Apigenin protects against ischemic stroke by increasing DNA repair.

Background and Objective: Oxidative stress is an important pathological process in ischemic stroke (IS). Apigenin (APG) is a natural product with favorable antioxidative effects, and some studies have already demonstrated the antioxidative mechanism of APG in the treatment of IS. However, the mechanism of APG on DNA damage and repair after IS is not clear. The aim of this study was to investigate the mechanism of APG on DNA repair after IS. Methods: Male Sprague-Dawley rats were used to establish a model of permanent middle cerebral artery occlusion (pMCAO) on one side, and were pre-treated with gavage of APG (30, 60, or 120 mg/kg) for 7 days. One day after pMCAO, the brain tissues were collected. Cerebral infarct volume, brain water content, HE staining and antioxidant index were analyzed to evaluated the brain damage. Molecular Docking, molecular dynamics (MD) simulation, immunohistochemistry, and Western blot were used to explore the potential proteins related to DNA damage repair. Results: APG has a low binding score with DNA repair-related proteins. APG treatment has improved the volume of cerebral infarction and neurological deficits, reduced brain edema, and decreased parthanatos and apoptosis by inhibiting PARP1/AIF pathway. In addition, APG improved the antioxidative capacity through reducing reactive oxygen species and malondialdehyde, and increasing glutathione and superoxide dismutase. Also, APG has reduced DNA damage- and cell death-related proteins such as PARP1, γH2A.X, 53BP1, AIF, cleaved caspase3, Cytochrome c, and increased DNA repair by BRCA1 and RAD51 through homologous recombination repair, and reduced non-homologous end link repair by KU70. Conclusion: APG can improve nerve damage after IS, and these protective effects were realized by reducing oxidative stress and DNA damage, and improving DNA repair.

Efficacy and safety of auricular therapy in the treatment of post-stroke constipation: A protocol for systematic review and meta-analysis.

BACKGROUND: Constipation is one of the common gastrointestinal complications after stroke. It not only aggravates the condition of stroke, but also brings huge medical burden to patients, and has a negative impact on the quality of life of patients. Auricular therapy, as a part of Chinese traditional acupuncture and moxibustion, has been found to be effective in the clinical treatment of constipation. However, no systematic review has investigated the efficacy and safety of auricular therapy in the treatment of post-stroke constipation. Therefore, the aim of this systematic review is to assess the effectiveness and safety of auricular therapy for post-stroke constipation. METHODS AND ANALYSIS: Eight electronic databases including PubMed, Cochrane Library/Cochrane Central Register of Controlled Trials, Web of Science, Embase, China National Knowledge Internet, Chinese Biomedical Literature Database, Wanfang, and VIP databases, will be searched for relevant studies published from inception to February 2023. Two reviewers will independently conduct research selection, data extraction, and evaluation of research quality. Only randomized controlled trials (RCTs) that assess the efficacy and safety of auricular therapy for the treatment of post-stroke constipation will be included in this study. We will use the Cochrane risk of bias assessment tool to evaluate the methodological qualities (including bias risk). If possible, a meta-analysis will be performed after screening. RESULTS: This study may provide high-quality evidence for the efficacy and safety of auricular therapy in treating post-stroke constipation. CONCLUSION: The conclusions of our study will provide an evidence to judge whether auricular therapy is an effective and safe intervention for patients with post-stroke constipation. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study was based on a review of published research. This review will be published in a peer-reviewed journal and disseminated electronically and in print. TRIAL REGISTRATION: Registration number: PROSPERO CRD42023402242.

Reliability, validity, and responsiveness of a smartphone-based manikin to support pain self-reporting.

