Wogonin alleviates NLRP3 inflammasome activation after cerebral ischemia-reperfusion injury by regulating AMPK/SIRT1.

Cerebral ischemia-reperfusion (IR) is the main pathophysiological process after stroke and can seriously impair neurological function. Wogonin, a natural flavonoid extracted from the roots of Scutellaria baicalensis, has potent anti-inflammatory properties. In this study, we investigated the protective mechanism of wogonin against middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) model-induced cerebral IR injury through adenosine 5'-monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome axis. Our results showed that wogonin (20 mg/kg, intraperitoneal injection) effectively reduced infarct size, attenuated brain edema, improved neurological deficits, and alleviated histopathological damage. In addition, wogonin reduced microglial cell activation and inflammatory factors, including tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6, and IL-10, in brain tissue and serum after cerebral IR injury. Wogonin also effectively activated the AMPK/SIRT1 signaling pathway and inhibited NLPR3 inflammasome-related molecules upregulation in cerebral IR injury as well as in OGD/R-stimulated HT-22 cells. Furthermore, inhibition of the AMPK/SIRT1 signaling pathway by Compound C, an AMPK inhibitor, significantly reversed the protective effect of wogonin on OGD/R-induced NLRP3 inflammasome. Meanwhile, the protective effect of wogonin against brain IR injury was also reversed in the presence of compound C. These results suggest that wogonin ameliorates cerebral IR injruy-induced inflammation by inhibiting NLRP3 inflammasome through the AMPK/SIRT1 signaling pathway.

Interaction between diabetes and body mass index on severe headache or migraine in adults: a cross-sectional study.

BACKGROUND: Research on the effects of body mass index (BMI) on severe headache or migraine is limited and controversial. The aim of this study was to explore the association between BMI and the prevalence of migraine, with particular interest in diabetes status difference. METHODS: The present study used analyzed data from people who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2004. Logistic regression models and restricted cubic spline (RCS) models were applied to investigate the relationship between body mass index and migraine. RESULTS: A total of 10,074 adults aged 20 years or older were included in this study. Body mass index was positively related to migraine, and the corresponding odds ratio (OR; 95% CI) was 1.02 (1.01, 1.03; p < 0.001). And compared to participants in the lowest group of body mass index (< 25 kg/m2), the adjusted ORs for migraine in medium group (25-29.9 kg/m2), and highest group (≥ 30 kg/m2) were 1.14 (95% CI: 0.98-1.32, p = 0.09) and 1.30 (95% CI: 1.11-1.52, p = 0.0022), respectively. The relationship between BMI and migraine exhibited a linear in overall in the RCS. Our findings also suggested an interaction between BMI and diabetes. The relationship between BMI and migraine in adults with diabetes was non-linear. The OR of developing migraine was 1.30 (95% CI: 1.10-1.54) in individuals with BMI ≥ 29.71 kg/m2 in adults with diabetes. CONCLUSION: A higher body mass index is significantly associated with an increased prevalence of migraine, and diabetes status can modify the association between them.

Corrigendum to "Endovascular treatment of acute basilar artery occlusion caused by vertebral artery stump syndrome: A clinical analysis of 37 cases" [Heliyon 9 (4X), (March 2023) Article e14956].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e14956.].

Endovascular treatment of acute basilar artery occlusion caused by vertebral artery stump syndrome: A clinical analysis of 37 cases.

Introduction: Acute basilar artery occlusion (ABAO) caused by vertebral artery stump syndrome (VASS) has a low incidence and is always underestimated. Due to the occlusion of the origin of the vertebral artery (VA), it is often combined with basilar artery (BA) endovascular diseases or non-dominant contralateral vertebral artery, making the endovascular treatment (EVT) challenging to implement. Objective: This article focuses on whether EVT and two interventional route options could bring clinical benefits to this group of patients: basilar artery thrombectomy through the occluded lateral vertebral artery and implementing revascularization of the occluded vertebral artery (dirty-road-path); thrombectomy through the non-occluded lateral vertebral artery (clean-road-path). Methods: We collected six cases of acute embolic basilar artery occlusion (ABAO) due to VASS from January 2020 to December 2021 at our hospital and retrospectively analyzed 31 patients previously reported in the literature and applied statistical analysis to investigate the treatment options and clinical prognosis of these patients. Results: The clean-road-path surgical protocol was applied in 4 of 37 patients, the dirty-road-path protocol was applied in 29 patients, and 4 patients did not recanalized the basilar artery. By statistical analysis we found that successful recanalization of the basilar artery was clinically significant in reducing the modified Rankin Scale (mRS) scores in these patients, the statistical difference in the benefit of the two surgical protocols was negative. There was a significant positive correlation between preoperative National Institute of Health Stroke Scale (NIHSS) and postoperative 90-day mRS scores. Conclusion: Endovascular treatment can benefit patients with ABAO due to VASS, and patients with higher preoperative NIHSS scores are more vulnerable to getting a poor prognosis. Comparison between the two endovascular options did not yield statistically significant results, but the dirty-road-path option may be superior to using the clean-road-path.

