Angiotensin-(1-7) improves intestinal microbiota disturbances and modulates fecal metabolic aberrations in acute pancreatitis.

Acute pancreatitis (AP) is a serious health problem that dysregulates intestinal microbiota. Angiotensin (Ang)-(1-7) plays a protective role in the intestinal barrier in AP, but its effect on intestinal microbiota remains clear. To investigate the impact of Ang-(1-7) on AP-induced intestinal microbiota disorder and metabolites. We collected blood and fecal samples from 31 AP patients within 48 h after admission to the hospital, including 11 with mild AP (MAP), 14 with moderately severe AP (MSAP), six with severe AP (SAP). Mice were divided into four groups: control, AP, AP + Ang-(1-7) via tail vein injection, and AP + Ang-(1-7) via oral administration. The samples of mice were collected 12 h after AP. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. Fecal microbiota and metabolites analysis was performed via 16S rDNA sequencing and nontargeted metabolomics analysis, respectively. In patients, the abundance of beneficial bacteria (Negativicutes) decreased and pathogenic bacteria (Clostridium bolteae and Ruminococcus gnavus) increased in SAP compared with MAP. Ang-(1-7) levels were associated with changes in the microbiota. There were differences in the intestinal microbiota between control and AP mice. Ang-(1-7) attenuated intestinal microbiota dysbiosis in AP mice, reflecting in the increase in beneficial bacteria (Odoribacter and Butyricimonas) than AP, as well as pancreatic and intestinal injuries. Oral administration of Ang-(1-7) reversing AP-induced decreases in metabolisms: secondary bile acids, emodin, and naringenin. Ang-(1-7) may improve intestinal microbiota dysbiosis and modulate fecal metabolites in AP, thereby reducing the damage of AP.

Mitochondrial (mt)DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis.

BACKGROUND: Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown. METHODS: Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS -/- and sting -/- mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro. RESULTS: SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis. CONCLUSIONS: Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.

The association between dyslipidaemia in the first trimester and adverse pregnancy outcomes in pregnant women with subclinical hypothyroidism: a cohort study.

BACKGROUND: Subclinical hypothyroidism (SCH) is linked to dyslipidaemia and adverse pregnancy outcomes. However, the impact of dyslipidaemia on the outcome of pregnancy in SCH is unclear. METHODS: We enrolled 36,256 pregnant women and evaluated their pregnancy outcomes. The following data was gathered during the first trimester (≤ 13+ 6 weeks of gestation): total cholesterol (TC), low-density lipoprotein (LDL-C), triglyceride (TG), high-density lipoprotein (HDL-C), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) concentrations. The reference ranges for lipids were estimated to range from the 5th to the 95th percentile. Logistic regression assessed the relationships between dyslipidaemia and adverse pregnancy outcomes, including abortion, preeclampsia/eclampsia, low birth weight, foetal growth restriction, premature rupture of foetal membranes, gestational hypertension, preterm birth, macrosomia and gestational diabetes mellitus (GDM). Additionally, the best thresholds for predicting adverse pregnancy outcomes based on TSH, FT4, and lipid levels were determined using receiver operating characteristic curves. RESULTS: In the first trimester, LDL-C > 3.24 mmol/L, TG > 1.92 mmol/L, HDL-C < 1.06 mmol/L, and TC > 5.39 mmol/L were used to define dyslipidaemia. In this cohort, 952 (3.56%) patients were diagnosed with SCH, and those who had dyslipidaemia in the first trimester had higher incidences of gestational hypertension (6.59% vs. 3.25%), preeclampsia/eclampsia (7.14% vs. 3.12%), GDM (22.53% vs. 13.77%), and low birth weight (4.95% vs. 2.08%) than did those without dyslipidaemia. However, after adjusting for prepregnancy body mass index (pre-BMI), dyslipidaemia was no longer related to these risks. Furthermore, elevated TG dyslipidaemia in SCH patients was connected to an enhanced potential of gestational hypertension (odds ratio [OR]: 2.687, 95% confidence interval [CI]: 1.074 ~ 6.722), and elevated LDL-C dyslipidaemia correlated with increased preeclampsia/eclampsia risk (OR: 3.172, 95% CI: 1.204 ~ 8.355) after accounting for age, smoking status, alcohol use, pre-BMI, and levothyroxine use. Additionally, the combination of TC, TG, LDL-C, pre-BMI, and TSH exhibited enhanced predictive capabilities for gestational hypertension, preeclampsia/eclampsia, and GDM. Values of 0.767, 0.704, and 0.706 were obtained from the area under the curve. CONCLUSIONS: Among pregnant women with SCH, dyslipidaemia in early pregnancy was related to elevated risks of adverse pregnancy consequences. The combined consideration of age, pre-BMI, TSH, and lipid levels in the first trimester could be beneficial for monitoring patients and implementing interventions to reduce adverse pregnancy outcomes.

