A Preliminary Finding: N-butyl-phthalide Plays a Neuroprotective Role by Blocking the TLR4/HMGB1 Pathway and Improves Mild Cognitive Impairment Induced by Acute Cerebral Infarction.

BACKGROUND: Most acute cerebral infarctions (ACI) may develop vascular dementia (VD), which involves almost all types of cognitive impairment. Unfortunately, there is currently no effective treatment for VD. Most patients exhibit mild cognitive impairment (MCI) before the development of VD. N-butyl-phthalide (NBP) is used to treat ACI and improve cognitive function. The oxygen and glucose deprivation (OGD) model of neurons is an in vitro model of ischemia, hypoxia, and cognitive dysfunction. METHODS: We conducted clinical studies and in vitro experiments to investigate the clinical efficacy and mechanism of action of NBP for treating ACI-induced MCI. Patients with ACI-induced MCI were randomly divided into control (Ctrl) and NBP groups. We assessed various indicators, such as clinical efficacy, montreal cognitive assessment scale (MOCA), activities of daily living (ADL), and cerebral infarct size in both groups before and after treatment. We observed the morphology of neurons and detected the survival rate, action potentials (APs), expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and the interaction between TLR4 and HMGB1. RESULTS: The MOCA and ADL scores increased significantly after treatment in the NBP group. A OGD model of neurons was established, and the neurons were divided into Ctrl and NBP groups. We observed that the survival rate and APs amplitude of the neurons were significantly increased in the NBP group, whereas TNF-α expression was decreased. Furthermore, the interaction between TLR4 and HMGB1 decreased in the NBP group. CONCLUSION: NBP plays a neuroprotective role by inhibiting the TLR4/HMGB1 pathway and ameliorating ACI-induced MCI.

[Effect of Xuming Decoction in Records of Proved Prescriptions, Ancient a nd Modern on cerebral ischemic injury and angiogenesis in rat model of acute cerebral infarction].

This paper aims to explore the effect of Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern on cerebral ischemic injury and angiogenesis in the rat model of acute cerebral infarction. SD rats were randomized into 6 groups: sham group, model group, low-, medium-, and high-dose(5.13, 10.26, and 20.52 g·kg~(-1), respectively) Xuming Decoction groups, and butylphthalide(0.06 g·kg~(-1)) group. After the successful establishment of the rat model by middle cerebral artery occlusion(MCAO), rats in the sham and model groups were administrated with distilled water and those in other groups with corresponding drugs for 7 consecutive days. After the neurological function was scored, all the rats were sacrificed, and the brain tissue samples were collected. The degree of cerebral ischemic injury was assessed by the neurological deficit score and staining with 2,3,5-triphenyltetrazolium chloride. Hematoxylin-eosin staining was performed to observe the pathological changes in the brain. Transmission electron microscopy was employed to observe the ultrastructures of neurons and microvascular endothelial cells(ECs) on the ischemic side of the brain tissue. Immunofluorescence assay was employed to detect the expression of von Willebrand factor(vWF) and hematopoietic progenitor cell antigen CD34(CD34) in the ischemic brain tissue. Real-time PCR and Western blot were employed to determine the mRNA and protein levels, respectively, of Runt-related transcription factor 1(RUNX1), vascular endothelial growth factor(VEGF), angiopoietin-1(Ang-1), angiopoietin-2(Ang-2), and VEGF receptor 2(VEGFR2) in the ischemic brain tissue. The results showed that compared with the sham group, the model group showed increased neurological deficit score and cerebral infarction area(P<0.01), pathological changes, and damaged ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Furthermore, the modeling up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.05 or P<0.01). Compared with the model group, high-dose Xuming Decoction and butylphthalide decreased the neurological deficit score and cerebral infarction area(P<0.01) and alleviated the pathological changes and damage of the ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Moreover, they up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01). The results suggest that Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern can promote the angiogenesis and collateral circulation establishment to alleviate neurological dysfunction of the ischemic brain tissue in MCAO rats by regulating the RUNX1/VEGF pathway.

Omentin-1 May Be One Treatment Factor for Intravenous Thrombolysis of Acute Cerebral Infarction Through the Inhibition of NLRP3 Ubiquitination by AMPK Function: Preliminary Findings.

