Ubiquitous regulation of cerebrovascular diseases by ubiquitin-modifying enzymes.

Cerebrovascular diseases (CVDs) are a major threat to global health. Elucidation of the molecular mechanisms underlying the pathology of CVDs is critical for the development of efficacious preventative and therapeutic approaches. Accumulating studies have highlighted the significance of ubiquitin-modifying enzymes (UMEs) in the regulation of CVDs. UMEs are a group of enzymes that orchestrate ubiquitination, a post-translational modification tightly involved in CVDs. Functionally, UMEs regulate multiple pathological processes in ischemic and hemorrhagic stroke, moyamoya disease, and atherosclerosis. Considering the important roles of UMEs in CVDs, they may become novel druggable targets for these diseases. Besides, techniques applying UMEs, such as proteolysis-targeting chimera and deubiquitinase-targeting chimera, may also revolutionize the therapy of CVDs in the future.

Identification of pleiotropic and specific therapeutic targets for cardio-cerebral diseases: A large-scale proteome-wide mendelian randomization and colocalization study.

BACKGROUND: The cardiac-brain connection has been identified as the basis for multiple cardio-cerebral diseases. However, effective therapeutic targets for these diseases are still limited. Therefore, this study aimed to identify pleiotropic and specific therapeutic targets for cardio-cerebral diseases using Mendelian randomization (MR) and colocalization analyses. METHODS: This study included two large protein quantitative trait loci studies with over 4,000 plasma proteins were included in the discovery and replication cohorts, respectively. We initially used MR to estimate the associations between protein and 20 cardio-cerebral diseases. Subsequently, Colocalization analysis was employed to enhance the credibility of the results. Protein target prioritization was based solely on including highly robust significant results from both the discovery and replication phases. Lastly, the Drug-Gene Interaction Database was utilized to investigate protein-gene-drug interactions further. RESULTS: A total of 46 target proteins for cardio-cerebral diseases were identified as robust in the discovery and replication phases by MR, comprising 7 pleiotropic therapeutic proteins and 39 specific target proteins. Followed by colocalization analysis and prioritization of evidence grades for target protein, 6 of these protein-disease pairs have achieved the highly recommended level. For instance, the PILRA protein presents a pleiotropic effect on sick sinus syndrome and Alzheimer's disease, whereas GRN exerts specific effects on the latter. APOL3, LRP4, and F11, on the other hand, have specific effects on cardiomyopathy and ischemic stroke, respectively. CONCLUSIONS: This study successfully identified important therapeutic targets for cardio-cerebral diseases, which benefits the development of preventive or therapeutic drugs.

Endotype-driven Co-module mechanisms of danhong injection in the Co-treatment of cardiovascular and cerebrovascular diseases: A modular-based drug and disease integrated analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiovascular and cerebrovascular diseases are the leading causes of death worldwide and interact closely with each other. Danhong Injection (DHI) is a widely used preparation for the co-treatment of brain and heart diseases (CTBH). However, the underlying molecular endotype mechanisms of DHI in the CTBH remain unclear. AIM OF THIS STUDY: To elucidate the underlying endotype mechanisms of DHI in the CTBH. MATERIALS AND METHODS: In this study, we proposed a modular-based disease and drug-integrated analysis (MDDIA) strategy for elucidating the systematic CTBH mechanisms of DHI using high-throughput transcriptome-wide sequencing datasets of DHI in the treatment of patients with stable angina pectoris (SAP) and cerebral infarction (CI). First, we identified drug-targeted modules of DHI and disease modules of SAP and CI based on the gene co-expression networks of DHI therapy and the protein-protein interaction networks of diseases. Moreover, module proximity-based topological analyses were applied to screen CTBH co-module pairs and driver genes of DHI. At the same time, the representative driver genes were validated via in vitro experiments on hypoxia/reoxygenation-related cardiomyocytes and neuronal cell lines of H9C2 and HT22. RESULTS: Seven drug-targeted modules of DHI and three disease modules of SAP and CI were identified by co-expression networks. Five modes of modular relationships between the drug and disease modules were distinguished by module proximity-based topological analyses. Moreover, 13 targeted module pairs and 17 driver genes associated with DHI in the CTBH were also screened. Finally, the representative driver genes AKT1, EDN1, and RHO were validated by in vitro experiments. CONCLUSIONS: This study, based on clinical sequencing data and modular topological analyses, integrated diseases and drug targets. The CTBH mechanism of DHI may involve the altered expression of certain driver genes (SRC, STAT3, EDN1, CYP1A1, RHO, RELA) through various enriched pathways, including the Wnt signaling pathway.

