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  1. Zain SM, Pung YF, Mohamed R
    J Diabetes Metab Disord, 2023 Jun;22(1):237-243.
    PMID: 37255815 DOI: 10.1007/s40200-022-01119-8
    BACKGROUND: Elevated circulating vaspin levels is linked with type 2 diabetes mellitus (T2DM) and obesity. The genetic basis of the association between vaspin rs2236242 and T2DM and obesity is still being investigated. We executed a meta-analysis to evaluate the magnitude of effect caused by vaspin rs2236242 on T2DM and obesity.

    METHODS: We searched Pubmed, Embase, MEDLINE, Scopus, Web of Science, and Google Scholar for relevant articles published up to 19 February 2022. Data were extracted and summary estimates of the association between vaspin rs2236242 and T2DM and obesity were assessed. Odds ratios (ORs) and confidence intervals (CIs) were used to measure the effect.

    RESULTS: This meta-analysis included 2206 cases and 2715 controls in the T2DM cohort, meanwhile 271 cases and 444 controls in the obesity cohort. The pooled estimates revealed no link between vaspin rs2236242 and T2DM, but allele-A was significantly higher in the controls of the obesity cohort, showing that this single nucleotide polymorphism (SNP) has a reduced obesity risk effect. Sensitivity analysis revealed no studies that would modify the estimates or the heterogeneity. Begg and Mazumdar's and Egger's tests indicated no substantial publication bias.

    CONCLUSION: Our meta-analysis provides evidence of significant association between vaspin rs2236242 and reduced risk of obesity but not T2DM.

    SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-022-01119-8.