BACKGROUND: Acute cerebral infarction (ACI) is a common neurological disease that is associated with high morbidity, disability and mortality rates. At present, antiplatelet therapy is a necessary treatment for ACI. The present study aimed to investigate the effects of omentin-1 on the intravenous thrombolysis of ACI. OBJECTIVE: The present study aimed to investigate the effects of omentin-1 on the intravenous thrombolysis of ACI. MATERIAL AND METHODS: The mouse model of ACI was induced using male C57BL/6 mice through middle cerebral artery occlusion (MCAO). Meanwhile, the murine BV2 microglial cells were pretreated with 0.1 mg/ml of lipopolysaccharide (LPS), and then induced with 2 mM of adenosine triphosphate (ATP). RESULTS: The omentin-1 mRNA expression in patients receiving intravenous thrombolysis for ACI was down-regulated compared with the normal group. Additionally, the serum level of omentin-1 was negatively correlated with National Institute of Health Stroke Scale (NIHSS) score or serum level of IL-1ß or MMP-2 in patients receiving intravenous thrombolysis for ACI. Meanwhile, the serum mRNA expression of omentin-1 was positively correlated with Barthel index or high-sensitivity C-reactive protein (hs-CRP) in patients undergoing intravenous thrombolysis for ACI. As observed from the in vitro model, Omentin-1 reduced inflammation, promoted cell growth, alleviated ROS-induced oxidative stress, and enhanced AMPK activity through activating NLRP3 ubiquitination. Omentin-1 presented ACI in the mouse model of ACI. Regulating AMPK activity contributed to controlling the effects of Omentin-1 on the in vitro model. CONCLUSIONS: Omentin-1 reduced neuroinflammation and ROS-induced oxidative stress in the mouse model of ACI, which was achieved by inhibiting NLRP3 ubiquitination through regulating AMPK activity. Therefore, omentin-1 may serve as a treatment factor for the intravenous thrombolysis of ACI in further clinical application.

Calpain as a Therapeutic Target for Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a complex pathophysiological process with multiple links and factors. It involves the interaction of inflammation, oxidative stress, and glucose metabolism, and results in acute and even long-term brain damage and impairment of brain function. Calpain is a family of Ca2+-dependent cysteine proteases that regulate cellular function. Calpain activation is involved in cerebral ischemic injury, and this involvement is achieved by the interaction among Ca2+, substrates, organelles, and multiple proteases in the neuronal necrosis and apoptosis pathways after cerebral ischemia. Many calpain inhibitors have been developed and tested in the biochemical and biomedical fields. This study reviewed the potential role of calpain in the treatment of HIE and related mechanism, providing new insights for future research on HIE.

[Initial Treatment of Cerebral Hemorrhage:Determining the Cause without Preconceived Notions].

In Japan, cerebral hemorrhage accounts for 19.5% of stroke patients, and its prognosis is poorer than that of cerebral infarction, with a mortality rate of 14.6%. In the initial treatment of cerebral hemorrhage, the airway, respiration, and circulation should be stabilized, and the intracranial pressure and body temperature should be controlled. Hypertensive cerebral hemorrhage is the most common cause; however, the cause should be carefully examined, and the treatment method should be selected according to the degree of urgency. Cerebral hemorrhage patients undergoing antithrombotic therapy show poor outcomes owing to increased hematoma. Therefore, antithrombotic drugs should be discontinued immediately. Blood products and neutralizing drugs should be administered in response to the administration of antithrombotic drugs. In young individuals, cerebrovascular disorders may be caused by the abuse of sympathomimetic drugs, such as stimulants and cocaine. Whether individuals or their family members are using illegal drugs should be confirmed.

The effect of butylphthalide on improving the neurological function of patients with acute anterior circulation cerebral infarction after mechanical thrombectomy.

Butylphthalide can improve blood circulation in patients with acute cerebral infarction. Complement 3a receptor 1 (C3aR1) is involved in the regulation of innate immune response and pathogen monitoring, which is closely related to the pathophysiological processes of breast cancer, neurogenesis and lipid catabolism. Our study explored the therapeutic effect of butylphthalide on improving the neurological function of patients with acute anterior circulation cerebral infarction after mechanical thrombectomy, and evaluated the correlation between serum C3aR1 and butylphthalide on improving the neurological function after mechanical thrombectomy. 288 patients with acute anterior circulation cerebral infarction who were admitted to our hospital from January 2019 to November 2022 and were treated with mechanical thrombectomy for the first time were included in this retrospective study and divided into the butylphthalide group and control group that they received treatment methods. The National Institutes of Health Stroke Scale (NIHSS) scale was used to evaluate the patient neurological function treatment efficacy, and the modified Rankin Scale (mRS) scale was used to measure the patient neurological function status 3 months after surgery. Enzyme-linked immunosorbent assay method was used to determine the content of C3aR1 in serum. Two weeks after thrombus removal, the NIHSS efficacy of the butylphthalide group and the control group were 94.44% and 72.22%, respectively. The butylphthalide group was significantly higher than the control group (P < .001). Three months after the operation, the mRS score of the butylphthalide group was significantly lower than that of the control group (P = .001), and the excellent and good rate was significantly higher than that of the control group (P < .001). The serum C3aR1 level of the butylphthalide group was significantly lower than that of the control group 2 weeks after operation and 3 months after operation (P < .001). The serum C3aR1 was positively correlated with the efficacy of NIHSS (R = 0.815, P = .004), which was positively correlated with mRS score (R = 0.774, P = .007). Butylphthalide can improve the therapeutic effect of neurological function in patients with acute anterior circulation cerebral infarction after mechanical thrombus removal. The patient serum C3aR1 is related to the patient neurotherapy efficacy and neurological function status, and its level can reflect the patient neurological function recovery to a certain extent.

