Celastrol Ameliorates Neuronal Mitochondrial Dysfunction Induced by Intracerebral Hemorrhage via Targeting cAMP-Activated Exchange Protein-1.

Mitochondrial dysfunction contributes to the development of secondary brain injury (SBI) following intracerebral hemorrhage (ICH) and represents a promising therapeutic target. Celastrol, the primary active component of Tripterygium wilfordii, is a natural product that exhibits mitochondrial and neuronal protection in various cell types. This study aims to investigate the neuroprotective effects of celastrol against ICH-induced SBI and explore its underlying mechanisms. Celastrol improves neurobehavioral and cognitive abilities in mice with autologous blood-induced ICH, reduces neuronal death in vivo and in vitro, and promotes mitochondrial function recovery in neurons. Single-cell nuclear sequencing reveals that the cyclic adenosine monophosphate (cAMP)/cAMP-activated exchange protein-1 (EPAC-1) signaling pathways are impacted by celastrol. Celastrol binds to cNMP (a domain of EPAC-1) to inhibit its interaction with voltage-dependent anion-selective channel protein 1 (VDAC1) and blocks the opening of mitochondrial permeability transition pores. After neuron-specific knockout of EPAC1, the neuroprotective effects of celastrol are diminished. In summary, this study demonstrates that celastrol, through its interaction with EPAC-1, ameliorates mitochondrial dysfunction in neurons, thus potentially improving SBI induced by ICH. These findings suggest that targeting EPAC-1 with celastrol can be a promising therapeutic approach for treating ICH-induced SBI.

Different dosage regimens of zuranolone in the treatment of major depressive disorder: A meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate the efficacy and safety of different dosage regimens of zuranolone in the treatment of patients with major depressive disorder (MDD). METHODS: PubMed, Embase, The Cochrane Library and other databases were searched from inception until July 2019. Randomized controlled trials (RCTs) related to the efficacy and safety of zuranolone in the treatment of MDD were included. The data were extracted independently by 2 investigators and assessed the study quality by the Cochrane risk-of-bias tool. The primary outcome includes the 17-item HAMILTON total score (HAMD-17) and the incidence of adverse events (AEs). RESULTS: Six high-quality RCTs with 1593 patients were finally included in our analysis. Zuranolone group achieve a notable treatment effect at day15 in HAMD-17 compared with placebo group (MD = -2.69, 95 % CI: -4.45 to -0.94, P < 0.05). For safety, no significant differences existed in the proportion of patients with AEs between zuranolone with placebo (RR = 1.25, 95 % CI: 0.99 to 1.58, P = 0.06). CONCLUSION: Zuranolone has a significant efficacy in improving depressive symptoms in the short term and is positively correlated with the dosage administered. However, the efficacy of zuranolone decreased significantly when the time of administration was extended. Zuranolone demonstrated a controllable safety issue. But adverse effects increased as the dose of zuranolone was gradually increased to 50 mg.

Relationship between Peripheral Blood Inflammatory Factors and Prognosis of Subarachnoid Hemorrhage: A Meta-Analysis.

INTRODUCTION: Subarachnoid hemorrhage (SAH) is a severe cerebrovascular event with high mortality and disability rate. Neuroinflammation is involved in the brain injury after SAH, but the exact association between SAH progression and peripheral blood inflammatory factors is unknown. Therefore, to determine the relationship between inflammatory factors and the prognosis of SAH, we performed a meta-analysis. METHOD: A systematic literature review was conducted in PubMed, Embase, and the Cochrane Library. Studies comparing the relationship between inflammatory factors (C-reactive protein [CRP], interleukin-6 [IL-6], interleukin-10 [IL-10], and tumor necrosis factor [TNF-α]) and prognosis of SAH were included in the study. A random-effects meta-analysis was conducted based on mRS, GOS, and the occurrence of cerebral vasospasm, delayed cerebral ischemia, and delayed ischemic neurologic deficits. Sensitivity analysis was performed using the leave-one-out method. The Newcastle-Ottawa Scale (NOS) for case-control studies was used to assess the quality of included studies. For continuous variables, we calculated the mean difference with a 95% confidence interval (CI). RESULTS: 1,469 patients from 18 case-control studies met the inclusion criteria. The results found that patients in the good outcome group had significantly lower CRP levels than those in the poor outcome group (SMD: -1.15, 95% CI: -1.64 to -0.66, p < 0.00001, I2 = 87%), and peripheral IL-6 levels were significantly lower in SAH patients with the good functional outcome than those with the poor functional outcome (SMD: -0.99, 95% CI: -1.48 to -0.51, p < 0.0001, I2 = 88%). As for IL-10 (SMD: -0.28, 95% CI: -0.97 to 0.42, p = 0.43, I2 = 88%) and TNF-α (SMD: -0.40, 95% CI: -0.98 to 0.19, p = 0.18, I2 = 79%), due to the small number of studies, heterogeneity, and uncontrollable factors, robust conclusions cannot be drawn. CONCLUSION: SAH patients with good prognoses have significantly lower peripheral CRP and IL-6 levels. In addition, due to the small number of studies, heterogeneity, and uncontrollable factors, robust conclusions cannot be drawn for IL-10 and TNF-α. More high-quality studies are needed in the future to provide more specific recommendations for the clinical practice of inflammatory factors.

Transient Receptor Potential Mucolipin-1 Participates in Intracerebral Hemorrhage-Induced Secondary Brain Injury by Inducing Neuroinflammation and Neuronal Cell Death.

