Early predictive value of lipocalin-type prostaglandin D synthase for 28-day mortality in cardiac arrest patients: study protocol for a prospective study.

INTRODUCTION: Public training in cardiopulmonary resuscitation and treatment in emergency and intensive care unit have made tremendous progress. However, cardiac arrest remains a major health burden worldwide, with brain damage being a significant contributor to disability and mortality. Lipocalin-type prostaglandin D synthase (L-PGDS), which is mainly localised in the central nervous system, has been previously shown to inhibit postischemia neuronal apoptosis. Therefore, we aim to observe whether serum L-PGDS can serve as a potential biomarker and explore its role in determining the severity and prognosis of patients who have achieved restoration of spontaneous circulation (ROSC). METHODS AND ANALYSIS: This is a prospective observational study. The participants (n = 60) who achieve ROSC will be distributed into two groups (non-survivor and survivor) based on 28-day survival. Healthy volunteers (n = 30) will be enrolled as controls. Each individual's relevant information will be extracted from Electronic Medical Record System in Xinhua Hospital, including demographic characteristics, clinical data, laboratory findings and so on. On days 1, 3 and 7 after ROSC, blood samples will be drawn and batch tested on the level of serum neuron-specific enolase, soluble protein 100ß, L-PGDS, procalcitonin, tumour necrosis factor-alpha and interleukin-6. The cerebral performance category score was assessed on the 28th day after ROSC. ETHICS AND DISSEMINATION: This study was performed with the approval of the Clinical Ethical Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Approval No. XHEC-C-2023-130-1). The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2300078564).

Hyperbaric oxygen therapy promotes the browning of white fat and contributes to the healing of diabetic wounds.

Non-healing wounds are one of the chronic complications of diabetes and have remained a worldwide challenge as one of the major health problems. Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic wound treatment, for which the molecular basis is not understood. Adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes. Endothelial cell-derived extracellular vesicles could promote wound healing in diabetes. To study the mechanism by which HBO promotes wound healing in diabetes, we investigated the effect of HBO on fat cells in diabetic mice. A diabetic wound mouse model was established and treated with HBO. Haematoxylin and eosin (H&E) staining and immunofluorescence were used for the analysis of wound healing. To further explore the mechanism, we performed whole-genome sequencing on extracellular vesicles (EVs). Furthermore, we conducted in vitro experiments. Specifically, exosomes were collected from human umbilical vein endothelial cell (HUVEC) cells after HBO treatment, and then these exosomes were co-incubated with adipose tissue. The wound healing rate in diabetic mice treated with HBO was significantly higher. HBO therapy promotes the proliferation of adipose precursor cells. HUVEC-derived exosomes treated with HBO significantly promoted fat cell browning. These data clarify that HBO therapy may promote vascular endothelial cell proliferation and migration, and promote browning of fat cells through vascular endothelial cells derived exosomes, thereby promoting diabetic wound healing. This provides new ideas for the application of HBO therapy in the treatment of diabetic trauma.

Intestinal Piezo1 aggravates intestinal barrier dysfunction during sepsis by mediating Ca2+ influx.

INTRODUCTION: Intestinal barrier dysfunction is a pivotal factor in sepsis progression. The mechanosensitive ion channel Piezo1 is associated with barrier function; however, its role in sepsis-induced intestinal barrier dysfunction remains poorly understood. METHODS: The application of cecal ligation and puncture (CLP) modeling was performed on both mice of the wild-type (WT) variety and those with Villin-Piezo1flox/flox genetic makeup to assess the barrier function using in vivo FITC-dextran permeability measurements and immunofluorescence microscopy analysis of tight junctions (TJs) and apoptosis levels. In vitro, Caco-2 monolayers were subjected to TNF-α incubation. Moreover, to modulate Piezo1 activation, GsMTx4 was applied to inhibit Piezo1 activation. The barrier function, intracellular calcium levels, and mitochondrial function were monitored using calcium imaging and immunofluorescence techniques. RESULTS: In the intestinal tissues of CLP-induced septic mice, Piezo1 protein levels were notably elevated compared with those in normal mice. Piezo1 has been implicated in the sepsis-mediated disruption of TJs, apoptosis of intestinal epithelial cells, elevated intestinal mucosal permeability, and systemic inflammation in WT mice, whereas these effects were absent in Villin-Piezo1flox/flox CLP mice. In Caco-2 cells, TNF-α prompted calcium influx, an effect reversed by GsMTx4 treatment. Elevated calcium concentrations are correlated with increased accumulation of reactive oxygen species, diminished mitochondrial membrane potential, and TJ disruption. CONCLUSIONS: Thus, Piezo1 is a potential contributor to sepsis-induced intestinal barrier dysfunction, influencing apoptosis and TJ modification through calcium influx-mediated mitochondrial dysfunction.