Angiotensin-(1-7) ameliorates intestinal barrier dysfunction by activating the Keap1/Nrf2/HO-1 signaling pathway in acute pancreatitis.

BACKGROUND: Intestinal barrier dysfunction is a serious complication associated with acute pancreatitis (AP). Angiotensin (Ang)-(1-7) plays a protective role in the intestinal barrier, but the underlying mechanism remains clear. This study investigated the impact of Ang-(1-7) on AP-induced intestinal dysfunction and its involvement in the Keap1/Nrf2/HO-1 pathway. METHODS AND RESULTS: We studied caerulein- and lipopolysaccharide (LPS)-induced AP in mice and an epithelial cell line (IEC-6) from the small intestinal crypt of rats. Ang-(1-7) was administered orally or via the tail vein. IEC-6 cells were divided into five groups: control; LPS; LPS + Ang-(1-7); LPS + Ang-(1-7) + ML385 (an Nrf2 inhibitor); and LPS + ML385. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. The expression of intestinal barrier-associated proteins and Keap1/Nrf2/HO-1 pathway constituents was assessed by RT-PCR and western blotting. The peroxide and antioxidant activities in the IEC-6 cells were measured. Compared to those in AP mice, Ang-(1-7) diminished the intestinal levels of proinflammatory factors (interleukin-1ß and tumor necrosis factor α) and serum levels of intestine permeability (D-lactate). Ang-(1-7) increased the expression of barrier-associated proteins (aquaporin-1, claudin-1, and occludin) compared to those in the AP and LPS group. Moreover, Ang-(1-7) promoted the Keap/Nrf2/HO-1 pathway, which resulted in significantly reduced malondialdehyde and increased superoxide dismutase levels.. However, ML385 abolished the effects of Ang-(1-7) on barrier-associated proteins and reversed the Keap1/Nrf2/HO-1 pathway. CONCLUSIONS: Ang-(1-7) reduces AP-induced intestinal inflammation and oxidative injuries by activating the Keap1/Nrf2/HO-1 pathway.

Association between Procalcitonin and Acute Kidney Injury in Patients with Bacterial Septic Shock.

OBJECTIVE: The objective of this study was to assess the relationship between serum procalcitonin (PCT) and acute kidney injury (AKI) induced by bacterial septic shock. METHODS: A retrospective study was designed which included patients who were admitted to the ICU from January 2015 to October 2018. Multiple logistic regression and receiver operating characteristic (ROC) as well as smooth curve fitting analysis were used to assess the relationship between the PCT level and AKI. RESULTS: Of the 1,631 patients screened, 157 patients were included in the primary analysis in which 84 (53.5%) patients were with AKI. Multiple logistic regression results showed that PCT (odds ratio [OR] = 1.017, 95% confidence interval [CI] 1.009-1.025, p < 0.001) was associated with AKI induced by septic shock. The ROC analysis showed that the cutoff point for PCT to predict AKI development was 14 ng/mL, with a sensitivity of 63% and specificity 67%. Specifically, in multivariate piecewise linear regression, the occurrence of AKI decreased with the elevation of PCT when PCT was between 25 ng/mL and 120 ng/mL (OR 0.963, 95% CI 0.929-0.999; p = 0.042). The AKI increased with the elevation of PCT when PCT was either <25 ng/mL (OR 1.077, 95% CI 1.022-1.136; p = 0.006) or >120 ng/mL (OR 1.042, 95% CI 1.009-1.076; p = 0.013). Moreover, the PCT level was significantly higher in the AKI group only in female patients aged ≤75 years (p = 0.001). CONCLUSIONS: Our data revealed a nonlinear relationship between PCT and AKI in septic shock patients, and PCT could be used as a potential biomarker of AKI in female patients younger than 75 years with bacterial septic shock.

