Ming-Yuh Shiau

Regulation of glucose/lipid metabolism and insulin sensitivity by interleukin-4

Objective:Abundant evidence has demonstrated that long-term cytokine-mediated inflammation is a risk factor for obesity and type 2 diabetes mellitus (T2DM). Our previous study reveals a significant association between promoter polymorphisms of Th2-derived cytokine interleukin-4 (IL-4) and T2DM, which suggests possible roles of IL-4 in metabolism. In this study, we focused on examining the putative regulation of glucose and lipid metabolism by IL-4.Methods:C57BL/6 mice were intraperitoneally injected with either adenovirus containing full-length IL-4 encoding gene (AdIL-4) or recombinant IL-4 for mimicking the status of transient and long-term IL-4 overexpression, respectively, and the effects of the overexpressed IL-4 to glucose/lipid metabolism and insulin sensitivity were subsequently investigated.Results:Our results reveal that IL-4 improves insulin sensitivity and glucose tolerance through upregulating Akt phosphorylation while attenuating GSK-3β activities. IL-4 is also involved in lipid metabolism by inhibiting lipid accumulation in fat tissues, which lead to decreased weight gain and fat mass.Conclusions:Our results suggest that IL-4 regulates glucose and lipid metabolism by promoting insulin sensitivity, glucose tolerance and inhibiting lipid deposits. This study uncovers the novel roles of IL-4 in metabolism and provides new insights in the interaction between cytokines/immune responses, insulin sensitivity and metabolism.

Interleukin-4 regulates lipid metabolism by inhibiting adipogenesis and promoting lipolysis

Long-term cytokine-mediated inflammation is a risk factor for obesity and type 2 diabetes mellitus (T2DM). Our previous studies reveal significant associations between promoter single nucleotide polymorphisms (SNPs) of interleukin (IL)-4 and T2DM, as well as between SNPs in genes encoding IL-4/IL-4 receptor and high density lipoproteins. Our animal study reveals that IL-4 regulates glucose/lipid metabolism by promoting glucose tolerance and inhibiting lipid deposits. The above results strongly suggest the involvement of IL-4 in energy homeostasis. In the present study, we focus on examining the regulatory mechanism of IL-4 to lipid metabolism. Our results show that IL-4 inhibits adipogenesis by downregulating the expression of peroxisome proliferator-activated receptor-γ and CCAAT/enhancer-binding protein-α. Additionally, IL-4 promotes lipolysis by enhancing the activity and translocation of hormone sensitive lipase (HSL) in mature adipocytes, which suggests that IL-4 plays a pro-lipolytic role in lipid metabolism by boosting HSL activity. Our results demonstrate that IL-4 harbors pro-lipolysis capacity by inhibiting adipocyte differentiation and lipid accumulation as well as by promoting lipolysis in mature adipocytes to decrease lipid deposits. The above findings uncover the novel roles of IL-4 in lipid metabolism and provide new insights into the interactions among cytokine/immune responses, insulin sensitivity, and metabolism.

Prevalence of antibiotics resistance and OXA carbapenemases genes in multidrug-resistant Acinetobacter baumannii isolates in central Taiwan

This study analyzed the prevalence of antibiotics resistance and the distribution of genes responsible for carbapenems resistance in Acinetobacter baumannii isolates. Clinical A. baumannii isolates were cultured, identified, and collected during the period from May 2007 to February 2009. Antibiotics resistance rates of the clinical isolates were analyzed by antimicrobial susceptibility testing. The distribution of carbapenemase alleles were investigated in the multidrug-resistant (MDR) A. baumannii isolates by multiplex polymerase chain reaction (PCR) techniques. A total of 1,265 independent A. baumannii isolates were identified. Approximately 70% of the clinical isolates were resistant to ampicillin/sulbactam, followed by imipenem, meropenem, cefepime, piperacillin/tazobactam, ceftazidime, and cefoperazone. Overall, 15.18% (192/1,265) of the isolates were characterized as MDR strains. All of the MDR A. baumannii isolates carried the blaOXA51-like allele. The detection rate of the blaOXA23-like and blaOXA24-like alleles was 96.35% (185/192) and 0.52% (1/192), respectively. Most of the isolates (185/192, 96.35%) carried genes which encode more than one carbapenemase. This report demonstrated that approximately 15% of A. baumannii clinical isolates in central Taiwan are MDR strains, with most of them harboring multiple carbapenemases. This study provides updated data regarding the prevalence of β-lactam resistance and genotyping information of carbapenems resistance of A. baumannii in central Taiwan.

