Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

Ferroptosis as a potential new therapeutic target for diabetes and its complications.

Diabetes is a complex metabolic disease. In recent years, diabetes and its chronic complications have become a health hotspot of global concern. It is very important to find promising therapeutic targets and directions. Ferroptosis is a new type of programmed cell death that is different from cell necrosis, apoptosis, and autophagy. Ferroptosis is mainly characterized by iron-dependent lipid peroxidation. With the reduction of the anti-oxidative capacity of cells, the accumulated reactive lipid oxygen species will cause oxidative cell death and lead to ferroptosis at lethal levels. Recent studies have shown that ferroptosis plays an important regulatory role in the initiation and development of diabetes, as well as various complications of diabetes. In this review, we will summarize new findings related to ferroptosis and diabetic complications and propose ferroptosis as a potential target for treating diabetic complications.

Identification of Genes as Potential Biomarkers for Sepsis-related ARDS using Weighted Gene Co-expression Network Analysis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) caused by sepsis presents a high mortality rate; therefore, identification of susceptibility genes of sepsis to ARDS at an early stage is particularly critical. METHODS: The GSE66890 dataset was downloaded and analyzed by WGCNA to obtain modules. Then, GO and KEGG analyses of the module genes were performed. Then, the PPI network and LASSO model were constructed to identify the key genes. Finally, expression levels of the screened genes were validated in clinical subjects. RESULTS: We obtained 17 genes merged modules via WGCNA, and the dark module and tan module were the most positively and negatively correlated with sepsis-induced ARDS, respectively. Based on gene intersections of the module genes, 11 hub genes were identified in the dark module, and 5 hub genes were identified in the tan module. Finally, the six key genes were identified by constructing the LASSO model. We further detected the screened genes expression in clinical samples, and as the bioinformatics analysis revealed, the expressions of NANOG, RAC1, TWIST1, and SNW1 were significantly upregulated in the ARDS group compared to the sepsis group, and IMP3 and TUBB4B were significantly downregulated. CONCLUSION: We identified six genes as the potential biomarkers in sepsis-related ARDS. Our findings may enhance the knowledge of the molecular mechanisms behind the development of sepsisinduced ARDS.

Electroacupuncture improves cognitive impairment in diabetic cognitive dysfunction rats by regulating the mitochondrial autophagy pathway.

BACKGROUND: Diabetes-associated cognitive dysfunction has become a major public health concern. However, the mechanisms driving this disease are elusive. Herein, we explored how electroacupuncture improves learning and memory function in diabetic rats. METHODS: The diabetic model was established by intraperitoneal injection of streptozotocin (STZ) in adult Sprague-Dawley rats. Rats were fed on high-fat and high-sugar diets. Learning and memory functions were assessed using behavioral tests. The hematoxylin and eosin (H&E) staining, Western blotting, real-time PCR, ELISA, immunohistochemistry, and transmission electronic microscopy (TEM) was performed to test related indicators. RESULTS: High-fat and high-sugar diets impaired learning and memory function in rats, while electroacupuncture treatment reversed these changes. The model group presented highly prolonged escape latency compared to the control group, indicating impaired learning and memory functions. The TEM examination showed that electroacupuncture enhanced Aß clearance and mitochondrial autophagy in hippocampal neuronal cells by increasing DISC1 expression. CONCLUSIONS: Electroacupuncture improves learning and memory function in diabetic rats by increasing DISC1 expression to promote mitophagy. This enhanced Aß clearance, alleviating cytotoxicity in hippocampal neuronal cells.

A Prospective Study of Using Chaihu Shugan Powder Combined with Zu San Li Acupoint Stimulation to Improve the Prognosis of Liver Stagnation and Qi Stagnation Syndrome in Acute Pancreatitis.

