Glyphosate, a widely used herbicide, has raised increasing concerns regarding its potential neurotoxic effects in humans. This study aimed to elucidate the underlying mechanisms of glyphosate-induced neurotoxicity by integrating network toxicology, molecular docking, and experimental validation. Using publicly available databases, we identified human-specific targets of glyphosate and overlapped them with neurotoxicity-associated genes to construct a protein-protein interaction (PPI) network. Analysis identified critical hub genes SRC, TNF, and CASP3, key regulators implicated in synaptic dysregulation, neuroinflammation, and apoptosis, respectively. Molecular docking revealed stable binding affinities between glyphosate and these targets. Experimental validation in BV2 microglial cells exposed to environmentally relevant glyphosate concentrations (0.5-5 mg/L) for 72 h confirmed increased phosphorylation of Src (Tyr419), elevated TNF-α, and cleaved caspase-3 expression. These results highlight Src as a previously unrecognized mediator of glyphosate-induced neurotoxicity and demonstrate the value of a combined in silico-in vitro strategy in environmental neurotoxicology.

Background: Capsaicin is commonly used as a flavoring and a riot control agent. However, long-term exposure or high doses can cause acute lung injury in military and police personnel. The mechanisms underlying capsaicin-induced pulmonary toxicity remain unclear. Therefore, this study investigated the molecular mechanisms involved in capsaicin-induced acute lung injury using C57BL/6N mice. Methods: Through both transcriptomic and proteomic analyses of mouse lung tissue, we identified the involvement of the TNF signaling pathway in capsaicin-mediated acute lung injury. Next, we explored the role of TNF signaling in the progression of acute lung injury to identify potential therapeutic targets. In a capsaicin-induced acute lung injury mouse model and A549 cells, we assessed the therapeutic potential of the TNF-α antibody Nerelimomab. Compared with the control group, TNF-α up-regulation was observed, which correlated with increased pathological changes and elevated IL-6 (p < 0.01) and IL-18 (p < 0.01) levels, both in vivo and in vitro. Results: Flow cytometry revealed that compared to the capsaicin group, Nerelimomab treatment reduced the number of capsaicin-induced apoptotic cells (p < 0.001) and was associated with an increased Bcl-2/Bax ratio (p < 0.01) and reduced cleaved caspase 3 expression (p < 0.001). Analysis of A549 cells treated with capsaicin and Nerelimomab corroborated these results. These findings confirm the involvement of the TNF signaling pathway in capsaicin-induced acute lung injury and the apoptosis of alveolar epithelial cells. Conclusions: In conclusion, capsaicin inhalation can cause acute lung injury, and targeting the TNF signaling pathway offers a promising therapeutic strategy. Nerelimomab demonstrates significant potential in alleviating acute lung injury by inhibiting inflammatory mediator release and diminishing apoptosis. Based on transcriptomic and proteomic analyses, this study highlights the crucial role of the TNF signaling pathway in capsaicin-induced acute lung injury and supports the therapeutic efficacy of Nerelimomab in reducing epithelial apoptosis.

BackgroundLung cancer is a significant health concern in China. There is limited available data of its burden and trends. This study aims to evaluate the trends of lung cancer across different age groups and genders in China and the Group of Twenty (G20) countries, explore the risk factors, and predict the future trends over a 20-year period.MethodsThe data were obtained from the GBD study 2019. The number of cases, age standardized rate (ASR), and average annual percentage changes (AAPC) were used to estimate the trend in lung cancer by age, gender, region and risk factor. The trend of lung cancer was predicted by autoregressive integrated moving average (ARIMA) model by the “xtarimau” command. The joinpoint regression analysis was conducted to identify periods with the highest changes in incidence and mortality. Additionally, the relationship between AAPCs and socio-demographic index (SDI) was explored.ResultsFrom 1990 to 2019, both the incidence and mortality of lung cancer in China and G20 significantly increased, with China experiencing a higher rate of increase. The years with the highest increase in incidence of lung cancer in China were 1998-2004 and 2007-2010. Among the G20 countries, the AAPC in incidence and mortality of lung cancer in the Republic of Korea was the highest, followed closely by China. Although India exhibited similarities, its AAPC in lung cancer incidence and mortality rates was lower than that of China. The prediction showed that the incidence in China will continue to increase. In terms of risk factors, smoking was the leading attributable cause of mortality in all countries, followed by occupational risk and ambient particulate matter pollution. Notably, smoking in China exhibited the largest increase among the G20 countries, with ambient particulate matter pollution ranking second.ConclusionLung cancer is a serious public health concern in China, with smoking and environmental particulate pollution identified as the most important risk factors. The incidence and mortality rates are expected to continue to increase, which places higher demands on China’s lung cancer prevention and control strategies. It is urgent to tailor intervention measures targeting smoking and environmental pollution to contain the burden of lung cancer.

