Mannitol inhibits the proliferation of neural stem cell by a p38 mitogen-activated protein kinase-dependent signaling pathway.

PURPOSE: Mannitol is one of the first-line drugs for reducing cerebral edema through increasing the extracellular osmotic pressure. However, long-term administration of mannitol in the treatment of cerebral edema triggers damage to neurons and astrocytes. Given that neural stem cell (NSC) is a subpopulation of main regenerative cells in the central nervous system after injury, the effect of mannitol on NSC is still elusive. The present study aims to elucidate the role of mannitol in NSC proliferation. METHODS: C57 mice were derived from the animal house of Zunyi Medical University. A total of 15 pregnant mice were employed for the purpose of isolating NSCs in this investigation. Initially, mouse primary NSCs were isolated from the embryonic cortex of mice and subsequently identified through immunofluorescence staining. In order to investigate the impact of mannitol on NSC proliferation, both cell counting kit-8 assays and neurospheres formation assays were conducted. The in vitro effects of mannitol were examined at various doses and time points. In order to elucidate the role of Aquaporin 4 (AQP4) in the suppressive effect of mannitol on NSC proliferation, various assays including reverse transcription polymerase chain reaction, western blotting, and immunocytochemistry were conducted on control and mannitol-treated groups. Additionally, the phosphorylated p38 (p-p38) was examined to explore the potential mechanism underlying the inhibitory effect of mannitol on NSC proliferation. Finally, to further confirm the involvement of the p38 mitogen-activated protein kinase-dependent (MAPK) signaling pathway in the observed inhibition of NSC proliferation by mannitol, SB203580 was employed. All data were analyzed using SPSS 20.0 software (SPSS, Inc., Chicago, IL). The statistical analysis among multiple comparisons was performed using one-way analysis of variance (ANOVA), followed by Turkey's post hoc test in case of the data following a normal distribution using a Shapiro-Wilk normality test. Comparisons between 2 groups were determined using Student's t-test, if the data exhibited a normal distribution using a Shapiro-Wilk normality test. Meanwhile, data were shown as median and interquartile range and analyzed using the Mann-Whitney U test, if the data failed the normality test. A p < 0.05 was considered as significant difference. RESULTS: Primary NSC were isolated from the mice, and the characteristics were identified using immunostaining analysis. Thereafter, the results indicated that mannitol held the capability of inhibiting NSC proliferation in a dose-dependent and time-dependent manner using cell counting kit-8, neurospheres formation, and immunostaining of Nestin and Ki67 assays. During the process of mannitol suppressing NSC proliferation, the expression of AQP4 mRNA and protein was downregulated, while the gene expression of p-p38 was elevated by reverse transcription polymerase chain reaction, immunostaining, and western blotting assays. Subsequently, the administration of SB203580, one of the p38 MAPK signaling pathway inhibitors, partially abrogated this inhibitory effect resulting from mannitol, supporting the fact that the p38 MAPK signaling pathway participated in curbing NSC proliferation induced by mannitol. CONCLUSIONS: Mannitol inhibits NSC proliferation through downregulating AQP4, while upregulating the expression of p-p38 MAPK.

Causes and global, regional, and national burdens of traumatic brain injury from 1990 to 2019.

