Exploring clinical indicator variations in stroke patients with multiple risk factors: focus on hypertension and inflammatory reactions.

BACKGROUND: Stroke stands as the second leading cause of death worldwide. Currently, extensive research has been conducted on stroke risk factors. However, when stroke patients contend with multiple risk factors, the impact on clinical indicators remains uncertain. OBJECTIVES: This study seeks to investigate potential significant variations among distinct ranges of clinical indicators in instances where stroke patients experience multiple risk factors and various ischemic stroke subtypes. MATERIAL AND METHODS: The research encompassed 440 stroke patients admitted to the First People's Hospital of Wenling City, Zhejiang Province, China. These patients were classified based on the type and quantity of risk factors and subtypes of ischemic stroke they presented. The χ2 test was employed to assess the relationship between the risk of comorbid diseases and clinical indicators in stroke patients. RESULTS: The results of our study have underscored a significant correlation between various comorbid risk factors in stroke patients and the patients' age (P < 0.010). Furthermore, we observed noteworthy disparities in the plasma levels of IL-2, IL-4, IL-6, IL-10, TNF-α, and INF-γ between patients devoid of risk factors and those presenting with comorbid risk factors associated with stroke. Significant differences in INF-γ were observed between the two subtypes of ischemic stroke, namely lacunar infarction and cardioembolic stroke. CONCLUSION: Age is correlated with an elevated risk of stroke. Individuals exhibiting multiple stroke risk factors and diverse ischemic stroke subtypes commonly present with abnormal lipid levels and imbalances in Th1/Th2 cytokines. These factors significantly contribute to the onset and progression of stroke. Furthermore, inflammatory responses, particularly those induced by atherosclerosis, play a pivotal role in the genesis of stroke and exert a substantial influence on its prognosis.

Genetic correlation for alcohol consumption between Europeans and East Asians.

Genome-wide association studies (GWAS) have identified many genetic variants associated with alcohol consumption in Europeans and East Asians, as well as other populations. However, the genetic homogeneity and heterogeneity between these populations have not been thoroughly investigated, despite evidence of varying effect sizes of variants between ethnicities and the presence of population-specific strong signals of selection on loci associated with alcohol consumption. In order to better understand the relationship between Europeans and East Asians in the genetic architecture of alcohol consumption, we compared their heritability and evaluated their genetic correlation using GWAS results from UK Biobank (UKB) and Biobank Japan (BBJ). We found that these two populations have low genetic correlation due to the large difference on chromosome 12. After excluding this chromosome, the genetic correlation was moderately high ([Formula: see text] = 0.544, p = 1.12e-4) and 44.31% of the genome-wide causal variants were inferred to be shared between Europeans and East Asians. Given those observations, we conducted a meta-analysis on UKB and BBJ and identified new signals, including the CADM2 gene on chromosome 3, which has been associated with various behavioral and metabolic traits. Overall, our findings suggest that the genetic architecture of alcohol consumption is largely shared between Europeans and East Asians, but there are exceptions such as the enrichment of heritability on chromosome 12 in East Asians.

Effect of PLA2G6 and SMPD1 Variants on the Lipid Metabolism in the Cerebrospinal Fluid of Patients with Parkinson's Disease: A Non-targeted Lipidomics Study.

