Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease

Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA–mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.     

Response of antioxidant system in rats to dietary fat and physical activity

The influence of feeding hydrogenated fat (HF) or refined peanut oil (PO) diet and regular swimming exercise on hepatic and skeletal muscle antioxidant enzymes i.e., catalase ,and glutathione peroxidase (GPX) as well as tissue lipid peroxidation was investigated in male Wistar rats. Two groups of rats were fed diet with HF or PO as the only fat source. Both the groups were further divided into 4 subgroups each according to physical activity: Two each for sedentary (HFS3, POS3) and two for swimming, HFE3 and POE3 [30 minutes a day, 6 days a week, for 3 months or HFS6, POS6, HFE6 and POE6 for 6 months. A mild increase in lipid peroxidation was observed in both liver and muscle tissues of PO-diet fed rats of E1. Swimming augmented further the lipid peroxidation in liver. GSH level was decreased in the liver of exercising rats, in contrast, it was increased in skeletal muscle by 70% in POE6 and 26% in HFE6. Compared to POS3 swimming elevated GPX activity of about 70% in liver from POE3 as well as about 60% in skeletal muscle from POE3 and POE6. The catalase activity was enhanced in muscle of HFE3 and POE3 by 250% while it remained unaltered in rats of 6 months. These data indicate an adaptive-response of antioxidant enzymes in liver and skeletal muscle to reduce oxidative stress induced by unsaturated fat (PO) and exercise.     

A technique to evaluate the thickness and density of nonvascular smooth muscle in the suburethral fibromuscular layer

OBJECTIVE: The suburethral fibromuscular layer (SUFML) contains nonvascular smooth muscle that may play an important role in the continence mechanism. This study was undertaken to develop a method to systematically quantify differences in the thickness and density of nonvascular smooth muscle within the SUFML and to demonstrate its use in assessing variation. STUDY DESIGN: Urethral and anterior vaginal wall sections from the urethrovesical junction of fresh cadavers were stained to define alpha actin in smooth muscle cells. The thickness of the SUFML was microscopically measured and the density of the nonvascular smooth muscle was determined with computer-aided analysis. RESULTS: The mean thickness of the SUFML was 3.04 mm (range 1.74-3.78 mm, SD +/-0.63 mm). The mean density of nonvascular smooth muscle within it was 17.94% (range 10.48%-42.84%, SD +/-9.4%). The mean age was 55 years (range 36-69 years, SD +/-10.75 years). CONCLUSION: The thickness and density of the nonvascular smooth muscle within the SUFML can be quantified and there is variation among individuals.     

Influence of atorvastatin on the pharmacokinetics and pharmacodynamics of glyburide in normal and diabetic rats

Atorvastatin is a selective HMG-CoA reductase competitive inhibitor, used for the treatment of hyperlipidaemia. It is metabolized by CYP 3A4 and 3A5 isoenzymes in liver. It also has moderate inhibition on metabolizing enzymes like CYP 2C9, 2D6 and 3A4. Hence there is more possibility of atorvastatin for inhibition of metabolism of glyburide, by both CYP 2C9 and 3A4. We have studied the effects of atorvastatin on the pharmacodynamics and pharmacokinetics of glyburide in experimental diabetic rats. Atorvastatin (20 mg/kg p.o.) was given to alloxan-induced diabetic rats for 7 consecutive days followed by glyburide (10 mg/kg p.o.). In the rats co-treated with atorvastatin and glyburide, fasting plasma glucose concentration (60.69 ± 5.70%) was further reduced, markedly as compared with glyburide-treated animals. In co-treated group, the pharmacokinetic parameters like clearance (27.83 ± 3.55 l/h) of glyburide was reduced, while peak plasma concentration (18.39 ± 5.29 μg/ml), area under the plasma concentration time curve (120.02 ± 15.17 μg/ml/h) and elimination half-life (4.09 ± 0.50 h) were significantly increased when compared to glyburide alone administered rats. The results of this study revealed that atorvastatin led to the PK/PD changes have been due to glyburide increased bioavailability, decrease volume of distribution, and/or decrease total clearance may be due to the inhibition of cytochrome P450 metobolic system.     

Determinants of resource utilization and outcomes in laparoscopic Roux-en-Y gastric bypass: a multicenter analysis of 14,251 patients

Background  

Outcomes for patients who undergo laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery have improved, but a subset of patients who significantly utilize more resources exists. We identified preoperative variables that increase resource utilization in patients who undergo LRYGB.     

Skin delivery of epigallocatechin-3-gallate (EGCG) and hyaluronic acid loaded nano-transfersomes for antioxidant and anti-aging effects in UV radiation induced skin damage

The present work attempts to develop and statistically optimize transfersomes containing EGCG and hyaluronic acid to synergize the UV radiation-protective ability of both compounds, along with imparting antioxidant and anti-aging effects. Transfersomes were prepared by thin film hydration technique, using soy phosphatidylcholine and sodium cholate, combined with high-pressure homogenization. They were characterized with respect to size, polydispersity index, zeta potential, morphology, entrapment efficiency, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), in vitro antioxidant activity and ex vivo skin permeation studies. Cell viability, lipid peroxidation, intracellular ROS levels and expression of MMPs (2 and 9) were determined in human keratinocyte cell lines (HaCaT). The composition of the transfersomes was statistically optimized by Design of Experiments using Box–Behnken design with four factors at three levels. The optimized transfersome formulation showed vesicle size, polydispersity index and zeta potential of 101.2?±?6.0?nm, 0.245?±?0.069 and ?44.8?±?5.24?mV, respectively. FTIR and DSC showed no interaction between EGCG and the selected excipients. XRD results revealed no form conversion of EGCG in its transfersomal form. The optimized transfersomes were found to increase the cell viability and reduce the lipid peroxidation, intracellular ROS and expression of MMPs in HaCaT cells. The optimized transfersomal formulation of EGCG and HA exhibited considerably higher skin permeation and deposition of EGCG than that observed with plain EGCG. The results underline the potential application of the developed transfersomes in sunscreen cream/lotions for improvement of UV radiation-protection along with deriving antioxidant and anti-aging effects.