Research Progress in Pharmacological Effects and Mechanisms of Angelica sinensis against Cardiovascular and Cerebrovascular Diseases.

Angelica sinensis (Oliv.) Diels (A. sinensis) is a medicinal and edible values substance, which could promote blood circulation and enrich blood. It possesses rich chemical components and nutrients, which have significant therapeutic effects on cardiovascular and cerebrovascular diseases. It is commonly used for the prevention and treatment of cardiovascular and cerebrovascular diseases in the elderly, especially in improving ischemic damage to the heart and brain, protecting vascular cells, and regulating inflammatory reactions. This article reviews the main pharmacological effects and clinical research of A. sinensis on cardiovascular and cerebrovascular diseases in recent years, explores the effect of its chemical components on cardiovascular and cerebrovascular diseases by regulating the expression of functional proteins and inhibiting inflammation, anti-apoptosis, and antioxidant mechanisms. It provides a reference for further research on A. sinensis and the development of related drugs. It provides a new reference direction for the in-depth research and application of A. sinensis in the prevention, improvement, and treatment of cardiovascular and cerebrovascular diseases.

Construction of a screening system for lipid-derived radical inhibitors and validation of hit compounds to target retinal and cerebrovascular diseases.

Recent studies have highlighted the indispensable role of oxidized lipids in inflammatory responses, cell death, and disease pathogenesis. Consequently, inhibitors targeting oxidized lipids, particularly lipid-derived radicals critical in lipid peroxidation, which are known as radical-trapping antioxidants (RTAs), have been actively pursued. We focused our investigation on nitroxide compounds that have rapid second-order reaction rate constants for reaction with lipid-derived radicals. A novel screening system was developed by employing competitive reactions between library compounds and a newly developed profluorescence nitroxide probe with lipid-derived radicals to identify RTA compounds. A PubMed search of the top hit compounds revealed their wide application as repositioned drugs. Notably, the inhibitory efficacy of methyldopa, selected from these compounds, against retinal damage and bilateral common carotid artery stenosis was confirmed in animal models. These findings underscore the efficacy of our screening system and suggest that it is an effective approach for the discovery of RTA compounds.

Role of glucagon-like peptide-1 receptor agonists in the treatment of obesity, cardiovascular disease, and cerebrovascular disease.

Worldwide prevalence of obesity is increasing dramatically, imposing a significant economic burden on our society. Treatment of obesity is challenging, potentially due to different disease phenotypes. Taking into consideration "obesities" rather than "obesity," and thus aiming to understand different pathophysiologic mechanisms of individual phenotypes, might help identify more tailored treatment strategies. Glucagon­like peptide­1 receptor agonists (GLP­1RAs), for example, dulaglutide and semaglutide, are routinely prescribed for the treatment of type 2 diabetes mellitus (T2DM) in patients with obesity or those at a high cardiovascular (CV) risk. Indeed, despite having been developed for T2DM, GLP­1RAs are being increasingly often recognized as antiobesity medications due to their weight loss effects. Furthermore, recent evidence has shown that the extent of CV prevention offered by these drugs goes beyond that associated with their weight loss and pleiotropic effects. For instance, they exert anti­inflammatory effects on vessels, enhance atherosclerotic plaque stability, reduce local advanced glycation end product receptor expression, lower monocyte­macrophage adhesion, and antagonize the effect of angiotensin II. In the heart, GLP­1RAs ameliorate cardiomyocyte survival and myocardial contractility, reduce cardiac hypertrophy, and are one of few drugs that can reduce epicardial fat thickness. In this review, we summarize recent evidence concerning the effects of GLP­1RAs on obesity / dysmetabolism and on cardio- / cerebrovascular health. We further highlight the possible role of GLP­1RAs in the treatment of obesity­related CV diseases by describing the principal molecular mechanisms reported in the current literature.

