Coronary heart disease (CHD) is a chronic disease that seriously threatens people's health and even their lives. Currently, there is no ideal drug without side effects for the treatment of CHD. ...Trichosanthis Pericarpium (TP) has been used for several years in the treatment of diseases associated with CHD. However, there is still a need for systematic research to unravel the pharmacodynamic substances and possible mechanism of TP in the treatment of coronary heart.
The purpose of current study was to explore the pharmacodynamic substances and potential mechanisms of TP in the treatment of CHD via integrating network pharmacology with plasma pharmacochemistry and experimental validation.
The effect of TP intervention in CHD was firstly assessed on high-fat diet combined with isoprenaline-induced CHD rats and H2O2-induced H9c2 cells, respectively. Then, the LC-MS was utilized to identify the absorbed components of TP in the plasma of CHD rats, and this was used to develop a network pharmacology prediction to obtain the possible active components and mechanisms of action. Molecular docking and immunohistochemistry were used to explore the interaction between TP and key targets. Subsequently, the efficacy of the active ingredients was investigated by in vitro cellular experiments, and their metabolic pathways in CHD rats were further analyzed.
The effects of TP on amelioration of CHD were verified by in vivo and in vitro experiments. Plasma pharmacochemistry and network pharmacology screened six active components in plasma including apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin. The interaction of these compounds with potential key targets AKT1, IL-1β, IL-6, TNF-α and VEGFA were preliminarily verified by molecular docking. And immunohistochemical results showed that TP reduced the expression of AKT1, IL-1β, IL-6, TNF-α and VEGFA in CHD rat hearts. Then cellular experiments confirmed that apigenin, phenylalanine, quercetin, linoleic acid, luteolin, and tangeretin were able to reduce the ROS level in H2O2-induced HUVEC cells and promote the migration and tubule formation of HUVEC cells, indicating the pharmacodynamic effects of the active components. Meanwhile, the metabolites of TP in CHD rats suggested that the pharmacological effects of TP might be the result of the combined effects of the active ingredients and their metabolites.
Our study found that TP intervention in CHD is characterized by multi-component and multi-target regulation. Apigenin, phenylalanine, linoleic acid, quercetin, luteolin, and tangeretin are the main active components of TP. TP could reduce inflammatory response and endothelial damage by regulating AKT1, IL-1β, IL-6, TNF-α and VEGFA, reduce ROS level to alleviate the oxidative stress situation and improve heart disease by promoting angiogenesis to regulate endothelial function. This study also provides an experimental and scientific basis for the clinical application and rational development of TP.
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► We confirm that BPA exposure may induce the accumulation of DNA damage in germ cells. ► BPA-induced DNA damage accumulation in germ cells is associated with oxidative stress. ► We ...show that melatonin effectively alleviates BPA-induced DNA damage.
Bisphenol A (BPA) is a well-known endocrine-disrupting chemical (EDC) that has received particular attention because of its widespread distribution in humans. Due to its chemical similarity to diethylstilbestrol, which is carcinogenic to mammals, the possible genotoxicity of BPA has already largely been evaluated. However, the results are still inconclusive and controversial. To investigate the genotoxic effects of BPA in rat germ cells and the potential protective action of melatonin against these effects, adult male Sprague-Dawley rats were orally administered BPA at a dose of 200mg/kg body weight per day for ten consecutive days with or without melatonin pretreatment. The thiobarbituric acid reactive substances (TBARS) level and superoxide dismutase (SOD) activity in the testes were evaluated. Subsequently, their spermatocytes were isolated, and DNA damage was assessed using an alkaline comet assay and the meiotic spread method. BPA administration did not significantly affect the weights of rats and their reproductive organs, and no alteration in sperm count was found. However, we demonstrated that BPA administration induced a significant increase in TBARS levels and a decrease in SOD activity that were concomitant with an increase in DNA migration within male germ cells and γH2AX foci formation on the autosomes of pachytene spermatocytes. Furthermore, a decrease in the proportion of 4C-cells was observed. These BPA effects were significantly alleviated by melatonin pretreatment. Nevertheless, the genotoxic effects of BPA were not accompanied by apoptosis in germ cells and morphological changes in the testes. These results indicate that BPA exposure may induce DNA damage accumulation in germ cells via oxidative stress. Moreover, melatonin may be a promising pharmacological candidate for preventing the potential genotoxicity of BPA following occupational or environmental exposure.
