ACE2 Rescues Sepsis-Associated Encephalopathy by Reducing Inflammation, Oxidative Stress, and Neuronal Apoptosis via the Nrf2/Sestrin2 Signaling Pathway.

Neuroinflammation and oxidative stress contribute to the progression of sepsis-associated encephalopathy (SAE). Angiotensin-converting enzyme 2 (ACE2) is considered to be a neuroprotective factor due to its anti-inflammatory and antioxidant properties. However, the role of ACE2 on myeloid cells in regulating SAE and the underlying mechanism warrants further exploration. SAE was induced in ACE2 transgenic (TG), knockout (KO), and bone marrow (BM) chimeric mice by cecal ligation and puncture (CLP). The expression levels of apoptosis-, oxidation- and neuroinflammation-associated mediators and morphological changes were monitored by quantitative real-time PCR analyses and histological examinations in the cortex of septic mice. The contents of angiotensin (Ang) II and Ang-(1-7) along with the activity of ACE2 were examined with commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2 was detected by immunoblotting analysis. Our results indicated that the expression of cortical ACE2 was significantly reduced in the early phase of CLP-induced sepsis. Moreover, ACE2 overexpression in TG mice conferred neuroprotection against sepsis, as evidenced by alleviated neuronal apoptosis, oxidative stress, and proinflammatory M1-like microglial polarization, accompanied by upregulation of the Ang-(1-7), Nrf2, and Sestrin2 protein levels. Conversely, ACE2 deficiency in KO mice exacerbated SAE. The neuroprotective effects of ACE2 were further confirmed in wild-type mice transplanted with ACE2-TG and KO BM cells. Therefore, our data suggest that myeloid ACE2 exerts a protective role in the pathogenesis of SAE, potentially by activating Ang-(1-7)-Nrf2/sestrin2 signaling pathway, and highlight that upregulating ACE2 expression and activity may represent a promising approach for the treatment of SAE in patients with sepsis.

ACE2 Expressed on Myeloid Cells Alleviates Sepsis-Induced Acute Liver Injury via the Ang-(1-7)-Mas Receptor Axis.

Sepsis-induced acute liver injury (ALI) is common in intensive care units. Angiotensin-converting enzyme 2 (ACE2) plays a vital role in hepatic fibrosis and steatosis; however, its role in sepsis-induced ALI remains unclear. This study found that hepatic ACE2 expression in cecal ligation and puncture (CLP)-treated mice significantly decreased 24 h after CLP. ACE2-transgenic (TG) mice exhibited a significant improvement in CLP-induced ALI, accompanied by the inhibition of hepatocyte apoptosis, oxidative stress, and inflammation, while ACE2-knockout mice demonstrated an opposite trend. During sepsis-induced ALI, ACE2-TG could also elevate the Ang-(1-7) and Mas receptor (MasR) levels in liver tissues. Interestingly, the MasR inhibitor A779 abrogated the favorable effects of ACE2 on CLP-induced ALI. In a bone marrow transplantation experiment, the ACE2-TG transplantation group showed significantly improved inflammation and liver dysfunction, less hepatocyte apoptosis, and reduced oxidative stress after CLP compared with the wild-type transplantation group. In contrast, the ACE2-knockout group showed poor inflammatory response and liver dysfunction, significantly more hepatocyte apoptosis, and elevated oxidative stress than the wild-type transplantation group after CLP. ACE2 protects against sepsis-induced ALI by inhibiting hepatocyte apoptosis, oxidative stress, and inflammation via the Ang-(1-7)-Mas receptor axis. Thus, targeting ACE2 may be a promising novel strategy for preventing and treating sepsis-induced ALI.

