SerpinA3N deficiency attenuates steatosis and enhances insulin signaling in male mice.

Aberrant hepatic lipid metabolism is the major cause of non-alcoholic fatty liver disease (NAFLD) and is associated with insulin resistance and type 2 diabetes. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) is highly expressed in the liver; however, its functional role in regulating NAFLD and associated metabolic disorders are not known. Male wildtype and hepatocyte Serpina3N knockout (HKO) mice were fed a control diet, methionine- and choline-deficient diet or high-fat high-sucrose diet to induce NAFLD and markers of lipid metabolism and glucose homeostasis were assessed. SerpinA3N protein was markedly induced in mice with fatty livers. Hepatic deletion of SerpinA3N attenuated steatosis which correlated with altered lipid metabolism genes, increased fatty acid oxidation activity and enhanced insulin signaling in mice with NAFLD. Additionally, SerpinA3N HKO mice had reduced epididymal white adipose tissue mass, leptin, and insulin levels, improved glucose tolerance, and enhanced insulin sensitivity which was associated with elevated insulin-like growth factor binding protein-1 (IGFBP1) and activation of the leptin receptor (LEPR)-STAT3 signaling pathway. Our findings provide a novel insight into the functional role of SerpinA3N in regulating NAFLD and glucose homeostasis.

Primary Jejunal Gastrointestinal Stromal Tumor: Diagnosis Delay of 3 Years but Successful Management in Early Stage (II) by Surgery and Adjuvant Therapy.

In the digestive system, mesenchymal origin of tumors is quite rare; in general, they are recognized as gastrointestinal stromal tumors (GISTs). The incidence of GISTs is very low (2 in 100,000), while jejunal GISTs are extremely rare, accounting for 0.1-3% of all gastrointestinal (GI) tumors. Small intestinal GISTs are the second most common (25%) site in the GI tract, usually occurring in the duodenum. We present the case of a 62-year-old Bangladeshi female with a history of GI bleeding 3 years earlier; the cause of the bleeding had not been found despite extensive investigations. In the meantime, the patient had developed occasional abdominal pain and lumpy feelings in the right side of the abdomen without any GI bleeding. Exploratory laparotomy was carried out in view of a small intestinal mesenteric mass in a computed tomography scan. On midline incision there was a 6 × 6 cm mass in the antimesenteric border of the jejunum approximately 30 cm from the duodenojejunal flexure, which was resected followed by anastomosis. The presentation of GISTs ranges from asymptomatic to mild abdominal pain and mass (5-50%) and mechanical obstruction (5%) as well as hemorrhage - perforation having rarely been reported (0.8%) - making the diagnosis difficult. Exophytic growth of these tumors has been noted in 18-30% of cases. In view of intermediate risk of malignancy, the patient was started with adjuvant imatinib 400 mg once daily due to probability of disease recurrence (24%).

Secondhand smoking, knowledge/attitudes and socioeconomic status among married Bangladeshi women: a cross-sectional study.

BACKGROUND: There is a paucity of research on knowledge/attitudes regarding the dangers of exposure to secondhand smoking (SHS) among women. The relationship between exposure to SHS, socioeconomic status (SES) and knowledge/attitudes regarding the risks of SHS has often been ignored. We therefore aimed to examine (1) whether SES and exposure to SHS were independently associated with knowledge/attitudes regarding the risks of SHS; and (2) whether women with low SES and exposure to SHS were uniquely disadvantaged in terms of deficient knowledge and more dismissive attitudes towards the risks of SHS. DESIGN AND SETTING: Cross-sectional study in the Rajshahi district, Bangladesh. METHODS: A total of 541 women were interviewed. Knowledge of and attitudes towards the risks of SHS were the outcomes of interest. RESULTS: A majority of the respondents were exposed to SHS at home (49.0%). Only 20.1% had higher levels of knowledge, and only 37.3% had non-dismissive attitudes towards the risks of SHS. Participants in the low SES group and those exposed to SHS had lower odds of higher knowledge and their attitudes towards the risks of SHS were more dismissive. Regarding deficient levels of knowledge and scores indicating more dismissive attitudes, women in the low SES group and who were exposed to SHS were not uniquely disadvantaged. CONCLUSIONS: Exposure to SHS and low SES were independently associated with deficient knowledge and scores indicating more dismissive attitudes. Regarding knowledge/attitudes, the negative effect of exposure to SHS extended across all socioeconomic backgrounds and was not limited to women in either the low or the high SES group.