  2. Pan Y, Ong CE, Pung YF, Chieng JY
    Xenobiotica, 2019 Jul;49(7):863-876.
    PMID: 30028220 DOI: 10.1080/00498254.2018.1503360
    Nanoparticles (NPs) have wide spectrum applications in the areas of industry and biomedicine. However, concerns about their toxic and negative impacts on the environments as well as human health have been raised. Cytochrome P450s (CYPs) are involved in endogenous and exogenous metabolism. Modulations of CYP can adversely damage drug metabolism, detoxification of xenobiotics and animal physiology functions. This article focused on NPs-CYP interactions for humans and animals available in the literature. It was found that different NPs process specific inhibitory potencies against CYPs involved in drug metabolism. Moreover, NPs were able to modify the expression of CYPs genes or protein in humans and other animals, which highlighted their detoxification functions. Nonetheless, changes of CYPs responsible for hormone synthesis and metabolism resulted in endocrine disturbances. Hence, there is a need to screen newly developed NPs to evaluate their interactions with CYPs. The future studies should further strategize the in vitro approaches to reveal the molecular mechanisms behind interactions by taking full considerations of the interference of co-factors, buffers, substrates and metabolites with NPs. Moreover, in vivo studies should compare the influences of NPs via different administration routes and different duration of treatments to reveal the physiological significance.
  3. Pung YF, Chilian WM, Bennett MR, Figg N, Kamarulzaman MH
    Am J Physiol Heart Circ Physiol, 2017 Mar 01;312(3):H541-H545.
    PMID: 27986661 DOI: 10.1152/ajpheart.00653.2016
    Although there are multiple rodent models of the metabolic syndrome, very few develop vascular complications. In contrast, the JCR:LA-cp rat develops both metabolic syndrome and early atherosclerosis in predisposed areas. However, the pathology of the normal vessel wall has not been described. We examined JCR:LA control (+/+) or cp/cp rats fed normal chow diet for 6 or 18 mo. JCR:LA-cp rats developed multiple features of advanced cystic medial necrosis including "cysts," increased collagen formation and proteoglycan deposition around cysts, apoptosis of vascular smooth muscle cells, and spotty medial calcification. These appearances began within 6 mo and were extensive by 18 mo. JCR:LA-cp rats had reduced medial cellularity, increased medial thickness, and vessel hypoxia that was most marked in the adventitia. In conclusion, the normal chow-fed JCR:LA-cp rat represents a novel rodent model of cystic medial necrosis, associated with multiple metabolic abnormalities, vascular smooth muscle cell apoptosis, and vessel hypoxia.NEW & NOTEWORTHY Triggers for cystic medial necrosis (CMN) have been difficult to study due to lack of animal models to recapitulate the pathologies seen in humans. Our study is the first description of CMN in the rat. Thus the JCR:LA-cp rat represents a useful model to investigate the underlying molecular changes leading to the development of CMN.
  4. Lee PY, Yeoh Y, Omar N, Pung YF, Lim LC, Low TY
    Crit Rev Clin Lab Sci, 2021 11;58(7):513-529.
    PMID: 34615421 DOI: 10.1080/10408363.2021.1942781
    Matrix-assisted laser desorption/ionization (MALDI) imaging is an emergent technology that has been increasingly adopted in cancer research. MALDI imaging is capable of providing global molecular mapping of the abundance and spatial information of biomolecules directly in the tissues without labeling. It enables the characterization of a wide spectrum of analytes, including proteins, peptides, glycans, lipids, drugs, and metabolites and is well suited for both discovery and targeted analysis. An advantage of MALDI imaging is that it maintains tissue integrity, which allows correlation with histological features. It has proven to be a valuable tool for probing tumor heterogeneity and has been increasingly applied to interrogate molecular events associated with cancer. It provides unique insights into both the molecular content and spatial details that are not accessible by other techniques, and it has allowed considerable progress in the field of cancer research. In this review, we first provide an overview of the MALDI imaging workflow and approach. We then highlight some useful applications in various niches of cancer research, followed by a discussion of the challenges, recent developments and future prospect of this technique in the field.
