Terrycombs7231

Trans-resveratrol (RES) is a naturally occurring stilbene found in numerous plants and foods. Due to its widespread human exposure and lack of toxicity and carcinogenicity data, RES was nominated to the National Toxicology Program for testing. To aid the toxicology studies, the dose, sex, and species differences in RES toxicokinetics was investigated in Harlan Sprague Dawley rats and B6C3F1/N mice following single intravenous (IV) (10 mg/kg) or oral gavage administration (312.5, 625, and 1250 mg/kg and 625, 1250, and 2500 mg/kg in rats and mice, respectively). Following IV and gavage administration, systemic exposure of RES based on AUC was trans-resveratrol-3-O-β-D-glucuronide (R3G)> > trans-resveratrol-3-sulfate (R3S) > RES in both species. Following gavage administration Tmax_predicted values were ≤ 263 min for both species and sexes. RES elimination half-life was longer in rats than mice, and shortest in male mice. Clearance was slower in mice with no apparent sex difference in both species. In both rats and mice, following gavage administration AUC increased proportionally to the dose. After gavage administration, enterohepatic recirculation of RES was observed in both rats and mice with secondary peaks occurring around 640 min in the concentration-time profiles. RES was rapidly metabolized to R3S and R3G in both species. Extensive first pass conjugation and metabolism resulted in low levels of the parent compound RES which was confirmed by the low estimates for bioavailability. The bioavailability of RES was low, ~12-31% and ~2-6% for rats and mice, respectively, with no apparent difference between sexes. The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients. Our previous experiments found that a suitable dose of vitamin A (VA) can affect neuronal apoptosis after hypoxic-ischemic brain damage (HIBD) by binding to RARα to activate the PI3K/AKT signaling pathway; however, the other neuroprotective effects of VA after HIBD, for example, whether it promotes neural stem cell (NSC) proliferation, remain unclear. In this study, in vivo and in vitro experiments revealed that VA regulates β-catenin signaling through RARɑ to affect NSC proliferation after HIBD and to improve neurocognitive outcomes. Because of the accumulation and suspended growth characteristics of NSCs, we performed in vitro experiments with PC12 cells to mimic NSCs. Flow cytometry, CCK8, EdU staining, immunofluorescence and behavioral tests were performed to explore the effects of retinoic acid (RA) on NSC proliferation and post-HIBD function. The expression of RARα and β-catenin pathway components were measured by real-time PCR and Western blotting. We found that the learning and memory of the VA-deficient (VAD) group was more seriously damaged than that of the VA normal (VAN) group. The proliferation of hippocampal NSCs was significantly decreased in the VAD group compared with the VAN group. The mRNA and protein expression of RARɑ, AKT, GSK-3β, β-catenin and Cyclin D1 were significantly lower in the VAD group than in the VAN group. In vitro, too high and too low of an RA intervention resulted in decreased proliferation, while an appropriate RA concentration (1-5 µmol/L) significantly promoted proliferation, S phase cells and high β-catenin pathway expression. These results suggested that VA can exert a neuroprotective effect by promoting the proliferation of hippocampal NSCs after neonatal HIBD injury at the appropriate concentration. VA activates RARɑ, which regulates the β-catenin signaling pathway, which in turn upregulates Cyclin D1 expression, promotes NSC proliferation, and finally plays a role in the neuroprotective effect. V.AIM Keloid is a benign dermal tumor with excessive hyperplasia and deposition of collagen. As a common tumor suppressor gene, miR-133a-3p has not been studied in keloid. This study will delve into the specific mechanism of miR-133a-3p in keloid. METHODS Normal skin fibroblasts and keloid fibroblasts (KFs) were first isolated from patients' normal skin and keloid, and cells were identified by morphological observation and immunofluorescence. The expressions of miR-133a-3p and extracellular matrix (ECM)-associated markers (Collagen I, III and α smooth muscle activin) were detected by Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Cell viability and apoptosis of KFs were examined by Cell Counting Kit-8 assay, flow cytometry, and Caspase-3 colorimetry. TargetScan predicted target gene for miR-133a-3p was verified by luciferase assay, qRT-PCR and Western Blot (WB). WB was used to study protein expression of TGFBR1, phosphorylated -Smad2 (p-Smad2) and Smad2. Finally, a series of rescue experiments were performed to verify the intervention of target genes on miR-133a-3p. CX5461 RESULTS MiR-133a-3p was lowly expressed in keloid tissue and KFs. Overexpression of miR-133a-3p inhibited the expression of ECM-associated markers, reduced KFs viability, and promoted apoptosis. It was verified that interference regulator 5 (IRF5) is miR-133a-3p target gene. The rescue experiments showed that IRF5 reversed the effect of miR-133a-3p mimic on inhibiting fibrosis, and reversed the effects on promoting apoptosis and reducing cell proliferation. CONCLUSION Overexpressed miR-133a-3p inhibits fibrosis by down-regulating IRF5 and thus inhibiting the TGF-β/Smad2 pathway. And it also promotes KFs apoptosis and reduces proliferation.