Unraveling the role of HIF-1α in sepsis: from pathophysiology to potential therapeutics-a narrative review.

Sepsis is characterized by organ dysfunction resulting from a dysregulated inflammatory response triggered by infection, involving multifactorial and intricate molecular mechanisms. Hypoxia-inducible factor-1α (HIF-1α), a notable transcription factor, assumes a pivotal role in the onset and progression of sepsis. This review aims to furnish a comprehensive overview of HIF-1α's mechanism of action in sepsis, scrutinizing its involvement in inflammatory regulation, hypoxia adaptation, immune response, and organ dysfunction. The review encompasses an analysis of the structural features, regulatory activation, and downstream signaling pathways of HIF-1α, alongside its mechanism of action in the pathophysiological processes of sepsis. Furthermore, it will delve into the roles of HIF-1α in modulating the inflammatory response, including its association with inflammatory mediators, immune cell activation, and vasodilation. Additionally, attention will be directed toward the regulatory function of HIF-1α in hypoxic environments and its linkage with intracellular signaling, oxidative stress, and mitochondrial damage. Finally, the potential therapeutic value of HIF-1α as a targeted therapy and its significance in the clinical management of sepsis will be discussed, aiming to serve as a significant reference for an in-depth understanding of sepsis pathogenesis and potential therapeutic targets, as well as to establish a theoretical foundation for clinical applications.

Dyslipidemia versus obesity as predictors of ischemic stroke prognosis: a multi-center study in China.

BACKGROUND: This multicenter observational study aimed to determine whether dyslipidemia or obesity contributes more significantly to unfavorable clinical outcomes in patients experiencing a first-ever ischemic stroke (IS). METHODS: The study employed a machine learning predictive model to investigate associations among body mass index (BMI), body fat percentage (BFP), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC) with adverse outcomes in IS patients. Extensive real-world clinical data was utilized, and risk factors significantly linked to adverse outcomes were identified through multivariate analysis, propensity score matching (PSM), and regression discontinuity design (RDD) techniques. Furthermore, these findings were validated via a nationwide multicenter prospective cohort study. RESULTS: In the derived cohort, a total of 45,162 patients diagnosed with IS were assessed, with 522 experiencing adverse outcomes. A multifactorial analysis incorporating PSM and RDD methods identified TG (adjusted odds ratio (OR) = 1.110; 95% confidence interval (CI): 1.041-1.183; P <  0.01) and TC (adjusted OR = 1.139; 95%CI: 1.039-1.248; P <  0.01) as risk factors. However, BMI, BFP, and HDL showed no significant effect. In the validation cohort, 1410 controls and 941 patients were enrolled, confirming that lipid levels are more strongly correlated with the prognosis of IS patients compared to obesity (TC, OR = 1.369; 95%CI: 1.069-1.754; P <  0.05; TG, OR = 1.332; 95%CI: 1.097-1.618; P <  0.01). CONCLUSION: This study suggests that dyslipidemia has a more substantial impact on the prognosis of IS patients compared to obesity. This highlights the importance of prioritizing dyslipidemia management in the treatment and prevention of adverse outcomes in IS patients.

Elevated MMP-8 levels, inversely associated with BMI, predict mortality in mechanically ventilated patients: an observational multicenter study.

BACKGROUND: The present study aimed to investigate the correlation between weight status and mortality in mechanically ventilated patients and explore the potential mediators. METHODS: Three medical centers encompassing 3301 critically ill patients receiving mechanical ventilation were assembled for retrospective analysis to compare mortality across various weight categories of patients using machine learning algorithms. Bioinformatics analysis identified genes exhibiting differential expression among distinct weight categories. A prospective study was then conducted on a distinct cohort of 50 healthy individuals and 193 other mechanically ventilated patients. The expression levels of the genes identified through bioinformatics analysis were quantified through enzyme-linked immunosorbent assay (ELISA). RESULTS: The retrospective analysis revealed that overweight individuals had a lower mortality rate than underweight individuals, and body mass index (BMI) was an independent protective factor. Bioinformatics analysis identified matrix metalloproteinase 8 (MMP-8) as a differentially expressed gene between overweight and underweight populations. The results of further prospective studies showed that overweight patients had significantly lower MMP-8 levels than underweight patients ((3.717 (2.628, 4.191) vs. 2.763 (1.923, 3.753), ng/ml, P = 0.002). High MMP-8 levels were associated with increased mortality risk (OR = 4.249, P = 0.005), indicating that elevated level of MMP-8 predicts the mortality risk of underweight patients receiving mechanical ventilation. CONCLUSIONS: This study provides evidence for a protective effect of obesity in mechanically ventilated patients and highlights the potential role of MMP-8 level as a biomarker for predicting mortality risk in this population.