ACE2 activation alleviates sepsis-induced cardiomyopathy by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Sepsis-induced cardiomyopathy (SIC), caused by a dysregulated host response to infection, is a major contributor to high mortality. Angiotensin-converting enzyme 2 (ACE2), a crucial component of the renin-angiotensin system (RAS), has protective effects against several cardiovascular diseases, such as myocardial infarction and heart failure. However, the role of ACE2 in the pathogenesis of SIC and underlying mechanisms remain unknown. The present study was designed to examine the effects of ACE2 activation or inhibition on SIC in C57BL/6 mice. The ACE2 activator diminazene aceturate (DIZE) and ACE2 inhibitor MLN-4760 were applied for treatment. Myocardial function, inflammatory response, oxidative stress, apoptosis and mitochondrial biogenesis were investigated. Major assays were echocardiography, H&E staining, immunofluorescence staining, DHE staining, TUNEL staining, Western blot, qPCR analysis, ELISA and corresponding kits. We confirmed that ACE2 was markedly downregulated in septic heart tissues. Pharmacological activation of ACE2 by DIZE ameliorated cecal ligation puncture (CLP)-induced mortality, cardiac dysfunction, inflammatory response, oxidative stress and the cardiomyocyte apoptosis by promoting MasR-Sirt1-mediated mitochondrial biogenesis. In contrast, SIC was aggravated via inhibiting MasR-Sirt1-mediated mitochondrial biogenesis by the use of ACE2 inhibitor MLN-4760. Consequently, activation of ACE2 may protect against SIC by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Anisodamine hydrobromide in the treatment of critically ill patients with septic shock: a multicenter randomized controlled trial.

BACKGROUND: Septic shock is the development of sepsis to refractory circulatory collapse and metabolic derangements, characterized by persistent hypotension and increased lactate levels. Anisodamine hydrobromide (Ani HBr) is a Chinese medicine used to improve blood flow in circulatory disorders. The purpose of this study was to determine the therapeutic efficacy of Ani HBr in the treatment of patients with septic shock. METHODS: This was a prospective, multicenter, randomized controlled trial focusing on patients with septic shock in 16 hospitals in China. Patients were randomly assigned in a 1:1 ratio to either the treatment group or the control group. The primary endpoint was 28-day mortality. The secondary outcomes included 7-day mortality, hospital mortality, hospital length of stay, vasopressor-free days within 7 days, etc. These indicators were measured and collected at 0, 6h, 24h, 48h, 72h and 7d after the diagnosis. RESULTS: Between September 2017 and March 2021, 404 subjects were enrolled. 203 subjects received Ani HBr and 201 subjects were assigned to the control group. The treated group showed lower 28-day mortality than the control group. Stratified analysis further showed significant differences in 28-day mortality between the two groups for patients with a high level of illness severity. We also observed significant differences in 7-day mortality, hospital mortality and some other clinical indicators between the two groups. CONCLUSION: Ani HBr might be an important adjuvant to conventional treatment to reduce 28-day mortality in patients with septic shock. A large-scale prospective randomized multicenter trial is warranted to confirm our results.

Blockage of S100A8/A9 ameliorates septic nephropathy in mice.

Septic acute kidney injury (AKI) is the commonest cause of complication of sepsis in intensive care units, but its pathophysiology remains unclear. Calprotectin (S100A8/A9), which is a damage-associated molecular patterns (DAMPs) molecule, exerts a critical role in modulating leukocyte recruitment and inflammatory response during various diseases. However, role of S100A8/A9 in septic AKI is largely unknown. In this research, Septic AKI was triggered by cecal ligation and puncture (CLP) operation in wild-type mice, which treated with or without an S100A9 inhibitor, Paquinimod (Paq, 10 mg/kg) that prevents S100A8/A9 to bind to Toll-like receptor 4 (TLR4). Renal function, pathological changes, cell death, and oxidative stress were evaluated. Our research indicated that the mRNA and protein expression of S100A9 are time-dependently elevated in the kidney following CLP. Moreover, the administration of Paq for 24 h significantly improved CLP-induced renal dysfunction and pathological alterations compared with vehicle treatment in mice. These beneficial effects were associated with the inhibition of CLP-triggered renal tubular epithelial cell apoptosis, inflammation, superoxide production, and mitochondrial dynamic imbalance. What's more, we further confirmed the above findings by cell co-culture experiments. Our study demonstrates that S100A9 is a prominent protein to lead to septic AKI, and the selective inhibition of S100A9 could represent a new therapeutic approach which can treat septic AKI.

