Stem cell therapies: a new era in the treatment of multiple sclerosis.

Multiple Sclerosis (MS) is an immune-mediated condition that persistently harms the central nervous system. While existing treatments can slow its course, a cure remains elusive. Stem cell therapy has gained attention as a promising approach, offering new perspectives with its regenerative and immunomodulatory properties. This article reviews the application of stem cells in MS, encompassing various stem cell types, therapeutic potential mechanisms, preclinical explorations, clinical research advancements, safety profiles of clinical applications, as well as limitations and challenges, aiming to provide new insights into the treatment research for MS.

Effects of Qishen Dihuang Granules on Intestinal Microbiota in Experimental Autoimmune Myasthenia Gravis Model Rats.

Objective: Effects of Qishen Dihuang (QSDH) granules on intestinal flora of an experimental autoimmune myasthenia gravis (EAMG) model rat were investigated (CNBI:PRJNA910532). Methods: Thirty-six female Lewis rats were assigned to Control, EAMG, QSDH-low-dose, QSDH-medium-dose, QSDH-high-dose, and Prednisone groups using the random number table method (6 rats/group). A rat EAMG model was established by injecting Rα97-116 peptide antigen. Each day for 30 days, gavages were administered to rats in the Chinese medicine group (QSDH granules in different concentrations), Prednisone group (prednisone), and Control and Model groups (0.5% CMC). After 30-day gavages, rat fecal samples were collected and the microbial community composition and diversity differences between intestinal microbiota of EAMG and QSDH granule-treated groups were analyzed using 16S amplicon sequencing to explore the effect underlying QSDH granules alleviation of EAMG. Results: The clinical symptoms of rats in each treatment group improved significantly after the intervention treatment with QSDH granules. Comparison of the relative abundance of microorganisms in the gut flora of different groups with that of the EAMG group rats revealed: significantly lower phylum-level Bacteroidetes abundance and significantly greater Actinobacteria abundance in the QSDH-high-dose group and a significantly greater Firmicutes/Bacteroidetes ratio in the QSDH-medium-dose group; significantly increased family-level QSDH-high-dose group abundances of Lachnospiraceae and Trichospiraceae (Firmicutes), significantly increased QSDH-medium-dose group Lactobacillaceae abundance, and significantly increased QSDH-low-dose group Bacteroidaceae abundance; genus-level, QSDH-high-dose group Prevotella and Coprococcus abundances were significantly increased and Turicibacter and Lactobacillus abundances were significantly decreased, while QSDH-medium-dose group Akkermansia and Lactobacillus abundances were significantly increased. Greater overall community richness, diversity, and genetic diversity were observed in QSDH granules-treated groups, but differences were insignificant (P > .05). The most significant inter-group genus-level community marker differences involved Prevotella, Ruminococcus, Coprococcus, and Turicibacter. Conclusion: QSDH granules may regulate EAMG rat intestinal flora by decreasing relative abundances of Turicibacter and Clostridium and increasing relative abundances of Bifidobacterium, Lachnospiraceae, and Prevotella.

Comparative the efficacy and acceptability of immunosuppressive agents for myasthenia gravis: A protocol for systematic review and network meta-analysis.

BACKGROUND: Immunosuppressive drugs are routinely used to treat myasthenia gravis (MG). However, current recommendations provide limited evidence to support treatment options, leading to considerable variation in practice among healthcare specialists. Hence, we present a protocol for a systematic review and network meta-analysis (NMA) to update the evidence by comparing the efficacy and acceptability of oral immunosuppressive drugs for the treatment of MG. METHODS: We will conduct a systematic review and NMA of all randomized controlled trials evaluating the following oral immunosuppressive drugs for the treatment of MG. Published studies will be searched using the following databases from inception to November 23, 2021: CENTRAL, the CINAHL, MEDLINE, Embase, PsycINFO, Web of Science, and 3 Chinese databases (Chinese Biomedical Literatures Database, CNKI, and Wan Fang database). Assessment of study eligibility and data extraction will be conducted independently by 2 reviewers. The main outcome will be a quantitative MG scoring system. We will conduct Bayesian NMA to synthesize all evidence for each outcome and obtain a comprehensive ranking of all treatments. The quality of the evidence will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: The objective of this study was to assess the relative clinical efficacy and acceptability of first-line immunosuppressants for the treatment of MG, using a systematic review and NMA approach. CONCLUSION: In the absence of head-to-head trials comparing therapies, evidence from this NMA of available clinical trials will inform clinicians, patients, and families the risk-benefit profiles of different treatment options.