Correlation Study of Chronic Renal Insufficiency and Long-Term Prognosis of Patients with Acute Ischemic Cerebral Apoplexy After Intravenous rt-PA Thrombolysis.

Objective: To investigate the correlation between chronic renal insufficiency and the long-term prognosis of patients with acute ischemic cerebral apoplexy after intravenous recombinant tissue plasminogen activator (rt-PA) thrombolysis. Methods: 290 patients (194 males and 96 females) with acute cerebral infarction who received intravenous rt-PA thrombolysis were admitted to Ningbo Medical Center Lihuili Hospital from May 2018 to December 2020. Their clinical baseline data were recorded. According to the estimated glomerular filtration rate (eGFR) level, patients were divided into the control group (252 cases) and the chronic kidney disease (CKD) group (38 cases). The prognosis of patients was evaluated by a modified Rankin Scale (mRS) 90 days after cerebral apoplexy by telephone interview or outpatient following-up (mRS ≤ 2 reflected good prognosis, mRS >2 reflected unfavorable prognosis). Multivariate logistic regression was used to analyze the prognosis risk relationship of acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis with CKD. Results: Acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis with CKD were older ((79.08 ± 8.96) years vs (65.84 ± 13.31) years, P = .00052, 95% CI = 0.00031-0.00072) than who without CKD, and were more likely to be suffering from hypertension (94.7% (36/38) and 66.3% (167/252), P = .00023, 95% CI = 0.00011-0.00033), atrial fibrillation (50.0% (19/38) and 26.6% (67/252), P = .007, 95% CI = 0.001-0.009), high Uric acidemia (68.4% (26/38) and 17.9% (45/252), P = .00044, 95% CI = 0.00027-0.00061), hyperhomocysteinemia (47.4% (18/38) and 13.1% (33/252), P = .00032, 95% CI=0.00022-0.00053), history of malignant tumor (13.2% (5/38) and 4.4% (11/252), P = .044, 95% CI = 0.0023-0.0053), cardiogenic embolism (Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification of cerebral infarction) (47.4% (18/38) and 29.0% (73/252), P = .038, 95% CI = 0.029-0.055). The mortality rate of the CKD group was higher than the control group (13.2% (5/38) and 4.0% (10/252), P = .033, 95% CI = 0.021-0.053), and the good prognosis rate in the CKD group was significantly lower than in the control group (42.1% (16/38) and 73.8% (186/252), P = .00032, 95% CI = 0.00012-0.00043). Multivariate logistic regression analysis showed that CKD was an independent risk factor for acute ischemic cerebral apoplexy patients undergoing intravenous rt-PA thrombolysis (OR = 4.606, 95%CI 1.176~18.041, P = .028, 95% CI = 0.022-0.043). Conclusion: CKD is an independent risk factor for acute ischemic cerebral apoplexy patients with intravenous rt-PA thrombolysis.

Study on the Difference of Protective Efficacy and Mechanism of Radix Aconiti Coreani and Rhizoma Typhonii in Gerbils with Ischemic Stroke.