Platelet count as a new biomarker for acute kidney injury induced by hemorrhagic shock.

The aim of this study was to investigate the association between nadir platelet count and acute kidney injury (AKI) or 28-day all-cause mortality induced by hemorrhagic shock (HS), and to determine the cutoff value of nadir platelet count in HS clinical practice. This retrospective study included hospitalized patients enrolled in a tertiary-care teaching hospital from January 1, 2010 to December 31, 2015. Clinical data from HS admitted to the intensive care unit (ICU) were evaluated. Nadir platelet count was defined as the lowest values in the first 48 h. Multivariate logistic regression and Cox proportional hazards regression were used to assess the correlation between nadir platelet count and AKI or 28-day all-cause mortality induced by HS, respectively; the area under receiver operating characteristic (AU-ROC) and Youde's index were used to determine the optimal cutoff value of nadir platelet count. Kaplan-Meier's method and log-rank test were assessed for the 28-day all-cause mortality in AKI and non-AKI groups. Of 1589 patients screened, 84 patients (mean age,37.1 years; 58 males) were included in the primary analysis in which 30 patients with AKI. Multiple logistic results indicated that nadir platelet count was a risk factor of AKI (OR = 0.71,95% confidence interval [CI] 0.54-0.93, P < 0.05). Cox regression analysis revealed that nadir platelet count was independent risk factors for 28-day all-cause mortality (Hazard ratios [HR]0.89,95%CI 0.76-0.99, P < 0.05). Kaplan-Meier curve showed that 28-day all-cause mortality was significantly higher in patients with AKI than non-AKI (P < 0.001).These results suggest that nadir platelet count in the first 48 h is a new biomarker for AKI and 28-day all-cause mortality induced by HS. Moreover, the risk for AKI and 28-day all-cause mortality in HS patients decreased by 29% and 11%, respectively, for every 10 × 109/L increase in platelet count. Additional studies are needed to investigate whether elevation of nadir platelet count reduces the risk in different genders.

Effect of TIPE1 on Immune Function of Dendritic Cells and Its Signaling Pathway in Septic Mice.

Dendritic cell (DC) dysfunction plays a pivotal role in sepsis-induced immunosuppression. Tumor necrosis factor α (TNF-α)-induced protein 8 like-1 (TIPE1), a new member of the tumor necrosis factor α-induced protein 8 family, may be related to cell death. The aim of the present study was to elucidate the effect of TIPE1 on the immune function of DCs and its regulatory mechanism via PD-L1/PD-1 signaling in mice. Sepsis was induced in adult C57BL/6 male mice via cecal ligation and puncture. In vitro, we found that expression of CD80, CD86, and major histocompatibility complex class II in DCs and levels of cytokines, including tumor necrosis factor α and interleukin 12p40, were elevated; similarly, T-cell proliferation and differentiation were promoted when the gene expressing TIPE1 was silenced. Next, we examined the in vivo role of TIPE1 in a cecal ligation and puncture animal model system. Flow cytometry of the immune functional status in DCs revealed negative regulation of TIPE1 on DC maturation, as well as activation. Moreover, changes in PD-L1/PD-1 levels confirmed the negative effect of TIPE1 in DCs. Collectively, we report that TIPE1 might exert negative regulation in sepsis, at least in part by inhibiting DC maturation and subsequent T-cell-mediated immunity via PD-L1/PD-1 signaling.

Baicalein improves the symptoms of polycystic ovary syndrome by mitigating oxidative stress and ferroptosis in the ovary and gravid placenta.

