Zhishe Tongluo capsule ameliorates experimental ischemic brain injury through regulating the CALB2/Ca2+/PKC pathway and glycerophospholipid metabolism.

Piperine ameliorates ischemic stroke-induced brain injury in rats by regulating the PI3K/AKT/mTOR pathway

Ischemic stroke is one of the most important complications of malignant tumors. The etiology and pathogenesis of ischemic stroke in patients with cancer are very complicated, it includes either traditional vascular risk factors such as hypertension, diabetes and hyperlipidemia or the risk factors associated with the pathophysiological state of tumors such as hypercoagulable state, tumor emboli, and thrombotic endocarditis. In addition, various treatment methods associated with tumors, such as radiotherapy, chemotherapy and endocrine therapy, can also increase the risk of ischemic stroke. Because of the complexity of the etiology and pathogenesis, the treatment methods for ischemic stroke in patients with cancer are also different with common practice. Identification of the causes and selection of targeted therapies are crucial for the prevention ad treatment of tumor-associated ischemic stroke. With the increase of the survival rate in patients with cancer, ischemic stroke in patients with cancer is also receiving increasing attention. This article reviews advances in etiology, pathogenesis and treatment of ischemic stroke in patients with cancer. Key words: Stroke; Brain Ischemia; Neoplasms

The analysis of alterations in the expression and functionality of brain-derived exosomal miRNAs within ischemic stroke lesions provides significant insights into the mechanisms that contribute to disease recovery. We assessed spontaneous motor function in a rat model of permanent middle cerebral artery occlusion (pMCAO) using motor function scores and magnetic resonance imaging (MRI). Brain-derived exosomes from the infarcted brain tissue of the animal model were extracted and high-throughput sequencing of them was performed followed by bioinformatics analysis for differentially expressed miRNAs target genes. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to measure expression levels of differentially expressed miRNAs at various time points. The oxygen-glucose deprivation (OGD) model was established to investigate gene function through the assessment of cell proliferation and apoptosis using EdU proliferation and JC-1 apoptosis assay. The rat model demonstrated a spontaneous recovery of motor function and a reduction in cerebral infarction area from day 1 to day 14 post-operation. Over the course of the recovery period, miR-24-3p, miR-129-1-3p, and miR-212-5p maintained consistent expression levels, reaching their peak on the initial day following surgery. In the cell model, EdU detection indicated that miR-129-1-3p promoted cellular proliferation, while JC-1 detection revealed its suppressive impact on cellular apoptosis. The current research findings indicated the presence of spontaneous motor function restoration in a rat model of ischemic stroke. MiR-24-3p, miR-129-1-3p, and miR-212-5p were identified as pivotal genes in this recovery process, with miR-129-1-3p potentially influencing the restoration of spontaneous motor function in ischemic stroke through the regulation of neuronal proliferation and apoptosis.

Danhong injection modulates microglial polarization and neuroinflammation via the JUNB/NF-κB pathway in ischemic stroke.

Dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) can reflect the angiogenesis of ischemic stroke. To investigate the value of DSC-MRI with ultrasmall superparamagnetic particles of iron oxides (USPIO) in evaluating angiogenesis in the peri-infarction zones in subacute ischemic stroke in a permanent middle cerebral artery occlusion (pMCAO) rat model. A total of 21 Sprague-Dawley rats were randomly divided into the pMCAO and sham operation groups. Every rat in each group underwent DSC-MRI with USPIO at 3, 5, and 7 days. DSC-MRI parameters of the relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), relative mean transit time (rMTT), and relative time to peak (rTTP) were measured, calculated, and compared among the different times. Sequential correlations were analyzed among the histopathological indexes with the microvascular density (MVD) and percentage of vascular area (%VA), the serum factors with vascular endothelial growth factor (VEGF), vascular cell adhesion molecule 1 (VCAM-1), and perfusion parameters, respectively. The rCBV and rCBF in the peri-infarction area of pMCAO rats were significantly higher on day 7 than on day 3, whereas no significant changes in rMTT and rTTP were observed at 3, 5, and 7 days. Significantly positive correlations were found between rCBV and MVD, %VA, VEGF, VCAM-1, between rCBF and MVD, %VA, VEGF, and VCAM-1 at 3, 5, and 7 days in the pMCAO group. The rCBV and rCBF deriving from USPIO-DSC may be potentially useful for evaluating the angiogenesis of the peri-infarction zones in the subacute phase of ischemic stroke.

