Gallic acid exerts protective effects in spinal cord injured rats through modulating microglial polarization.

BACKGROUND: Spinal cord injury (SCI) is a highly traumatic injury that causes mechanical damage to the spinal cord. Our study aimed to investigate whether gallic acid has protective effects against SCI injury. METHODS: Adult male rats were subjected to contusive spinal cord injuries. For behavioural evaluation, the rats were given gallic acid by i.p. injection at the doses of 10, 50 or 100 mg/kg immediately after SCI once daily for consecutive 28 days. Behavioral tests were used to evaluate locomotor functions, mechanical sensitivity and nerve conduction functions. For biochemical experiments, the rats were randomly divided into three groups: sham group, SCI group and SCI+gallic acid group. The rats in the SCI+gallic acid group were given gallic acid at the dose of 100 mg/kg immediately after SCI once daily for consecutive 14 days. The levels of inflammatory factors were evaluated. RESULTS: Gallic acid treatment could improve locomotive and sensory function and reduce the functional impairments in SCI rats. The effects were more effective with increasing gallic acid dose. The levels of M1 markers (inducible nitric oxide synthase and cyclooxygenase-2) were decreased in gallic acid-treated SCI rats, whereas the levels of M2 markers (arginase 1 and cluster of differentiation 206) were increased in response to gallic acid administration. Gallic acid treatment resulted in a significant reduction in pro-inflammatory cytokines and an increase in anti-inflammatory cytokine levels. CONCLUSION: Gallic acid enhances the recovery in SCI rats by regulating microglial polarization. The underlying mechanism may involve the promotion of M2 polarization and the suppression of M1 polarization in microglia.

Risk factors and a prediction model for unruptured intracranial aneurysms in patients with ischemic stroke using carotid intima-media thickness and systemic atherosclerosis.

Background: Systemic atherosclerosis and carotid intima-media thickness (IMT) have been widely used in clinical practice for ischemic stroke; however, little is known about the risk factors for unruptured intracranial aneurysms (UIAs) in patients with ischemic stroke (IS). Therefore, we performed this study to identify the risk factors and construct a prediction model for UIA in patients with IS. Methods: Data were retrospectively collected from patients with IS from 2015 to 2022 at the First Hospital of Quanzhou City, Quanzhou, Fujian, China. Risk factors for UIA in patients with IS were identified using a multivariate logistic regression model, and a receiver operating characteristic (ROC) curve was applied to construct the prediction model. Results: Out of the 122 patients with IS, 52 who presented with UIA (ISUIA) were categorized into the study group and the remaining 70 IS patients without UIA into the control group. Patients in the ISUIA group had lower carotid IMT and carotid artery plaque scores than those in the IS group (P < 0.05). Multivariate analyses found that aspirin use (OR: 12.987; P = 0.031), elevated C-reactive protein (CRP) level (OR: 1.019; P = 0.004), and carotid IMT > 0.09 mm (OR: 0.218; P < 0.001) were significantly associated with the risk of UIA in patients with IS. However, UIA in patients with IS was unaffected by the carotid artery plaque score (P = 0.114). The constricted prediction model based on the abovementioned factors for UIA in IS patients was 0.79 (95% CI: 0.71-0.87). Conclusion: The findings revealed that the risk factors for UIA in patients with IS included aspirin use, elevated CRP level, and smaller carotid IMT, and the predictive value of the prediction model was relatively better.

Coenzyme Q10 inhibits intracranial aneurysm formation and progression in a mouse model.

BACKGROUND: The aim of this study was to investigate the effect of coenzyme Q10 (CoQ10), a commonly used nutritional supplement, on intracranial aneurysm (IA) initiation and progression in a mouse model, as well as the mechanism. METHODS: Hydrogen peroxide (H2O2) was used to treat mouse-derived vascular smooth muscle cells (VSMCs) to induce oxidative injury, followed by incubation with CoQ10. In the mouse IA model established by elastase injection, CoQ10 was orally administered at 10 mg/kg every other day for 14 days, during which the incidence of IA, rupture rate, symptom-free survival, and systolic blood pressure were recorded. RESULTS: CoQ10 promoted the expression of nuclear factor erythroid 2-related factor 2 and antioxidant enzymes. In H2O2-treated VSMCs, reactive oxygen species and cell apoptosis were reduced by CoQ10. In IA mice, CoQ10 treatment decreased the rupture rate of IA, improved the symptom-free survival, and reduced systolic blood pressure. Macrophage infiltration and expression of pro-inflammatory cytokines in the cerebral arteries were mitigated by CoQ10 treatment. CONCLUSIONS: CoQ10 is effective in reducing oxidative stress in VSMCs, thereby attenuating IA formation and rupture in mice. CoQ10 also alleviates inflammation and restores normal phenotypes of VSMCs in the cerebral arteries. Our data suggest that CoQ10 is a potentially effective drug for managing IA. IMPACT: To investigate the effect of CoQ10, a commonly used nutritional supplement, on IA initiation and progression in a mouse model, as well as the mechanism. CoQ10 promoted the expression of Nrf2 and antioxidant enzymes. In H2O2-treated VSMCs, ROS and cell apoptosis were reduced by CoQ10. CoQ10 is effective in reducing oxidative stress in VSMCs, thereby attenuating IA formation and rupture in mice.