Piezo1 Knockout Improves Post-Stroke Cognitive Dysfunction by Inhibiting the Interleukin-6 (IL-6)/Glutathione Peroxidase 4 (GPX4) Pathway.

Background: Cerebral infarction often results in post-stroke cognitive impairment, which impairs the quality of life and causes long-term disability. Astrocytes, the most abundant glial cells in the central nervous system, have a crucial role in cerebral ischemia and neuroinflammation. We explored the possible advantages of interleukin-6 (IL-6), a powerful pro-inflammatory cytokine produced by astrocytes, for post-stroke cognitive function. Methods: Mendelian randomization was applied to analyze the GWAS database of stroke patients, obtaining a causal relationship between IL-6 and stroke. Further validation of this relationship and its mechanisms was conducted. Using a mouse model of cerebral infarction, we demonstrated a significant increase in IL-6 expression in astrocytes surrounding the ischemic lesion. This protective effect of Piezo1 knockout was attributed to the downregulation of matrix metalloproteinases and upregulation of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1). Results: Two-step Mendelian randomization revealed that IL-6 exposure is a risk factor for stroke. Moreover, we conducted behavioral assessments and observed that Piezo1 knockout mice that received intranasal administration of astrocyte-derived IL-6 showed notable improvement in cognitive function compared to control mice. This enhancement was associated with reduced neuronal cell death and suppressed astrocyte activation, preserving ZO-1. Conclusion: Our study shows that astrocyte-derived IL-6 causes cognitive decline after stroke by protecting the blood-brain barrier. This suggests that piezo1 knockout may reduce cognitive impairment after brain ischemia. Further research on the mechanisms and IL-6 delivery methods may lead to new therapies for post-stroke cognition.

A national survey on current state and development needs of clinical and academic emergency medicine in China.

BACKGROUND: To characterize the current state of emergency medicine (EM) and the requirements for advancing EM clinical practice, education and research in China. METHODS: An anonymous electronic survey was conducted by Chinese Society of Emergency Medicine during September to October 2021. The survey contained 30 questions divided into 2 sections: the current state of EM development and the requirements for EM growth. RESULTS: 722 hospitals were included, of 487 were Level III and 235 were Level II hospitals. We found that after 40 years of development, EM had established a mature disciplinary system and refined sub-specialties including critical care, cardiopulmonary resuscitation, toxicology, disaster and emergency rescue. In Level III hospitals, 70.8% of EDs were standardized training centers for EM residents, but master's degree program, Doctor Degree program and post-doctoral degree program was approved in only 37.8%, 8.4% and 2.9% of EDs respectively and postgraduate curriculum was available in 1/4 of EDs. Only 8% have national or provincial key laboratories. In addition to advance clinical practice, there was also a high demand to improve teaching and research capacities, mainly focusing on literature review, research design and delivery, paper writing, residency training. CONCLUSIONS: EM has built a mature discipline system and refined sub-specialties in China. Teaching and research developed parallel with clinical practice. However, there was still a lack of EM master's and doctoral programs and research capacities need to be improved. More outstanding clinical and academic training should be provided to promote the rapid growth of EM in China.

