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rence, may be regulated by CAR and VDR. Therefore, co-administration of ZGGJP with other drugs, especially using CYP2C9 and CYP3A substrates in females, may need dose adjustment to avoid herb-drug interaction.
ZGGJP had inductive effects on CYP1A2 and CYP2B6 in both male and female rats. The results showed that ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but had no effect in male rats. This may suggest that the influence of ZGGJP on CYP2C9 and CYP3A exhibit gender difference. The inductive effects of ZGGJP on the activities of CYPs, exhibiting gender difference, may be regulated by CAR and VDR. Therefore, co-administration of ZGGJP with other drugs, especially using CYP2C9 and CYP3A substrates in females, may need dose adjustment to avoid herb-drug interaction.
Histone lysine-specific demethylase 1 (LSD1) has become a potential anticancer target for the novel drug discovery. Recent reports have shown that SP2509 and its derivatives strongly inhibit LSD1 as allosteric inhibitors. However, the binding mechanism of these allosteric inhibitors in the allosteric site of LSD1 is not known yet.
The stability and binding mechanism of allosteric inhibitors in the binding site of LSD1 were evaluated by molecular docking, ligand-based pharmacophore, molecular dynamics (MD) simulations, molecular mechanics generalized born surface area (MM/GBSA) analysis, quantum mechanics/molecular mechanics (QM/MM) calculation and Hirshfeld surface analysis.
The conformational geometry and the intermolecular interactions of allosteric inhibitors showed high binding affinity towards allosteric site of LSD1 with the neighboring amino acids (Gly358, Cys360, Leu362, Asp375 and Glu379). Meanwhile, MD simulations and MM/GBSA analysis were performed on selected allosteric inhibitors in complex with LSD1 protein, which confirmed the high stability and binding affinity of these inhibitors in the allosteric site of LSD1.
The simulation results revealed the crucial factors accounting for allosteric inhibitors of LSD1, including different protein-ligand interactions, the positions and conformations of key residues, and the ligands flexibilities. Meanwhile, a halogen bond interaction between chlorine atom of ligand and key residues Trp531 and His532 was recurrent in our analysis confirming its importance.
Overall, our research analyzed in depth the binding modes of allosteric inhibitors with LSD1 and could provide useful information for the design of novel allosteric inhibitors.
Overall, our research analyzed in depth the binding modes of allosteric inhibitors with LSD1 and could provide useful information for the design of novel allosteric inhibitors.
Thiamine deficiency (TD) has a number of features in common with the neurodegenerative diseases development and close relationship between TD and oxidative stress (OS) has been repeatedly reported in the literature. The aim of this study is to understand how alimentary TD, accompanied by OS, affects the expression and level of two thiamine metabolism proteins in rat brain, namely, thiamine transporter 1 (THTR1) and thiamine pyrophosphokinase (TPK1), and what factors are responsible for the observed changes.
The effects of OS caused by TD on the THTR1and TPK1 expression in rat cortex, cerebellum and hippocampus were examined. The levels of active and oxidized forms of ThDP (enzymatically measured) in the blood and brain, ROS and SH-groups in the brain were also analyzed.
TD increased the expression of THTR1 and protein level in all studied regions. In contrast, expression of TPK1 was depressed. TD-induced OS led to the accumulation of ThDP oxidized inactive form (ThDP
) in the blood and brain. In vitro reduction of ThDP
by dithiothreitol regenerates active ThDP suggesting that ThDP
is in disulfide form. A single high-dose thiamine administration to TD animals had no effect on THTR1 expression, partly raised TPK1 mRNA and protein levels, but is unable to normalize TPK1 enzyme activity. Brain and blood ThDP levels were increased in these conditions, but ThDP
was not decreased.
It is likely, that the accumulation of ThDP
in tissue could be seen as a potential marker of neurocellular dysfunction and thiamine metabolic state.
It is likely, that the accumulation of ThDPox in tissue could be seen as a potential marker of neurocellular dysfunction and thiamine metabolic state.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with thrombotic complications such as deep vein thrombosis or stroke. Recently, numerous cases of acute limb ischemia (ALI) have been reported although pooled data are lacking.
We systematically searched PubMed, Embase, Scopus, and the Cochrane Library for studies published online up to January 2021 that reported cases with SARS-CoV-2 infection and ALI. Eligible studies should have reported early outcomes including mortality. Primary endpoints included also pooled amputation, clinical improvement, and reoperation rates.
In total, 34 studies (19 case reports and 15 case series/cohort studies) including a total of 540 patients (199 patients were eligible for analysis) were evaluated. All studies were published in 2020. Erastin2 order Mean age of patients was 61.6years (range, 39-84years; data from 32 studies) and 78.4% of patients were of male gender (data from 32 studies). There was a low incidence of comorbidities arterial hyper, including ALI. COVID-associated ALI presents in patients with a low incidence of comorbidities, and it is associated with a high mortality and amputation risk. Conservative treatment seems to have a higher mortality risk compared with any intervention, although amputation risk is similar.