Didang Tang inhibits intracerebral hemorrhage-induced neuronal injury via ASK1/MKK7/JNK signaling pathway, network pharmacology-based analyses combined with experimental validation.

Background: Intracerebral hemorrhage (ICH) is an acute cerebrovascular disease, which is also a principal consideration for disability. Didang tang (DDT) is a classic traditional Chinese medicine formula for treating ICH. However, its pharmacological mechanism of action has not been elucidated. Materials and methods: The TCMSP and BATMAN-TCM databases were used to collect chemical compounds and predict targets of DDT. Protein targets in ICH were identified by GeneCards, OMIM, and DrugBank databases. DDT compounds-ICH targets and protein-protein interaction (PPI) networks were constructed for topological analysis and hub-targets screening. Further, Key biological processes and signaling pathways were identified by GO and KEGG enrichment analyses. Then, an ICH rat model and a Cobaltous Chloride (CoCl2)-induced PC12 cells model were established. Cell viability and lactate dehydrogenase (LDH) release were detected using cck8 and LDH kits. Apoptosis levels were detected by TUNEL assessment and flow cytometry. IL-1ß levels were detected by ELISA, while key protein expressions were determined by Western blot. Results: A total of 126 active compounds related to DDT and 3,263 therapeutic targets for ICH were predicted. The functional enrichment of the GO and KEGG pathways combined with literature studies suggested that DDT is most likely to influence MAPK and apoptotic signaling pathways for ICH treatment. In vitro and in vivo experiments have shown that DDT remarkably inhibited apoptosis and increased the expression of Bcl-2, while inhibiting Bax and cleaved-Caspase 3. For other enriched core proteins, DDT suppressed the phosphorylation of Src and the expression of c-Myc and IL-1ß, and up-regulated the level of MMP-9. The further results showed that, DDT decreased the phosphorylation of ASK1, MKK7, JNK and c-JUN. Conclusion: Based on network pharmacology and experimental validation results, our in vivo and in vitro study indicated that ASK1/MKK7/JNK pathway might be the critical target for DDT against ICH.

The prevention of stroke by statins: A meta-analysis.

PURPOSE: The objectives of this study were to determine the preventive effects of statins on stroke. METHODS: The published randomized controlled trials of statins for stroke prevention were searched from PubMed, EMBASE, Cochrane Library, and China Journal databases. We performed the meta-analysis via calculating the odds ratio (OR) and 95% confidence interval (CI) to study the mortality rate, incidence, and recurrence rate of patients with stroke in the prevention group and the control group. Chi-square-based Q test and I2 statistics were performed to test the potential heterogeneity; we conducted the sensitivity analysis to assess the stability of our analysis. Moreover, we performed the Begg and Egger tests to assess the publication bias. RESULTS: Nine studies were included to perform meta-analysis, which included 15,497 patients (prevention group [n = 4114]; control group [n = 11383]). We found that the statins were not associated with the patients with stroke in mortality rate (OR = 1.00, 95% CI [0.82, 1.23]) and incidence (OR = 0.94, 95% CI [0.46, 1.92]) between the 2 groups. However, there was a significant differences in recurrence rate between the 2 groups (OR = 0.31, 95% CI [0.19, 0.51]). CONCLUSIONS: Our findings indicated that the statins were associated with the patients with stroke in recurrence rate, but there was no significant correlation with the mortality and morbidity of patients with stroke.

Correlation of serum ferritin levels with neurological function-related indices and cognitive dysfunction in patients with cerebral hemorrhage.

