Vitamin D Supplementation for Patients with Dysmenorrhoea: A Meta-Analysis with Trial Sequential Analysis of Randomised Controlled Trials.

Vitamin D reduces prostaglandin levels and inflammation, making it a promising treatment option for dysmenorrhoea. However, its effects on pain intensity in different types of dysmenorrhoea remain unclear. We examined whether vitamin D supplementation decreases pain intensity in patients with dysmenorrhoea. The Cochrane Library, Embase, Google Scholar, Medline, and Scopus databases were searched from inception to 30 December 2023. Randomised controlled trials (RCTs) evaluating vitamin D supplementation effects on such patients were included. The primary and secondary outcomes were measured by the changes in pain intensity and rescue analgesic use, respectively. Pooled mean differences and rate ratios were calculated using a random-effect model; trial sequential analysis (TSA) was also performed. Overall, 11 studies involving 687 participants were included. Vitamin D supplementation significantly decreased pain intensity in patients with dysmenorrhoea compared with controls (pooled mean difference, -1.64; 95% confidence interval, -2.27 to -1.00; p < 0.001; CoE, moderate; I2 statistic, 79.43%) and indicated substantial heterogeneity among the included studies. TSA revealed that the current RCTs provide sufficient information. In subgroup analyses, vitamin D supplement reduced primary dysmenorrhoea pain but not secondary dysmenorrhoea pain. In conclusion, although substantial heterogeneity persists, vitamin D supplementation decreased pain intensity in patients with dysmenorrhea, especially in those with primary dysmenorrhoea.

Neonatal di-(2-ethylhexyl)phthalate exposure induces permanent alterations in secretory CRH neuron characteristics in the hypothalamus paraventricular region of adult male rats.

Corticotrophin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) play a critical role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis. Early-life exposure to di-(2-ethylhexyl) phthalate (DEHP) has been associated with an increased risk of developing psychiatric disorders in adulthood. The present work was designed to explore the impact of neonatal exposure to DEHP on adult PVN CRH neuronal activity. DEHP or vehicle was given to male rat pups from PND16 to PND22. Then, anxiety-like behaviors, serum corticosterone and testosterone, immunohistochemistry, western blotting, fluorescence in situ hybridization and acute ex vivo slice electrophysiological recordings were used to evaluate the influence of DEHP on adult PVN secretory CRH neurons. Neonatal DEHP-exposed rats exhibited enhanced anxiety-like behaviors in adults, with an increase in CORT. Secretory CRH neurons showed higher spontaneous firing activity but could be inhibited by GABAAR blockers. CRH neurons displayed fewer firing spikes, prolonged first-spike latency, depolarizing shifts in GABA reversal potential and strengthened GABAergic inputs, as indicated by increases in the frequency and amplitude of sIPSCs. Enhancement of GABAergic transmission was accompanied by upregulated expression of GAD67 and downregulated expression of GABABR1, KCC2 and GAT1. These findings suggest that neonatal exposure to DEHP permanently altered the characteristics of secretory CRH neurons in the PVN, which may contribute to the development of psychiatric disorders later in life.

Hepatic Effect of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside, the Signature Component of Traditional Chinese Medicine Heshouwu: Advances and Prospects.

Traditional Chinese medicine Heshouwu, named Polygoni Multiflori Radix in Pharmacopoeia of the People's Republic of China (PPRC, 2020), is derived from the root tuber of Polygonum multiflorum Thunb., Heshouwu or processed Heshouwu is well known for its function in reducing lipids and nourishing the liver. However, increasing cases of Heshouwu-induced hepatotoxicity were reported in recent years. Researchers have begun to study the paradoxical effects of Heshouwu on the liver. 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG), an abundant functional component of Heshouwu, shows various biological activities, among which its effect on the liver is worthy of attention. This paper reviews the current studies of TSG on hepatoprotection and hepatotoxicity, and summarizes the doses, experimental models, effects, and mechanisms of action involved in TSG's hepatoprotection and hepatotoxicity, aiming to provide insight for future study of TSG and understanding the effects of Heshouwu on the liver. Emerging evidence suggests that TSG ameliorates both pathological liver injury and chemical-induced liver injury by modulating lipid metabolism, inhibiting the inflammatory response and oxidative stress in the liver. However, with the reports of clinical cases of Heshouwu induced liver injury, it has been found that long-term exposure to a high dose of TSG cause hepatocyte or hepatic tissue damage. Moreover, TSG may cause hepatotoxicity by affecting the transport and metabolism of other possible hepatoxic compounds in Heshouwu. Studies indicate that trans-TSG can be isomerized into cis-TSG under illumination, and cis-TSG had a less detrimental dose to liver function than trans- TSG in LPS-treated rats. In brief, TSG has protective effects on the liver, but liver injury usually occurs under highdose TSG or is idiosyncratic TSG-induced liver injury.

