174/1567202615666180319151244] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 01/23/2018] [Accepted: 02/07/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND With the global increase in lifespan expectancy, neurodegenerative disorders continue to affect an ever-increasing number of individuals throughout the world. New treatment strategies for neurodegenerative diseases are desperately required given the lack of current treatment modalities. METHODS Here, we examine novel strategies for neurodegenerative disorders that include circadian clock genes, non-coding Ribonucleic Acids (RNAs), and the mammalian forkhead transcription factors of the O class (FoxOs). RESULTS Circadian clock genes, non-coding RNAs, and FoxOs offer exciting prospects to potentially limit or remove the significant disability and death associated with neurodegenerative disorders. Each of these pathways has an intimate relationship with the programmed death pathways of autophagy and apoptosis and share a common link to the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and the mechanistic target of rapamycin (mTOR). Circadian clock genes are necessary to modulate autophagy, limit cognitive loss, and prevent neuronal injury. Non-coding RNAs can control neuronal stem cell development and neuronal differentiation and offer protection against vascular disease such as atherosclerosis. FoxOs provide exciting prospects to block neuronal apoptotic death and to activate pathways of autophagy to remove toxic accumulations in neurons that can lead to neurodegenerative disorders. CONCLUSION Continued work with circadian clock genes, non-coding RNAs, and FoxOs can offer new prospects and hope for the development of vital strategies for the treatment of neurodegenerative diseases. These innovative investigative avenues have the potential to significantly limit disability and death from these devastating disorders.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, Newark, New Jersey 07101
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Simões ICM, Fontes A, Pinton P, Zischka H, Wieckowski MR. Mitochondria in non-alcoholic fatty liver disease. Int J Biochem Cell Biol 2017; 95:93-99. [PMID: 29288054 DOI: 10.1016/j.biocel.2017.12.019] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 12/18/2017] [Accepted: 12/20/2017] [Indexed: 12/11/2022]
Abstract
NAFLD is a common disease in Western society and ranges from steatosis to steatohepatitis and to end-stage liver disease. The molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood. One suggested mechanism involves the oxidation of biomolecules by mitochondrial ROS which initiates a vicious cycle of exacerbated mitochondrial dysfunction and increased hepatocellular oxidative damage. This may ultimately pave the way for hepatic inflammation and liver failure. This review updates our current understanding of mitochondria-derived oxidative stress in the progression of NAFLD.
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Affiliation(s)
- Inês C M Simões
- Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur 3 Str., 02-093 Warsaw, Poland
| | - Adriana Fontes
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstraße 1, D-85764, Neuherberg, Germany
| | - Paolo Pinton
- Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
| | - Hans Zischka
- Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Ingolstaedter Landstraße 1, D-85764, Neuherberg, Germany; Institute of Toxicology and Environmental Hygiene, Technical University Munich, Biedersteiner Straße 29, D-80802 Munich, Germany
| | - Mariusz R Wieckowski
- Department of Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur 3 Str., 02-093 Warsaw, Poland.
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