Transient receptor potential mucolipin-1 (TRPML1) is the most abundantly and widely expressed channel protein in the TRP family. While numerous studies have been conducted involving many aspects of TRPML1, such as its role in cell biology, oncology, and neurodegenerative diseases, there are limited reports about what role it plays in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Here we examined the function of TRPML1 in ICH-induced SBI. The caudal arterial blood of rats was injected into the caudate nucleus of basal ganglia to establish an experimental ICH model. We observed that lentivirus downregulated the expression level of TRPML1 and chemical agonist promoted the enzyme activity of TRPML1. The results indicated that the protein levels of TRPML1 in brain tissues increased 24 h after ICH. These results suggested that downregulated TRPML1 could significantly reduce inflammatory cytokines, and ICH induced the production of LDH and ROS. Furthermore, TRPML1 knockout relieved ICH-induced neuronal cell death and degeneration, and declines in learning and memory after ICH could be improved by downregulating the expression of TRPML1. In addition, chemical agonist-expressed TRPML1 showed the opposite effect and exacerbated SBI after ICH. In summary, this study demonstrated that TRPML1 contributed to brain injury after ICH, and downregulating TRPML1 could improve ICH-induced SBI, suggesting a potential target for ICH therapy.

Different Dosage Regimens of Tanezumab for the Treatment of Chronic Low Back Pain: A Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The aim of this study was to assess the efficacy of different dosage regimens of tanezumab among individuals living with chronic low back pain (CLBP). METHODS: PubMed, Embase, The Cochrane Library, and other databases were searched from inception until August 2021. Randomized controlled trials investigating the efficacy and safety of tanezumab in individuals with CLBP were included. Data were extracted independently by 2 investigators and assessed the study quality by the Cochrane risk-of-bias tool. The measurements include low back pain intensity and Roland-Morris Disability Questionnaire. The incidence of adverse events and serious adverse events was set to assess the safety of tanezumab for CLBP. RESULTS AND DISCUSSION: Three high-quality randomized controlled trials with 3414 patients were finally included in our analysis. Tanezumab, respectively, led to a notable decrease compared with placebo in low back pain intensity (mean difference, -0.62; 95% confidence interval [CI], -0.77 to -0.46; P < 0.01) and Roland-Morris Disability Questionnaire (mean difference, -0.64; 95% CI, -0.80 to -0.47; P = 0.01). In addition, no significant difference existed between tanezumab and placebo groups (risk ratio, 1.10; 95% CI, 0.81-1.49; P = 0.55) in the adverse events and (risk ratio, 1.06; 95% CI, 0.34-3.27; P = 0.93) serious adverse events. CONCLUSIONS: Intravenous and subcutaneous tanezumab injections as treatment for improving CLBP have promising clinical application as its great improvement on all efficacy and its controllable safety issues. Furthermore, intravenous and subcutaneous tanezumab injections were proved to achieve excellent and long-term curative effect on CLBP through our subgroup analysis and comparison.

The role of Tenascin C in intracerebral hemorrhage-induced secondary brain injury in rats via induction of neuronal cell death and neuroinflammation.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a major cause of stroke that causes high rates of disability and mortality in adults. Tenascin C (TNC) protein, one of the matricellular proteins associated with platelet-derived growth factor receptor (PDGFR) activation, has been reported to induce neuronal apoptosis. However, the role and underlying mechanisms of TNC in ICH-induced secondary brain injury (SBI) have not yet been fully explained. The main purpose of this study was to explore the role of TNC and its potential mechanisms in ICH. METHODS: An ICH model was established by injecting autologous blood into the right basal ganglia in male Sprague Dawley (SD) rats, and imatinib, an inhibitor of PDGFR, was used to inhibit the release of TNC. RESULTS: We found that TNC protein was significantly increased in the brain tissues after ICH and expressed in both neurons and microglia. We also found that the TNC level was elevated in the cerebrospinal fluid (CSF) after ICH. Additionally, we observed that the infiltration of activated microglia and the release of TNFα and IL-1ß induced by ICH were decreased after inhibition of the protein levels of TNC and cleaved-TNC by a chemical inhibitor (imatinib). Furthermore, imatinib improved neuronal cell death and neurobehavioral abnormalities induced by ICH. CONCLUSION: In summary, our study revealed that TNC protein plays an important role in ICH-induced SBI, and inhibition of TNC could alleviate ICH-induced neuroinflammation, neuronal cell death, and neurobehaviour. Therefore, TNC may be a potential therapeutic target for ICH-induced SBI.

Effects of saffron supplementation on improving sleep quality: a meta-analysis of randomized controlled trials.

OBJECTIVE: To compare the efficacy of different dosage regimens of saffron supplementation on improving sleep quality among healthy adults, patients with insomnia or type 2 diabetes and patients under Methadone maintenance treatment (MMT). METHODS: PubMed, Embase, The Cochrane Library and other databases were searched from inception until October 2021. Randomized controlled trials (RCTs) investigating the efficacy saffron supplementation on sleep quality were included. Data were extracted independently by 2 investigators and assessed the study quality by the Cochrane risk-of-bias tool. The measurements include Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Restorative Sleep Questionnaire (RSQ). RESULTS: The pooling of the effect sizes showed that saffron group achieve a notable treatment effect on PSQI (MD: -2.14; 95% CI: -2.86 to -1.42; P < 0.01), ISI (MD: -2.63; 95% CI: -3.70 to -2.55; P < 0.01) and RSQ (MD: 7.05; 95% CI: 1.48 to 12.62; P = 0.01) compared with placebo group. CONCLUSION: Saffron supplementation as a treatment for improving sleep quality have promising clinical application as its great improvement on all efficacy outcomes and no serious adverse advents occurred as the dose was increased. The dose of 100 mg saffron supplementation per day was proved to achieve excellent and more stable curative effect on improving sleep quality in our subgroup analysis. However, further investigation is necessary to confirm the efficacy and long-term safety of different doses of saffron for insomnia.