Circular RNA circPRDX3 mediates neuronal survival apoptosis in ischemic stroke by targeting miR-641 and NPR3.

OBJECTIVE: circPRDX3 is a circular RNA (circRNA) that has received little attention yet. The purpose of this research is to elucidate circPRDX3 expression pattern and its underlying network in ischemic stroke (IS). METHODS: Oxygen-glucose deprivation on/reoxygenation (OGD/R) and mice model of middle cerebral artery occlusion (MCAO) were used to generate IS model in N2a cells or mice, respectively. Expression levels of circPRDX3, miR-641, Natriuretic Peptide Receptor 3 (NPR3), and members of the mitogen-activated protein kinases (MAPK) pathway were determined using real-time quantitative PCR (qRT-PCR) and western blot. Cell viability was assessed by CCK-8 assay and apoptosis was evaluated using TUNEL staining and flow cytometry. Molecule-molecule interactions were verified by dual luciferase and RNA immunoprecipitation (RIP) assays. The infarcted area was depicted by Triphenyl tetrazolium chloride (TTC) staining and the level of neurological function was measured using National Institute of Health stroke scale (NIHSS). RESULTS: CircPRDX3 and NPR3 were shown to be considerably downregulated in IS samples, as well as OGD/R cells or MCAO mice, while miR-641 was found to be significantly upregulated. A circPRDX3/miR-641/NPR3 mechinary was verified using luciferase and RIP assays. Overexpression of circPRDX3 dramatically reduced miR-641 expression and increased NPR3 expression, boosting cell survival and lowering apoptosis in an OGD/R model, either with inactivated MAPK signaling pathways. Moreover, overexpression of circPRDX3 lowered infarct volume and enhanced neurobehavioral outcomes in mice after MCAO, and these protective effects were dramatically abrogated by depletion of NPR3. CONCLUSION: Altogether, circPRDX3 inhibited the development of IS by sponging miR-641, hence increasing NPR3 expression and inactivating MAPK pathway. These results may aid in the search of potential therapy targets for IS.

IKKß Alleviates Neuron Injury in Alzheimer's Disease via Regulating Autophagy and RIPK1-Mediated Necroptosis.

Alzheimer's disease (AD), featured with memory loss and multiple cognitive impairments, is a devastating neurodegenerative disease that affects millions of people in the world, especially the elder people. IKKß plays important role in the development of neurodegenerative diseases. However, the molecular mechanism of IKKß, especially related with autophagy and necroptosis, in AD, is still unclear. Here, we studied the function of IKKß in regulating autophagy and RIPK1-induced necroptosis in SH-SY5Y cells and APP/PS1 mice. By silencing IKKß in the SH-SY5Y cells, we found that inhibition of IKKß could promote the RIPK1-induced necroptosis caused by Aß accumulation as well as suppress the autophagy of SH-SY5Y cells. Furthermore, we discovered that autophagy was significantly enhanced, and RIPK1-induced necroptosis was inhibited when IKKß was constitutively activated in SH-SY5Y cells. Then, using APP/PS1 mouse model, we demonstrated that silencing IKKß could significantly enhance the accumulation of Aß but have not impact on the mice behavior and cognitive ability. Even the controversial results about the role of IKKß in AD is not fully understood, our results might provide an important potential therapeutic target for slowing AD. .

MicroRNA-155-5p Targets SKP2, Activates IKKß, Increases Aß Aggregation, and Aggravates a Mouse Alzheimer Disease Model.