Ethoxyquin, a Lipid Peroxidation Inhibitor, Has Protective Effects against White Matter Lesions in a Mouse Model of Chronic Cerebral Hypoperfusion.

White matter lesions induced by chronic cerebral hypoperfusion can cause vascular dementia; however, no appropriate treatments are currently available for these diseases. In this study, we investigated lipid peroxidation, which has recently been pointed out to be associated with cerebrovascular disease and vascular dementia, as a therapeutic target for chronic cerebral hypoperfusion. We used ethoxyquin, a lipid-soluble antioxidant, in a neuronal cell line and mouse model of the disease. The cytoprotective effect of ethoxyquin on glutamate-stimulated HT-22 cells, a mouse hippocampal cell line, was comparable to that of a ferroptosis inhibitor. In addition, the administration of ethoxyquin to bilateral common carotid artery stenosis model mice suppressed white matter lesions, blood-brain barrier disruption, and glial cell activation. Taken together, we propose that the inhibition of lipid peroxidation may be a useful therapeutic approach for chronic cerebrovascular disease and the resulting white matter lesions.

Protective mechanism of Paeonol on central nervous system.

Cerebrovascular diseases involve neuronal damage, resulting in degenerative neuropathy and posing a serious threat to human health. The discovery of effective drug components from natural plants and the study of their mechanism are a research idea different from chemical synthetic medicines. Paeonol is the main active component of traditional Chinese medicine Paeonia lactiflora Pall. It widely exists in many medicinal plants and has pharmacological effects such as anti-atherosclerosis, antiplatelet aggregation, anti-oxidation, and anti-inflammatory, which keeps generally used in the treatment of cardiovascular and cerebrovascular diseases. Based on the therapeutic effects of Paeonol for cardiovascular and cerebrovascular diseases, this article reviewed the pharmacological effects of Paeonol in Alzheimer's disease, Parkinson's disease, stroke, epilepsy, diabetes encephalopathy, and other neurological diseases, providing a reference for the research of the mechanism of Paeonol in central nervous system diseases.

[Features of pharmacotherapy of vascular cognitive impairment in the elderly]. / Osobennosti farmakoterapii sosudistykh kognitivnykh narushenii u lits pozhilogo vozrasta.

The problem of pharmacotherapy of elderly and senile people is currently extremely relevant due to the aging of the population and the increase in the prevalence of cardiovascular diseases. One of the most serious problems of the elderly is the development of cognitive decline due to cerebrovascular pathology. However, elderly patients often have a large number of comorbid diseases, which leads to difficulties in diagnosing and managing these patients, and often to the development of polypharmacy, which can lead to deterioration in functional status, cognitive impairment, adverse reactions and drug interactions. In addition, in elderly patients, there may be changes in pharmacokinetics and pharmacodynamics due to anatomical and physiological involutive processes. At the same time, the number of drugs whose clinical efficacy and tolerability were evaluated specifically in elderly and senile patients is relatively small. In a randomized clinical trial of sequential parenteral and oral therapy with Mexidol in patients with mild vascular cognitive impairment syndrome, a positive effect of this therapy on various domains (cognitive, emotional, autonomic, motor) of chronic cerebrovascular disease was confirmed compared with placebo, which allows us to recommend it for use in elderly and senile patients.