Introduction: Many people worldwide suffer from chronic pain. Improving our knowledge on chronic pain prevalence and management requires methods to collect pain self-reports in large populations. Smartphone-based tools could aid data collection by allowing people to use their own device, but the measurement properties of such tools are largely unknown. Objectives: To assess the reliability, validity, and responsiveness of a smartphone-based manikin to support pain self-reporting. Methods: We recruited people with fibromyalgia, rheumatoid arthritis, and/or osteoarthritis and access to a smartphone and the internet. Data collection included the Global Pain Scale at baseline and follow-up, and 30 daily pain drawings completed on a 2-dimensional, gender-neutral manikin. After deriving participants' pain extent from their manikin drawings, we evaluated convergent and discriminative validity, test-retest reliability, and responsiveness and assessed findings against internationally agreed criteria for good measurement properties. Results: We recruited 131 people; 104 were included in the full sample, submitting 2185 unique pain drawings. Manikin-derived pain extent had excellent test-retest reliability (intraclass correlation coefficient, 0.94), moderate convergent validity (ρ, 0.46), and an ability to distinguish fibromyalgia and osteoarthritis from rheumatoid arthritis (F statistics, 30.41 and 14.36, respectively; P < 0.001). Responsiveness was poor (ρ, 0.2; P, 0.06) and did not meet the respective criterion for good measurement properties. Conclusion: Our findings suggest that smartphone-based manikins can be a reliable and valid method for pain self-reporting, but that further research is warranted to explore, enhance, and confirm the ability of such manikins to detect a change in pain over time.

Identification of immune and Toll-like receptor signaling pathway related feature lncRNAs to construct diagnostic nomograms for acute ischemic stroke.

We aimed to identify the immune and Toll-like receptor (TLR) signaling pathway related feature lncRNAs to construct the diagnostic nomograms for acute ischemic stroke (AIS). Two AIS-associated expression profiles GSE16561 and GSE22255 were downloaded from NCBI Gene Expression Omnibus, the former was the training set and the latter was the validation set. The differential expression genes (DEGs) and lncRNAs (DElncRNAs) related to TLR signaling pathway were identified between AIS and control groups. The single sample gene set enrichment analysis (ssGSEA) was applied to evaluate the immune infiltration. The immune and TLR signaling pathway related DElncRNAs were determined. Three optimization algorithms were utilized to select the immune and TLR signaling pathway related feature lncRNAs to construct the diagnostic nomograms of AIS. Based on the lncRNA signature, a ceRNA network was constructed. 37 DEGs and 28 DElncRNAs related to TLR signaling pathway were identified in GSE16561. 16 immune cell types exhibited significant differences in distribution between AIS and control groups. 28 immune and TLR signaling pathway related DElncRNAs were determined. 8 immune and TLR signaling pathway related feature lncRNAs were selected. The diagnostic nomograms of AIS performed well in both datasets. A ceRNA network was constructed consisting of 7 immune and TLR signaling pathway related feature lncRNAs as well as 19 AIS related miRNAs and 21 TLR signaling pathway related genes. LINC00173, LINC01089, LINC02210, MIR600HG, SNHG14, TP73-AS1, LINC00680 and CASC2 may be the potential biomarkers of AIS diagnosis, and TLR signaling pathway may be a promising immune related therapeutic target for AIS.

Clarifying the mechanism of apigenin against blood-brain barrier disruption in ischemic stroke using systems pharmacology.

Currently, recombinant tissue plasminogen activator (rtPA) is an effective therapy for ischemic stroke (IS). However, blood-brain barrier (BBB) disruption is a serious side effect of rtPA therapy and may lead to patients' death. The natural polyphenol apigenin has a good therapeutic effect on IS. Apigenin has potential BBB protection, but the mechanism by which it protects the BBB integrity is not clear. In this study, we used network pharmacology, bioinformatics, molecular docking and molecular dynamics simulation to reveal the mechanisms by which apigenin protects the BBB. Among the 146 targets of apigenin for the treatment of IS, 20 proteins were identified as core targets (e.g., MMP-9, TLR4, STAT3). Apigenin protects BBB integrity by inhibiting the activity of MMPs through anti-inflammation and anti-oxidative stress. These mechanisms included JAK/STAT, the toll-like receptor signaling pathway, and Nitrogen metabolism signaling pathways. The findings of this study contribute to a more comprehensive understanding of the mechanism of apigenin in the treatment of BBB disruption and provide ideas for the development of drugs to treat IS.