Multiple overlapping stent-assisted coiling improves efficacy and safety of treatment for complex intracranial aneurysms: a randomized trial.

BACKGROUND: Intracranial aneurysm rupture is the main cause of subarachnoid hemorrhage, leading to high disability and mortality. This study aimed to evaluate the clinical treatment effects of multiple overlapping stent-assisted coiling for complex intracranial aneurysms. METHODS: We conducted a randomized, controlled, single-blinded clinical trial among 168 patients diagnosed with complex intracranial aneurysms. Treatment allocation to either single stent (SS) group or multiple stent (MS) group was randomized at 1:1 ratio using a Web-based platform. The O'Kelly-Marotta (OKM) grading scale was used to evaluate the degree of aneurysm occlusion after operation and during follow-up. Good aneurysm occlusion was defined as OKM grade C-D. The modified Rankin Scale (mRS) was used to evaluate the neurological status and the clinical outcome of patients. RESULTS: Efficacy comparative analysis demonstrated that major recurrence of aneurysms was significantly reduced in the MS group (P = 0.012). In addition, the MS group displayed significantly reduced number of patients with mRS between 3 and 6 (P = 0.007) and increased number of patients with mRS between 0 and 1 (P = 0.034). Furthermore, the MS group showed increased percentage of patients with OKM grade C-D (P = 0.041). Compared with the SS group, the MS group exhibited decreased mortality (P = 0.037) and morbidity (P = 0.035). CONCLUSIONS: Multiple overlapping stent-assisted coiling significantly improved the clinical treatment effects and provided a new method for complex intracranial aneurysms.

Protective effects of BP-1-102 against intracranial aneurysms-induced impairments in mice.

The development of non-invasive pharmacological therapies to prevent the progression and rupture of intracranial aneurysms (IAs) is an important field of research. This study attempts to reveal the role of BP-1-102, an oral bioavailable signal transducer and activator of transcription 3 (STAT3) inhibitor, in IA. We first constructed an IA mouse model by injecting elastase into the cerebrospinal fluid with simultaneous induction of hypertension by deoxycorticosterone acetate (DOCA) implantation. The results showed that the proportion of IA rupture in mice after BP-1-102 administration was significantly reduced, and the survival time was significantly extended. Further research showed that compared with the vehicle group, the proportion of macrophages infiltrated at the aneurysm and the expression of pro-inflammatory cytokines in the BP-1-102 administration group were significantly reduced. The contractile phenotype vascular smooth muscle cell (VSMC) specific markers, SM22α and αSMA, were significantly upregulated in the BP-1-102 group. Furthermore, we found that BP-1-102 inhibited the expression of critical proteins in the nuclear factor kappa-B and Janus kinase 2/STAT3 signalling pathways. Our study shows that BP-1-102 significantly decreases the rupture of IA, reduces the inflammatory responses and modulates the phenotype of VSMCs, suggesting that BP-1-102 could be utilised as a potential intervention drug for IA.

Pharmacological inhibition of STAT3 by BP-1-102 inhibits intracranial aneurysm formation and rupture in mice through modulating inflammatory response.

As an inhibitor of STAT3, BP-1-102 can regulate the inflammation response caused by vascular smooth muscle cells (VSMCs) by inhibiting the JAK/STAT3/NF-κB pathway, thereby attenuating the symptoms of intracranial aneurysm (IA). IA mouse model was established by stereotactic injection of elastase to evaluate the effect of BP-1-102. The expression levels of smooth muscle markers and matrix metalloproteinases (MMPs) were detected by qRT-PCR, and the levels of inflammatory factors were detected by ELISA and qRT-PCR. The protein levels of the NF-κB signaling pathway factors were examined by Western blot. BP-1-102 reduced blood pressure in aneurysm mice, up-regulated smooth muscle cell markers MHC, SMA, and SM22, and down-regulated the expression of MMP2 and MMP9 in vascular tissues. At the same time, BP-1-102 also down-regulated the expression levels of inflammatory response factors and the NF-κB pathway proteins. In the IA model, BP-1-102 can reduce the expression of inflammatory factors and MMPs bound to NF-κB by inhibiting the activation of the JAK/STAT3/NF-κB pathway proteins, and then restore the vascular wall elastin to reduce blood pressure, thereby treating aneurysm.