PAI-1 genetic polymorphisms influence septic patients' outcomes by regulating neutrophil activity.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathophysiology of sepsis, but the exact mechanism remains debatable. In this study, we investigated the associations among the serum levels of PAI-1, the incidence of 4G/5G promoter PAI-1 gene polymorphisms, immunological indicators, and clinical outcomes in septic patients. METHODS: A total of 181 patients aged 18-80 years with sepsis between November 2016 and August 2018 in the intensive care unit in the Xinhua Hospital were recruited in this retrospective study, with 28-day mortality as the primary outcome. The initial serum level of PAI-1 and the presence of rs1799768 single nucleotide polymorphisms (SNPs) were examined. Univariate logistic regression and multivariate analyses were performed to determine the factors associated with different genotypes of PAI-1, serum level of PAI-1, and 28-day mortality. RESULTS: The logistic analysis suggested that a high serum level of PAI-1 was associated with the rs1799768 SNP of PAI-1 (4G/4G and 4G/5G) (Odds ratio [OR]: 2.49; 95% confidence interval [CI]: 1.09, 5.68). Furthermore, a high serum level of PAI-1 strongly influenced 28-day mortality (OR 3.36; 95% CI 1.51, 7.49). The expression and activation of neutrophils (OR 0.96; 95% CI 0.93, 0.99), as well as the changes in the expression patterns of cytokines and chemokine-associated neutrophils (OR: 1.00; 95% CI: 1.00, 1.00), were both regulated by the genotype of PAI-1. CONCLUSIONS: Genetic polymorphisms of PAI-1 can influence the serum levels of PAI-1, which might contribute to mortality by affecting neutrophil activity. Thus, patients with severe sepsis might clinically benefit from enhanced neutrophil clearance and the resolution of inflammation via the regulation of PAI-1 expression and activity.

Clinical scoring approach for detection of histiocytic necrotising lymphadenitis in adults.

BACKGROUND: Histiocytic necrotising lymphadenitis (HNL) is rare and can be easily ignored. AIMS: To summarise the characteristics of HNL and find a simple scoring approach to detect HNL in adult patients. METHODS: Adult patients with lymphadenopathy diagnosed by lymph node biopsy were enrolled. Chi-squared test and t-test were used to determine the significant variables. The cut-off values and scores assigned to each factor were performed by receiver operating characteristic (ROC) curves and coefficients in the logistic regression respectively. The performance of the scoring system was evaluated by ROC curves. RESULTS: There were 32 HNL cases and 1162 other cases in the present study. These features, including age, the frequency of presentations of fever, cervical and painful lymph nodes, decrease of white blood cells (WBC), ratio of neutrophil to WBC (N ratio) and elevated lactate dehydrogenase (LDH), were different between patients with HNL and other diseases. Based on the multivariate analysis, the scoring approach was defined as follows: score = 3 (fever) + 2 (cervical lymphadenopathy) + 2 (decreased WBC) + 1 (decreased N ratio) + 2 (elevated LDH). The cut-off was score 4. This approach performed will detect HNL with an area under the curve of 0.889. CONCLUSION: The present study suggests that the novel scoring approach we put forward might be useful to detect HNL in adult patients though further studies are needed.

Trimethylamine N-Oxide Promotes Cell Proliferation and Angiogenesis in Colorectal Cancer.

Background. Of all intestinal microbiome-derived metabolites, trimethylamine N-oxide (TMAO) has received increasing attention because of its potent role in colorectal cancer development. Accumulating evidence suggests that TMAO generated by the gut microbiota is a new and important player in the etiological process of colorectal cancer. Nevertheless, the carcinogenic mechanism of TMAO in colorectal cancer remains unclear. In this study, TMAO induced colorectal cancer cell proliferation and produced higher vascular endothelial growth factor A (VEGFA) levels in vitro. In vivo, after long-term choline feeding in tumor-bearing mice, circulating TMAO levels, tumor volume, new blood vessel formation, and VEGFA and CD31 amounts were increased significantly. This study revealed that TMAO exerts oncogenic effects by promoting cell proliferation and angiogenesis in colorectal cancer.

Multi-omic Profiling Reveals that Intra-abdominal-Hypertension-Induced Intestinal Damage Can Be Prevented by Microbiome and Metabolic Modulations with 5-Hydroxyindoleacetic Acid as a Diagnostic Marker.