AIMS: The purpose of this study was to explore the correlation of serum ferritin (FS) levels with neurological function-related indices, such as neuron-specific enolase (NSE) and S100ß protein levels, and cognitive dysfunction in patients with cerebral hemorrhage. MATERIALS AND METHODS: Patients with acute non-traumatic cerebral hemorrhage (cerebrovascular disease (VD), n = 128) and healthy controls (CON, n = 128) were included. FS, NSE, and S100ß levels were measured using ELISA. Cognitive functions were evaluated using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). The receiver operating characteristic (ROC) curve was used to assess the ability of SE, NSE, and serum S100ß to predict the diagnosis of cognitive dysfunction in patients with cerebral hemorrhage. Multivariate logistic regression analysis was used to assess the risk factors of cognitive impairment in patients with cerebral hemorrhage. RESULTS: Cognitive impairment in patients with VD was closely related to the increased levels of SE, NSE, and S100ß. There was a strong correlation between MoCA and MMSE scores and the levels of FS, NSE, and S100ß. The independent risk factors leading to cognitive impairment in cerebral hemorrhage mainly include family history of cerebrovascular disease, body mass index, hypertension, smoking frequency, and elevated levels of low-density lipoproteins, NSE, FS, and S100ß. CONCLUSION: NSE, FS, and S100ß can be used as important markers for the diagnosis of cognitive impairment in patients with cerebral hemorrhage.

Optimal intervention time and risk of the activating blood and removing stasis method in acute cerebral hemorrhage patients: A randomized placebo-controlled trial.

INTRODUCTION: Stroke is the leading cause of disability-adjusted life years in neurological diseases and has become one of the top 3 fatal diseases in the world. Cerebral hemorrhage accounts for approximately 18% to 24% of all strokes in Asian countries. Cerebral hemorrhage is one of the most destructive subtypes of stroke and has high morbidity and mortality. Based on the current research, it has been confirmed that neither surgical treatment nor current drug treatment is the most preferred treatment. Traditional Chinese medicine (TCM) is increasingly being used to treat cerebral hemorrhage, and the activating blood and removing stasis (ABRS) method has received more attention. At present, there is still a lack of high-quality clinical research on the treatment of acute cerebral hemorrhage. METHOD: We designed a multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial. We aim to recruit 312 cerebral hemorrhage patients aged 18 to 80 years within 24 to 72 hours after onset. In addition to routine treatment, participants will randomly receive ABRS granules or placebo for 14 days. Those enrolled within 24 to 48 hours after onset will enter strata A, and those enrolled within 49 to 72 hours (including 48-49 hours) after onset will enter strata B. The strata sample size ratio will be 1:1. The primary outcome is the disability degree (modified Rankin Scale score, mRS) at 6 months after onset. The secondary outcomes include the percentage of hematoma enlargement after treatment, Barthel index (BI), National Institutes of Health stroke scale (NIHSS) score, mortality rate, all-cause mortality rate, TCM stroke syndrome evaluation scale score, and adverse events. DISCUSSION: The study is expected to confirm the safety and effect of acute cerebral hemorrhage within 24 to 72 hours treated with the ABRS method and to determine the optimal time for intervention in this period. TRIAL REGISTRATION NUMBER: ChiCTR1900022627.

The Protective Effect of DiDang Tang Against AlCl3-Induced Oxidative Stress and Apoptosis in PC12 Cells Through the Activation of SIRT1-Mediated Akt/Nrf2/HO-1 Pathway.

Aluminum (Al) is considered a pathological factor for various neurological and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The neurotoxicity of aluminum can cause oxidative brain damage, trigger apoptosis, and ultimately cause irreversible damage to neurons. DiDang Tang (DDT), a classic formula within traditional Chinese medicine for promoting blood circulation and removing blood stasis and collaterals, is widely used for the treatment of stroke and AD. In this study, models of oxidative stress and apoptosis were established using AlCl3, and the effects of DDT were evaluated. We found that DDT treatment for 48 h significantly increased cell viability and reduced the release of lactate dehydrogenase (LDH) in AlCl3-induced PC12 cells. Moreover, DDT attenuated AlCl3-induced oxidative stress damage by increasing antioxidant activities and apoptosis through mitochondrial apoptotic pathways. Additionally, DDT treatment significantly activated the Sirtuin 1 (SIRT1) -mediated Akt/nuclear factor E2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathways to limit AlCl3-mediated neurotoxicity. Our data indicated that DDT potently inhibited AlCl3-induced oxidative-stress damage and apoptosis in neural cells by activating the SIRT1-mediated Akt/Nrf2/HO-1 pathway, which provides further support for the beneficial effects of DDT on Al-induced neurotoxicity.

