Associations between polyunsaturated fatty acid concentrations and Parkinson's disease: A two-sample Mendelian randomization study.

Introduction: Observational studies demonstrated controversial effect of polyunsaturated fatty acids (PUFAs) on Parkinson's disease (PD) with limited causality evidence. Randomized control trials showed possible improvement in PD symptoms with PUFA supplement but had small study population and limited intervention time. Methods: A two-sample Mendelian randomization was designed to evaluate the causal relevance between PUFAs and PD, using genetic variants of PUFAs as instrumental variables and PD data from the largest genome-wide association study as outcome. Inverse variance weighted (IVW) method was applied to obtain the primary outcome. Mendelian randomization Egger regression, weighted median and weighted mode methods were exploited to assist result analyses. Strict Mendelian randomization and multivariable Mendelian randomization (MVMR) were used to estimate direct effects of PUFAs on PD, eliminating pleiotropic effect. Debiased inverse variance weighted estimator was implemented when weak instrument bias was introduced into the analysis. A variety of sensitivity analyses were utilized to assess validity of the results. Results: Our study included 33,674 PD cases and 449,056 controls. Higher plasma level of arachidonic acid (AA) was associated with a 3% increase of PD risk per 1-standard deviation (SD) increase of AA (IVW; Odds ratio (OR)=1.03 [95% confidence interval (CI) 1.01-1.04], P = 2.24E-04). After MVMR (IVW; OR=1.03 [95% CI 1.02-1.04], P =6.15E-08) and deletion of pleiotropic single-nucleotide polymorphisms overlapping with other lipids (IVW; OR=1.03 [95% CI 1.01-1.05], P =5.88E-04), result was still significant. Increased level of eicosapentaenoic acid (EPA) showed possible relevance with increased PD risk after adjustment of pleiotropy (MVMR; OR=1.05 [95% CI 1.01-1.08], P =5.40E-03). Linoleic acid (LA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were found not causally relevant to PD risk. Various sensitivity analyses verified the validity of our results. In conclusion, our findings from Mendelian randomization suggested that elevated levels of AA and possibly EPA might be linked to a higher risk of PD. No association between PD risk and LA, DHA, DPA, or ALA was found. Discussion: The odds ratio for plasma AA and PD risk was weak. It is important to approach our results with caution in clinical practice and to conduct additional studies on the relationship between PUFAs and PD risk.

Plasma 25(OH)D Level is Associated with the Nucleic Acid Negative Conversion Time of COVID-19 Patients: An Exploratory Study.

Purpose: Vitamin D, an essential nutrient and a pleiotropic steroid hormone, has been reported to be associated with the risk and severity in patients infected with Coronavirus Disease-2019 (COVID-19). The role of vitamin D in predicting clinical outcome for COVID-19 patients is unknown. Here, we aimed to determine the prognostic value of plasma 25(OH)D level in COVID-19 patients. Patients and Methods: A total of 158 patients infected with novel COVID-19 Omicron variants in Shanghai were recruited in this study and were categorized into three groups by the tertile levels of plasma 25(OH)D. Plasma 25(OH)D level was determined along with routine blood tests related to liver and renal functions in newly diagnosed COVID-19 patients at admission. The nucleic acid negative conversion time of throat swab samples was evaluated as the primary clinical outcome. The prognostic value of clinical characteristics and plasma 25(OH)D level was assessed using the Kaplan-Meier plot and Cox proportional hazards regression tests. Results: Higher level of plasma 25(OH)D level in COVID-19 patients was independently associated with shorter nucleic acid negative conversion time from COVID-19 infection (multivariate adjusted HR: 0.54, 95%CI: 0.35-0.82, P=0.004, tertile 2 vs 1; multivariate adjusted HR: 0.60, 95%CI: 0.39-0.90, P=0.014, tertile 3 vs 1). Conclusion: Plasma 25(OH)D level may serve as an independent prognostic factor in COVID-19 patient. Our findings indicate the protective roles of vitamin D supplementation in the regiment of patients with COVID-19.

Polymorphisms of genes related to vitamin D metabolism and transportation and its relationship with the risk of osteoporosis: protocol for a multicentre prospective cohort study in China.