STAT3 Contributes to Intracranial Aneurysm Formation and Rupture by Modulating Inflammatory Response.

Intracranial aneurysm (IA) is a common type of refractory cerebrovascular diseases. Inflammatory responses have been reported to be associated with the pathogenesis of IA. We aimed to study the role of STAT3 on IA formation and inflammatory response. STAT3 expression and clinicopathological factors were analyzed in IA and normal cerebral arteries. mRNA level of STAT3 was detected in normal, unruptured, and ruptured IA tissues by RT-PCR and Western blot. Inflammatory cytokines were examined by ELISA in unruptured, ruptured IA tissues, as well as cells with STAT3 overexpression or knockdown. mRNA of phenotypic modulation-related factors was tested by RT-PCR in STAT3 overexpressing or knockdown VSMCs. STAT3 expression was upregulated in ruptured IA tissues and highly associated with IA diameter and IA type. Inflammatory cytokine secretion was increased in ruptured IA samples and positively correlated with STAT3 expression. STAT3 overexpression led to enhanced expression of SM-α actin, SM-MHC, MMP2, and MMP9, and increased secretion of inflammatory cytokines. Our findings have demonstrated that STAT3 is a key regulator in IA formation by modulating inflammatory cytokine expression.

Glycyrrhizin treatment ameliorates post-traumatic stress disorder-like behaviours and restores circadian oscillation of intracranial serotonin.

Post-traumatic stress disorder (PTSD) has become a major disease that threatens human health. Neurotransmitters and the amygdala are found to be critical in the development and maintenance of PTSD. We aim to investigate the role of glycyrrhizin in treating PTSD. Contextual fear extinction and elevated plus maze test were applied to evaluate the anxiety and fear memory. Microdialysis and high-performance liquid chromatography were used to analyze the expression of amygdala neurotransmitters in PTSD animal models and to verify the effects of glycyrrhizin on major neurotransmitters. The protein levels of tryptophan hydroxylase 2 (TPH2) were examined by western bolt. Glycyrrhizin treatment significantly reduced anxiety and fear memory after 1 and 7 days of PTSD modelling. In addition, glycyrrhizin treatment restored the circadian rhythm changes of serotonin and TPH2. The present study found a significant circadian rhythm change of serotonin in the amygdala in PTSD rats. Besides, glycyrrhizin treatment restored the altered serotonin diurnal fluctuations, which raises important implications for PTSD treatment.

SNHG9/miR-199a-5p/Wnt2 Axis Regulates Cell Growth and Aerobic Glycolysis in Glioblastoma.

Aerobic glycolysis is a characteristic in cancers that is important for cancer cell proliferation. Emerging evidence shows that long non-coding RNA (LncRNA) participates in glucose metabolism and cell proliferation in cancer. This study explored the effect of LncRNA: SNHG9 in glioblastoma. The mRNA expression of SNHG9 in human glioma tissues and glioblastoma cell lines was measured by qRT-PCR. Glioblastoma cell lines (U87 and U251) were transfected with miR-199a-5p or SNHG9-expressing plasmid and cell viability as well as concentrations of glucose and lactate were measured. The extracellular acidification was evaluated by glycolysis stress test. The Wnt2 levels were determined by qRT-PCR and Western blot. Results showed that the mRNA expression of SNHG9 was elevated in glioblastoma tissues. The elevated SNHG9 expression was related to lower survival rate in patients with glioma. SNHG9 could downregulate miR-199a-5p and upregulate Wnt2 in glioblastoma cells. Overexpression of SNHG9 in glioblastoma cells promoted aerobic glycolysis and cell proliferation, which could be attenuated by miR-199a-5p. Results of this study indicated an effect of SNHG9/miR-199a-5p/Wnt2 axis in regulating cell growth and aerobic glycolysis in glioblastoma.