[Risk factors and adherence to treatment of patients with cerebrovascular diseases]. / Faktory riska i priverzhennost' lecheniyu patsientov s tserebrovaskulyarnymi zabolevaniyami.

OBJECTIVE: To assess the representation of risk factors and treatment adherence in patients with cerebrovascular diseases. MATERIAL AND METHODS: A single-stage cross-sectional non-comparable study was conducted, which included 492 patients, of whom 133 had an ischemic stroke/transient ischemic attack (main group, MG), 344 had chronic cerebrovascular pathology (comparison group, CG). The representation of risk factors, the state of cognitive functions, the severity of anxiety and depression were evaluated. RESULTS: MG respondents visit specialized specialists more often than CG (p<0.001), are more committed to taking antiplatelet agents (p<0.003), statins (p<0.005), antihypertensive drugs (p<0.005). Regular intake of antithrombotic drugs was associated with the history of ischemic stroke (r=0.483; p<0.01), type 2 diabetes (r=0.637; p<0.011), atrial fibrillation (r=0.481; p<0.001), living in a family (r=0.493; p<0.03). An inverse correlation was established between the systematic intake of antiplatelet drugs and the age of the respondents (r=-0.637; p<0.002), cognitive impairment (r=-0.433; p<0.05), the history of the gastrointestinal tract diseases (gastric ulcer and duodenal ulcer) (r=-0.563; p<0.001). Irregular medication intake was observed in patients aged over 60 years compared with younger (17.3% and 6.4%, respectively, p=0.001), patients living in a family compared with single (85.6% and 65.1%, p=0.032). The history of ischemic stroke or myocardial infarction is associated with increased adherence to regular medication. CONCLUSION: The study of risk factors and the assessment of treatment adherence can ensure the formation of an effective strategy for primary and secondary prevention of cerebrovascular diseases.

Genotype-guided dual antiplatelet therapy in cerebrovascular disease: assessing the risk and benefits for ethnic populations.

INTRODUCTION: Cerebrovascular disease is a leading cause of morbidity and mortality in the world and antiplatelet therapy is a main pharmacologic means of secondary prevention. Clinical information has accumulated about benefit of dual antiplatelet therapy in certain clinical scenarios, genetic causes of antiplatelet resistance and its effect on clinical outcomes, and ethnic and geographic distributions of genetic polymorphisms. AREAS COVERED: This review covers literature related to the pharmacogenomics of antiplatelet agents with a focus on ethnic variability, antiplatelet resistance, and dual antiplatelet therapy in cerebrovascular disease. EXPERT OPINION: Selecting patients for dual antiplatelet therapy and specific agents require consideration of multiple factors. Ethnic factors should be considered in certain circumstances, but additional research is needed to determine the generalizability of the findings.

Association Between Migraine and Ischemic Cardio-Cerebrovascular Disease (CCVD) and Effects of Triptans and Ergotamine on the Risk of Ischemic CCVD in Patients with Migraine in the Korean NHIS-HEALS Cohort.

