Mechanisms of dysregulation of low-density lipoprotein receptor expression in vascular smooth muscle cells by inflammatory cytokines

Objective - Although inflammation is a recognized feature of atherosclerosis, the impact of inflammation on cellular cholesterol homeostasis is unclear. This study focuses on the molecular mechanisms by which inflammatory cytokines disrupt low-density lipoprotein (LDL) receptor regulation.Methods and Results - IL-1 beta enhanced transformation of vascular smooth muscle cells into foam cells by increasing uptake of unmodified LDL via LDL receptors and by enhancing cholesterol esterification as demonstrated by Oil Red O staining and direct assay of intracellular cholesterol concentrations. In the absence of IL-1 beta, a high concentration of LDL decreased LDL receptor promoter activity, mRNA synthesis and protein expression. However, IL-1 beta enhanced LDL receptor expression, overriding the suppression usually induced by a high concentration of LDL and inappropriately increasing LDL uptake. Exposure to IL-1 beta also caused overexpression of the sterol regulatory element binding protein ( SREBP) cleavage-activating protein ( SCAP), and enhanced its translocation from the endoplasmic reticulum to the Golgi, where it is known to cleave SREBP, thereby enhancing LDL receptor gene expression.Conclusions - These observations demonstrate that IL-1 beta disrupts cholesterol-mediated LDL receptor feedback regulation, permitting intracellular accumulation of unmodified LDL and causing foam cell formation. The implication of these findings is that inflammatory cytokines may contribute to intracellular LDL accumulation without previous modification of the lipoprotein

Nonesterified free fatty acids enhance the inflammatory response in renal tubules by inducing extracellular ATP release

In proteinuric renal diseases, excessive plasma nonesterified free fatty acids bound to albumin can leak across damaged glomeruli to be reabsorbed by renal proximal tubular cells and cause inflammatory tubular cells damage by as yet unknown mechanisms. The present study was designed to investigate these mechanisms induced by palmitic acid (PA; one of the nonesterified free fatty acids) overload. Our results show that excess PA stimulates ATP release through the pannexin 1 channel in human renal tubule epithelial cells (HK-2), increasing extracellular ATP concentration approximately threefold compared with control. The ATP release is dependent on caspase-3/7 activation induced by mitochondrial reactive oxygen species. Furthermore, extracellular ATP aggravates PA-induced monocyte chemoattractant protein-1 secretion and monocyte infiltration of tubular cells, enlarging the inflammatory response in both macrophages and HK-2 cells via the purinergic P2X7 receptor-mammalian target of rapamycin-forkhead box O1-thioredoxin-interacting protein/NOD-like receptor protein 3 inflammasome pathway. Hence, PA increases mitochondrial reactive oxygen species-induced ATP release and inflammatory stress, which cause a “first hit,” while ATP itself is a “second hit” in amplifying the renal tubular inflammatory response. Thus, inhibition of ATP release or the purinergic P2X7 receptor may be an approach to reduce renal inflammation and improve renal function

Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis

A recent meta-analysis demonstrated that statin therapy was associated with a risk of diabetes. The present study investigated whether the relative reduction in low-density lipoprotein cholesterol (LDL-c) was a good indicator of the risk of new-onset diabetes. We searched the PubMed, Embase, Cochrane Central Register, Lilacs, Food and Drug Administration, and European Medicines Agency databases for randomized controlled trials of statins. Fourteen trials were included in the study. Eight trials with target LDL-c levels ≤100 mg/dL (2.6 mmol/L) or LDL-c reductions of at least 30% were extracted separately. The results showed that the overall risk of incident diabetes increased by 11% (OR = 1.11; 95% CI 1.03–1.20). The group with intensive LDL-c-lowering statin had an 18% increase in the likelihood of developing diabetes (OR = 1.18; 95% CI, 1.10–1.28). Furthermore, the risks of incident diabetes were 13% (OR = 1.13; 95% CI 1.01–1.26) and 29% (OR = 1.29; 95% CI 1.13–1.47) in the subgroups with 30–40% and 40–50% reductions in LDL-c, respectively, suggesting that LDL-c reduction may provide a dynamic risk assessment parameter for new-onset diabetes. In conclusion, LDL-c reduction is positively related to the risk of new-onset diabetes. When LDL-c is reduced by more than 30% during lipid-lowering therapy, blood glucose monitoring is suggested to detect incident diabetes in high-risk populations