Background: This study aimed to explore the clinical efficacy of Chaihu Shugan powder combined with Zu San Li acupoint stimulation on the acute pancreatitis of liver and qi stagnation syndromes, the protection of intestinal barrier function, the prevention of severe tendency, and safety evaluation. Method: Data were collected from October 2019-June 2021 at Xinhua Hospital, which is affiliated with Shanghai Jiao Tong University School of Medicine, Emergency Department. Eighty patients with acute pancreatitis were randomly divided into a control treatment group (40 people) and a combined traditional Chinese medicine (TCM) treatment group (40 people). Detailed records of hospitalised patients were obtained, including the general situation of patients' clinical diagnosis and clinical examination before and after treatment. The changes in inflammatory and immune indexes before and after treatment were recorded. Result: Compared with the standard treatment group, the relief time of abdominal pain in the TCM treatment group was significantly shortened with statistically significant differences. Compared with the standard treatment group, the levels of WBC, ALT, CA, hemodiastase, lipase, TG, and other factors in the TCM treatment group decreased, whereas the levels of DB, SCR, cholesterol, K+, and other factors increased. The differences were statistically significant (P < 0.05). Conclusion: Chaihu Shugan powder combined with Zu San Li acupoint stimulation can reduce the clinical manifestations of liver and qi stagnation syndromes of acute pancreatitis, protect the intestinal barrier function, prevent the tendency of severe illness and improve the prognosis.

Research progress on the relationship between autophagy and chronic complications of diabetes.

Diabetes is a common metabolic disease whose hyperglycemic state can induce diverse complications and even threaten human health and life security. Currently, the treatment of diabetes is restricted to drugs that regulate blood glucose and have certain accompanying side effects. Autophagy, a research hotspot, has been proven to be involved in the occurrence and progression of the chronic complications of diabetes. Autophagy, as an essential organismal defense mechanism, refers to the wrapping of cytoplasmic proteins, broken organelles or pathogens by vesicles, which are then degraded by lysosomes to maintain the stability of the intracellular environment. Here, we review the relevant aspects of autophagy and the molecular mechanisms of autophagy in diabetic chronic complications, and further analyze the impact of improving autophagy on diabetic chronic complications, which will contribute to a new direction for further prevention and treatment of diabetic chronic complications.

LncRNA Gaplinc promotes the pyroptosis of vascular endothelial cells through SP1 binding to enhance NLRP3 transcription in atherosclerosis.

Pyroptosis, characterized by activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and its downstream effector inflammatory factors, has been shown to play a crucial role in atherosclerosis development. Long noncoding RNAs (lncRNAs) are involved in the progression of pyroptosis. However, the role and mechanism of the novel lncRNA gastric adenocarcinoma associated, positive CD44 regulator (Gaplinc), in endothelial cell pyroptosis during atherosclerosis development remain unexplored. Bioinformatics was performed to evaluate dysregulated lncRNAs in atherosclerotic mice fed a high-fat diet. The effect of Gaplinc on atherosclerosis progression in vivo was assessed via Oil Red O staining and fluorescence in situ hybridization. Its function in oxidized low-density lipoprotein (ox-LDL)-induced pyroptosis of endothelial cells was determined through ectopic expression. Additionally, RNA pull-down and immunoprecipitation (RIP) assays were performed to determine Gaplinc and transcription factor SP1 interactions. Then the pyroptosis pathway proteins were analyzed via immunofluorescence and western blotting. We found that lncRNA Gaplinc was highly expressed in ox-LDL-induced endothelial cells as well as in the plaque and plasma of high-fat diet-treated ApoE-/- mice. Gaplinc silencing significantly inhibited endothelial cell pyroptosis and atherosclerotic plaque formation. Mechanistically, Gaplinc could interact with SP1 to bind to the NLRP3 promoter and upregulate the target gene expression of NLRP3, facilitating endothelial cell pyroptosis and atherosclerotic plaque enlargement in high- fat diet-fed mice. In conclusion, our results revealed the underlying mechanism of the lncRNA Gaplinc /SP1/NLRP3 axis in endothelial cell pyroptosis, which may provide new potential targets for the treatment of atherosclerosis.