The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase ß (IKKß) are involved in Alzheimer disease (AD) pathogenesis. This study explored the mechanisms underlying IKKß-mediated Aß aggregation and neuron regeneration in APP.PS1 mice. Adenoviral transduction particles were injected into the hippocampal CA1 region of the mice to knock down or inhibit target genes. Morris water maze was performed to evaluate the cognitive function of the mice. Aß deposition was determined by histological examination. sh-IKKß plasmids and microRNA (miR)-155-5p inhibitor were transfected into Aß1-42-induced N2a cells. The expressions of AD-related proteins were detected by Western blot. The interaction between S-phase kinase-associated protein 2 (SKP2) and IKKß was assessed by co-immunoprecipitation. IKKß knockdown (KD) and miR-155-5p inhibition ameliorated cognitive impairment, improved neuron regeneration, and attenuated Aß deposition in APP/PS1 mice. SKP2 KD aggravated cognitive impairment, inhibited neuron regeneration, and promoted Aß deposition in the mice. SKP2 regulated the stability of IKKß protein via ubiquitination. MiR-155-5p regulates Aß deposition and the expression of Aß generation-related proteins in N2a cells via targeting SKP2. These results indicate that the miR-155-5p/SKP2/IKKß axis was critical for pathogenesis in this AD model and suggest the potential of miR-155-5p as a target for AD treatment.

Inhibitor Kappa B Kinase ß, Modulated by DJ-1/p-VHL, Reduces Phosphorylated Tau (p-Tau) Accumulation via Autophagy in Alzheimer's Disease Model.

It has been demonstrated Inhibitor Kappa B Kinase ß (IKKß) facilitates autophagy, which in turn mediates p-Tau protein clearance. However, the specific regulatory mechanism in Alzheimer's disease (AD) remains unclear. Firstly, AD model was generated by the intracerebroventricular (ICV) injection of the Β-amyloid 1-42 (Aß1-42) peptide. Subsequently, mice were injected with shRNA adenoviral transduction particles designed to target DJ-1 or Aß1-42 or Aß1-42 + shNC or Aß1-42 + shRNA against DJ-1. shRNA against DJ-1 were injected into hippocampus of mice (8 × 104 viral particles for each mice) for seven consecutive days. Immunohistochemistry was performed to detect the accumulation of Aß in the hippocampus of mice, and Hematoxylin-Eosin (HE) staining assay was carried to detect pathological changes in the hippocampus of mice. Further, sh-IKKß, shDJ-1, pcDNA-IKKß and pcDNA-DJ-1 plasmids were transfected into HT-22 cells, MTT assay, TUNEL staining and Hoechst staining were performed to detect cell viability and apoptosis, respectively. Western blotting was carried to measure the relative expression of proteins. Findings indicated that Aß1-42 inhibited autophagy and up-regulated p-Tau protein expression; Overexpression of IKKß and DJ-1 all rescued the autophagy inhibited by Aß1-42 and down-regulated p-Tau protein expression induced by Aß1-42; DJ-1 up-regulated IKKß via p-VHL, further promoted autophagy and reduced the expression of p-Tau protein; DJ-1 knockdown inhibited autophagy and up-regulated p-Tau protein expression, resulting in delayed behavior in mice. In conclusion, IKKß, modulated by DJ-1/p-VHL, reduces p-Tau accumulation via autophagy in AD's disease model. This study may provide theoretical basis for the treatment of AD.

EGb761 ameliorates cell necroptosis by attenuating RIP1-mediated mitochondrial dysfunction and ROS production in both in vivo and in vitro models of Alzheimer's disease.

OBJECTIVES: To investigate the neuroprotective effect of Gingko biloba extract 761 (EGb761) in Alzheimer's disease (AD) models both in vivo and in vitro and the underlying molecular mechanism. METHODS: Cultured BV2 microglial cells were treated with Aß1-42 to establish an in vitro AD model. The in vivo rat AD model was established by injecting Aß1-42. Cells were pre-treated with EGb761, and the proliferation and necroptosis were examined by MTT or flow cytometry assays, respectively. In addition, the membrane potential and oxidative stress were measured. Cognitive function was evaluated by the Morris water maze, and the activation of the JNK signaling pathway was quantified by Western blotting. RESULTS: Cultured BV2 cells exhibited prominent cell death after Aß1-42 induction, and this cell death was alleviated by EGb761 pre-treatment. EGb761 was found to relieve oxidative stress and suppress the membrane potential and calcium overload. EGb761 treatment in AD model rats also improved cognitive function deficits. Both cultured microglial cells and the rat hippocampus exhibited activation of the JNK signaling pathway, and EGb761 relieved this activation in cells. CONCLUSION: Our results showed that EGb761 regulated cell proliferation, suppressed necroptosis and apoptosis, relieved mitochondrial damage, and ameliorated tissue damage to improve cognitive function in AD models. All of these effects may involve the suppression of the JNK signaling pathway.