Secondhand smoking, knowledge/attitudes and socioeconomic status among married Bangladeshi women: a cross-sectional study

ABSTRACT BACKGROUND: There is a paucity of research on knowledge/attitudes regarding the dangers of exposure to secondhand smoking (SHS) among women. The relationship between exposure to SHS, socioeconomic status (SES) and knowledge/attitudes regarding the risks of SHS has often been ignored. We therefore aimed to examine (1) whether SES and exposure to SHS were independently associated with knowledge/attitudes regarding the risks of SHS; and (2) whether women with low SES and exposure to SHS were uniquely disadvantaged in terms of deficient knowledge and more dismissive attitudes towards the risks of SHS. DESIGN AND SETTING: Cross-sectional study in the Rajshahi district, Bangladesh. METHODS: A total of 541 women were interviewed. Knowledge of and attitudes towards the risks of SHS were the outcomes of interest. RESULTS: A majority of the respondents were exposed to SHS at home (49.0%). Only 20.1% had higher levels of knowledge, and only 37.3% had non-dismissive attitudes towards the risks of SHS. Participants in the low SES group and those exposed to SHS had lower odds of higher knowledge and their attitudes towards the risks of SHS were more dismissive. Regarding deficient levels of knowledge and scores indicating more dismissive attitudes, women in the low SES group and who were exposed to SHS were not uniquely disadvantaged. CONCLUSIONS: Exposure to SHS and low SES were independently associated with deficient knowledge and scores indicating more dismissive attitudes. Regarding knowledge/attitudes, the negative effect of exposure to SHS extended across all socioeconomic backgrounds and was not limited to women in either the low or the high SES group.

Regulation of gasdermin D by miR-379-5p is involved in arsenite-induced activation of hepatic stellate cells and in fibrosis via secretion of IL-1ß from human hepatic cells.

Arsenic is an environmental toxicant and human carcinogen. The liver is the main site of arsenic storage and metabolism. Exposure to excessive arsenic causes liver damage and release of pro-inflammatory factors, which in turn lead to liver fibrosis. Gasdermin D (GSDMD), a mediator of pyroptosis, has low expression in hepatic tumor cells. In L-02 cells, arsenite caused increases of GSDMD and cleaved caspase-1 levels and decreases of caspase-1 and miR-379-5p levels. It also promoted the release of IL-1ß in a concentration- and time-dependent manner. Luciferase reporter assays showed that GSDMD was a direct target of miR-379-5p. In L-02 cells, the over-expression of miR-379-5p blocked the arsenite-induced increases of GSDMD levels and the release of IL-1ß, effects that were reversed by up-regulation of GSDMD. LX-2 cells, cultured in the media from arsenite-treated L-02 cells, showed elevated levels of proliferating cell nuclear antigen (PCNA), collagen I, vimentin, and α-smooth muscle actin (α-SMA), which indicated activation of these cells. Activation of LX-2 cells by media from arsenite-treated L-02 cells was inhibited by IL-1ß neutralizing antibody. The media from arsenite-treated L-02 cells transfected with an miR-379-5p mimic inhibited the activation of LX-2 cells, a process that was reversed by up-regulation of GSDMD and by co-treatment with human recombinant IL-1ß. Chronic exposure to arsenite induced, in liver tissue of mice, morphological damage, collagen deposition, and activation of hepatic stellate cells (HSCs). In liver tissue of arsenite-exposed mice, the levels of miR-379-5p were lower, but the levels of GSDMD and cleaved caspase-1 were elevated, and in sera from arsenite-exposed mice, the IL-1ß levels were elevated. These results indicate that, by elevating the secretion of IL-1ß, miR-379-5p regulation of GSDMD is involved in arsenite-induced activation of HSCs and in hepatic fibrosis. This establishes a previously unknown molecular mechanism for arsenite-induced liver damage, inflammation, and fibrosis.