PURPOSE: Traumatic brain injury (TBI), currently a major global public health problem, imposes a significant economic burden on society and families. We aimed to quantify and predict the incidence and severity of TBI by analyzing its incidence, prevalence, and years lived with disability (YLDs). The epidemiological changes in TBI from 1990 to 2019 were described and updated to provide a reference for developing prevention, treatment, and incidence-reducing measures for TBI. METHODS: A secondary analysis was performed on the incidence, prevalence, and YLDs of TBI by sex, age group, and region (n = 21,204 countries and territories) between 1990 and 2019 using the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Proportions in the age-standardized incidence rate due to underlying causes of TBI and proportions of minor and moderate or severe TBI were also reported. RESULTS: In 2019, there were 27.16 million (95% uncertainty intervals (UI): 23.36 - 31.42) new cases of TBI worldwide, with age-standardized incidence and prevalence rates of 346 per 100,000 population (95% UI: 298-401) and 599 per 100,000 population (95% UI: 573-627), respectively. From 1990 to 2019, there were no significant trends in global age-standardized incidence (estimated annual percentage changes: -0.11%, 95% UI: -0.18% - -0.04%) or prevalence (estimated annual percentage changes: 0.01%, 95% UI: -0.04% - 0.06%). TBI caused 7.08 million (95% UI: 5.00 - 9.59) YLDs in 2019, with age-standardized rates of 86.5 per 100,000 population (95% UI: 61.1 - 117.2). In 2019, the countries with higher incidence rates were mainly distributed in Central Europe, Eastern Europe, and Australia. The 2019 global age-standardized incidence rate was higher in males than in females. The 2019 global incidence of moderate and severe TBI was 182.7 per 100,000 population, accounting for 52.8% of all TBI, with falls and road traffic injuries being the main causes in most regions. CONCLUSIONS: The incidence of moderate and severe TBI was slightly higher in 2019, and TBI still accounts for a significant portion of the global injury burden. The likelihood of moderate to severe TBI and the trend of major injury under each injury cause from 1990 to 2019 and the characteristics of injury mechanisms in each age group are presented, providing a basis for further research on injury causes in each age group and the future establishment of corresponding policies and protective measures.

Road traffic mortality in Zunyi city, China: A 10 - year data analysis (2013-2022).

PURPOSE: The study aimed to examine the pattern of motorization and the mortality rate related to road traffic crashes in Zunyi (a city in northern Guizhou province of China) from 2013 to 2022, and to identify the epidemiological characteristics of these crashes with to provide insights that could help improve road safety. METHODS: Data were obtained from the Zunyi traffic management data platform, and the mortality rates were calculated. We deployed various analytical methods, including descriptive analysis, Chi-square test or Fisher's exact test of categorical variable, circular distribution map analysis, and Rayleigh test to characterize the traits of road traffic crashes in the region. RESULTS: During the 10-year study period, 7488 people died due to road traffic accidents, with males accounting for 70.4% and females 29.6% (χ2 = 101.97, p < 0.001). The mortality rate increased from 7.80 deaths per 100,000 people in 2013 to 10.70 deaths per 100,000 people in 2016, but then decreased to 9.54 deaths per 100,000 people in 2019. A notable finding was that the death rate per 10,000 vehicles declined from 16.09 deaths per 10,000 vehicles in 2013 to 5.48 deaths per 10,000 vehicles in 2022. The study also found that vulnerable road users represented nearly half (48.76%) of all accident fatalities, and unlicensed or inexperienced driving contributed significantly to the occurrence of road traffic accidents. CONCLUSION: Although the number of road traffic accidents in Zunyi has decreased, there are still some critical issues that need to be addressed, particularly for vulnerable road users and unlicensed drivers. Our results highlight the need of targeted interventions to address the specific risk factors of road traffic crashes, particularly those affecting vulnerable road users and drivers without sufficient experience or license.

Influence of road types on road traffic accidents in northern Guizhou Province, China.

PURPOSE: The increasing number of deaths due to road traffic accidents (RTAs) has attracted global attention. However, the influence of road types is rarely considered in the study of RTAs. This study evaluates the influence of different road types in RTAs in northern Guizhou to provide a basis for the formulation of evidence-based policies and measures. METHODS: We obtained the data from the Zunyi Traffic Management Data Platform for the years 2009-2018. The mortality rates of RTAs were calculated. Descriptive methods and Chi-square tests were used to analyze the characteristics of road traffic collisions on different road types. We also examined the associations between the mortality rate per 10,000 vehicles and the growth of per capital gross domestic product (GDP) with Spearman's rank correlation analysis. According to the passing volume and the infrastructure, we defined different types of roads, like administrative road, functional road, general urban road and urban expressway. RESULTS: In 2012, the traffic mortality rate of administrative roads was 8.9 per 100,000 people, and the mortality rate of functional roads was 7.4 per 100,000 people, which decreased in 2018 to 6.1 deaths per 100,000 people and 5.2 deaths per 100,000 people, respectively. The mortality rate per 10,000 vehicles reached the highest level in 2011 (28.8 per 10,000 vehicles and 22.5 per 10,000 vehicles on administrative and functional roads, respectively). The death rate of county roads was the highest among administrative roads (χ2 = 17.389, p < 0.05) and that of fourth-class roads was the highest among functional roads (χ2 = 21.785, p < 0.05). The mortality rate per 10,000 vehicles was negatively correlated with per capital GDP. CONCLUSION: Although our research shows that RTAs in northern Guizhou have steadily declined in recent years, the range of decline is relatively small. Many measures and sustainable efforts are needed to control road traffic death and accelerate the progress in road traffic safety in northern Guizhou.