BACKGROUND: Polycystic ovary syndrome is a metabolic and hormonal disorder that is closely linked to oxidative stress. Within individuals diagnosed with PCOS, changes occur in the ovaries, resulting in an excessive buildup of iron and peroxidation of lipids, both of which may be associated with the occurrence of ferroptosis. Baicalein, a flavonoid found in the roots of Scutellaria baicalensis and widely known as Chinese skullcap, is known for its anti-inflammatory and anti-ferroptotic properties, which protect against various diseases. Nevertheless, there has been no investigation into the impact of baicalein on polycystic ovary syndrome. PURPOSE: This study aimed to correlate ferroptosis with polycystic ovary syndrome and to assess the effects of baicalein on ovarian dysfunction and placental development in pregnant patients. STUDY DESIGN AND METHODS: Polycystic ovary syndrome was induced in a rat model through the administration of dehydroepiandrosterone, and these rats were treated with baicalein. Oxidative stress and inflammation levels were assessed in serum and ovaries, and tissue samples were collected for histological and protein analyses. Furthermore, different groups of female rats were mated with male rats to observe pregnancy outcomes and tissue samples were obtained for histological, protein, and RNA sequencing. Then, RNA sequencing of the placenta was performed to determine the key genes involved in ferroptosis negative regulation (FNR) signatures. RESULTS: Baicalein was shown to reduce ovarian oxidative stress and pathology. Baicalein also ameliorated polycystic ovary syndrome by decreasing lipid peroxidation and chronic inflammation and modulating mitochondrial functions and ferroptosis in the ovaries. Specifically, glutathione peroxidase and ferritin heavy chain 1 were considerably downregulated in polycystic ovary syndrome gravid rats compared to their expression in the control group, and most of these differences were reversed after baicalein intervention. CONCLUSIONS: Our findings, initially, indicated that baicalein could potentially enhance the prognosis of individuals suffering from polycystic ovary syndrome by reducing oxidative stress and ferroptosis, thus potentially influencing the formulation of a therapeutic approach to address this condition.

Association Between Maternal Thyroid Function in Early Pregnancy and Gestational Diabetes: A Prospective Cohort Study.

CONTEXT: Previous studies on the relationship between thyroid gland function and the development of gestational diabetes mellitus (GDM) have reported different results, leading to the need for a cohort study design with a large sample size. OBJECTIVE: We aimed to investigate the relationship between thyroid function in early pregnancy and GDM. METHODS: This was a prospective cohort study based on the China Birth Cohort Study (CBCS), from February 2018 to December 2020. The study took place at a tertiary maternal and child health hospital. A total of 36 256 pregnant women were successfully recruited based on the CBCS. The main outcome measure was GDM. RESULTS: This study consisted of 26 742 pregnant women who met the inclusion criteria, of whom 3985 (14.90%) were diagnosed with GDM, and the women with GDM were older than their healthy counterparts (33.26 ± 4.01 vs 31.51 ± 3.76 years, P < .001). After removing potential influencing variables, we found that increased thyroid-stimulating hormone (TSH) (adjusted odds ratio [aOR] 1.030, 95% CI 1.007, 1.054, P = .012) and subclinical hypothyroidism (aOR 1.211, 95% CI 1.010, 1.451, P = .039), but not free thyroxine or thyroid peroxidase antibody, were associated with the occurrence of GDM. Further analysis indicated a nonlinear relationship between TSH and GDM (P < .05): when TSH ≤ 1.24 mIU/L, the occurrence of GDM was elevated with increasing TSH, but when TSH > 1.24 mIU/L, this trend was not obvious. CONCLUSION: High TSH might be associated with increased risk of GDM.

SGMS1 facilitates osteogenic differentiation of MSCs and strengthens osteogenesis-angiogenesis coupling by modulating Cer/PP2A/Akt pathway.

Mesenchymal stem cell (MSC)-mediated coupling of osteogenesis and angiogenesis is a critical phenomenon in bone formation. Herein, we investigated the role and mechanism of SGMS1 in the osteogenic differentiation of MSCs and, in combination with osteogenesis and angiogenesis, to discover new therapeutic targets for skeletal dysplasia and bone defects. SGMS1 addition accelerated MSC osteogenic differentiation, whereas SGMS1 silencing suppressed this process. Moreover, SGMS1 overexpression inhibited ceramide (Cer) and promoted sphingomyelin (SM) levels. SM treatment neutralized the suppressive effect of shSGMS1 on osteogenesis. SGMS1 restrained PP2A activity by regulating Cer/SM metabolism and thus enhanced the levels of phosphorylated Akt, Runx2, and vascular endothelial growth factor (VEGF). Furthermore, SGMS1 transcription was regulated by Runx2. SGMS1 increased MSC-mediated angiogenesis by promoting VEGF expression. SGMS1 addition promoted rat bone regeneration in vivo. In conclusion, SGMS1 induces osteogenic differentiation of MSCs and osteogenic-angiogenic coupling through the regulation of the Cer/PP2A/Akt signaling pathway.

Role of stem cell derivatives in inflammatory diseases.

