Background and Purpose Heatstroke is a life-threatening condition characterised by severe inflammation and often linked to necroptosis, a form of programmed cell death mediated by receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). Annexin A1 (AnxA1) is known to play a role in resolving inflammation, but its effects on heatstroke remain unclear. This study investigates the role of AnxA1 in heatstroke and its potential mechanisms.Experimental Approach The levels of AnxA1 were measured in patients with heatstroke and in a mouse model of heatstroke. The severity of heatstroke symptoms was compared between wild-type (WT) male C57BL/6 mice and those lacking AnxA1 or its receptor FPR2 on a C57BL/6 background. Additionally, recombinant AnxA1 was administered in vivo and in vitro to assess its therapeutic potential and to investigate underlying mechanisms.Key Results The expression of AnxA1 increased significantly in response to heat stress in both heatstroke patients and mice. The absence of AnxA1 or FPR2 exacerbated heatstroke severity, while administering AnxA1 alleviated the symptoms in heat-stressed mice and cell models. These protective effects were mediated through the FPR2 receptor. Further analysis of the mechanism revealed that AnxA1 treatment inhibited the phosphorylation of key necroptosis proteins, RIPK3 and MLKL.Conclusion and Implications This study highlights the activation of the endogenous AnxA1-FPR2 signalling pathway following heat exposure and demonstrates that AnxA1 can mitigate heatstroke by inhibiting RIPK3/MLKL-mediated necroptosis. These findings suggest that enhancing endogenous AnxA1 levels or administering recombinant AnxA1 may be promising therapeutic strategies for managing heatstroke.

Background & AimsSepsis-induced disseminated intravascular coagulation (DIC) is characterized by abnormal blood clotting resulting from severe infection, contributing to organ dysfunction in sepsis. Resolvin D1 (RvD1) is an endogenous lipid mediator, synthesized from the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) through enzymatic processes involving 15-LOX and 5-LOX. RvD1 is recognised for its protective properties against various inflammatory conditions. This study aims to investigate its potential to modulate coagulation dysfunction in sepsis and to evaluate coagulation disorders in septic patients.MethodsSepsis models were established by intraperitoneal injection LPS (20 mg/kg) or cecal ligation and puncture (CLP) followed by injection of RvD1 (10 μg/kg) or saline. The impact of RvD1 on coagulation dysfunction was assessed by clotting time and coagulation indicators such as TAT, D-dimer, PAI-1, and fibrinogen. The activity of the coagulation system in vivo was observed by evaluating dynamic microcirculation, platelets and thrombin in mice using intravital microscopy. The effect of RvD1 on pyroptosis was investigated by measuring NOD-like receptor protein 3 (NLRP3), Caspase-1, Caspase-11, and Gasdermin D (GSDMD) levels via western blot. Caspase-1 knockout mice, GSDMD knockout mice and bone marrow-derived macrophages (BMDMs) were used to elucidate the underlying mechanisms. Lastly, the concentration of RvD1 in plasma from septic patients was quantified to explore its relationship with coagulation and pyroptosis.ResultsRvD1 significantly attenuated coagulation dysfunction in septic mice induced by LPS and CLP, and inhibited Caspase-1/GSDMD-dependent pyroptosis in septic mice and bone marrow-derived macrophages. In septic patients, the plasma concentrations of RvD1 was negatively correlated with both coagulation-related indicators and markers of GSDMD activation.ConclusionThe results suggest that RvD1 can improve coagulation dysfunction in sepsis by regulating the Caspase-1/GSDMD pyroptotic pathway. Additionally, the concentration of RvD1 in septic patient plasma is related to prognosis and DIC development. RvD1 could be a potential biomarker and a promising therapeutic alternative in sepsis-induced DIC.

Background: Traumatic brain injury (TBI) is a head trauma usually associated with death and endothelial glycocalyx damage. Syndecan-1 (SDC-1)-a biomarker of glycocalyx degradation-has rarely been reported in meta-analyses to determine the clinical prognostic value in TBI patients. Methods: We looked into PubMed, EMBASE, Cochrane Library, and Web of Science databases from January 1, 1990, to May 1, 2023, to identify eligible studies. A meta-analysis was conducted using RevMan 5.4 and Stata 16.0 with the search terms "SDC-1" and "traumatic brain injury." Results: The present study included five studies with a total of 640 enrolled patients included. Syndecan-1 concentrations were higher in the isotrauma TBI group than in the non-TBI group (standardized mean difference [SMD] = 0.52; 95% CI: 0.03-1.00; P = 0.04). Subgroup analysis revealed statistical significance when comparing the SDC-1 level of multitrauma TBI (TBI + other injuries) group with the isotrauma TBI group (SMD = 0.74; 95% CI: 0.42-1.05; P < 0.001), and the SDC-1 level of the TBI coagulopathy (+) group (TBI with early coagulopathy) with the TBI coagulopathy (-) group (SMD = 1.75; 95% CI: 0.41-3.10; P = 0.01). Isotrauma TBI patients with higher SDC-1 level were at a higher risk of 30-day in-hospital mortality (odds ratio = 3.32; 95% CI: 1.67-6.60; P = 0.0006). Conclusion: This meta-analysis suggests that SDC-1 could be a biomarker of endotheliopathy and coagulopathy in TBI, as it was increased in isotrauma TBI patients and was higher in multitrauma TBI patients. There is a need for additional research into the use of SDC-1 as a prognostic biomarker in TBI, especially in isotrauma TBI patients.