Knowledge, attitudes and practices of the Chinese public with respect to coronavirus disease (COVID-19): an online cross-sectional survey.

BACKGROUND: Coronavirus disease (COVID-19) has become a pandemic. The knowledge, attitudes, and practices (KAP) of the public play a major role in the prevention and control of infectious diseases. The objective of the present study was to evaluate the KAP of the Chinese public and to assess potential influencing factors related to practices. METHODS: A cross-sectional online survey was conducted in China in February 2020 via a self-designed questionnaire comprising 33 questions assessing KAP. RESULTS: For the 2136 respondents from 30 provinces or municipalities in China, the accurate response rate for the knowledge section ranged from 72.7 to 99.5%, and the average was 91.2%. Regarding attitude section, the percentage of positive attitudes ("strongly agree" and "agree") ranged from 94.7 to 99.7%, and the average value was 98.0%. The good practices ("always" and "often") results ranged from 76.1 to 99.5%, and the average value was 96.8%. The independent samples t-test revealed that gender and ethnic differences had no effect on knowledge, attitude or behaviour (P > 0.05). However, knowledge was associated with age (t = 4.842, p < 0.001), marital status (t = - 5.323, p < 0.001), education level (t = 8.441, p < 0.001), occupation (t = - 10.858, p < 0.001), and place of residence (t = 7.929, p < 0.001). Similarly, attitude was associated with marital status (t = - 2.383, p = 0.017), education level (t = 2.106, p = 0.035), occupation (t = - 4.834, p < 0.001), and place of residence (t = 4.242, p < 0.001). The multiple linear regression analysis results showed that the factors influencing practices were knowledge (t = - 3.281, p = 0.001), attitude (t = 18.756, p < 0.001), occupation (t = - 3.860, p < 0.001), education level (t = 3.136, p = 0.002), and place of residence (t = 3.257, p = 0.001). CONCLUSIONS: The Chinese public exhibited a good level of knowledge of COVID-19, a positive attitude, and high adherence to good practices. COVID-19-related knowledge, attitudes and practices were affected by age, marital status, education level, occupation, and place of residence to varying degrees. In addition, practices were affected by knowledge and attitudes towards COVID-19.

Upregulation of miR-133a by adiponectin inhibits pyroptosis pathway and rescues acute aortic dissection.

Acute aortic dissection (AAD) is a cardiovascular emergency caused by the formation of hematoma in the middle layer of the aortic wall. Adiponectin (APN) is an adipose tissue-specific protein that has anti-inflammation and anti-atherosclerosis functions. Pyroptosis, as an inflammatory cell death, depends on the activation of caspase1, while nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) is a typical representative of the pyroptosis pathway. In this study, we aimed to find whether APN affects the AAD process. The results showed that APN overexpression (OE) inhibited the AAD development and the levels of glucose, triglyceride, and total cholesterol in mice model. In addition, APN OE inhibited the productions of gasdermin D (GSDMD), NLRP3, caspase1, interleukin-1ß (IL-1ß), IL-18, and osteopontin (OPN), as well as α-smooth muscle actin (α-SMA) downregulation in vitro and in vivo. In addition, NLRP3 was found to be a target gene of miR-133a and miR-133a OE showed similar effects to APN OE in attenuating the LPS-induced productions of GSDMD, NLRP3, caspase1, IL-1ß, IL-18, and OPN, as well as α-SMA downregulation in vascular smooth muscle cells (vSMCs). Moreover, the beneficial effects of APN OE were abolished by miR-133a knockdown in vSMCs. In conclusion, our present results indicated that the upregulation of miR-133a by APN inhibits pyroptosis pathway, which potentially rescues AAD.