Geopung-Chunghyuldan (GCD), which is a mixture of Chunghyuldan (CD), Radix Salviae Miltiorrhizae, Radix Notoginseng, and Borneolum Syntheticum, is used to treat ischemic stroke in traditional Korean medicine. This study aimed to investigate the effects of GCD and CD on ischemic brain damage using in vitro and in vivo stroke models, as well as to elucidate the synergistic effects of GCD against ischemic insult. To study the effect of GCD in an in vitro ischemia model, SH-SY5Y cells were exposed to oxygen–glucose deprivation (OGD). Cell death after 16 h of OGD exposure was measured using the MTT assay and live/dead cell counting methods. An in vivo ischemia mice model was established through permanent middle cerebral artery occlusion (pMCAO). To determine the neuroprotective effect of GCD, it was orally administered immediately and 2 h after pMCAO. The infarct volume was measured through 2,3,5-triphenyltetrazolium chloride staining at 24 h after pMCAO. Compared with the control group, GCD treatment significantly reduced OGD-induced cell death in SH-SY5Y cells; however, CD treatment did not show a significant protective effect. In the pMCAO model, compared with the control group, treatment with GCD and CD significantly and mildly reduced the infarct volume, respectively. Our findings indicate that compared with CD, GCD may allow a more enhanced neuroprotective effect in acute ischemic stroke, indicating a potential synergistic neuroprotective effect. The possibility of GCD as a novel alternative choice for the prevention and treatment of ischemic stroke is suggested.

Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats

To date, the only effective pharmacological treatment for ischemic stroke is limited to the clinical use of recombinant tissue plasminogen activator (rtPA), although endovascular therapy has also emerged as an effective treatment for acute ischemic stroke. Unfortunately, the benefit of this treatment is limited to a 4.5-h time window. Most importantly, the use of rtPA is contraindicated in the case of hemorrhagic stroke. Therefore, the identification of a reliable biomarker to distinguish hemorrhagic from ischemic stroke could provide several advantages, including an earlier diagnosis, a better treatment, and a faster decision on ruling out hemorrhage so that tPA may be administered earlier. microRNAs (miRNAs) are stable non-coding RNAs crucially involved in the downregulation of gene expression via mRNA cleavage or translational repression. In the present paper, taking advantage of three preclinical animal models of stroke, we compared the miRNA blood levels of animals subjected to permanent or transient middle cerebral artery occlusion (MCAO) or to collagenase-induced hemorrhagic stroke. Preliminarily, we examined the rat miRNome in the brain tissue of ischemic and sham-operated rats; then, we selected those miRNAs whose expression was significantly modulated after stroke to create a list of miRNAs potentially involved in stroke damage. These selected miRNAs were then evaluated at different time intervals in the blood of rats subjected to permanent or transient focal ischemia or to hemorrhagic stroke. We found that four miRNAs—miR-16-5p, miR-101a-3p, miR-218-5p, and miR-27b-3p—were significantly upregulated in the plasma of rats 3 h after permanent MCAO, whereas four other different miRNAs—miR-150-5p, let-7b-5p, let-7c-5p, and miR-181b-5p—were selectively upregulated by collagenase-induced hemorrhagic stroke. Collectively, our study identified some selective miRNAs expressed in the plasma of hemorrhagic rats and pointed out the importance of a precise time point measurement to render more reliable the use of miRNAs as stroke biomarkers.