Peripheral blood monocyte status is a predictor for judging occurrence and development on sepsis in older adult population: a case control study.

BACKGROUND: Peripheral blood monocytes are important immune modulatory cells that change during aging. Previous studies on sepsis and monocytes did not distinguish between age groups, especially in the older adult population. The mechanisms of monocyte subsets and function are not well-understood in the aging context with sepsis. METHODS: Monocyte subsets were measured using flow cytometry in 80 sepsis patients and 40 healthy controls. Plasma cytokine levels were measured using cytokine antibody arrays. RESULTS: The percentage of MO3 (CD14 + CD16 + +)/monocytes was higher in sepsis patients than in controls (P = 0.011), whereas the percentage of MO1 (CD14 + + CD16 -)/monocytes was higher in septic shock patients and 28-day death group than in those without shock and 28-day survival group (P = 0.034, 0.038). Logistic regression analysis showed that the percentage of MO3/monocytes (OR = 1.120, P = 0.046) and plasma level of monocyte chemoattractant protein (MCP)-1 (OR = 1.006, P = 0.023) were independently associated with the occurrence of sepsis, whereas the percentage of MO1/monocytes (OR = 1.255, P = 0.048) was independently associated with septic shock. The receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of MO3/monocyte percentage in combination with MCP-1 plasma level (AUC = 0.799) for predicting sepsis was higher than that of each parameter alone (P < 0.001). The AUC of MO1/monocyte percentage with the value 0.706 (P = 0.003) was lower than the AUC of SOFA (sequential organ failure assessment) score with the value 0.966 (P < 0.001) for predicting septic shock, but the value of the two AUCs were similar for predicting 28-day mortality (AUC = 0.705, 0.827; P = 0.020, P < 0.001). The AUC of MO1/monocytes percentage in combination with SOFA score for predicting 28-day mortality was higher than that of each parameter alone (AUC = 0.867, P < 0.001). Using a cut-off of 58.5% (for MO1/monocytes determined by ROC) could discriminate between survivors and non-survivors on Kaplan-Meier curves for 28-day mortality with a positive predictive value of 77.4%. CONCLUSION: The MO3/monocyte percentage and plasma MCP-1 level were independent predictors of sepsis occurrence, whereas the percentage of MO1/monocytes was an independent predictor of prognosis in the Chinese Han older adult population. TRIAL REGISTRATION: Registration number: ChiCTR2200061490, date of registration: 2022-6-26 (retrospectively registered).

Adipose Triglyceride Lipase Deficiency Aggravates Angiotensin II-Induced Atrial Fibrillation by Reducing Peroxisome Proliferator-Activated Receptor α Activation in Mice.

Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in the intracellular degradation of triacylglycerol and plays an important role in lipid and energy metabolism. However, the role of ATGL in the regulation of AF remains unclear. In this study, AF was induced by infusion of angiotensin II (Ang II, 2000 ng/kg/min) for 3 weeks in male ATGL knockout (KO) mice and age-matched C57BL/6 wild-type mice. The atrial volume was measured by echocardiography. Atrial fibrosis, inflammatory cells, and superoxide production were detected by histologic examinations. The results showed that ATGL expression was significantly downregulated in the atrial tissue of the Ang II-infused mice. Moreover, Ang II-induced increase in the inducibility and duration of AF, atrial dilation, fibrosis, inflammation, and oxidative stress in wild-type mice were markedly accelerated in ATGL KO mice; however, these effects were dramatically reversed in the ATGL KO mice administered with peroxisome proliferator-activated receptor (PPAR)-α agonist clofibric acid. Mechanistically, Ang II downregulated ATGL expression and inhibited PPAR-α activity, activated multiple signaling pathways (inhibiting kappa B kinase α/ß-nuclear factor-κB, nicotinamide adenine dinucleotide phosphate oxidase, and transforming growth factor-ß1/SMAD2/3) and reducing Kv1.5, Cx40, and Cx43 expression, thereby contributing to atrial structural and electrical remodeling and subsequent AF. In summary, our results indicate that ATGL KO enhances AF inducibility, possibly through inhibiting PPAR-α activation and suggest that activating ATGL might be a new therapeutic option for treating hypertensive AF.