BACKGROUND Quetiapine, known as a non-classical antipsychotic drug, is frequently used for the treatment of mental diseases, such as schizophrenia, bipolar disorder, and major depressive disorder. Acute lung injury, a rarely reported side effect of quetiapine, is described in this case report. CASE SUMMARY Due to terminal delirium, a 66-year-old man took a large dose of quetiapine and then developed severe pulmonary disease. His symptoms were not resolved after routine treatment, such as antibiotics, diuretic, and supportive therapies. Quetiapine-related acute lung injury was therefore suspected and hormonal therapy was initiated. Subsequently, his symptoms were alleviated and the radiological results improved dramatically. CONCLUSION Our findings in the present report highlight a potential adverse effect of quetiapine, drug-related acute lung injury, which deserves awareness in clinical practice.

目的 探讨重症肺炎患者应用头孢哌酮/舒巴坦的药代及药效动力学影响.方法 20例重症肺炎患者随机分为观察组和对照组,每组各10例,均接受头孢哌酮/舒巴坦抗感染治疗,对照组静脉给药输注30?min,观察组采用静脉给药输注3?h.分别于第1次治疗给药前及给药后的不同时间点采集患者动脉血2?ml,选择超高效液相色谱-电喷雾串联质谱分析方法测定头孢哌酮和舒巴坦的浓度,计算药动学数据(C?max、AUC0-∞、t1/2、CL、Vd等),结合不同细菌的MIC值进行计算％T>MIC比值.结果 对照组患者头孢哌酮的药动学参数为Cmax(83.85±15.44)mg/L、AUC0-∞(924.19±141.27)mg·?L-1·h-1、t1/2(3.30±0.64)h、CL(7.61±0.28)L/h、Vd(36.16±6.93)L/kg,舒巴坦的药动学参数为Cmax(66.97±1.54)mg/L、AUC0-∞(323.31±161.27)mg·?L-1·h-1、t1/2(1.74±0.07)h、CL(18.49±1.00)L/h、Vd(46.28±3.03)L/kg.观察组患者头孢哌酮的药动学参数为Cmax(68.19±3.95)mg/L、AUC0-∞(811.00±382.08)mg·?L-1·h-1、t1/2(4.02±1.18)h、CL(6.66±0.35)L/h、Vd(26.28±3.33)L/kg,舒巴坦的药动学参数为Cmax(22.28±2.74)mg/L,AUC0-∞(324.39±183.04)mg·?L-1·h-1、t1/2(1.49±0.34)h、CL(17.98±5.06)L/h、Vd(36.58±4.77)L/kg.观察组％T>MIC优于对照组.结论 头孢哌酮/舒巴坦临床应用于重症肺炎,可采取3?h延长输注时间抗感染.

Background Acinetobacter baumannii is a gram-negative aerobic bacillus that is commonly causes of hospital-acquired infections. Community-acquired pneumonia caused by Acinetobacter baumannii (CAP-Ab) is rare but fatal if diagnosis and treatment are delayed. Conventional culture of clinical specimens is the main method for clinical diagnosis of A. baumannii infections which may suffer from limited positive rate and is time consuming. Timely and precise diagnosis of CAP-Ab remains challenging. Case presentation A 66-year-old man with 24 h history of acute fever and dyspnea was admitted to our hospital. He was diagnosed as severe community acquired pneumonia (CAP), septic shock, respiratory failure and acute kidney injury. Next-generation sequencing (NGS) was performed on the patient’s sputum and blood, which identified numerous A. baumannii nucleotide sequences in the sample of sputum and led to the rapid diagnosis and treatment of community acquired pneumonia caused by A. baumannii . This result was confirmed by subsequent sputum culture. Conclusions This case described that the successful application of the next generation sequencing assisting the speedy diagnosis of A. baumannii infection provides a new idea for the timely diagnosis of CAP-Ab and highlights that NGS is a promising tool in rapid etiological diagnosis of acute and severe infectious diseases.