Interventional treatment experience in multiple injury with major abdominal or pelvic injuries: 160 cases analysis.

PURPOSE: To observe the therapeutic effect of interventional embolization and haemorrhage control in multiple trauma patients with a major abdominal or pelvic injury. METHODS: Data of 160 multiple trauma patients with a major abdominal or pelvic injury were retrospectively analyzed. They were admitted into the Department of Emergency of the First Affiliated Hospital of Zunyi Medical College from October 2013 to April 2016. Eighty-seven patients who received emergent intervention for embolization and haemorrhage control were set as group A, including 72 males and 15 females, with an average age of (39.32 ± 14.0) years. Patients underwent emergent intervention for embolization and hemostasis. The other 73 patients who received traditional surgeries were set as group B, including 62 males and 11 females, with an average age of (38.48 ± 13.12) years. The time from admission to emergency intervention, the time of interventional embolization, transfusion during hospitalization, length of stay and prognosis were observed. The whole treatment and prognosis were compared between group A and group B. RESULTS: In group A, the average time from admission to intervention exploration was (132.05 ± 86.80) min, the average operation time was (149 ± 49.69) min, the average hospitalization time was (18.37 ± 4.71) days, the average amount of RBC transfusion during hospitalization was (7.2 ± 4.33) units, and the mortality was 4.60% (4 patients died). The corresponding data in group B were respectively (138.95 ± 82.49) min, (183 ± 52.39) min, (22.72 ± 6.63) days, (12.23 ± 5.43) units, and 9.59% (7 cases died). There was no statistical difference in the time from admission to operation between the two groups (p > 0.05), but there was statistical difference in operation time, RBC transfusion, hospitalization time, prognosis, and mortality between the two groups (all p < 0.05). CONCLUSION: The emergent intervention for embolization and haemorrhage control of multiple trauma patients with a major abdominal or pelvic injury and visceral organ haemorrhage has the advantages of less trauma, shorter operation time, shorter hospital stay, less blood transfusion in comparison to the traditional emergency surgeries.

Three-dimensional computed tomography reconstructive diagnosis of snakebite-induced cerebral infarction.

Despite common injury caused by snakebite, snakebite-induced ischemic stroke is rare. We reported on a patient who incurred a large cerebral infarction after being bitten by a Deinagkistrodon acutus, one of the most poisonous snakes in the southwestern of China. Applying 3D computed tomography (CT) of head combined with cerebral angiography examinations showed a large cerebral infarction, hernia in the right brain, developmental abnormalities of the right middle cerebral artery and cerebral artery of right brain. In conclusion, head CT imaging combined with cerebral angiography provides an efficient approach in diagnosis of stroke caused by snakebites.

Dihydroartemisinin exhibits anti-glioma stem cell activity through inhibiting p-AKT and activating caspase-3.

Glioma stem cells (GSCs) have been proven to play key roles in tumorigenesis, metastasis and recurrence. Although dihydroartemisinin (DHA), a derivative of the antimalaria drug artemisinin, has been shown to have anti-cancer activity, it is still unclear whether DHA affects GSCs. This study investigated the effects of DHA on the growth and apoptosis of GSCs, as well as the possible molecular mechanism involved in these processes. GSCs were enriched using a non-adhesive culture system with serum-free neural stem cell medium. Their stemness characteristics were identified by assessment of tumor sphere formation, mRNA expression analysis, and immunofluorescence staining of stem cell markers (CD133, SOX2, and nestin). We found that DHA not only inhibited proliferation, which was determined with the cell counting kit-8 (CCK8) assay, but also induced apoptosis of GSCs, as evaluated with the annexin-V/PI flowcytometric assay. Interestingly, DHA treatment also induced a concentration-dependent cell cycle arrest in the G1 phase according to the cell cycle assay. To reveal the underlying mechanisms, we detected the expression levels of p-Akt and Cleaved Caspase-3. The data showed that Cleaved Caspase-3 increased significantly in a dose-dependent manner (p < 0.05) after the GSCs sphere cells were treated with 20, 40, and 80 µM of DHA for 24 h, which correlated with significantly decreased expression levels of p-Akt (p < 0.05). These data indicate that DHA selectively inhibits proliferation and induces apoptosis of GSCs through the down-regulation of Akt phosphorylation, which is followed by Caspase-3 activation, and these findings offer a new approach for treating gliomas.