S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction.

Sepsis-induced cardiomyopathy (SIC) is the main complication and a leading cause of death in intensive care units. S100a8/a9 is a calcium-binding protein that participates in various inflammatory diseases; however, its role in sepsis-induced cardiomyopathy and the underlying mechanism remains to be explored. Here, septic cardiomyopathy was induced with cecal ligation and puncture (CLP) in S100a9-knockout (KO) mice lacking the heterodimer S100a8/a9 or wild-type (WT) mice administered with an S100a9-specific inhibitor Paquinimod (Paq), which prevents the binding of S100a9 toTLR4. Our results showed that S100a8/a9 expression in the heart peaked 24 h following the CLP operation, declined at 48 h and returned to baseline at 72 h. Loss of S100a9 by knockout in mice protected against CLP-induced mortality, cardiac dysfunction, myocyte apoptosis, recruitment of Mac-2+ macrophages, superoxide production, and the expression of pro-inflammatory cytokines genes compared with WT mice. Moreover, S100a9-KO significantly attenuated CLP-induced activation of the ERK1/2-Drp1 (S616) pathway, excessive mitochondrial fission, and mitochondrial respiration dysfunction. In contrast, activation of ERK1/2 with its agonist tBHQ reversed the inhibitory effects of S100a9-knockout on CLP-induced cardiomyopathy and mitochondrial dysfunction. Finally, administration of Paq to WT mice markedly prevented the CLP-induced cardiomyopathy mitochondrial fission and dysfunction compared with vehicle control. In summary, our data reveal, for the first time, that S100a8/a9 plays a critical role in mediating SIC, presumably by activating TLR4-ERK1/2-Drp1-dependent mitochondrial fission and dysfunction and highlight that blockage of S100a8/a9 may be a promising therapeutic strategy to prevent SIC in patients with sepsis.

Nutritional status and prognostic factors for mortality in patients admitted to emergency department observation units: a national multi-center study in China.

BACKGROUND: Nutritional risk is common among patients admitted to the emergency department and is associated with adverse clinical outcomes. Despite its large population, few comprehensive studies have been conducted in China concerning the nutritional status of patients admitted to emergency department observation units (EDOUs). METHODS: Patients admitted to EDOUs of 90 tertiary hospitals in China between June 2020 and December 2020 were enrolled. Demographic information, laboratory parameters, nutritional support therapies, and 28-day mortality were recorded. Risk factors for mortality were examined using multi-variate-adjusted logistic regression analysis. Receiver operating characteristic (ROC) curves for each predictor of mortality were plotted, and the area under the ROC (AUROC) curves was compared. RESULTS: A total of 2,005 eligible patients were finally enrolled. At the 28-day follow-up, 1,911 patients survived, and 94 died. The group with a Nutritional Risk Screening 2002 (NRS 2002) score of 3-4 points was the largest (52.01%). The number of patients receiving oral nutritional supplements, enteral nutrition (EN), parenteral nutrition (PN), and the combination of EN and PN was 425, 314, 853, and 413, respectively. Among the total, 77.55% of patients had nutritional risk (NRS 2002 ≥3). The proportion of patients with high nutritional risk (NRS2002≥5) in the age group >80 years was significantly higher than that in the age group 66-80 years (29.00% vs. 23.93%, P=0.032), but not significantly higher than that in the age group 18-65 years (29.00% vs. 26.54%, P=0.449). Logistic regression analysis revealed that heart failure (odds ratio [OR] 1.856, 95% confidence interval [CI] 1.087-3.167, P=0.023), consciousness (OR 2.967, 95% CI 1.894-4.648, P<0.001), Acute Physiology and Chronic Health Evaluation II (APACHE II) score (OR 1.037, 95% CI 1.017-1.058, P<0.001), NRS 2002 score (OR 1.286, 95% CI 1.115-1.483, P=0.001), and Mini Nutritional Assessment-Short Form score (OR 0.946, 95% CI 0.898-0.997, P=0.039) were all independent risk factors for 28-day mortality. APACHE II and NRS 2002 scores were superior to other predictors according to the comparison of AUROC. CONCLUSIONS: Nutritional risk is prevalent among older patients in EDOUs in China. APACHE II and NRS 2002 scores are important risk factors for mortality in patients admitted to the EDOU. Timely and appropriate nutritional screening and support measures are critical to reduce patients' length of hospital stay and mortality.

ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway.

Persistent myocardial hypertrophy frequently leads to heart failure (HF). Intramyocardial triacylglycerol (TAG) accumulation is closely related with cardiac remodeling and abnormal contractile function. Adipose triglyceride lipase (ATGL), a key enzyme in TAG metabolism, regulates cardiac function. However, its associated molecular pathways have not been fully defined. Here, cardiac hypertrophy and HF were induced in wild-type (WT) or ATGL knockout (KO) mice through transverse aortic constriction (TAC) for up to 4 weeks. TAC in WT mice significantly reduced cardiac function and autophagy while enhancing left ventricular hypertrophy, interstitial fibrosis, inflammatory response, superoxide generation, and cardiomyocyte apoptosis, accompanied with upregulation of the proteasome activity, reduction of PTEN level and activation of AKT-mTOR signaling, and these effects were further aggravated in ATGL KO mice. Interestingly, ATGL KO-mediated cardiac dysfunction and remodeling were markedly reversed by proteasome inhibitor (epoxomicin) or autophagic activator (rapamycin), but accelerated by PTEN inhibitor (VO-OHpic) or autophagy inhibitor 3-MA. Mechanistically, ATGL KO upregulated proteasome expression and activity, which in turn mediates PTEN degradation leading to activation of AKT-mTOR signaling and inhibition of autophagy, thereby enhancing hypertrophic remodeling and HF. In conclusion, ATGL KO contributes to TAC-induced cardiac dysfunction and adverse remodeling probably associated with the proteasome-PTEN-mTOR-autophagy pathway. Therefore, modulation of this pathway may have a therapeutic effect potential for hypertrophic heart disease. TAC-induced downregulation of ATGL results in increased proteasome (ß1i/ß2i/ß5i) activity, which in turn promotes degradation of PTEN and activation of AKT-mTOR signaling and then inhibits autophagy and ATP production, thereby leading to cardiac hypertrophic remodeling and dysfunction. Conversely, blocking proteasome activity or activating autophagy attenuates these effects.

The tissue factor expression on CD14++CD16-monocytes is a new markers in the Chinese Han older adult population with sepsis: A prospective study.

OBJECTIVE: To investigate the tissue factor (TF) expression on different subsets of monocyte and tissue factor secretion of peripheral blood and evaluate their association with the prognosis of sepsis in the Chinese older adult population. METHODS: Monocyte subsets and TF expression on different subsets of monocyte were measured using flow cytometry in 80 older adult sepsis patients and 40 age and sex matched healthy controls. Plasma level of TF was measured using ELISA (enzyme-linked immunosorbent assay) method. RESULTS: TF expression on CD14++CD16- (MO1) monocyte was lower in death (28-day non-survivor) group compared with survival (28-day survivor) groups [1.01 % (0.58 %, 1.62 %) vs. 3.66 % (1.32 %, 6.93 %), p = 0.001]. The plasma level of TF was increased in death group compared to survival group according to the 28-day mortality [109.2 (67.3, 154.2) vs. 62.1 (44.7, 115.5) pg/mL, p = 0.031]. Logistic regression analysis showed TF expression on MO1 monocyte (ß = -0.776, OR = 0.460, CI: 0.251, 0.843, p = 0.012) was independently associated with the 28-day mortality. The ROC (receiver operating characteristic) curve showed that the AUC (area under the curve) of the TF expression on MO1 monocyte for predicting 28-day mortality was 0.846 (p < 0.001). CONCLUSION: The TF expression on CD14++CD16- monocyte is a new marker for the prognosis of older adult sepsis.

Time Series Transcriptomic Analysis by RNA Sequencing Reveals a Key Role of PI3K in Sepsis-Induced Myocardial Injury in Mice.