Clemastine protects against sepsis-induced myocardial injury in vivo and in vitro.

Sepsis-induced myocardial dysfunction (SIMD) is associated with high morbidity and mortality rates; however, it lacks targeted therapies. Modulating cardiomyocyte autophagy maintains intracellular homeostasis during SIMD. Clemastine, a histamine receptor inhibitor, promotes autophagy and other effective biological functions. Nevertheless, the effect of clemastine on SIMD remains unclear. This study aimed to explore the underlying mechanism of clemastine in cardiomyocyte injury in cecum ligation and perforation (CLP)-induced rats and lipopolysaccharide (LPS)-stimulated H9c2 cells. Clemastine (10 mg/kg, 30 mg/kg, and 50 mg/kg) was intraperitoneally injected after 30 min of CLP surgery. Serum cTnI levels and the 7-day survival rate were evaluated. Echocardiograms and H&E staining were used to evaluate cardiac function and structure. TEM was used to detect the mitochondrial ultrastructure and autophagosomes. Clemastine significantly improved the survival rate and reduced cTnI production in serum. Clemastine ameliorated cellular apoptosis, improved mitochondrial ultrastructure both in vivo and in vitro, increased ATP content, decreased dynamin-related protein 1 (DRP1) expression, and decreased mitochondrial ROS levels. Additionally, clemastine treatment increased autophagosome concentration, LC3II/LC3I rate, and Beclin 1 expression. However, 3-methyladenine (3-MA), an autophagy inhibitor, could abolish the effect of clemastine on alleviating myocardial apoptosis. In conclusion, clemastine protected against cardiac structure destruction and function dysfunction, mitochondrial damage, apoptosis, and autophagy in vivo and in vitro. Moreover, clemastine attenuated myocardial apoptosis by promoting autophagy. This study provides a novel favorable perspective for SIMD therapy.

Study on the medication rule of traditional Chinese medicine in the treatment of acute pancreatitis based on machine learning technology.

BACKGROUND: To analyze the rule of traditional Chinese medicine in the treatment of acute pancreatitis (AP). METHODS: Using machine learning technology and artificial intelligence, we collected 516 traditional Chinese medicine compounds for treating AP in the recent past 20 years, and analyzed the application of Chinese medicine in the field of AP. The data set was established by the ingredients of each prescription and its corresponding effectiveness. 90% of the data was divided into the training set, and the remaining 10% of the data was used as the test set. We employed random forest method to build a model to predict the efficacy of the prescriptions in the treatment of AP. The R-squared score and mean absolute error was used to evaluate the model's performance. RESULTS: The most frequently used drugs were rhubarb, Radix Bupleuri, Fructus Aurantii Immaturus, and Mirabilite. Rhubarb and Rhizoma Corydalis had the greatest curative effect. The random forest model that fit all data showed that its R-squared score reached 0.8021. And the results predicted on the test set showed that the R-squared score reached 0.7318. CONCLUSIONS: Soothing the liver, promoting qi, clearing heat, removing obstructions of organs, activating blood, and resolving stagnation are the treatment methods for AP.

The role of gut microbiota in the pathogenesis and treatment of acute pancreatitis: a narrative review.

To investigate the role played by gut microbiota in the development and treatment of acute pancreatitis. Gut microbiota is the largest micro-ecosystem in the human body, and is related to various system diseases. Acute pancreatitis is one of the common acute critical diseases in clinical practice, and there are various causative factors for the occurrence of this disease, such as alcohol, infection, obstruction and intestinal microecological factors. The dysbiosis of gut microbiota may play an important role in the pathogenesis of acute pancreatitis and affect prognoses, including gut microbiota structure disorder and bacterial translocation. It can also affect host metabolism and increase the production of toxic metabolites and affect the treatment of acute pancreatitis. Probiotics are live microorganisms that can give health benefits to the host when applied in sufficient quantities, which can effectively stimulate the growth and reproduction of the normal flora of the body, inhibit the overgrowth of pathogenic bacteria, and have a protective effect on the intestinal barrier function. A search of electronic databases (PubMed, EMBASE, Cochrane) has been realized to summarize the information. The paper briefly describes the concept of gut microbiota and acute pancreatitis, examines the role of gut microbiota in the development and treatment of acute pancreatitis, concludes the investigations of the therapeutic effect of probiotics for dysbiosis of gut microbiota in acute pancreatitis in order to provide a valid reference for the development of subsequent clinical strategies.