INTRODUCTION: Sleep patterns are more frequently interrupted in patients with Parkinson's disease (PD), and it is still unclear whether genetic factors are involved in PD-related sleep disorders. In this study, we hypothesize that PD-associated genetic risk affects lipid metabolism, which in turn contributes to different types of sleep disorders. METHODS: We used a non-targeted lipidomics to explore the lipid composition of cerebrospinal fluid (CSF) exosomes derived from patients with PD carrying phospholipase A2 Group VI (PLA2G6) and sphingomyelin phosphodiesterase 1 (SMPD1) mutations. RESULTS: PLA2G6 mutations (c.1966C > G, Leu656Val; c.2077C > G, Leu693Val; c.1791delC, His597fx69) significantly increase the exosomal content of glycerophospholipids and lysophospholipids, specifically phosphatidylcholine (PC) and lysophosphatidylcholine (LPC). Exosome surface presence of melatomin receptor 1A (MTNR1A) was detectable only in patients with PLA2G6 mutations. We have further shown that, in patients with PD carrying PLA2G6 mutations, sleep latency was significantly longer compared to those carrying WT PLA2G6, and we speculate that functional PLA2G6 mutations lead to structural changes and lipid deregulation of exosomes, which in turn alters exosomal cargo and affects PD-related sleep disorders. In SMPD1, G508R variant-carrying patients with PD abundance of sphingomyelins was significantly higher and had significantly shorter rapid eye movement sleep. CONCLUSIONS: Our study demonstrated that the disturbed composition and function of CSF-derived exosome lipidome during the pathological stage of PD may affect different types of sleep disorder in PD.

Increased serum fibroblast growth factor 21 levels are associated with adverse clinical outcomes after intracerebral hemorrhage.

Introduction: Intracerebral hemorrhage (ICH) is the most prevalent cause of death. We sought to explore whether serum Fibroblast growth factor 21 (FGF21) is of substantial benefit in predicting poor prognosis in ICH patient. Methods: A prospective, multicenter cohort analysis of serum FGF21 levels in 418 ICH patients was carried out. At three months following ICH start, the primary endpoint was death or major disability, whereas the secondary endpoint was death. We investigated the association between serum FGF21 and clinical outcomes. We added FGF21 to the existing rating scale to assess whether it enhanced the prediction ability of the original model. Effectiveness was determined by calculating the C-statistic, net reclassification index (NRI), absolute integrated discrimination improvement (IDI) index. Results: Among 418 enrolled patients, 217 (51.9%) of the all subjects had death or significant disability. Compared with patients in the lowest quartile group, those in the first quartile group had higher risk of the primary outcome (Odds ratio, 2.73 [95%CI,1.42-5.26, p < 0.05]) and second outcome (Hazard ratio, 4.28 [95%CI,1.61-11.42, p < 0.001]). The integration of FGF21 into many current ICH scales improved the discrimination and calibration quality for the integrated discrimination index's prediction of main and secondary findings (all p < 0.05). Conclusion: Elevated serum FGF21 is associated with increased risks of adverse clinical outcomes at 3 months in ICH patients, suggesting FGF21 may be a valuable prognostic factor.

Necroptosis signaling and mitochondrial dysfunction cross-talking facilitate cell death mediated by chelerythrine in glioma.

Glioma is the most common primary malignant brain tumor with poor survival and limited therapeutic options. Chelerythrine (CHE), a natural benzophenanthridine alkaloid, has been reported to exhibit the anti-tumor effects in a variety of cancer cells. However, the molecular target and the signaling process of CHE in glioma remain elusive. Here we investigated the underlying mechanisms of CHE in glioma cell lines and glioma xenograft mice model. Our results found that CHE-induced cell death is associated with RIP1/RIP3-dependent necroptosis rather than apoptotic cell death in glioma cells at the early time. Mechanism investigation revealed the cross-talking between necroptosis and mitochondria dysfunction that CHE triggered generation of mitochondrial ROS, mitochondrial depolarization, reduction of ATP level and mitochondrial fragmentation, which was the important trigger for RIP1-dependent necroptosis activation. Meanwhile, PINK1 and parkin-dependent mitophagy promoted clearance of impaired mitochondria in CHE-incubated glioma cells, and inhibition of mitophagy with CQ selectively enhanced CHE-induced necroptosis. Furthermore, early cytosolic calcium from the influx of extracellular Ca2+ induced by CHE acted as important "priming signals" for impairment of mitochondrial dysfunction and necroptosis. Suppression of mitochondrial ROS contributed to interrupting positive feedback between mitochondrial damage and RIPK1/RIPK3 necrosome. Lastly, subcutaneous tumor growth in U87 xenograft was suppressed by CHE without significant body weight loss and multi-organ toxicities. In summary, the present study helped to elucidate necroptosis was induced by CHE via mtROS-mediated formation of the RIP1-RIP3-Drp1 complex that promoted Drp1 mitochondrial translocation to enhance necroptosis. Our findings indicated that CHE could potentially be further developed as a novel therapeutic strategy for treatment of glioma.

