H-151 attenuates lipopolysaccharide-induced acute kidney injury by inhibiting the STING-TBK1 pathway.

Sepsis is a severe systemic infectious disease that often leads to multi-organ dysfunction. One of the common and serious complications of sepsis is renal injury. In this study, we aimed to investigate the potential mechanistic role of a novel compound called H-151 in septic kidney injury. We also examined its impact on renal function and mouse survival rates. Initially, we confirmed abnormal activation of the STING-TBK1 signaling pathway in the kidneys of septic mice. Subsequently, we treated the mice with H-151 and observed significant improvement in sepsis-induced renal dysfunction. This was evidenced by reductions in blood creatinine and urea nitrogen levels, as well as a marked decrease in inflammatory cytokine levels. Furthermore, H-151 substantially improved the seven-day survival rate of septic mice, indicating its therapeutic potential. Importantly, H-151 also exhibited an inhibitory effect on renal apoptosis levels, further highlighting its mechanism of protecting against septic kidney injury. These study findings not only offer new insights into the treatment of septic renal injury but also provide crucial clues for further investigations into the regulatory mechanisms of the STING-TBK1 signaling pathway and potential drug targets.

Psychosomatic mechanisms of heart failure symptoms on quality of life in patients with chronic heart failure: A multi-centre cross-sectional study.

AIMS: To determine the contributions of different kinds of symptoms to the quality of life and mediating effect of psychological and physical symptoms between heart failure symptoms and quality of life. DESIGN: A multi-centre cross-sectional study. METHODS: 2006 chronic heart failure patients from four cities were recruited in China from January 2021 to December 2022. Patients' symptoms and quality of life were self-reported, and data were analysed using correlation analysis, dominance analysis and mediating effects analysis. RESULTS: The dominance analysis revealed that the overall mean contributions of heart failure, psychological and physical symptoms were .083, .085 and .111; 29.5%, 30.2% and 39.5% of the known variance. And heart failure symptoms could negatively affect quality of life through psychological and physical symptoms, accounting for 28.39% and 22.95% of the total effect. Heart failure symptoms could also affect quality of life through the chain-mediated effect of physical and psychological symptoms, accounting for 16.74%. CONCLUSIONS: Physiological symptoms had the strongest effect on quality of life and heart failure symptoms had the weakest. Most of the effect for heart failure symptoms on quality of life in chronic heart failure patients was mediated by psychological and physiological symptoms. RELEVANCE TO CLINICAL PRACTICE: It is important to design non-pharmacological intervention plans for the enhancement of physical and psychological symptoms' management skills, to reduce the adverse impact of heart failure symptoms on quality of life. REPORTING METHOD: Study methods and results reported in adherence to the STROBE checklist. NO PATIENT OR PUBLIC CONTRIBUTION: No patients or members of the public were involved in the study.

Angiotensin-(1-7) ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response and mitochondrial damage through the NF-κB and MAPK pathways.

BACKGROUND: There is no available viable treatment for Sepsis-Induced Cardiomyopathy (SIC), a common sepsis complication with a higher fatality risk. The septic patients showed an abnormal activation of the renin angiotensin (Ang) aldosterone system (RAAS). However, it is not known how the Ang II and Ang-(1-7) affect SIC. METHODS: Peripheral plasma was collected from the Healthy Control (HC) and septic patients and Ang II and Ang-(1-7) protein concentrations were measured. The in vitro and in vivo models of SIC were developed using Lipopolysaccharide (LPS) to preliminarily explore the relationship between the SIC state, Ang II, and Ang-(1-7) levels, along with the protective function of exogenous Ang-(1-7) on SIC. RESULTS: Peripheral plasma Ang II and the Ang II/Ang-(1-7) levels in SIC-affected patients were elevated compared to the levels in HC and non-SIC patients, however, the HC showed higher Ang-(1-7) levels. Furthermore, peripheral plasma Ang II, Ang II/Ang-(1-7), and Ang-(1-7) levels in SIC patients were significantly correlated with the degree of myocardial injury. Additionally, exogenous Ang-(1-7) can attenuate inflammatory response, reduce oxidative stress, maintain mitochondrial dynamics homeostasis, and alleviate mitochondrial structural and functional damage by inhibiting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thus alleviating SIC. CONCLUSIONS: Plasma Ang-(1-7), Ang II, and Ang II/Ang-(1-7) levels were regarded as significant SIC biomarkers. In SIC, therapeutic targeting of RAAS, for example with Ang-(1-7), may exert protective roles against myocardial damage.