Emerging evidence shows that modulation of the microbiome can suppress intra-abdominal hypertension (IAH)-induced intestinal barrier damage through the regulation of amino acid (AA) biosynthesis. Here, we investigated the protective effects of orally gavaged Lactobacillus acidophilus L-92 (L92) and a mixture of AA in rats with induced IAH. The results showed that both L92 and AA pretreatments effectively mitigated IAH-induced intestinal damage. Interestingly, L92 but not AA prevented metagenomic changes induced by IAH. Bacteroides fragilis, Bacteroides eggerthii, Bacteroides ovatus, Faecalibacterium prausnitzii, Prevotella, and extensively altered functional pathways were associated with L92-mediated host protection. Metabolomic profiling revealed that tryptophan metabolism was involved in both L92- and AA-mediated gut protection. The tryptophan metabolite 5-hydroxyindoleacetic acid (5-HIAA) is a sensitive biomarker for IAH in rats and patients with either gut-derived sepsis (n = 41) or all-source sepsis (n = 293). In conclusion, we show that microbiome and metabolic modulations can effectively prevent IAH-induced intestinal damage and that 5-HIAA is a potential metabolic marker for IAH and sepsis. IMPORTANCE Gut protection through modulation of the microbiome for critically ill patients has been gaining much attention recently. Intra-abdominal hypertension (IAH) is a prevailing clinical feature of acute gastrointestinal injuries in critically ill patients, characterized by nonspecific intestinal barrier damage. Prolonged IAH can induce or aggravate the development of sepsis and multiorgan dysfunctions. Therefore, the prevention of IAH-induced damage in rats through microbiome and metabolic interventions by commercially available L92 and AA treatments and the identification of 5-HIAA as an important marker for IAH/sepsis have important clinical implications for the treatment and early diagnosis of critically ill patients.

Initial CT-based radiomics nomogram for predicting in-hospital mortality in patients with traumatic brain injury: a multicenter development and validation study.

OBJECTIVE: To develop and validate a radiomic prediction model using initial noncontrast computed tomography (CT) at admission to predict in-hospital mortality in patients with traumatic brain injury (TBI). METHODS: A total of 379 TBI patients from three cohorts were categorized into training, internal validation, and external validation sets. After filtering the unstable features with the minimum redundancy maximum relevance approach, the CT-based radiomics signature was selected by using the least absolute shrinkage and selection operator (LASSO) approach. A personalized predictive nomogram incorporating the radiomic signature and clinical features was developed using a multivariate logistic model to predict in-hospital mortality in patients with TBI. The calibration, discrimination, and clinical usefulness of the radiomics signature and nomogram were evaluated. RESULTS: The radiomic signature consisting of 12 features had areas under the curve (AUCs) of 0.734, 0.716, and 0.706 in the prediction of in-hospital mortality in the internal and two external validation cohorts. The personalized predictive nomogram integrating the radiomic and clinical features demonstrated significant calibration and discrimination with AUCs of 0.843, 0.811, and 0.834 in the internal and two external validation cohorts. Based on decision curve analysis (DCA), both the radiomic features and nomogram were found to be clinically significant and useful. CONCLUSION: This predictive nomogram incorporating the CT-based radiomic signature and clinical features had maximum accuracy and played an optimized role in the early prediction of in-hospital mortality. The results of this study provide vital insights for the early warning of death in TBI patients.

Chinese Admission Warning Strategy for Predicting the Hospital Discharge Outcome in Patients with Traumatic Brain Injury.

OBJECTIVE: To develop and validate an admission warning strategy that incorporates the general emergency department indicators for predicting the hospital discharge outcome of patients with traumatic brain injury (TBI) in China. METHODS: This admission warning strategy was developed in a primary cohort that consisted of 605 patients with TBI who were admitted within 6 h of injury. The least absolute shrinkage and selection operator and multivariable logistic regression analysis were used to develop the early warning strategy of selected indicators. Two sub-cohorts consisting of 180 and 107 patients with TBI were used for the external validation. RESULTS: Indicators of the strategy included three categories: baseline characteristics, imaging and laboratory indicators. This strategy displayed good calibration and good discrimination. A high C-index was reached in the internal validation. The multicenter external validation cohort still showed good discrimination C-indices. Decision curve analysis (DCA) showed the actual needs of this strategy when the possibility threshold was 0.01 for the primary cohort, and at thresholds of 0.02-0.83 and 0.01-0.88 for the two sub-cohorts, respectively. In addition, this strategy exhibited a significant prognostic capacity compared to the traditional single predictors, and this optimization was also observed in two external validation cohorts. CONCLUSIONS: We developed and validated an admission warning strategy that can be quickly deployed in the emergency department. This strategy can be used as an ideal tool for predicting hospital discharge outcomes and providing objective evidence for early informed consent of the hospital discharge outcome to the family members of TBI patients.