BackgroundLiver cirrhosis-related death is a serious threat worldwide. The number of studies exploring the mortality trend of cirrhosis caused by specific etiologies was limited. This study aimed to demonstrate the pattern and trend based on the data of global burden of disease (GBD).MethodsThe data of cirrhosis mortality were collected from the GBD 2017. The Age standardized mortality rate (ASR) and estimated annual percentage changes (EAPC) were used to estimate the temporal trend of liver cirrhosis mortality by etiologies, regions, sociodemographic index (SDI), and sexes.ResultsGlobally, mortality cases of cirrhosis increased by 47.15%. Although the global ASR of cirrhosis mortality remained stable during this period, the temporal trend varied in etiologies. The ASR of mortality caused by hepatitis C virus (HCV), alcohol consumption, and non-alcoholic steatohepatitis (NASH) increased with an EAPC of 0.17 (95% CI, 0.14–0.20), 0.20 (95% CI, 0.16–0.24), 1.00 (95% CI, 0.97–1.04), respectively. A decreasing trend of ASR was found among the causes of hepatitis B virus (BV) and other causes. The increased pattern was heterogeneous worldwide. The most pronounced increase trend was found in middle-high SDI regions and Eastern Europe. Contrarily, the most pronounced decrease trend was found in low SDI regions and Western Sub-Saharan Africa.ConclusionCirrhosis is still a public health problem. The growth trend of cirrhosis mortality caused by HCV was slowed by promoting direct-acting antiviral therapy. Unfortunately, we observed an unfavorable trend in etiologies for alcohol consumption and NASH, which indicated that more targeted and specific strategies should be established to limit alcohol consumption and promote healthy lifestyles in high-risk countries, especially in middle-high SDI regions and Eastern Europe.

Current guidelines recommend consideration of endoscopic therapy (ET) when treating selected early gastric cancers. However, clinical decision-making on ET versus gastrectomy for early adenocarcinoma of esophagogastric junction (AEGJ) remains challenging because of uncertain long-term outcomes. We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results database from 2004 to 2017 of early AEGJ patients underwent ET or gastrectomy. Multivariate models were used to compare cancer-specific survival (CSS). Of 881 included early AEGJ patients, 227 (36.2%) patients underwent ET and 654 (63.8%) patients underwent gastrectomy. Early AEGJ patients who underwent ET experienced a similar hazard of cancer-specific death compared with those underwent gastrectomy in both multivariate Cox regression (HR [hazard ratio], 0.93; 95% CI [confidence interval], 0.55–1.56; P = 0.78) and the multivariate competing risk model (subdistribution HR [SHR], 0.86; 95% CI 0.50–1.45; P = 0.56). Propensity score matching was used, 210 patients underwent ET were matched with 210 patients underwent gastrectomy. Patients underwent ET experienced a similar hazard of cancer-specific death compared with those underwent gastrectomy in both multivariate Cox regression (HR, 0.97; 95% CI 0.53–1.77; P = 0.92) and the multivariate competing risk model (SHR, 0.96; 95% CI 0.52–1.77; P = 0.89). Early AEGJ patients who received ET or gastrectomy had comparable long-term outcomes, which lend support to the role of ET in the treatment of these patients.

