|
1
|
Massidda MW, Demkov A, Sices A, Lee M, Lee J, Paull TT, Kim J, Baker AB. Mechanical Rejuvenation of Mesenchymal Stem Cells from Aged Patients. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.06.597781. [PMID: 38895474 PMCID: PMC11185588 DOI: 10.1101/2024.06.06.597781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Mesenchymal stem cells (MSC) are an appealing therapeutic cell type for many diseases. However, patients with poor health or advanced age often have MSCs with poor regenerative properties. A major limiter of MSC therapies is cellular senescence, which is marked by limited proliferation capability, diminished multipotency, and reduced regenerative properties. In this work, we explored the ability of applied mechanical forces to reduce cellular senescence in MSCs. Our studies revealed that mechanical conditioning caused a lasting enhancement in proliferation, overall cell culture expansion potential, multipotency, and a reduction of senescence in MSCs from aged donors. Mechanistic studies suggested that these functional enhancements were mediated by oxidative stress and DNA damage repair signaling with mechanical load altering the expression of proteins of the sirtuin pathway, the DNA damage repair protein ATM, and antioxidant proteins. In addition, our results suggest a biophysical mechanism in which mechanical stretch leads to improved recognition of damaged DNA in the nucleus. Analysis of the cells through RNA-seq and ATAC-seq, demonstrated that mechanical loading alters the cell's genetic landscape to cause broad shifts in transcriptomic patterns that related to senescence. Overall, our results demonstrate that mechanical conditioning can rejuvenate mesenchymal stem cells derived from aged patients and improve their potential as a therapeutic cell type. GRAPHICAL ABSTRACT
Collapse
|
|
2
|
Su F, Koeberle A. Regulation and targeting of SREBP-1 in hepatocellular carcinoma. Cancer Metastasis Rev 2024; 43:673-708. [PMID: 38036934 PMCID: PMC11156753 DOI: 10.1007/s10555-023-10156-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/10/2023] [Indexed: 12/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic reprogramming. De novo lipogenesis is under the control of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1) and essentially contributes to HCC progression. Here, we summarize the current knowledge on the regulation of SREBP-1 isoforms in HCC based on cellular, animal, and clinical data. Specifically, we (i) address the overarching mechanisms for regulating SREBP-1 transcription, proteolytic processing, nuclear stability, and transactivation and (ii) critically discuss their impact on HCC, taking into account (iii) insights from pharmacological approaches. Emphasis is placed on cross-talk with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) axis, AMP-activated protein kinase (AMPK), protein kinase A (PKA), and other kinases that directly phosphorylate SREBP-1; transcription factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), proliferator-activated receptor γ co-activator 1 (PGC-1), signal transducers and activators of transcription (STATs), and Myc; epigenetic mechanisms; post-translational modifications of SREBP-1; and SREBP-1-regulatory metabolites such as oxysterols and polyunsaturated fatty acids. By carefully scrutinizing the role of SREBP-1 in HCC development, progression, metastasis, and therapy resistance, we shed light on the potential of SREBP-1-targeting strategies in HCC prevention and treatment.
Collapse
Affiliation(s)
- Fengting Su
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria
| | - Andreas Koeberle
- Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria.
| |
Collapse
|
|
3
|
Deng Y, Hu M, Huang S, Fu N. Molecular mechanism and therapeutic significance of essential amino acids in metabolically associated fatty liver disease. J Nutr Biochem 2024; 126:109581. [PMID: 38219809 DOI: 10.1016/j.jnutbio.2024.109581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 01/01/2024] [Accepted: 01/06/2024] [Indexed: 01/16/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD), also known as metabolically associated fatty liver disease (MAFLD), is a systemic metabolic disease characterized by lipid accumulation in the liver, lipid toxicity, insulin resistance, intestinal dysbiosis, and inflammation that can progress from simple steatosis to nonalcoholic steatohepatitis (NASH) and even cirrhosis or cancer. It is the most prevalent illness threatening world health. Currently, there are almost no approved drug interventions for MAFLD, mainly dietary changes and exercise to control weight and regulate metabolic disorders. Meanwhile, the metabolic pathway involved in amino acid metabolism also influences the onset and development of MAFLD in the body, and most amino acid metabolism takes place in the liver. Essential amino acids are those amino acids that must be supplemented from outside the diet and that cannot be synthesized in the body or cannot be synthesized at a rate sufficient to meet the body's needs, including leucine, isoleucine, valine (collectively known as branched-chain amino acids), tryptophan, phenylalanine (which are aromatic amino acids), histidine, methionine, threonine and lysine. The metabolic balance of the body is closely linked to these essential amino acids, and essential amino acids are closely linked to the pathophysiological process of MAFLD. In this paper, we will focus on the metabolism of essential amino acids in the body and further explore the therapeutic strategies for MAFLD based on the studies conducted in recent years.
Collapse
Affiliation(s)
- Yuting Deng
- The Affiliated Nanhua Hospital, Department of Gastroenterology, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China
| | - Mengsi Hu
- The Affiliated Nanhua Hospital, Department of Gastroenterology, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China
| | - Shufang Huang
- The Affiliated Nanhua Hospital, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China.
| | - Nian Fu
- The Affiliated Nanhua Hospital, Department of Gastroenterology, Hunan Provincial Clinical Research Center of Metabolic Associated Fatty Liver Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China; The Affiliated Nanhua Hospital, Institute of Clinical Research, Hengyang Medical School, University of South China, Hengyang, Hunan, 421002, China.
| |
Collapse
|
|
4
|
Shen S, Shen M, Kuang L, Yang K, Wu S, Liu X, Wang Y, Wang Y. SIRT1/SREBPs-mediated regulation of lipid metabolism. Pharmacol Res 2024; 199:107037. [PMID: 38070792 DOI: 10.1016/j.phrs.2023.107037] [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: 09/01/2023] [Revised: 12/05/2023] [Accepted: 12/05/2023] [Indexed: 01/13/2024]
Abstract
Sirtuins, also called silent information regulator 2, are enzymes that rely on nicotinamide adenine dinucleotide (NAD+) to function as histone deacetylases. Further investigation is warranted to explore the advantageous impacts of Sirtuin 1 (SIRT1), a constituent of the sirtuin group, on lipid metabolism, in addition to its well-researched involvement in extending lifespan. The regulation of gene expression has been extensively linked to SIRT1. Sterol regulatory element-binding protein (SREBP) is a substrate of SIRT1 that has attracted significant interest due to its role in multiple cellular processes including cell cycle regulation, DNA damage repair, and metabolic functions. Hence, the objective of this analysis was to investigate and elucidate the correlation between SIRT1 and SREBPs, as well as assess the contribution of SIRT1/SREBPs in mitigating lipid metabolism dysfunction. The objective of this research was to investigate whether SIRT1 and SREBPs could be utilized as viable targets for therapeutic intervention in managing complications associated with diabetes.