Insights into optimizing exosome therapies for acute skin wound healing and other tissue repair.

Exosome therapy holds great promise as a novel approach to improve acute skin wound healing. This review provides a comprehensive overview of the current understanding of exosome biology and its potential applications in acute skin wound healing and beyond. Exosomes, small extracellular vesicles secreted by various stem cells, have emerged as potent mediators of intercellular communication and tissue repair. One advantage of exosome therapy is its ability to avoid potential risks associated with stem cell therapy, such as immune rejection or stem cells differentiating into unwanted cell types. However, further research is necessary to optimize exosome therapy, not only in the areas of exosome isolation, characterization, and engineering, but also in determining the optimal dose, timing, administration, and frequency of exosome therapy. Thus, optimization of exosome therapy is critical for the development of more effective and safer exosome-based therapies for acute skin wound healing and other diseases induced by cancer, ischemia, or inflammation. This review provides valuable insights into the potential of exosome therapy and highlights the need for further research to optimize exosome therapy for clinical use.

Targeting Ferroptosis Promotes Functional Recovery by Mitigating White Matter Injury Following Acute Carbon Monoxide Poisoning.

Survivors experiencing acute carbon monoxide poisoning (ACMP) tend to develop white matter injury (WMI). The mechanism of ACMP-induced WMI remains unclear. Considering the role of ferroptosis in initiating oligodendrocyte damage to deteriorate WMI, exploring therapeutic options to attenuate ferroptosis is a feasible approach to alleviating WMI. Our results indicated that ACMP induced accumulation of iron and reactive oxygen species (ROS) eventually leading to WMI and motor impairment after ACMP. Furthermore, ferrostatin-1 reduced iron and ROS deposition to alleviate ferroptosis, thereafter reducing WMI to promote the recovery of motor function. The nuclear factor erythroid-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway was found to be involved in alleviating ferroptosis as seen with the administration of ferrostatin-1. The present study rationalizes that targeting ferroptosis to alleviate WMI is a feasible therapeutic strategy for managing ACMP.

Prescription of potentially inappropriate medicines and comparison with lists of essential medicines for treatment of chronic disorders in older patients.

OBJECTIVES: To examine the current situation of potentially inappropriate medicines (PIM) for treatment of chronicity in older patients and whether the inappropriate medicines were included in the 22nd World Health Organization (WHO) Model List of Essential Medicines (EMLs), China National Model list of Essential Medicines (China EMLs), or supplementary list of essential medicines in Guizhou Province 2018 (Guizhou EMLs) through real world data, so as to promote the development of lists of essential medicines suitable for older patients and provide a reference for the revision of lists of essential medicines to reduce adverse effects, drug-induced diseases and even possible death due to use of inappropriate medicines existing in lists of essential medicines. METHODS: A retrospectively study was conducted. Dispensing records of patients aged ≥ 65 admitted to convenience clinic of a tertiary hospital from January 1, 2021 to December 31, 2021 were extracted through electronic information system. Then, we merged dispensing records of the same patient on the same date as one record and patients with at least one chronic disease were included. The American Geriatrics Society(AGS)/Beers Criteria 2019 (Beers 2019) was used to evaluate the PIM status. Thereafter, the inappropriate medicines were compared with WHO EMLs, China EMLs, and Guizhou EMLs to find out percentages of drugs of PIMs existing in above lists of essential medicines in all drugs of PIMs. The above evaluation was conducted using Excel software (version 2019). RESULTS: A total of 5314 dispensing reports were included in this study. 5.95% (316/5314), 7.88% (419/5314) of PIMs met Table 2 (medicines that are potentially inappropriate in most older adults), Table 4 (medicines that should be used with caution) of Beers 2019, respectively. Among PIM drugs which met Table 2 of Beers 2019, 47.37%, 78.95%, and 78.95% were respectively included in WHO EMLs, China EMLs, and Guizhou EMLs, and that was 47.06%, 76.47%, and 82.35% for Table 4 of Beers 2019. CONCLUSIONS: PIM in older patients is common in clinical practice. Patients with diabetes, hypertension, arthritis, depression and/or anxiety and Parkinson' diseases were more frequently prescribed drugs of PIM according to Beers 2019. Take older patients into consideration and formulate List of essential medicines special for older patients may be a key way to reduce PIM.