鹦鹉热是由鹦鹉热衣原体引起的一种人畜共患传染病,人类可通过吸入来自受感染禽类的尿液、粪便或其他排泄物的气溶胶感染[1],主要表现为社区获得性肺炎(CAP).一项 Meta分析显示,由鹦鹉热衣原体引起的肺炎约占CAP的1％[2],由于其临床特点不易与其他肺炎相鉴别,且诊断方法有限,易被漏诊、误诊,患者不能获得及时有效防治而影响预后.近年来,随着宏基因组二代测序技术(mNGS)在临床的广泛应用,越来越多的鹦鹉热衣原体肺炎得以确诊[3-4],从而使患者得到及时有效的治疗.本研究报道5 例鹦鹉热衣原体肺炎患者的临床特点及治疗转归,为鹦鹉热衣原体肺炎的诊治提供参考经验.

Background Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease in the world, especially in China. Few studies have explored the trend of COPD in China and its provinces. This study aimed to demonstrate and predict the trend of COPD DALY in China and its provinces based on the global burden of disease (GBD) data. Methods The data on COPD disability-adjusted life year (DALY) were collected from GBD 2017, GBD 2019, and the National Bureau of Statistics of China. The age-standardized rate (ASR) was used to evaluate the trend of COPD DALY by gender, age, and risk factors in China and its provinces. In addition, the trend of COPD considering the aging population in the next 10 years was also predicted. Results In China, the COPD DALY was 20.4 million in 2017, which decreased to 24.16% from 1990 to 2017. Most provinces showed a downward trend, with the exception of Taiwan which increased by 127.78%. The ASR of DALY was 1445.53 per 100,000 people in 2017 and demonstrated a significant decrease. Among all provinces, only Taiwan (97.78%) and Hubei (2.21%) demonstrated an increased trend of ASR. In addition, Tibet ranked third with a decline of 56.95%, although its ASR was the highest in 1990. Smoking and air pollution were the main risk factors for COPD and varied with regions, gender, and age. The proportion of COPD DALY attributable to smoking was higher in the middle-aged and elderly male population and did not decrease in China. Moreover, the ASR attributable to air pollution of the elderly decreased significantly in China. Socio-demographic index (SDI) and educational level were also found to be related to ASR. By predicting the ASR trend in the next 10 years, we found that the ASR attributable to smoking might increase significantly among men. The ASR attributable to air pollution showed a significant decrease in women. Unfortunately, ASR attributable to second-hand smoke was found to increase in women. Conclusion Chronic obstructive pulmonary disease is the leading contributor to the burden of global diseases. Although China and its provinces demonstrated a downward trend of COPD DALY, some provinces still faced challenges. Moreover, ASR attributable to risk factors was different in regions, gender, age, and years. The predicted trend of COPD was also different. Therefore, more targeted strategies should be formulated to reduce the burden of COPD in China and its provinces.

Background: Restenosis after airway stenting needs to be addressed urgently. Rapamycin has been proven to inhibit restenosis elsewhere. This study aimed at observing its effects on the respiratory tract. Methods: CCK-8, wound healing, Transwell and apoptosis assays were performed to detect the effects of rapamycin on the survival, migration, and apoptosis, respectively, of human tracheal fibroblasts (HTrF) and human tracheal epithelial cells (HTEpiC). Results: The effective concentrations of paclitaxel, mitomycin C and rapamycin on HTrF were 10−7–10−4 mol/L, 10−6–10−4 mol/L, and 10−5–10−4 mol/L, respectively. At the effective concentrations, the inhibition rates of paclitaxel on HTEpiC were (43.03 ± 1.12)%, (49.49 ± 0.86)%, (55.22 ± 1.43)%, and (93.19 ± 0.45)%; the inhibition rates of mitomycin C on HTEpiC were (88.11 ± 0.69)%, (93.82 ± 0.96)%, and (94.94 ± 0.54)%; the inhibition rates of rapamycin on HTEpiC were (10.19 ± 0.35)% and (94.55 ± 0.71)%. At the concentration of (1–4) × 10−5 mol/L, the inhibition rate of rapamycin on HTrF was more than 50%, and that on HTEpiC was less than 20% (p < 0.05). Conclusions: Compared to paclitaxel and mitomycin C, rapamycin had the least effect on HTEpiC while effectively inhibiting HTrF. The optimum concentration range was (1–4) × 10−5 mol/L.

