The emerging role of adaptor proteins in regulating innate immunity of sepsis.

Sepsis is a life-threatening syndrome caused by a dysregulated immune response. A large number of adaptor proteins have been found to play a pivotal role in sepsis via protein-protein interactions, thus participating in inflammatory cascades, leading to the generation of numerous inflammatory cytokines, as well as oxidative stress and regulated cell death. Although available strategies for the diagnosis and management of sepsis have improved, effective and specific treatments are lacking. This review focuses on the emerging role of adaptor proteins in regulating the innate immunity of sepsis and evaluates the potential value of adaptor protein-associated therapeutic strategy for sepsis.

Identification of 18ß-glycyrrhetinic acid as an AGT inhibitor against LPS-induced myocardial dysfunction via high throughput screening.

Sepsis induced myocardial dysfunction (SIMD) is a serious complication of sepsis. There is increasing evidence that the renin-angiotensin system (RAS) is activated in SIMD. Angiotensinogen (AGT) is a precursor of the RAS, and the inhibition of AGT may have significant cardiovascular benefits. But until now, there have been no reports of small molecule drugs targeting AGT. In this study, we designed a promoter-luciferase based system to screen for novel AGT inhibitors to alleviate SIMD. As a result of high-throughput screening, a total of 5 compounds from 351 medicinal herb-derived natural compounds were found inhibiting AGT. 18ß-glycyrrhetinic acid (18ßGA) was further identified as a potent suppressor of AGT. In vitro experiments, 18ßGA could inhibit the secretion of AGT by HepG2 cells and alleviate the elevated level of mitochondrial oxidative stress in cardiomyocytes co-cultured with HepG2 supernatants. In vivo, 18ßGA prolonged the survival rate of SIMD mice, enhanced cardiac function, and inhibited the damage of mitochondrial function and inflammation. In addition, the results showed that 18ßGA may reduce AGT transcription by downregulating hepatocyte nuclear factor 4 (HNF4) and that further alleviated SIMD. In conclusion, we provided a more efficient screening strategy for AGT inhibitors and expanded the novel role of 18ßGA as a promising lead compound in rescuing cardiovascular disease associated with RAS overactivation.

The Emerging Role of Ferroptosis in Cardiovascular Diseases.

Ferroptosis is one type of programmed cell death discovered in recent years, which is characterized by iron-dependent lipid peroxidation and participating in iron, lipid and antioxidant metabolism. Ferroptosis is different from the traditional cell death types such as apoptosis, necroptosis and autophagy in morphology, biochemistry and genetics. Cardiovascular diseases are considered as an important cause of death from non-communicable diseases in the global population and poses a serious threat to human health. Apoptosis has long been thought to be the major type of cardiomyocyte death, but now ferroptosis has been shown to play a major role in cardiovascular diseases as well. This review will discuss related issues such as the mechanisms of ferroptosis and its effects on the occurrence and development of cardiovascular diseases, aiming to provide a novel target for the prevention and treatment of cardiovascular diseases.

Loss of Hepatic Angiotensinogen Attenuates Sepsis-Induced Myocardial Dysfunction.

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Silent existence of eosinopenia in sepsis: a systematic review and meta-analysis.