Collapse
Affiliation(s)
- Shan Shen
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Mingyang Shen
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Lirun Kuang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Keyu Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Shiran Wu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Xinde Liu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Yuting Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Yong Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| |
Collapse
|
|
5
|
Meng D, Zhang F, Yu W, Zhang X, Yin G, Liang P, Feng Y, Chen S, Liu H. Biological Role and Related Natural Products of SIRT1 in Nonalcoholic Fatty Liver. Diabetes Metab Syndr Obes 2023; 16:4043-4064. [PMID: 38089432 PMCID: PMC10715014 DOI: 10.2147/dmso.s437865] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/26/2023] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties.
Collapse
Affiliation(s)
- Decheng Meng
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China
| | - Fengxia Zhang
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China
| | - Wenfei Yu
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China
| | - Xin Zhang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China
| | - Guoliang Yin
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China
| | - Pengpeng Liang
- Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, Shenzhen, 518001, People’s Republic of China
| | - Yanan Feng
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China
| | - Suwen Chen
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China
| | - Hongshuai Liu
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China
| |
Collapse
|
|
6
|
Tun KM, Noureddin N, Noureddin M. Noninvasive tests in the evaluation of nonalcoholic fatty liver disease: A review. Clin Liver Dis (Hoboken) 2023; 22:103-112. [PMID: 37799634 PMCID: PMC10550044 DOI: 10.1097/cld.0000000000000066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/08/2023] [Indexed: 10/07/2023] Open
Abstract
1_kpnc0f20Kaltura.
Collapse
Affiliation(s)
- Kyaw Min Tun
- Department of Internal Medicine, Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, Nevada, USA
| | - Nabil Noureddin
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine, California, USA
| | - Mazen Noureddin
- Houston Research Institute and Houston Liver Institute, Texas, USA
| |
Collapse
|
|
7
|
Mosca A, Maggiore G. Malattia grassa del fegato: tra fattori ambientali e predisposizione genetica. MEDICO E BAMBINO 2023; 42:355-362. [DOI: 10.53126/meb42355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now recognized as the hepatic manifestation of the metabolic syndrome and is the most common cause of chronic liver disease in both adults and children. It is assumed that a genetic predisposition associated with epigenetic factors participates in the evolution of this condition. Visceral obesity and insulin-resistence (IR) have always been considered as key factors linking Metabolic Syndrome (MetS) and NAFLD, but a multifactorial pathogenesis characterized by the interaction between genetic background and environmental factors is increasingly recognized as a key point in the development of metabolic disorders associated with NAFLD. In fact, in patients with NAFLD, insulin resistance, arterial hypertension, abdominal obesity, dyslipidemia and reduced intestinal permeability have often been found, as well as a higher prevalence of comorbidities such as coronary artery disease, obstructive sleep apnea, polycystic ovary syndrome and osteopenia, which define a MetS framework. Early diagnosis is needed to prevent disease progression through primarily lifestyle interventions. Unfortunately, to date, there is no recommended pharmacological intervention in a pediatric setting. However, a variety of new pharmacological agents are under clinical study. To achieve this, studies on the pathways that link the genetic background to the environment before and after birth to the development of NAFLD and MetS and on the molecular mechanisms that define NASH should be increased. Therefore, it is desirable that future studies may be useful in terms of population screening to identify individuals at risk for NAFLD and Mets.
Collapse
Affiliation(s)
- Antonella Mosca
- Epatogastroenterologia, Nutrizione, Endoscopia Digestiva e Clinica del Trapianto di Fegato, Ospedal
| | - Giuseppe Maggiore
- Epatogastroenterologia, Nutrizione, Endoscopia Digestiva e Clinica del Trapianto di Fegato, Ospedal
| |
Collapse
|
|
8
|
Nedrud MA, Chaudhry M, Middleton MS, Moylan CA, Lerebours R, Luo S, Farjat A, Guy C, Loomba R, Abdelmalek MF, Sirlin CB, Bashir MR. MRI Quantification of Placebo Effect in Nonalcoholic Steatohepatitis Clinical Trials. Radiology 2023; 306:e220743. [PMID: 36318027 PMCID: PMC9968769 DOI: 10.1148/radiol.220743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/21/2022] [Accepted: 09/09/2022] [Indexed: 02/22/2023]
Abstract
Background Several early-phase clinical trials for the treatment of nonalcoholic steatohepatitis (NASH) use liver fat content as measured with the MRI-derived proton density fat fraction (PDFF) for a primary outcome. These trials have shown relative reductions in liver fat content with placebo treatment alone, a phenomenon termed "the placebo effect." This phenomenon confounds the results and limits generalizability to future trials. Purpose To quantify the effect of placebo treatment on change in the absolute PDFF value and to identify variables associated with this observed change. Materials and Methods This is a secondary analysis of prospectively collected data from seven early phase clinical trials that included participants with a diagnosis of NASH based on MRI and/or liver biopsy who received placebo treatment. The primary outcome was a greater than or equal to 30% relative reduction in PDFF after placebo treatment. Normalization of PDFF, relative change in alanine aminotransferase (ALT) level, and normalization of ALT level were also examined. An exploratory linear mixed-effects model was used to estimate an overall change in absolute PDFF and to explore parameters associated with this response. Results A total of 187 participants (median age, 52 years [IQR, 43-60 years]; 114 women) who received placebo treatment were evaluated. A greater than or equal to 30% relative reduction in baseline PDFF was seen in 20% of participants after 12 weeks of placebo treatment (10 of 49), 9% of participants after 16 weeks (two of 22), and 28% of participants after 24 weeks (34 of 122). A repeated-measures linear mixed-effects model estimated a decrease of 2.3 units (median relative reduction of 13%) in absolute PDFF values after 24 weeks of placebo treatment (95% CI: 3.2, 1.4; P < .001). Conclusion In this analysis of 187 participants, a clinically relevant decrease in PDFF was observed with placebo treatment. Based on the study model, assuming an absolute PDFF decrease of approximately 3 units (upper limit of 95% CI) to account for this "placebo effect" in sample size calculations for future clinical trials is suggested. Clinical trial registration nos. NCT01066364, NCT01766713, NCT01963845, NCT02443116, NCT02546609, NCT02316717, and NCT02442687 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Yoon in this issue.