Objective:To compare and analyze the difference of oxygen-driven nebulization therapy for inpatients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in different periods.Methods:A total of 180 patients with AECOPD who were hospitalized in the general ward of the Department of Respiratory and Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, from January 1, 2016 to December 31, 2016 and from January 1, 2019 to December 31, 2019 were selected.They were divided into two groups according to the year of hospitalization.A retrospective study method was used to compare the use ratio of oxygen-driven nebulization, the composition ratio, use ratio and dosage of combined nebulization drugs in the two groups, and to compare the average hospitalization days of the two groups.Results:There were differences in the total oxygen-driven nebulization ratio, combined nebulization drug composition, ipratropium bromide, acetylcysteine use ratio, and acetylcysteine dosage (all P<0.05). There was no difference in the ratio and dosage of budesonide and salbutamol, and the dosage of ipratropium bromide (all P>0.05), but there was significant difference in the average hospital stay between the two groups ( Z=2.51, P<0.05). Conclusions:Oxygen-driven nebulization therapy has been paid more and more attention in AECOPD inpatients, mainly multi-drug nebulization.Ipratropium bromide and acetylcysteine use ratio has been increased significantly, the average hospital stay in 2019 is shorter than that in 2016 may be related to multi-drug nebulization therapy.

目的 比较不同剂量去甲万古霉素治疗老年肺部感染患者的血药谷浓度.方法 将34例老年肺部感染患者按给药剂量分为对照组11例和试验组23例.对照组给予去甲万古霉素每次0.4 g,q12 h,静脉输注;试验组给予去甲万古霉素每次0.4 g,q8 h,静脉输注.2组患者均治疗4～20 d.比较2组患者的临床疗效、去甲万古霉素稳态血药谷浓度和血药谷浓度分布范围,以及药物不良反应的发生情况.结果 治疗后,试验组和对照组的有效率分别为60.87％(14例/23例)和100.00％(11例/11例),平均血药谷浓度分别为(16.13±8.55)和(9.78±5.04)μg·mL-1,差异均有统计学意义(均P<0.05).试验组和对照组的血药谷浓度分别为波动于1.18～32.40和1.58～20.64μg·mL-1.对照组发生的药物不良反应以肾功能损伤伴发热为主,试验组发生的药物不良反应以肾功能损伤、皮疹和胃肠道反应为主.试验组和对照组的总药物不良反应发生率分别为17.39％和9.09％,差异无统计学意义(P>0.05).结论 老年肺部感染患者用去甲万古霉素静脉治疗时,血药谷浓度个体差异大,应尽量选择较小的有效剂量进行治疗.

Background: To evaluate the pattern and prevalence trends of liver cirrhosis caused by specific etiologies. Results: Globally, the number of prevalent cases increased 74.53% from 1990 to 2017. The ASR increased 0.75 per year. The most pronounced increases were found in middle-high and high socio-demographic index (SDI) regions, especially in the Caribbean and Latin America. Among the etiologies, non-alcoholic steatohepatitis (NASH) related liver cirrhosis accounted for 59.46% of the cases. The ASR increased 1.74 per year, and the increase was observed in all 5 SDI regions. In addition, the ASR of liver cirrhosis caused by alcohol also increased in both sexes and all SDI regions. In contrast, the ASR of liver cirrhosis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) decreased, especially in middle and low-middle SDI regions. Conclusions: Though the number of people suffering from HBV and HCV decreases, liver cirrhosis is still a major threat to health. Additionally, the number of people with cirrhosis caused by alcohol and NASH continues to grow. Thus, more targeted and specific strategies should be established based on etiology and prevalence trends of liver cirrhosis. Methods: We collected data based on Global Burden of Disease (GBD) 2017 study. The age standardized prevalence rate (ASR) and estimated annual percentage changes (EAPC) were used to estimate the trends in prevalence by population, etiologies and regions.

