Intracerebral haemorrhage (ICH) remains a devastating stroke subtype with limited therapeutic options, creating an urgent need for complementary strategies that target secondary brain injury and recovery. Traditional Chinese herbal medicines (TCHMs) have attracted interest because of their potential multitarget actions on neuroinflammation, oxidative stress, apoptosis, ferroptosis, blood–brain barrier dysfunction, haematoma resolution, gut microbiota dysbiosis and neurovascular repair. Relevant preclinical, clinical and translational studies were identified through a structured search of international and Chinese bibliographic databases. Preclinical studies suggest that selected TCHM-derived bioactive compounds and multicomponent formulae may modulate key pathological processes after ICH, although compound-level mechanisms should not be directly extrapolated to formula-level effects without further validation. Clinically, several small-scale randomized trials, observational studies and meta-analyses have reported potential benefits of selected TCHM preparations, including improved neurological scores, haematoma absorption, oedema reduction and functional recovery when used as adjuncts to conventional care. However, the clinical evidence remains heterogeneous. Larger and more rigorously designed multicentre trials, including CHAIN and CRRICH, have either failed to confirm clear functional benefit or raised safety concerns under specific conditions, particularly regarding ultra-early use of potent blood-activating formulations. Translation into mainstream ICH management is further hindered by variable study quality, insufficient risk-of-bias control, uncertainty regarding active material basis, potential synergistic or antagonistic interactions within multicomponent formulae and limited standardisation of herbal preparations. Future research should focus on formulation-specific, stage-specific and patient-stratified evaluation using rigorous randomized controlled trials, transparent pharmacological characterization, standardised quality control and careful safety monitoring. This review synthesises current evidence from bench to bedside and highlights a cautious pathway toward evidence-based integration of selected TCHMs into ICH management.

BACKGROUND:Neurovascular uncoupling is a critical yet underrecognized pathological mechanism that exacerbates neurological injury after cerebral ischemic stroke. An-Gong-Niu-Huang-Wan (AGNHW), a well-established traditional Chinese formula, has been clinically utilized for stroke management for over two centuries owing to its multi-target neuroprotective properties. However, its potential to ameliorate impaired neurovascular coupling following ischemic insult remains largely unexplored. PURPOSE:This study aimed to elucidate the therapeutic mechanism of AGNHW in restoring neurovascular coupling, with a focus on the purinergic P2X7 receptor (P2X7R) signaling pathway. METHODS:A distal middle cerebral artery occlusion model was induced in male C57BL/6 mice. AGNHW was administered intragastrically 1 hour post-occlusion. Cortical neurovascular coupling was evaluated using laser speckle contrast imaging during whisker stimulation. Functional recovery was assessed via gait analysis and grip strength, while tissue injury was examined through hematoxylin and eosin staining. Neuronal activity, monitored in rAAV2/9-CaMKIIα-GCaMP6s mice, and arterial hemodynamics were visualized using two-photon microscopy during functional hyperemia. RNA sequencing was employed to identify potential mechanistic targets of AGNHW, followed by molecular biology techniques to investigate the role of purinergic signaling, particularly P2X7R-mediated regulation of neurovascular coupling. RESULTS:Compared with the control group, AGNHW treatment significantly enhanced the cerebral blood flow response and increased the area under the curve during whisker stimulation, accompanied by alleviated neuronal damage and improved motor function-reflected by prolonged stance time and elevated peak pressure in the affected forelimb and enhanced grip strength. AGNHW also markedly increased the signal intensity of calcium activity (ΔF/F₀) following ischemia. Furthermore, AGNHW improved arterial hemodynamics by promoting arterial dilation, increasing red blood cell velocity, and elevating red blood cell flux during functional hyperemia. It also ameliorated blood-brain barrier integrity and upregulated the expression of tight junction proteins (ZO-1, occludin, claudin5). Mechanistically, AGNHW downregulated the genes expression of P2rx7, P2ry12, and Adora2a, and inhibited P2X7R activation by reducing ATP release, thereby inhibited inflammatory cell infiltration and alleviating the secretion of inflammatory mediators such as IL-1β, IL-18, and TNF-α. Notably, activation of P2X7R signaling abolished the protective effects of AGNHW on cerebral blood flow response and blood-brain barrier integrity. CONCLUSIONS:AGNHW attenuated neurovascular uncoupling and improved cerebral blood flow response and neuronal activity during whisker stimulation after cerebral ischemia, mediated by inhibition of the P2X7R-driven purinergic-inflammatory cascade. These findings elucidated a mechanism through which AGNHW preserves neurovascular function.