Potential biomarkers screening of Polygonum multiflorum radix-induced liver injury based on metabonomics analysis of clinical samples.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Radix (PMR) is the dried root tuber of Polygonum multiflorum Thunb., which has been used in the clinic for a variety of pharmacological activities. However, Polygonum multiflorum Radix-induced liver injury (PMR-ILI) has been reported in recent years, which has limited its clinical use to some extent. The occurrence of PMR-ILI is not universal, so finding the different metabolic characteristics between PMR-ILI and Polygonum multiflorum Radix-tolerance group (PMR-T) is very important for the PMR rational clinical application and PMR-ILI early clinical diagnosis. METHODS: In this study, 6 clinical plasma samples of PMR-ILI and 13 PMR-T were collected and analyzed by high-resolution liquid chromatography-mass spectrometry. Firstly, the differential metabolites of the two groups were screened by conventional screening methods such as multivariate statistical analysis. Secondly, the characteristic metabolites with greater contribution, correlation with liver injury and high sensitivity were screened by correlation analysis with clinical liver injury indicators, random forest analysis, and receiver operating characteristic curve (ROC). RESULTS: After multivariate statistical analysis and screening analysis, 29 differential metabolites were identified. Compared with PMR-T group, the metabolism of glycerol and phospholipid, glutamine and glutamate, phenylalanine, sphingolipid and tryptophan in PMR-ILI group were disturbed. After correlation analysis with liver injury indexes and random forest screening, 8 potential biomarkers closely related to clinical liver injury were obtained. Finally, 3 potential biomarkers with high expression in PMR-ILI, hypoxanthine, LysoPC(P-16:0/0:0) and taurochenodesoxycholic acid, were screened out through the analysis of ROC, which can provide a basis for the early clinical diagnosis. CONCLUSION: Based on the analysis of the PMR-ILI and PMR-T plasma samples by LC-MS, three biomarkers of clinical liver injury of Polygonum multiflorum Radix were selected: hypoxanthine, LysoPC(P-16:0/0:0) and taurochenodeoxycholic acid.

Inhibition of CYP3A4 enhances aloe-emodin induced hepatocyte injury.

Aloe-emodin (AE) is a natural hydroxyanthraquinone derivative that was found in many medicinal plants and ethnic medicines. AE showed a wide array of pharmacological activities including anticancer, antifungal, laxative, antiviral, and antibacterial effects. However, increasing number of published studies have shown that AE may have some hepatotoxicity effects but the mechanism is not fully understood. Studies have shown that the liver injury induced by some free hydroxyanthraquinone compounds is associated with the inhibition of some metabolic enzymes. In this study, the CYP3A4 and CYP3A1 were found to be the main metabolic enzymes of AE in human and rat liver microsomes respectively. And AE was metabolized by liver microsomes to produce hydroxyl metabolites and rhein. When CYP3A4 was knocked down in L02 and HepaRG cells, the cytotoxicity of AE was increased significantly. Furthermore, AE increased the rates of apoptosis of L02 and HepaRG cells, accompanied by Ca2+ elevation, mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS) overproduction. The mRNA expression of heme oxygenase-1 in L02 and HepaRG cells increased significantly in the high-dose of AE (40 µmol/L) group, and the mRNA expression of quinone oxidoreductase-1 was activated by AE in all concentrations. Taken together, the inhibition of CYP3A4 enhances the hepatocyte injury of AE. AE can induce mitochondrial injury and the imbalance of oxidative stress of hepatocytes, which results in hepatocyte apoptosis.

Exploration of components and mechanisms of Polygoni Multiflori Radix-induced hepatotoxicity using siRNA -mediated CYP3A4 or UGT1A1 knockdown liver cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygoni Multiflori Radix, the dried root of Polygonum multiflorum Thunb., and its processed products have been used as restoratives for centuries in China. However, the reports of Polygoni Multiflori Radix-induced liver injury (PMR-ILI) have received wide attention in recent years, and the components and mechanism of PMR-ILI are not completely clear yet. Our previous studies found that the PMR-ILI was related to the down-regulation of some drug metabolism enzymes (DME). AIM OF THE STUDY: To explore the effect of the inhibition of CYP3A4 or UGT1A1 on PMR-ILI, screen the relevant hepatotoxic components and unveil its mechanism. METHODS: RT-qPCR was used to detect the effects of water extract of Polygoni Multiflori Radix (PMR) and its main components on the mRNA expression of CYP3A4 and UGT1A1 in human hepatic parenchyma cell line L02. High-performance liquid chromatography (HPLC) was employed to detect the content of major components in the PMR. And then, the stable CYP3A4 or UGT1A1 knockdown cells were generated using short hairpin RNAs (shRNA) in L02 and HepaRG cells. Hepatotoxic components were identified by cell viability assay when PMR and its four representative components, 2,3,5,4'-tetrahydroxy stilbene glycoside (TSG), emodin (EM), emodin-8-O-ß-D-glucoside (EG), and gallic acid (GA), acted on CYP3A4 or UGT1A1 knockdown cell lines. The PMR-ILI mechanism of oxidative stress injury and apoptosis in L02 and HepaRG cells were detected by flow cytometry. Finally, the network toxicology prediction analysis was employed to excavate the targets of its possible toxic components and the influence on the metabolic pathway. RESULTS: PMR and EM significantly inhibited the mRNA expression of CYP3A4 and UGT1A1 in L02 cells, while TSG and GA activated the mRNA expression of CYP3A4 and UGT1A1, and EG activated CYP3A4 expression while inhibited UGT1A1 expression. The contents of TSG, EG, EM and GA were 34.93 mg/g, 1.39 mg/g, 0.43 mg/g and 0.44 mg/g, respectively. The CYP3A4 or UGT1A1 knockdown cells were successfully constructed in both L02 and HepaRG cells. Low expression of CYP3A4 or UGT1A1 increased PMR cytotoxicity remarkably. Same as PMR, the toxicity of EM and GA increased in shCYP3A4 and shUGT1A1 cells, which suggested EM and GA may be the main components of hepatotoxicity in PMR. Besides, EM not only inhibited the expression of metabolic enzymes but also reduced the cytotoxicity threshold. EM and GA affected the level of ROS, mitochondrial membrane potential, Ca2+ concentration, and dose-dependent induced hepatocyte apoptosis in L02 and HepaRG cells. The network toxicology analysis showed that PMR-ILI was related to drug metabolism-cytochrome P450, glutathione metabolism, and steroid hormone biosynthesis. CONCLUSION: The inhibition of mRNA expression of CYP3A4 or UGT1A1 enhanced hepatotoxicity of PMR. EM and GA, especially EM, may be the main hepatotoxic components in PMR. The mechanism of PMR, EM and GA induced hepatotoxicity was proved to be related to elevated levels of ROS, mitochondrial membrane potential, Ca2+ concentration, and induction of apoptosis in liver cells.