Diosgenin Attenuates Lipopolysaccharide-Induced Parkinson's Disease by Inhibiting the TLR/NF-κB Pathway.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Diosgenin is a natural steroid saponin which was shown to play a beneficial role in Alzheimer's disease. OBJECTIVE: This study sought to investigate the potential effect of diosgenin on a rat model of PD. METHODS: Sprague Dawley rats were subjected to intra-striatal injection of lipopolysaccharide (LPS) and treated with diosgenin. Stepping, Whisker, and Cylinder tests were carried out to determine the motor function, and the expression of tyrosine hydroxylase was detected by immunohistochemistry. The levels of multiple proinflammatory cytokines, oxidative stress related factors and proteins involved in Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) pathway were measured. The synergistic effect of environment enrichment on diosgenin was also investigated. RESULTS: Intra-striatal injection of LPS caused motor deficits in rats, induced inflammatory response and oxidative stress response, and activated the TLR/NF-κB pathway both in vivo and in vitro. Diosgenin could attenuate the LPS-induced alterations. Enriched environment enhanced the effect of diosgenin to ameliorate the LPS-induced motor deficits in rats and decreased the protein levels of TLR2, TLR4, and nuclear NF-κB in diosgenin treated PD rats. CONCLUSION: Diosgenin had a beneficial effect in LPS-induced rat PD models, by suppressing the TLR/NF-κB signaling pathway. Environmental enrichment could play a synergistic effect with diosgenin, by enhancing the inhibitory effect of diosgenin on the TLR/ NF-κB signaling pathway.

Glycyrrhizin Treatment Facilitates Extinction of Conditioned Fear Responses After a Single Prolonged Stress Exposure in Rats.

BACKGROUND/AIMS: Impaired fear memory extinction is widely considered a key mechanism of post-traumatic stress disorder (PTSD). Recent studies have suggested that neuroinflammation after a single prolonged stress (SPS) exposure may play a critical role in the impaired fear memory extinction. Studies have shown that high mobility group box chromosomal protein 1 (HMGB-1) is critically involved in neuroinflammation. However, the role of HMGB-1 underlying the development of impairment of fear memory extinction is still not known. METHODS: Thus, we examined the levels of HMGB-1 in the basolateral amygdala (BLA) following SPS using Western blot and evaluated the levels of microglia and astrocytes activation in the BLA after SPS using immunohistochemical staining. We then examined the effects of pre-SPS intra-BLA administration of glycyrrhizin, an HMGB1 inhibitor, or LPS-RS, a competitive TLR4 antagonist, on subsequent post-SPS fear extinction. RESULTS: We found that SPS treatment prolonged the extinction of contextual fear memory after the SPS. The impairment of SPS-induced extinction of contextual fear memory was associated with increased HMGB1 and Toll-like receptor 4 (TLR4) levels in the BLA. Additionally, the impairment of SPS-induced extinction of contextual fear memory was associated with increased activation of microglia and astrocyte in the BLA. Intra-BLA administrations of glycyrrhizin (HMGB-1 inhibitor) or LPS-RS (TLR4 antagonist) can prevent the development of SPS-induced fear extinction impairment. CONCLUSION: Taken together, these results suggested that SPS treatment may not only produce short term effects on the HMGB1/TLR4-mediated pro-inflammation, but alter the response of microglia and astrocytes to the exposure to fear associated contextual stimuli.

Catechin attenuates traumatic brain injury-induced blood-brain barrier damage and improves longer-term neurological outcomes in rats.

NEW FINDINGS: What is the central question of this study? We investigated the potential neuroprotective effects of catechin after traumatic brain injury and explored the underlying mechanisms. What is the main finding and its importance? Catechin treatment had neuroprotective effects in a rat model of traumatic brain injury, and these effects might be mediated by intervention in the self-perpetuating process of blood-brain barrier disruption and excessive inflammatory reaction. Traumatic brain injury (TBI) resulting from external force on the head usually leads to long-term deficits in motor and cognitive functions. Catechin has shown neuroprotective effects in neurodegenerative diseases and ischaemia models. We therefore investigated the potential neuroprotective effects of catechin after TBI and explored the underlying mechanisms. Male rats were subjected to controlled cortical impact injury and then treated with catechin. Brain damage, motor and cognitive functions, blood-brain barrier (BBB) integrity and neuro-inflammation were examined. Catechin treatment ameliorated brain damage and motor and cognitive deficits after TBI. Catechin was shown to protect BBB integrity, alleviate the TBI-induced loss of the junction proteins occludin and zonula occludens protein-1 and suppress local inflammatory reactions. Catechin treatment had neuroprotective effects in a rat model of TBI, and these effects might be mediated by intervention in the self-perpetuating process of BBB disruption and excessive inflammatory reaction.