BACKGROUND AND OBJECTIVES: Triptans and ergotamine are commonly used to treat migraine, a risk factor for ischemic stroke. This study aimed to investigate the association between migraine and ischemic cardio-cerebrovascular disease (CCVD). Further analyses were performed to examine whether symptom-relieving treatment of migraine with triptans and ergotamine reduces ischemic CCVD in migraineurs. METHODS: Participants from the Korean NHIS-HEALS cohort database were divided into patients reporting headache without migraine (HA), migraineurs who received at least one prescription for triptans or ergotamine (TE), and migraineurs who were prescribed neither triptans nor ergotamine (NTNE). Ischemic CCVDs comprised ischemic cerebrovascular diseases and cardiovascular diseases. Using cox proportional hazards regression models, primary and secondary analysis for risk of ischemic CCVDs was compared. RESULTS: Among 62,272 patients diagnosed with migraine or HA, men with migraine or HA numbered 14,747 and 8935, respectively, while the numbers of women were 27,836 and 10,754, respectively. The median follow-up was 6.65 years. The overall incidence rate of CCVDs was 4728/38,590 (12.25%) in females and 3158/23,682 (13.33%) in males. Compared with the HA group, the hazard ratios (HRs) (95% CIs) of the TE and NTNE groups for ischemic CCVDs were 1.18 (1.01-1.39) and 1.39 (1.28-1.50), respectively, in males, and 1.22 (1.09-1.37) and 1.53 (1.42-1.65), respectively, in females, after full adjustment for confounding variables. Compared with the NTNE group, the HRs (95% CIs) of the TE group for ischemic CCVDs were 0.86 (0.73-0.999) in males and 0.80 (0.72-0.88) in females. CONCLUSIONS: Migraine increased the risk of ischemic CCVDs in both sexes, and migraineurs treated with triptans and ergotamine were at lower risk of ischemic CCVDs than migraineurs who did not take those medications, especially in women.

[Efficacy of Mexidol in the correction of postcovid syndrome in patients with chronic cerebrovascular diseases]. / Effektivnost' preparata Meksidol v korrektsii postkovidnogo sindroma u patsientov s khronicheskimi tserebrovaskulyarnymi zabolevaniyami.

OBJECTIVE: To evaluate the effectiveness of sequential therapy with Mexidol and Mexidol FORTE 250 in the correction of postcovoid syndrome (PKS) in patients with chronic cerebrovascular diseases (CVD). MATERIAL AND METHODS: The analysis of the results of examination and treatment of 110 patients with CVD who underwent COVID-19 was carried out. Patients of the main group (OH, n=55) received Mexidol (5 ml IV drip for 14 days, followed by the transition to the tablet form of Mexidol FORTE 250 1 table 3 times/day for 2 months); 55 patients of the comparison group (GS) did not receive antioxidants. All patients included in the study were conducted MRI examination and extensive neuropsychological testing. RESULTS: There was a significant improvement in the state of cognitive functions, regression of symptoms of asthenia, improvement of night sleep in patients with OG. The differences were statistically significant both in comparison with the baseline level and the HS. CONCLUSION: The administration of the drug does not require age-related dose adjustment and is well combined with basic therapy. The recommended regimen for the use of Mexidol: 14 days of 5 ml i/v or i/m, then taking the drug Mexidol FORTE 250 at a dose of 1 table 3 times/day for 2 months.

VEGFA Isoforms as Pro-Angiogenic Therapeutics for Cerebrovascular Diseases.

Therapeutic angiogenesis has long been considered a viable treatment for vasculature disruptions, including cerebral vasculature diseases. One widely-discussed treatment method to increase angiogenesis is vascular endothelial growth factor (VEGF) A. In animal models, treatment with VEGFA proved beneficial, resulting in increased angiogenesis, increased neuronal density, and improved outcome. However, VEGFA administration in clinical trials has thus far failed to replicate the promising results seen in animal models. The lack of beneficial effects in humans and the difficulty in medicinal translation may be due in part to administration methods and VEGFA's ability to increase vascular permeability. One solution to mitigate the side effects of VEGFA may be found in the VEGFA isoforms. VEGFA is able to produce several different isoforms through alternative splicing. Each VEGFA isoform interacts differently with both the cellular components and the VEGF receptors. Because of the different biological effects elicited, VEGFA isoforms may hold promise as a tangible potential therapeutic for cerebrovascular diseases.

Disparities in PCSK9 Initiation Among US Veterans with Peripheral Arterial Disease or Cerebrovascular Disease.