Abstract Background and Aim Understanding the dynamics of serum Mac‐2 binding protein glycosylation isomer (M2BPGi) remains pivotal for hepatitis C virus (HCV) patients' post‐sustained virologic ...response (SVR 12 ) through direct‐acting antivirals (DAAs). Methods We compared areas under receiver operating characteristic curves (AUROCs) of M2BPGi, FIB‐4, and APRI and assess M2BPGi cutoff levels in predicting fibrosis stages of ≥F3 and F4 utilizing transient elastography in 638 patients. Variations in M2BPGi levels from pretreatment to SVR 12 and their association with pretreatment alanine transaminase (ALT) levels and fibrosis stage were investigated. Results The AUROCs of M2BPGi were comparable to FIB‐4 in predicting ≥F3 (0.914 vs 0.902, P = 0.48) and F4 (0.947 vs 0.915, P = 0.05) but were superior to APRI in predicting ≥F3 (0.914 vs 0.851, P = 0.001) and F4 (0.947 vs 0.857, P < 0.001). Using M2BPGi cutoff values of 2.83 and 3.98, fibrosis stages of ≥F3 and F4 were confirmed with a positive likelihood ratio ≥10. The median M2BPGi change was −0.55. Patients with ALT levels ≥5 times ULN or ≥F3 demonstrated more pronounced median decreases in M2BPGi level compared to those with ALT levels 2–5 times ULN and <2 times ULN (−0.97 vs −0.68 and −0.44; P < 0.001) or with < F3 (−1.52 vs −0.44; P < 0.001). Conclusions Serum M2BPGi is a reliable marker for advanced hepatic fibrosis. Following viral clearance, there is a notable M2BPGi decrease, with the extent of reduction influenced by ALT levels and fibrosis stage.
The high device efficiencies of 50.5 cd A−1 and 14.9% for device B were achieved, which are 21% and 42% higher than that of device A, respectively. At the luminance of 60,000 cd m−2, the efficiency ...roll off value of device B (64%) is smaller than that of device A (70%). The better performance of device B is attributed to the bicyclo 2.2.2 oct-2-ene group.
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•A series of iridium complexes 1–4, has been easily synthesized, complexes 2 and 4 containing steric groups.•Using complexes 2 and 4 as dopant, the OLEDs show good performance at 2.5 wt% doping concentration.•Device based on complex 4 containing steric groups displays the highest peak luminance of 105689 cd m−2, and exhibits a maximum current efficiency of 50.5 cd A−1 and a maximum external quantum efficiency of 14.9% with small efficiency roll-off values.
Four bis-cyclometalated iridium complexes (Ir(tpp)2(pic) (1), Ir(tpp)2(paz) (2), (Ir(ttp)2(pic) (3) and (Ir(ttp)2(paz) (4) with phenylpyridazine derivative ligands were synthesized under mild reaction conditions, in which tpp (tppH = 3, 6-bis(4- (trifluoromethyl)phenyl)pyridazine) or ttp (ttpH = (5 s, 8 s)-1,4-bis(4- (trifluoromethyl))-diphenyl-5,6,7,8-tetrahydro-5,8-thanophthalazine) was used as the primary ligand and pyridine-2-carboxylate (pic) or paz (pazH = 2-(3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridine) were used as ancillary ligand. The coordination arrangement of complexes 1–3 was revealed by the single X-ray structural analyses. All complexes showed strong emissions with peaks ranged from 519 to 547 nm and quantum efficiencies of 0.55–0.80. By introducing sterically hindered bicyclo 2.2.2 oct-2-ene groups in the primary ligands of complexes 3 and 4, their molecular interactions are strongly restrained in solid. The organic light-emitting diodes (OLEDs) were fabricated with complexes 2 (device A) and 4 (device B) as dopants. The better device performances with a maximum current efficiency of 50.5 cd A−1 and a maximum external quantum efficiency of 14.9% are achieved by device B, along with smaller efficiency roll-off, which is attributed to the effect of alkyl steric groups and relative more matched energy levels in device.