Nuclear receptors and their coregulators in kidney

Nuclear receptors and their coregulators in kidney. Nuclear receptors are transcription factors that are essential in embryonic development, maintenance of differentiated cellular phenotypes, metabolism, and apoptosis. Dysfunction of nuclear receptor signaling leads to a wide spectra of proliferative, reproductive, and metabolic diseases, including cancers, infertility, obesity, and diabetes. In addition, many proteins have been identified as coregulators which can be recruited by DNA-binding nuclear receptors to affect transcriptional regulation. The cellular level of coregulators is crucial for nuclear receptor-mediated transcription and many coregulators have been shown to be targets for diverse intracellular signaling pathways and posttranslational modifications. This review provides a general overview of the roles and mechanism of action of nuclear receptors and their coregulators. Since progression of renal diseases is almost always associated with inflammatory processes and/or involve metabolic disorders of lipid and glucose, cell proliferation, hypertrophy, apoptosis, and hypertension, the importance of nuclear receptors and their coregulators in these contexts will be addressed

Adverse Events among HIV/MDR-TB Co-Infected Patients Receiving Antiretroviral and Second Line Anti-TB Treatment in Mumbai, India.

Significant adverse events (AE) have been reported in patients receiving medications for multidrug- and extensively-drug-resistant tuberculosis (MDR-TB & XDR-TB). However, there is little prospective data on AE in MDR- or XDR-TB/HIV co-infected patients on antituberculosis and antiretroviral therapy (ART) in programmatic settings

Design and prototyping of a bio-inspired kinematic sensing suit for the shoulder joint: precursor to a multi-DoF shoulder exosuit

Soft wearable robots represent a promising new design paradigm for rehabilitation and active assistance applications. Their compliant nature makes them ideal for complex joints, but intuitive control of these robots require robust and compliant sensing mechanisms. In this work, we introduce the sensing framework for a multiple degrees-of-freedom shoulder exosuit capable of sensing the kinematics of the joint. The proposed sensing system is inspired by the body's embodied kinematic sensing, and the organisation of muscles and muscle synergies responsible for shoulder movements. A motion-capture-based evaluation study of the developed framework confirmed conformance with the behaviour of the muscles that inspired its routing. This validation of the tendon-routing hypothesis allows for it to be extended to the actuation framework of the exosuit in the future. The sensor-to-joint-space mapping is based on multivariate multiple regression and derived using an Artificial Neural Network. Evaluation of the derived mapping achieved root mean square error of ≈5.43° and ≃3.65° for the azimuth and elevation joint angles measured over 29,500 frames (4+ minutes) of motion-capture data

Paradoxical effect of rapamycin on inflammatory stress-induced insulin resistance in vitro and in vivo

Insulin resistance is closely related to inflammatory stress and the mammalian target of rapamycin/S6 kinase (mTOR/S6K) pathway. The present study investigated whether rapamycin, a specific inhibitor of mTOR, ameliorates inflammatory stress-induced insulin resistance in vitro and in vivo. We used tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) stimulation in HepG2 hepatocytes, C2C12 myoblasts and 3T3-L1 adipocytes and casein injection in C57BL/6J mice to induce inflammatory stress. Our results showed that inflammatory stress impairs insulin signaling by reducing the expression of total IRS-1, p-IRS-1 (tyr632), and p-AKT (ser473); it also activates the mTOR/S6K signaling pathway both in vitro and in vivo. In vitro, rapamycin treatment reversed inflammatory cytokine-stimulated IRS-1 serine phosphorylation, increased insulin signaling to AKT and enhanced glucose utilization. In vivo, rapamycin treatment also ameliorated the impaired insulin signaling induced by inflammatory stress, but it induced pancreatic β-cell apoptosis, reduced pancreatic β-cell function and enhanced hepatic gluconeogenesis, thereby resulting in hyperglycemia and glucose intolerance in casein-injected mice. Our results indicate a paradoxical effect of rapamycin on insulin resistance between the in vitro and in vivo environments under inflammatory stress and provide additional insight into the clinical application of rapamycin