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Fulltext Therapeutic Effects of microRNAs on Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH): A Systematic Review and Meta-Analysis

Zhu Y, Tan JK, Wong SK, Goon JA

Int J Mol Sci, 2023 May 23;24(11).
PMID: 37298120 DOI: 10.3390/ijms24119168

Nonalcoholic fatty liver disease (NAFLD) has emerged as a global health problem that affects people even at young ages due to unhealthy lifestyles. Without intervention, NAFLD will develop into nonalcoholic steatohepatitis (NASH) and eventually liver cirrhosis and hepatocellular carcinoma. Although lifestyle interventions are therapeutic, effective implementation remains challenging. In the efforts to establish effective treatment for NAFLD/NASH, microRNA (miRNA)-based therapies began to evolve in the last decade. Therefore, this systematic review aims to summarize current knowledge on the promising miRNA-based approaches in NAFLD/NASH therapies. A current systematic evaluation and a meta-analysis were conducted according to the PRISMA statement. In addition, a comprehensive exploration of PubMed, Cochrane, and Scopus databases was conducted to perform article searches. A total of 56 different miRNAs were reported as potential therapeutic agents in these studies. miRNA-34a antagonist/inhibitor was found to be the most studied variant (n = 7), and it significantly improved the hepatic total cholesterol, total triglyceride, Aspartate Aminotransferase (AST), and Alanine Transaminase (ALT) levels based on a meta-analysis. The biological processes mediated by these miRNAs involved hepatic fat accumulation, inflammation, and fibrosis. miRNAs have shown enormous therapeutic potential in the management of NAFLD/NASH, wherein miRNA-34a antagonist has been found to be an exceptional potential agent for the treatment of NAFLD/NASH.

Matched MeSH terms: Liver Cirrhosis/genetics
Association of deleted in liver cancer-1 gene polymorphism with increased risk of chronicity of disease among Malaysian patients with hepatitis B infection

Riazalhosseini B, Mohamed R, Devi Apalasamy Y, Mohamed Z

Pharmacogenet Genomics, 2021 Dec 01;31(9):185-190.
PMID: 34320605 DOI: 10.1097/FPC.0000000000000439

OBJECTIVE: The aim of this study is to examine the association between genetic variations in deleted in liver cancer 1 (DLC1) gene with progression of the hepatitis B virus (HBV) infection.
METHODS: A total of 623 subjects were included in this study, of whom, 423 were chronic hepatitis B (CHB) patients without liver cirrhosis or hepatocellular carcinoma (HCC), 103 CHB with either liver cirrhosis ± HCC and 97 individuals who had resolved HBV. Two single-nucleotide polymorphisms rs3739298 and rs532841 of DLC1 gene were genotyped using the Sequenom MassARRAY platform.
RESULTS: Our results indicated significant differences between the chronic HBV and resolved HBV groups in genotype and allele frequencies of DLC1-rs3739298 [odds ratio (OR) = 2.23; 95% confidence interval (CI): 1.24-3.99; P = 0.007] and (OR = 1.54; 95% CI: 1.07-2.22; P = 0.021), respectively. Moreover, haplotype analysis revealed significant associations between chronicity of HBV with TG and GA haplotypes (P = 0.041 and P = 0.042), respectively.
CONCLUSION: A significant association exists between the rs3739298 variant and susceptibility to CHB infection.

Matched MeSH terms: Liver Cirrhosis/genetics
The Malaysian experience in the typing of genetic variants of alpha-1-antitrypsin

Desa NM, Ismail Z, Beran Z, Musa SH

Southeast Asian J. Trop. Med. Public Health, 1995;26 Suppl 1:311-4.
PMID: 8629132

It is known that alpha1-antitrypsin deficiency is associated with emphysema in adults and liver cirrhosis in neonates. The phenotypes PiZZ and PiSZ are considered to be high risk groups. alpha1-antitrypsin deficiency is one of the most common lethal congenital disorders in Europe and the USA, occurring in approximately 1 in 2,000 caucasians of North European descent. Studies in Malaysia have found that the phenotypes PiZ and PiS are present in our population. Out of 950 samples analyzed, it was found that 10 samples were shown to be apparently Z homozygous phenotype. The phenotype is determined by high resolution isoelectrofocusing on an ultra-thin polyacrylamide gel embedded with narrow range Pi phamarlyte. The isoelectrofocused bands are confirmed by immunofixation and the plasma alpha1-antitrypsin levels determined by electroimmunoassay. The abnormal phenotypes are further confirmed by polymerase chain reaction using allele specific oligonucleotides.

Matched MeSH terms: Liver Cirrhosis/genetics
Fulltext A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease

Zain SM, Mohamed R, Mahadeva S, Cheah PL, Rampal S, Basu RC, et al.