INTRODUCTION: Osteoporotic fracture is one of the most common causes of disability and a major contributor to medical care costs in many regions of the world. The polymorphisms of genes related to vitamin D metabolism and transportation are associated with variation in bone mineral density and the risk of osteoporosis. METHODS AND ANALYSIS: The China Community-based Cohort of Osteoporosis study is an observational, longitudinal, multicentre, prospective cohort study for middle-aged and older permanent residents of China, which has been ongoing in six cities since 2016. Female residents aged 45-80 years old and male residents aged 50-80 years old are identified through permanent resident lists. All the enrolled participants will complete questionnaires on their personal characteristics and histories. The bone mineral density of their lumbar vertebrae and left hip will be measured and serum bone metabolism parameters assessed. Polymorphisms of genes related to vitamin D metabolism and transportation will be detected, and their relationship with the risk of osteoporosis, and osteoporotic fracture, will be analysed. About 18 000 residents will be involved in the study. ETHICS AND DISSEMINATION: The study was approved by Institutional Ethics Board of Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine (2016LCSY065). Results will be published in peer-reviewed journals. The results of this study are expected to improve the understanding of the association between polymorphisms of genes related to vitamin D metabolism and transportation and the risk of osteoporosis and osteoporotic fracture among middle-aged and older residents of China. TRIAL REGISTRATION NUMBER: NCT02958020.

Epigenetic regulation of UDP-Glucuronosyltransferase by microRNA-200a/-183: implications for responses to sorafenib treatment in patients with hepatocellular carcinoma.

Patients receiving sorafenib treatment for hepatocellular carcinoma (HCC) experience different treatment efficacy. Personalized sorafenib treatment should be achieved through the identification of predictors of therapeutic response. In the current study, we found that high UGT1A9 expression indicated better prognosis for HCC patients treated with sorafenib after surgery. In silico analysis predicted microRNA-200a/-183 as potential regulators of the UGT1A gene family via binding to the shared UGT1A9 3'-UTR. A significant inverse correlation between microRNA-200a/-183 and UGT1A9 mRNA level was observed in a panel of HCC specimens. Direct binding was further demonstrated by luciferase reporter gene vector carrying wild-type or binding site truncated UGT1A9 3'-UTR. MicroRNA-200a/-183 downregulated UGT1A9 expression in a dose-dependent manner and significantly reduced sorafenib ß-D-glucuronide formation in HCC cells. These data indicated that UGT1A9, under epigenetic regulation of microRNA-200a/-183, could predict patients who might benefit from adjuvant sorafenib treatment after surgery.

Pharmacokinetics and effects of demographic factors on blood 25(OH)D3 levels after a single orally administered high dose of vitamin D3.

AIM: To examine the biological consequences and demographic factors that might affect the pharmacokinetics of vitamin D3 after a single high dose intervention in a young Chinese population with vitamin D insufficiency status. METHODS: A total of 28 young subjects (25 to 35 years old) with vitamin D insufficiency status [serum 25(OH)D <30 ng/mL] was recruited in Shanghai, China. The subjects were orally administered a single high dose of vitamin D3 (300 000 IU). Baseline characteristics and blood samples were collected at d 0, 1, 2, 3, 7, 28, 56, 84 and 112 after the intervention. The blood biomarker levels were determined with standardized methods. RESULTS: The intervention markedly increased the blood 25(OH)D3 levels within the first five days (mean Tmax=5.1±2.1 d) and sustained an optimal circulating level of 25(OH)D3 (≥30 ng/mL) for 56 d. After the intervention, body weight and baseline 25(OH)D3 levels were significantly correlated with circulating 25(OH)D3 levels. No adverse events and no consistently significant changes in serum calcium, creatinine, glucose, parathyroid hormone, vitamin D binding protein, or the urinary calcium/reatinine ratio were observed. However, there was a significant increase in phosphorus after the vitamin D3 intervention. Total cholesterol and triglyceride levels were decreased at the end of the trial. CONCLUSION: The pharmacokinetics of vitamin D after intervention were influenced by baseline 25(OH)D3 levels and the body weight of the subjects. The results suggest that a single high oral vitamin D3 intervention is safe and efficient for improving the vitamin D status of young Chinese people with vitamin D insufficiency.

Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish.

AIM: To investigate the embryotoxicity of dihydroartemisinin (DHA), the main active metabolite of artemisinin, in zebrafish, and explore the corresponding mechanisms. METHODS: The embryos of wild type and TG (flk1:GFP) transgenic zebrafish were exposed to DHA. Developmental phenotypes of the embryos were observed. Development of blood vessels was directly observed in living embryos of TG (flk1:GFP) transgenic zebrafish under fluorescence microscope. The expression of angiogenesis marker genes vegfa, flk1, and flt1 in the embryos was detected using real-time PCR and RNA in situ hybridization assays. RESULTS: Exposure to DHA (1-10 mg/L) dose-dependently caused abnormal zebrafish embryonic phenotypes in the early developmental stage. Furthermore, exposure to DHA (10 mg/L) resulted in more pronounced embryonic angiogenesis in TG (flk1:GFP) zebrafish line. Exposure to DHA (10 mg/L) significantly increased the mRNA expression of vegfa, flk1, and flt1 in the embryos. Knockdown of the flk1 protein partially blocked the effects of DHA on embryogenesis. CONCLUSION: DHA causes abnormal embryonic phenotypes and promotes angiogenesis in zebrafish early embryonic development, demonstrating the potential embryotoxicity of DHA.