Collapse
Affiliation(s)
| | | | - Michael S. Middleton
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Cynthia A. Moylan
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Reginald Lerebours
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Sheng Luo
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Alfredo Farjat
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Cynthia Guy
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Rohit Loomba
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Manal F. Abdelmalek
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Claude B. Sirlin
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| | - Mustafa R. Bashir
- From the Department of Radiology (M.A.N., M.R.B.), Division of
Gastroenterology, Department of Medicine (C.A.M., M.R.B.), Department of
Biostatistics & Bioinformatics (R. Lerebours, S.L., A.F.), Department of
Pathology (C.G.), and Center for Advanced Magnetic Resonance Development
(M.R.B.), Duke University Medical Center, Department of Radiology, Box 3808,
Durham, NC 27710; Rutgers University Hospital, School of Medicine, Newark, NJ
(M.C.); Liver Imaging Group, Department of Radiology (M.S.M., C.B.S.), and
Division of Gastroenterology, Department of Medicine (R. Loomba), University of
California at San Diego School of Medicine, San Diego, Calif; Department of
Medicine, Durham Veterans Affairs Medical Center, Durham, NC (C.A.M.); and
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
(M.F.A.)
| |
Collapse
|
|
9
|
Anggreini P, Kuncoro H, Sumiwi SA, Levita J. Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review). Mol Med Rep 2022; 27:35. [PMID: 36562343 PMCID: PMC9827347 DOI: 10.3892/mmr.2022.12922] [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] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/26/2022] [Indexed: 12/24/2022] Open
Abstract
Non‑alcoholic fatty liver disease (NAFLD) is an increasingly prevalent ailment worldwide. Moreover, de novo lipogenesis (DNL) is considered a critical factor in the development of NAFLD; hence, its inhibition is a promising target for the prevention of fatty liver disease. There is evidence to indicate that AMP‑activated protein kinase (AMPK) and sirtuin 1 (SIRT1) may play a crucial role in DNL and are the regulatory proteins in type 2 diabetes mellitus, obesity and cardiovascular disease. Therefore, AMPK and SIRT1 may be promising targets for the treatment of NAFLD. The present review article thus aimed to summarize the findings of clinical studies published during the past decade that suggested the beneficial effects of AMPK and SIRT1, using their specific activators and their combined effects on fatty liver disease.
Collapse
Affiliation(s)
- Putri Anggreini
- Doctoral Program in Pharmacy, Faculty of Pharmacy, Padjadjaran University, Sumedang, West Java 46363, Indonesia,Laboratory of Pharmaceutical Research and Development, Faculty of Pharmacy, Mulawarman University, Samarinda, East Borneo 75119, Indonesia
| | - Hadi Kuncoro
- Laboratory of Pharmaceutical Research and Development, Faculty of Pharmacy, Mulawarman University, Samarinda, East Borneo 75119, Indonesia,Correspondence to: Dr Hadi Kuncoro, Laboratory of Pharmaceutical Research and Development, Faculty of Pharmacy, Mulawarman University, Muara Muntai Street, Gunung Kelua, Samarinda, East Borneo 75119, Indonesia, E-mail:
| | - Sri Adi Sumiwi
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Padjadjaran University, Sumedang, West Java 46363, Indonesia
| | - Jutti Levita
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Padjadjaran University, Sumedang, West Java 46363, Indonesia
| |
Collapse
|
|
10
|
Shao M, Lu Y, Xiang H, Wang J, Ji G, Wu T. Application of metabolomics in the diagnosis of non-alcoholic fatty liver disease and the treatment of traditional Chinese medicine. Front Pharmacol 2022; 13:971561. [PMID: 36091827 PMCID: PMC9453477 DOI: 10.3389/fphar.2022.971561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 07/25/2022] [Indexed: 12/01/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease around the world, and it often coexists with insulin resistance-related diseases including obesity, diabetes, hyperlipidemia, and hypertension, which seriously threatens human health. Better prevention and treatment strategies are required to improve the impact of NAFLD. Although needle biopsy is an effective tool for diagnosing NAFLD, this method is invasive and difficult to perform. Therefore, it is very important to develop more efficient approaches for the early diagnosis of NAFLD. Traditional Chinese medicine (TCM) can play a certain role in improving symptoms and protecting target organs, and its mechanism of action needs to be further studied. Metabolomics, the study of all metabolites that is thought to be most closely associated with the patients’ characters, can provide useful clinically biomarkers that can be applied to NAFLD and may open up new methods for diagnosis. Metabolomics technology is consistent with the overall concept of TCM, and it can also be used as a potential mechanism to explain the effects of TCM by measuring biomarkers by metabolomics. Based on PubMed/MEDLINE and other databases, this paper retrieved relevant literature NAFLD and TCM intervention in NAFLD using metabolomics technology in the past 5 years were searched, and the specific metabolites associated with the development of NAFLD and the potential mechanism of Chinese medicine on improving symptoms were summarized.
Collapse
Affiliation(s)
- Mingmei Shao
- Baoshan District Hospital of Intergrated Traditional Chinese and Western Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yifei Lu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Baoshan District Hospital of Intergrated Traditional Chinese and Western Medicine, Shanghai, China
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Guang Ji, , ; Tao Wu, ,
| |
Collapse
|
|
11
|
Gart E, van Duyvenvoorde W, Caspers MPM, van Trigt N, Snabel J, Menke A, Keijer J, Salic K, Morrison MC, Kleemann R. Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr-/-.Leiden mice with manifest obesity-associated NASH. FASEB J 2022; 36:e22435. [PMID: 35830259 DOI: 10.1096/fj.202200111r] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 06/08/2022] [Accepted: 06/21/2022] [Indexed: 11/11/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver, insulin resistance, and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however, it remains unclear whether individual BCAAs can attenuate already established NASH and associated oxidative-inflammatory stress. After a 26 weeks run-in on fast food diet (FFD), obese Ldlr-/-.Leiden mice were treated for another 12 weeks with either valine or isoleucine (3% of FFD) and then compared to FFD controls. Valine and isoleucine did not affect obesity, dyslipidemia, gut permeability, or fecal fatty acid excretion, but significantly reduced hyperinsulinemia. Valine and isoleucine reduced ALT, CK18-M30, and liver steatosis with a particularly pronounced suppression of the microvesicular component (-61% by valine and -71% by isoleucine). Both BCAAs decreased intrahepatic diacylglycerols and 4-hydroxynonenal immunoreactivity, a marker for oxidative stress-induced lipid peroxidation. Functional genomics analysis demonstrated that valine and isoleucine affected BCAA metabolism genes, deactivated master regulators of anabolic pathways related to steatosis (e.g., SREBPF1), and activated master regulators of mitochondrial biogenesis (e.g., PPARGC1A) and lipid catabolism (e.g., ACOX1, AMPK). This correction of critical metabolic pathways on gene expression level was accompanied by a significant decrease in histological liver inflammation, and suppression of FFD-stimulated cytokine and chemokine proteins KC/CXCL1, MCP-1/CCL2, and MIP-2/CXCL2 and their pathways. In conclusion, dietary intervention with either valine or isoleucine corrected liver diacylglycerols, gene expression of multiple metabolic processes, and reduced NASH histology with profound hepatoprotective effects on oxidative stress and inflammatory proteins.