To evaluate right stellate ganglion block (SGB) plus dexmedetomidine (Dex) in a rat model of atrial fibrillation-like (AF-like) atrial tachyarrhythmia. Methods: Male Sprague-Dawley rats were assigned to Sham, AF, AF+amiodarone, AF + SGB and AF + SGB+Dex groups. AF-like atrial tachyarrhythmia was induced by daily CaCl₂-acetylcholine injections for 7 days, and interventions were administered 1 h before modelling. ECG, echocardiography, electrophysiology, histology, ELISA, Western blot/qPCR, immunofluorescence and electron microscopy were performed. Results: Compared with the AF group, SGB + Dex reduced arrhythmia duration (5.0 ± 1.5 vs. 16.3 ± 2.5 s, p < 0.001) and ventricular rate (344.3 ± 19.9 vs. 398.1 ± 19.2 bpm, p = 0.004), preserved LVEF (83.3

Background Ischemic stroke remains a lethal disease with high morbidity and disability, yet effective therapeutic options for chronic recovery are still limited. Angiogenesis facilitates post-stroke blood supply restoration by reconstructing vascular networks, which helps rescue the penumbra and recover neurological function. Rhodiosin is a bioactive compound derived from rhodiola crenulata, exhibiting multiple pharmacological activities. However, whether rhodiosin exerts protective effects by promoting angiogenesis after stroke, as well as the underlying mechanisms, remains unclear. Purpose This study aimed to investigate whether rhodiosin promotes cerebral angiogenesis and neurological functional recovery after stroke, and to explore the underlying mechanisms. Study design and methods Stroke was induced in mice by distal middle cerebral artery occlusion (dMCAO). Rhodiosin was administered intraperitoneally daily post-surgery. Therapeutic efficacy was assessed based on neurological deficits and infarct volume. Microvascular density and pericyte/astrocyte coverage were evaluated using immunofluorescence staining. Cerebral blood flow (CBF) was monitored by laser speckle imaging. Two-photon microscopy was employed to measure dynamic changes in cerebrovascular diameter and density. RNA sequencing was performed to identify rhodiosin-associated pathways. PI3K/Akt pathway factors were examined by Western blot and qRT-PCR. The human cerebral microvascular endothelial cells (hCMEC/D3) were utilized to explore the underlying mechanisms in vitro. Results Rhodiosin enhanced neurological recovery and reduced infarct volume post-stroke. It improved CBF and increased vascular diameter and density in the penumbra. It also promoted angiogenesis by increasing BrdU⁺/CD31⁺ cells and enhancing pericyte/astrocyte coverage around microvessels. Moreover, rhodiosin facilitated endothelial cell migration and tube formation under OGD conditions. Rhodiosin upregulated PI3K/Akt phosphorylation and the expression of their downstream targets (HIF-1α, Ang1, VEGF). These effects were partially or fully reversed by PI3K/Akt inhibition (LY294002/MK-2206 in vivo, shRNA transfection in vitro). Integrating RNA-seq with experimental validation, we confirmed that activation of PI3K/Akt mediates rhodiosin’s pro-angiogenic effect. Conclusion Rhodiosin promotes neurological recovery post-stroke by enhancing cerebral angiogenesis via PI3K/Akt pathway activation, highlighting its potential as a therapeutic candidate for ischemic stroke during the subacute/chronic recovery phase.