Abstract Background There are no reports on the incidence of chronic mercury poisoning in a large population in China. This study investigated the epidemiology, clinical manifestations, treatment, and follow-up of Chinese patients with chronic mercury poisoning. Methods Data for 288 mercury poisoning patients were collected at our hospital from July 2014 to September 2019, including sex, age, admission time, blood mercury content, urine mercury content, creatinine, urinary mercury/creatinine ratio, 24-h urinary protein levels, electromyography (EMG) findings, renal biopsy, and follow-up. Patient characteristics were evaluated by statistical and correlation analyses. Results First, mercury poisoning in China mainly occurred through occupational exposure and the inappropriate use of mercury-containing cosmetics and Chinese folk remedies (CFRs). Second, the most common symptoms were nervous system (50.3 %), kidney (16.4 %) and breathing (8.0 %). Mercury poisoning-induced Nephrotic syndrome (NS) and peripheral neuropathy are common long-term complications. The complications of occupational and cosmetics-induced mercury poisoning are consistent with international belief. However, the NS caused by CFRs is mainly membranous nephropathy and the probability of peripheral neuropathy caused by CFRs is higher than other pathogens. Third, follow-up data shows that 13 patients with EMG-confirmed neurological injury, 10 showed full recovery after 38.50 ± 8.03 months. Furthermore, among 18 patients with NS, 15 had normal urine protein and serum albumin levels after 22.67 ± 10.26 months. Conclusions Regulation of skin-lightening cosmetic products, safety surveillance of CFRs, and prevention and control of occupational exposure must be improved to decrease the incidence of mercury poisoning in China.

OBJECTIVES:Carbon monoxide (CO) poisoning is one of the most frequent causes of fatal poisoning worldwide. Few studies have explored the mortality trends of CO poisoning grouped by age and gender, at the regional, national and global levels. We therefore aimed to determine the pattern of CO poisoning mortality, as well as temporal trends at all levels.DESIGN:A cross-sectional survey design was used in this study.SETTING:CO poisoning data collected from the Global Burden of Diseases (GBDs), from 1990 to 2017, was arranged by sex, age, region and country. In addition, we used human development index data at the national level from the World Bank.PARTICIPANTS:We collected over 100 000 information on CO poisoning mortality between 1990 and 2017, derived from the GBD study in 2017.MAIN OUTCOMES AND MEASURES:We have calculated the estimated annual percentage changes in CO poisoning age-standardised mortality rate (ASR), by sex and age at different regions and countries to quantify the temporal trends in CO poisoning ASR.RESULTS:Globally, death cases of CO poisoning decreased 7.2% from 38 210 in 1990 to 35 480 in 2017. The overall ASR decreased by an average of 1.83% (95% CI 2.10% to 1.56%) per year in this period. This decreasing pattern was heterogeneous across ages, regions and countries. The most pronounced decreases were generally observed in countries with a high sociodemographic index, including Estonia, South Korea and Puerto Rico.CONCLUSIONS:Current prevention strategies should be reoriented, and much more targeted and specific strategies should be established in some countries to forestall CO poisoning.

Nonalcoholic steatohepatitis (NASH) has rapidly become the most common cause of chronic liver diseases. We aimed to explore the incidence and distribution characteristics of NASH by sex, region and sociodemographic index (SDI). We collected data, including sex and region, on NASH-related liver cirrhosis from the 2017 GBD study. The age-standardized incidence rates (ASRs) and estimated annual percentage changes (EAPCs) were used to estimate the incidence trend and distribution characteristics. Globally, the incidence of liver cirrhosis caused by NASH increased from 178,430 cases in 1990 to 367,780 cases in 2017, an increase of approximately 105.56%. The ASR of NASH increased by an average of 1.35% per year (95% CI 1.28-1.42). Meanwhile, large differences in the ASR and the EAPC were observed across regions. The middle-high SDI region had the highest increase among all five SDI regions, followed by middle SDI region. In addition, Eastern Europe, Andean Latin America and Central Asia showed a more significant growth trend of ASR. In contrast, the high SDI region demonstrated the slowest increasing trend of ASR, and the high-income Asia Pacific demonstrated a decreasing trend among the 21 regions. Liver cirrhosis has caused a huge and rising health burden in many countries and regions. In addition, with the growth of obesity, population and aging, NASH might replace viral hepatitis as the most important cause of liver cirrhosis in the near future. Therefore, appropriate interventions are needed in coming decades to realize early diagnosis and prevention of NASH-related liver cirrhosis.