Up-regulation of interleukin-17 expression by human papillomavirus type 16 E6 in nonsmall cell lung cancer

Human papillomavirus (HPV) 16/18 infection is associated with nonsmoking lung cancer. In this study, the authors investigated a putative correlation between interleukin (IL)‐17 expression and HPV infection in clinical nonsmall cell lung cancer (NSCLC) tissues and examined the effects of HPV infection on a human NSCLC cell line.

Human Papillomavirus Up-Regulates MMP-2 and MMP-9 Expression and Activity by Inducing Interleukin-8 in Lung Adenocarcinomas

Human papillomavirus (HPV) infection is associated with non-smoking female lung cancer. Our previous report demonstrated that HPV 16 promotes lung tumor cell progression by up-regulating interleukin-17 (IL-17). IL-17 and its downstream signaling mediator, interleukin-8 (IL-8), have been implicated to modulate a variety of pro-angiogenic factors and play important roles in tumor angiogenesis and metastasis. Accordingly, we hypothesized that HPV infection may potentiate tumorigenic and metastatic characteristics of the infected cells through IL-8. The goal of the present study was to determine whether HPV infection in lung adenocarcinoma cells can promote the expression of IL-8 and metalloproteinases (MMPs) to make the transformed cells equipped with angiogenic and metastatic characteristics. The expression of IL-8 and MMPs in HPV 16 E6-transfected H1299 cells was analyzed to examine the hypothesis. HPV 16 E6 up-regulates pro-angiogenic MMP-2 and MMP-9 through inducing IL-8 expression in lung cancer cells. The results indicate that, in addition to cell proliferation-related machinery, HPV infection promotes the expression and activities of angiogenic and metastatic molecules in lung adenocarcinoma cells. The cytokines induced by HPV infection may work together to confer the malignant and tumorigenic potentials on the infected cells by promoting machineries of growth, angiogenic and metastatic characteristics.

Association of interleukin-4 promoter polymorphisms in Taiwanese patients with type 2 diabetes mellitus

Many factors have been implicated in the onset of type 2 diabetes mellitus (T2DM). Recently, immune response and inflammation were suggested to play certain roles in the development and complications of T2DM. The aim of this study is to investigate the putative correlation between the promoter polymorphisms of interleukin-4 (IL-4), one of the immune-regulatory type 2 helper T-cell cytokines, and T2DM. Genomic DNA from 425 Taiwanese T2DM patients and 148 nondiabetic control study subjects were extracted, and their IL-4 promoter polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Both of the distribution of IL-4 C-589T (P = .013) and C-34T (P = .05) genotypes were significantly different between T2DM patients and control subjects. Significant association between IL-4 C-589T alleles (P = .002) and T2DM, as well as C-34T alleles and T2DM (P =.024), was also identified. In addition, a statistically significant association between homologous IL-4 -589 C/C genotype and lower circulatory high-density lipoprotein cholesterol levels was observed. Our results suggested that IL-4 promoter polymorphisms are associated with T2DM. A significant association between IL-4 -589 C/C genotype and lower circulatory high-density lipoprotein cholesterol level was observed as well. The above results suggested that IL-4 may participate in lipid metabolism and diabetic susceptibility.

Prevalence of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in Taiwanese patients with Type 2 diabetic mellitus.

OBJECTIVES Deficiency and/or decreased activity of methyltetrahydrofolate reductase (MTHFR) resulted from MTHFR variants are associated with hyperhomocysteinemia, an independent risk factor for vasculopathies in diabetic patients. The aim of this study was to examine MTHFR genotypes between healthy and type 2 diabetes mellitus (T2DM) subjects. DESIGN AND METHODS MTHFR C677T and A1298C genotypes were analyzed in 56 T2DM and 62 healthy subjects by PCR-RFLP. Association between MTHFR genotypes and T2DM as well as the lipid/glucose metabolic indexes among T2DM subjects was statistically analyzed. RESULTS No significance in the distribution of MTHFR genotypes between healthy and T2DM subjects is found. Besides, no significant associations between lipid/glucose metabolic indexes with MTHFR genotypes among diabetic patients are observed. CONCLUSIONS These data indicate the previous observation that MTHFR polymorphisms may play some roles in the pathogenesis and complications of T2DM in Caucasians are unlikely to be applied in Taiwanese patients.