AimsAstrocytes provide crucial metabolic support for neurons and undergo significant metabolic changes in Alzheimer’s disease (AD). Aldolase C (ALDOC), an astrocyte-enriched glycolytic enzyme, may play a role in this process. This study aimed to investigate whether ALDOC modulates astrocytic metabolism to support neuronal energy supply in patients with AD and to assess its therapeutic potential.MethodsHippocampal and cortical tissues from 6-month-old APP/PS1 and wild-type mice were subjected to western blotting, qPCR, and immunofluorescence staining for ALDOC and glycolytic proteins. An in vitro AD model was created using oligomeric β-amyloid (oAβ)-treated SVGp12 astrocytes. ALDOC was overexpressed or knocked down via plasmid or siRNA. Downstream effects on AMPK/mTOR/HIF-1α signaling and the expression of glycolytic markers (LDHA and PKM2) were evaluated by western blot and qPCR, as well as by lactate/ATP assays and extracellular acidification rate (ECAR) measurements. Neuron–astrocyte interactions were assessed in an SVGp12/SH-SY5Y coculture. Furthermore, the ability of magnesium ions to restore ALDOC expression was tested.ResultsALDOC was specifically expressed in astrocytes but was downregulated in APP/PS1 mice, accompanied by reduced HIF-1α and LDHA levels, suggesting glycolytic impairment. Similar downregulation occurred in oAβ-treated SVGp12 cells. ALDOC overexpression was associated with altered AMPK/mTOR/HIF-1α signaling, enhanced glycolysis, and increased lactate and ATP production, whereas its knockdown had the opposite effects. These outcomes appeared to depend on HIF-1α, as suggested by the rescue experiments. In coculture, ALDOC overexpression in astrocytes supported neuronal metabolic function. Moreover, magnesium ions restored ALDOC activity and glycolysis in oAβ-treated astrocytes.ConclusionThese results suggest that ALDOC is downregulated in APP/PS1 mice and is associated with glycolytic impairment. In oAβ-treated astrocytes, ALDOC appears to regulate glycolysis through the AMPK/mTOR/HIF-1α axis and may support neuronal energy via the lactate shuttle. Magnesium ions appear to offer a potential strategy for addressing the metabolic deficits in AD.

Ethnopharmacological relevance: The role of herbal medicines in the treatment of stroke is receiving increasing attention. Polygala tenuifolia Willd, as a traditional Chinese herb, has been used in clinical practice for a long time to treat stroke and its related sequelae. It has a long history of application. It is notable that the active component derived from the roots of Polygala tenuifolia - Tenuigenin (TEN) - has been identified as the main active ingredient of this herb. However, the specific role of this herb in cerebral ischemia-reperfusion injury remains unclear, and the mechanism of action in treating neuroinflammation and inhibiting neuronal apoptosis still needs to be clarified.Aim of study: The purpose of this study was to explore the impacts of tenuigenin administration after cerebral ischemia-reperfusion injury on improving the neurological deficits in stroke mice, and to investigate the influence of regulating microglial polarization in reducing neuroinflammation and cell apoptosis, as well as the possible mechanisms.Materials and methods: A transient middle cerebral artery occlusion (tMCAO) model was established in mice. From day 1 to day 3, young male mice with cerebral ischemia-reperfusion injury were administered tenuigenin daily through behavioral tests such as mNSS score and rod transfer test, and neurological deficits were measured. One day after stroke, the volume of cerebral infarction was determined by TTC staining. The possible signaling pathways involved were predicted through network pharmacology and molecular docking analysis. The expression of microglia and M1/M2 markers (CD86, iNOS, CD206, Arg-1) and EGLN3 pathways was detected in vitro and in vivo by IF, qRT-PCR and WB after stroke. Inflammatory molecules were determined by ELISA and apoptosis was detected by Tune. It is worth noting that in vitro BV2 cells were simulated for cerebral ischemia-reperfusion using the OGD/R model.Results: The number of M1 microglia/macrophages (CD16/32/Iba1+) was decreased, and the number of M2 microglia/macrophages (CD206+/Iba1+) was increased. Subsequent in vivo and in vitro experiments demonstrated that tenuigenin downregulated the expression of M1 markers (CD86, iNOS, TNFα, IL-1β) and upregulated the expression of M2 markers (CD206, Arg-1), and also had the effect of reducing neuronal apoptosis. Integrated network pharmacology and molecular docking analyses revealed that the EGLN3/HIF-1α/NF-κB axis is the central signaling pathway involved in these changes. Western blotting confirmed that tenuigenin promoted EGLN3 expression while suppressing the phosphorylation of HIF-1α and NF-κB. Crucially, these protective effects were reversed by administration of the EGLN3 inhibitor FG-4592.Conclusion: Tenuigenin can restore neural function, improve cerebral blood flow, reduce the volume of cerebral infarction and neuronal apoptosis, and regulate microglial polarization through the EGLN3/HIF-1α/NF-κB signaling pathway to alleviate neuroinflammation, thereby exerting neuroprotective effects on ischemic stroke.

