Vitamin D and ischemic stroke - Association, mechanisms, and therapeutics.

Confronting the rising tide of ischemic stroke and its associated mortality and morbidity with ageing, prevention and acute management of ischemic stroke is of paramount importance. Mounting observational studies have established a non-linear association of vitamin D status with cardiovascular diseases, including ischemic stroke. Paradoxically, current clinical trials fail to demonstrate the cardiovascular benefits of vitamin D supplementation. We aim to update recent clinical and experimental findings on the role of vitamin D in the disease course of ischemic stroke, from its onset, progression, recovery, to recurrence, and the established and alternative possible pathophysiological mechanisms. This review justifies the necessities to address stroke etiological subtypes and focus on vitamin D-deficient subjects for investigating the potential of vitamin D supplementation as a preventive and therapeutic approach for ischemic stroke. Well-powered clinical trials are warranted to determine the efficacy, safety, timing, target individuals, optimal dosages, and target 25OHD concentrations of vitamin D supplementation in the prevention and treatment of ischemic stroke.

Higher Circulating Vitamin D Levels Are Associated With Decreased Migraine Risk: A Mendelian Randomization Study.

Background: Evidence showed the supplementation of vitamin D might have beneficial effects for migraine patients. We aimed to investigate the causal effects of serum vitamin D levels on migraine risk using two-sample Mendelian randomization (MR) method. Methods: A total of 184 independent genetic instruments for serum vitamin D levels were selected from a study in 417,580 Europeans from UK biobank. Six variants from an independent study were obtained to perform replication analysis. Summary-level data for migraine were obtained from three studies with 48,975 migraine cases, 28,852 migraine cases and 10,536 migraine cases, respectively. Results: The estimated odds ratios (ORs) per standard deviation increase in circulating vitamin D levels based on the three migraine datasets were 0.948 (95% CI = 0.883-1.016, p = 0.133), 0.902 (95% confidence intervals [CI] = 0.825-0.986, p = 0.023), and 0.880 (95% CI = 0.786-0.984, p = 0.025), respectively. Using pooled migraine summary data with no sample overlap, MR analysis showed per standard deviation increase in circulating vitamin D levels was significantly associated with a decreased migraine risk (OR = 0.916, 95% CI = 0.859-0.977, p = 0.008). Multivariable MR analyses, sensitivity analyses and replication analysis confirmed the association. MR analyses showed similar estimates for migraine with aura and migraine without aura but with wider 95% CIs. Mediation analysis showed the effect of vitamin D on migraine risk via pathway of serum calcium was corresponding to an OR of 1.003 (95% CI = 1.001-1.005) and a proportion mediated of 3.42%. The reverse MR analysis showed migraine might not affect vitamin D levels. Conclusion: This two-sample MR study showed genetically determined increased circulating vitamin D levels are associated with decreased migraine risk. The effect seems consistent across different migraine subtypes. In addition, the role of serum calcium in mediating the association between vitamin D and migraine is negligible. Future large well-designed randomized trials are warranted to assess the effects of vitamin D supplementation for migraine patients, especially in those with vitamin D deficiency.

A Bidirectional Mendelian Randomization Study of Selenium Levels and Ischemic Stroke.

Background: Previous observational studies have shown that circulating selenium levels are inversely associated with ischemic stroke (IS). Our aims were to evaluate the causal links between selenium levels and IS, and its subtypes by Mendelian randomization (MR) analysis. Methods: We used the two-sample Mendelian randomization (MR) method to determine whether the circulating selenium levels are causally associated with the risk of stroke. We extracted the genetic variants (SNPs) associated with blood and toenail selenium levels from a large genome-wide association study (GWAS) meta-analysis. Inverse variance-weighted (IVW) method was used as the determinant of the causal effects of exposures on outcomes. Results: A total of 4 SNPs (rs921943, rs6859667, rs6586282, and rs1789953) significantly associated with selenium levels were obtained. The results indicated no causal effects of selenium levels on ischemic stroke by MR analysis (OR = 0.968, 95% CI 0.914-1.026, p = 0.269). Meanwhile, there was no evidence of a causal link between circulating selenium levels and subtypes of IS. Conclusion: The MR study indicated no evidence to support the causal links between genetically predicted selenium levels and IS. Our results also did not support the use of selenium supplementation for IS prevention at the genetic level.

Effectiveness of Traditional Chinese Health-Promoting Exercise as an Adjunct Therapy for Drug Use Disorders: A Systematic Review and Meta-Analysis.