  5. Nguyen DND, Chilian WM, Zain SM, Daud MF, Pung YF
    Can J Physiol Pharmacol, 2021 Sep;99(9):827-838.
    PMID: 33529092 DOI: 10.1139/cjpp-2020-0581
    Cardiovascular disease (CVD) is among the leading causes of death worldwide. MicroRNAs (miRNAs), regulatory molecules that repress protein expression, have attracted considerable attention in CVD research. The vasculature plays a big role in CVD development and progression and dysregulation of vascular cells underlies the root of many vascular diseases. This review provides a brief introduction of the biogenesis of miRNAs and exosomes, followed by overview of the regulatory mechanisms of miRNAs in vascular smooth muscle cells (VSMCs) intracellular signaling during phenotypic switching, senescence, calcification, and neointimal hyperplasia. Evidence of extracellular signaling of VSMCs and other cells via exosomal and circulating miRNAs is also presented. Lastly, current drawbacks and limitations of miRNA studies in CVD research and potential ways to overcome these disadvantages are discussed in detail. In-depth understanding of VSMC regulation via miRNAs will add substantial knowledge and advance research in diagnosis, disease progression, and (or) miRNA-derived therapeutic approaches in CVD research.
  6. Jamalpour S, Zain SM, Vazifehmand R, Mohamed Z, Pung YF, Kamyab H, et al.
    Sci Rep, 2022 Nov 24;12(1):20295.
    PMID: 36434110 DOI: 10.1038/s41598-022-23816-3
    Gestational diabetes mellitus (GDM) is a severe global issue that requires immediate attention. MicroRNA expression abnormalities are possibly disease-specific and may contribute to GDM pathological processes. To date, there is limited data on miRNA profiling in GDM, especially that involves a longitudinal study. Here, we performed miRNA expression profiling in the entire duration of pregnancy (during pregnancy until parturition and postpartum) using a miRNA- polymerase chain reaction array (miRNA-PCRArray) and in-silico analysis to identify unique miRNAs expression and their anticipated target genes in Malay maternal serum. MiRNA expression levels and their unique potential as biomarkers were explored in this work. In GDM patients, the expression levels of hsa-miR-193a, hsa-miR-21, hsa-miR-23a, and hsa-miR-361 were significantly increased, but miR-130a was significantly downregulated. The area under the curve (AUC) and receiver operating characteristic (ROC) curve study demonstrated that hsa-miR-193a (AUC = 0.89060 ± 04,470, P = 0.0001), hsa-miR-21 (AUC = 0.89500 ± 04,411, P = 0.0001), and miR-130a (AUC = 0.6939 ± 0.05845, P = 0.0025) had potential biomarker features in GDM. In-silico analysis also revealed that KLF (Kruppel-Like family of transcription factor), ZNF25 (Zinc finger protein 25), AFF4 (ALF transcription elongation factor 4), C1orf143 (long intergenic non-protein coding RNA 2869), SRSF2 (serine and arginine rich splicing factor 2), and ZNF655 (Zinc finger protein 655) were prominent genes targeted by the common nodes of miR23a, miR130, miR193a, miR21, and miR361.Our findings suggest that circulating microRNAs in the first trimester has the potential for GDM screening in the Malay population.
  7. Ting YW, Kong AS, Zain SM, Chan WK, Tan HL, Mohamed Z, et al.
    Clin Mol Hepatol, 2021 Jul;27(3):486-498.
    PMID: 33618508 DOI: 10.3350/cmh.2020.0162
    BACKGROUND/AIMS: 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients.