Application of Magnetic Resonance Imaging Molecular Probe in the Study of Pluripotent Stem Cell-Derived Neural Stem Cells for the Treatment of Posttraumatic Paralysis of Cerebral Infarction.

The feasibility and efficacy of magnetic resonance imaging molecular probe application and pluripotent stem cell-derived neural stem cell (NSC) transplantation for the treatment of hind limb paralysis in mice with cerebral infarction were studied. A model of middle cerebral artery infarction using adult mice was established to stimulate hind limb reactions. After the model was successfully established, the mice were first divided into an experimental group and a control group, with 25 mice in each group. Cultured neural cells were obtained from the cerebral cortex and hippocampus of a mouse 15 days pregnant to prepare pluripotent stem cells. Pluripotent stem cell-derived NSCs were identified by positive expression of Nestin. The experimental group was injected with 1 µL of NSC suspension through the tail vein, and the control group was injected with 1 µL of saline through the tail vein. The neurologic function of mice in each group was scored 1 day, 3 days, 7 days, 14 days, and 28 days after transplantation according to the Garcia 18 subscale. Finally, the differentiation, migration, and integration of pluripotent stem cell-derived NSCs after transplantation were observed using a magnetic resonance imaging molecular probe method. The results showed that the neurologic function scores of the ischemic transplantation group were significantly higher than those of the control group, and the results were significantly different (P < 0.05). Through research, it was found that after transplantation of pluripotent stem cell-derived NSCs, the transplanted cells migrated and differentiated around the body at 28 days and participated in angiogenesis, and the blood vessels in the infarcted area were obviously proliferated. The NSCs cultured in vitro were transplanted to the small infarction after cerebral infarction. In rats, it plays a positive role in the repair of nerve function in mice with cerebral infarction. NSCs cultured in vitro can survive, migrate, and differentiate in the brain tissue of mouse ischemic models and play a positive role in the repair of neurologic function in mice with cerebral infarction. Magnetic resonance imaging molecular probes have a good adjuvant effect on the use of pluripotent stem cell-derived NSCs to treat hind limb paralysis in mice with cerebral infarction.

DiDang Tang Inhibits Endoplasmic Reticulum Stress-Mediated Apoptosis Induced by Oxygen Glucose Deprivation and Intracerebral Hemorrhage Through Blockade of the GRP78-IRE1/PERK Pathways.

DiDang Tang (DDT), a Chinese traditional medicine formula, contains 4 Chinese traditional medicine substances, has been widely used to treat intracerebral hemorrhage (ICH) patients. However, the molecular mechanisms of DDT for protecting neurons from oxygen and glucose deprivation (OGD)-induced endoplasmic reticulum (ER) stress and apoptosis after ICH still remains elusive. In this study, high-performance liquid chromatography fingerprint analysis was performed to learn the features of the chemical compositions of DDT. OGD-induced ER stress, Ca2+ overload, and mitochondrial apoptosis were investigated in nerve growth factor -induced PC12, primary neuronal cells, and ICH rats to evaluate the protective effect of DDT. We found that DDT treatment protected neurons against OGD-induced damage and apoptosis by increasing cell viability and reducing the release of lactate dehydrogenase. DDT decreased OGD-induced Ca2+ overload and ER stress through the blockade of the glucose-regulated protein 78 (GRP78)- inositol-requiring protein 1α (IRE1)/ protein kinase RNA-like ER kinase (PERK) pathways and also inhibited apoptosis by decreasing mitochondrial damage. Moreover, we observed similar findings when we studied DDT for inhibition of ER stress in a rat model of ICH. In addition, our experiments further confirmed the neuroprotective potential of DDT against tunicamycin (TM)-induced neural damage. Our in vitro and in vivo results indicated that the neuroprotective effect of DDT against ER stress damage and apoptosis occurred mainly by blocking the GPR78-IRE1/PERK pathways. Taken together, it provides reliable experimental evidence and explains the molecular mechanism of DDT for the treatment of patients with ICH.