Trends of mycobacterial clinical isolates in Taiwan

Non-tuberculous mycobacteria (NTM) can cause chronic pulmonary infection, however, NTM infection is generally overlooked. This retrospective study analyzed the frequencies of Mycobacterium tuberculosis complex (MTBC) and NTM clinical isolates from 99 200 specimens of patients suspected with pulmonary mycobacterial infection in Taiwan from 2002-2007. A total of 8024 mycobacterial isolates, including 5349 MTBC and 2675 NTM, were obtained from the 99 200 specimens in the study period. The overall mycobacterial isolation rate was 8.09% (8024/99 200), and the overall MTBC and NTM isolation rate was 5.39% (5349/99 200) and 2.7% (2675/99 200), respectively. Notably, the prevalence of NTM isolates among the identified mycobacteria strains was increased 2.6 fold from 2002 (17.54%, 147/838) to 2007 (45.80%, 659/1439). The frequencies of MTBC and NTM isolates showed a reciprocal trend: the NTM isolation rates were steadily increasing while the overall mycobacterial isolation rates remained stable over the study period. Our results suggest that the diagnosis, identification and susceptibility tests for NTM should be standardized and integrated in clinical routines, for providing the information of NTM infection and prescribing clinical treatment in a more precise and efficient way to reduce the increasing NTM in the studied area.

Role of PARL-PINK1-Parkin pathway in adipocyte differentiation

OBJECTIVE Adipogenesis determines the number of adipocytes which is increased when individuals become obese. Mitochondria undergo remarkable morphological and functional changes during adipogenesis. PTEN-induced kinase 1 (PINK1) is pivotal to maintain mitochondrial homeostasis in neural cells. The present study aimed at investigating effects of PINK1 on adipogenesis and energy metabolism. METHODS Expression of presenilin associated rhomboid-like protein (PARL), PINK1 and Parkin, as well as the interaction among these proteins was temporally examined during adipogenesis. In addition, the alterations of mitochondrial mass and the energy metabolism were also analyzed. RESULTS Adipogenic process can be dissected into 3 stages according to the participation of PARL-PINK1-Parkin system. (1) When pre-adipocytes are switched to differentiation, f-PINK1 is subjected to PARL cleavage to generate s-PINK1 at the early stage of differentiation (0-4day). Mitochondrial mass is increased for generating ambient energy to meet the demands for cellular remodeling. (2) At the second stage (5-6day), s-PINK1 persistently accumulates in mitochondria and translocates into cytoplasm to mediate Parkin degradation. Mitochondria are fragmented to reduce their mass. (3) At the late stage (7-8day), only residual autophagy activity is remained when excess mitochondria have been eliminated. This mitochondria clearance maintains energy consumption of mature adipocytes at the minimal levels for storing energy. PARL silencing aborts adipogenesis by inhibiting PPARγ expression and the finely-orchestrated events. CONCLUSIONS Our findings reveal the sequential adipogenic events directed by PARL-PINK1-Parkin system, add more evidence supporting the convergence of pathogenesis leading to neurodegenerative and metabolic diseases, and provide substantial information for developing novel therapeutic strategies by manipulating adipogenesis.

Mycobacterial Prevalence and Antibiotic Resistance Frequency Trends in Taiwan of Mycobacterial Clinical Isolates From 2002 to 2014.

AbstractTuberculosis, caused by Mycobacterium tuberculosis complex (MTBC) infections, is one of the most widespread infectious diseases worldwide. Nontuberculous mycobacteria (NTM) also cause chronic pulmonary infections, however, NTM infection is generally overlooked.This study analyzed the frequencies of MTBC and NTM clinical isolates from 181,132 specimens obtained from patients in Taiwan suspected of having a pulmonary mycobacterial infection from 2002 to 2014. The resistant rates to 4 first-line antibiotics (isoniazid, ethambutol, rifampicin, and streptomycin) of 9079 clinical MTBC isolates were also examined by the modified agar proportion method.Overall, the mycobacterial isolation rate was 8.65%, and this consisted of MTBC isolation rate of 5.01% and NTM isolation rate of 3.63%. The prevalence of MTBC isolates among the identified mycobacterial strains could be seen to decrease significantly from 82.5% in 2002 to 41.18% in 2014. Notably, the corresponding NTM prevalence increased 3.36 fold from 17.54% in 2002 to 58.82% in 2014. The frequencies of MTBC and NTM isolates showed a reciprocal trend with the crossing over occurring in the years 2010 and 2011. Although the resistance rates of the MTBC isolates to isoniazid and streptomycin were relatively stable over the study period, resistance rates of the MTBC isolates against rifampicin and ethambutol fluctuated across the study period. Overall, the incidence of multidrug resistance was relatively consistent at about 1.74%.The diagnosis, identification, and susceptibility tests for NTM should be standardized and integrated into appropriate clinical settings to cope with the increase in NTM infections. In addition, the documentation of the antibiotic resistance rates of MTBC clinical isolates to the antibiotic treatments most often clinically prescribed over a decade provides valuable clues and reference points for effective mycobacterial control.