Lower clearance of sodium tanshinone IIA sulfonate in coronary heart disease patients and the effect of total bilirubin: a population pharmacokinetics analysis.

This study developed a population pharmacokinetic model for sodium tanshinone IIA sulfonate (STS) in healthy volunteers and coronary heart disease (CHD) patients in order to identify significant covariates for the pharmacokinetics of STS. Blood samples were obtained by intense sampling approach from 10 healthy volunteers and sparse sampling from 25 CHD patients, and a population pharmacokinetic analysis was performed by nonlinear mixed-effect modeling. The final model was evaluated by bootstrap and visual predictive check. A total of 230 plasma concentrations were included, 137 from healthy volunteers and 93 from CHD patients. It was a two-compartment model with first-order elimination. The typical value of the apparent clearance (CL) of STS in CHD patients with total bilirubin (TBIL) level of 10 µmol(L-1 was 48.7 L(h-1 with inter individual variability of 27.4%, whereas that in healthy volunteers with the same TBIL level was 63.1 L(h-1. Residual variability was described by a proportional error model and estimated at 5.2%. The CL of STS in CHD patients was lower than that in healthy volunteers and decreased when TBIL levels increased. The bootstrap and visual predictive check confirmed the stability and validity of the final model. These results suggested that STS dosage adjustment might be considered based on TBIL levels in CHD patients.

Efficacy of different doses of dexmedetomidine as a rapid bolus for children: a double-blind, prospective, randomized study.

BACKGROUND: Dexmedetomidine (DEX), a highly sensitive α2-adrenoceptor agonist that possesses anxiolytic, sedative, and analgesic effects, has been documented as a preventative and treatment for emergence agitation (EA). The therapeutic should be given as a loading dose that is infused during a 10 min period, but if a rapid bolus injection is deemed to be hemodynamically appropriate, it would be a more opportune route of administration. So we studied the efficacy of different doses of DEX as a rapid bolus for children to prevent and treat EA. METHODS: One hundred patients were enrolled and randomly divided into five groups: the control group (group D1), the 0.25 µg/kg DEX group (group D2), the 0.5 µg/kg DEX group (group D3), the 0.75 µg/kg DEX group (group D4), and the 1 µg/kg DEX group (group D5). Heart rate (HR), mean blood pressure (MBP) and blood oxygen saturation (SaO2) were recorded immediately before the study drug injection (baseline) and every minute for 5 min thereafter and at the time points of the skin cut and hernial sac pull. EA and pain were assessed in the post -anesthesia care unit, and any complementary medicine and adverse events were recorded too. RESULTS: The incidence of EA was significantly decreased in group D4 and group D5 compared with D1.All groups exhibited similar baseline HR and MBP. After administered, HR and MBP were significantly decreased in all DEX group compared with group D1.In groups D3, D4 and D5, the minimal HR was decreased significantly compared with the groups D1 and duration time of minimal HR significantly prolonged in group D5, but no patient needed treatment. As the dosage increased, the recovery time was significantly prolonged. There were no significant differences in occurrence time of minimal HR, the incidence of complementary medicine and adverse events among groups. CONCLUSION: Rapid intravenous injection (IV) bolus administration of 0.75 and 1.0 µg/kg of DEX could improve the recovery profile by reducing the incidence of EA in children. Although its use resulted in a transient decreases in HR and MBP, DEX was clinically well-tolerated in children. TRIAL REGISTRATION: No. ChiCTR-IPR-17010658 . Registered 17 February 2017.