Collapse
Affiliation(s)
- Eveline Gart
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.,Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | - Wim van Duyvenvoorde
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Martien P M Caspers
- Department of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), Zeist, the Netherlands
| | - Nikki van Trigt
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Jessica Snabel
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Aswin Menke
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | - Kanita Salic
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands
| | - Martine C Morrison
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.,Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | - Robert Kleemann
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.,Department of Vascular Surgery, Leiden University Medical Center, Leiden, the Netherlands
| |
Collapse
|
|
12
|
Duan T, Jiang HY, Ling WW, Song B. Noninvasive imaging of hepatic dysfunction: A state-of-the-art review. World J Gastroenterol 2022; 28:1625-1640. [PMID: 35581963 PMCID: PMC9048786 DOI: 10.3748/wjg.v28.i16.1625] [Citation(s) in RCA: 4] [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: 03/18/2021] [Revised: 07/17/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatic dysfunction represents a wide spectrum of pathological changes, which can be frequently found in hepatitis, cholestasis, metabolic diseases, and focal liver lesions. As hepatic dysfunction is often clinically silent until advanced stages, there remains an unmet need to identify affected patients at early stages to enable individualized intervention which can improve prognosis. Passive liver function tests include biochemical parameters and clinical grading systems (e.g., the Child-Pugh score and Model for End-Stage Liver Disease score). Despite widely used and readily available, these approaches provide indirect and limited information regarding hepatic function. Dynamic quantitative tests of liver function are based on clearance capacity tests such as the indocyanine green (ICG) clearance test. However, controversial results have been reported for the ICG clearance test in relation with clinical outcome and the accuracy is easily affected by various factors. Imaging techniques, including ultrasound, computed tomography, and magnetic resonance imaging, allow morphological and functional assessment of the entire hepatobiliary system, hence demonstrating great potential in evaluating hepatic dysfunction noninvasively. In this article, we provide a state-of-the-art summary of noninvasive imaging modalities for hepatic dysfunction assessment along the pathophysiological track, with special emphasis on the imaging modality comparison and selection for each clinical scenario.
Collapse
Affiliation(s)
- Ting Duan
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Han-Yu Jiang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Wu Ling
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| |
Collapse
|
|
13
|
Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022; 10:274. [PMID: 35203484 PMCID: PMC8869100 DOI: 10.3390/biomedicines10020274] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.
Collapse
Affiliation(s)
- Veronika A. Prikhodko
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
| | - Natalia N. Bezborodkina
- Zoological Institute, Russian Academy of Sciences, 1 Universitetskaya emb., 199034 St. Petersburg, Russia;
| | - Sergey V. Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia
| |
Collapse
|
|
14
|
Foresight regarding drug candidates acting on the succinate-GPR91 signalling pathway for non-alcoholic steatohepatitis (NASH) treatment. Biomed Pharmacother 2021; 144:112298. [PMID: 34649219 DOI: 10.1016/j.biopha.2021.112298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/29/2021] [Accepted: 10/05/2021] [Indexed: 11/24/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and it is a liver manifestation of metabolic syndrome, with a histological spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH can evolve into progressive liver fibrosis and eventually lead to liver cirrhosis. The pathological mechanism of NASH is multifactorial, involving a series of metabolic disorders and changes that trigger low-level inflammation in the liver and other organs. In the pathogenesis of NASH, the signal transduction pathway involving succinate and the succinate receptor (G-protein-coupled receptor 91, GPR91) regulates inflammatory cell activation and liver fibrosis. This review describes the mechanism of the succinate-GPR91 signalling pathway in NASH and summarizes the drugs that act on this pathway, with the aim of providing a new approach to NASH treatment.
Collapse
|
|
15
|
Cariou B, Byrne CD, Loomba R, Sanyal AJ. Nonalcoholic fatty liver disease as a metabolic disease in humans: A literature review. Diabetes Obes Metab 2021; 23:1069-1083. [PMID: 33464677 PMCID: PMC8248154 DOI: 10.1111/dom.14322] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 02/06/2023]
Abstract
AIMS To conduct a systematic literature review to identify recent epidemiological, biomarker, genetic and clinical evidence that expands our understanding of nonalcoholic fatty liver disease (NAFLD) as a metabolic disorder. MATERIALS AND METHODS We performed a literature search using PubMed to identify trials, observational studies and meta-analyses published in the past 5 years. RESULTS A total of 95 publications met prespecified inclusion criteria and reported on the interplay between NAFLD/nonalcoholic steatohepatitis (NASH) and metabolic dysfunction, in terms of disease burden and/or epidemiology (n = 10), pathophysiology, risk factors and associated conditions (n = 29), diagnosis and biomarkers (n = 34), and treatment approaches (n = 22). There is a growing body of evidence on the links between NAFLD/NASH pathogenesis and mechanisms of metabolic dysfunction, through liver lipid accumulation, insulin resistance, inflammation, apoptosis, and fibrogenic remodelling within the liver. The frequent co-occurrence of NAFLD with obesity, metabolic syndrome and type 2 diabetes supports this premise. Therapeutic approaches originally envisaged for type 2 diabetes or obesity (such as glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, insulin sensitizers and bariatric surgery) have shown promising signs of benefit for patients with NAFLD/NASH. CONCLUSIONS Given the complex interplay between NAFLD and metabolic dysfunction, there is an urgent need for multidisciplinary collaboration and established protocols for care of patients with NAFLD that are individualized and ideally support reduction of overall metabolic risk as well as treatment for NASH.
Collapse
Affiliation(s)
- Bertrand Cariou
- L'institut du Thorax, Department of EndocrinologyUNIV Nantes, Inserm, CNRS, CHU NantesNantesFrance
| | - Christopher D. Byrne
- Endocrinology and Metabolism, Human Development and Health, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
- Southampton National Institute for Health Research, Biomedical Research Centre, University Hospital SouthamptonSouthamptonUK
| | - Rohit Loomba
- NAFLD Research Center, Division of GastroenterologyUniversity of California San DiegoSan DiegoCaliforniaUSA
| | - Arun J. Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth UniversityRichmondVirginiaUSA
| |
Collapse
|
|
16
|
Ala M, Mohammad Jafari R, Dehpour AR. Sildenafil beyond erectile dysfunction and pulmonary arterial hypertension: Thinking about new indications. Fundam Clin Pharmacol 2021; 35:235-259. [PMID: 33226665 DOI: 10.1111/fcp.12633] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/06/2020] [Accepted: 11/20/2020] [Indexed: 12/13/2022]
Abstract
Sildenafil, approved two decades ago, is the inhibitor of phosphodiesterase 5 (PDE5). First of all, it was designated for angina pectoris, but soon it showed a wonderful efficacy in erectile dysfunction (ED) and then pulmonary arterial hypertension (PAH). Due to the distribution of phosphodiesterase (PDE) in almost all organs, maybe it effects other diseases. Hence, a great number of investigations began to understand the role of PDEi in different organs. Preliminary research on sildenafil in cell culture and animal models has yielded promising results. Soon, a greater number of animal researches and clinical trials joined them. The results disclosed sildenafil can have beneficial effects in each organ such as heart, liver, kidney, brain, and intestines. Furthermore, it has significantly improved the prognosis of organ ischemia in various animal models. Clinical trials in several diseases, such as recurrent spontaneous miscarriage, fatty liver disease, bronchopulmonary dysplasia (BPD), heart failure, and premature ejaculation (PE) brought promising results. Although some clinical trials are available on the effects of sildenafil on various diseases, further studies on humans are needed to consolidate the ultimate effects of sildenafil. The aim of this review was to describe the effects of sildenafil on each organ and explain its mechanisms of action. Further, other PDE inhibitors such as tadalafil and vardenafil have been briefly discussed in parts of this review.