Background/Objectives: The aim of this study was to investigate the effects of cranio-cervical artery stenosis (CAS) and cerebral infarction (CI) on the function of the glymphatic system (GS). Methods: Hospitalised patients with CI and/or CAS were enrolled, along with a control group. A total of 111 participants (62.68 ± 9.85 years; 37% female) were enrolled in this study. GS function was assessed using the diffusion tensor imaging analysis along with the perivascular space (DTI-ALPS) method. The influencing factors and the individual and combined effects of CI and CAS on the DTI-ALPS index were analysed. Results: Age (p = 0.024), CI (p < 0.001), and CAS (p = 0.001) were independent predictors of a lower DTI-ALPS index. There were statistically significant differences in the DTI-ALPS index among the four groups (CI, CAS, CI + CAS, control) (F(3, 107) = 91.4, p < 0.0001). The DTI-ALPS index was lower in the CI, CAS, and CI + CAS groups compared with the control group (p < 0.0001); in the CI group compared with the CAS group (p < 0.0001); and in the CI + CAS group compared with the CI group (p < 0.05). CI and CAS were found to have a significant interaction effect on the DTI-ALPS index (F(1, 107) = 6.43, p = 0.013). Conclusions: Aging, CAS, and CI independently impair GS function, with CI having a stronger effect. All three are independent predictors of GS dysfunction. Patients with CAS experience more significant GS dysfunction after suffering CI than patients without CAS. CI and CAS have a synergistic effect on GS impairment.

Ethnopharmacological relevance Astragalus membranaceus (Fisch.) Bunge is a fundamental herb in traditional Chinese medicine. It has a long history of use in clinical practice for treating stroke and its associated sequelae. Notably, Formononetin (FN) has been identified as a primary bioactive isoflavone in this herb. However, its specific function in cerebral ischemia‒reperfusion injury remains unclear, especially regarding the area of immunometabolic regulation. Aim of study Ischemic stroke remains a major cause of neurological disability worldwide. Although reperfusion is crucial for salvaging the ischemic penumbra, it also contributes to secondary injury driven by microglial activation. Emerging evidence suggests that targeting metabolic immune interactions may help mitigate postreperfusion neuroinflammation. This study aimed to investigate whether FN attenuates cerebral ischemia‒reperfusion injury by modulating microglial metabolism and polarization. Materials and methods A transient middle cerebral artery occlusion (tMCAO) model was established in mice. Formononetin (FN) was administered immediately after reperfusion. Neurological deficit scores were assessed daily for three days. Twenty-four hours after reperfusion, pathological injury was evaluated by hematoxylin and eosin (H&E) staining and a TUNEL assay. Microglial polarization markers were analyzed using immunofluorescence and Western blotting. Inflammatory cytokines were measured by real-time quantitative polymerase chain reaction (RT‒qPCR) and enzyme-linked immunosorbent assay (ELISA). RNA sequencing was performed on peri-infarct cortical tissue to identify affected pathways. Glycolytic protein levels in the same region were measured by western blotting. Molecular docking was employed to predict key bioactive compounds and their potential targets. These predictions were further validated by Western blot analysis. For in vitro studies, BV2 cells were subjected to oxygen‒glucose deprivation and reperfusion (OGD/R). Polarization markers were subsequently detected by flow cytometry and RT‒qPCR. Cellular ATP and lactate levels, glucose uptake, the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) were measured. An AMPK inhibitor was used for intervention in both in vivo and in vitro experiments. Key indicators related to AMPK signaling, microglial polarization, and glycolysis were examined via immunofluorescence and Western blotting. Results FN treatment improved neurological function scores, reduced infarct volume, and attenuated pathological injury in tMCAO mice. Both in vivo and in vitro, FN treatment inhibited glycolysis and enhanced mitochondrial oxidative metabolism. It also decreased M1-like polarization while increasing M2-like polarization markers, leading to a reduction in proinflammatory cytokine production. RNA sequencing and molecular docking analysis revealed the AMPK/mTOR/HIF-1⍺ pathway, which was subsequently confirmed at the protein level. An AMPK inhibitor reversed the FN-induced changes in both metabolic and microglial phenotypes. Conclusions FN suppresses glycolytic metabolism in microglia through AMPK signaling, thereby influencing microglial polarization and attenuating neuroinflammation.