Mesenchymal stem cells (MSCs) are pluripotent stem cells of mesodermal origin with the ability of self-renewal and multidirectional differentiation, which have all the common characteristics of stem cells and the ability to differentiate into adipocytes, osteoblasts, neuron-like cells and other cells. Stem cell derivatives are extracellular vesicles(EVs) released from mesenchymal stem cells that are involved in the process of body's immune response, antigen presentation, cell differentiation, and anti-inflammatory. EVs are further divided into ectosomes and exosomes are widely used in degenerative diseases, cancer, and inflammatory diseases due to their parental cell characteristics. However, most diseases are closely related to inflammation, and exosomes can mitigate the damage caused by inflammation in terms of suppressing the inflammatory response, anti-apoptosis and promoting tissue repair. Stem cell-derived exosomes have become an emerging modality for cell-free therapy because of their high safety and ease of preservation and transportation through intercellular communication. In this review, we highlight the characteristics and functions of MSCs-derived exosomes and discuss the regulatory mechanisms of MSCs-derived exosomes in inflammatory diseases and their potential applications in clinical diagnosis and therapy.

Exosome and virus infection.

Exosomes are messengers of intercellular communication in monolayer vesicles derived from cells. It affects the pathophysiological process of the body in various diseases, such as tumors, inflammation, and infection. It has been confirmed that exosomes are similar to viruses in biogenesis, and exosome cargo is widely involved in many viruses' replication, transmission, and infection. Simultaneously, virus-associated exosomes can promote immune escape and activate the antiviral immune response of the body, which bidirectionally modulates the immune response. This review focuses on the role of exosomes in HIV, HBV, HCV, and SARS-CoV-2 infection and explores the prospects of exosome development. These insights may be translated into therapeutic measures for viral infections and reduce the disease burden.

The Role and Potential Regulatory Mechanism of STING Modulated Macrophage Apoptosis and Differentiation in Severe Acute Pancreatitis-Associated Lung Injury.

This study aims to investigate the role of STING in promoting macrophage apoptosis and regulating macrophage polarization in severe acute pancreatitis (SAP)-associated lung injury in vitro and in vivo. A murine model was established by intraperitoneal injection of caerulein and lipopolysaccharide (LPS). Meanwhile, ANA-1 cells were stimulated with LPS to induce apoptosis in vitro. More primary alveolar macrophages underwent apoptosis and M1 macrophage polarization in the SAP group compared with the control group, which was reversed by inhibiting STING. When ANA-1 cells were induced into M2-type macrophages, the reduction of M1 macrophage markers was accompanied by a decrease of LPS-induced apoptosis. Finally, the inhibitory effect of C-176 on STING ameliorates lung injury and inflammation by adjusting macrophage polarization and rescuing apoptosis. Therefore, inhibiting STING could be a new therapeutic strategy for treating acute pancreatitis-associated lung injury.

Serum myoglobin modulates kidney injury via inducing ferroptosis after exertional heatstroke.

Background and Objectives: Myoglobin released by rhabdomyolysis (RM) is considered to be involved in pathogenesis of kidney disease caused by crush injury, but whether high level of serum myoglobin predisposes patients to acute kidney injury (AKI) and its molecular mechanisms are still unclear in exertional heatstroke (EHS). We aimed to determine the association and potential mechanism of myoglobin and AKI, and further investigate the targeted therapeutic agents for myoglobinemia. Methods: Serum myoglobin concentrations in patients with EHS were measured at admission, 24 h and 48 h after admission and discharge. The risk of AKI at 48 h was the primary outcome; the secondary outcome was composite outcome events with myoglobin levels and AKI at discharge and death at 90 days. In experimental studies, we further investigated the mechanisms of human kidney proximal tubular (HK-2) cells that were exposed to human myoglobin under heat stress conditions and the effect of baicalein. Results: Our measurements showed that the highest myoglobin quartile (vs. the lowest) had an adjusted odds ratio (OR) of 18.95 (95% confidence interval [CI], 6.00-59.83) for AKI and that the OR (vs. quartile 2) was 7.92 (95% CI, 1.62-38.89) for the secondary outcome. The survival rate of HK-2 cells treated with myoglobin under heat stress was significantly decreased, and the production of Fe2+ and reactive oxygen species (ROS) was markedly increased, accompanied by changes in ferroptosis proteins, including increased p53, decreased SLC7A11 and GPX4, and alterations in endoplasmic reticulum stress (ERS) marker proteins. Treatment with baicalein attenuated HK-2 cell ferroptosis induced by myoglobin under heat stress through inhibition of ERS. Conclusions: High myoglobin was associated with AKI in the EHS, and its mechanisms involved ERS-associated ferroptosis. Baicalein may be a potential therapeutic drug for the treatment of AKI in patients with high myoglobin induced by rhabdomyolysis following EHS.