BACKGROUND: Sepsis is a life-threatening and time-critical medical emergency; therefore, the early diagnosis of sepsis is essential to timely treatment and favorable outcomes for patients susceptible to sepsis. Eosinopenia has been identified as a potential biomarker of sepsis in the past decade. However, its clinical application progress is slow and its recognition is low. Recent studies have again focused on the potential association between Eosinopenia and severe infections. This study analyzed the efficacy of Eosinopenia as a biomarker for diagnosis of sepsis and its correlation with pathophysiology of sepsis. METHOD: The protocol for this meta-analysis is available in PROSPERO (CRD42020197664). We searched PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials CENTRAL databases to identify studies that met the inclusion criteria. Two authors performed data extraction independently. The pooled outcomes were calculated by TP (true positive), FP (false positive), FN (false negative), TN (true negative) by using bivariate meta-analysis model in STATA 14.0 software. Meanwhile, possible mechanisms of sepsis induced Eosinopenia was also analyzed. RESULTS: Seven studies were included in the present study with a total number of 3842 subjects. The incidence of Eosinopenia based on the enrolled studies varied from 23.2 to 92.7%. For diagnosis of sepsis, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio of Eosinopenia were 0.66 (95%CI [0.53-0.77]), 0.68 (95%CI [0.56-0.79]), 2.09 (95%CI [1.44-3.02]), 0.49 (95%CI [0.34-0.71]) and 4.23 (95%CI [2.15-8.31]), respectively. The area under the summary receiver operator characteristic curve (SROC) was 0.73 (95%CI [0.68-0.76]). Meta-regression analysis revealed that no single parameter accounted for the heterogeneity of pooled outcomes. For each subgroup of different eosinopenia cutoff values (50, 40, ≤25, 100), the sensitivity was 0.61, 0.79, 0.57, 0.54, and the specificity was 0.61, 0.75, 0.83, 0.51, respectively. CONCLUSIONS: Our findings suggested that Eosinopenia has a high incidence in sepsis but has no superiority in comparison with conventional biomarkers for diagnosis of sepsis. However, eosinopenia can still be used in clinical diagnosis for sepsis as a simple, convenient, fast and inexpensive biomarker. Therefore, further large clinical trials are still needed to re-evaluate eosinopenia as a biomarker of sepsis.

Therapeutic approaches targeting renin-angiotensin system in sepsis and its complications.

Sepsis, caused by the inappropriate host response to infection, is characterized by excessive inflammatory response and organ dysfunction, thus becomes a critical clinical problem. Commonly, sepsis may progress to septic shock and severe complications, including acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), sepsis-induced myocardial dysfunction (SIMD), liver dysfunction, cerebral dysfunction, and skeletal muscle atrophy, which predominantly contribute to high mortality. Additionally, the global pandemic of coronavirus disease 2019 (COVID-19) raised the concern of development of effectve therapeutic strategies for viral sepsis. Renin-angiotensin system (RAS) may represent as a potent therapeutic target for sepsis therapy. The emerging role of RAS in the pathogenesis of sepsis has been investigated and several preclinical and clinical trials targeting RAS for sepsis treatment revealed promising outcomes. Herein, we attempt to review the effects and mechanisms of RAS manipulation on sepsis and its complications and provide new insights into optimizing RAS interventions for sepsis treatment.

The emerging role of angiotensinogen in cardiovascular diseases.

Angiotensinogen (AGT) is the unique precursor of all angiotensin peptides. Many of the basic understandings of AGT in cardiovascular diseases have come from research efforts to define its effects on blood pressure regulation. The development of novel techniques targeting AGT manipulation such as genetic animal models, adeno-associated viral approaches, and antisense oligonucleotides made it possible to deeply investigate the relationship between AGT and cardiovascular diseases. In this brief review, we provide contemporary insights into the emerging role of AGT in cardiovascular diseases. In light of the recent progress, we emphasize some newly recognized features and mechanisms of AGT in heart failure, hypertension, atherosclerosis, and cardiovascular risk factors.

Induction of thoracic aortic dissection: a mini-review of ß-aminopropionitrile-related mouse models.

Thoracic aortic dissection (TAD) is one of the most lethal aortic diseases due to its acute onset, rapid progress, and high rate of aortic rupture. The pathogenesis of TAD is not completely understood. In this mini-review, we introduce three emerging experimental mouse TAD models using ß-aminopropionitrile (BAPN) alone, BAPN for a prolonged duration (four weeks) and then with added infusion of angiotensin II (AngII), or co-administration of BAPN and AngII chronically. We aim to provide insights into appropriate application of these three mouse models, thereby enhancing the understanding of the molecular mechanisms of TAD.

Sirt3 is a novel target to treat sepsis induced myocardial dysfunction by acetylated modulation of critical enzymes within cardiac tricarboxylic acid cycle.