Exosomes rich in Wnt5 improved circadian rhythm dysfunction via enhanced PPARγ activity in the 6-hydroxydopamine model of Parkinson's disease.

Sleep disorder is one of the most common non-motor symptoms in Parkinson's disease (PD) and even appear as early symptoms. Here we investigated the therapeutic potential of mesenchymal stem cell-derived exosomes (MSC-EXOs) on sleep disorder in PD rats. 6-hydroxydopa (6-OHDA) was used to establish the PD rat model. BMSCquiescent-EXO and BMSCinduced-EXO groups were given intravenous injection 100 µg/g per day for 4 weeks, while control groups were given intravenous injection of the same volume of normal saline. The total sleep time, slow-wave sleep time and fast-wave sleep time in the BMSCquiescent-EXO and BMSCinduced-EXO groups were significantly prolonged (P < 0.05) compared with PD group, while the awakening time was significantly shortened (P < 0.05). In addition, increased levels of dopamine (P < 0.05) and 5-hydroxytryptamine (P < 0.05) levels were observed in the striatum of BMSCquiescent-EXO and BMSCinduced-EXO groups. Further, qPCR and western blot revealed that the mRNA levels of CLOCK, BMAL1 and PER2 in suprachiasmatic nucleus (SCN) were notably increased in BMSCquiescent-EXO and BMSCinduced-EXO groups compared to those from PD rats. More importantly, peroxisome proliferation-activated receptor γ (PPARγ) activities were significantly enhanced after treatment with BMSCquiescent-EXO and BMSCinduced-EXO. JC-1 fluorescence staining showed that mitochondrial membrane potential imbalance was repaired after inoculation of BMSCinduced-EXO. In summary, MSC-EXOs showed the improvement of sleep disorder in PD rats through recovering circadian rhythm associated gene expression. The potential mechanisms may be related with increased PPARγ activities and rescued mitochondrial membrane potential imbalance in Parkinson striatum.

Cerebrospinal Fluid Extracellular Vesicles with Distinct Properties in Autoimmune Encephalitis and Herpes Simplex Encephalitis.

Encephalitis mediated by autoantibodies against neuronal antigens and herpes simplex encephalitis (HSE) are seemingly separate causes of encephalopathy in adults. Autoimmune encephalitis (AE) is autoimmune in origin, and herpes simplex encephalitis is infectious. The purpose of this study was to examine the role of cerebrospinal fluid (CSF) exosomes from patients with antibody-positive AE and HSE. Towards this, exosomes were isolated from CSF from 13 patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, 11 patients with anti-gamma-aminobutyric acid-B (GABAB) receptor encephalitis, 9 patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, and 8 patients with anti-contactin-associated protein-like 2 (CASPR2) encephalitis, and 12 control individuals negative of antibodies against neuronal autoantigens. There were ten miRNAs highly expressed in patients with anti-NMDAR encephalitis compared to those in control subjects. Eight miRNAs were found to be lower expressed in anti-NMDAR encephalitis CSF-derived exosomes. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched by AE differential expressed exosomic miRNAs demonstrated that AE-related exosomic miRNAs may participate as a feedback regulation in cancer development. In addition, the exosome concentration in CSF of 9 HSE patients was significantly higher compared to those from 9 HSV( -) patients. This observation was consistent with the results that exosome concentration was found to be higher in the animal model which was inoculated intranasally with HSV-1 compared to controls. Furthermore, western blot demonstrated that the subunits of NMDAR, GABABR, and AMPAR were detected highly expressed in exosomes derived from sera of HSV-1-treated animal model compared to controls. More importantly, exosomes isolated from CSF of HSE patients contained higher expression levels of two miRNAs encoded by HSV, miR-H2-3p, and miR-H4-3p compared to those from HSV( -) patients. In summary, HSV may trigger brain autoimmunity in HSE by presentation of surface autoantigens via exosomes.