Efficacy and safety of blood-activating herbs combined with edaravone in the treatment of acute ischemic stroke: A protocol for systematic review and meta-analysis.

BACKGROUND: Although the combination of blood-activating herbs and western drugs has shown advantages in the treatment of ischemic stroke, there is no consensus on the safety and efficacy. This study aimed to systematically evaluate the safety and efficacy of the combination of blood-activating herbs with edaravone (EDA) in the treatment of acute ischemic stroke (AIS). METHODS: We will implement the search strategy in 8 English and Chinese databases: Cochrane Central Register of Controlled Trials, Web of Science, PubMed, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, EMBASE and MEDLINE. The search included relevant clinical randomized controlled trials and quasi-randomized controlled trials that had been registered for publication by November 2022. Literature screening, data extraction and quality assessment will be performed by 2 authors. We will assess the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method classification will be used to assess the quality of the literature. Meta-analysis was performed using RevMan V.5.4 and STATA 16 software. RESULTS: This study will provide a comprehensive analysis of the current clinical evidence on the application of blood-activating herbs combined with EDA in the treatment of AIS. CONCLUSION: This study will clarify the safety and efficacy of the combination of blood-activating herbs with EDA in the treatment of AIS.

Pharmacological mechanism and therapeutic efficacy of Icariside II in the treatment of acute ischemic stroke: a systematic review and network pharmacological analysis.

BACKGROUND AND OBJECTIVE: Epimedii has long been used as a traditional medicine in Asia for the treatment of various common diseases, including Alzheimer's disease, cancer, erectile dysfunction, and stroke. Studies have reported the ameliorative effects of Icariside II (ICS II), a major metabolite of Epimedii, on acute ischemic stroke (AIS) in animal models. Based on network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we conducted a systematic review to evaluate the effects and neuroprotective mechanisms of ICS II on AIS. METHODS: First, we have searched 6 databases using studies with ICS II treatment on AIS animal models to explore the efficacy of ICS II on AIS in preclinical studies. The literature retrieval time ended on March 8, 2022 (Systematic Review Registration ID: CRD42022306291). There were no restrictions on the language of the search strategy. Systematic review follows the Patient, Intervention, Comparison and Outcome (PICO) methodology and framework. SYCLE's RoB tool was used to evaluate the the risk of bias. In network pharmacology, AIS-related genes were identified and the target-pathway network was constructed. Then, these targets were used in the enrichments of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO). Molecular docking and MD simulation were finally employed between ICS II and the potential target genes. RESULTS: Twelve publications were included describing outcomes of 1993 animals. The literature details, animal strains, induction models, doses administered, duration of administration, and outcome measures were extracted from the 12 included studies. ICS II has a good protective effect against AIS. Most of the studies in this systematic review had the appropriate methodological quality, but some did not clearly state the controlling for bias of potential study. Network pharmacology identified 246 targets with SRC, CTNNB1, HSP90AA1, MAPK1, and RELA as the core target proteins. Besides, 215 potential pathways of ICS II were identified, such as PI3K-Akt, MAPK, and cGMP-PKG signaling pathway. GO enrichment analysis showed that ICS II was significantly enriched in subsequent regulation such as MAPK cascade. Molecular docking and MD simulations showed that ICS II can closely bind with important targets. CONCLUSIONS: ICS II is a promising drug in the treatment of AIS. However, this systematic review reveals key knowledge gaps (i.e., the protective role of ICS II in women) that ICS II must address before it can be used for the treatment of human AIS. Our study shows that ICS II plays a protective role in AIS through multi-target and multi-pathway characteristics, providing ideas for the development of drugs for the treatment of AIS.