RNF20 deletion causes inflammation in model of sepsis through the NLRP3 activation.

Aim: Sepsis is an extremely complex, threatening and difficult-to-treat disease, which can occur at any age and under any underlying disease. RNF20 regulate NF-kappaB (NF-κB) signaling pathway and the transcription of inflammatory factors of target genes. Therefore, it is of great significance to study the function of RNF20 in the clinical treatment of sepsis and its underlying mechanisms.Methods: C57BL/6 mice were subjected to cecal ligation and puncture (CLP) surgery. THP-1 cells were induced with Lipopolysaccharide for 4 h.Results: RNF20 gene, mRNA expression and protein expression were reduced in patients with sepsis and mice with sepsis. Based on RNF20 deletion (RNF20-/-) mice, these were found to be increased inflammation reactions in RNF20-/- mice. However, the RNF20 human protein reduced inflammation reactions in mice with sepsis. In vitro model of sepsis, over-expression of RNF20 inhibited inflammation reactions by inducing Vitamin D Receptor (VDR), while down-regulation of RNF20 promoted inflammation reactions through the suppression of VDR. RNF20 protein was interlinked with VDR protein, and VDR protein was also interlinked with NLRP3. Furthermore, VDR promoted NLRP3 ubiquitination and reduced NLRP3 function in vitro model of sepsis.Conclusion: These studies demonstrate that RNF20 suppressed inflammation reactions in models with sepsis through NLRP3 inflammasome and NLRP3 ubiquitination by activating VDR.

Losartan attenuates sepsis-induced cardiomyopathy by regulating macrophage polarization via TLR4-mediated NF-κB and MAPK signaling.

Sepsis-induced cardiomyopathy (SIC) is a serious complication of sepsis with high mortality but no effective treatment. The renin angiotensin (Ang) aldosterone system (RAAS) is activated in patients with sepsis but it is unclear how the Ang II/Ang II type 1 receptor (AT1R) axis contributes to SIC. This study examined the link between the Ang II/AT1R axis and SIC as well as the protective effect of AT1R blockers (ARBs). The Ang II level in peripheral plasma and AT1R expression on monocytes were significantly higher in patients with SIC compared with those in non-SIC patients and healthy controls and were correlated with the degree of myocardial injury. The ARB losartan reduced the infiltration of neutrophils, monocytes, and macrophages into the heart and spleen of SIC mice. Additionally, losartan regulated macrophage polarization from the M1 to the M2 subtype via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby maintaining the mitochondrial dynamics balance in cardiomyocytes and reducing oxidative stress and cardiomyocyte apoptosis. In conclusion, the plasma Ang II level and AT1R expression on plasma monocytes are an important biomarker in SIC. Therapeutic targeting of AT1R, for example with losartan, can potentially protect against myocardial injury in SIC.

Frequency and mortality of sepsis and septic shock in China: a systematic review and meta-analysis.