Ischemic stroke is a prominent cause of morbidity and mortality, affecting numerous people worldwide. The exact role of Maixuekang capsule in cerebral ischemia/reperfusion injury (CI/RI) remains elusive. The present study aimed to delve into the neuroprotective potential of Maixuekang in CI/RI rats. Utilizing the HREB database, leech ingredients were retrieved, while GeneCards, therapeutic target database (TTD), and DisGeNET databases were used to predict cerebral infarction targets. Search tool for the retrieval of interacting genes/proteins (STRING) database was adopted to identify overlapping genes, and Cytoscape 3.9.1 to analyze core targets. The gene ontology (GO)/ Kyoto encyclopedia of genes and genomes (KEGG) pathway were analyzed and neurological function was assessed via Longa scoring. The 2,3,5-triphenyltetrazolium chloride (TTC), Golgi, hematoxylin and eosin (H&E), and Nissl stains were adopted to observe cerebral infarction and pathological changes. The neuronal apoptosis, hypoxia inducible factor 1 alpha (HIF1A), myeloperoxidase (MPO) and inflammatory factors in rat were measured. Results suggested Maixuekang reduced the neurological function score and the cerebral infarction incidence in CI/RI rats. After taking Maixuekang, the number of dendritic spines of CI/RI rats increased, the neuronal damage degree in the ischemic cortical area reduced, and the neurons morphology improved. In addition, Maixuekang reduced the blood-brain barrier (BBB) damage and brain tissue water content by decreasing neuronal apoptosis rate, Bax expression, neutrophil infiltration, inflammatory factor levels, and increasing Bcl2 by decreasing HIF1A in CI/RI rat tissues. Collectively, Maixuekang could reduce neurological function, cerebral infarction rate, blood-brain barrier damage, neuroinflammation and downregulates HIF1A in tissues of CI/RI rats.

Damage following ischemic stroke is worsened by microglial activation and subsequent neuroinflammation. Polypyrimidine tract binding protein 2 (Ptbp2) can influence the chemotaxis and repolarization of cancer-related macrophages; however, its specific role in microglial polarization and the underlying mechanisms are not yet fully understood. This study aimed to elucidate the neuroprotective mechanisms of Ptbp2 and examine its effects on microglial activation, neuroinflammation, and glucose metabolism following cerebral ischemia. Mice model of ischemic stroke was developed using temporary middle cerebral artery occlusion (tMCAO). Adeno-associated viruses were used for overexpression and knockdown in C57 mice, and microglial polarization, blood–brain barrier (BBB) integrity, and glycolytic parameters in the peri-infarct cortex were evaluated. RNA sequencing (RNA-seq) was performed on mouse brain tissues. To investigate the underlying mechanisms, the mouse brain microvascular endothelial cell line bEnd.3 and BV2 microglial cell line were used. The protective effect of Ptbp2 on BBB integrity following stroke was evaluated by targeted overexpression and knockdown. We found that Ptbp2 overexpression reduced microglia-mediated neuroinflammation and BBB damage while inhibiting pathological glycolysis, according to findings from both in vitro and in vivo studies. Additionally, Ptbp2 level was significantly downregulated in patients with stroke compared to controls, and was inversely correlated with the severity of neural impairment. Our study unveils novel immunomodulatory mechanisms in stroke and highlights Ptbp2 and its regulatory network as potential therapeutic targets for stroke. Following ischemic stroke, Ptbp2 reduces neuroinflammatory symptoms and the breakdown of the blood–brain barrier by regulating microglial polarization both in vivo and in vitro.

To explore the effects of Complement Component 5a (C5a) on central nervous system vasculitis and its molecular mechanism. Bioinformatics analysis was conducted using the GSE68004 dataset (comprising 76 cases of vasculitis and 37 control samples).Endothelial cells were subjected to different treatments, and protein expression was determined by Western blot. Fibroblasts were cultured after different stimulations. Immunofluorescence was employed to detect the fluorescence intensity of α-SMA, and the CCK-8 assay was used to detect cell proliferation. Bioinformatics analysis reveals a significant positive correlation between C5a and the activation of the PI3K/ERK/AKT pathway (p < 0.05). In vitro experiments shows that stimulation with C5a (10 nM) significantly increases the protein expression of P-PI3K, P-ERK1/2, HIF1α and ROBO4 in endothelial cells (p < 0.05), while significantly reducing the expression of tight junction proteins (ZO-1, occludin, claudin-5) (p < 0.05). In fibroblasts, C5a stimulation increases the protein expression of P-CREB, fibronectin and α-SMA (p < 0.05), and promotes TGF-β1 secretion (p < 0.05). The use of PI3K/ERK inhibitor D-87503 or specific siRNA knockdown of ERK/CREB can significantly reverse these effects. In vitro, Complement C5a may disrupt the endothelial barrier function and promote fibrosis and proliferation of fibroblasts, potentially through activating the PI3K/ERK/HIF1α/ROBO4 pathway in endothelial cells or the CREB pathway in fibroblasts. These processes are recognized as key pathological features of central nervous system vasculitis, suggesting that C5a may contribute to their progression.