Associations Among Disseminated Intravascular Coagulation, Thrombocytopenia Cytokines/Chemokines and Genetic Polymorphisms of Toll-Like Receptor 2/4 in Chinese Patients with Sepsis.

OBJECTIVESS: Toll-like receptors (TLRs) on platelets have been extensively studied. Both TLR2 and TLR4 have been shown to augment platelet activation and alter its function from a hemostatic regulator to an immune sentinel. However, few studies have investigated the relationship between genetic polymorphisms in TLR2, TLR4 and platelets. We investigated whether genetic polymorphisms of TLR2 and TLR4 were related to thrombocytopenia and coagulation failure in Chinese patients with sepsis. BASIC METHODS: Adult Chinese patients with sepsis in the intensive care unit of a university medical center were monitored for up to 28 days. Thrombocytopenia and disseminated intravascular coagulation (DIC), diagnosed using Japanese Association for Acute Medicine (JAAM) criteria, were observed as the primary outcomes. Single-nucleotide polymorphisms (SNPs) in TLR2 (rs111200466, rs5743708) and TLR4 (rs11536889, rs145801336, rs11536896, rs7869402) in patients with sepsis were detected by polymerase chain reaction. The data were analyzed using chi-square and rank sum tests. RESULTS: The genotype of TLR2 (rs111200466) (Del/Del) was associated with the initial DIC. The genotype of TLR4 (rs11536889) (C/C&C/G) was associated with initial DIC, DIC onset during hospitalization and platelet counts. Furthermore, both DIC and platelet counts were associated with cytokines and chemokines, especially the IL10. CONCLUSION: Our results demonstrate that in Chinese sepsis patients, the rs111200466 SNP in TLR2 and rs11536889 SNP in TLR4 are associated with thrombocytopenia and DIC, with potential effects on the TLR4 pathways of platelets.

USF2 knockdown downregulates THBS1 to inhibit the TGF-ß signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury.

OBJECTIVE: Acute kidney injury (AKI) is a serious complication of sepsis. This study was performed to explore the mechanism that THBS1 mediated pyroptosis by regulating the TGF-ß signaling pathway in sepsis-induced AKI. METHODS: Gene expression microarray related to sepsis-induced AKI was obtained from the GEO database, and the mechanism in sepsis-induced AKI was predicted by bioinformatics analysis. qRT-PCR and ELISA were performed to detect expressions of THBS1, USF2, TNF-α, IL-1ß, and IL-18 in sepsis-induced AKI patients and healthy volunteers. The mouse model of sepsis-induced AKI was established, with serum creatinine, urea nitrogen, 24-h urine output measured, and renal tissue lesions observed by HE staining. The cell model of sepsis-induced AKI was cultured in vitro, with expressions of TNF-α, IL-1ß, and IL-18, pyroptosis, Caspase-1 and GSDMD-N, and activation of TGF-ß/Smad3 pathway detected. The upstream transcription factor USF2 was knocked down in cells to explore its effect on sepsis-induced AKI. RESULTS: THBS1 and USF2 were highly expressed in patients with sepsis-induced AKI. Silencing THBS1 protected mice against sepsis-induced AKI, and significantly decreased the expressions of NLRP3, Caspase-1, GSDMD-N, IL-1ß, and IL-18, increased cell viability, and decreased LDH activity, thus partially reversing the changes in cell morphology. Mechanistically, USF2 promoted oxidative stress responses by transcriptionally activating THBS1 to activate the TGF-ß/Smad3/NLRP3/Caspase-1 signaling pathway and stimulate pyroptosis, and finally exacerbated sepsis-induced AKI. CONCLUSION: USF2 knockdown downregulates THBS1 to inhibit the TGF-ß/Smad3 signaling pathway and reduce pyroptosis and further ameliorate sepsis-induced AKI.

