Irreversible effects of trichloroethylene on the gut microbial community and gut‐associated immune responses in autoimmune‐prone mice

The developing immune system is particularly sensitive to immunotoxicants. This study assessed trichloroethylene (TCE)‐induced effects on the gut microbiome and cytokine production during the development in mice. Mice were exposed to TCE (0.05 or 500 μg/mL) at the levels that approximate to environmental or occupational exposure, respectively. Mice were subjected to a continuous developmental exposure to these doses encompassing gestation, lactation and continuing directly in the drinking water postnatally for 154 days (PND154) or PND259. To observe persistence of the effect TCE was removed from the drinking water in a subset of mice on PND154 and were provided regular drinking water until the study terminus (PND259). Abundance of total tissue‐associated bacteria reduced only in mice exposed to TCE until PND259. The ratio of Firmicutes/Bacteroidetes did not alter during this continuos exposure; however, cessation of high‐dose TCE at PND154 resulted in the increased abundance Bacteroidetes at PND259. Furthermore, high‐dose TCE exposure until PND259 resulted in a lower abundance of the genera Bacteroides and Lactobaccilus and increased abundance of genus Bifidobactrium and bacterial family Enterobacteriaceae. TCE exposure until PND154 showed significant changes in the production of interleukin‐33; that might play a dual role in maintaining the balance and homeostasis between commensal microbiota and mucosal health. At PND259, interleukin‐3, granulocyte‐macrophage colony‐stimulating factor and Eotaxin were altered in both, the continuous exposure and cessation groups, whereas only a cessation group had a higher level of KC that may facilitate infiltration of neutrophils. The irreversible effects of TCE after a period of exposure cessation suggested a unique programming and potential toxicity of TCE even at the environmental level exposure.     

Apoptogenic activity of ethyl acetate extract of leaves of Memecylon edule on human gastric carcinoma cells via mitochondrial dependent pathway

ObjectiveTo evaluate the anti-proliferative and apoptogenic activity of ethyl acetate extract from the leaves of Memecylon edule (EtAc-LME) in MKN-74, NUGC gastric cancer cells and non cancerous gastric mucous cells (GES-1), and to explore the mechanism of EtAc-LME induced apoptosis.MethodsThe mechanism of EtAc-LME induced apoptosis was explored by analysing the activation of pro-caspases, PARP cleavage, expression of cytochrome-c (Cyt-c) was determined by western blotting, mRNA expression of Bcl-2, Bax by RT-PCR, loss of mitochondrial potential using DiOC6 dye, annexin binding assay and its influence on cell cycle arrest by flow cytometry.ResultsThe results indicated that EtAc-LME inhibited the gastric cancer cell growth in dose-dependent manner and cytotoxicity was more towards the gastric cancer cells (NUGC and MKN-74) compared to normal gastric cells (GES-1), suggesting more specific cytotoxicity to the malignant cells. Over expression of Cyt-c and subsequent activation of caspases-3 and down regulation of Bcl-2 and loss in mitochondrial potential in EtAc-LME treated MKN-74 and NUGC cells suggested that EtAc-LME induced apoptosis by mitochondrial dependent pathway.ConclusionsThe present findings suggest that ethyl acetate extract of Memecylon edule induces apoptosis selectively in gastric cancer cells emphasizing the importance of this traditional medicine for its potential in the treatment of gastric cancer.     

Oxidized low-density lipoprotein and intimal medial thickness in subjects with glucose intolerance: the Chennai Urban Rural Epidemiology Study-25

The aim of the present study was to assess the association of oxidized low-density lipoprotein (OX-LDL) with carotid intimal medial thickness (IMT) in different grades of glucose intolerance in Asian Indians. Three groups were recruited from the Chennai Urban Rural Epidemiology Study, a population-based study: group 1, normal glucose tolerance (NGT) (n = 175); group 2, impaired glucose tolerance (IGT) (n = 175); and group 3, type 2 diabetes mellitus (n = 175). Oxidized LDL (enzyme-linked immunosorbent assay) and carotid IMT (high-resolution B-mode ultrasonography) were assessed. Subjects with diabetes had higher IMT values (0.85 +/- 0.30 mm) compared with those who have IGT (0.79 +/- 0.16 mm, P < .05) and NGT (0.71 +/- 0.12 mm, P < .001). Subjects with diabetes (40.1 +/- 13.1 U/L) and IGT (34.3 +/- 12.8 U/L) had significantly higher mean OX-LDL values compared with the NGT group (26.2 +/- 16.6 U/L, P < .001). Oxidized LDL showed a correlation with IMT (total population: r = 0.294, P < .001; subjects with NGT: r = 0.444, P < .001; and subjects with IGT: r = 0.481, P < .001). In multiple linear regression analysis, OX-LDL showed a strong association with IMT (beta = .005, P < .001), even after adjusting for age, sex (beta = .003, P < .001), and glucose intolerance (beta = .002, P < .001). In conclusion, OX-LDL levels increase with increasing glucose intolerance. Oxidized LDL is associated with carotid IMT and this is independent of age, sex, and glucose intolerance status.     