Ischemic stroke is a common type of stroke, but effective treatment methods are still imperfect and new effective therapies need to be explored. Radix Aconiti Coreani and Rhizoma Typhonii used as Baifuzi in the treatment of stroke or symptoms associated with stroke have been recorded in ancient Chinese books and are widely used. Modern pharmacological studies have demonstrated that both of them have antioxidant and anti-inflammatory effects. The purpose of this study is to investigate whether Radix Aconiti Coreani and Rhizoma Typhonii have therapeutical effects on gerbils with ischemic stroke, to investigate their potential mechanisms of action, and to provide a reference for rational clinical application by comparing the differences between them. In this manuscript, the right unilateral ligation of the carotid artery of gerbils was used to cause an ischemic stroke model. The neurological deficits of gerbils in each group were scored by Longa scale. The area of cerebral infarction was detected by 2,3,5-tribenzotetrazolchloride staining. The levels of inflammatory factors, oxidative stress indexes, and vascular endothelial function indexes in brain homogenate and serum were determined by ELISA. The expression levels of P-Akt PI3K, HO-1, and KEAP1 proteins in brain tissue were determined by Western blot. Immunofluorescence staining was used to observe the recovery of neuronal cells in the hippocampal CA1 region of the gerbil brain tissue and the expression of proteins related to PI3K/Akt and KEAP1/Nrf2 signaling pathways in neuronal cells in the hippocampal CA1 region. It was found that Radix Aconiti Coreani and Rhizoma Typhonii could improve neurological deficits and reduce cerebral infarction rate in gerbils. The results showed that Radix Aconiti Coreani and Rhizoma Typhonii could significantly decrease the expression of inflammatory factors, increase the expression of antioxidative stress indexes and vascular endothelial function factors, activate the PI3K/Akt, KEAP1/Nrf2 signaling pathway, reduce the inflammatory response, inhibit the oxidative stress, enhance the vascular endothelial cell function, and thus protect against ischemic brain injury. From the experimental results, both Radix Aconiti Coreani and Rhizoma Typhonii had neuroprotective effects on ischemic brain injury. Compared with Rhizoma Typhonii, the effects of Radix Aconiti Coreani on anti-inflammatory and antioxidative stress were more significant, while Rhizoma Typhonii had showed more significant effects in promoting angiogenesis after ischemic stroke by increasing the level of NO.

Butylphthalide regulation of nerve cells in rats with cerebral infarction through jnk/p38mapk signaling pathway15.

To investigate the regulatory effect of butylphthalide (NBP) on the nerve cells of rats with cerebral infarction (CI) through the JNK/p38MAPK signaling pathway, 135 SPF SD male rats were and randomly assigned into the control group (n=45, sham surgery + peanut oil gavage), model group (n=45, CI model + peanut oil gavage), and NBP group (n= 45, CI model + NBP gavage). The comparison of the neurological function score between the model group and the NBP group, as well as the integrated locomotor ability score, Slit2 expression level, blood-brain barrier permeability, micro vessel density (MVD), CI volume, neuronal apoptosis rate of the brain tissue and expression levels of brain tissue p-JNK and p-p38MAPK protein among three groups was conducted. NBP inhibits the expression of JNK/p38MAPK signaling pathway, promotes the expression of Slit2 in CI rats, improves the neurological function and locomotor ability of CI rats, while promoting micro vascularization of the brain tissue, protecting the blood-brain barrier, reducing the volume of CI and the apoptosis of nerve cells.

Butylphthalide regulation of nerve cells in rats with cerebral infarction through jnk/p38mapk signaling pathway.

To investigate the regulatory effect of n-butylphthalide (NBP) on the nerve cells of rats with cerebral infarction (CI) through the JNK/p38MAPK signaling pathway, 135 SPF SD male rats were and randomly assigned into the control group (n=45, sham surgery + peanut oil gavage), model group (n=45, CI model + peanut oil gavage), and NBP group (n= 45, CI model + NBP gavage). The comparison of the neurological function score between the model group and the NBP group, as well as the integrated locomotor ability score, Slit2 expression level, blood-brain barrier permeability, micro vessel density (MVD), CI volume, neuronal apoptosis rate of the brain tissue and expression levels of brain tissue p-JNK and p-p38MAPK protein among three groups was conducted. NBP inhibits the expression of JNK/p38MAPK signaling pathway, promotes the expression of Slit2 in CI rats, improves the neurological function and locomotor ability of CI rats, while promoting micro vascularization of the brain tissue, protecting the blood-brain barrier, reducing the volume of CI and the apoptosis of nerve cells.