Objective: Meta-analysis was used to quantitatively examine the effectiveness of Traditional Chinese Health-Promoting Exercise (TCE) as an adjuvant therapy for drug use disorders and rehabilitation based on previously published studies. Methods: Potential literature was retrieved by searching eight electronic databases (China National Knowledge Infrastructure [CNKI], Wanfang, Chinese Scientific Journal Database, China Biology Medicine [CBM], PubMed, Embase, Cochrane Library, and EBSCOhost) from January 2000 to May 2021, as well as through manual searches, including email. These literature reports comprised randomized, controlled trial studies and nonrandomized, controlled trial studies assessing the effects of TCE intervention on the physical and psychological (mental) health of drug addicts. The quality and bias risk of each study were assessed using the Cochrane bias risk assessment tool. The RevMan5.3 statistical software was employed to evaluate the methodological quality of the included studies, and sensitivity and subgroup analyses using the Stata16.0 MP software were performed to explore the sources of heterogeneity among the data. This study is registered on PROSPERO (CRD42021254124). Results: Data from 14 studies (1094 individuals with drug abuse) meeting the inclusion criteria were extracted for meta-analysis. Compared to the control group, TCE intervention induced significant improvements in the systolic blood pressure (standardized mean difference [SMD] = -0.42, p < 0.05), diastolic blood pressure (SMD = -0.34, p < 0.05), one-leg stand with eyes closed (SMD = 0.74, p < 0.05), Symptom Check List (SMD = -0.42, p < 0.05), anxiety scale (self-rating anxiety scale/STI) (SMD = -0.49, p < 0.05), and depression scale (self-rating depression scale/Beck Depression Inventory/Hamilton Depression Rating Scale for Depression) (SMD = -0.37, p < 0.05). Sensitivity and subgroup analyses of the individual outcome indicators with high heterogeneity (I2 ≥ 50%, p < 0.10) were performed to further explore the source of heterogeneity. The results of the sensitivity analysis showed that, after removing studies one by one, the heterogeneity of the data remained high (I2 > 50), and the difference of synthetic overall effect did not change (p < 0.05), indicating that the sensitivity was low and that the results were robust and reliable. The results of the subgroup analysis results indicated that the gender of the participants and the drug type were the sources of heterogeneity. Conclusion: As an effective mind-body movement intervention, long-term TCE is beneficial to improving the physical and mental health of drug addicts. The specific intervention methods are dependent on the gender of the addict and the drug type, and longer intervention times yielded greater impacts on their physical health.

Matrine Treatment Blocks NogoA-Induced Neural Inhibitory Signaling Pathway in Ongoing Experimental Autoimmune Encephalomyelitis.

Myelin-associated inhibitors, such as NogoA, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp), play a pivotal role in the lack of neuroregeneration in multiple sclerosis, an inflammatory demyelinating disease of the central nervous system (CNS). Matrine (MAT), a monomer that is used in traditional Chinese medicine as an anti-inflammatory agent, has shown beneficial effects in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, the underlying mechanisms of MAT-induced EAE amelioration are not fully understood. In the present study, we show that MAT treatment suppressed ongoing EAE, and this effect correlated with an increased expression of growth-associated protein 43, an established marker for axonal regeneration. MAT treatment significantly reduced the levels of NogoA, its receptor complex NgR/p75NTR/LINGO-1, and their downstream RhoA/ROCK signaling pathway in the CNS. In contrast, intracellular cyclic AMP (cAMP) levels and its protein kinase (protein kinase A (PKA)), which can promote axonal regrowth by inactivating the RhoA, were upregulated. Importantly, adding MAT in primary astrocytes in vitro largely induced cAMP/PKA expression, and blockade of cAMP significantly diminished MAT-induced expression of PKA and production of BDNF, a potent neurotrophic factor for neuroregeneration. Taken together, our findings demonstrate that the beneficial effects of MAT on EAE can be attributed not only to its capacity for immunomodulation, but also to its directly promoting regeneration of the injured CNS.

Protective effects of matrine on experimental autoimmune encephalomyelitis via regulation of ProNGF and NGF signaling.

Inflammation, demyelination, oligodendrocyte (OLG) death, and axonal degeneration are primary characteristics of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). OLGs generate myelin sheaths that surround axons, while damage to OLGs leads to demyelination and neurological functional deficit. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to effectively ameliorate clinical signs in EAE. Its therapeutic mechanism has, however, not been completely elucidated. In the present study, we found that MAT retarded the disease process, attenuated the clinical severity of EAE rats, ameliorated inflammation and demyelination, and suppressed the apoptosis of OLGs in the central nervous system (CNS) of EAE rats. In addition, MAT markedly blocked increased expression of the proNGF-p75(NTR) death signaling complex, which is known to mediate OLG death in EAE animals. At the same time, MAT also prevented a decrease in the levels of NGF and its receptor TrkA, which together mediate the cell survival pathway and differentiation of OLGs. ProNGF, NGF, and the downstream effector proteins play an important role in the growth, differentiation, and apoptosis of OLGs as well as the reparative response to neuronal damage. These findings thus indicate that MAT improves clinical severity of EAE in part by reducing OLG apoptosis via restoring the ratios of proNGF:NGF and the respective receptors p75(NTR):TrkA in vivo. Taken together, these results suggest that MAT may be a promising agent for MS treatment based on its protective effect on OLGs.