    METHODS: Consecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded.

    RESULTS: HSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00-0.64; P=0.033 and HR, 0.01; 95% CI, 0.00-0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese.

    CONCLUSION: HSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.

  8. Tan PPS, Sandhu RS, Zain SM, Hall D, Tan NC, Lim HM, et al.
    PLoS One, 2022;17(12):e0278761.
    PMID: 36477162 DOI: 10.1371/journal.pone.0278761
    INTRODUCTION: Self-care behaviour is fundamental in preventing hypertension in the general population. According to the Health Belief Model, health beliefs and perceptions influence the success in adopting disease prevention strategies. While factors influencing hypertension self-care behaviour have been examined previously in patient populations, they have not been assessed in the general community.

    METHODS: This was a cross-sectional study conducted between 12 June 2020 to 26 July 2021. An online survey was administered via email and social media to Malaysians in the Selangor and Kuala Lumpur communities. Respondents were over 18 years old, without a formal diagnosis of hypertension. The survey evaluated hypertension knowledge, Health Belief Model constructs, self-care behaviour frequency, and motivators and barriers to self-care behaviour. Multiple linear regression was performed to determine the main predictors of self-care behaviour, and descriptive statistics were used to characterise motivators and barriers of each self-care behaviour.

    RESULTS: Only health motivations (β = 0.217, p < 0.001) and perceived barriers (β = 0.571, p < 0.001) significantly influenced self-care behaviour. Maintaining a healthy diet, regular physical activity and blood pressure checks need to be improved in the community, particularly in reducing salt and calorie intake. Lack of time, limited choices and laziness are the biggest challenges that need to be tackled in adopting a healthy diet and an active lifestyle in the community. Many are ignorant towards their health status, therefore, do not prioritize blood pressure screenings, suggesting a need to enhance community blood pressure checks for early diagnosis of hypertension.

    CONCLUSION AND IMPLICATIONS: Motivations and barriers were the main determinants of self-care behaviour in the Selangor and Kuala Lumpur community. Targeting these aspects of self-care behaviour should be considered when developing interventions and education programmes tailored to local cultural, environmental and personal factors, to more effectively reduce the hypertension prevalence and burden.