Endothelial-to-mesenchymal transition (EndMT) plays an important role in the progression of cardiac fibrosis but its mechanism and treatment need to be further understood. Herein, we have found that mitochondrial unfolded protein response (mtUPR) played a critical role in transforming growth factor beta 1 (TGF-beta 1)-induced EndMT in endothelial cells (ECs). MtUPR was repressed in endothelial cells after exposure to TGF-beta 1. NAD + precursor nicotinamide riboside (NR) could attenuate TGF-beta 1-induced EndMT and improve the levels of mtUPR. Significantly, prohibitin proteins (PHB and PHB2) was also regulated by nicotinamide riboside. Moreover, we found that inhibition of prohibitin proteins could prevent the protective effect of nicotinamide riboside on mtUPR and TGF-beta 1-induced EndMT. Overexpression of prohibitin proteins could alleviate mitochondrial function and TGF-beta 1-induced EndMT through improving mtUPR. In vivo, The EndMT of ECs induced by Transverse aortic constriction (TAC) in mouse was inhibited by NR. In conclusion, our results indicate that nicotinamide riboside improved the expression of prohibitin proteins to ameliorate EndMT via promotion of mtUPR. Nicotinamide riboside is a potential therapeutic target for cardiac fibrosis.

目的 探讨大剂量阿托伐他汀对急性脑梗死经静脉重组组织型纤溶酶原激活剂(rt-PA)溶栓效果的影响.方法 130例4.5h内接受静脉溶栓治疗的急性脑梗死患者中,40例rt-PA静脉溶栓联合阿托伐他汀治疗(观察组),90例仅rt-PA静脉溶栓治疗(对照组).比较两组患者静脉溶栓的安全性及90d预后,分析影响急性脑梗死溶栓预后的因素.结果 两组患者性别、年龄、吸烟、饮酒、溶栓前美国国立卫生研究院卒中量表(NIHSS)评分、脑卒中史以及患有糖尿病、高血压、动脉粥样硬化、心房颤动的比例等方面比较,差异均无统计学意义(均P>0.05).观察组第90天溶栓预后良好率(70.0％)明显高于对照组(45.6％),差异有统计学意义(P<0.05).二元Iogistic回归分析显示溶栓前NIHSS评分(OR=0.68,95％CI:0.581～0.796)是急性脑梗死患者静脉溶栓预后的危险因素,溶栓时联合使用大剂量阿托伐他汀(OR=2.848,95％CI:1.072～7.564)是急性脑梗死患者静脉溶栓预后的保护因素.结论 在急性脑梗死患者静脉溶栓时应用大剂量阿托伐他汀可以改善患者预后.

The adult mammalian heart doesn't regenerate after cardiomyocyte injury, which was mainly caused by the severe and persistent effects of cardiomyopathy. Recently, some studies reported that the mammalian heart can regenerate under low oxygen environment. However, the mechanism that the mammalian heart can regenerate remains unknown. Here, we used cardiac stem cells (CSCs) to be planted in serum-free medium under hypoxia environment to understand the mechanism of HIF1α/NDUFA4L2 in the regulation of hypoxia-alleviated apoptosis. Our results revealed that hypoxia can alleviated CSCs apoptosis. Hypoxia inhibited the level of cleaved-caspase3 and stimulated the expression of stabilized HIF-1α. DMOG promotes the survival of CSCs and the protein expression of NDUFA4L2. 2-ME repressed the survival of CSCs and the protein expression of NDUFA4L2. CHIP assay showed that HIF-1α regulated the survival of CSCs by augmenting the combination of HIF-1α and NDUFA4L2's HRE. Knockdown of NDUFA4L2 reversed the role of hypoxia in the survival of CSCs. Taken together, hypoxia promotes the viability of CSCs in serum-free medium by HIF-1α/NDUFA4L2 signaling pathway.

目的 观察连续静脉-静脉血液滤过(continuous veno-venous hemofihration,CVVH)治疗脓毒性休克的临床疗效及其对血清肾素、血管紧张素Ⅱ水平的影响.方法 对8例健康自愿者及30例脓毒性休克患者分别检测血清肾素活性及血管紧张素Ⅱ浓度,比较两组肾素活性及血管紧张素Ⅱ浓度,同时将30例脓毒性休克患者按数字随机法分成常规治疗组(A组,n=14)及常规治疗+CVVH治疗组(B组,n=16),监测治疗前后临床疗效及预后,并分别在治疗前和治疗后12h、24 h、72 h各时间点采用放射免疫分析法检测两组患者血浆肾素活性及血管紧张素Ⅱ浓度的变化.结果 脓毒性休克患者肾素活性及血管紧张素Ⅱ浓度明显高于健康自愿者(P＜0.01),B组患者CVVH治疗后24 h及72 h肾素活性、血管紧张素Ⅱ浓度较治疗前及A组明显下降(P＜0.05或P＜0.01),B组ICU住院时间少于A组,B组APACHEⅡ评分明显优于A组(P＜0.05),A组28 d存活率高于B组,但无统计学差异.结论 脓毒性休克患者使用CVVH治疗可以减少患者住院时间,改善症状,增加存活率,可能是通过清除血清内肾素、血管紧张素Ⅱ,抑制原本激活的RAS系统.

