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W. tinctoria, an Indian herb Indrajao, has significant therapeutic potential. While studies have highlighted the anti-inflammatory potential of the leaves and bark of this plant, similar efficacy of the seed-pods remains unexplored. We demonstrate significant anti-inflammatory effects of the hexane fraction (Fr-B) of ethyl acetate extract of the seedpods in reducing lipopolysaccharide and palmitate mediated inflammation in RAW264.7 macrophages and HepG2 cells. GC-MS and NMR profiling of Fr-B revealed the existence of hexadecanoic acid, ethyl hexadecanoate, 9,12-octadecanoic acid, 9,12,15-octadecatrienoic acid, 9,12,15-octadecatrienoic acid ethyl ester, ethyl linoleate and octadecanoic acid ethyl esters. [ABSTRACT FROM AUTHOR]

Aims: To pool the effects of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors on gout and to investigate the association of these effects with baseline serum uric acid (SUA), SUA lowering, and underlying conditions, such as type 2 diabetes mellitus (T2DM)/heart failure (HF). Methods: PubMed, Embase, Web of Science, Cochrane Library and clinical trial registry websites were searched for randomized controlled trials (RCTs) or post hoc analyses (≥1‐year duration; PROSPERO:CRD42023418525). The primary outcome was a composite of gouty arthritis/gout flares and commencement of anti‐gout drugs (SUA‐lowering drugs/colchicine). Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using a generic inverse‐variance method with a random‐effects model. Mixed‐effects model univariate meta‐regression analysis was performed. Results: Five RCTs involving 29 776 patients (T2DM, n = 23 780) and 1052 gout‐related events were identified. Compared to placebo, SGLT2 inhibitor use was significantly associated with reduced risk of composite gout outcomes (HR 0.55, 95% CI 0.45‐0.67; I2 = 61%, P < 0.001). Treatment benefits did not differ between trials being conducted exclusively in baseline HF versus those conducted in patients with T2DM (P‐interaction = 0.37), but were greater with dapagliflozin 10 mg and canagliflozin 100/300 mg (P < 0.01 for subgroup differences). Sensitivity analysis excluding trials that evaluated the effects of empagliflozin 10/25 mg (HR 0.68, 95% CI 0.57‐0.81; I2 = 0%) accentuated the benefits of SGLT2 inhibitors with no between‐trial heterogeneity (HR 0.46, 95% CI 0.39‐0.55; I2 = 0%). Univariate meta‐regression found no impact of baseline SUA, SUA lowering on follow‐up, diuretic use, or other variables on their anti‐gout effects. Conclusion: We found that SGLT2 inhibitors significantly reduced the risk of gout in individuals with T2DM/HF. Lack of an association with SUA‐lowering effects suggests that metabolic and anti‐inflammatory effects of SGLT2 inhibitors may predominantly mediate their anti‐gout benefits. [ABSTRACT FROM AUTHOR]

46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases. [ABSTRACT FROM AUTHOR]

Hyperglycemia impairs healing of diabetic foot ulcer (DFU). But there is no evidence regarding benefit of intensive glucose control for healing of DFU. We plan to conduct a randomized, parallel arm, controlled study to assess the role of intensive glycemic management in comparison to conventional glucose control for healing of DFU. Participants with neuropathic DFU (infected or uninfected) having hemoglobin A1c (HbA1c) >8% and without evidence of osteomyelitis from 7 tertiary care hospitals will be enrolled. They will undergo a 2-week run-in phase for optimization of comorbidities, ulcer debridement, and counseling regarding self-monitoring of blood glucose (SMBG). Subsequently, they will be randomized to "intensive glycemic control" arm defined by glycemic targets of fasting blood glucose (FBG) <130 mg/dL, postprandial BG <180 mg/dL, and HbA1c <8%, with basal-bolus insulin regimen and frequent titration of insulin to achieve glycemic targets. The "conventional" arm will continue on prior treatment (oral antidiabetic drugs) with no titration unless meeting rescue criteria. Ulcer area will be calculated by automated wound assessment device (WoundlyClinial app) weekly for first 4 weeks, and less frequently until the 24th week. Standard treatment for DFU, off-loading, and counseling for foot care will be provided in both arms. The primary outcome measure will be number of wounds closed at 12th and 24th weeks. A multivariate regression analysis will be performed to identify the predictors of wound healing with baseline HbA1c, diabetes duration, wound size, wound duration, and background therapies as independent variable. This study will provide the much needed guidance to set optimum glucose targets in people with DFU. [ABSTRACT FROM AUTHOR]