Herpangina, usually caused by coxsackie virus A, is prevalent in children spreading through the fecal-oral transmission and the respiratory droplets dissemination. Also, it is mostly asymptomatic and ...self-limiting. In our study, we found that large outbreak of herpangina in children occurred in the summer of 2015 in Hangzhou, China. From May 1th to August 31th, a total of 10 210 children were diagnosed with herpangina in Children's Hospital of Zhejiang University School of Medicine. 2 310 throat swabs were collected and tested for enterovirus detection by real-time RT-PCR, while 1 651 cases were positive with the rate of 71.5%. Based on VP1 gene or 5'UTR region sequences, Coxsackievirus A2, A4, A6, A10, B2, B4 and echovirus 30 were detected in these cases. More importantly, Coxsackievirus A2 may be the major subtype of enterovirus resulting in children with herpangina in hangzhou, China.
Background: Alzheimer’s disease and related dementias (AD/ADRD) are terminal conditions impacting families and caregivers, particularly at end-of-life. Longitudinal, secondary data analyses present ...opportunities for insight into dementia caregiving and decision-making over time; however, joining complex datasets and preparing them for analysis poses many challenges. Objectives: To describe an approach to linking national survey data of older adults with their primary caregivers to build a prospective, longitudinal dataset, and to share the Statistical Analysis System (SAS) coding statement algorithms with other researchers. Methods: The National Health and Aging Trends Study (NHATS) and National Study of Caregiving (NSOC) are joined using a series of algorithms based on conceptual and operational definitions of dementia, primary caregivers, and the occurrence of death. A series of SAS algorithms resulting in the final longitudinal dataset was created. Results: NHATS/NSOC participants were linked using three preliminary data files (n = 12 427) and one final data join (n = 3305) over nine rounds of data collection. Presence of dementia was defined based on the indicator in the year preceding the last month-of-life (LML) interview. Primary caregivers were defined as the person providing the most frequent care over time. Additional flag variables (LML interview, dementia classification, and cohort (2011 vs 2015)) were created. The SAS algorithms are presented herein. Discussion: The SAS coding statement algorithms provide an opportunity to conduct longitudinal analysis of care for both members of the dyad in the context of dementia and end-of-life. Future research using the proposed dataset can further explore care and caregiving in these populations.
Corticosteroid therapy and delayed neuraminidase inhibitor (NAI) treatment were associated with prolonged influenza A(H7N9) viral RNA shedding. Our findings suggest that NAI treatment should be ...started as soon as possible in patients with suspected A(H7N9) infection and that use of corticosteroids should be prudent.
Abstract
Background
Data are limited on the impact of neuraminidase inhibitor (NAI) treatment on avian influenza A(H7N9) virus RNA shedding.
Methods
In this multicenter, retrospective study, data were collected from adults hospitalized with A(H7N9) infection during 2013–2017 in China. We compared clinical features and A(H7N9) shedding among patients with different NAI doses and combination therapies and evaluated factors associated with A(H7N9) shedding, using Cox proportional hazards regression.
Results
Among 478 patients, the median age was 56 years, 71% were male, and 37% died. The median time from illness onset to NAI treatment initiation was 8 days (interquartile range IQR, 6–10 days), and the median duration of A(H7N9) RNA detection from onset was 15.5 days (IQR, 12–20 days). A(H7N9) RNA shedding was shorter in survivors than in patients who died (P < .001). Corticosteroid administration (hazard ratio HR, 0.62 95% confidence interval {CI}, .50–.77) and delayed NAI treatment (HR, 0.90 95% CI, .91–.96) were independent risk factors for prolonged A(H7N9) shedding. There was no significant difference in A(H7N9) shedding duration between NAI combination treatment and monotherapy (P = .65) or between standard-dose and double-dose oseltamivir treatment (P = .70).
Conclusions
Corticosteroid therapy and delayed NAI treatment were associated with prolonged A(H7N9) RNA shedding. NAI combination therapy and double-dose oseltamivir treatment were not associated with a reduced A(H7N9) shedding duration as compared to standard-dose oseltamivir.