Collapse
Affiliation(s)
- Moein Ala
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, 13145-784, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, 13145-784, Iran
| | - Razieh Mohammad Jafari
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, 13145-784, Iran
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, 13145-784, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, 13145-784, Iran
| |
Collapse
|
|
17
|
Sharma M, Premkumar M, Kulkarni AV, Kumar P, Reddy DN, Rao NP. Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail. J Clin Transl Hepatol 2021; 9:40-50. [PMID: 33604254 PMCID: PMC7868704 DOI: 10.14218/jcth.2020.00055] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/29/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic that is likely to become the most common cause of chronic liver disease in the next decade, worldwide. Though numerous drugs have been evaluated in clinical trials, most of them have returned inconclusive results and shown poorly-tolerated adverse effects. None of the drugs have been approved by the Food and Drug Administration for treating biopsy-proven non-alcoholic steatohepatitis (NASH). Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic NASH patients. Although some amelioration of inflammation has been seen, these drugs did not improve the fibrosis component of NASH. Therefore, dietary modification and weight reduction have remained the cornerstone of treatment of NASH; moreover, they have shown to improve histological activity as well as fibrosis. The search for an ideal drug or 'Holy Grail' within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for NASH which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.
Collapse
Affiliation(s)
- Mithun Sharma
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | | | - Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Pramod Kumar
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - D Nageshwar Reddy
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Nagaraja Padaki Rao
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| |
Collapse
|
|
18
|
Rebello CJ, Zemel MB, Kolterman O, Fleming GA, Greenway FL. Leucine and Sildenafil Combination Therapy Reduces Body Weight and Metformin Enhances the Effect at Low Dose: A Randomized Controlled Trial. Am J Ther 2021; 28:e1-e13. [PMID: 33369909 PMCID: PMC9035320 DOI: 10.1097/mjt.0000000000001303] [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] [Indexed: 01/28/2023]
Abstract
BACKGROUND This study evaluated the potential of activating the fuel-sensing enzymes Adenine monophosphate (AMP)-activated protein kinase and the deacetylase sirtuin1, to promote weight loss. We tested the efficacy of a fixed dose combination of the amino acid leucine and 2 well-characterized agents with established safety profiles to modulate energy metabolism and facilitate weight loss. STUDY QUESTION Will a combination of l-leucine with low-dose metformin and sildenafil produce a novel synergistic interaction that reduces body weight? STUDY DESIGN We conducted a 24-week randomized controlled trial evaluating the effect on weight loss of leucine 1.1 g and sildenafil 1.0 mg or 4.0 mg, with and without metformin 500 mg (Leu/Sil 1.0, Leu/Sil 4.0, Leu/Met/Sil 1.0, and Leu/Met/Sil 4.0 twice/day). We enrolled 267 participants who were 18-65 years of age without diabetes and with the body mass index (BMI) of 30-45 kg/m2. MEASURES AND OUTCOMES The primary endpoint was percentage weight change after 24 weeks. Adverse events were evaluated. The primary analysis was performed using the perprotocol population analysis of covariance estimation. Subgroup analyses of patients residing above certain threshold limits at baseline and in populations at increased risk of obesity were assessed post-hoc as exploratory end points. RESULTS Placebo-adjusted mean bodyweight reductions in the Leu/Met/Sil 1.0, Leu/Met/Sil 4.0, and Leu/Sil 4.0 groups were -1.99%, -1.69%, and -1.67% (P = 0.015, 0.035, and 0.036, respectively). The most common adverse events were gastrointestinal-related and occurred in the metformin-treated groups consistent with metformin treatment. In African Americans, Leu/Met/Sil 1.0 produced 5.4% mean weight loss. In participants with BMI <40 kg/m2 treated with Leu/Met/Sil 1.0, the weight loss increased to 2.84%, particularly in participants with baseline insulin ≥12mU/L (3.5%). CONCLUSIONS Leu/Met/Sil 1.0 and 4.0 and Leu/Sil 4.0 reduced body weight, but Leu/Met/Sil 1.0 was associated with robust weight loss in African Americans, and individuals with BMI 30-39.9 kg/m2, especially participants with hyperinsulinemia.
Collapse
Affiliation(s)
- Candida J. Rebello
- Pharmacology Clinical Trials, Pennington Biomedical Research Center (PBRC), Baton Rouge, LA
| | | | | | | | - Frank L. Greenway
- Pharmacology Clinical Trials, Pennington Biomedical Research Center (PBRC), Baton Rouge, LA
| |
Collapse
|
|
19
|
Lee HW, Lee JS, Kim BK, Park JY, Kim DY, Ahn SH, Kim SU. Evolution of liver fibrosis and steatosis markers in patients with type 2 diabetes after metformin treatment for 2 years. J Diabetes Complications 2021; 35:107747. [PMID: 33616043 DOI: 10.1016/j.jdiacomp.2020.107747] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/09/2020] [Accepted: 09/09/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIMS Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) share pathophysiological mechanism. Metformin is a widely used first-line anti-diabetic drug. We investigated the evolution of liver fibrosis and steatosis during 2-year use of metformin in patients with T2DM. METHODS Between 2006 and August 2010, patients newly diagnosed with T2DM who received metformin as the first-line treatment were recruited. Fibrosis-4 index (FIB-4) > 2.67 and hepatic steatosis index (HSI) > 36.0 was used to define advanced liver fibrosis and fatty liver, respectively. RESULTS A total of 1292 (mean age 60.8 years, 57% men and 43% women) patients were recruited. The mean FIB-4 and HSI scores were 1.38 and 27.3, respectively. At enrollment, 83 (6.4%) patients had advanced liver fibrosis and 429 (33.2%) had fatty liver. After 2 years of metformin treatment, the mean FIB-4 score increased from 1.38 to 1.51 (p < 0.001), whereas the mean HSI score decreased from 27.3 to 26.5 (p < 0.001). During follow-up, advanced liver fibrosis additionally developed in 52/1209 (4.3%) patients, whereas 48/83 (57.8%) experienced fibrosis regression. Older age (odds ratio [OR] = 1.007), lower platelet count (OR = 0.993), and lower serum albumin (OR = 0.325) were independently associated with the increased risk of advanced liver fibrosis development after 2-years of metformin treatment. CONCLUSION In our cohort of patients with metformin treatment, a small proportion of patients developed liver fibrosis and steatosis after 2 years. Optimized follow-up strategy is required according to different risk of liver fibrosis progression in patients with T2DM.
Collapse
Affiliation(s)
- Hye Won Lee
- Department of Internal medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Jae Seung Lee
- Department of Internal medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Seung Up Kim
- Department of Internal medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea.
| |
Collapse
|
|
20
|
Petrocelli JJ, Drummond MJ. PGC-1α-Targeted Therapeutic Approaches to Enhance Muscle Recovery in Aging. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17228650. [PMID: 33233350 PMCID: PMC7700690 DOI: 10.3390/ijerph17228650] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022]
Abstract
Impaired muscle recovery (size and strength) following a disuse period commonly occurs in older adults. Many of these individuals are not able to adequately exercise due to pain and logistic barriers. Thus, nutritional and pharmacological therapeutics, that are translatable, are needed to promote muscle recovery following disuse in older individuals. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may be a suitable therapeutic target due to pleiotropic regulation of skeletal muscle. This review focuses on nutritional and pharmacological interventions that target PGC-1α and related Sirtuin 1 (SIRT1) and 5' AMP-activated protein kinase (AMPKα) signaling in muscle and thus may be rapidly translated to prevent muscle disuse atrophy and promote recovery. In this review, we present several therapeutics that target PGC-1α in skeletal muscle such as leucine, β-hydroxy-β-methylbuyrate (HMB), arginine, resveratrol, metformin and combination therapies that may have future application to conditions of disuse and recovery in humans.