Calcium intake and the risk of stroke: an up-dated meta-analysis of prospective studies.

BACKGROUND AND PURPOSE: Calcium intake has been associated with stroke risk in a prior meta-analysis, however, newly published results are inconsistent. Dairy food benefits on stroke incidence may involve a calcium-related mechanism. We have therefore updated this meta-analysis with particular references to any possibility of a calcium-mediated dairy food risk reduction of stroke risk. METHODS: We searched multiple databases and bibliographies for prospective cohort studies. Reports with multivariate-adjusted relative risk (RR) and corresponding 95% confidence intervals (CI) for the association of calcium intake with stroke incidence were considered. RESULTS: Ten studies with 371,495 participants and 10,408 stroke events were analyzed. The pooled analysis showed no statistically significant association of the risk of total stroke (RR=0.96; 95% CI: 0.89-1.04) and stroke subtypes with the highest and lowest calcium intake quantiles. Nevertheless, high dairy calcium intake was significantly associated with an approximately 24% reduction of stroke risk. (RR=0.76; 95% CI: 0.66-0.86). Furthermore, a long-term follow-up (>=14 years) was helpful to reduce the risk of stroke (RR=0.67; 95% CI: 0.51-0.88). Additionally, a non-linear dose-response relationship was predicted between calcium intake and stroke risk. CONCLUSIONS: Dairy calcium intake is inversely associated with stroke incidence. There is a non-linear dose-response relationship between calcium intake and stroke risk. However, when the follow-up time is long enough, the inverse relationship is independent of dose. Additional large cohort studies are required to illustrate this relationship in detail.

Matrine protects neuro-axon from CNS inflammation-induced injury.

Neuro-axonal injury in the central nervous system (CNS) is one of the major pathological hallmarks of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has recently been shown to effectively suppress EAE through an anti-inflammatory mechanism. However, whether MAT can also protect myelin/axons from damage is not known. In the present study we show that, while untreated rats developed severe clinical disease, CNS inflammatory demyelination, and axonal damage, these clinical and pathological signs were significantly reduced by MAT treatment. Consistently, MAT treatment reduced the concentration of myelin basic protein in serum and downregulated expression of ß-amyloid (Aß) and B-site APP cleaving enzyme 1 (BACE-1) in the CNS. Further, the CNS of MAT-treated rats exhibited increased expression of brain-derived neurotrophic factor (BDNF), an important factor for neuronal survival and axonal growth. Together, these results demonstrate that MAT effectively prevented neuro-axonal injury, which can likely be attributed to inhibiting risk factors such as BACE-1 and upregulating neuroprotective factors such as BDNF. We conclude that this novel natural reagent, MAT, which effectively protects neuro-axons from CNS inflammation-induced damage, could be a potential candidate for the treatment of neurodegenerative diseases such as MS.

Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: a meta-analysis.

OBJECTIVE: To perform a meta-analysis on the effect of lowering homocysteine levels via B vitamin supplementation on cerebrovascular disease risk. METHODS: Using clinical trials published before August 2012 to assess stroke events, we used relative risks (RRs) with 95% confidence intervals (95% CIs) to measure the association between B vitamin supplementation and endpoint events using a fixed-effects model and χ(2) tests. We included 14 randomized controlled trials with 54,913 participants in this analysis. RESULTS: We observed a reduction in overall stroke events resulting from reduction in homocysteine levels following B vitamin supplementation (RR 0.93; 95% CI 0.86-1.00; p = 0.04) but not in subgroups divided according to primary or secondary prevention measures, ischemic vs hemorrhagic stroke, or occurrence of fatal stroke. There were beneficial effects in reducing stroke events in subgroups with ≥3 years follow-up time, and without background of cereal folate fortification or chronic kidney disease (CKD). Some trials that included CKD patients reported decreased glomerular filtration rate with B vitamin supplementation. We conducted detailed subgroup analyses for cyanocobalamin (vitamin B12) but did not find a significant benefit regarding intervention dose of vitamin B12 or baseline blood B12 concentration. Stratified analysis for blood pressure and baseline participant medication use showed benefits with >130 mm Hg systolic blood pressure and lower antiplatelet drug use in reducing stroke risk. CONCLUSIONS: B vitamin supplementation for homocysteine reduction significantly reduced stroke events, especially in subjects with certain characteristics who received appropriate intervention measures.