E3 ligase Nedd4L promotes macrophage M1 polarization and exacerbates brain damage by TRAF3/TBK1 signaling pathway after ICH in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a serious medical problem, and promising strategy is limited. Macrophage initiated brain inflammatory injury following ICH, but the molecular mechanism had not been well identified. E3 ligase Nedd4L is implicated in the pathogenesis of the inflammatory immune response. METHODS: In the present study, we detected the levels of Nedd4L in macrophages following ICH. Furthermore, Macrophage M1 polarization, pro-inflammatory cytokine production, BBB disruption, brain water content and neurological function were examined in ICH mice. RESULTS: Here, we demonstrated that E3 ligase Nedd4L levels of macrophage increased following ICH, promoted M1 polarization inflammation by TRAF3. Nedd4L promoted BBB disruption, as well as neurological deficits. Inhibition of Nedd4L significantly attenuated M1 polarization in vivo. Inhibition of Nedd4L decreased TRAF3 and TBK1 levels, and subsequent phosphorylation of p38 and NF-κB p65 subunit following ICH. CONCLUSIONS: Our data demonstrated that Nedd4L was involved in the pathogenesis of ICH, which promoted inflammatory responses and exacerbated brain damage by TRAF3 following ICH.

Aconitine induces brain tissue damage by increasing the permeability of the cerebral blood-brain barrier and over-activating endoplasmic reticulum stress.

OBJECTIVE: This study aimed to explore the neurotoxicity of aconitine and its underlying mechanism. METHODS: The rats were administered with the aconitine solution intragastrically at different dosages (0.5 mg/kg, 1.5 mg/kg, and 2.5 mg/kg). Evans blue (EB) extravasation and evaluation of tight junction protein expression were performed to determine the permeability of the blood-brain barrier. Cellular damage, apoptosis, and levels of endoplasmic reticulum (ER) stress markers were determined using H&E staining, Tunnel assay, and western blotting. The effects of aconitine on cell viability, apoptosis, and activation of the ER stress signaling in PC12 cells were assessed in vitro using the MTT assay, flow cytometry, western blot, and immunofluorescence analysis. RESULTS: Aconitine was observed to significantly increase the murine blood-brain barrier penetrability in a dose-dependent manner. The in vivo experimental results revealed that aconitine could stimulate the pathway for endoplasmic reticulum stress. The increase in the endoplasmic reticulum stress in the brain tissue promoted apoptosis, leading to brain damage. Moreover, PC12 cell proliferation was inhibited upon treatment with aconitine in a dose-dependent manner. In addition, cell apoptosis was increased upon treatment with aconitine also in a dose-dependent manner. These findings indicated that aconitine caused damage to PC12 cells via endoplasmic reticulum stress. CONCLUSION: Aconitine induces brain tissue damage by increasing the penetrability of the blood-brain barrier in the cerebral region and over-activating the endoplasmic reticulum stress.

Multiple miscarriages in a female patient with two-chambered heart and situs inversus totalis: A case report.

BACKGROUND: Single atrium with single ventricle, or a two-chambered heart, is an extremely rare congenital malformation. Few cases with two-chambered heart surviving to adulthood have been reported. CASE SUMMARY: We reported an adult female patient with a two-chambered heart and situs inversus totalis accompanied by multiple pregnancies and abortions. Magnetic resonance imaging detected a two-chambered heart. B-ultrasound-guided uterine aspiration was performed to absorb 8 g and 10 g of organized villus and decidual tissues, respectively, with a small amount of bleeding. Postoperatively, cyanosis and fatigue-induced shortness of breath were gradually relieved. The patient has currently outlived all similar cases reported so far. CONCLUSION: Hemodynamic changes in pregnant women with two-chambered heart impaired cardiac function, responsible for hypoperfusion and miscarriage.