Collapse
|
|
21
|
Patel P, Muller C, Paul S. Racial disparities in nonalcoholic fatty liver disease clinical trial enrollment: A systematic review and meta-analysis. World J Hepatol 2020; 12:506-518. [PMID: 32952877 PMCID: PMC7475777 DOI: 10.4254/wjh.v12.i8.506] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/09/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has a heterogeneous distribution across racial and ethnic groups, with a disproportionate burden among Hispanics. Although there are currently no approved therapies for treatment of NAFLD, several therapies have been investigated in clinical trials.
AIM To analyze the inclusion of racial and ethnic minority groups in clinical trials for NAFLD.
METHODS We performed a systematic review of North American, English-language, prospective studies for NAFLD therapies published from 2005 to 2019. Racial and ethnic enrollment data were recorded for each eligible study. Meta-analysis was performed to compute pooled prevalence of different racial and ethnic groups, followed by further subgroup analyses. These analyses were based on diagnosis of non-alcoholic steatohepatitis (NASH) and timing of study on enrollment by ethnicity. Descriptive statistics were performed to compare racial and ethnic study enrollment to previously reported NAFLD population prevalence.
RESULTS Thirty-eight studies met criteria for inclusion in the systematic review. When reported, median age of enrolled subjects was 49 years (range 41.5-58) with 56% female participants. NAFLD was defined through biopsy findings in 79% (n = 30) of the studies. Of the included articles, treatment modalities ranged from medications (n = 28, 74%), lifestyle interventions (n = 5, 13%), bariatric surgery (n = 4, 11%) and phlebotomy (n = 1, 2%). Twenty-eight studies (73%) included racial and/or ethnic demographic information, while only 17 (45%) included information regarding Hispanic participation. Of the 2983 patients enrolled in all eligible trials, a total of only 346 (11.6%) Hispanic participants was reported. Meta-analysis revealed a pooled Hispanic prevalence of 24.3% (95% confidence interval 16.6-32.0, I2 94.6%) among studies documenting Hispanic enrollment. Hispanic enrollment increased over time from 15% from 2005-2014 to 37% from 2015-2019.
CONCLUSION In a meta-analysis of NAFLD trials, documentation of racial/ethnic demographic data occurred in less than half of studies. Standardization of reporting of race/ethnicity and targeted interventions toward minority recruitment are needed to improve diversity of enrollment.
Collapse
Affiliation(s)
- Parita Patel
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
| | - Charles Muller
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
| | - Sonali Paul
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
| |
Collapse
|
|
22
|
Attia SL, Softic S, Mouzaki M. Evolving Role for Pharmacotherapy in NAFLD/NASH. Clin Transl Sci 2020; 14:11-19. [PMID: 32583961 PMCID: PMC7877845 DOI: 10.1111/cts.12839] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO‐NASH, which investigates thyroid hormone receptor‐β agonist MGL‐3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co‐transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF‐06835919, the acetyl‐coenzyme A carboxylase inhibitor GS‐0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.
Collapse
Affiliation(s)
- Suzanna L Attia
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Kentucky College of Medicine, University of Kentucky, Lexington, Kentucky, USA
| | - Samir Softic
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Kentucky College of Medicine, University of Kentucky, Lexington, Kentucky, USA.,Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA.,Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Marialena Mouzaki
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| |
Collapse
|
|
23
|
Zemel MB. Modulation of Energy Sensing by Leucine Synergy with Natural Sirtuin Activators: Effects on Health Span. J Med Food 2020; 23:1129-1135. [PMID: 32758058 DOI: 10.1089/jmf.2020.0105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Sirt1 and 5' adenosine monophosphate-activated protein kinase (AMPK) are energy-sensing systems that work cooperatively and regulate mitochondrial biogenesis and fuel metabolism, and mediate, in part, the salutary effects of caloric restriction on lifespan and healthspan. We have shown that leucine activates Sirt1 and enables synergy with sirtuin co-activators. Resveratrol is a widely recognized activator of Sirt1; however, poor bioavailability and rapid metabolism limit effective clinical translation of promising animal data. However, we found that combining low resveratrol doses with leucine increased skeletal muscle and adipocyte Sirt1 activity, mitochondrial biogenesis and fatty acid oxidation; these effects result in increased lifespan and marked reductions in insulin resistance, inflammatory markers, body weight, and visceral adiposity in preclinical models. To translate these data to humans, we assessed the effects of resveratrol (50 mg)/leucine (1.11 g) on glucose dynamics in a 4-week placebo-controlled trial of 36 prediabetic subjects. Leucine-resveratrol reduced insulin resistance (homeostatic model assessment for insulin resistance) 33% with corresponding reductions in glucose and insulin area under the curve in oral glucose tolerance tests. We extended these concepts in preclinical studies using both direct Sirt1 activators and Sirt1 pathway activators. Low-dose (10 nM) NAD+ precursors (nicotinic acid, nicotinamide mononucleotide, and nicotinamide riboside) synergized with leucine to increase Sirt1 activity in adipocytes, hepatocytes, and muscle cells (30-100%, P < .01) and lifespan in Caenorhabditis elegans (25%, P = .025) and to significantly regress atherosclerotic lesion size and macrophage infiltration in a mouse model of atherosclerosis. Thus, synergistic activation of Sirt1 using leucine and a co-activator exerts pleiotropic effects impacting cardiometabolic endpoints.
Collapse
Affiliation(s)
- Michael B Zemel
- NuSirt Biopharma, Research and Development, Knoxville, Tennessee, USA
| |
Collapse
|
|
24
|
Xin FZ, Zhao ZH, Zhang RN, Pan Q, Gong ZZ, Sun C, Fan JG. Folic acid attenuates high-fat diet-induced steatohepatitis via deacetylase SIRT1-dependent restoration of PPARα. World J Gastroenterol 2020; 26:2203-2220. [PMID: 32476787 PMCID: PMC7235203 DOI: 10.3748/wjg.v26.i18.2203] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/27/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Folic acid has been shown to improve non-alcoholic steatohepatitis (NASH), but its roles in hepatic lipid metabolism, hepatic one-carbon metabolism, and gut microbiota are still unknown.
AIM To demonstrate the role of folic acid in lipid metabolism and gut microbiota in NASH.
METHODS Twenty-four Sprague-Dawley rats were assigned into three groups: Chow diet, high-fat diet (HFD), and HFD with folic acid administration. At the end of 16 wk, the liver histology, the expression of hepatic genes related to lipid metabolism, one-carbon metabolism, and gut microbiota structure analysis of fecal samples based on 16S rRNA sequencing were measured to evaluate the effect of folic acid. Palmitic acid-exposed Huh7 cell line was used to evaluate the role of folic acid in hepatic lipid metabolism.