BACKGROUND: Sepsis, a life-threatening organ dysfunction induced by infection, is a major public health problem. This study aimed to evaluate the frequency and mortality of sepsis, severe sepsis, and septic shock in China. METHODS: We Searched MEDLINE, Embase, PubMed, and Cochrane Library from 1 January 1992 to 1 June 2020 for studies that reported on the frequency and mortality of sepsis, severe sepsis, and septic shock conducted in China. Random effects models were performed to estimate the pooled frequency and mortality of sepsis, severe sepsis, and septic shock. RESULTS: Our search yielded 846 results, of which 29 studies were included in this review. The pooled frequency of sepsis was estimated at 33.6% (95% CI 25.9% to 41.3%, I2 = 99.2%; p < 0.001), and the pooled mortality of sepsis, severe sepsis and septic shock were 29.0% (95% CI 25.3%-32.8%, I2 = 92.1%; p = 0), 31.1% (95% CI 25.3% to 36.9%, I2 = 85.8%; p < 0.001) and 37.3% (95% CI 28.6%-46.0%, I2 = 93.5%; p < 0.001). There was significant heterogeneity between studies. With a small number of included studies and the changing definition of sepsis, trends in sepsis frequency and mortality were not sufficient for analysis. Epidemiological data on sepsis in the emergency department (ED) are severely lacking, and more research is urgently needed in this area is urgently needed. CONCLUSIONS: Our findings indicated that the frequency and mortality of sepsis and septic shock in China were much higher than North America and Europe countries. Based on our results, an extremely high incidence and mortality of sepsis and septic shock in China's mainland requires more healthcare budget support. Epidemiological data on sepsis and septic shock in ED are severely lacking, and more research is urgently needed in this area. Trial registration This systematic review was conducted according to the statement of the preferred reporting items for systematic review (PROSPERO CRD42021243325) and the meta-analysis protocols (PRISMA-P).

Targeting Neuropilin-1 Suppresses the Stability of CD4+ CD25+ Regulatory T Cells via the NF-κB Signaling Pathway in Sepsis.

Neuropilin-1 (Nrp-1) contributes to maintaining the stability of CD4+ CD25+ regulatory T cells (Tregs). We investigated the impact of Nrp-1 on the stability of CD4+ CD25+ Tregs, and the underlying signaling pathways, in a model of sepsis. Splenic CD4+ CD25+ Tregs were either treated with anti-Nrp-1, transfected to silence Nrp-1 and inhibitor of NF-κB kinase subunit beta (IKKß), or administered ammonium pyrrolidine dithiocarbamate (PDTC), followed by recombinant semaphorin 3A (rSema3A), in a simulation of sepsis. After the creation of a sepsis model in mice, anti-Nrp-1 was administered. The expression of the gene encoding forkhead box protein P-3 foxp3-Treg-specific demethylated region (foxp3-TSDR), the apoptosis rate, the expression of Foxp-3, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and transforming growth factor ß1 (TGF-ß1), interleukin 10 (IL-10) and TGF-ß1 secretion, and the NF-κB signaling activity of CD4+ CD25+ Tregs were determined. Sepsis simulation with or without rSema3A increased the stability of CD4+ CD25+ Tregs, including an increase in the expression of Foxp-3, CTLA-4, and TGF-ß1, decreases in apoptosis and the methylation of foxp3-TSDR, increases in the secretion of TGF-ß1 and IL-10, and an increase in the immunosuppressive effect on CD4+ T lymphocytes. Silencing of Nrp-1 or anti-Nrp-1 treatment abrogated lipopolysaccharide (LPS) stimulation with or without an rSema3A-mediated effect. Sepsis simulation increased the DNA-binding activity of NF-κB, as well as the ratios of phosphorylated IKKß (p-IKKß) to IKKß and p-P65 to P65 in vitro and vivo Silencing of IKKß expression or PDTC treatment suppressed the stability of CD4+ CD25+ Tregs in LPS-induced sepsis. Weakening Nrp-1 reduced the stability of CD4+ CD25+ Tregs by regulating the NF-κB signaling pathway; thus, Nrp-1 could be a new target for immunoregulation in sepsis.

Effect of health literacy on quality of life among patients with chronic heart failure in China.