VSIG4 Attenuates NLRP3 and Ameliorates Neuroinflammation via JAK2-STAT3-A20 Pathway after Intracerebral Hemorrhage in Mice.

Intracerebral hemorrhage (ICH) is a fatal cerebrovascular disease. Neuroinflammation plays an important pathological role in brain injury after ICH. NLRP3 contributes to the pathogenesis of ICH, but the underlying mechanisms regulating of NLRP3 remain elusive. V-set and immunoglobulin domain containing 4 (VSIG4), specifically expressed in resting tissue-resident macrophages, can deliver anti-inflammatory signals into various inflammatory diseases. However, the interaction between VSIG4 and NLRP3, as well as the underlying mechanisms after ICH have not been reported. C57BL/6 mice were subjected to the autologous blood injection ICH model. VSIG4 and NLRP3 levels of macrophages were detected following ICH. Ad-VSIG4 or controls were administered via intracerebroventricular (i.c.v) injection before ICH induction. STAT3 inhibitor (S31-201), JAK2 inhibitor (TG101348), or Ad-A20 RNAi was administered to investigate the role of JAK2-STAT3-A20 pathway in VSIG4-mediated neuroinflammation after ICH. Pro-inflammatory cytokine production, BBB disruption, brain water content, and neurological test were examined in ICH mice. VSIG4 levels were significantly decreased, and NLRP3 levels were significantly increased in the perihematomal brain tissues after ICH. Ad-VSIG4 attenuated NLRP3 levels and inhibited inflammation, as well as improved neurological function and reduced BBB disruption and brain water content. Furthermore, Ad-VSIG4 increased the protein levels of phosphorylated JAK2 and STAT3, and A20 levels at 24 h after ICH. STAT3 inhibitor, JAK2 inhibitor, and A20 RNAi abolished the beneficial effects of Ad-VSIG4 after ICH. In summary, these data suggested that VSIG4 attenuated NLRP3 and ameliorated neuroinflammation via JAK2-STAT3-A20 pathway after intracerebral hemorrhage in mice. VSIG4 might be an ideal therapeutic target for ICH patients.

TIPE2 attenuates neuroinflammation and brain injury through Bcl-2/Bax/cleaved caspase-3 apoptotic pathways after intracerebral hemorrhage in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a serious disease with high mortality and morbidity, and effective treatment is limited. A large amount of evidence suggests that the inflammatory response contributes to secondary brain damage following ICH. TIPE2 is an essential negative regulator of both innate and adaptive immunity, and depletion of TIPE2 causes inflammatory disease. However, the possible role of TIPE2 following ICH has not been reported. METHODS: In this study, we investigated TIPE2 levels and inflammation in microglia treated with erythrocyte lysate in vitro. In addition, we analyzed the role of Bcl-2/Bax/cleaved caspase-3 apoptotic pathways in ICH mice. Furthermore, we observed proinflammatory cytokine production, BBB disruption, cerebral water content and neurological damage in ICH mice. RESULTS: We found that TIPE2 levels were significantly decreased in erythrocyte lysate-treated microglia compared to control microglia.Upregulation of TIPE2 decreased microglia activation and cytokine production and accelerated brain damage in ICH mice. Furthermore, upregulation of TIPE2 decreased the higher ratio of Blc-2/Bax and increased cleaved caspase-3 levels in ICH mice. In addition, upregulation of TIPE2 attenuated proinflammatory cytokine production, BBB disruption, and severe brain inflammation after ICH. CONCLUSION: These results demonstrated that TIPE2 was negatively correlated with the pathogenesis of ICH, which prevented brain injury and attenuated deleterious inflammatory responses following ICH. TIPE2 might serve as a novel target for ICH therapy.

Mild Hypothermia Protects Brain Injury After Intracerebral Hemorrhage in Mice Via Enhancing the Nrdp1/MyD88 Signaling Pathway.