Valeriana jatamansi constituent IVHD-valtrate as a novel therapeutic agent to human ovarian cancer: in vitro and in vivo activities and mechanisms.

Identification of novel chemotherapeutic agents from traditional medicines and elucidation of the molecular basis of their anticancer effects are critical and urgently needed for modern pharmacotherapy. We previously found that analogs of the compounds present in Valeriana jatamansi, a traditional medicine used to treat mental disorders, possess notable antitumor properties; however, the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the anticancer effects of IVHD-valtrate, one of the most active Valeriana jatamansi derivatives, against human ovarian cancer cells in vitro and in vivo. IVHD-valtrate inhibited the growth and proliferation of the A2780 and OVCAR-3 ovarian cancer cell lines in a concentration-dependent manner, while relatively low cytotoxicity to immortalized non-tumorigenic human ovarian surface epithelial cells (IOSE-144) was observed. Treatment with IVHD-valtrate arrested the ovarian cancer cells in the G2/M phase and induced apoptosis, and significantly suppressed the growth of A2780 and OVCAR3 xenograft tumors in a dose-dependent manner. The detailed in vitro and in vivo study on the molecular mechanisms of this compound demonstrated that IVHD-valtrate exposure modulated the expression of numerous molecules involved in cell cycle progression and apoptosis regardless of p53 status, leading to increase the level of p53, Rb, p21, p27 and decrease Mdm2, E2F1, Cyclin B1, Cdc25C and Cdc2. It also down-regulated Bcl-2/Bax and Bcl-2/Bad ratio and enhanced the cleavage of PARP and Caspases. Our preclinical results indicated IVHD-valtrate is a potential therapeutic agent for ovarian cancer, providing a basis for development of the compound as a novel chemotherapeutic agent.

Meta-analysis of vitamin D, calcium and the prevention of breast cancer.

Vitamin D and calcium intake have been suggested to have protective effects against breast cancer; however, the data have been inconclusive. The present meta-analysis examined the overall effects of vitamin D intake, circulating 25(OH)D and 1alpha,25(OH)(2)D levels, and calcium intake on breast cancer risk. Data from 11 studies on vitamin D intake, 7 studies on circulating 25(OH)D levels, 3 studies of circulating 1alpha,25(OH)(2)D levels, and 15 studies on calcium intake and breast cancer risk were included in this analysis. From the meta-analysis, there was a significant inverse relationship between vitamin D intake and breast cancer risk, with an overall relative risk (RR) of high versus low vitamin D intake for breast cancer of 0.91 (95% CI = 0.85-0.97). The highest quantile of circulating 25(OH)D was found to be associated with a 45% (OR = 0.55, 95% CI = 0.38-0.80) decrease in breast cancer when compared with the lowest quantile. No significant association for the circulating 1alpha,25(OH)(2)D level and breast cancer was found (OR = 0.99, 95% CI = 0.68-1.44). For calcium, a 19% (RR = 0.81, 95% CI = 0.72-0.90) decrease in breast cancer risk was found for those with highest quantile of calcium intake compared to the lowest quantile. These results provide strong evidence that vitamin D and calcium have a chemopreventive effect against breast cancer.

Structure-activity relationship and substrate-dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes.

Ginseng, a traditional herbal medicine, may interact with several co-administered drugs in clinical settings, and ginsenosides, the major active components of ginseng, may be responsible for these ginseng-drug interactions (GDIs). Results from previous studies on ginsenosides' effects on human drug-metabolizing P450 enzymes are inconsistent and confusing. Herein, we first evaluated the inhibitory effects of fifteen ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by using commercially available fluorescent probes. The structure-activity relationship of their effects on the P450s was also explored and a pharmacophore model was established for CYP3A4. Moreover, substrate-dependent phenomena were found in ginsenosides' effects on CYP3A4 when another fluorescent probe was used, and were further confirmed in tests with conventional drug probes and human liver microsomes. These substrate-dependent effects of the ginsenosides may provide an explanation for the inconsistent results obtained in previous GDI reports.