PURPOSE: Despite advances in treatment and management, Chronic heart failure (CHF) is still associated with poor prognosis, a high rate of hospitalization and readmission, and reduced quality of life (QOL). However, the relationship between QOL and health literacy in patients with CHF remains unclear. This study aimed to examine the association between health literacy and QOL, among Chinese patients with CHF. METHOD: This is a cross-sectional study of a convenience sample from a cardiovascular hospital in Henan Province in China. Subjects completed a self-administered questionnaire that assessed the heart failure-specific health literacy score. QOL was measured using the Minnesota Living with heart failure scale. Unadjusted and adjusted multiple linear regression were used to explore the association between health literacy and QOL. RESULTS: This study sampled 299 patients, with a mean age of 61.9 ± 14.9 years old. The association between health literacy and QOL was significant only in the unadjusted model (P < 0.001) and was no longer statistically significant after controlling for covariates. The final best-fitted model identified 9 significant predictors, accounting for 38.6% of the variance in quality of life. CONCLUSIONS: This study suggests that there is no relationship between health literacy and QOL in Chinese CHF patients after adjusting for covariates. Residence, monthly income, self-care management, self-efficacy and social support are significantly associated with QOL. Compared patients with high health literacy, patients with low health literacy may have problems comprehending healthcare information and following disease management instructions, which might contribute to diminished QOL. Therefore, in clinical practice, effective interventions such as creating appropriate materials for low-literacy patients and performing education to raise self-care management, self-efficacy, might improve the QOL of patients with CHF.

Bioinformatics Analysis for Multiple Gene Expression Profiles in Sepsis.

BACKGROUND This work aimed to screen key biomarkers related to sepsis progression by bioinformatics analyses. MATERIAL AND METHODS The microarray datasets of blood and neutrophils from patients with sepsis or septic shock were downloaded from Gene Expression Omnibus database. Then, differentially expressed genes (DEGs) from 4 groups (sepsis versus normal blood samples; septic shock versus normal blood samples; sepsis neutrophils versus normal controls and septic shock neutrophils versus controls) were respectively identified followed by functional analyses. Subsequently, protein-protein network was constructed, and key functional sub-modules were extracted. Finally, receiver operating characteristic analysis was conducted to evaluate diagnostic values of key genes. RESULTS There were 2082 DEGs between blood samples of sepsis patients and controls, 2079 DEGs between blood samples of septic shock patients and healthy individuals, 6590 DEGs between neutrophils from sepsis and controls, and 1056 DEGs between neutrophils from septic shock patients and normal controls. Functional analysis showed that numerous DEGs were significantly enriched in ribosome-related pathway, cell cycle, and neutrophil activation involved in immune response. In addition, TRIM25 and MYC acted as hub genes in protein-protein interaction (PPI) analyses of DEGs from microarray datasets of blood samples. Moreover, MYC (AUC=0.912) and TRIM25 (AUC=0.843) had great diagnostic values for discriminating septic shock blood samples and normal controls. RNF4 was a hub gene from PPI analyses based on datasets from neutrophils and RNF4 (AUC=0.909) was capable of distinguishing neutrophil samples from septic shock samples and controls. CONCLUSIONS Our findings identified several key genes and pathways related to sepsis development.

The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression.

Cellular immunosuppression appears to be involved in sepsis and sepsis-induced multiple organ dysfunction syndrome (MODS). Recent evidence showed that parenteral vitamin C (Vit C) had the ability to attenuate sepsis and sepsis-induced MODS. Herein, we investigated the impact of parenteral Vit C on cellular immunosuppression and the therapeutic value in sepsis. Using cecal ligation and puncture (CLP), sepsis was induced in WT and Gulo-/- mice followed with 200 mg/Kg parenteral Vit C administration. The immunologic functions of CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25- T cells, as well as the organ functions, were determined. Administration of parenteral Vit C per se markedly improved the outcome of sepsis and sepsis-induced MODS of WT and Gulo-/- mice. The negative immunoregulation of Tregs was inhibited, mainly including inhibiting the expression of forkhead helix transcription factor- (Foxp-) 3, cytotoxic T lymphocyte associated antigen- (CTLA-) 4, membrane associated transforming growth factor-ß (TGF-ßm+), and the secretion of inhibitory cytokines [including TGF-ß and interleukin- (IL-) 10], as well as CD4+ T cells-mediated cellular immunosuppression which was improved by parenteral Vit C in WT and Gulo-/- septic mice. These results suggested that parenteral Vit C has the ability to improve the outcome of sepsis and sepsis-induced MODS and is associated with improvement in cellular immunosuppression.