Blockade of C3a/C3aR axis alleviates severe acute pancreatitis-induced intestinal barrier injury.

Severe acute pancreatitis (SAP) contributes to multiple organ dysfunction and intestine is one of the most susceptible targets. This study aims to explore the role of C3a/C3aR axis in SAP-induced intestinal barrier injury. Adult male Sprague Dawley rats were randomly divided into control, SAP, C3aRA (0.06 mg/kg) and C3aRA (0.12 mg/kg) groups. SAP rat models were established by retrograde injection of 3.5% sodium taurocholate solutions into pancreatic ducts. Histopathological changes and dysfunction in pancreatitis and intestine were measured by hematoxylin and eosin (H&E) staining and detection of amylase (AMY), lipase (LIPA), endotoxins and diamine oxidase (DAO) levels in serum. Cell apoptosis was evaluated by TUNEL assay and western blot analysis. In addition, the expressions of caudin-1, caudin-2, occludin and ZO-1 were detected by western blot assay and immunohistochemical staining. Inflammatory cytokines and oxidative stress levels in SAP rats were determined. The C3a/C3aR expression was increased in pancreatic and intestinal tissues of successfully established SAP rat models. C3a receptor antagonist (C3aRA) alleviated pancreatic and intestinal pathological lesions and dysfunction induced by SAP. C3aRA inhibited cell apoptosis and promoted the expressions of caudin-1, caudin-2, occludin and ZO-1 in intestinal tissues. Moreover, C3aRA repressed inflammatory cytokines by reduction of TNF-α, IL-1ß, IL-6 and MCP-1 levels, and ameliorated oxidative stress through regulation of ROS, MPO and SOD activity in rats with SAP-induced intestinal barrier injury. Our findings suggested that inhibition of C3a/C3aR axis diminished pancreatic damage and SAP-induced intestinal barrier injury in vivo, which may provide a new therapeutic strategy for SAP-induced intestinal injury.

Tetraspanin CD9 interacts with α-secretase to enhance its oncogenic function in pancreatic cancer.

Pancreatic cancer is one of the most lethal cancers and its prognosis remains poor. ADAM family proteins like ADAM10, ADAM9 and ADAM17 function as α-secretase to cleavage cell surface proteins like Notch to facilitate oncogenesis in various tumors. The oncogenic roles of α-secretase in PDAC have been demonstrated but it remains unknown that whether and how α-secretase is regulated in PDAC. Here, we report that the expression of tetraspanin CD9 was increased and strongly associated with poor prognosis in PDAC. CD9 expression was positively associated with α-secretase activity in PDAC tissues and CD9 knock-down inhibited α-secretase activity in PDAC cell lines. Co-immunoprecipitation and GST pull down demonstrates that CD9 directly interacted with ADAM10, ADAM9 and ADAM17, respectively. Cell surface biotin labeling and immunostaining of tagged ADAM proteins show that CD9 promoted cell surface trafficking of ADAM family proteins. In addition, the antibody targeting extracellular domain of CD9 disrupted the interactions between CD9 and ADAM family proteins, reduced cell surface trafficking of ADAM proteins and inhibited α-secretase activity. Notch signaling was inhibited by CD9 knockdown or CD9 antibody in cell lines. Finally, CD9 antibody showed anti-tumor effects in cell proliferation MTT assay, transwell migration assay and colony formation assay. Our study reveals a novel CD9/ADAM/Notch signaling network in PDAC and it supports that targeting CD9-ADAM interaction with antibody may be a potential therapeutic intervention for PDAC.