The compatibility between Danggui (Angelicae Sinensis Radix) and Honghua (Carthami Flos) is a known herb pair, which could activate blood circulation and dissipate blood stasis effects. In this ...paper, we quantified seven main bio-active components (hydroxysafflor yellow A, caffeic acid,
-coumaric acid, kaempferol-3-
-rutinoside, ferulic acid, 3-
-butylphthalide, and ligustilide) in plasma samples in vivo by UPLC-TQ/MS method and investigatedwhether the pharmacokinetic (PK) behaviors of the seven components could be altered in blood stasis rats after oral administration of the Gui-Hong extracts. It was found that the
and
of these components in blood stasis rats had increasing tendency compared with normal rats. Most components in model and normal rats had significant difference in some pharmacokinetic parameters, which indicated that the metabolism enzymes and transporters involved in the metabolism and disposition of these bio-active componentsmay bealtered in blood stasis rats. This study was the first report about the pharmacokinetic investigation between normal and blood stasis rats after oral administrationof Gui-Hong extracts, and these results are important and valuable for better clinical applications of Gui-Hong herb pair and relatedTCM formulae.
Quercetin and rutin are popular flavonoids in plant foods, herbs, and dietary supplements. Cyclosporine (CSP), an immunosuppressant with a narrow therapeutic window, is a substrate of P-glycoprotein ...(P-gp) and cytochrome P-450 3A4 (CYP3A4). This study investigated the effects of quercetin and rutin on CSP pharmacokinetics from Neoral and relevant mechanisms. Rats were orally administered Neoral with and without quercetin or rutin. The blood CSP concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. The results showed that quercetin and rutin significantly decreased the C max of CSP by 67.8 and 63.2% and reduced the AUC0−540 by 43.3 and 57.2%, respectively. The in vitro studies indicated that the quercetin and rutin induced the functions of P-gp and CYP3A4. In conclusion, quercetin and rutin decreased the bioavailability of CSP through activating P-gp and CYP3A. Transplant patients treated with Neoral should avoid concurrent consumption of quercetin or rutin to minimize the risk of allograft rejection.
The impact of melamine exposure on kidney outcomes in type 2 diabetes mellitus (T2D) patients remains unclear. In this prospective cohort study, 561 T2D patients during October 2016 and June 2020 ...were enrolled and followed until December 2021. Baseline one-spot urinary corrected melamine levels were measured by LC-MS/MS. Average daily intake (ADI) of melamine represented environmental melamine exposure in daily life, and was estimated using urinary corrected melamine level by creatinine excretion (CE)-based model. Primary kidney outcomes were defined as doubling of serum creatinine levels or end stage kidney disease (ESKD), and secondary kidney outcomes included rapid decline in kidney function as estimated glomerular filtration rate (eGFR) decline >5 ml/min/1.73 m2/year. Baseline median urinary corrected melamine levels and estimated DI of melamine were 0.8 μg/mmol and 0.3 μg/kg/day in 561 T2D patients. During 3.7 years of follow-up, urinary corrected melamine level was positively correlated with reaching composite outcomes of either doubling of serum creation levels or ESKD and rapid decline in kidney function. Those with the highest quartile of urinary corrected melamine had 2.96-fold risk of composite outcomes of either doubling of serum creation levels or ESKD and 2.47-fold risk of eGFR decline >5 ml/min/1.73 m2/year. Estimated ADI of melamine also had significant correlation with adverse kidney outcomes. Furthermore, the positive relationship between melamine exposure and rapid decline in kidney function was only found in T2D patients with male, baseline eGFR ≥60 ml/min/1.73 m2 or glycated hemoglobin ≤7%. In conclusion, melamine exposure is significantly associated with adverse kidney outcomes in T2D patients, especially in those with male, well sugar control or good baseline kidney function.
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•Melamine levels in urine were significantly associated with adverse kidney outcome in type 2 diabetes mellitus (T2D).•This association was pronounced in male T2D and in those with well controlled sugar.•Physicians need to consider the potential hazard of environmental melamine on kidney function deterioration in well-controlled T2D.
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