Rutaecarpine, an Alkaloid from Evodia rutaecarpa, Can Prevent Platelet Activation in Humans and Reduce Microvascular Thrombosis in Mice: Crucial Role of the PI3K/Akt/GSK3ß Signal Axis through a Cyclic Nucleotides/VASP-Independent Mechanism.

The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1-5 µM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca2+]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3ß (GSK3ß) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3ß pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.

Coffeeberry Activates the CaMKII/CREB/BDNF Pathway, Normalizes Autophagy and Apoptosis Signaling in Nonalcoholic Fatty Liver Rodent Model.

Nonalcoholic fatty liver disease (NAFLD) shows extensive liver cell destruction with lipid accumulation, which is frequently accompanied by metabolic comorbidities and increases mortality. This study aimed to investigate the effects of coffeeberry (CB) on regulating the redox status, the CaMKII/CREB/BDNF pathway, autophagy, and apoptosis signaling by a NAFLD rodent model senescence-accelerated mice prone 8 (SAMP8). Three-month-old male SAMP8 mice were divided into a control group and three CB groups (50, 100, and 200 mg/kg BW), and fed for 12 weeks. The results show that CB reduced hepatic malondialdehyde and carbonyl protein levels. CB significantly enhanced Ca2+/calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) and reduced the phospho-cAMP response element-binding protein (p-CREB)/CREB ratio. In addition, CB increased the silent information regulator T1 level, promoted Beclin 1 and microtubule-associated protein light chain 3 II expressions, and reduced phosphorylated mammalian target of rapamycin and its downstream p-p70s6k levels. CB also inhibited the expressions of apoptosis-related factors poly (ADP-ribose) polymerase-1 and the apoptosis-inducing factor. In conclusion, CB might protect the liver by reducing oxidative stress, activating the CaMKII/CREB/BDNF pathway, and improving autophagic and apoptotic expressions in a dose-dependent manner.

Vitamin D supplementation and the outcomes of critically ill adult patients: a systematic review and meta-analysis of randomized controlled trials.

This meta-analysis assessed the association between vitamin D supplementation and the outcomes of critically ill adult patients. A literature search was conducted using the PubMed, Web of Science, EBSCO, Cochrane Library, Ovid MEDLINE, and Embase databases until March 21, 2020. We only included randomized controlled trials (RCTs) comparing the efficacy of vitamin D supplementation with placebo in critically ill adult patients. The primary outcome was their 28-day mortality. Overall, 9 RCTs with 1867 patients were included. In the pooled analysis of the 9 RCTs, no significant difference was observed in 28-day mortality between the vitamin D supplementation and placebo groups (20.4% vs 21.7%, OR, 0.73; 95% CI, 0.46-1.15; I2 = 51%). This result did not change as per the method of vitamin D supplementation (enteral route only: 19.9% vs 18.2%, OR, 1.19; 95% CI, 0.88-1.57; I2 = 10%; intramuscular or intravenous injection route: 25.6% vs 40.8%, OR, 0.48; 95% CI, 0.21-1.06; I2 = 19%) or daily dose (high dose: 20.9% vs 19.8%, OR, 0.83; 95% CI, 0.51-1.36; I2 = 53%; low dose: 15.6% vs 21.3%, OR, 0.74; 95% CI, 0.32-1.68; I2 = 0%). No significant difference was observed between the vitamin D supplementation and placebo groups regarding the length of ICU stay (standard mean difference [SMD], - 0.30; 95% CI, - 0.61 to 0.01; I2 = 60%), length of hospital stay (SMD, - 0.17; 95% CI, - 041 to 0.08; I2 = 65%), and duration of mechanical ventilation (SMD, - 0.41; 95% CI, - 081 to 0.00; I2 = 72%). In conclusion, this meta-analysis suggested that the administration of vitamin D did not provide additional advantages over placebo for critically ill patients. However, additional studies are needed to confirm our findings.

Traditional Chinese medicine perspective on constitution transformations in perinatal women: A prospective longitudinal study.

BACKGROUND: Pregnancy is an important stage in life for many women. Humans are complex organisms that are prone to exhibiting gradual alterations in their constitutions that fluctuate with age, diet, and living environment. This is particularly true during the pre- and postnatal periods, in which qi and blood are required to ensure foetal growth. AIM: To examine women's constitutional transformation of pre-pregnancy, pregnancy, and postpartum. METHODS: A prospective, longitudinal study was conducted, and structural questionnaires were used to collect data. The participants were healthy pregnant women 21-49 years of age. Data were collected at six times: during the first (weeks 6-13), second (weeks 14-27), and third (weeks 28-40) trimesters and during the postnatal admission (1-week postnatal) and home self-care (6-week and 6-month postnatal) periods, yielding 86 valid questionnaires. A cubic polynomial regression analyses with generalised estimation equations (GEEs) method was used to reveal the trend of constitution score by different constitutions. FINDINGS: Significant differences (p < .0001) for the scores of Yang-Xu (yang-deficiency), Yin-Xu (yin-deficiency), and Tan-Shi-Yu-Zhi (phlegm-dampness and blood-stasis) constitutions were observed at pre-pregnancy, pregnancy, and 6 months postpartum. A least significant difference test showed that the scores obtained in the pregnancy period and at 6 months postpartum were higher than those of pre-pregnancy, indicating mitigated constitutional imbalance during postpartum. The highest scores of the Yang-Xu and Tan-Shi-Yu-Zhi constitutions occurred in the first trimester (36.02 ± 8.00 vs. 30.00 ± 7.21), and the highest scores of Yin-Xu constitution occurred in the third trimester (32.95 ± 7.48). The lowest scores of the Yang-Xu constitution were obtained at 6 months postpartum (25.24 ± 5.63) and during pre-pregnancy (25.26 ± 4.82), and those of the Yin-Xu and Tan-Shi-Yu-Zhi constitutions were observed in the pre-pregnancy (25.48 ± 4.46 vs. 19.94 ± 3.09). The 6-month postnatal scores of the Yang-Xu constitution nearly recovered to the prenatal level, whereas those of the other two constitutions did not. CONCLUSION: The results indicate that women's constitutions underwent changes throughout the perinatal stages. These findings provide a valuable reference for healthcare professionals in administering perinatal care and demonstrate empirical evidence for use in future intervention-based research.