The protective effect of an extract of Salvia miltiorrhiza Bunge (Danshen) on cerebral ischemic injury in animal models: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Cerebral ischemia is a common disease that seriously threatens the health of human beings. Tanshinone IIA (TSA) is a fat-soluble compound isolated from the traditional Chinese medicine Danshen. Recent studies have shown that TSA plays a significant protective role in the animal models of cerebral ischemic injury. AIM OF THE STUDY: The meta-analysis was to evaluate the protective effect of Danshen (Salvia miltiorrhiza Bunge) extract (TSA) in cerebral ischemic injury, aiming at providing scientific evidence for clinical application of TSA in the treatment of cerebral ischemia in patients. MATERIALS AND METHODS: All relevant studies published in PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Scientific Journals Database (VIP) and Chinese Biomedicine Database (CBM) before Jan 2023 were systematically retrieved. The methodological quality was assessed by SYRCLE's risk of bias tool for the animal studies. Data was analyzed using Rev Man 5.3 software. RESULTS: A total of 13 studies were included. Compared with the control group, TSA significantly reduced the expression of glial fibrillary acidic protein (GFAP) (mean difference [MD], -1.78; 95% CI, [-2.13, -1.44]; P < 0.00001) and high mobility group protein B1 (HMGB1) (MD, -0.69; 95% CI, [-0.87, -0.52]; P < 0.00001). TSA also inhibited the activation of brain nuclear factor κB (NF-κB) (MD, - 0.36; 95% CI, [-0.41, -0.32]; P < 0.00001), malondialdehyde (MDA) (MD, -0.90; 95% CI, [-1.66, -0.13]; P = 0.02), cysteine protease-3 (Caspase-3) (MD, -1.39; 95% CI, [-1.98, -0.81]; P < 0.00001), and reduced cerebral infarction volume(MD, -16.26; 95% CI, [-20.76, -11.77]; P < 0.00001), brain water content (MD, -4.89; 95% CI, [-7.06, -2.71]; P < 0.0001) and neurological deficit scores (MD, -1.19; 95% CI, [-1.48, -0.89]; P < 0.00001). Additionally, TSA increased the brain content of superoxide dismutase (SOD) (MD, 68.31; 95% CI, [10.41, 126.22]; P = 0.02). CONCLUSIONS: The result of this study showed that TSA had a protective effect on cerebral ischemic injury in animal models, and the mechanism is associated with the reduction of inflammation and oxidative stress, and the inhibition of cell apoptosis. However, the quality of included studies may affect the accuracy of positive results. Therefore, more high-quality randomized controlled animal experiments are need for meta-analysis in the future.

A case report of Trousseau syndrome.

RATIONALE: In 1865, Trousseau first discovered pulmonary embolism caused by multiple venous thrombosis in patients with gastric cancer, and later all clinical manifestations of malignant patients during pathogenesis due to abnormal coagulation and fibrinolysis were referred to collectively as Trousseau syndrome. Trousseau syndrome is not a benign thrombophlebitis, and when diagnosed it requires immediate treatment. The survival rate over 1 year is only 12%. Stroke in cancer patients has distinct characteristics different from conventional stroke and has higher mortality. PATIENT CONCERNS: A 54-year-old female presented to the Department of Otolaryngology with recurrent right nasal bleeding for 4 days. After surgery, the patient experienced 7 different cerebral infarction courses. Finally died of brain herniation. DIAGNOSIS: The specific abnormal laboratory index is the increase of D-dimer, suggesting the hypercoagulation state. The patient developed multiple cerebral infarction, myocardial injury, renal infarction, splenic infarction, and lower extremity arterial thrombosis, and finally was diagnosed Trousseau syndrome. INTERVENTIONS: In the treatment, aspirin and atorvastatin were selected, but it did not work very well. D-dimer were high, we used low molecular weight heparin, and D-dimer decreased significantly. OUTCOMES: Finally the patient died of brain herniation. CONCLUSION: The raise of D-dimer and typical magnetic resonance imaging manifestation which provides a greater basis for diagnosis. The specific abnormal laboratory index is the increase of D-dimer, which provides direction for treatment and helps to evaluate treatment effect.

Increased human immunodeficiency virus viral load with cerebral infarction due to varicella zoster virus vasculopathy on treatment with bictegravir/emtricitabine/tenofovir alafenamide suspension: a case report and literature review.

BACKGROUND: Varicella-Zoster virus (VZV) vasculopathy occasionally occurs in immunocompromised patients and is difficult to treat. The risk factor and optimal therapy remain unclear. Patients with human immunodeficiency virus (HIV) and dysphagia or difficulty in oral intake receive antiretroviral therapy (ART) suspension. However, there remains little evidence regarding ART suspension. CASE PRESENTATION: We experienced a case of a 55-year-old man diagnosed with HIV and severe multiple cerebral infarctions due to VZV vasculopathy. We started on bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) and acyclovir (ACV), and prednisone. He was started on BIC/TAF/FTC suspension because of deteriorated swallowing. The HIV viral load was increased; however, no drug-resistance genes were detected. We successfully treated him with doltegravir/abacavir/lamibudine suspension. We performed two literature reviews of the administration of BIC/TAF/3TC suspension and VZV vasculopathy in patients with HIV. Three cases of BIC/TAF/3TC suspension were considered treatment failures. Recent history of VZV infection and a CD4 count under 200 µL may be risk factors for VZV vasculopathy. The effective treatment may be using steroid and ACV; however, treatment duration could differ. CONCLUSIONS: BIC/TAF/FTC suspension administration may be unstable, and treating ACV and steroid may be optimal therapy for VZV vasculopathy; however, the evidence level is low.