Early structural and functional neurovascular changes in the retina in the prediabetic stage

PurposeThis study was undertaken to investigate the neurovascular changes in the retina of prediabetic subjects.MethodsSubjects enroled in a prospective study were separated into prediabetic and normal control groups based on their glycosylated haemoglobin (HbA1C) levels, fasting and postprandial blood sugar levels and glucose tolerance test. All the subjects underwent detailed ophthalmic evaluation, which included fundus examination, fundus photography, optical coherence tomography angiography (OCTA), and multifocal electroretinogram (mfERG). Comparisons were done between the groups using the Wilcoxon signed rank test.ResultsThe median age was 48 years for the normal controls (n = 40), and 49.5 years for prediabetic subjects (n = 45) (p = 0.306). There was no difference in the vision, contrast sensitivity, thickness of the ganglion cell complex or the foveal avascular zone parameters between the groups. But the central foveal thickness and subfoveal choroidal thickness were significantly reduced in prediabetics (p < 0.01). The mfERG showed significant differences in the amplitude. The average amplitude was 35 ± 12 nv/deg² in the normals and 29 ± 11 nv/deg² in the prediabetics (p = 0.003). A weak positive correlation was noted between the mfERG and vascular parameters in the prediabetic group.ConclusionsThe prediabetic stage reveals earliest functional neuronal changes in the retina. The neuronal function seems to be affected much earlier than clinically appreciable structural changes in the ganglion cell complex and precedes vascular changes in the retina.Subject terms: Predictive markers, Blood flow     

Serum Total Adiponectin Is Associated with Impaired Glucose Tolerance in Asian Indian Females but Not in Males

Objective

Adiponectin may play a role in the development of type 2 diabetes and cardiovascular disease (CVD). However, little is known about the relationship between adiponectin and impaired glucose tolerance (IGT). We investigated the association between adiponectin and IGT and between adiponectin and cardiovascular risk factors among subjects with IGT.

Research Design and Methods

Subjects with normal glucose tolerance (NGT)(n = 571) and impaired glucose tolerance (n = 167) were recruited from the Chennai Urban Rural Epidemiology Study in south India. Serum total adiponectin levels were measured using a radioimmunoassay (Linco Research, St. Charles, MO). High sensitivity C-reactive protein (hsCRP) was estimated by nephelometry.

Results

In sex-stratified analyses, adiponectin was significantly associated with IGT in females [odds ratio (OR): 0.93, 95% confidence interval (CI): 0.872–0.991, p = 0.026] after controlling for age, waist circumference, blood pressure, alcohol consumption, smoking, lipid profile, and glycemic indices; in males there was no significant association (OR = 0.90, 95% CI: 0.798–1.012, p = 0.078). In prediabetic females, adiponectin was not associated with any CVD risk factors (age, waist circumference, blood pressure, cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, fasting glucose, fasting insulin, and insulin resistance level), but was associated negatively with 2-hour postplasma glucose levels (r = –0.243, p < 0.05) and hsCRP (r = –0.219, p < 0.05) after adjusting for demographic and biomedical indices. No associations with CVD risk factors were observed in males with IGT.

Conclusion

Serum total adiponectin levels are associated with IGT, 2-hour postplasma glucose, and hsCRP in Asian Indian females but not in males.     

Oxidative stress is independently associated with non-alcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes

ObjectiveOur work is aimed at exploring the interrelationship of oxidative stress and insulin resistance in NAFLD subjects with and without type 2 diabetes in a population-based study.MethodsSubjects [n = 200] were recruited from the Chennai Urban Rural Epidemiology Study. 1: Normal glucose tolerance (NGT) subjects without NAFLD; 2: NGT with NAFLD; 3: type 2 diabetic subjects [T2DM] without NAFLD and 4: T2DM with NAFLD. Thiobarbituric acid reactive substances (TBARS), protein carbonyl (PCC) and glutathione levels were measured by standard methods. Ultrasound of the liver was used to diagnose NAFLD.ResultsTBARS and PCC levels were significantly elevated and GSH/GSSG ratio was significantly decreased in diabetic subjects with NAFLD compared to all other groups (p trend < 0.001). Oxidative stress markers significantly associated with NAFLD even after adjusting for age, gender, BMI and glycemic status.ConclusionsIncreased oxidative stress is independently associated with NAFLD in Asian Indians without and with T2DM.     