Effectiveness of early heparin therapy on outcomes in critically ill patients with sepsis-induced coagulopathy.

Background: This study aimed to investigate whether early unfractionated heparin (UFH) administration provides a survival advantage for patients with sepsis-induced coagulopathy (SIC). Methods: Patients hospitalized with sepsis-induced coagulopathy from the Medical Information Mart for Intensive Care (MIMIC)-IV database were identified. Patients were divided into two groups, who received unfractionated heparin (UFH) subcutaneously within 24 h after intensive care unit (ICU) admission, and the control group, who received not. The primary endpoint was intensive care unit mortality, the secondary outcomes were 7, 14, and 28-day and hospital mortality. Propensity score matching (PSM) the marginal structural Cox model (MSCM) and E-value analysis were used to account for baseline differences, time-varying and unmeasured confounding factors. Results: A total of 3,377 patients with sepsis-induced coagulopathy were enrolled in the study, of which 815 in unfractionated heparin group and 2,562 in control group. There was significant effect on primary and secondary outcomes with unfractionated heparin after propensity score matching (intensive care unit mortality, hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.52-0.92; 7-day, HR 0.70, 95% CI 0.49-0.99; 14-day, HR 0.68.95% CI 0.50-0.92; 28-day, HR 0.72, 95% CI 0.54-0.96; hospital mortality, HR 0.74, 95% CI 0.57-0.96), marginal structural Cox model manifested unfractionated heparin associated with decreased intensive care unit mortality in all populations (HR 0.64, 95% CI 0.49-0.84), and stratification with the marginal structural Cox model indicated analysis further indicated the survival advantage only among patients with an sepsis-induced coagulopathy score of 4 (HR 0.56, 95% CI 0.38-0.81). Further analysis showed that treatment with 6,250-13750 IU/day of unfractionated heparin associated with a decreased risk of intensive care unit mortality. Similar results were replicated in subgroup analysis with propensity score matching only for patients with an sepsis-induced coagulopathy score of 4 (intensive care unit mortality, HR 0.51, 95% CI 0.34-0.76). Conclusion: This study found early unfractionated heparin therapy to patients with sepsis-induced coagulopathy appears to be associated with improved outcomes. Subgroup analysis further demonstrates heparin therapy decreased intensive care unit mortality primarily in patients only with SIC score of 4.

Impact of early heparin therapy on outcomes in patients with solid malignancy associated sepsis: a marginal structural model causal analyse.

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear. Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables. Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41-0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26-0.68); hospital mortality HR 0.70, 95% CI 0.50-0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34-0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26-0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50-0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16-0.69). Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

Impact of early heparin therapy on mortality in critically ill patients with sepsis associated acute kidney injury: a retrospective study from the MIMIC-IV database.

Background: Inflammatory-coagulation dysfunction plays an increasingly important role in sepsis associated acute kidney injury (SAKI). This study aimed to investigate whether early heparin therapy improves survival in patients with SAKI. Methods: Patients with SAKI were identified from the Medical Information Mart for Intensive Care-IV database. The patients were divided into two groups: those who received heparin subcutaneously within 48 h after intensive care unit (ICU) admission and the control group, who received no heparin. The primary endpoint was ICU mortality, the secondary outcomes were 7-day, 14-day, 28-day, and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), and E-value analyses were performed. Results: The study included 5623 individuals with SAKI, 2410 of whom received heparin and 3213 of whom did not. There were significant effects on ICU and 28-day mortality in the overall population with PSM. MSCM further reinforces the efficacy of heparin administration reduces ICU mortality in the general population. Stratification analysis with MSCM showed that heparin administration was associated with decreased ICU mortality at various AKI stages. Heparin use was also associated with reduced 28-day mortality in patients with only female, age >60 years, and AKI stage 3, with HRs of 0.79, 0.77, and 0.60, respectively (p < 0.05). E-value analysis suggests robustness to unmeasured confounding. Conclusion: Early heparin therapy for patients with SAKI decreased ICU mortality. Further analysis demonstrated that heparin therapy was associated with reduced 28-day mortality rate in patients only among female, age > 60 years and AKI stage 3.

