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.

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.

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.

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.

Acute appendicitis presenting as acute diarrhea accompanying hypokalemia.

Acute appendicitis, characterized as periumbilical pain, migrating to the right iliac fossa, is one of the most common acute surgical conditions. It is usually diagnosed on the basis of clinical signs and symptoms. However, some patients may present atypically and are prone to be misdiagnosed. We report this first case of acute appendicitis who presented initially with complain of diarrhea accompanying hypokalemia. There have been no published data suggesting its existence in any parts of the world.

Concurrent infectious mononucleosis and community-associated methicillin-resistant Staphylococcus aureus bacteremia.

It is rare to see a concurrent infection with infectious mononucleosis and community-associated methicillin-resistant Staphylococcus aureus in Tianjin, China. Until now, there is still no any single recorded case of concurrent infectious mononucleosis and community-associated methicillin-resistant Staphylococcus aureus bacteremia.

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.

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.

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.

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.

Rutin Inhibits Cardiac Apoptosis and Prevents Sepsis-Induced Cardiomyopathy.

Rutin is a flavanol-type polyphenol that consists of flavanol quercetin and the disaccharide rutinose, which has been reported to exert various biological effects such as antioxidant and anti-inflammatory activities. It is not clear whether rutin has a protective effect on sepsis-induced cardiomyopathy (SIC). In this study, we used male C57BL/6 mice and cecal ligation and puncture (CLP) surgery to establish the model of SIC. Rutin was precautionarily treated (50, 100, 200 mg/kg per day, 7 days) before CLP. The results showed that rutin pretreatment (100, 200 mg/kg per day, 7 days) reduced the mortality of murine sepsis. We chose the 100 mg/kg dose for further studies. Mice were pretreatment with rutin (100 mg/kg per day, 7 days) before subjected to CLP, and myocardial tissue and blood samples were collected 24 h after CLP. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cTNT decreased, while interleukin-10 (IL-10) increased with rutin pretreatment. The cardiomyocytes apoptosis and mitochondrial dysfunction were also alleviated with rutin pretreatment. In conclusion, this study confirmed the efficacy of rutin-enriched diet in the prophylaxis of cardiac apoptosis and cardiac injury induced by CLP in mouse model. It provides a potential new approach on SIC prophylaxis in sepsis.

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.

Thyroid hormone disorders: a predictor of mortality in patients with septic shock defined by Sepsis-3?

Decreased serum thyroid hormone levels and their prediction of mortality in septic patients are still controversial, especially with the evolution of the definition of sepsis. This study aimed to assess the ability of thyroid hormone disorders to predict the early mortality of patients with septic shock defined by Sepsis-3. Sixty-three adult patients with septic shock admitted to a university hospital emergency intensive care unit (EICU) were studied. Serum free T3 (FT3), free T4 (FT4), thyroid stimulating hormone (TSH), C-reactive protein (CRP), procalcitonin (PCT), and lactate levels were determined and compared with survival status and organ dysfunction. Among the 63 patients studied, lower serum FT3 and FT4 levels were significantly associated with higher sequential organ failure assessment (SOFA) scores. Patients with septic shock with lower levels of FT3 (≤ 1.70 pmol/L) and FT4 (≤ 9.99 pmol/L) had significantly increased 28-day mortality. There was no significant difference in the serum TSH level between the survivor and nonsurvivor groups. The areas under the receiver operating characteristic curves for FT3 and FT4 levels were associated with 28-day mortality (0.92 and 0.89, respectively) and were higher than that for SOFA (0.82), CRP (0.65) and lactate (0.59). The decrease in serum levels of FT3 and FT4 in patients with septic shock is associated with the severity of organ dysfunction and 28-day mortality. Early detection of serum FT3 and FT4 levels could help clinicians to identify patients at high risk of clinical deterioration.

Quick Sequential Organ Failure Assessment as a prognostic factor for infected patients outside the intensive care unit: a systematic review and meta-analysis.