Introduction: The studies in animal models of cirrhosis suggest that dipeptidyl peptidase type 4 (DPP-4) enzymes play a crucial role in disease pathogenesis. In this clinical observational study, activity of DPP-4 and related gene expression were analysed in chronic liver disease patients. Objectives: To understand the DPP-4 enzyme activity variation in the common types of chronic liver disease by assessing plasma and peripheral blood mononuclear cell (PBMC) DPP-4 activity and comparing with healthy controls and to explore DPP-4 gene expression in PBMC. Methods: We recruited 130 study subjects in four cohorts—46 nonalcoholic fatty liver disease (NAFLD), 23 non-alcoholic cirrhosis (NAC) excluding viral aetiology, 21 alcoholic liver disease (ALC), and 40 control subjects. Blood samples were analysed for relevant biochemical parameters and plasma DPP-4 activity. PBMC fraction was used for the DPP-4 activity assay and gene expression analysis. Results: We found that lower plasma DPP-4 activity among patient cohorts but this was not statistically significant. The PBMC DPP-4 activity was significantly lower in NAFLD cohort. In the same cohort, DPP-4 gene expression in PBMC fraction was significantly increased (P < 0.05). There was significant correlation between plasma DPP-4 activity and liver injury marker alanine aminotransferase (ALT) among NAFLD (rho = 0.459, P < 0.01), NAC (rho = 0.475, P < 0.05), and ALC (rho = –0.572, P < 0.01) patients. Plasma DPP-4 activity modestly predicted ALT plasma level (beta coefficient = 0.489, P < 0.01). Conclusions: The PBMC DPP-4 activity and DPP-4 gene expression gets significantly altered in NAFLD patients. Plasma DPP-4 activity also shows correlation with ALT levels in CLD patients. The role of DPP-4 in disease pathology in NAFLD and other forms of CLD needs to be explored. [ABSTRACT FROM AUTHOR]

Toll-like receptor 4 (TLR4) has a key role in innate immunity by activating an inflammatory signaling pathway. Free fatty acids (FFAs) stimulate adipose tissue inflammation through the TLR4 pathway, resulting in insulin resistance (1-7). However, current evidence suggests that FFAs do not directly bind to TLR4 (8), (9), but an endogenous ligand for TLR4 remains to be identified. Here we show that fetuin-A (FetA) could be this endogenous ligand and that it has a crucial role in regulating insulin sensitivity via Tlr4 signaling in mice. FetA (officially known as Ahsg) knockdown in mice with insulin resistance caused by a high-fat diet (HFD) resulted in downregulation of Tlr4-mediated inflammatory signaling in adipose tissue, whereas selective administration of FetA induced inflammatory signaling and insulin resistance. FFA-induced proinflammatory cytokine expression in adipocytes occurred only in the presence of both FetA and Tlr4; removing either of them prevented FFA-induced insulin resistance. We further found that FetA, through its terminal galactoside moiety, directly binds the residues of Leu100-Gly123 and Thr493-Thr516 in Tlr4. FFAs did not produce insulin resistance in adipocytes with mutated Tlr4 or galactoside-cleaved FetA. Taken together, our results suggest that FetA fulfills the requirement of an endogenous ligand for TLR4 through which lipids induce insulin resistance. This may position FetA as a new therapeutic target for managing insulin resistance and type 2 diabetes., Insulin resistance is one of the major outcomes of chronic inflammation fueled by FFAs (10-13). There has been growing evidence over the last few years that FFA-induced production of proinflammatory [...]