Objective:To evaluate the efficacy and safety of bronchoscopic cryodebridement for tracheal obstruction and summarize our experiences.Methods:The medical records of patients undergoing bronchoscopic cryodebridement for tracheal obstruction in Beijing Tiantan Hospital, Capital Medical University, from August 2009 to August 2020 were reviewed retrospectively.The reason of lesion, the degree, length, type, shape, location of obstruction, the method of anesthesia and ventilation, combined endoscopic instruments, duration and outcome of operation, and complications were recorded.Results:A total of 67 patients were included, all of which were wide-based endogenic or mixed type obstruction.The main reasons were malignant (43 cases, 64.2%) and granulation tissue hyperplasia (18 cases, 26.9%). Subglottic tracheal obstruction occurred in 28 cases (41.2%). Before operation, the degree and length of tracheal obstruction was 80.0% (20.0%) and (29.04±14.71) mm, respectively.The postoperative tracheal recanalization rate and the dyspnea relief rate were both 100.0%.Intraoperative bleeding was mild to moderate, there was no severe bleeding.Severe complication occurred in 1 case (1.5%) and there was no intraoperative or postoperative death.Conclusions:Bronchoscopic cryodebridement is safe and effective in the treatment of endoluminal or mixed type tracheal obstruction, and can be used to rescue severe tracheal obstruction caused by granulation tissue and various type of tumors.It has advantages for wide-based, extended obstruction, bulky tissues and subglottic obstruction.

BACKGROUND:Thyroid cancer is a growing threat to human health. Few studies have explored trends of thyroid cancer and relationships with social development factors. In this study, we explored the trend and relationship based on GBD. METHODS:By using GBD study, we obtained detailed data of thyroid cancer. Incidence, mortality and DALY were used to assess epidemiological characteristics. ASR and EAPC were used to estimate the trend. RESULTS:Globally, the incidence significantly increased from 1990 to 2017, especially in high-income regions. Males and middle SDI region demonstrated a higher increase of age-standardized incidence rates. Unlike incidence trend, mortality trend showed a minor increase, and even showed a decreasing trend in some regions such as Eastern Sub-Saharan Africa. Additionally, the DALY trend also demonstrated a slightly increase with an EAPC of 0.77 (95% CI 0.73-0.81). More significant increase of DALY was found in males, middle SDI region and high-income Asia Pacific. The incidence of thyroid cancer peaked in middle-aged people, while the mortality and DALY peaked in elder-aged. Moreover, the proportion of thyroid cancer deaths contributable to high BMI was highest in developed countries and middle-aged people. CONCLUSIONS:Thyroid cancer is a public health problem worldwide. Over-diagnosis might be partly responsible for its rising trend. It remains us to revise the guidelines to avoid unnecessary burdens. Moreover, we should pay attention to the risk factors of thyroid cancer. More targeted measures should be formulated to improve potential environmental and lifestyle-related factors which might contribute to rising trend of thyroid cancer.

Nerve agents are used in civil wars and terrorist attacks, posing a threat to public safety. Acute exposure to nerve agents such as soman (GD) causes serious brain damage, leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and neuroinflammation. However, data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are limited. Here, we evaluated the potential effects of transient receptor vanilloid 4 (TRPV4) in the treatment of soman-induced status epilepticus (SE) and secondary brain injury. We demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced seizures. Administration of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE intensity. TRPV4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman exposure. Further in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate excitotoxicity. The protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1β and IL-18 increased in soman-exposed rat hippocampus. However, TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome pathway. In conclusion, our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated neuroinflammation. To our knowledge, this is the first study regarding the "dual-switch" function of TRPV4 in the treatment of soman intoxication.