  9. Kevin-Tey WF, Wen WX, Bee PC, Eng HS, Ho KW, Tan SM, et al.
    Hum Immunol, 2023 Mar;84(3):172-185.
    PMID: 36517321 DOI: 10.1016/j.humimm.2022.11.006
    Killer cell immunoglobulin-like receptors (KIR) genotype and haplotype frequencies have been reported to vary distinctly between populations, which in turn contributes to variation in the alloreactivity of natural killer (NK) cells. Utilizing the diverse KIR genes to identify suitable transplant donors would prove challenging in multi-ethnic countries, even more in resource-limited countries where KIR genotyping has not been established. In this study, we determined the KIR genotypes from 124 unrelated Malaysians consisting of the Malays, Chinese, Indians, and aboriginal people through polymerase chain reaction sequence-specific primer (PCR-SSP) genotyping and employing an expectation-maximization (EM) algorithm to assign haplotypes based on pre-established reference haplotypes. A total of 27 distinct KIR haplotypes were discerned with higher frequencies of haplotype A (55.2%) than haplotype B (44.8%). The most frequent haplotypes were cA01:tA01 (55.2%), cB01:tB01 (18.1%), and cB02:tA01 (13.3%), while the least frequent haplotypes were cB03:tB01 (1.2%), cB04:tB03 (0.4%), and cB03:tA01 (0.4%). Several haplotypes were identified to be unique to a specific ethnic group. The genotype with the highest frequency was genotype AB (71.8%), followed by AA (19.4%), and BB (8.9%). The Indians exhibited the lowest genotype AA but the highest genotype BB, whereas genotype BB was absent in the aboriginal people. Despite the limitations, the genotype and haplotypes in the Malaysian population were successfully highlighted. The identification of ethnic-specific KIR genotypes and haplotypes provides the first step to utilizing KIR in identifying suitable transplant donors to further improve the transplant outcome in the Malaysian population.
  10. Low HC, Chilian WM, Ratnam W, Karupaiah T, Md Noh MF, Mansor F, et al.
    Br J Biomed Sci, 2023;80:10884.
    PMID: 36866104 DOI: 10.3389/bjbs.2023.10884
    Type 2 Diabetes Mellitus is a major chronic metabolic disorder in public health. Due to mitochondria's indispensable role in the body, its dysfunction has been implicated in the development and progression of multiple diseases, including Type 2 Diabetes mellitus. Thus, factors that can regulate mitochondrial function, like mtDNA methylation, are of significant interest in managing T2DM. In this paper, the overview of epigenetics and the mechanism of nuclear and mitochondrial DNA methylation were briefly discussed, followed by other mitochondrial epigenetics. Subsequently, the association between mtDNA methylation with T2DM and the challenges of mtDNA methylation studies were also reviewed. This review will aid in understanding the impact of mtDNA methylation on T2DM and future advancements in T2DM treatment.
  11. Low TY, Syafruddin SE, Mohtar MA, Vellaichamy A, A Rahman NS, Pung YF, et al.
    Cell Mol Life Sci, 2021 Jul;78(13):5325-5339.
    PMID: 34046695 DOI: 10.1007/s00018-021-03856-0
    Protein-protein interactions are fundamental to various aspects of cell biology with many protein complexes participating in numerous fundamental biological processes such as transcription, translation and cell cycle. MS-based proteomics techniques are routinely applied for characterising the interactome, such as affinity purification coupled to mass spectrometry that has been used to selectively enrich and identify interacting partners of a bait protein. In recent years, many orthogonal MS-based techniques and approaches have surfaced including proximity-dependent labelling of neighbouring proteins, chemical cross-linking of two interacting proteins, as well as inferring PPIs from the co-behaviour of proteins such as the co-fractionating profiles and the thermal solubility profiles of proteins. This review discusses the underlying principles, advantages, limitations and experimental considerations of these emerging techniques. In addition, a brief account on how MS-based techniques are used to investigate the structural and functional properties of protein complexes, including their topology, stoichiometry, copy number and dynamics, are discussed.
  12. Tan PPS, Hall D, Chilian WM, Chia YC, Mohd Zain S, Lim HM, et al.
    Am J Physiol Heart Circ Physiol, 2021 04 01;320(4):H1486-H1497.
    PMID: 33577433 DOI: 10.1152/ajpheart.00888.2020
    MicroRNAs (miRNAs) are small regulatory molecules that are involved in posttranscriptional modifications. These noncoding RNAs are usually ferried by extracellular carriers such as exosomes or other protein and lipid carriers inside a range of body fluids including plasma and urine. Due to their ability to withstand harsh external conditions, exosomal miRNAs possess enormous potential as noninvasive disease biomarkers for, notably hypertension, whereby exosomal miRNAs have been implicated in its pathophysiological processes. More importantly, alterations in the microenvironment as a result of disease progression can induce active and selective loading of miRNAs into exosomes. In this paper, we first review the mechanisms of miRNA loading into exosomes, followed by the roles of exosomal miRNAs in the development of hypertension, and the potentials of exosomal miRNAs as biomarkers in comparison with other free circulating miRNAs. Finally, challenges and future research surrounding exosomal miRNAs will also be discussed. This review will aid in the understanding of noninvasive biomarkers for the early diagnosis of hypertension and for probing therapeutic efficacy.
  13. Yu EPK, Reinhold J, Yu H, Starks L, Uryga AK, Foote K, et al.
    Arterioscler Thromb Vasc Biol, 2017 12;37(12):2322-2332.
    PMID: 28970293 DOI: 10.1161/ATVBAHA.117.310042
    OBJECTIVE: Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis.