BACKGROUND: Effective lipid lowering is essential in patients with peripheral arterial disease (PAD) and cerebrovascular disease (CeVD). Proprotein convertase subtilsin/kexin type 9 inhibitors (PCSK9i) efficiently lower low-density lipoprotein (LDL) levels; however, use in PAD and CeVD patients is limited. Therefore, our aim was to evaluate the use of PCSK9i among US Veterans and compare rates between patients with PAD, CeVD, and coronary artery disease (CAD). METHODS: We evaluated PCSK9i initiation (2016-2019) in US Veterans with CAD, PAD, or CeVD treated at 124 Veterans Affairs (VA) hospitals. We fit a hierarchical logistic regression model to evaluate the association of the patient's primary diagnosis, baseline low-density lipoprotein cholesterol (LDL-C) levels, socioeconomic indicators, and the Department of Veterans Affairs medical center enrollment with PCSK9i initiation. RESULTS: Of 519,566 patients with atherosclerotic vascular disease, 337,766 (65%), 79,926 (15%) and 101,874 (20%) had CAD, PAD, and CeVD, respectively. Among 2115/519,566 (0.4%) initiated on PCSK9i therapy, 84.3% had CAD, while only 7.2% and 8.5% had PAD and CeVD, respectively. Compared with CAD patients, PAD {odds ratio [OR] 0.50 (0.36-0.70)} and CeVD [OR 0.24 (0.15-0.37)] patients were less likely to receive PCSK9i. Relative to under $40K per year, PCSK9i initiation was higher if earning $40,000-$80,000 [OR 1.13 (1.01-1.27)] or > $80,000 [OR 1.41 (1.14-1.75)]. Even moderate community deprivation [OR 0.87 (0.77-0.97)] was associated with lower PCSK9i therapy. CONCLUSIONS: Adjusted for LDL-C levels, PAD and CeVD patients are much less likely to receive PCSK9i therapy. Despite low co-pay, PCSK9i initiation rates among US veterans, nationwide, is low, with household income and community deprivation appearing to predict PCSK9i use.

Comparison between clevidipine and nicardipine in cerebrovascular diseases: A systematic review and meta-analysis.

PURPOSE: The term "cerebrovascular diseases (CVDs)" refers to a broad category of diseases that affect the brain's blood vessels and cerebral circulation. Controlling acute hypertension (HTN) by antihypertensive drugs such as clevidipine and nicardipine can be a highly efficient method of lowering the incidence of CVDs. METHODS: This is a systematic review and meta-analysis study. The PubMed, Scopus, and Web of Science online databases and a gray literature search were performed to identify potentially eligible studies. The included studies were observational studies that compared adult patients receiving clevidipine or nicardipine for controlling HTN in the setting of CVD. RESULTS: We reviewed 5 final included articles, including 546 patients. The pooled standardized mean difference (SMD) for time to goal SBP was - 0.04 (95 % CI: [-0.66; 0.58], p-value: 0.86, I2: 79.0 %, pooled MD: -12.90 min), meaning that the clevidipine group had a shorter time to goal systolic blood pressure (SBP) than the nicardipine group. The pooled SMD for total volume infusion was - 0.52 (95 % CI: [-0.93; -0.12], p-value: 0.03, I2: 0.0 %, pooled MD: -1118.81 mL), showing a notably lower total volume infused into patients in the clevidipine group. CONCLUSIONS: We found that clevidipine reaches the SBP goal faster than nicardipine; however, there was no statistically significant difference between the two drugs. The total volume infused to achieve the goal SBP was significantly lower in the clevidipine group. Further prospective studies are needed to compare clevidipine and nicardipine in CVD patients on a large scale.

How low should blood pressure be in patients with chronic coronary and cerebrovascular diseases.