Exosomes isolated during dopaminergic neuron differentiation suppressed neuronal inflammation in a rodent model of Parkinson's disease.

Our previous investigation showed Wnt signal pathway was significantly activated during DA neuron differentiation of epiblast-derived stem cells. In this study, we next attempt to examine the therapeutic potential of the purified exosomes derived bone marrow mesenchymal stem cells (BMSCs) by administrating exosomes into the rat striatum of parkinson's disease (PD) animal model. Results revealed that the protein levels of interleukin (IL)-6, IL-1ß, tumor necrosis factor-alpha (TNF-α), and reactive oxygen species (ROS) in the substantia nigra of PD rats were down regulated after injection of BMSC induced-Exosomes into the striatum of PD model compared to BMSC quiescent-Exosomes. In addition, the expression of ionized calcium binding adaptor molecule 1 (Iba1) mRNA was significantly decreased, while the expression of tyrosine hydroxylase (TH) mRNA was increased after injection of BMSC induced-Exosomes. Injection of BMSC induced-Exosomes into the striatum rescued the rotation behavior and climbing speed in the PD rats. More importantly, Wnt5a was found to be enriched in BMSC induced Exosomes, which could be effectively transferred to the substantia nigra of PD rats. In conclusion, these findings demonstrated that exosomes isolated during dopaminergic neuron differentiation could rescue the pathogenic features of Parkinson's disease by reshaping the inflammatory microenvironment in the substantia nigra and repairing the injury to DA nerves.

Neuroprotective Effect of Trans-Resveratrol in Mild to Moderate Alzheimer Disease: A Randomized, Double-Blind Trial.

INTRODUCTION: Amyloid-beta (Aß) protein is a major component of the extracellular plaque found in the brains of individuals with Alzheimer's disease (AD). In this study, we investigated the effect of trans-resveratrol as an antagonist treatment for moderate to mild AD, as well as its safety and tolerability. METHODS: This was a case-control study that enrolled 30 selected patients who had been clinically diagnosed with moderate to mild AD. These patients were randomly divided into two groups, namely, a placebo group (n = 15) and a trans-resveratrol group (n = 15) who received 500 mg trans-resveratrol orally once daily for 52 weeks. Brain magnetic resonance imaging (MRI) examinations were performed on and cerebrospinal fluid (CSF) samples were obtained from all participants before (baseline) and after the study (52 weeks). Enzyme-linked immunosorbent assays were used to determine the levels of plasma Aß40 and Aß42 and CSF Aß40 and Aß42. RESULTS: The results showed that the changes over the study period in the levels of Aß40 in the blood and CSF of the patients treated with trans-resveratrol were not statistically significant (P > 0.05). In contrast, patients who received placebo showed a significant decrease in Aß40 levels compared with that at the beginning of the study (CSF Aß40: P = 0.024, plasma Aß40: P = 0.036). Analysis of the images on the brain MRI scans revealed that the brain volume of the patients treated with trans-resveratrol was significantly reduced at 52 weeks (P = 0.011) compared with that of patients in the placebo treatment group, Further analysis indicated that the level of matrix metallopeptidase 9 in the CSF of the patients treated with trans-resveratrol at 52 weeks decreased by 46% compared with that of patients in the placebo group (P = 0.033). CONCLUSION: These results indicate that trans-resveratrol has potential neuroprotective roles in the treatment of moderate to mild AD and that its mechanism may involve a reduction in the accumulation and toxicity of Aß in the brain of patients, thereby reducing neuroinflammation. TRIAL REGISTRATION: Chinese clinical trial registry: CTR20151780X.