Clinical Strains of Pseudomonas aeruginosa Secrete LasB Elastase to Induce Hemorrhagic Diffuse Alveolar Damage in Mice.

BACKGROUND: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are most often caused by bacterial pneumonia and characterized by severe dyspnea and high mortality. Knowledge about the lung injury effects of current clinical bacterial strains is lacking. The aim of this study was to investigate the ability of representative pathogenic bacteria isolated from patients to cause ALI/ARDS in mice and identify the major virulence factor. METHODS: Seven major bacterial species were isolated from clinical sputum and unilaterally instilled into the mouse airway. A histology study was performed to determine the lung injury effect. Virulence genes were examined by PCR. Sequence types of P. aeruginosa strains were identified by MLST. LC-MS/MS was used to analysis the bacterial exoproducts proteome. LasB was purified through a DEAE-cellulose column, and its toxicity was tested both in vitro and in vivo. RESULTS: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus agalactiae, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli were randomly separated and tested 3 times. Among them, gram-negative bacteria have much more potential to cause acute lung injury than gram-positive bacteria. However, P. aeruginosa is the only pathogen that induces diffuse alveolar damage, hemorrhage and hyaline membranes in the lungs of mice. The lung injury effect is associated with the excreted LasB elastase. Purified LasB recapitulated lung injury similar to P. aeruginosa infection in vivo. We found that this was due to the powerful degradation effect of LasB on the extracellular matrix of the lung and key proteins in the coagulation cascade without inducing obvious cellular apoptosis. We also report for the first time that LasB could induce DIC-like coagulopathy in vitro. CONCLUSION: P. aeruginosa strains are most capable of inducing ALI/ARDS in mice among major clinical pathogenic bacteria tested, and this ability is specifically attributed to their LasB production.

BMSC-Derived Exosomes Ameliorate LPS-Induced Acute Lung Injury by miR-384-5p-Controlled Alveolar Macrophage Autophagy.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common critical diseases. Bone marrow mesenchymal stem cell (BMSC) transplantation is previously shown to effectively rescue injured lung tissues. The therapeutic mechanism of BMSC-derived exosomes is not fully understood. Here, we investigated the BMSC-derived exosomal microRNAs (miRNAs) on effecting lipopolysaccharide- (LPS-) induced ALI and its mechanism. In vitro, rat alveolar macrophages were treated with or without exosomes in the presence of 10 µg/ml LPS for 24 h. Cell viability was determined with Cell Counting Kit-8 assay. Apoptotic ratio was determined with TUNEL and Annexin V-FITC/PI double staining. The levels of miR-384-5p and autophagy-associated genes were measured by RT-qPCR and western blot. Autophagy was observed by TEM and assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay. In vivo, we constructed LPS-induced ALI rat models. Exosomes were injected into rats via the caudal vein or trachea 4 h later after LPS treatment. The lung histological pathology was determined by H&E staining. Pulmonary vascular permeability was assessed by wet-to-dry weight ratio and Evans blue dye leakage assay, and inflammatory cytokines in serum and BALF were measured by ELISA. Furthermore, the therapeutic mechanism involved in miR-384-5p and Beclin-1 was determined. The results showed that BMSC-derived exosomes were taken up by the alveolar macrophages and attenuated LPS-induced alveolar macrophage viability loss and apoptosis. Exosomes effectively improved the survival rate of ALI rats within 7 days, which was associated with alleviating lung pathological changes and pulmonary vascular permeability and attenuating inflammatory response. Furthermore, this study for the first time found that miR-384-5p was enriched in BMSC-derived exosomes, and exosomal miR-384-5p resulted in relieving LPS-injured autophagy disorder in alveolar macrophages by targeting Beclin-1. Therefore, exosomal miR-384-5p could be demonstrated as a promising therapeutic strategy for ALI/ARDS.

Neuroprotective Effect of the Inhibitor Salubrinal after Cardiac Arrest in a Rodent Model.