Risk factors for gastrointestinal bleeding in patients with cerebral infarction after dual antiplatelet therapy.

BACKGROUND: To investigate the risk factors for gastrointestinal bleeding in patients with cerebral infarction after dual antiplatelet therapy. METHODS: Cerebral infarction patients who received dual antiplatelet therapy during January 2019 and December 2021 in Nanchang University Affiliated Ganzhou Hospital were included. Patients were divided into a bleeding group and a nonbleeding group. Propensity score matching was used to match the data between the two groups. The risk factors for cerebral infarction with gastrointestinal bleeding after receiving dual antiplatelet therapy were analyzed by conditional logistic regression. RESULTS: There were 2370 cerebral infarction patients who received dual antiplatelet therapy included in the study. There were significant differences between the bleeding group and the nonbleeding group in terms of sex, age, smoking, drinking, hypertension, coronary heart disease, diabetes and peptic ulcer before matching. After matching, 85 patients were included in the bleeding group and nonbleeding group, and there was no significant difference between the two groups in terms of sex, age, smoking, drinking, previous cerebral infarction, hypertension, coronary heart disease, diabetes, gout or peptic ulcer. Conditional logistic regression analysis showed that long-term use of aspirin and severity of cerebral infarction were risk factors for gastrointestinal bleeding in cerebral infarction patients receiving dual antiplatelet therapy, whereas the use of PPI was a protective factor against gastrointestinal bleeding. CONCLUSIONS: Long-term use of aspirin and severity of cerebral infarction are risk factors for gastrointestinal bleeding in cerebral infarction patients receiving dual antiplatelet therapy. The use of PPIs could reduce the risk of gastrointestinal bleeding.

Klotho gene might antagonize ischemic injury in stroke rats by reducing the expression of AQP4 via P38MAPK pathway.

OBJECTIVES: This study was aimed at exploring whether klotho improved neurologic function in rats with cerebral infarction by inhibiting P38 mitogen-activated protein kinase (MAPK) activation and thus down-regulating aquaporin 4 (AQP4). METHODS: In this study, we induced intracerebral Klotho overexpression in 6-week-old Sprague Dawley rats by injecting lentivirus carrying full-length rat Klotho cDNA into the lateral ventricle of the brain, followed by middle cerebral artery occlusion (MCAO) surgery after three days. Neurologic function was evaluated by neurological deficit scores. Infarct volume was assessed by 2,3,5-triphenyl tetrazolium chloride (TTC) staining. The expressions of Klotho, AQP4, and P38 MAPK were detected by Western blot and Immunofluorescence. RESULTS: when rats were subjected to cerebral ischemia, their neurologic function was impaired, the protein expressions of klotho downregulated, the protein expressions of AQP4 and P38 MAPK increased, and the ratios of AQP4 and P-P38-positive area were significantly increased compared with the sham group rats. LV-KL-induced Klotho overexpression greatly improved neurobehavioral deficits and reduced infarct volume in MCAO rats. Klotho overexpression significantly reduced AQP4 and P38 MAPK pathway-related protein expression levels and the ratios of P-P38 and AQP4-positive area in MCAO rats. In addition, SB203580, a P38 MAPK signal pathway inhibitor, improved neurobehavioral deficits, reduced infarct volume, downregulated the expressions levels of AQP4 and P38 MAPK, and reduced the size of P-P38 and AQP4-positive area in MCAO rats. CONCLUSION: Klotho could alleviate the infraction volume and neurological dysfunction in MCAO rats, and its mechanism may involve AQP4 expression downregulation by suppressing P38-MAPK activation.

Dexmedetomidine alleviates cerebral ischemia-reperfusion injury via inhibiting autophagy through PI3K/Akt/mTOR pathway.