Hua Feng Dan (HFD) has demonstrated definitive efficacy in the treatment of ischemic stroke (IS); however, its active components and underlying mechanisms of action remain unclear. This study employed a rat model of middle cerebral artery occlusion (MACO) to evaluate the neuroprotective effects of HFD against cerebral ischemia. Metabolomics approaches were used to demonstrate the complexity of HFD for the treatment of IS. Liquid chromatography/mass spectrometry (LC/MS) was used to identify the main chemical constituents of HFD. Network pharmacology and molecular docking were employed to predict the targets and mechanisms of HFD for IS. Experimental validation was performed to elucidate the underlying mechanisms. HFD demonstrated the ability to enhance neurological function, decrease the area of cerebral infarction, and improve brain structure in rats subjected to MCAO. Twenty-nine distinct metabolites were identified using non-targeted metabolomics analysis of urine. It was determined that HFD mediated its therapeutic effects on IS via amino sugar, nucleotide sugar metabolism, and glycerophospholipid metabolism. Additionally, a total of fifty-six compounds were identified from the alcoholic extracts of HFD, mainly alkaloids, bile acids, flavonoids, and coumarins. The results of network pharmacology and molecular docking suggest that AKT1, STAT3, EGFR, ERK2, and ERK1 are key therapeutic targets. Additionally, HFD upregulates the levels of AKT1 while downregulating those of ERK1/2. This may represent an intrinsic mechanism underlying its anti-cerebral ischemia effects. This study preliminarily elucidates the mechanism of action of HFD in the treatment of IS, providing guidance for its clinical application in this context.

Ischemic stroke is one of the main causes of high morbidity, mortality, and disability worldwide; however, the treatment methods are limited and do not always achieve satisfactory results. The pathogenesis of ischemic stroke is complex, defined by multiple mechanisms; among them, programmed death of neuronal cells plays a significant role. Ferroptosis is a novel type of regulated cell death characterized by iron redistribution or accumulation and increased lipid peroxidation in the membrane. Ferroptosis is implicated in many pathological conditions, such as cancer, neurodegenerative diseases, and ischemia-reperfusion injury. In this review, we summarize current research findings on ferroptosis, including possible molecular mechanisms and therapeutic applications of ferroptosis regulators, with a focus on the involvement of ferroptosis in the pathogenesis and treatment of ischemic stroke. Understanding the role of ferroptosis in ischemic stroke will throw some light on the development of methods for diagnosis, treatment, and prevention of this devastating disease.

Regulation of histidine metabolism by Lactobacillus Reuteri mediates the pathogenesis and treatment of ischemic stroke

Ischemic stroke (IS) is a major cause of mortality and disability worldwide. However, the pathogenesis of IS remains unknown, and methods for early prediction and diagnosis of IS are lacking. Metabolomics can be applied to biomarker discovery and mechanism exploration of IS by exploring metabolic alterations. In this review, 62 IS metabolomics studies in the murine model published from January 2006 to December 2020 in the PubMed and Web of Science databases were systematically reviewed. Twenty metabolites (e.g., lysine, phenylalanine, methionine, tryptophan, leucine, lactate, serine, N-acetyl-aspartic acid, and glutathione) were reported consistently in more than two-third murine studies. The disturbance of metabolic pathways, such as arginine biosynthesis; alanine, aspartate and glutamate metabolism; aminoacyl-tRNA biosynthesis; and citrate cycle, may be implicated in the development of IS by influencing the biological processes such as energy failure, oxidative stress, apoptosis, and glutamate toxicity. The transient middle cerebral artery occlusion model and permanent middle cerebral artery occlusion model exhibit both common and distinct metabolic patterns. Furthermore, five metabolites (proline, serine, LysoPC (16:0), uric acid, glutamate) in the blood sample and 7 metabolic pathways (e.g., alanine, aspartate, and glutamate metabolism) are shared in animal and clinical studies. The potential biomarkers and related pathways of IS in the murine model may facilitate the biomarker discovery for early diagnosis of IS and the development of novel therapeutic targets.