Synaptic plasticity plays a crucial role in the extinction of fearful memories. Low-intensity transcranial ultrasound stimulation (TUS) can modulate synaptic plasticity and promote the extinction of fear memories. However, the mechanism by which TUS promotes the extinction of fear memory remains unclear. This study aimed to explore whether and how synaptic plasticity under TUS is involved in modulating fear memory and the role of the brain-derived neurotrophic factor (BDNF)-the tropomyosin-related kinase B (TrkB) signaling pathway in this process. We used behavioral tests and two-photon fluorescence imaging to investigate the modulatory effects of TUS on fear memory and examined the formation/elimination of dendritic spines and the calcium activity of pyramidal neurons in the prefrontal cortex in mice in vivo. We found that TUS of the prefrontal cortex can promote fear memory extinction in mice while promoting dendritic spine formation, reducing dendritic spine elimination, increasing pyramidal neuron activity, and enhancing the expression of BDNF and its receptor TrkB. Conversely, inhibiting the BDNF-TrkB signaling pathway weakened these effects of ultrasound stimulation. Our study demonstrated that TUS could promote the extinction of fear memories, indicating that TUS has the potential to be used in the clinical treatment of patients with fear memory.

Apoptosis is a significant occurrence of cell death in the cerebral ischemia process, potentially revealing specific treatment points. Silibinin (SIL) has been proven to regulate a range of biological effects on inflammation, oxidative stress and apoptosis. Meanwhile, the epidermal growth factor receptor (EGFR) has been reported to impact cell apoptosis owing to its proliferative activity, which is in the opposite direction of apoptosis. This brings up the question of whether silibinin modulates apoptosis after cerebral ischemic injury and whether EGFR is involved in mediating this effect. We therefore examined the potential protective role of silibinin in ischemic brain and the underlying mechanisms. We assigned CD1 mice into groups and assessed neurological function via behavioral tests, infarct volume staining, and edema measurement. Neuronal vitality in the infarcted hemisphere was assessed using Nissl staining, while the level of apoptosis was evaluated by detecting cleaved Caspase-3, Bcl-2, and Bax. Penumbra vascular conditions were examined by immunofluorescence and two-photon imaging. Western Blot and immunohistochemistry detected EGFR/ERK level changes. An EGFR inhibitor was used to confirm the involvement of the EGFR/ERK pathway in the disease process. Our findings indicated that silibinin substantially diminished infarct volume and brain edema, reduced neuronal apoptosis following stroke, enhancing neurological function. These effects were accompanied by up-regulation of p-EGFR/EGFR, p-ERK/ERK, and Bcl-2, as well as down-regulation of Bax and cleaved-Caspase3 in ischemic brain tissue post-stroke, while inhibiting EGFR activation attenuated or reversed the anti-apoptotic effects of silibinin. We concluded that silibinin protected the brain after cerebral ischemia by exerting anti-apoptotic effects via the activation of EGFR/ERK signaling pathway.