Dexmedetomidine has been shown to protect against cerebral ischemia-reperfusion injury (CIRI). Nevertheless, the precise mechanism is obscure. In order to explore the effect of dexmedetomidine pre-conditioning on autophagy against CIRI in rats, middle cerebral artery occlusion (MCAO) was conducted to establish cerebral ischemia-reperfusion (I/R) model in male SD rats with 2 h ischemia and 24 h reperfusion. Dexmedetomidine was delivered to rats at 10, 50 and 100 µg/kg doses respectively, and LY294002, a PI3K/Akt/mTOR pathway inhibitor, was administered at 10 mg/kg intraperitoneally 30 min before MCAO. Neurological deficit score was assessed and cerebral infarct size was detected by TTC staining. Morris water maze (MWM) was performed to estimate spatial learning and memory ability. Furthermore, to detect activity of PI3K/Akt/mTOR pathway and autophagy, p-Akt, p-mTOR, Beclin-1 and LC3 were measured by western blot. Our findings revealed that 50 and 100 µg/kg of dexmedetomidine pretreatment could improve the neurological deficit score and reduce cerebral infarct size after CIRI, while these effects were markedly suppressed by LY294002. In MWM test, dexmedetomidine was confirmed to shorten escape latency and increase times across platform after CIRI. Nevertheless, LY294002 pretreatment eliminated the improvement of dexmedetomidine on spatial learning and memory ability. Furthermore, dexmedetomidine pretreatment reduced ratios of Beclin-1 and LC3II/LC3I and elevated p-Akt/Akt and p-mTOR/mTOR after CIRI. However, above effects of dexmedetomidine were partly reversed by LY294002. Overall, dexmedetomidine pretreatment exerted neuroprotection against CIRI in rats by attenuating autophagy via the PI3K/Akt/mTOR pathway.

USE OF INFLIXIMAB TO ATTENUATE CEREBRAL APOPTOSIS INDUCED BY CEREBRAL ISCHEMIA/REPERFUSION IN MALE RATS.

OBJECTIVE: The aim: The purpose of the research was to study the role of infiximab global cerebral ischemia-reperfusion injury. PATIENTS AND METHODS: Materials and methods: The rats were split into five groups: Sham group; Control group: occlusion of the common carotid artery for 60 minutes, and sub-sequently reperfusion for an hour without receiving any medication; Vehicle group: as the control group, but 72 hours before to the ischemia, they were given the medication 0.9 NaCl intraperitoneally (i.p); Treated group-1: as the control group, plus 3 mg/kg of IFX intraperitoneally (i.p) 72 hours prior to ischemia; Treated group-2: as the control group, plus 7 mg/kg of IFX intraperitoneally (i.p) 72 hours prior to ischemia. RESULTS: Results: Pre-treatment with IFX significantly reduced the percentage of infarct area, but in the IFX (7 mg/kg) group, the infarct area was smaller than at the low dose. The ischemia group had a significant elevated of TNF- α and caspase-3 while a significant lowered in CAT and SOD levels. The pre-treatment with IFX, the TNF- α and caspase-3 levels lowered significantly, furthermore, significantly increased CAT and SOD levels activity (P≤0.05) as compared with IR group. Among effective groups, I/R+IFX (7mg/kg) group more effective in lowering TNF- α and caspase than I/R+IFX (3mg/kg) group. CONCLUSION: Conclusions: Infiximab has neuroprotective effective due to its powerful TNF- α blocker and limit ROS release and cell death signaling which protects the neurons from injury during cerebral ischemia reperfusion.

Effects of NBP injection on the inflammatory response, oxidative stress response and vascular endothelial function in patients with ACI: A systematic review and meta-analysis.

BACKGROUND: Acute cerebral infarction (ACI) is a common medical emergency. This study is the first systematic review of the use of Dl-3-n-butylphthalide (NBP) injection in the treatment of ACI. The purpose of this study was to systematically evaluate the effects of NBP injection on the inflammatory response, oxidative stress response and vascular endothelial function in patients with acute ACI. The objective is to provide reference for clinical application. METHODS: From the establishment of the database until August 2022, we systematically searched EMbase, PubMed, Cochrane Library, Web of Science, CNKI, VIP, and Wanfang Database. RCTs and retrospective studies were included in this study, and the results that qualified for inclusion were screened by 2 researchers and cross-checked. After the relevant data were extracted, a meta-analysis was performed using RevMan5.3 software. RESULTS: A total of 3307 patients with ACI from 34 studies were analyzed. The meta-analysis showed that the C-reactive protein levels in the NBP combined group were effectively reduced compared with those in the control group (MD = -3.75, 95% confidence intervals [95% CI] [-4.95, -2.56], P < .00001). Based on comparison with the control group, it is evident that combination treatment with NBP is more effective than control group in reducing the oxidative stress response of ACI (MD[superoxide dismutase levels] = 22.16, 95% CI [14.20,30.11], P < .00001; MD[malondialdehyde levels] = -1.97, 95% CI [-2.62, -1.32], P < .00001). Comparison with the control group shows that combination treatment with NBP is more effective in improving vascular endothelial function in ACI patients (MD[vascular endothelial growth factor levels] = 71.44, 95% CI [41.22, 101.66], P < .00001; MD[endothelin-1 levels] = -11.47, 95% CI [-17.39, -5.55], P = .0001; MD[nitric oxide levels] = 9.54, 95% CI [8.39, 10.68], P < .00001) than control group. The NBP combined group also showed a greater reduction in cerebral infarct volume (CIV) and cerebral infarct size (CIS) of ACI (MD[CIV] = -1.52, 95% CI [-2.23, -0.81], P < .0001; MD[CIS] = -2.79, 95% CI [-3.65, -1.94], P < .00001). The NBP combined group did not show an increase in the incidence of adverse reactions compared with the control group (odds ratio = 1.06, 95% CI [0.73, 1.53], P = .77). CONCLUSION: In summary, the use of NBP in combination with control group for ACI can reduce the degree of nerve damage, reduce inflammation and oxidative stress, improve vascular endothelial function, and reduce CIS and CIV in ACI patients, without increasing the incidence of clinical adverse events.