Quick Sequential Organ Failure Assessment (qSOFA) was proposed to replace SIRS as a new screening tool for the identification of septic patients at high mortality. However, researches from infected patients outside of ICU especially in Emergency Department (ED) drew contradictory conclusions on the prognostic value of qSOFA. This systematic review evaluated qSOFA as a prognostic marker of infected patients outside of ICU. The primary outcome was hospital mortality or 28- or 30-day mortality. Data were pooled based on sensitivity and specificity. Twenty-four trials with 121,237 participants were included. qSOFA had a poor sensitivity (0.58 [95% CI 0.47-0.67], 0.54 [95% CI 0.43-0.65]) and moderate specificity (0.69 [95% CI 0.48-0.84], 0.77 [95% CI 0.66-0.86]) for prediction of mortality in patients outside of ICU and ED patients only. Studies that used in-hospital mortality showed a higher sensitivity (0.61 [95% CI 0.50-0.71] vs 0.32 [95% CI 0.15-0.49]) and lower specificity (0.70 [95% CI 0.59-0.82] vs 0.92 [95% CI 0.85-0.99]) than studies that used 28 or 30-day mortality. Studies with overall mortality < 10% showed higher specificity (0.89 [95% CI 0.82-0.95] vs 0.62 [95% CI 0.48-0.76]) than studies with overall mortality ≥ 10%. There is no difference in the accuracy of diagnosis of sepsis between positive qSOFA scores and SIRS criteria. qSOFA was poor sensitivity and moderate specificity in predicting mortality of infected patients outside of ICU especially in ED. Combining qSOFA and SIRS may be helpful in predicting mortality.

Sialic Acids in the Immune Response during Sepsis.

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a group of cell surface transmembrane receptors expressed on immune cells, and regulate immune balance in inflammatory diseases. Sepsis is a life-threatened inflammatory syndrome induced by infection, and the pathogenesis of sepsis includes immune dysregulation, inflammation, and coagulation disorder. Here, we reviewed the various roles acted by Siglecs family in the pathogenesis of sepsis. Siglec-1, Siglec-5, and Siglec-14 play bidirectional roles through modulation of inflammation and immunity. Siglec-2 regulates the immune balance during infection by modulating B cell and T cell response. Siglec-9 helps endocytosis of toll-like receptor 4, regulates macrophages polarization, and inhibits the function of neutrophils during infection. Siglec-10 inhibits danger-associated molecular patterns induced inflammation, helps the initiation of antigen response by T cells, and decreases B-1a cell population to weaken inflammation. Regulating the Siglecs function in the different stages of sepsis holds great potential in the therapy of sepsis.

Sepsis-Induced Cardiomyopathy: Mechanisms and Treatments.

Sepsis is a lethal syndrome with a high incidence and a weighty economy burden. The pathophysiology of sepsis includes inflammation, immune dysfunction, and dysfunction of coagulation, while sepsis-induced cardiomyopathy (SIC), defined as a global but reversible dysfunction of both sides of the heart induced by sepsis, plays a significant role in all of the aspects above in the pathogenesis of sepsis. The complex pathogenesis of SIC involves a combination of dysregulation of inflammatory mediators, mitochondrial dysfunction, oxidative stress, disorder of calcium regulation, autonomic nervous system dysregulation, and endothelial dysfunction. The treatments for SIC include the signal pathway intervention, Chinese traditional medicine, and other specific therapy. Here, we reviewed the latest literatures on the mechanisms and treatments of SIC and hope to provide further insights to researchers and create a new road for the therapy of sepsis.

Tuftsin prevents the negative immunoregulation of neuropilin-1highCD4+CD25+Regulatory T cells and improves survival rate in septic mice.

Our previous research showed that neuropilin (Nrp) -1highCD4+CD25+Regulatory T cells (Tregs) exhibited primary negative immunoregulation in sepsis induced immune dysfunction. Tuftsin is the typical ligand of Nrp-1. Herein, we investigated the potential therapeutic value and mechanisms of tuftsin in sepsis. Sepsis per se markedly decreased the serum concentration of tuftsin, administration of tuftsin improved the survival rate of septic mice with cecal ligation and puncture (CLP). In vitro study, tuftsin prevented the negative immunoregulation of Nrp-1highCD4+CD25+Tregs, including weakening the expression of forkhead/winged helix transcription factor (Foxp)- 3/cytotoxic T lymphocyte associated antigen (CTLA)-4, inhibiting the secretion of transforming growth factor (TGF)-ß, and weakening the immunosuppressive function of Nrp-1highCD4+CD25+Tregs to conventional CD4+CD25-T cells. Tuftsin markedly inhibited the demethylation of Foxp3-Tregs specific demethylated region (TSDR) of Nrp-1highCD4+CD25+Tregs. Tuftsin could represent a new potential therapeutic agentia to improve the outcome of septic mice, and associate with preventing the negative immunoregulation of Tregs via Nrp-1.