Septic cardiomyopathy is the main complication and cause of death of severe sepsis with limited therapeutic strategy. However, the molecular mechanism of sepsis-induced cardiac injury remains unclear. The present study was designed to investigate differentially expressed genes (DEGs) involved in the pathogenesis of septic cardiomyopathy induced by cecal ligation and puncture (CLP) in mice. Male C57BL/6J mice (8-10 weeks old) were subjected to CLP with 21-gauge needles for 24, 48, and 72 h. Myocardial function was assessed by echocardiography. The pathological changes of the heart were evaluated by hematoxylin and eosin as well as immunohistochemical staining. Time series RNA sequencing was utilized to investigate the gene expression profiles. CLP surgery resulted in a significant decrease of animal survival rate and left ventricle contractile function, and an increase in cardiac dilation and infiltration of proinflammatory cells including Mac-2+ macrophages in a time-dependent manner. RNA sequencing identified 5,607 DEGs in septic myocardium at 24, 48, and 72 h after CLP operation. Moreover, gene ontology analysis revealed that these DEGs were mainly associated with the biological processes, including cell adhesion, immune system process, inflammatory response, and positive regulation of cell migration. KEGG pathway enrichment analysis indicated that Staphylococcus aureus infection, osteoclast differentiation, leishmaniasis, and ECM-receptor interaction were significantly altered in septic hearts. Notably, Pik3r1 and Pik3r5 were localized in the center of the gene co-expression network, and were markedly upregulated in CLP-induced septic myocardium. Further, blocking PI3Kγ by the specific inhibitor CZC24832 significantly protected against sepsis-induced cardiac impairment. The present study uncovers the gene expression signatures of CLP-induced myocardial injury and sheds light on the role of Pik3r5 in septic cardiomyopathy.

Anisodamine hydrobromide ameliorates cardiac damage after resuscitation.

The microcirculation is correlated with the prognosis of patients with cardiac arrest and changes after resuscitation. In the present study, the effects of anisodamine hydrobromide (AH) on microcirculation was investigated and its potential mechanisms were explored. A total of 24 pigs were randomly grouped into three groups (n=8): Sham, Saline and AH group. After pigs were anesthetized, intubated and mechanically ventilated, ventricular fibrillation was induced by electrical stimulation. After 8 min, cardiopulmonary resuscitation was given to the restoration of spontaneous circulation (ROSC). Arteriovenous blood was collected at baseline and 0, 1, 2, 4 and 6 h after ROSC to measure blood gas and cytokines. Perfused vessel density (PVD) and microvascular flow index (MFI) were measured to reflect the microcirculation. Continuous cardiac output and global ejection fraction were measured to indicate hemodynamics. Compared with Sham group, PVD and MFI in the intestines and the sublingual regions decreased significantly after resuscitation. The microcirculation recovered faster in the AH group than the SA group. The decrease of intestinal microcirculatory blood flow was closely related to the decrease of sublingual microcirculatory blood flow. The cardiac function was impaired after resuscitation, and a decrease of IFN-γ as well as IL-2 and an increase of IL-4 as well as IL-10 suggested the immune imbalance. The microcirculation changes in sublingual regions were closely related to the changes in intestines. AH could improve the immune imbalance after resuscitation and was beneficial to the recovery of cardiac function.

Influence of Microcirculatory Dysfunction on Myocardial Injury after Cardiopulmonary Resuscitation.

Objective: This study aimed to examine the effects of microcirculatory dysfunction and 654-1 intervention after cardiopulmonary resuscitation on myocardial injury. Methods: Landrace pigs were divided into a sham operation group (S group, n= 6), ventricular fibrillation control group (VF-C group, n= 8) and 654-1 intervention group (VF-I group, n= 8). Hemodynamics was recorded at baseline, at recovery of spontaneous circulation (ROSC), and 1 h, 2 h, 4 h and 6 h thereafter. Sidestream dark field (SDF) technology was used to evaluate and monitor the microcirculation flow index, total vessel density, perfusion vessel ratio, De-Backer score, and perfusion vessel density in animal viscera at various time points. Results: After administration of 654-1 at 1.5 h post-ROSC, the hemodynamics in the VF-I group, as compared with the VF-C group, was significantly improved. The visceral microcirculation detected by SDF was also significantly improved in the VF-I group. As observed through electron microscopy, significantly less myocardial tissue injury was present in the VF-I group than the VF-C group. Conclusion: Administration of 654-1 inhibited excessive inflammatory by improving the state of visceral microcirculation.