Hydrogen sulfide treatment alleviated ventilator-induced lung injury through regulation of autophagy and endoplasmic reticulum stress.

Mechanical ventilation has significant therapeutic benefits, but it may cause or aggravate lung injury, which is called ventilator-induced lung injury (VILI). Endogenous hydrogen sulfide (H2S) has roles including regulating inflammation, and promoting vasodilatation; it also exhibits anti-oxidative stress and anti-fibrosis effects. H2S has been reported to alleviate lung injury, but the effects and mechanism of H2S on VILI remain unclear. The present study established a rat model of VILI and treated them with H2S, then measured the changes in respiratory function indicators, lung tissue histopathology, and oxidative, inflammatory, and apoptotic indicators. The effect of H2S on autophagy in the VILI model and the involvement of endoplasmic reticulum (ER) stress were also investigated. To further explore the mechanism, L2 alveolar epithelial cells were treated with cyclic strain to mimic mechanical strain along with the H2S donor NaHS, and the involvement of the NF-κB/MAPK signaling pathway was examined. The results showed that H2S significantly alleviated VILI and inhibited the inflammation and oxidative stress induced by VILI. H2S also significantly reduced autophagy and ER stress in rats. The phosphorylation of IRE1α, PERK and eIF2α and the expression of nuclear ATF4, and GADD34 in L2 cells were all significantly reduced with NaHS. Nuclear NF-κB p65, MAPK p38, JNK, and ERK were all activated by cyclic strain, but inhibited by the ER stress inhibitor 4-PBA or NaHS. Our findings revealed that H2S treatment alleviated VILI by regulating autophagy and ER stress, and the PERK/eIF2α/ATF4/GADD34 and NF-κB/MAPK pathways were involved in the underlying mechanism.

Phosphocreatine Attenuates Isoproterenol-Induced Cardiac Fibrosis and Cardiomyocyte Apoptosis.

The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis in vivo. Isoproterenol (ISO) was used to induce cardiac fibrosis in rats. PCr administration ameliorated fibrosis by reducing collagen accumulation and fibrosis-related signals, including transforming growth factor beta 1 (TGF-ß1), alpha smooth muscle actin (α-SMA), collagen type I, and collagen type III. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways, including p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p65, were highly activated by ISO and blocked by PCr. Moreover, PCr decreased ISO-induced matrix metalloproteinase-9 (MMP-9) and increased the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. Furthermore, PCr suppressed cardiomyocyte apoptosis induced by ISO, as shown by downregulated expression of the proapoptotic caspase-3, Bax, and upregulated expression of the antiapoptotic Bcl-2. Taken together, PCr can be an effective agent for preventing cardiac fibrosis and cardiomyocyte apoptosis.

BDNF contributes to the skeletal muscle anti-atrophic effect of exercise training through AMPK-PGC1α signaling in heart failure mice.

INTRODUCTION: Exercise training is a coadjuvant therapy in preventive cardiology, and it delays cardiac dysfunction and exercise intolerance in heart failure (HF). However, the mechanisms underlying muscle function improvement and cardioprotection are poorly understood. In this study, we tested whether exercise training would counteract skeletal muscle atrophy via activation of the BDNF pathway in myocardial infarction (MI)-induced HF mice. MATERIAL AND METHODS: A cohort of male Sham-operated and MI mice were assigned into 8-week moderate exercise training, and untrained counterparters were used as control. Exercise capacity, plasma norepinephrine (NE) level, heart rate (HR), fractional shortening (FS) and ejection fraction (EF) were measured. The protein expression of BDNF, p-TrkB, p-AMPK and PGC1α were analyzed by Western blot. RESULTS: Compared with the Sham-operated mice, MI mice displayed reduced total distance run and elevated plasma NE level (both p < 0.05). Exercise training significantly improved distance run and plasma NE levels in HF mice (both p < 0.05). Significantly increased HR, decreased FS and EF were observed in the MI group as compared to the Sham-operated group, and exercise training prevent the hemodynamic status and systolic dysfunction in MI mice (all p < 0.05). The expression of BDNF, p-TrkB, p-AMPK and PGC1α were significantly decreased in the skeletal muscle from MI compared to Sham-operated mice, which were significantly increased by exercise training (all p < 0.05). In addition, BDNF siRNA markedly decreased the protein level of p-AMPK and PGC1α in C2C12 myoblasts. CONCLUSIONS: Taken together, our data provide evidence for exercise training may counteract HF-induced muscle atrophy through induced activation of BDNF pathway.