Hum Genet, 2012 Jul;131(7):1145-52.
PMID: 22258181 DOI: 10.1007/s00439-012-1141-y

The adiponutrin (PNPLA3) rs738409 polymorphism has been found to be associated with susceptibility to non-alcoholic fatty liver disease (NAFLD) in various cohorts. We further investigated the association of this polymorphism with non-alcoholic steatohepatitis (NASH) severity and with histological features of NAFLD. A total of 144 biopsy-proven NAFLD patients and 198 controls were genotyped for PNPLA3 gene polymorphism (rs738409 C>G). The biopsy specimens were histologically graded by a qualified pathologist. We observed an association of G allele with susceptibility to NAFLD in the pooled subjects (OR 2.34, 95% CI 1.69-3.24, p < 0.0001), and following stratification, in each of the three ethnic subgroups, namely Chinese, Indian and Malay (OR 1.94, 95% CI 1.12-3.37, p = 0.018; OR 3.51, 95% CI 1.69-7.26, p = 0.001 and OR 2.05, 95% CI 1.25-3.35, p = 0.005, respectively). The G allele is associated with susceptibility to NASH (OR 2.64, 95% CI 1.85-3.75, p < 0.0001), with NASH severity (OR 1.85, 95% CI 1.05-3.26, p = 0.035) and with presence of fibrosis (OR 1.95, 95% CI 1.17-3.26, p = 0.013) but not with simple steatosis nor with other histological parameters. Although the serum triglyceride level is significantly higher in NAFLD patients compared to controls, the G allele is associated with decreased level of triglycerides (p = 0.029) in the NAFLD patients. Overall, the rs738409 G allele is associated with severity of NASH and occurrence of fibrosis in patients with NAFLD.

Matched MeSH terms: Liver Cirrhosis/genetics
Fulltext Transplantation of human bone marrow mesenchymal stromal cells reduces liver fibrosis more effectively than Wharton's jelly mesenchymal stromal cells

Rengasamy M, Singh G, Fakharuzi NA, Siddikuzzaman, Balasubramanian S, Swamynathan P, et al.

Stem Cell Res Ther, 2017 06 13;8(1):143.
PMID: 28610623 DOI: 10.1186/s13287-017-0595-1

BACKGROUND: Mesenchymal stromal cells (MSCs) from various tissues have shown moderate therapeutic efficacy in reversing liver fibrosis in preclinical models. Here, we compared the relative therapeutic potential of pooled, adult human bone marrow (BM)- and neonatal Wharton's jelly (WJ)-derived MSCs to treat CCl4-induced liver fibrosis in rats.
METHODS: Sprague-Dawley rats were injected with CCl4 for 8 weeks to induce irreversible liver fibrosis. Ex-vivo expanded, pooled human MSCs obtained from BM and WJ were intravenously administered into rats with liver fibrosis at a dose of 10 × 106 cells/animal. Sham control and vehicle-treated animals served as negative and disease controls, respectively. The animals were sacrificed at 30 and 70 days after cell transplantation and hepatic-hydroxyproline content, histopathological, and immunohistochemical analyses were performed.
RESULTS: BM-MSCs treatment showed a marked reduction in liver fibrosis as determined by Masson's trichrome and Sirius red staining as compared to those treated with the vehicle. Furthermore, hepatic-hydroxyproline content and percentage collagen proportionate area were found to be significantly lower in the BM-MSCs-treated group. In contrast, WJ-MSCs treatment showed less reduction of fibrosis at both time points. Immunohistochemical analysis of BM-MSCs-treated liver samples showed a reduction in α-SMA+ myofibroblasts and increased number of EpCAM+ hepatic progenitor cells, along with Ki-67+ and human matrix metalloprotease-1+ (MMP-1+) cells as compared to WJ-MSCs-treated rat livers.
CONCLUSIONS: Our findings suggest that BM-MSCs are more effective than WJ-MSCs in treating liver fibrosis in a CCl4-induced model in rats. The superior therapeutic activity of BM-MSCs may be attributed to their expression of certain MMPs and angiogenic factors.

Matched MeSH terms: Liver Cirrhosis/genetics
Fulltext Circulating microRNA as a marker for predicting liver disease progression in patients with chronic hepatitis B

Riazalhosseini B, Mohamed R, Apalasamy YD, Langmia IM, Mohamed Z

Rev Soc Bras Med Trop, 2017 Mar-Apr;50(2):161-166.
PMID: 28562750 DOI: 10.1590/0037-8682-0416-2016

INTRODUCTION: Hepatitis B virus (HBV) constitutes an important risk factor for cirrhosis and hepatocellular carcinoma (HCC). The link between circulating microRNAs and HBV has been previously reported, although not as a marker of liver disease progression in chronic hepatitis B (CHB). The aim of this study was to characterize miRNA expression profiles between CHB with and without cirrhosis or HCC.

METHODS:: A total of 12 subjects were recruited in this study. We employed an Affymetrix Gene Chip miRNA 3.0 Array to provide universal miRNA coverage. We compared microRNA expression profiles between CHB with and without cirrhosis/HCC to discover possible prognostic markers associated with the progression of CHB.

RESULTS:: Our results indicated 8 differently expressed microRNAs, of which miRNA-935, miRNA-342, miRNA-339, miRNA-4508, miRNA-3615, and miRNA-3200 were up-regulated, whereas miRNA-182 and miRNA-4485 were down-regulated in patients with CHB who progressed to cirrhosis/HCC as compared to those without progression.

CONCLUSIONS:: We demonstrated the differential expression of miRNA-935, miRNA-342, miRNA-339, miRNA-4508, miRNA-3615, miRNA-3200, miRNA-182, and miRNA-4485 between patients with HBV without cirrhosis/HCC and those who had progressed to these more severe conditions. These miRNAs may serve as novel and non-invasive prognostic markers for early detection of CHB-infected patients who are at risk of progression to cirrhosis and/or HCC.

Matched MeSH terms: Liver Cirrhosis/genetics