Ischemic stroke (IS) is a complex syndrome of neurological deficits due to stenosis or occlusion of the carotid and vertebral arteries for which there is still no effective treatment. Melatonin, a hormone secreted by the pineal gland, has multiple biological effects, such as antioxidant and anti-inflammatory properties, circadian rhythm regulation, and tissue regeneration, demonstrating potential applications in the treatment of IS. The aim of this study was to investigate key melatonin-regulated genes associated with IS using transcriptome sequencing and bioinformatics analyses and to explore their potential mechanisms of action in the disease process. We obtained gene expression data related to ischemic stroke (IS) from the Gene Expression Omnibus (GEO) database and identified candidate genes using machine learning algorithms. We then assessed the predictive power of these genes using PPI network analysis and diagnostic models. Finally, a series of enrichment analyses identified four key genes: ADM, PTGS2, MMP9, and VCAN. In addition, we determined the mRNA levels of these four key genes in an IS rat model using qPCR and found that all of these genes were significantly upregulated in the IS model compared to the control group, which is consistent with the results of previous analyses. Meanwhile, these genes have biological functions such as regulating vascular tone, participating in the inflammatory response, influencing tissue remodeling, and regulating cell adhesion and proliferation, playing key roles in the pathogenesis of IS. Therefore, we suggest that these four key genes may serve as prospective biomarkers for IS and help predict the risk of developing IS. In conclusion, this study elucidates for the first time the potential role of melatonin in the pathogenesis of IS and lays the foundation for in-depth studies on the functions of these key genes in the pathophysiology of IS and their potential applications in clinical diagnosis and treatment.

Leptin is an adipose hormone endowed with angiopoietic, neurotrophic, and neuroprotective properties. We tested the hypothesis that leptin might act as an endogenous mediator of recovery after ischemic stroke and investigated whether nuclear transcription factors kappaB activation is involved in leptin-mediated neuroprotection. The antiapoptotic effects of leptin were evaluated in cultured mouse cortical neurons from wild-type or NF-kappaB/c-Rel(-/-) mice exposed to oxygen-glucose deprivation. Wild-type, c-Rel(-/-) and leptin-deficient ob/ob mice were subjected to permanent middle cerebral artery occlusion. Leptin production was measured in brains from wild-type mice with quantitative reverse transcriptase-polymerase chain reaction and immunostaining. Mice received a leptin bolus (20 microg/g) intraperitoneally at the onset of ischemia. Leptin treatment activated the nuclear translocation of nuclear transcription factors kappaB dimers containing the c-Rel subunit, induced the expression of the antiapoptotic c-Rel target gene Bcl-xL in both control and oxygen-glucose deprivation conditions, and counteracted the oxygen-glucose deprivation-mediated apoptotic death of cultured cortical neurons. Leptin-mediated Bcl-xL induction and neuroprotection against oxygen-glucose deprivation were hampered in cortical neurons from c-Rel(-/-) mice. Leptin mRNA was induced and the protein was detectable in microglia/macrophage cells from the ischemic penumbra of wild-type mice subjected to permanent middle cerebral artery occlusion. Ob/ob mice were more susceptible than wild-type mice to the permanent middle cerebral artery occlusion injury. Leptin injection significantly reduced the permanent middle cerebral artery occlusion-mediated cortical damage in wild-type and ob/ob mice, but not in c-Rel(-/-) mice. Leptin acts as an endogenous mediator of neuroprotection during cerebral ischemia. Exogenous leptin administration protects against ischemic neuronal injury in vitro and in vivo in a c-Rel-dependent manner.

Ischemic stroke (IS) poses a significant threat to human health. Research has demonstrated that microglia (MG)-mediated neuroinflammatory responses play a crucial role in the pathogenesis of IS. Consequently, inhibiting MG activation and reducing the inflammatory response may be key strategies for the clinical treatment of stroke and neurodegenerative diseases. Edaravone (EDA), a potent anti-inflammatory and antioxidant, is currently used in the clinical treatment of IS; however, its anti-inflammatory mechanisms remain inadequately understood. To address this, network pharmacology (NP) analysis is employed to identify the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway as a potential mediator of the inflammatory response triggered by activated microglia following EDA treatment. In vitro oxygen-glucose deprivation (OGD) is used to induce BV-2 MG activation, and an in vivo middle cerebral artery occlusion (MCAO) mouse model is established. Western blot and immunofluorescence staining are used to detect changes in the phosphorylation levels of pathway-related proteins and the expression of inflammatory factors. Additionally, the PI3K pathway inhibitor LY294002 and a PI3K overexpression plasmid are introduced to further analyze the expression changes of these markers. The results suggest that EDA may alleviate the inflammatory response mediated by activated MG through the PI3K/Akt signaling pathway.