Neuropilin-1highCD4⁺CD25⁺ Regulatory T Cells Exhibit Primary Negative Immunoregulation in Sepsis.

Regulatory T cells (Tregs) appear to be involved in sepsis-induced immune dysfunction; neuropilin-1 (Nrp-1) was identified as a surface marker for CD4(+)CD25(+)Tregs. In the current study, we investigated the negative immunoregulation of Nrp-1(high)CD4(+)CD25(+)Tregs and the potential therapeutic value of Nrp-1 in sepsis. Splenic CD4(+)CD25(+)Tregs from cecal ligation and puncture (CLP) mouse models were further segregated into Nrp-1(high)Tregs and Nrp-1(low)Tregs; they were cocultured with CD4(+)CD25(-) T cells. The expression of forkhead/winged helix transcription factor-3 (Foxp-3), cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), membrane associated transforming growth factor-ß (TGF-ß(m+)), apoptotic rate, and secretive ability [including TGF-ß and interleukin-10 (IL-10)] for various types of Tregs, as well as the immunosuppressive ability of Tregs on CD4(+)CD25(-) T cells, were determined. Meanwhile, the impact of recombinant Nrp-1 polyclonal antibody on the demethylation of Foxp-3-TSDR (Treg-specific demethylated region) was measured in in vitro study. Sepsis per se markedly promoted the expression of Nrp-1 of CD4(+)CD25(+)Tregs. Foxp-3/CTLA-4/TGF-ß(m+) of Nrp-1(high)Tregs were upregulated by septic challenge. Nrp-1(high)Tregs showed strong resilience to apoptosis and secretive ability and the strongest immunosuppressive ability on CD4(+)CD25(-) T cells. In the presence of lipopolysaccharide (LPS), the recombinant Nrp-1 polyclonal antibody reduced the demethylation of Foxp-3-TSDR. Nrp-1(high)Tregs might reveal primary negative immunoregulation in sepsis; Nrp-1 could represent a new potential therapeutic target for the study of immune regulation in sepsis.

Non-Canonical STING-PERK Pathway Modulation of Cellular Senescence and Therapeutic Response in Sepsis-Associated Acute Kidney Injury.

Abstract-This study explored the role of the non-canonical STING-PERK signaling pathway in sepsis-associated acute kidney injury (SA-AKI). Gene expression data from the GEO database and serum STING protein levels in patients with SA-AKI were analyzed. An LPS-induced mouse model and an in vitro model using HK-2 cells were used to investigate the role of STING in SA-AKI. STING expression was suppressed using shRNA silencing technology and the STING inhibitor C176. Kidney function, inflammatory markers, apoptosis, and senescence were measured. The role of the STING-PERK pathway was investigated by silencing PERK in HK-2 cells and administering the PERK inhibitor GSK2606414. STING mRNA expression and serum STING protein levels were significantly higher in patients with SA-AKI. Suppressing STING expression improved kidney function, reduced inflammation, and inhibited apoptosis and senescence. Silencing PERK or administering GSK2606414 suppressed the inflammatory response, cell apoptosis, and senescence, suggesting that PERK is a downstream effector in the STING signaling pathway. The STING-PERK signaling pathway exacerbates cell senescence and apoptosis in SA-AKI. Inhibiting this pathway could provide potential therapeutic targets for SA-AKI treatment.