Over the last three decades, there are an increasing number of investigators and meta-analyses focusing on the fact that lowering blood pressure levels below a critical point is no longer beneficial and possibly even deleterious. In recent years, several trials and meta-analyses assessing intensive blood pressure (BP) lowering found that intensive treatment and lower blood pressure levels are associated with a reduction in CV events and mortality. However, a careful examination of the results shows that current data are not easily applicable to the general hypertensive population. In addition, recommendations of different guidelines since 2017 so far suggest different BP levels regarding the systolic and diastolic thresholds to be achieved and maintained, particularly in specific clinical situations such as patients with coronary artery disease and stroke. The challenge is to better define the limits of intervention and to define phenotypes of patients who are particularly vulnerable to over-aggressive lowering of blood pressure. This article reviews the evidence, controversies and current state of knowledge regarding intensive BP lowering and the lower thresholds of BP to be achieved in patients with chronic coronary or cerebrovascular diseases.

Xanthine oxidase mediates chronic stress-induced cerebrovascular dysfunction and cognitive impairment.

Xanthine oxidase (XO) mediates vascular function. Chronic stress impairs cerebrovascular function and increases the risk of stroke and cognitive decline. Our study determined the role of XO on stress-induced cerebrovascular dysfunction and cognitive decline. We measured middle cerebral artery (MCA) function, free radical formation, and working memory in 6-month-old C57BL/6 mice who underwent 8 weeks of control conditions or unpredictable chronic mild stress (UCMS) with or without febuxostat (50 mg/L), a XO inhibitor. UCMS mice had an impaired MCA dilation to acetylcholine vs. controls (p < 0.0001), and increased total free radical formation, XOR protein levels, and hydrogen peroxide production in the liver compared to controls. UCMS increased hydrogen peroxide production in the brain and cerebrovasculature compared to controls. Working memory, using the y-maze test, was impaired (p < 0.05) in UCMS mice compared to control mice. However, blocking XO using febuxostat prevented the UCMS-induced impaired MCA response, while free radical production and hydrogen peroxide levels were similar to controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory. These data suggest that the cerebrovascular dysfunction associated with chronic stress may be driven by XO, which leads to a reduction in working memory.

Vitamin D as therapeutic modulator in cerebrovascular diseases: a mechanistic perspectives.

Vitamin D deficiency has been linked to several major chronic diseases, such as cardiovascular and neurodegenerative diseases, diabetes, and cancer, linked to oxidative stress, inflammation, and aging. Vitamin D deficiency appears to be particularly harmful to the cardiovascular system, as it can cause endothelial dysfunctioning and vascular abnormalities through the modulation of various downstream mechanisms. As a result, new research indicates that therapeutic approaches targeting vitamin D inadequacies or its significant downstream effects, such as impaired autophagy, abnormal pro-inflammatory and pro-oxidant reactions, may delay the onset and severity of major cerebrovascular disorders such as stroke and neurologic malformations. Vitamin D modulates the various molecular pathways, i.e., Nitric Oxide, PI3K-Akt Pathway, cAMP pathway, NF-kB Pathway, Sirtuin 1, Nrf2, FOXO, in cerebrovascular disorder. The current review shows evidence for vitamin D's mitigating or slowing the progression of these cerebrovascular disorders, which are significant causes of disability and death worldwide.

Nanozyme-Enabled Treatment of Cardio- and Cerebrovascular Diseases.

Cardio- and cerebrovascular diseases are two major vascular-related diseases that lead to death worldwide. Reactive oxygen species (ROS) play a vital role in the occurrence and exacerbation of diseases. Excessive ROS induce cellular context damage and lead to tissue dysfunction. Nanozymes, as emerging enzyme mimics, offer a unique perspective for therapy through multifunctional activities, achieving essential results in the treatment of ROS-related cardio- and cerebrovascular diseases by directly scavenging excess ROS or regulating pathologically related molecules. This review first introduces nanozyme-enabled therapeutic mechanisms at the cellular level. Then, the therapies for several typical cardio- and cerebrovascular diseases with nanozymes are discussed, mainly including cardiovascular diseases, ischemia reperfusion injury, and neurological disorders. Finally, the challenges and outlooks for the application of nanozymes are also presented. This review will provide some instructive perspectives on nanozymes and promote the development of enzyme-mimicking strategies in cardio- and cerebrovascular disease therapy.