Atorvastatin Pretreatment Attenuates Ischemic Brain Edema by Suppressing Aquaporin 4.

BACKGROUND: Cerebral edema, a serious complication of acute cerebral infarction, has a crucial impact on morbidity and mortality in the early stage of cerebral infarction. And aquaporin 4 (AQP4), a bidirectional water transporting protein, plays a pivotal role in edema formation. At experimental model, it has proven that atorvastatin could exert pleiotropic neuroprotection on acute cerebral infarction independent of its cholesterol-lowering action. It was a common protective manifestation that atorvastatin can reduce the infarct volume and cerebral edema. However, little is known about atorvastatin improving ischemic brain edema by regulating AQP4 expression. This study intended to investigate the neuroprotection effects of atorvastatin pretreatment in rats with cerebral ischemia and further explore the potential relationship between atorvastatin and AQP4 expression. METHODS: Fifty-one adult male Sprague Dawley rats were randomly divided into 3 groups: sham, middle cerebral artery occlusion (MCAO), and atorvastatin pretreatment (Ator) group. For Ator group, 20 mg/kg of atorvastatin injectable suspension was administered once for 7days by gavage before operation, whereas the others were administered the same volume of saline matching. Except for sham group, MCAO and Ator groups were subjected to permanent MCAO by modified intraluminal suture method. Infarct volume, neurological deficit, brain water content (BWC), immunohistochemistry, western blot, and polymerase chain reaction (PCR) were measured at 24 hours after MCAO. RESULTS: Compared with sham group, the mNSS, infarct volume, and BWC of ischemic hemisphere were significantly increased (P < 0.001) in MCAO group. Positive cells and protein levels of p-p38MAPK and AQP4 in peri-infarction were significantly increased (P < 0.01). The mRNA levels of p38MAPK and AQP4 were also prominently upregulated (P < 0.01). Interestingly, preadministration of atorvastatin dramatically decreased infarct volume and the BWC of ischemic hemisphere compared with MCAO group (P < 0.05). The overexpressions of p-p38MAPK and AQP4 in peri-infarction were significantly decreased (P < 0.05) and their mRNA levels were downregulated by atorvastatin pretreatment (P < 0.05). Neurological deficits were also dramatically improved (P < 0.001). CONCLUSION: To the best of our knowledge, this is the first study that demonstrates an effect of atorvastatin on expression of AQP4, and we propose that decreased AQP4 expression through a p38MAPK-suppression pathway may be the mechanism of atorvastatin alleviating ischemic cerebral edema.

Rapidly progressive cognitive impairment caused by intracranial dural arteriovenous fistulas (DAVFs): a case report.

Intracranial dural arteriovenous fistulas (DAVFs), constituting approximately 10 to15% of intracranial vascular malformations, are anomalous direct connections between dural arteries and venous sinuses, meningeal veins, or cortical veins; the arterial feeders are various, usually fed by branches of internal carotid, external carotid, or vertebral artery (Santillan et al. CNN 115(3):241-251, 2013; Holoekamp et al. JN 124(6):1752-65, 2016; Terada T et al. JN 80(5):884-9, 1994). Spectrums of clinical presentations are widespread, arranging from pulsatile tinnitus to intracranial hemorrhage. Such DAVFs with rapidly progressive dementia as primary presentation, which has been reported in several literature, are still extremely scarce (Santillan et al. CNN 115(3):241-251, 2013; Holoekamp et al JN 124(6):1752-65, 2016). Up to 2015, similar reports are less than 20 cases (Holoekamp et al. JN 124(6):1752-65, 2016). Herein, we report a patient who was misdiagnosed with encephalitis, presented thalamic dementia, and was ultimately diagnosed of DAVFs.