Colchicine poisoning: Case report of three homicides in a family.

Background: Colchicine is a common therapeutic agent for inflammatory conditions such as gout, yet its narrow therapeutic range frequently results in cases of overdose and subsequent poisoning. Acute colchicine poisoning can be difficult to identify due to its nonspecific clinical manifestations, posing a diagnostic challenge for emergency physicians without a clear history of colchicine ingestion. Case presentation: This report describes a tragic case of acute colchicine poisoning that resulted in three familial homicides. The patients presented with fever, abdominal pain, and diarrhea, which rapidly escalated to shock during their emergency department visits. Laboratory tests revealed a marked leukocytosis, mild elevation in procalcitonin (PCT), significantly elevated creatine kinase (CK) and CK-MB levels, and liver function abnormalities. Despite treatment with carbapenem antibiotics and aggressive fluid resuscitation, the patients' condition deteriorated, marked by a progressive decline in leukocytes and neutrophils. Initially misdiagnosed as septic shock, the ineffectiveness of the standard treatment protocols led to a fatal outcome for all three individuals. Conclusion: Emergency physicians should consider acute colchicine poisoning as a differential diagnosis in patients presenting with shock and the following clinical indicators: (1) pronounced increase in peripheral leukocytes with a disproportionate rise in neutrophils; (2) discordance between the level of serum procalcitonin and the severity of presumed septic shock; (3) early increase in serum creatine kinase (CK) and CK-MB; (4) poor response to antibiotics and resuscitative efforts, accompanied by a continuous decrease in white blood cells and neutrophils. This case underscores the critical need for awareness of colchicine toxicity in the emergency setting, particularly when the clinical presentation mimics septic shock but fails to respond to standard treatments.

The roles of tissue-resident macrophages in sepsis-associated organ dysfunction.

Sepsis, a syndrome caused by a dysregulated host response to infection and characterized by life-threatening organ dysfunction, particularly septic shock and sepsis-associated organ dysfunction (SAOD), is a medical emergency associated with high morbidity, high mortality, and long-term sequelae. Tissue-resident macrophages (TRMs) are a subpopulation of macrophages derived primarily from yolk sac progenitors and fetal liver during embryogenesis, located primarily in non-lymphoid tissues in adulthood, capable of local self-renewal independent of hematopoiesis, and developmentally and functionally restricted to the non-lymphoid organs in which they reside. TRMs are the first line of defense against life-threatening conditions such as sepsis, tumor growth, traumatic-associated organ injury, and surgical-associated injury. In the context of sepsis, TRMs can be considered as angels or demons involved in organ injury. Our proposal is that sepsis, septic shock, and SAOD can be attenuated by modulating TRMs in different organs. This review summarizes the pathophysiological mechanisms of TRMs in different organs or tissues involved in the development and progression of sepsis.

Omega-3 polyunsaturated fatty acids inhibit cardiomyocyte apoptosis and attenuate sepsis-induced cardiomyopathy.

OBJECTIVES: Sepsis can cause myocardial injury, which is one of the leading causes of death in critically ill patients. Fish oil rich in omega-3 polyunsaturated fatty acids (PUFAs) in ultralong chains has immunomodulatory effects and can inhibit the production of various critically ill proinflammatory cytokines. Therefore, this study focused on whether ω-3 PUFAs have a protective effect on sepsis-induced cardiomyopathy (SIC). METHODS: Male 6-8 weeks old C57BL/6 mice were pretreated with 3% special fish oil supplement rat food for seven consecutive days prior to surgery. Cecal ligation and puncture (CLP) was perfromed to induce polymicrobial sepsis.The cardiac function was assessed by echocardiography, apoptosis of cardiomyocyte were detected by TUNEL assay and Western blotting, and the level of TNF-α, IL-6, and IL-1ß in plasma was determined 24h after CLP. RESULTS: Pretreatment with omega-3 PUFAs attenuated cardiomyocyte apoptosis, decreased the production of proinflammatory cytokines, attenuated the SIC, and improved the survival rate of septic mice induced by CLP. CONCLUSIONS: ω-3 PUFAs alleviate SIC through attenuating cardiomyocyte apoptosis, which provides a new direction for the prevention and treatment of SIC.