RESULTS Folic acid treatment attenuated steatosis, lobular inflammation, and hepatocellular ballooning in rats with HFD-induced steatohepatitis. Genes related to lipid de novo lipogenesis, β-oxidation, and lipid uptake were improved in HFD-fed folic acid-treated rats. Furthermore, peroxisome proliferator-activated receptor alpha (PPARα) and silence information regulation factor 1 (SIRT1) were restored by folic acid in HFD-fed rats and palmitic acid-exposed Huh7 cell line. The restoration of PPARα by folic acid was blocked after transfection with SIRT1 siRNA in the Huh7 cell line. Additionally, folic acid administration ameliorated depleted hepatic one-carbon metabolism and restored the diversity of the gut microbiota in rats with HFD-induced steatohepatitis.
CONCLUSION Folic acid improves hepatic lipid metabolism by upregulating PPARα levels via a SIRT1-dependent mechanism and restores hepatic one-carbon metabolism and diversity of gut microbiota, thereby attenuating HFD-induced NASH in rats.
Collapse
Affiliation(s)
- Feng-Zhi Xin
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ze-Hua Zhao
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Rui-Nan Zhang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Qin Pan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Zi-Zhen Gong
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
- Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Chao Sun
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China
| |
Collapse
|
|
25
|
Iruarrizaga-Lejarreta M, Arretxe E, Alonso C. Using metabolomics to develop precision medicine strategies to treat nonalcoholic steatohepatitis. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2019. [DOI: 10.1080/23808993.2019.1685379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | - Enara Arretxe
- OWL Metabolomics, Parque Tecnológico de Bizkaia, Derio, Spain
| | - Cristina Alonso
- OWL Metabolomics, Parque Tecnológico de Bizkaia, Derio, Spain
| |
Collapse
|
|
26
|
Banerjee J, Bruckbauer A, Thorpe T, Zemel MB. Biphasic Effect of Sildenafil on Energy Sensing is Mediated by Phosphodiesterases 2 and 3 in Adipocytes and Hepatocytes. Int J Mol Sci 2019; 20:ijms20122992. [PMID: 31248114 PMCID: PMC6627652 DOI: 10.3390/ijms20122992] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 06/17/2019] [Indexed: 12/14/2022] Open
Abstract
Sirt1 (Sirtuin 1), AMPK (AMP-activated protein kinase), and eNOS (endothelial nitric oxide synthase) modulate hepatic energy metabolism and inflammation and play a major role in the development of NASH. Cyclic nucleotide phosphodiesterases (PDEs) play an important role in signal transduction by modulating intracellular levels of cyclic nucleotides. We previously found the PDE5 inhibitor sildenafil to synergize with leucine and leucine-metformin combinations in preclinical studies of NASH and obesity. However, efficacy is diminished at higher sildenafil concentrations. Herein, we have successfully modeled the U-shaped sildenafil dose-response in vitro and utilized this model to assess potential mechanisms of this dose-response relationship. Adipocytes and liver cells were treated with leucine (0.5 mM) and different concentrations of sildenafil (1 nM to 100 µM). cAMP, cGMP, and P-AMPK protein expression were used to demonstrate the biphasic response for increasing concentrations of sildenafil. The reversal with higher sildenafil levels was blunted by PDE2 inhibition. These data indicate that sildenafil-mediated increases in cGMP inhibits PDE3 at lower concentrations, which increases cAMP. However, further increases in cGMP from higher sildenafil concentrations activate PDE2 and consequently decrease cAMP, which demonstrates crosstalk between cAMP and cGMP via PDE2, PDE3, and PDE5. These changes in cAMP concentration are further reflected in downstream effects, including AMPK activation.
Collapse
Affiliation(s)
- Jheelam Banerjee
- NuSirt Biopharma Inc., 11020 Solway School Rd, Knoxville, TN 37931, USA.
| | - Antje Bruckbauer
- NuSirt Biopharma Inc., 11020 Solway School Rd, Knoxville, TN 37931, USA.
| | - Teresa Thorpe
- NuSirt Biopharma Inc., 11020 Solway School Rd, Knoxville, TN 37931, USA.
| | - Michael B Zemel
- NuSirt Biopharma Inc., 11020 Solway School Rd, Knoxville, TN 37931, USA.
| |
Collapse
|
|
27
|
Lee SJ, Kim SU. Noninvasive monitoring of hepatic steatosis: controlled attenuation parameter and magnetic resonance imaging-proton density fat fraction in patients with nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2019; 13:523-530. [PMID: 31018719 DOI: 10.1080/17474124.2019.1608820] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
With an increase in the worldwide prevalence of obesity, the incidence of non-alcoholic fatty liver disease (NAFLD) has been on the rise, such that it has been recently considered to be a major public health concern. Traditional interventions, such as lifestyle modifications, regular exercise, and healthy diet, have been significant in improving NAFLD with reduction of liver fat. Areas covered: Although liver biopsy is still the gold standard for diagnosis of NAFLD, there is a need for non-invasive, quantitative assessments of hepatic steatosis, especially in clinical trials of anti-steatotic medications or in the follow-up of patients undergoing lifestyle modifications. Liver biopsy has various shortcomings, such as invasive nature, risk of complications and possibility of sampling error. Therefore, it is impractical to use liver biopsy routinely in patients with NAFLD, clearly indicating the need for non-invasive and accurate diagnostic methods. Recently, controlled attenuation parameter (CAP) and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) have been employed in various studies to monitor the dynamic changes of hepatic steatosis in response to treatment in patients with NAFLD. Expert commentary: Although further validations are required, CAP and MRI-PDFF could be used as potential diagnostic and monitoring tools in clinical setting.
Collapse
Affiliation(s)
- Sol Jae Lee
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , South Korea.,b Yonsei Liver Center , Severance Hospital , Seoul , South Korea
| | - Seung Up Kim
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , South Korea.,b Yonsei Liver Center , Severance Hospital , Seoul , South Korea.,c Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , South Korea
| |
Collapse
|
|
28
|
Schulte L, Scheiner B, Voigtländer T, Koch S, Schweitzer N, Marhenke S, Ivanyi P, Manns MP, Rodt T, Hinrichs JB, Weinmann A, Pinter M, Vogel A, Kirstein MM. Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma. Liver Int 2019; 39:714-726. [PMID: 30663219 DOI: 10.1111/liv.14048] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 01/07/2019] [Accepted: 01/09/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed with HCC. RESULTS Among 5093 patients with HCC, 1917 patients (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin. Compared to diabetic patients not treated with metformin, patients on metformin had a significantly better hepatic function (Child-Pugh-Score A: 69.2% vs 47.4%, P < 0.001) and underwent significantly more often tumour resection (22.1% vs 16.5%, P = 0.024). Patients on metformin had a significantly longer median OS (mOS) compared to diabetic patients not treated with metformin (22 vs 15 months, P = 0.019). The prolongation of survival was most significant in patients treated with surgery. Using a propensity score match (PSM), patients were adjusted for hepatic function and initial therapy. In the matched cohorts, mOS remained significantly longer in metformin-treated patients (22 vs 16 months, P = 0.021). Co-treatment of metformin and sorafenib was associated with a survival disadvantage. CONCLUSION Treatment with metformin was associated with an improved survival in patients with T2DM and HCC. This effect was most pronounced in patients at potentially curative tumour stages.