A1C Cut Points to Define Various Glucose Intolerance Groups in Asian Indians

OBJECTIVE

To determine A1C cut points for glucose intolerance in Asian Indians.

RESEARCH DESIGN AND METHODS

A total of 2,188 participants without known diabetes were randomly selected from the Chennai Urban Rural Epidemiology Study. All had fasting plasma glucose (FPG) and 2-h postload plasma glucose measurements after a 75-g load and were classified as having impaired fasting glucose (IFG) (American Diabetes Association [ADA] criteria, FPG ≥5.5 and <7 mmol/l, and World Health Organization [WHO] criteria, FPG ≥6.1 and <7 mmol/l), impaired glucose tolerance (IGT) (2-h postload plasma glucose ≥7.8 and <11.1 mmol/l), or diabetes (FPG ≥7 mmol/l and/or 2-h postload plasma glucose ≥11.1 mmol/l). A1C was measured using the Bio-Rad Variant machine. Based on receiver operating characteristic curves, optimum sensitivity and specificity were derived for defining A1C cut points for diabetes, IGT, and IFG.

RESULTS

Mean ± SD values of A1C among subjects with normal glucose tolerance, IGT, and diabetes were 5.5 ± 0.4, 5.9 ± 0.6, and 8.3 ± 2.0%, respectively (P_trend < 0.001) with considerable overlap. To identify diabetes based on 2-h postload plasma glucose, the A1C cut point of 6.1% had an area under the curve (AUC) of 0.941 with 88.0% sensitivity and 87.9% specificity. When diabetes was defined as FPG ≥7.0 mmol/l, the A1C cut point was 6.4% (AUC = 0.966, sensitivity 93.3%, and specificity 92.3%). For IGT, AUC = 0.708; for IFG, AUC = 0.632 (WHO criteria) and 0.708 (ADA criteria), and the A1C cut point was 5.6%.

CONCLUSIONS

In Asian Indians, A1C cut points of 6.1 and 6.4% defined diabetes by 2-h postload plasma glucose or FPG criteria, respectively. A value of 5.6% optimally identified IGT or IFG but was <70% accurate.A1C is an indicator of the average blood glucose concentrations over the preceding 2–3 months and is currently considered the best index of metabolic control in individuals with diabetes (1). The Diabetes Control and Complications Trial and the UK Prospective Diabetes Study (UKPDS) have demonstrated that lowering A1C can reduce the risk of diabetes microvascular complications (2,3). An association between A1C and cardiovascular risk factors in subjects with normal glucose tolerance (NGT) was also reported (4).Until recently, A1C had not been recommended as a diagnostic or a screening tool because of several factors: lack of standardization, low sensitivity, and high cost (5). However, after efforts to improve standardization of the A1C assay and the introduction of the new International Federation of Clinical Chemists (IFCC) standards, A1C is now being considered for diagnostic and screening purposes (6). A1C does not need to be measured in a fasting state or with a glucose load and, therefore, offers potential ease and convenience. A recent American Diabetes Association (ADA) International Expert Committee proposed an A1C cut point of 6.5% as a diagnostic test for diabetes (7). It is important to investigate whether these cut points for A1C apply to all populations worldwide. The normative distribution for A1C levels has been described in western populations in subjects with NGT as well as those with impaired glucose tolerance (IGT) (8). However, there are no reports of the normative A1C distributions, to our knowledge, from India, which currently has the largest number of individuals with diabetes in the world. Here, we examine the distribution of A1C in a south Indian population and explore optimal cut points for identifying diabetes and high-risk pre-diabetic groups.     

Drug resistance in Mycobacterium tuberculosis and targeting the l,d-transpeptidase enzyme

Tuberculosis (TB) is a disease that has afflicted mankind for thousands of years, but in the last seven decades, much progress has been made in anti-TB therapy. Early drugs, such as para-aminosalicylic acid, streptomycin, isoniazid, and rifamycins were very effective in combatting the disease, giving rise to the hope that TB would be eradicated from the face of the earth by 2010. Despite that optimism, TB continues to kill more than a million people annually worldwide. A major reason for our inability to contain TB is the emergence drug resistance in Mycobacterium tuberculosis. This commentary is based on our recent publication on the structure of l ,d -transpeptidase enzyme, relevant to drug resistance. As a background, we briefly outline the history and development of anti-TB therapy. Based on the crystal structure, we suggest a potential direction for designing more potent drugs against TB.