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.

APG can exert various protective effects against cerebral ischemia. Moreover, APG has shown a highly promising ability to prevent cerebral ischemia in terms of regulating blood glucose, blood pressure, lipids and gut microbes.

Background and objective: Ischemic stroke (IS) is one of the major global health problems. It is not clear whether there is a causal relationship between lactate dehydrogenase (LDH) and the risk of IS attacks. The purpose of this study was to investigate whether LDH has a causal relationship with the development of IS.Methods: The genome‐wide association data of LDH and IS were obtained through a Mendelian randomization‐based platform. Single nucleotide polymorphisms (SNP) that were significantly associated with LDH were identified and used as instrumental variables, and a two‐sample Mendelian randomization study was used to examine the causal relationship between LDH and IS. The statistical methods included Inverse‐variance weighted approach, MR‐Egger regression, and weighted median estimator.Results: We selected 15 SNPs of genome‐wide significance from Genome‐wide association study database with LDH as instrumental variables. A consistent causal association between LDH and IS was observed by different assessment methods. The results of the inverse‐variance weighted method suggested an inverse association between LDH and higher genetic predictability of IS risk (OR, 0.997; 95%CI 0.995–0.999). The weighted median estimate showed consistent results with the MR‐Egger method (weighted median estimate: OR, 0.995; 95%CI 0.992–0.999; MR‐Egger method: OR, 0.996; 95%CI 0.992–0.999). The inverse‐variance weighted method indicates a causal association between LDH and IS (β = −0.002563, SE = 0.00128, p = .0453). MR‐Egger analysis (β = −0.004498, SE = 0.001877, p = .03) and the weighted median method suggested that LDH and IS also existed causal relationship (β = −0.004861, SE = 0.001801, p = .00695).Conclusions: Our Mendelian randomization results suggest that LDH is inversely associated with the risk of developing IS, and are contrary to the results of previous observational studies.

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.

Stroke is a serious disease that leads to high morbidity and mortality, and ischemic stroke accounts for more than 80% of strokes. At present, the only effective drug recombinant tissue plasminogen activator is limited by its indications, and its clinical application rate is not high. Therefore, it is urgent to develop effective new drugs according to the pathological mechanism. In the hypoxic state after ischemic stroke, anaerobic glycolysis has become the main way to provide energy to the brain. This process is essential for the maintenance of important brain functions and has important implications for recovery after stroke. However, acidosis caused by anaerobic glycolysis and lactic acid accumulation is an important pathological process after ischemic stroke. Dichloroacetate (DCA) is an orphan drug that has been used for decades to treat children with genetic mitochondrial diseases. Some studies have confirmed the role of DCA in stroke, but the conclusions are conflicting because some believe that DCA is not effective for ischemic stroke and may aggravate hemorrhagic stroke. This study reviews these studies and finds that DCA has a good effect on ischemic stroke. DCA can protect ischemic stroke by improving oxidative stress, reducing neuroinflammation, inhibiting apoptosis, protecting blood–brain barrier, and regulating metabolism. We also describe the differences in the outcomes of DCA in the treatment of ischemic stroke and the reasons why DCA aggravate hemorrhagic stroke. In addition, DCA, as a water disinfection byproduct, has been concerned about its toxicity. We describe the causes and solutions of peripheral neuropathy caused by DCA. In summary, this study analyzes the neuroprotective mechanism of DCA in ischemic stroke and the contradiction of the different research results, and discusses the causes and solutions of its adverse effects.