Endovascular thrombectomy can be beneficial to acute ischemic stroke patients with large infarcts.

OBJECTIVE: This study aimed to assess whether patients with acute ischemic stroke (AIS) and large infarct lesions benefit from reperfusion management. To determine the efficacy of different recanalization managements on AIS patients with Alberta Stroke Program Early CT Score (ASPECTS) < 6, the authors retrospectively analyzed hospitalized patients with AIS. METHODS: Eighty-nine patients with AIS and ASPECTS < 6 were screened from 13,285 hospitalized patients treated by thrombolysis, thrombectomy, or conventional care in two stroke medical centers. Logistic regression or Fisher's exact test was performed for comparison of the outcome and risk events between patients treated by thrombectomy (or thrombolysis) and conventional care. The modified Rankin Scale (mRS) score was used to assess the major clinical outcome of patients 3 months after disease onset. Disease outcome was also examined by analyzing symptom improvement at discharge. In particular, mortality and symptomatic intracranial hemorrhage (sICH) were evaluated as risk factors. RESULTS: This study included 21 patients who received thrombolysis, 36 patients receiving thrombectomy, and 32 patients receiving conventional treatment. Among these 3 treatments, only the thrombectomy group clearly showed the most encouraging clinical outcome (mRS score 0-2; p < 0.05, Fisher's exact test) and marked improvement (OR 25.84, 95% CI 2.44-273.59) compared with conventional treatment. It is noteworthy that the mortality rate of the thrombectomy and thrombolysis group was similar to that of the conventional group, and thrombectomy and thrombolysis increased the risk of sICH in comparison with conventional care (p < 0.05, Fisher's exact test). CONCLUSIONS: Patients with AIS and ASPECTS < 6 definitely benefited from thrombectomy with higher sICH risk, whereas thrombolysis management showed similar efficacy to the control group.

Degradation of TRPML1 in Neurons Reduces Neuron Survival in Transient Global Cerebral Ischemia.

Postcardiac arrest syndrome yields poor neurological outcomes, but the mechanisms underlying this condition remain poorly understood. Autophagy plays an important role in neuronal apoptosis induced by ischemia. However, whether autophagy is involved in neuron apoptosis induced by cardiac arrest has been less studied. This study found that TRPML1 participates in cerebral ischemic reperfusion injury. Primary neurons were isolated and treated with mucolipin synthetic agonist 1 (ML-SA1), as well as infected with the recombinant lentivirus TRPML1 overexpression vector in vitro. ML-SA1 was delivered intracerebroventricularly in transient global ischemia model. Protein expression levels were determined by western blot. Neurological deficit score and the infarct volume were analyzed for the detection of neuronal damage. We found that TRPML1 was significantly downregulated in vivo and in vitro ischemic reperfusion model. We also observed that TRPML1 overexpression or treatment with the ML-SA1 attenuated neuronal death in primary neurons and ameliorated neurological dysfunction in vivo. Our findings suggested that autophagy and apoptosis were activated after transient global ischemia. Administration of ML-SA1 before transient global ischemia ameliorated neurological dysfunction possibly through the promotion of autophagy and the inhibition of apoptosis.