目的:通过观察血必净注射液对急性氧乐果中毒大鼠肺组织炎症反应与脂质过氧化影响研究,探索血必净注射液对氧乐果中毒大鼠急性肺损伤保护作用的机制.方法:54只雄性SD大鼠随机分成3组,即正常对照组(n=18)、中毒组(AOMP组,n=18)和血必净治疗组(XBJ组,n=18),各组给药后6、24及72h3个时间点随机分成3个亚组(n=6).AOMP组及XBJ组以40％氧乐果20mg/kg灌胃建立氧乐果中毒急性肺损伤模型,正常对照组予等量生理盐水灌胃,XBJ组灌胃后立即后给予血必净注射液10 mL/kg腹腔注射,正常对照组及AOMP组腹腔内注射等量生理盐水(10 mL/kg),每12h1次.给药6、24及72 h后以水合氯醛麻醉后取右上肺组织行石蜡切片行病理学检查,观察肺泡、间质炎性改变、出血和肺水肿的程度.同时提取左肺组织,通过比色法检测肺组织中MDA的含量及SOD、GSH-Px、Na-K-ATPase的活性,通过ELISA法测定肺组织TNF-α浓度.结果:AOMP后6、24及72 h,与正常对照组比较,肺组织TNF-α、MDA浓度均显著性升高(P＜0.01),肺组织SOD、GSH-Px、Na-K-ATPase的活性均显著性下降(P＜0.01).与AOMP组比较,血必净注射液干预后XBJ组各时间点肺组织TNF-α、MDA均显著性下降(P＜0.01或P＜0.05),肺组织SOD、GSH-Px的活性均显著性升高(P＜0.01或P＜0.05),肺组织Na-K-ATPase的活性未见显著升高(P＞0.05).同时血必净注射液干预后肺组织形态学损伤明显减轻.结论:血必净注射液可通过抑制炎症反应、降低急性氧乐果中毒大鼠MDA的生成并增加SOD、GSH-Px的活力改善脂质过氧化损害对氧乐果中毒大鼠急性肺损伤起保护作用.

Objective To investigate the changes in ATPase activity of diaphragm in rats with acute organophosphorus poisoning (AOPP) and to explore the effect of Xuebijing injection on the ATPase activity. Methods 24 clean healthy Spraue-Dawley(SD)rats were divided into control group,model group and Xuebijing treatment group by means of random number table,with 8 rats in each group. AOPP model was established by intra-gastrical administration of 50 mg/kg oxide dimethoate. In Xuebijing treatment group,after oxide dimethoate administration,intraperitoneal injection of Xuebijing(10 mL/kg)was given at the same time,while in control group and model group,equal amount of normal saline(NS)was injected via the same route. The rats were sacrificed at 6 hours after model formation,and their diaphragms were taken sterilely. The activities of Na+-K+-ATPase and Ca2+-ATPsae of diaphragms were detected by enzyme linked immunosorbent assay(ELISA). The histopathological changes in diaphragms of rats were observed with light microscopy. Results 6 hours after intoxication,the diaphragm Na+-K+-ATPase activity of rats in model group was markedly lower than that in control group(mmol?h-1?g-1:5.22±0.74 vs. 9.98±0.37,P<0.01),while the Na+-K+-ATPase activity in Xuebijing treatment group(6.93±1.14) was markedly higher than that in model group(P<0.05). The diaphragm Ca2+-ATPase activity of rats in model group was markedly lower than that in control group(mmol?h-1?g-1:7.45±0.74 vs. 12.08±0.74,P<0.01),while the Ca2+-ATPase activity in Xuebijing treatment group(9.35±1.67)was obviously higher than that in model group(P<0.05)after intoxication for 6 hours. Light microscope observation indicated that there were swelling and necrosis in diaphragm in model group,while in Xuebijing treatment group no necrosis was found. Conclusion The diaphragm was degenerated and necrotic in AOPP rats,Xuebijing injection can lessen the injury in such rats,and the curative effect may be related to the improvement of the Na+-K+-ATPase and Ca2+-ATPsae activities of diaphragm.