A cross sectional study of anemia and iron deficiency as risk factors for arsenic-induced skin lesions in Bangladeshi women.

BACKGROUND: In the Ganges Delta, chronic arsenic poisoning is a health concern affecting millions of people who rely on groundwater as their potable water source. The prevalence of anemia is also high in this region, particularly among women. Moreover, arsenic is known to affect heme synthesis and erythrocytes and the risk of arsenic-induced skin lesions appears to differ by sex. METHODS: We conducted a case-control study in 147 arsenic-exposed Bangladeshi women to assess the association between anemia and arsenic-induced skin lesions. RESULTS: We observed that the odds of arsenic-related skin lesions were approximately three times higher among women who were anemic (hemoglobin < 120 g/L) compared to women with normal hemoglobin levels [Odds Ratio (OR) = 3.32, 95% Confidence Intervals (CI): 1.29, 8.52] after adjusting for arsenic levels in drinking water and other covariates. Furthermore, 75% of the women with anemia had adequate iron stores (serum ferritin ≥ 12 µg/L), suggesting that the majority of anemia detected in this population was unrelated to iron depletion. CONCLUSIONS: Considering the magnitude of arsenic exposure and prevalence of anemia in Bangladeshi women, additional research is warranted that identifies the causes of anemia so that effective interventions can be implemented while arsenic remediation efforts continue.

A distinct and replicable variant of the squamous cell carcinoma gene inositol polyphosphate-5-phosphatase modifies the susceptibility of arsenic-associated skin lesions in Bangladesh.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in inflammation, one-carbon metabolism, and skin cancer genes might influence susceptibility to arsenic-induced skin lesions. METHODS: A case-control study was conducted in Pabna, Bangladesh (2001-2003), and the drinking-water arsenic concentration was measured for each participant. A panel of 25 candidate SNPs was analyzed in 540 cases and 400 controls. Logistic regression was used to estimate the association between each SNP and the potential for gene-environment interactions in the skin lesion risk, with adjustments for relevant covariates. Replication testing was conducted in an independent Bangladesh population with 488 cases and 2,794 controls. RESULTS: In the discovery population, genetic variants in the one-carbon metabolism genes phosphatidylethanolamine N-methyltransferase (rs2278952, P for interaction = .004; rs897453, P for interaction = .05) and dihydrofolate reductase (rs1650697, P for interaction = .02), the inflammation gene interleukin 10 (rs3024496, P for interaction =.04), and the skin cancer genes inositol polyphosphate-5-phosphatase (INPP5A; rs1133400, P for interaction = .03) and xeroderma pigmentosum complementation group C (rs2228000, P for interaction = .01) significantly modified the association between arsenic and skin lesions after adjustments for multiple comparisons. The significant gene-environment interaction between a SNP in the INPP5A gene (rs1133400) and water arsenic with respect to the skin lesion risk was successfully replicated in an independent population (P for interaction = .03). CONCLUSIONS: Minor allele carriers of the skin cancer gene INPP5A modified the odds of arsenic-induced skin lesions in both main and replicative populations. Genetic variation in INPP5A appears to have a role in susceptibility to arsenic toxicity.

Epigenome-wide DNA methylation changes with development of arsenic-induced skin lesions in Bangladesh: a case-control follow-up study.