Sepsis induced myocardial dysfunction (SIMD) results in high morbidity and mortality. However, the effective therapeutic strategies for SIMD treatment remain limited. Sirt3 is the main mitochondrial Sirtuin member and is a key modulator of mitochondrial metabolism and function. In this study, we aimed to investigate the effect and mechanism of Sirt3 on SIMD. SIMD was induced by 20 mg/kg Lipopolysaccharides (LPS) injection for 6 h in mice. Sepsis could induce the reduction of cardiac Sirt3 expression and global deficiency of Sirt3 exacerbated cardiac function. Quantitative acetyl-proteomics and cardiac metabolomics analysis revealed that loss of Sirt3 led to hyper-acetylation of critical enzymes within cardiac tricarboxylic acid (TCA) cycle and generation of lactate and NADH, subsequently promotion of cardiac dysfunction after sepsis. Additionally, to evaluate whether Emodin could be utilized as a potential Sirt3 modulator to treat SIMD, male wild type mice (WT mice) or global Sirt3 deficient mice (Sirt3-/- mice) were intraperitoneally injected with 40 mg/kg Emodin for 5 days followed by 20 mg/kg LPS administration for another 6 h and observed that exogenous administration of Emodin could attenuate myocardial dysfunction in septic WT mice. However, septic Sirt3-/- mice can not gain benefit on cardiac performance from Emodin infusion. In conclusion, this study presented the protective role of Sirt3 targeting SIMD, which may provide a potential novel approach to maintain normal cardiac performance after sepsis.

Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis.

Nonalcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that the renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of the RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here, we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT+/+) and hepatocyte-specific AGT-deficient mice (hepAGT-/-) were fed a Western diet and a normal laboratory diet for 12 weeks, respectively. Compared with hepAGT+/+ mice, Western diet-fed hepAGT-/- mice gained less body weight with improved insulin sensitivity. The attenuated severity of liver steatosis in hepAGT-/- mice was evidenced by histologic changes and reduced intrahepatic triglycerides. The abundance of SREBP1 and its downstream molecules, acetyl-CoA carboxylase and FASN, was suppressed in hepAGT-/- mice. Furthermore, serum derived from hepAGT+/+ mice stimulated hepatocyte SREBP1 expression, which could be diminished by protein kinase B (Akt)/mammalian target of rapamycin (mTOR) inhibition in vitro. Administration of losartan did not affect diet-induced body weight gain, liver steatosis severity, and hepatic p-Akt, p-mTOR, and SREBP1 protein abundance in hepAGT+/+ mice. These data suggest that attenuation of Western diet-induced liver steatosis in hepAGT-/- mice is associated with the alternation of the Akt/mTOR/SREBP-1c pathway.

Interleukin 33 in tumor microenvironment is crucial for the accumulation and function of myeloid-derived suppressor cells.

Tumor-induced, myeloid-derived suppressor cells (MDSCs)-mediated immune dysfunction is an important mechanism that leads to tumor immune escape and the inefficacy of cancer immunotherapy. Importantly, tumor-infiltrating MDSCs have much stronger ability compared to MDSCs in the periphery. However, the mechanisms that tumor microenvironment induces the accumulation and function of MDSCs are poorly understood. Here, we report that Interleukin-33 (IL-33) - a cytokine which can be abundantly released in tumor tissues both in 4T1-bearing mice and breast cancer patients, is crucial for facilitating the expansion of MDSCs. IL-33 in tumor microenvironment reduces the apoptosis and sustains the survival of MDSCs through induction of autocrine secretion of GM-CSF, which forms a positive amplifying loop for MDSC accumulation. This is in conjunction with IL-33-driven induction of arginase-1 expression and activation of NF-κB and MAPK signaling in MDSCs which augments their immunosuppressive ability, and histone modifications were involved in IL-33 signaling in MDSCs. In ST2-/- mice, the defect of IL-33 signaling in MDSCs attenuates the immunosuppressive and pro-tumoral capacity of MDSCs. Our results identify IL-33 as a critical mediator that contributes to the abnormal expansion and enhanced immunosuppressive function of MDSCs within tumor microenvironment, which can be potentially targeted to reverse MDSC-mediated tumor immune evasion.