Preparation and characterization of a novel polysialic acid/gelatin composite hydrogels cross-linked by tannic acid to improve wound healing after cesarean section dressing.

The infections and delayed wound healing after cesarean delivery is one of the most complicated issues in surgical medicinal field. In the present investigation, designed novel polysialic acid loaded gelatin (PSA-Gel) composite hydrogels cross-linked by tannic acid (TA) has been developed and used as a facile wound dressing to improve cesarean wound healing ability with prevent bactericidal infections. The cross-linking effect was predominant when the TA content was lower, resulting in the formation of a cross-linked network. An effective TA cross-linking effect on the PSA-Gel hydrogel matrix was achieved when the amount of TA was around 15 wt %. The morphology of as-fabricated hydrogels was characterized using scanning electron microscopy (SEM) with an average pore sizes of PSA-Gel, PSA-Gel-TA-5%, PSA-Gel-TA-10%, and PSA-Gel-TA-15% hydrogels were 95.4 ± 12.6 µm, 120.4 ± 8.2 µm, 165.3 ± 21.6 µm, and 270.2 ± 32.5 µm, respectively. The effects of hydrogels on the swelling ratio, in vitro degradation, and mechanical properties were systemically evaluated. The TA cross-linked PSA-Gel hydrogels display strong antimicrobial behavior against gram-positive (Staphylococcus aureus) gram-negative (Escherichia coli) bacteria strains. Moreover, PSA-Gel-TA hydrogels also displayed favorable cytotoxicity toward L929 fibroblast cell lines. Finally, the therapeutic and wound healing potential of the PSA-Gel-TA hydrogels has been studied in vivo using the excision wound model in rats. The results indicate that the PSA-Gel-TA hydrogels have a greater and significant effect on wound closure and increased the wound healing rate compared with native PSA-Gel hydrogels and untreated control group at 94%, 73% and 65% on day 21. The findings suggest that PSA-Gel-TA hydrogels are promising dressing materials for the treatment of wound healing.

A novel synthesis of selenium nanoparticles encapsulated PLGA nanospheres with curcumin molecules for the inhibition of amyloid ß aggregation in Alzheimer's disease.

The main factors of Alzheimer's disease (AD) are the cerebral accumulation and the formation of extracellular amyloid plaques. The Aß peptides are highly able to accumulative and produce fibrils that are placed to form these plaques in the AD. The biological action and drug delivery properties of curcumin (Cur) nanoformulation in the Alzheimer's disease therapeutics can be developed by the altering surface of the Poly-lactide-co-glycolide (PLGA) polymer and encapsulation of selenium nanoparticles (Se NPs). The morphological structure, size distributions of nanospheres, chemical interactions between the polymer and nanoformulations of synthesized curcumin and Se NPs loaded PLGA nanospheres have been studied by using the techniques of analytical instruments. The microscopic and nano observation results of synthesized Cur loaded nanospheres are exhibited that the mono-dispersed distributions of particles with spherical shaped structure. The present drug delivery system of Cur loaded Se-PLGA nanospheres could be decreases the amyloid-ß load in the brains samples of AD mice, and greatly cured the memory deficiency of the model mice. The specific binding of Cur loaded Se-PLGA nanospheres with Aß plaques were visualized by fluorescence microscopic technique. Se-PLGA targeting delivery system to amyloid plaques might be providing the enhanced therapeutic efficacy in AD lesions, which was studied by using transgenic mice (5XFAD). In conclusion, Cur loaded Se-PLGA nanoformulation has been demonstrated that valued delivery system for the targeted delivery and effective way to treat AD.