    APPROACH AND RESULTS: Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis.

    CONCLUSIONS: Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.

  14. Nguyen DDN, Zain SM, Kamarulzaman MH, Low TY, Chilian WM, Pan Y, et al.
    Am J Physiol Heart Circ Physiol, 2021 10 01;321(4):H770-H783.
    PMID: 34506226 DOI: 10.1152/ajpheart.00058.2021
    Vascular aging is highly associated with cardiovascular morbidity and mortality. Although the senescence of vascular smooth muscle cells (VSMCs) has been well established as a major contributor to vascular aging, intracellular and exosomal microRNA (miRNA) signaling pathways in senescent VSMCs have not been fully elucidated. This study aimed to identify the differential expression of intracellular and exosomal miRNA in human VSMCs (hVSMCs) during replicative senescence. To achieve this aim, intracellular and exosomal miRNAs were isolated from hVSMCs and subsequently subjected to whole genome small RNA next-generation sequencing, bioinformatics analyses, and qPCR validation. Three significant findings were obtained. First, senescent hVSMC-derived exosomes tended to cluster together during replicative senescence and the molecular weight of the exosomal protein tumor susceptibility gene 101 (TSG-101) increased relative to the intracellular TSG-101, suggesting potential posttranslational modifications of exosomal TSG-101. Second, there was a significant decrease in both intracellular and exosomal hsa-miR-155-5p expression [n = 3, false discovery rate (FDR) < 0.05], potentially being a cell type-specific biomarker of hVSMCs during replicative senescence. Importantly, hsa-miR-155-5p was found to associate with cell-cycle arrest and elevated oxidative stress. Lastly, miRNAs from the intracellular pool, that is, hsa-miR-664a-3p, hsa-miR-664a-5p, hsa-miR-664b-3p, hsa-miR-4485-3p, hsa-miR-10527-5p, and hsa-miR-12136, and that from the exosomal pool, that is, hsa-miR-7704, were upregulated in hVSMCs during replicative senescence (n = 3, FDR < 0.05). Interestingly, these novel upregulated miRNAs were not functionally well annotated in hVSMCs to date. In conclusion, hVSMC-specific miRNA expression profiles during replicative senescence potentially provide valuable insights into the signaling pathways leading to vascular aging.NEW & NOTEWORTHY This is the first study on intracellular and exosomal miRNA profiling on human vascular smooth muscle cells during replicative senescence. Specific dysregulated sets of miRNAs were identified from human vascular smooth muscle cells. Hsa-miR-155-5p was significantly downregulated in both intracellular and exosomal hVSMCs, suggesting its crucial role in cellular senescence. Hsa-miR-155-5p might be the mediator in linking cellular senescence to vascular aging and atherosclerosis.
  15. Esa E, Hashim AK, Mohamed EHM, Zakaria Z, Abu Hassan AN, Mat Yusoff Y, et al.
    Genet Test Mol Biomarkers, 2021 Mar;25(3):199-210.
    PMID: 33734890 DOI: 10.1089/gtmb.2020.0182
    Background: The association between dysregulated microRNAs (miRNAs) and acute myeloid leukemia (AML) is well known. However, our understanding of the regulatory role of miRNAs in the cytogenetically normal AML (CN-AML) subtype pathway is still poor. The current study integrated miRNA and mRNA profiles to explore novel miRNA-mRNA interactions that affect the regulatory patterns of de novo CN-AML. Methods: We utilized a multiplexed nanoString nCounter platform to profile both miRNAs and mRNAs using similar sets of patient samples (n = 24). Correlations were assessed, and an miRNA-mRNA network was constructed. The underlying biological functions of the mRNAs were predicted by gene enrichment. Finally, the interacting pairs were assessed using TargetScan and microT-CDS. We identified 637 significant negative correlations (false discovery rate <0.05). Results: Network analysis revealed a cluster of 12 miRNAs representing the majority of mRNA targets. Within the cluster, five miRNAs (miR-495-3p, miR-185-5p, let-7i-5p, miR-409-3p, and miR-127-3p) were posited to play a pivotal role in the regulation of CN-AML, as they are associated with the negative regulation of myeloid leukocyte differentiation, negative regulation of myeloid cell differentiation, and positive regulation of hematopoiesis. Conclusion: Three novel interactions in CN-AML were predicted as let-7i-5p:HOXA9, miR-495-3p:PIK3R1, and miR-495-3p:CDK6 may be responsible for regulating myeloid cell differentiation in CN-AML.
  16. Guarini G, Kiyooka T, Ohanyan V, Pung YF, Marzilli M, Chen YR, et al.
    Basic Res Cardiol, 2016 May;111(3):29.
    PMID: 27040114 DOI: 10.1007/s00395-016-0547-4
    Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H2O2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H2O2. In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.
  17. Kiyooka T, Ohanyan V, Yin L, Pung YF, Chen YR, Chen CL, et al.
    Basic Res Cardiol, 2022 Jan 17;117(1):3.
    PMID: 35039940 DOI: 10.1007/s00395-021-00908-1
    Endothelial dysfunction in diabetes is generally attributed to oxidative stress, but this view is challenged by observations showing antioxidants do not eliminate diabetic vasculopathy. As an alternative to oxidative stress-induced dysfunction, we interrogated if impaired mitochondrial function in endothelial cells is central to endothelial dysfunction in the metabolic syndrome. We observed reduced coronary arteriolar vasodilation to the endothelium-dependent dilator, acetylcholine (Ach), in Zucker Obese Fatty rats (ZOF, 34 ± 15% [mean ± standard deviation] 10-3 M) compared to Zucker Lean rats (ZLN, 98 ± 11%). This reduction in dilation occurred concomitantly with mitochondrial DNA (mtDNA) strand lesions and reduced mitochondrial complex activities in the endothelium of ZOF versus ZLN. To demonstrate endothelial dysfunction is linked to impaired mitochondrial function, administration of a cell-permeable, mitochondria-directed endonuclease (mt-tat-EndoIII), to repair oxidatively modified DNA in ZOF, restored mitochondrial function and vasodilation to Ach (94 ± 13%). Conversely, administration of a cell-permeable, mitochondria-directed exonuclease (mt-tat-ExoIII) produced mtDNA strand breaks in ZLN, reduced mitochondrial complex activities and vasodilation to Ach in ZLN (42 ± 16%). To demonstrate that mitochondrial function is central to endothelium-dependent vasodilation, we introduced (via electroporation) liver mitochondria (from ZLN) into the endothelium of a mesenteric vessel from ZOF and restored endothelium-dependent dilation to vasoactive intestinal peptide (VIP at 10-5 M, 4 ± 3% vasodilation before mitochondrial transfer and 48 ± 36% after transfer). Finally, to demonstrate mitochondrial function is key to endothelium-dependent dilation, we administered oligomycin (mitochondrial ATP synthase inhibitor) and observed a reduction in endothelium-dependent dilation. We conclude that mitochondrial function is critical for endothelium-dependent vasodilation.
  18. Runcharoen C, Fukunaga K, Sensorn I, Iemwimangsa N, Klumsathian S, Tong H, et al.
    Hum Genome Var, 2021 Feb 04;8(1):7.
    PMID: 33542200 DOI: 10.1038/s41439-021-00135-z
    Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.
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