Sevoflurane preconditioning improves neuroinflammation in cerebral ischemia/reperfusion induced rats through ROS-NLRP3 pathway.

AIM: We aimed to study the influence of sevoflurane on the nucleotide-binding domain and Leucine-rich repeat protein 3 (NLRP3) pathways in rats with cerebral ischemia/reperfusion (I/R) injury. METHODS: Sixty Sprague-Dawley rats were equally divided into five groups randomly: sham-operated, cerebral I/R, sevoflurane (Sevo), NLRP3 inhibitor-treated (MCC950), and sevoflurane and NLRP3 inducer-treated groups. Rats' neurological functions were assessed using Longa scoring after 24 h of reperfusion, after which they were sacrificed, and cerebral infarction area was determined by triphenyl tetrazolium chloride staining. Pathological changes in damaged portions were assessed using hematoxylin-eosin and Nissl staining, and cell apoptosis was detected by terminal-deoxynucleotidyl transferase-mediated nick end labeling staining. Interleukin 1 beta (IL-1ß), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18), malondialdehyde (MDA), and superoxide dismutase (SOD) levels in brain tissues were determined using enzyme-linked immunosorbent assay. Reactive oxygen species (ROS) levels were analyzed using a ROS assay kit. Protein levels of NLRP3, caspase-1, and IL-1ß were determined by western blot. RESULTS: Neurological function scores, cerebral infarction areas, and neuronal apoptosis index were decreased in the Sevo and MCC950 groups than in the I/R group. IL-1ß, TNF-α, IL-6, IL-18, NLRP3, caspase-1, and IL-1ß levels decreased in the Sevo and MCC950 groups (p < 0.05). ROS and MDA levels increased, but SOD levels increased in the Sevo and MCC950 groups than in the I/R group. NLPR3-inducer nigericin eliminated the protective effects of sevoflurane on cerebral I/R injury in rats. CONCLUSION: Sevoflurane could alleviate cerebral I/R-induced brain damage by inhibiting the ROS-NLRP3 pathway.

To explore the regulatory effect of Buyang Huanwu Decoction on cerebral infarction based on quantitative proteomics.

Buyang Huanwu Decoction (BYHW) contains chemical components such as ligustrazine, oxypaeoniflora, chlorogenic acid, and others. To explore the neuroprotective effect and potential target protein of BYHW in cerebral infarction (CI). A double-blind, randomized controlled trial was established and patients with CI were divided into the BYHW group (n = 35) and the control group (n = 30). To evaluate the efficacy by TCM syndrome score and clinical indicators, and to explore the changes of serum proteins by proteomics technology, so as to explore the mechanism of BYHW and potential target proteins. The study found that compared with the control group, the TCM syndrome score, including Deficiency of Vital Energy (DVE), Blood Stasis (BS), and NIHSS in the BYHW group decreased significantly (p < 0.05), and the Barthel Index (BI) score was significantly higher. A total of 99 differential regulatory proteins were identified by proteomics, which act on lipids and atherosclerosis, complement and coagulation cascade, and TNF-α signaling pathway. In addition, Elisa verified the results of proteomics and found that BYHW can reduce the neurological impairments focus on IL-1ß, IL-6, TNF-α, MCP-1, MMP-9, and PAI-1. Significance: In this study, quantitative proteomics was used in combination with liquid chromatography-mass spectrometry (LC-MS/MS) to study the therapeutic effect of BYHW on cerebral infarction (CI) and potential changes in serum proteomics. In addition, the public proteomics database was used for bioinformatics analysis, and Elisa experiment verified the results of proteomics, further clarifying the potential protection mechanism of BYHW on CI.