The potential role and regulatory mechanism of IL-33/ST2 axis on T lymphocytes during lipopolysaccharide stimulation or perinatal Listeria infection.

BACKGROUND: Interleukin-33 (IL-33) is a member of the interleukin-1 family, which is reported to be important across a range of diseases. However, the mechanisms underlying IL-33/ST2 axis in infectious diseases have not yet been fully addressed. METHODS: We established both lipopolysaccharide (LPS)-induced injuryin T cells and Listeria monocytogenes (Lm) infection model to determine the effect of IL-33 on infectious immunity. RESULTS: The T cell proliferation was inhibited by LPS while IL-33 could reverse the outcome. Further, apoptosis was significantly promoted after serum stimulation (ST)2 knockdown, suggesting IL-33, acting through its receptor ST2, may attenuate the inhibitory effect of LPS on T cells through the apoptotic signaling pathway. In this study, we also identified an IL-33-mediated mechanism of T cell differentiation in pregnant mice infected with Lm. Here, we observed the elevated expression of IL-33 in pregnant mice infected with Lm. Furthermore, we revealed that blocking IL-33 markedly decreased the abortion rate and placental bacterial load, but weakened placental inflammatory repair, by inhibiting Th2 cell-mediated immune responses and relatively intensifying Th1-dominent immunoreaction. CONCLUSIONS: These findings reveal a previously unidentified mechanism underlying IL-33/ST2 axis. IL-33 signaling and targeting T cell-mediated immunity may present a new therapeutic strategy for the treatment of infectious diseases.

STING modulates necrotic cell death in CD4 T cells via activation of PARP-1/PAR following acute systemic inflammation.

Regulated cell death profoundly affects on the progress of inflammatory and immune responses in various acute inflammatory diseases, as seen in sepsis and trauma. However, the mechanisms underlying CD4 T cells death have not yet been fully addressed. We demonstrated that interferon genes (STING) promoted excessive Poly (ADP-ribose) polymerase 1 (PARP-1) activity stimulated by endotoxin, which in turn induced apoptosis-inducing factor (AIF)-independent but PARP-1 dependent programmed cell death. Elevated PARP-1 activity triggered a cascade of molecular events, including PAR polymer release from the nucleus and the nicotinamide adenine dinucleotide (NAD+) and ATP depletion. Interestingly, translocation of AIF, a biochemical signature for PARP-1-dependent parthanatos, was not observed in the present study, suggesting a non-canonical mechanism of CD4 T cells parthanatos. In this study, we also identify a STING-mediated mechanism of necrotic cell death in CD4 T cells in septic animals. Furthermore, we revealed wider effects of STING on the mortality in mice when PARP-1 gene inhibited. These findings reveal that STING signaling and targeting PARP-1/PAR pathway in CD4 T cells may present a new therapeutic strategy for the treatment of acute systemic inflammatory diseases.

Immune regulation in polycystic ovary syndrome.

A polycystic ovarian syndrome (PCOS) is the most common endocrine disorder affecting females. Furthermore, it is a heterogeneous disease with a variety of etiologies and outcomes. Patients frequently complain about infertility, irregular menstruation, acne, seborrheic dermatitis, hirsutism, and obesity. PCOS can be caused by hypothalamic-pituitary-ovarian axis dysfunction, heredity, or metabolic abnormalities. PCOS is characterized by chronic low-level inflammation, which includes an imbalance in pro-inflammatory factor secretion, endothelial cell dysfunction, and leukocytosis. PCOS is also distinguished by hormonal and immune dysregulation. During PCOS, immune cells and immune regulatory molecules play critical roles in maintaining metabolic homeostasis and regulating immune responses. Because of oligo/anovulation, patients with PCOS have low progesterone levels. Therefore, low progesterone levels in PCOS overstimulate the immune system, causing it to produce more estrogen, which leads to a variety of autoantibodies. This review aims to summarize the immune regulation involved in the pathogenesis of PCOS and pave the way for the development of better PCOS treatment options in the near future.