Factors affecting do-not-attempt-resuscitation (DNAR) decisions among adult patients in the emergency department of a general tertiary teaching hospital in China: a retrospective observational study.

OBJECTIVE: Do-not-attempt-resuscitation (DNAR) orders are designed to allow patients to opt out of receiving cardiopulmonary resuscitation in the event of a cardiac arrest. While DNAR has become a standard component of medical care, there is limited research available specifically focusing on DNAR orders in the context of emergency departments in China. This study aimed to fill that gap by examining the factors related to DNAR orders among patients in the emergency department of a general tertiary teaching hospital in China. DESIGN: Retrospective observational study. SETTING: Emergency department. PARTICIPANTS: This study and analysis on adult patients with DNAR or no DNAR data between 1 January 2022 and 1 January 2023 in the emergency department of a large academic comprehensive tertiary teaching hospital. A total of 689 were included in our study. PRIMARY OUTCOME MEASURES: Whether the patient received DNAR was our dependent variable. RESULTS: Among the total patients, 365 individuals (53.0%) had DNAR orders. The following variables, including age, sex, age-adjusted Charlson comorbidity index (ACCI), primary diagnosis of cardiogenic or cancer related, history of neurological dysfunction or cancer, were independently associated with the difference between the DNAR group and the no DNAR group. Furthermore, there were significant statistical differences observed in the choice of DNAR among patients with different stages of cancer. CONCLUSIONS: In comparison to the no DNAR group, patients with DNAR were characterised by being older, having a higher proportion of female patients, higher ACCI scores, a lower number of patients with a primary diagnosis of cardiogenic and a higher number of patients with a primary diagnosis of cancer related, history of neurological dysfunction or cancer.

Immune checkpoints in sepsis: New hopes and challenges.

Sepsis is a life-threatening syndrome with a high incidence and a weighty economic burden. The cytokines storm in the early stage and the state of immunosuppression in the late stage contribute to the mortality of sepsis. Immune checkpoints expressed on lymphocytes and APCs, including CD28, CTLA-4, CD80, CD86, PD-1 and PD-L1, CD40 and CD40L, OX40 and OX40L, 4-1BB and 4-1BBL, BTLA, TIM family, play significant roles in the pathogenesis of sepsis through regulating the immune disorder. The specific therapies targeting immune checkpoints exhibit great potentials in the animal and preclinical studies, and further clinical trials are planning to implement. Here, we review the current literature on the roles played by immune checkpoints in the pathogenesis and treatment of sepsis. We hope to provide further insights into this novel immunomodulatory strategy.

Insight Into Regulatory T Cells in Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a diffuse central nervous system (CNS) dysfunction during sepsis, and is associated with increased mortality and poor outcomes in septic patients. Despite the high incidence and clinical relevance, the exact mechanisms driving SAE pathogenesis are not yet fully understood, and no specific therapeutic strategies are available. Regulatory T cells (Tregs) have a role in SAE pathogenesis, thought to be related with alleviation of sepsis-induced hyper-inflammation and immune responses, promotion of T helper (Th) 2 cells functional shift, neuroinflammation resolution, improvement of the blood-brain barrier (BBB) function, among others. Moreover, in a clinical point of view, these cells have the potential value of improving neurological and psychiatric/mental symptoms in SAE patients. This review aims to provide a general overview of SAE from its initial clinical presentation to long-term cognitive impairment and summarizes the main features of its pathogenesis. Additionally, a detailed overview on the main mechanisms by which Tregs may impact SAE pathogenesis is given. Finally, and considering that Tregs may be a novel target for immunomodulatory intervention in SAE, different therapeutic options, aiming to boost peripheral and brain infiltration of Tregs, are discussed.