Cardiac arrest (CA) yields poor neurological outcomes. Salubrinal (Sal), an endoplasmic reticulum (ER) stress inhibitor, has been shown to have neuroprotective effects in both in vivo and in vitro brain injury models. This study investigated the neuroprotective mechanisms of Sal in postresuscitation brain damage in a rodent model of CA. In the present study, rats were subjected to 6 min of CA and then successfully resuscitated. Either Sal (1 mg/kg) or vehicle (DMSO) was injected blindly 30 min before the induction of CA. Neurological status was assessed 24 h after CA, and the cortex was collected for analysis. As a result, we observed that, compared with the vehicle-treated animals, the rats pretreated with Sal exhibited markedly improved neurological performance and cortical mitochondrial morphology 24 h after CA. Moreover, Sal pretreatment was associated with the following: (1) upregulation of superoxide dismutase activity and a reduction in maleic dialdehyde content; (2) preserved mitochondrial membrane potential; (3) amelioration of the abnormal distribution of cytochrome C; and (4) an increased Bcl-2/Bax ratio, decreased cleaved caspase 3 upregulation, and enhanced HIF-1α expression. Our findings suggested that Sal treatment improved neurological dysfunction 24 h after CPR (cardiopulmonary resuscitation), possibly through mitochondrial preservation and stabilizing the structure of HIF-1α.

Clemastine improves hypomyelination in rats with hypoxic-ischemic brain injury by reducing microglia-derived IL-1ß via P38 signaling pathway.

BACKGROUND: Microglia activation is associated with the development of hypoxic-ischemic brain injury (HIBI). Neuroinflammation suppression might be a suitable therapeutic target in hypoxic oligodendrocyte injury. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated microglia and promoting the maturation of oligodendrocyte progenitor cells (OPCs) in HIBI. METHODS: A bilateral common carotid artery occlusion (BCCAO) rat model that received continuous intraperitoneal injection (1 mg/kg) for 14 days was employed to elaborate the neuroprotection effects of clemastine. Interleukin-1ß (IL-1ß), nod-like receptor protein 3 (NLRP3), histamine H1 receptor, and OPC differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of microglia and OPCs were used to explore the link between microglia activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher's protected least significant difference test. RESULTS: Clemastine treatment could reverse hypomyelination and restrain the upregulation of IL-1ß and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1ß showed failed maturation. However, clemastine could also reverse the OPC maturation arrest by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Co-culture of microglia and OPCs with oxygen glucose deprivation treatment exhibited IL-1ß and NLRP3 upregulation. Clemastine could downregulate NLRP3 and IL-1ß and reverse hypomyelination by inhibiting the p38 signaling pathway. CONCLUSIONS: Clemastine could restrain microglia activation, improve axonal hypomyelination in BCCAO rats, and thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI.

A pulmonary source of infection in patients with sepsis-associated acute kidney injury leads to a worse outcome and poor recovery of kidney function.

BACKGROUND: Hospital mortality rates are higher among patients with sepsis-associated acute kidney injury (SA-AKI) than among patients with sepsis. However, the pathogenesis underlying SA-AKI remains unclear. We hypothesized that the source of infection affects development of SA-AKI. We aim to explore the relationship between the anatomical source of infection and outcome in patients with SA-AKI. METHODS: Between January 2013 and January 2018, 113 patients with SA-AKI admitted to our Emergency Center were identified and divided into two groups: those with pulmonary infections and those with other sources of infection. For each patient, we collected data from admission until either discharge or death. We also recorded the clinical outcome after 90 days for the discharged patients. RESULTS: The most common source of infection was the lung (52/113 cases, 46%), followed by gastrointestinal (GI) (25/113 cases, 22.1%) and urinary (22/113, 19.5%) sources. Our analysis showed that patients with SA-AKI had a significantly worse outcome (30/52 cases, P<0.001) and poorer kidney recovery (P=0.015) with pulmonary sources of infection than those infected by another source. Data also showed that patients not infected by a pulmonary source more likely experienced shock (28/61 cases, P=0.037). CONCLUSION: This study demonstrated that the source of infection influenced the outcome of SA-AKI patients in an independent manner. Lung injury may influence renal function in an as-yet undetermined manner as the recovery of kidney function was poorer in SA-AKI patients with a pulmonary source of infection.