Intravenous polymyxins: Revival with puzzle.

With the increasing incidence of multi-drug resistant strains, especially carbapenem resistant strains, polymyxsins (mainly colistin and polymyxin B) based regimens seem to be a revival as an effective treatment of last resort in these infections. Evidence from 47 clinical trials or case series we reviewed showed that polymyxins based regimens are effective and have less toxicity compared with previous trials. When used alone, the mortality of intravenous polymyxsins ranged from 0% to 74.3%, clinical response (cure and improvement) rate was 7-82.1%, and microbiological eradication was 27.3-73.9%. The main reasons for the combination therapy are to get potential synergistic effects and to prevent the selection of heteroresistant strains. Several studies showed combination therapy seemed to be more effective than monotherapy, though a few doubts remain. Clinically, polymyxsins can be used in combination with several antibiotics, such as carberpenem, sulbactam, tigecycline, fosfomycin, glycopeptide, rifampicin and so on, but the optimal combination regimen is yet to be confirmed. The optimal dose of polymyxins is also controversial. With the limited clinical evidence, it's suggested loading dose regimens may be more effective, but more attention should be paid to adverse effects. Although recommended in some studies, high dose polymxins regimens with inconsistent clinical evidence need more trials to confirm. It is important to note that concerning dosing regimens, colistin and polymyxin B are not quite the same. In renal impaired patients polymyxin B should be prescribed without dosing adjustment. Risk of renal failure may increase in the following situations, such as the combination of intravenous colistin plus intravenous vancomycin, higher doses-colistin, and intravenous colistin combined with inhalational colistin. In conclusion, there're still controversies in combination regimens, dosing strategies and so on. Prospective trials of lager sample size are needed.

Aortic intramural hemorrhage: A distinct disease entity with mystery.

Aortic intramural hemorrhage (IMH) is one of the disease processes that comprise the spectrum of acute aortic syndrome (AAS) with clinical manifestations and a mortality rate similar to those of classic aortic dissection (AD). However, IMH should be considered as a distinct disease entity rather than a precursor to classic dissection because of differences in their pathology, etiology, natural history, and imaging findings. Multidetector computed tomography (CT) is recommended as the first-line diagnostic imaging modality for IMH, but transesophageal echocardiography (TEE) and magnetic resonance imaging (MRI) are also helpful. There is still debate over the appropriate treatment of IMH. Medical treatment of type B IMH appears effective and safe, while surgical treatment is recommended for type A IMH. Thoracic endovascular aortic repair (TEVAR) is a promising treatment for selected patients, and more clinical evidence needs to be assembled.

Isoquercetin activates the ERK1/2-Nrf2 pathway and protects against cerebral ischemia-reperfusion injury in vivo and in vitro.

Isoquercetin has exhibited a wide range of therapeutic properties, including antioxidant, anti-inflammatory and anti-allergic activities. The aim of the present study was to investigate the effect of isoquercetin on rats with 2 h middle cerebral artery occlusion (MCAO) and evaluate the neuroprotective effect of isoquercetin on a primary culture of rat hippocampal neuronal cells subjected to oxygen-glucose deprivation followed by reoxygenation (OGD/R). In vivo, the rats treated with isoquercetin exhibited a lower degree of neurological dysfunction and smaller infarct volume than the vehicle-treated rats. In vitro, it was found that isoquercetin prevented the OGD/R-induced increase in apoptosis, lactate dehydrogenase release and reduction in cell viability. Additionally, isoquercetin induced the upregulation of nuclear factor erythroid 2-related factor 2 gene and protein expression, and increased extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation. This indicates that the ERK1/2 pathway may contribute to the neuroprotective effect of isoquercetin against OGD/R-induced oxidative damage in rat hippocampal neurons. These findings suggest the potential importance of isoquercetin in the treatment of ischemia/reperfusion-related brain injury and associated diseases.