Studies have found an association between aberrant DNA methylation and arsenic-induced skin lesions. However, little is known about DNA methylation changes over time in people who develop arsenic-induced skin lesions. We sought to investigate epigenome-wide changes of DNA methylation in people who developed arsenic-induced skin lesions in a 10-year period. In 2009-2011, we conducted a follow-up study of 900 skin lesion cases and 900 controls and identified 10 people who developed skin lesions since a baseline survey in 2001-2003. The 10 cases ("New Cases") were matched with 10 controls who did not have skin lesions at baseline or follow-up ("Persistent Controls"). Drinking water and blood samples were collected, and skin lesion was diagnosed by the same physician at both time points. We measured DNA methylation in blood using Infinium HumanMethylation450K BeadChip, followed by quantitative validation using pyrosequencing. Two-sample t-tests were used to compare changes in percent methylation between New Cases and Persistent Controls. Six CpG (cytosine-phosphate-guanine) sites with greatest changes of DNA methylation over time among New Cases were further validated with a correlation of 93% using pyrosequencing. One of the validated CpG site (cg03333116; change of %methylation was 13.2 in New Cases versus -0.09 in Persistent Controls; P < 0.001) belonged to the RHBDF1 gene, which was previously reported to be hypermethylated in arsenic-exposed cases. We examined DNA methylation changes with the development of arsenic-induced skin lesions over time but nothing was statistically significant given the small sample size of this exploratory study and the high dimensionality of data.

Association of low to moderate levels of arsenic exposure with risk of type 2 diabetes in Bangladesh.

Chronic exposure to high levels of arsenic in drinking water is associated with increased risk of type 2 diabetes mellitus (T2DM), but the association between lower levels of arsenic and T2DM is more controversial. Therefore, this study evaluated the association between low to moderate arsenic exposure and T2DM. In 2009-2011, we conducted a study of 957 Bangladeshi adults who participated in a case-control study of skin lesions in 2001-2003. The odds ratio of T2DM was evaluated in relationship to arsenic exposure measured in drinking water and in subjects' toenails (in 2001-2003) prior to the diagnosis of T2DM (in 2009-2011). Compared with those exposed to the lowest quartile of arsenic in water (≤ 1.7 µg/L), the adjusted odds ratio for T2DM was 1.92 (95% confidence interval (CI): 0.82, 4.35) for those in the second quartile, 3.07 (95% CI: 1.38, 6.85) for those in the third quartile, and 4.51 (95% CI: 2.01, 10.09) for those in the fourth quartile. The relative excess risk of T2DM was 4.78 for individuals who smoked and 8.93 for people who had a body mass index (weight (kg)/height (m)(2)) greater than 25. These findings suggest that exposure to modest levels of arsenic in drinking water was associated with increased risk of T2DM in Bangladesh. Being overweight or smoking was also associated with increased risk of T2DM.

Prenatal arsenic exposure and DNA methylation in maternal and umbilical cord blood leukocytes.

BACKGROUND: Arsenic is an epigenetic toxicant and could influence fetal developmental programming. OBJECTIVES: We evaluated the association between arsenic exposure and DNA methylation in maternal and umbilical cord leukocytes. METHODS: Drinking-water and urine samples were collected when women were at ≤ 28 weeks gestation; the samples were analyzed for arsenic using inductively coupled plasma mass spectrometry. DNA methylation at CpG sites in p16 (n = 7) and p53 (n = 4), and in LINE-1 and Alu repetitive elements (3 CpG sites in each), was quantified using pyrosequencing in 113 pairs of maternal and umbilical blood samples. We used general linear models to evaluate the relationship between DNA methylation and tertiles of arsenic exposure. RESULTS: Mean (± SD) drinking-water arsenic concentration was 14.8 ± 36.2 µg/L (range: < 1-230 µg/L). Methylation in LINE-1 increased by 1.36% [95% confidence interval (CI): 0.52, 2.21%] and 1.08% (95% CI: 0.07, 2.10%) in umbilical cord and maternal leukocytes, respectively, in association with the highest versus lowest tertile of total urinary arsenic per gram creatinine. Arsenic exposure was also associated with higher methylation of some of the tested CpG sites in the promoter region of p16 in umbilical cord and maternal leukocytes. No associations were observed for Alu or p53 methylation. CONCLUSIONS: Exposure to higher levels of arsenic was positively associated with DNA methylation in LINE-1 repeated elements, and to a lesser degree at CpG sites within the promoter region of the tumor suppressor gene p16. Associations were observed in both maternal and fetal leukocytes. Future research is needed to confirm these results and determine if these small increases in methylation are associated with any health effects.