Acrylamide (AA) constitutes an important industrial chemical agent and well-known neurotoxin. However, the mechanism underlying AA-mediated neurotoxicity is extremely complicated and controversial. In this study, we found that activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and its subsequent downstream inflammatory responses plays an important role in AA-induced neurotoxicity mechanisms. In vitro experiments revealed that AA (2.5 mM) induced BV2 microglial cytotoxicity and triggered NLRP3 inflammasome activation along with downstream proinflammatory cytokine interleukin-1β and interleukin-18 expression. Treatment with inhibitor or NLRP3 siRNA efficiently protected BV2 microglial cells against AA-induced cytotoxicity and reversed NLRP3 inflammasome activation and its mediated inflammatory reaction. Similarly, AA exposure (50 mg/kg) for 10 consecutive days caused significant activation of NLRP3 inflammasomes and neuroinflammation in C57BL/6 mice, whereas inhibiting these effects through specific NLRP3 inflammasome blocker MCC950 (5 mg/kg) intervention or NLRP3 knock-out significantly ameliorated AA-induced ataxia, cerebellar Purkinje cells degeneration, and apoptosis. Furthermore, we demonstrated that antagonism of NLRP3 could also up-regulate the Nrf2 signalling pathway and related antioxidant genes. In conclusion, our findings indicate that activation of the NLRP3 inflammasome pathway is involved in AA-induced neurotoxicity, whereas MCC950 treatment or NLRP3 knock-out could effectively protect against AA-induced neurotoxic injury through the inhibition of neuroinflammation and activation of the Nrf2 antioxidant pathway. Therefore, the NLRP3 inflammasome might serve as a promising therapeutic target, with drugs designed to specifically inhibit this pathway potentially providing new avenues for preventing or ameliorating AA poisoning.

目的 研究我国一氧化碳(CO)中毒死亡的变化趋势.方法 从2017年全球疾病负担研究中收集1990至2017年我国及全球CO中毒的详细信息,根据性别、年龄、社会人口指数(SDI)等计算CO中毒年龄标准化死亡率(ASMR)的估计年百分比变化(EAPC),以量化CO中毒ASMR的变化趋势,并将我国及全球趋势进行对比.结果 2017年全球CO中毒死亡人数较1990年有所下降,而我国死亡人数上升,从1990年的13779例增长至2017年的14255例,增长了3.45％;在此期间全球及我国的CO中毒ASMR均呈下降趋势,但我国ASMR下降趋势(EAPC=-0.46;95％CI-0.56～-0.36)明显低于全球水平(EAPC=-1.83;95％CI-2.10～-1.56);我国CO中毒ASMR的下降趋势在不同性别及年龄中是不同的,其中,男性呈下降趋势,女性呈上升趋势;最明显的下降为<5岁的人群,而≥50岁的人群呈明显的上升趋势.结论 CO中毒在我国仍是一个重要的公共卫生问题,尤其应针对老年人建立更有效的预防及治疗方案.

Trimethyltin (TMT), a neurotoxic organotin compound, is selectively localized within the limbic system. The mechanisms of TMT-induced hippocampal neurodegeneration include inflammatory responses, oxidative stress, and neuronal death. Increasing evidence shows that the inflammatory response, mediated by activated inflammasomes, is involved in apoptosis and cellular dysfunction during brain injury. This study aimed to assess the role of the nucleotide-binding oligomerization domain-like receptor pyrin-domain-containing protein 3 (NLRP3) inflammasome in TMT-induced central nervous system (CNS) injury. In addition, the mechanisms underlying TMT neurotoxicity are similar to those involved in the pathogenesis of multiple neurodegenerative diseases; hence, a study on TMT cytotoxicity may be informative for the understanding of human CNS diseases. Microglia were significantly activated in the rat hippocampal dentate gyrus after TMT treatment. The mRNA expression of pro-inflammatory cytokines, interleukin-1β and interleukin-18, was induced both in vitro and in vivo. TMT treatment activated the NLRP3 inflammasome in the microglial cell line BV2. NLRP3 RNA interference significantly protected these cells from TMT-induced neuroinflammation. Our results demonstrate that the NLRP3 inflammasome is a key mediator of neuroinflammation and plays an important role in TMT-induced neuroinflammation.