Collapse
Affiliation(s)
- Lena Schulte
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Torsten Voigtländer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Sandra Koch
- Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Nora Schweitzer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Silke Marhenke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Philipp Ivanyi
- Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas Rodt
- Hannover Medical School, Institute for Diagnostic and Interventional Radiology, Hannover, Germany
| | - Jan B Hinrichs
- Hannover Medical School, Institute for Diagnostic and Interventional Radiology, Hannover, Germany
| | - Arndt Weinmann
- Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| |
Collapse
|
|
29
|
Zemel MB, Kolterman O, Rinella M, Vuppalanchi R, Flores O, Barritt AS, Siddiqui M, Chalasani N. Randomized Controlled Trial of a Leucine-Metformin-Sildenafil Combination (NS-0200) on Weight and Metabolic Parameters. Obesity (Silver Spring) 2019; 27:59-67. [PMID: 30569637 DOI: 10.1002/oby.22346] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 09/20/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Leucine was previously demonstrated to allosterically activate mammalian sirtuin 1 and synergize with other sirtuin 1/AMP-activated protein kinase/nitric oxide pathway activators to modulate energy metabolism. The objective of this study was to evaluate the effects of a triple combination of leucine, metformin, and sildenafil (NS-0200) on body weight and obesity comorbidities in a phase 2 randomized trial. METHODS A total of 91 subjects with obesity were randomized to placebo, low dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil), or high dose (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) twice daily for 16 weeks. Seventy subjects completed the trial and met all a priori compliance criteria. Hypertensive (n = 35) and hypertriglyceridemic (n = 22) subcohorts were also analyzed. RESULTS NS-0200 dose-responsively reduced weight; high dose reduced weight by 2.4 and 5.0 kg in the full and high-triglyceride cohorts, respectively (P < 0.0001). High-dose NS-0200 treatment also decreased blood pressure (-5.5 mm Hg diastolic pressure; P = 0.011), with greater effects among hypertensive subjects. NS-0200 also significantly reduced triglycerides and hemoglobin A1c. Significant improvement in ≥ 2 comorbidities was exhibited by 54% of subjects in the high-dose arm versus 5% of placebo subjects (P = 0.0009). Treatment-emergent adverse events did not significantly differ among groups. CONCLUSIONS These data support further study of NS-0200 as a therapy for obesity and associated comorbidities.
Collapse
Affiliation(s)
| | | | - Mary Rinella
- Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Illinois, USA
| | | | - A Sidney Barritt
- Division of Gastroenterology and Hepatology, UNC School of Medicine, Chapel Hill, North Carolina, USA
| | - Mohammad Siddiqui
- Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Illinois, USA
| |
Collapse
|
|
30
|
Evaluation of a High Concentrate Omega-3 for Correcting the Omega-3 Fatty Acid Nutritional Deficiency in Non-Alcoholic Fatty Liver Disease (CONDIN). Nutrients 2018; 10:nu10081126. [PMID: 30127297 PMCID: PMC6115838 DOI: 10.3390/nu10081126] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 08/13/2018] [Accepted: 08/16/2018] [Indexed: 02/06/2023] Open
Abstract
This randomized controlled trial investigated the safety and efficacy of MF4637, a high concentrate omega-3 fatty acid preparation, in correcting the omega-3 fatty acid nutritional deficiency in non-alcoholic fatty liver disease (NAFLD). The primary end point of the study was set as the change of red blood cell (RBC) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by MF4637. Whether the omega-3 concentrate could lower liver fat was evaluated in a subset of patients. Furthermore, 176 subjects with NAFLD were randomized to receive the omega-3 concentrate (n = 87) or placebo (n = 89) for 24 weeks, in addition to following standard-of-care dietary guidelines. The omega-3 index, omega-6: omega-3 fatty acid ratio and quantitative measurements of RBC EPA and DHA were determined at baseline and study completion. Magnetic resonance imaging of liver fat was conducted in a subset of patients. Administration of high concentrate omega-3 for 24 weeks significantly increased the omega-3 index and absolute values of RBC EPA and DHA, and decreased the RBC omega-6: omega-3 fatty acid ratio (p < 0.0001). A significant reduction in liver fat content was reported in both groups.
Collapse
|
|
31
|
Noureddin M, Loomba R. Editorial: role of leucine-metformin-sildenafil combination in the treatment of nonalcoholic fatty liver disease (NAFLD). Aliment Pharmacol Ther 2018; 48:378-379. [PMID: 29998503 DOI: 10.1111/apt.14819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- M Noureddin
- Division of Digestive and Liver Diseases, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - R Loomba
- Division of Gastroenterology, NAFLD Research Center, University of California at San Diego, San Diego, CA, USA
| |
Collapse
|
|
32
|
Cuyàs E, Verdura S, Llorach-Parés L, Fernández-Arroyo S, Joven J, Martin-Castillo B, Bosch-Barrera J, Brunet J, Nonell-Canals A, Sanchez-Martinez M, Menendez JA. Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation. Front Endocrinol (Lausanne) 2018; 9:657. [PMID: 30459716 PMCID: PMC6232372 DOI: 10.3389/fendo.2018.00657] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 10/19/2018] [Indexed: 01/28/2023] Open
Abstract
Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a "C-pocket"-related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline.
Collapse
Affiliation(s)
- Elisabet Cuyàs
- ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain
- Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | - Sara Verdura
- ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain
- Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | | | - Salvador Fernández-Arroyo
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Rovira i Virgili University, Reus, Spain
| | - Jorge Joven
- Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Rovira i Virgili University, Reus, Spain
| | - Begoña Martin-Castillo
- Girona Biomedical Research Institute (IDIBGI), Girona, Spain
- Unit of Clinical Research, Catalan Institute of Oncology (ICO), Girona, Spain
| | - Joaquim Bosch-Barrera
- Girona Biomedical Research Institute (IDIBGI), Girona, Spain
- Department of Medical Sciences, Medical SchoolUniversity of Girona, Girona, Spain
- Medical Oncology, Catalan Institute of Oncology (ICO)Dr. Josep Trueta University Hospital, Girona, Spain
| | - Joan Brunet
- Medical Oncology, Catalan Institute of Oncology (ICO)Dr. Josep Trueta University Hospital, Girona, Spain
- Hereditary Cancer Programme, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL)L'Hospitalet del Llobregat, Barcelona, Spain
- Hereditary Cancer Programme, Catalan Institute of Oncology (ICO)Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | | | | | - Javier A. Menendez
- ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain
- Girona Biomedical Research Institute (IDIBGI), Girona, Spain
- *Correspondence: Javier A. Menendez ;
| |
Collapse
|