SARS-CoV-2 infection is associated with a high risk for thrombotic complications, including ALI. COVID-associated ALI presents in patients with a low incidence of comorbidities, and it is associated with a high mortality and amputation risk. Conservative treatment seems to have a higher mortality risk compared with any intervention, although amputation risk is similar.
Recently Doi etal. argued that risk ratios should be replaced with odds ratios in clinical research. We disagreed, and empirically documented the lack of portability of odds ratios, while Doi etal. defended their position. In this response we highlight important errors in their position.
We counter Doi etal.'s arguments by further examining the correlations of odds ratios, and risk ratios, with baseline risks in 20,198 meta-analyses from the Cochrane Database of Systematic Reviews.
Doi etal.'s claim that odds ratios are portable is invalid because 1) their reasoning is circular they assume a model under which the odds ratio is constant and show that under such a model the odds ratio is portable; 2) the method they advocate to convert odds ratios to risk ratios is biased; 3) their empirical example is readily-refuted by counter-examples of meta-analyses in which the risk ratio is portable but the odds ratio isn't; and 4) they fail to consider the causal determinants of meta-analytic inclusion criteria Donce. Neither the odds ratio nor the risk ratio is universally portable. To address this lack of portability, we reinforce our suggestion to report variation in effect measures conditioning on modifying factors such as baseline risk; understanding such variation is essential to patient-centered practice.The dysfunction of vascular smooth muscle cells (VSMCs) is critical for atherosclerosis (AS) progression. Autophagy is indispensable during phenotypic switching and proliferation of VSMCs, contribute to AS development. Cellular Sloan-Kettering Institute (c-Ski), the repressor of TGF-β signaling, is involved in diverse physiological and pathological processes. We previously defined c-Ski also as an endogenous protective molecule against AS via inhibiting abnormal proliferation and autophagy of VSMCs. However, the endogenous level of c-Ski in VSMCs is markedly decreased during the progression of AS, so that the protective effect is drastically weakened. Elucidating the molecular mechanisms is key to the understanding of AS development and treatment. We determined that oxidized low-density lipoprotein (ox-LDL) and platelet-derived growth factor (PDGF) directly induced the degradation of c-Ski protein, closely associated with reducing its phosphorylation. Serine383 (S383) was identified as the crucial phosphorylation site for stabilizing protein expression and nuclear location of c-Ski, which was responsible for its transcriptional suppression of autophagy-related genes. Decreased S383 phosphorylation facilitated nuclear export and degradation of c-Ski, thereby lessened its inhibitory effect on induction of autophagy genes. These findings provide a novel view of c-Ski modification and function modulation under some vascular injury factors, which point to a new potential therapeutic strategy by targeting c-Ski.
Ammonium persulfate (APS), an oxidizing agent used in hair products, manufacturing, and pool/spa water, can cause skin reactions, including allergic contact dermatitis.
To characterize positive patch test reactions to APS (2.5% petrolatum).
Retrospective analysis of patients tested to the North American Contact Dermatitis Group screening series from 2015 to 2018.
Of 10,526 patients, 193 (1.8%) had positive patch test reactions to APS. Compared with APS-negative patients, APS-positive patients were significantly more likely to be male (43.2% vs 28.0%; P<.0001); have primary hand dermatitis (30.2% vs 22.0%; P=.0064), scattered generalized dermatitis (25.5% vs 17.9%; P=.0064), or trunk dermatitis (8.9% vs 4.9%; P=.0123); and have dermatitis that is occupationally related (22.2% vs 10.9%; P<.0001). More than half of the APS-positive reactions were currently relevant (57.0%); 19 (9.8%) were related to occupation, especially hairdressers (68.4%). Swimming pools/spas (23.3%) and hair care products (19.2%) were the most common sources of APS.
Immediate reactions and follow-up testing were not captured.
The proportion of patients positive to APS was 1.8%. APS positivity was significantly associated with male sex and hand dermatitis. Swimming pool/spa chemicals were important sources of APS exposure.
The proportion of patients positive to APS was 1.8%. APS positivity was significantly associated with male sex and hand dermatitis. Swimming pool/spa chemicals were important sources of APS exposure.
Port wine birthmarks (PWBs) are congenital capillary malformations. Vessel characteristics, such as diameter and depth, may impact presentation and outcomes. They can be imaged using dynamic optical coherence tomography, a high-resolution, noninvasive imaging method.
We conducted a cross-sectional observational study to measure invivo vascular characteristics as a function of PWB color.
Patients undergoing treatment for PWB were recruited from 3 sites. PWBs were classified by color. Dynamic optical coherence tomography images with calculations were obtained.
One hundred eight patients were enrolled. Mean age correlated with PWB color, with birthmarks being lighter in younger patients and darker in older patients (P<.01). Mean superficial plexus depth was significantly shallower in purple PWBs than in pink PWBs. Color was not associated with significant differences in mean superficial vessel density or diameter. Among pink PWBs, each 10-year increase in age was associated with a 10.6-μm increase in superficial plexus depth.