Alzheimer’s disease (AD) is identified as the prevalent neurodegenerative condition globally, ultimately resulting in dementia. Currently, the mechanisms that contribute to AD are not well comprehended, and there are few therapeutic alternatives available. Bicyclol, a substance extracted from the Chinese herb Schisandra Chinensis, has shown remarkable antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective characteristics. However, there is a shortage of research focusing on the therapeutic effects of bicyclol on AD as well as the molecular pathways that may be involved. This study sought to evaluate the effects of bicyclol on cognitive impairments in a mouse model of AD, explore its neuroprotective benefits associated with antioxidant functions and apoptosis suppression, and reveal the mechanisms involved. In this study, APP/PS1 mice underwent a 2-month treatment with bicyclol administered via gavage, after which their cognitive abilities were evaluated through behavioral assessments. The apoptosis of cortical neurons was evaluated using TUNEL staining and immunofluorescence techniques. N2A cells, which were exposed to Aβ1–42 oligomers, received a pretreatment with bicyclol, and their viability was subsequently measured. The expression levels of proteins such as nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P) H-quinine oxidoreductase-1 (NQO1), BCL2 associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2), and Cleaved caspase-3 were quantified in vitro and in vivo using western blotting and qPCR methods. Moreover, N2A cells lacking Nrf2 were utilized to investigate the underlying mechanisms through which bicyclol exerts its effects in Alzheimer’s disease. Bicyclol has been shown to enhance cognitive function while simultaneously reducing the levels of cortical Aβ1–40 and Aβ1–42, and it also protects against neuronal degeneration in the APP/PS1 mouse model. Moreover, it increases the activity of cortical SOD and GSH-Px, concurrently decreasing levels of ROS and MDA in vivo. Additionally, bicyclol significantly lessened oxidative stress and apoptosis induced by Aβ1–42 in N2A cells. It further elevated the expression of proteins such as Nrf2, HO-1, and NQO1, along with mRNA levels in both in vitro and in vivo experiments. Furthermore, the silencing of Nrf2 via siRNA transfection counteracted the regulatory effects of bicyclol on apoptotic markers including Bax, Bcl-2, and Cleaved caspase-3 in vitro. Our study provides compelling evidence that bicyclol effectively alleviates cognitive impairments observed in APP/PS1 mice. Furthermore, our findings indicate that bicyclol plays a significant role in reducing oxidative stress-induced injury and neuronal apoptosis. This protective effect is associated with the activation of the Nrf2/HO-1 signaling pathway. These results suggest that bicyclol has the potential to be developed as a therapeutic agent for the treatment of Alzheimer’s disease, highlighting its promise in addressing the cognitive decline associated with this debilitating condition.

ObjectiveThe study aimed to explore the correlation between the systemic inflammatory response index (SIRI) and acute ischemic stroke in youth.MethodsA retrospective study was conducted. A total of 90 patients aged 18–45 years with acute ischemic stroke were included in the youth cerebral infarction (YCI) group, and 50 patients within the same age bracket without stroke or intracranial atherosclerosis, who were hospitalized during the same period, were included in the control group. Clinical information, blood biochemical indicators, and imaging data of the participants were analyzed. Binary logistic regression was used to assess the independent association between the SIRI and YCI. Furthermore, a subgroup analysis was performed on YCI patients. The subgroup classification included (i) infarct volume grouping; (ii) intracranial artery stenosis grouping; (iii) the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification grouping; (iv) infarct distribution grouping; and (v) vasculopathy grouping.ResultsThe SIRI values were higher in the YCI group compared to the control group (p = 0.005). After adjusting for confounding factors, multivariate logistic regression confirmed that the SIRI is an independent factor associated with YCI (OR = 1.692,95% CI:1.045–2.739, p = 0.032). The receiver operating characteristic (ROC) curve showed that the optimal cutoff value for the SIRI as a predictor of YCI was 0.83*10^9/L, with corresponding sensitivity and specificity of 77.8 and 50%, respectively. The AUC was 0.643, with a 95%CI of 0.54–0.74 and a p-value of = 0.005. The subgroup analysis results were as follows: (i) There was no statistically significant difference in the SIRI values among the infarct volume groups (p = 0.633). (ii) The SIRI values in the severe stenosis group were higher than those in the non-stenosis and mild-to-moderate stenosis groups (p < 0.001). Binary logistic regression analysis showed that the SIRI was an independent associated factor for severe stenosis (original OR = 3.346,95% CI = 1.761–6.359, p < 0.001; corrected OR = 5.278,95% CI = 2.317–12.022, p < 0.001). (iii) The SIRI values in the large-vessel atherothromboembolic (LAA) group were higher than those in the small-vessel disease (SVD) group (p = 0.003). (iv) There was no statistically significant difference in the SIRI values between the infarct distribution groups (p = 0.572). (v) There was no statistically significant difference in the SIRI values between the vasculopathy groups (p = 0.345).ConclusionThe SIRI is independently associated with YCI and is significantly linked to severe intracranial arterial stenosis and the LAA subtype.