The contribution of neuropilin-1 in the stability of CD4+ CD25+ regulatory T cells through the TGF-ß1/Smads signaling pathway in the presence of lipopolysaccharides.

INTRODUCTION: This study investigates the synergistic effect of TGF-ß1 and Nrp-1 on CD4+ CD25+ Tregs ' stabilization, and the associated pathways of signal transduction, in vitro models in the presence of LPS. MATERIALS AND METHODS: Spleen CD4+ CD25+ Tregs cells of mice models in the presence of LPS, were transfected with an shRNA targeting Nrp-1, Smad2, or Smad3, may or may not be treated with recombinant TGF-ß1. Followed by subsequent determination of cellular proliferation, rate of apoptosis, observation of the Foxp3, CTLA-4, and TGF-ß1m+ expression levels, foxp3-TSDR methylation, secretion levels of the inhibitory cytokines IL-10 and TGF-ß1, and Smad2/3 of CD4+ CD25+ Tregs expression. RESULTS: A remarkable stimulation in CD4+ CD25+ Tregs ' stability is noted after administering recombinant TGF-ß1 in the presence of LPS, and promoted cellular viability, increased Foxp3, CTLA-4, and TGF-ß1m+ expression, and elevated secretion of IL-10 and TGF-ß1. This also inhibited the apoptosis and methylation of foxp3- TSDR of CD4+ CD25+ Tregs . The shRNA transfection silenced Nrp-1 and Smad3, but not Smad2, resulting in the suppression of the recombinant TGF-ß1-mediated effects in the presence of LPS. CONCLUSIONS: According to the results, Nrp-1 mediates TGF-ß1 to improve the stability of regulatory CD4+ CD25+ T cells and maybe a possible therapeutic target with the ability to improve the CD4+ CD25+ Tregs associated negative immunoregulation that is related to the TGF-ß1/Smads cell signaling during sepsis.

S100A9 and SOCS3 as diagnostic biomarkers of acute myocardial infarction and their association with immune infiltration.

Acute myocardial infarction (AMI) is one of the leading causes of death globally, with a mortality rate of over 20%. However, the diagnostic biomarkers frequently used in current clinical practice have limitations in both sensitivity and specificity, likely resulting in delayed diagnosis. This study aimed to identify potential diagnostic biomarkers for AMI and explored the possible mechanisms involved. Datasets were retrieved from the Gene Expression Omnibus. First, we identified differentially expressed genes (DEGs) and preserved modules, from which we identified candidate genes by LASSO (least absolute shrinkage and selection operator) regression and the SVM-RFE (support vector machine-recursive feature elimination) algorithm. Subsequently, we used ROC (receiver operating characteristic) analysis to evaluate the diagnostic accuracy of the candidate genes. Thereafter, functional enrichment analysis and an analysis of immune infiltration were implemented. Finally, we assessed the association between biomarkers and biological processes, infiltrated cells, clinical traits, tissues and time points. We identified nine preserved modules containing 1,016 DEGs and managed to construct a diagnostic model with high accuracy (GSE48060: AUC = 0.923; GSE66360: AUC = 0.973) incorporating two genes named S100A9 and SOCS3. Functional analysis revealed the pivotal role of inflammation; immune infiltration analysis indicated that eight cell types (monocytes, epithelial cells, neutrophils, CD8+ T cells, Th2 cells, NK cells, NKT cells and platelets) were likely involved in AMI. Furthermore, we observed that S100A9 and SOCS3 were correlated with inflammation, variably infiltrated cells, clinical traits of patients, sampling tissues and sampling time points. In conclusion, we suggested S100A9 and SOCS3 as diagnostic biomarkers of AMI and discovered their association with inflammation, infiltrated immune cells and other factors.