Correction: Transcriptional Effects of E3 Ligase Atrogin-1/MAFbx on Apoptosis, Hypertrophy and Inflammation in Neonatal Rat Cardiomyocytes.

[This corrects the article DOI: 10.1371/journal.pone.0053831.].

Low serum thyroid-stimulating hormone levels may be an early predictor of sepsis.

OBJECTIVE: This study aimed to explore whether thyroid-stimulating hormone (TSH) plays an early warning role in detecting progression of bacterial infection to sepsis and can serve as a novel marker for the diagnosis of sepsis. METHOD: This was a prospective study of patients treated for 'bacterial infection' in the emergency department of Beijing Chaoyang Hospital from 1 January 2021 to 31 August 2021. Subjects were divided into a sepsis group (SG) and a non-SG (NSG), according to whether their condition had progressed to sepsis within 72 hours of admission. Routine blood test results as well as biochemical and thyroid function indices (T4, FT4, T3, FT3) were recorded at the time of admission. TSH, Acute Physiology and Chronic Health Evaluation II scores and Sequential Organ Failure Assessment scores were likewise documented. RESULTS: A total of 62 patients were enrolled, the SG and the NSG showed significant differences in their levels of TSH. The results indicate that TSH is an early warning marker for sepsis. CONCLUSIONS: TSH plays an early warning role in the diagnosis of bacterial infection progressing to sepsis, having a strong predictive value.

Pheochromocytoma with abdominal aortic aneurysm presenting as recurrent dyspnea, hemoptysis, and hypotension: A case report.

BACKGROUND: Pheochromocytomas are rare endocrine tumors with various clinical manifestations, and few of them might present with profound, life-threatening conditions. CASE SUMMARY: We report the case of a 65-year-old man who complained of sudden dyspnea and hemoptysis for half a day. There was no obvious cause for the patient to have dyspnea, coughing, or coughing up to approximately 100 mL of fresh blood. Finally, he was diagnosed with pheochromocytoma crisis (PCC), coexisting with an abdominal aortic aneurysm (AAA). CONCLUSION: We report a case of pheochromocytoma presenting with recurrent hemoptysis, dyspnea and hypotension coexisting with an AAA. It not only proved the uncommon manifestations of pheochromocytoma but also directed clinicians to consider PCC among the possible diagnoses when meeting similar cases. Moreover, surgical excision is the most beneficial method for the treatment of pheochromocytoma coexisting with AAA when the situation is stable.

Gallic Acid Ameliorates Angiotensin II-Induced Atrial Fibrillation by Inhibiting Immunoproteasome- Mediated PTEN Degradation in Mice.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and is a major cause of stroke and heart failure. We and others have found that gallic acid (GA) plays a beneficial role in cardiac hypertrophic remodeling and hypertension. However, the effect of GA on angiotensin II (Ang II)-induced AF and atrial remodeling as well as the underlying mechanisms remain unknown. AF was induced in mice by Ang II infusion (2000 ng/kg/min) for 3 weeks. Blood pressure was measured using the tail-cuff method. Atrial volume was evaluated by echocardiography. Atrial remodeling was studied using hematoxylin and eosin, Masson's trichrome, and immunohistochemical staining. Atrial oxidative stress was assessed by dihydroethidium staining. The gene expression of fibrotic and inflammatory markers and protein levels of signaling mediators were measured by quantitative real-time PCR and western blot analysis. In mice, GA administration significantly attenuated Ang II-induced elevation of blood pressure, AF incidence and duration, atrial dilation, fibrosis, inflammation, and oxidative stress compared with the vehicle control. Furthermore, GA downregulated Ang II-induced activity and expression of immunoproteasome subunits (ß2i and ß5i), which reduced PTEN degradation and led to the inactivation of AKT1 and downstream signaling mediators. Importantly, blocking PTEN activity by VO-Ohpic markedly reversed the GA-mediated protective effects on Ang II-induced AF and atrial remodeling. Therefore, our results provide novel evidence that GA exerts a cardioprotective role by inhibiting immunoproteasome activity, which attenuates PTEN degradation and activation of downstream signaling, and may represent a promising candidate for treating hypertensive AF.