Platelet count and function may be closely related to survival and prognosis of stroke and cancer. However, little is known on the impact of platelet count on the patients with a history of stroke and cancer. This study aimed to examine the association between baseline platelet level and all-cause mortality in this population using a cross-sectional analysis. Participants with a history of stroke and cancer were selected from the database of the National Health and Nutrition Examination Survey from 2007 to 2018. A maximum selected rank statistic was conducted to determine platelet cutoff with the most significant association with mortality. The association between platelet and mortality was characterized visually using restricted cubic spline (RCS). Weighted multivariable Cox regression models were performed to evaluate the association between platelet count and mortality. Time-dependent receiver operating characteristic (ROC) analysis was conducted to assess the accuracy of platelet count in predicting mortality. Forty-three (43/113, 38.05

Angiogenesis in the ischemic penumbra compensates for microcirculatory dysfunction and promotes neuronal plasticity after stroke. However, the current understanding may be highly biased because the contribution of veins to angiogenesis has been overlooked. This study revealed that the remodeling processes of veins differ from those of arteries after ischemia. Ligation of the right jugular vein increased the infarct volume, decreased cerebral blood flow and impaired long-term functional restoration after stroke. RNA-seq analysis revealed significant upregulation of the expression of genes associated with angiogenesis in the infarct core during the recovery period. By using gelatin ink-alkaline phosphatase-oil red O (GIAO) staining, we found that venogenesis, the process of creating new veins, was the predominant angiogenic event in the infarct core. Macrophage infiltration and transformation are closely associated with venogenesis in the infarct core. However, depletion of macrophages in the circulation by clodronate liposomes in the acute phase inhibited the proliferation of endothelial progenitor cells and decreased the vascular density in the infarct core. This study demonstrated that dynamic vein remodeling is crucial for cerebral ischemic damage and subsequent neuronal restoration. Angiogenesis occurs in the infarct core during the recovery period, promotes the absorption of necrotic tissue and facilitates functional recovery after stroke.

Synchronized neurogenesis and angiogenesis after stroke have been well documented, and inducing neurovascular remodeling may provide a promising strategy to promote tissue repair and functional recovery. Dl-3-n-Butylphthalide (NBP) was reported to exert a potent angiogenic activity in rodent models of stroke. However, little is currently known regarding the effects and mechanisms of NBP on neurogenesis in ischemic stroke. This study aimed to determine whether and how NBP promotes neurogenesis in cerebral ischemic injury. Adult C57BL/6 mice, subjected to distal middle cerebral artery occlusion (dMCAO), were treated with NBP. The efficacy of NBP was assessed using neurologic deficits and infarct volume. Immunofluorescent staining was applied to evaluate neurogenesis. The regulation of the Wnt/β-catenin signaling pathway and the expression of neurotrophic factors were detected by western blotting and qRT-PCR. Administration of NBP reduced infarct volume and ameliorated neurological deficits after stroke. NBP promoted the proliferation of NSCs in the SVZ, migration of neuroblasts along the corpus callosum, and differentiation of neuroblasts toward neurons in the peri-infarct zone, resulting in restored neural function. Moreover, we revealed that NBP-induced neurogenesis was associated with the activation of the Wnt/β-catenin pathway, which was reversed by DKK1. In addition, NBP increased the production of VEGF and BDNF. Our data have unveiled the potentials of NBP to promote neurogenesis and neural functional recovery after stroke, depending on Wnt/β-catenin signaling activation and neurotrophic factor production. Thus, NBP may be a promising candidate for delayed treatment of ischemic stroke.

Functional connectivity between the cerebellum and the motor cortex is critical for motor function. Low-intensity transcranial ultrasound stimulation (TUS) has been proved to directly activate cerebellar neural activity. However, whether and how TUS of the cerebellum modulates neural activity in the motor cortex is unclear.In the study, TUS with different parameters was used to stimulate the mouse cerebellar region while local field potentials (LFP) in the cerebellum and the motor cortex were simultaneously recorded, as well as neuronal calcium ion activity. We discovered that: (1) TUS can increase the amplitude and power intensity of LFP in the cerebellum and motor cortex, which linearly increasing with the increase of ultrasound intensity, and nonlinearly increasing with the increase of the duty cycle; (2) TUS in the cerebellum significantly increased the firing time and peak of neurons of the motor cortex, which also increased linearly with the increase of ultrasound intensity and nonlinearly with the increase of duty cycle; (3) The cross-correlation information of the LFP between the cerebellum and motor cortex was enhanced, which depends on ultrasound intensity and duty cycle; (4) TUS in the cerebellum for 7 days improved the motor ability of ischemic stroke mice. Taken together, the above findings indicate that TUS of the cerebellum can modulate the excitability of neural activity in the motor cortex, which is important in modulating the symptoms of motor cortex-related diseases. We also describe the ameliorative effect of TUS of the cerebellum on movement disorders caused by cerebral ischemia.