BACKGROUND: Mild hypothermia has been identified to reduce brain injury following intracerebral hemorrhage (ICH) by protecting neuron cells through several pathways. However, the role of hypothermia in brain function following ICH and the related mechanisms have not been well identified. Ubiquitination-mediated inflammation plays important roles in the pathogenesis of immune diseases. The experiment analyzed anti-inflammatory effects of mild hypothermia following ICH. METHODS: The model of ICH was induced by injecting autologous blood. Neuregulin receptor degradation protein-1 (Nrdp1) and downstream molecule were analyzed. In addition, brain inflammatory response, brain edema, and neurological functions of ICH mice were also assessed. RESULTS: We found that mild hypothermia attenuated proinflammatory factors production after ICH. Mild hypothermia significantly inhibited BBB injury, water content, and neurological damage following ICH in vivo. Moreover, mild hypothermia also increased Nrdp1/MyD88 levels and thus affect neuronal apoptosis and inflammation. CONCLUSIONS: Taken together, these results suggest that mild hypothermia can attenuate the neuroinflammatory response and neuronal apoptosis after ICH through the regulation of the Nrdp1 levels.

Actin Alpha 2 Downregulation Inhibits Neural Stem Cell Proliferation and Differentiation into Neurons through Canonical Wnt/ß-Catenin Signaling Pathway.

Our previous study has shown that actin alpha 2 (ACTA2) is expressed in NSC and ACTA2 downregulation inhibits NSC migration by increasing RhoA expression and decreasing the expression of Rac1 to curb actin filament polymerization. Given that proliferation and differentiation are the two main characteristics of NSC, the role of ACTA2 downregulation in the proliferation and differentiation of NSC remains elusive. Here, the results demonstrated that ACTA2 downregulation using ACTA2 siRNA held the potential of inhibiting NSC proliferation using cell counting kit-8 (CCK8) and immunostaining. Then, our data illustrated that ACTA2 downregulation attenuated NSC differentiation into neurons, while directing NSC into astrocytes and oligodendrocytes using immunostaining and immunoblotting. Thereafter, the results revealed that the canonical Wnt/ß-catenin pathway was involved in the effect of ACTA2 downregulation on the proliferation and differentiation of NSC through upregulating p-ß-catenin and decreasing ß-catenin due to inactivating GSK-3ß, while this effect could be partially abolished with administration of CHIR99012, a GSK-3 inhibitor. Collectively, these results indicate that ACTA2 downregulation inhibits NSC proliferation and differentiation into neurons through inactivation of the canonical Wnt/ß-catenin pathway. The aim of the present study is to elucidate the role of ACTA2 in proliferation and differentiation of NSC and to provide an intervention target for promoting NSC proliferation and properly directing NSC differentiation.

The Effect of Hemoglobin Concentration on Hyperbaric Oxygen and Non-hyperbaric Oxygen in the Treatment of Hypertensive Intracerebral Hemorrhage After Operation at the High Altitude.

Background: The prognosis of hypertensive intracerebral hemorrhage (HICH) is poor at high altitudes. The objective of this study was to explore whether hyperbaric oxygen (HBO) can improve the results of computed tomography perfusion (CTP) imaging and the neurological function of patients with HICH, and influence the hemoglobin concentration. Method: The patients with HICH were treated with puncture and drainage. Twenty-one patients (51.22% of 41 patients in total) were treated with HBO after the operation, and the other patients received conventional treatment. CTP was performed twice, and all indices were measured. Scatter plots were used to determine the effect of hemoglobin concentration on CTP imaging. Receiver operating characteristic (ROC) curves were plotted to analyze the effects of hemoglobin concentration and hematoma volume on recovery results. The patients were followed up for 6 months. Results: Forty-one patients with HICH were treated with puncture and drainage. In total, 21 were treated with HBO after the operation, and 20 received conventional treatment as the control group. No significant differences in the CBV and CBF values of the two groups were noted before treatment. After 10 days, the values of CBV and CBF in the HBO group were significantly higher than those in the control group. A scatter diagram showed there was no significant in the HBO group, but significant correlation for the CBV and CBF values in the control group's hematoma center and margin. The ROC curves showed that hematoma volume had an influence on prognosis of the control group. The Glasgow Coma Scale (GOS) scores of the HBO group were significantly higher than those of the control group (p < 0.05). Conclusions: HBO therapy can improve the postoperative CBV and CBF values of patients with HICH and ameliorate their prognoses. There was no significant correlation between HBO group and hemoglobin concentration on admission.