Outcome prediction value of National Early Warning Score in septic patients with community-acquired pneumonia in emergency department: A single-center retrospective cohort study.

BACKGROUND: To evaluate the accuracy of National Early Warning Score (NEWS) in predicting clinical outcomes (28-day mortality, intensive care unit [ICU] admission, and mechanical ventilation use) for septic patients with community-acquired pneumonia (CAP) compared with other commonly used severity scores (CURB65, Pneumonia Severity Index [PSI], Sequential Organ Failure Assessment [SOFA], quick SOFA [qSOFA], and Mortality in Emergency Department Sepsis [MEDS]) and admission lactate level. METHODS: Adult patients diagnosed with CAP admitted between January 2017 and May 2019 with admission SOFA ≥2 from baseline were enrolled. Demographic characteristics were collected. The primary outcome was the 28-day mortality after admission, and the secondary outcome included ICU admission and mechanical ventilation use. Outcome prediction value of parameters above was compared using receiver operating characteristics (ROC) curves. Cox regression analyses were carried out to determine the risk factors for the 28-day mortality. Kaplan-Meier survival curves were plotted and compared using optimal cut-off values of qSOFA and NEWS. RESULTS: Among the 340 enrolled patients, 90 patients were dead after a 28-day follow-up, 62 patients were admitted to ICU, and 84 patients underwent mechanical ventilation. Among single predictors, NEWS achieved the largest area under the receiver operating characteristic (AUROC) curve in predicting the 28-day mortality (0.861), ICU admission (0.895), and use of mechanical ventilation (0.873). NEWS+lactate, similar to MEDS+lactate, outperformed other combinations of severity score and admission lactate in predicting the 28-day mortality (AUROC 0.866) and ICU admission (AUROC 0.905), while NEWS+lactate did not outperform other combinations in predicting mechanical ventilation (AUROC 0.886). Admission lactate only improved the predicting performance of CURB65 and qSOFA in predicting the 28-day mortality and ICU admission. CONCLUSIONS: NEWS could be a valuable predictor in septic patients with CAP in emergency departments. Admission lactate did not predict well the outcomes or improve the severity scores. A qSOFA ≥2 and a NEWS ≥9 were strongly associated with the 28-day mortality, ICU admission, and mechanical ventilation of septic patients with CAP in the emergency departments.

Selective blocking of CXCR2 prevents and reverses atrial fibrillation in spontaneously hypertensive rats.

Atrial fibrillation (AF) is associated with inflammation and oxidative stress. Recently, we demonstrated that the chemokine-receptor CXCR2 plays a critical role in the recruitment of monocytes/macrophages and the development of hypertension and cardiac remodelling. However, the role of CXCR2 in the pathogenesis of hypertensive AF remains unclear. AF was induced in Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) administered with the CXCR2 inhibitor SB225002. Atrial remodelling, pathological changes and electrophysiology were examined. Our results showed that the chemokine CXCL1 and its receptor CXCR2 were markedly increased in atrial tissue of SHRs compared with WKYs. The administration of SB225002 to SHRs significantly reduced the elevation of blood pressure, AF inducibility and duration, atrial remodelling, recruitment of macrophages, superoxide production and conduction abnormalities compared with vehicle treatment. The administration of SB225002 to SHRs also reversed pre-existing AF development, atrial remodelling, inflammation and oxidative stress. These effects were associated with the inhibition of multiple signalling pathways, including TGF-ß1/Smad2/3, NF-κB-P65, NOX1, NOX2, Kir2.1, Kv1.5 and Cx43. In conclusion, this study provides new evidence that blocking CXCR2 prevents and reverses the development of AF in SHRs, and suggests that CXCR2 may be a potential therapeutic target for hypertensive AF.