IDENTIFICATION AND CLINICAL VALIDATION OF HYPOXIA-INDUCIBLE FACTOR 1α PROTEIN AS THE POTENTIAL BIOMARKER IN PATIENTS WITH SEPSIS.

ABSTRACT: Objective: Sepsis is a complex disease characterized by an inflammatory response and tissue hypoxia. Hypoxia-inducible factor 1α (HIF-1α) expression level is regulated by hypoxia and inflammation. This study aimed to explore the correlation between HIF-1α expression level and sepsis by bioinformatics analysis and clinical investigation. Methods: Bioinformatics tools were used to identify differentially expressed genes between sepsis and nonsepsis groups using the Gene Expression Omnibus data set. A clinical investigation was carried out to validate HIF-1α protein level in 54 nonseptic patients and 173 septic patients who were followed up for 28 days. Results: Bioinformatics analysis revealed that HIF-1α messenger RNA level was significantly different between septic and nonseptic patients ( P < 0.05). Consistent with the study hypothesis, higher HIF-1α levels in plasma were found in septic patients compared with those in nonseptic patients. The diagnostic accuracy for sepsis, as quantified by the area under the curve, was 0.926 (0.885-0.968) for HIF-1α expression level combined with oxygen saturation to fraction of inspired oxygen (SpO 2 /FiO 2 ), white blood cell, and blood urea nitrogen. The HIF-1α expression level was also significantly correlated with the severity of the disease. The results of the restricted cubic splines model indicated a U-shaped relationship between HIF-1α expression level and intensive care unit (ICU) mortality. Univariate and multivariate linear regression analyses indicated that septic patients with the elevated HIF-1α expression levels had shorter length of ICU stay versus those with the lower HIF-1α expression levels. Conclusion: Hypoxia-inducible factor 1α expression level can be used for diagnosing disease, assessing severity, and predicting length of ICU stay in septic patients.

Endoscopic therapy combined with photodynamic therapy for intratracheal inflammatory myofibroblastic tumor.

Inflammatory myofibroblastic tumor (IMT) is a rare intermediate tumor that exhibits both benign and malignant behaviors. Whether IMT is an inflammatory or a neoplastic disease remains controversial, and there is currently no standard treatment for this disease. The treatment strategies include surgical tumor removal and drug therapy; however, several patients experience tumor recurrence post-treatment. Herein, we report the endoscopic manifestations and treatment process in a case of IMT. We performed photodynamic therapy (PDT) after endoscopic tumor resection, and no recurrence was found in the patient's re-examination a year later. This indicates that PDT can improve IMT prognosis and reduce its local recurrence, signifying the therapy's potential application value for IMT.

Retrospective Study of Critically Ill COVID-19 Patients With and Without Extracorporeal Membrane Oxygenation Support in Wuhan, China.

Background: Extracorporeal membrane oxygenation (ECMO) might benefit critically ill COVID-19 patients. But the considerations besides indications guiding ECMO initiation under extreme pressure during the COVID-19 epidemic was not clear. We aimed to analyze the clinical characteristics and in-hospital mortality of severe critically ill COVID-19 patients supported with ECMO and without ECMO, exploring potential parameters for guiding the initiation during the COVID-19 epidemic. Methods: Observational cohort study of all the critically ill patients indicated for ECMO support from January 1 to May 1, 2020, in all 62 authorized hospitals in Wuhan, China. Results: Among the 168 patients enrolled, 74 patients actually received ECMO support and 94 not were analyzed. The in-hospital mortality of the ECMO supported patients was significantly lower than non-ECMO ones (71.6 vs. 85.1%, P = 0.033), but the role of ECMO was affected by patients' age (Logistic regression OR 0.62, P = 0.24). As for the ECMO patients, the median age was 58 (47-66) years old and 62.2% (46/74) were male. The 28-day, 60-day, and 90-day mortality of these ECMO supported patients were 32.4, 68.9, and 74.3% respectively. Patients survived to discharge were younger (49 vs. 62 years, P = 0.042), demonstrated higher lymphocyte count (886 vs. 638 cells/uL, P = 0.022), and better CO2 removal (PaCO2 immediately after ECMO initiation 39.7 vs. 46.9 mmHg, P = 0.041). Age was an independent risk factor for in-hospital mortality of the ECMO supported patients, and a cutoff age of 51 years enabled prediction of in-hospital mortality with a sensitivity of 84.3% and specificity of 55%. The surviving ECMO supported patients had longer ICU and hospital stays (26 vs. 18 days, P = 0.018; 49 vs. 29 days, P = 0.001 respectively), and ECMO procedure was widely carried out after the supplement of medical resources after February 15 (67.6%, 50/74). Conclusions: ECMO might be a benefit for severe critically ill COVID-19 patients at the early stage of epidemic, although the in-hospital mortality was still high. To initiate ECMO therapy under tremendous pressure, patients' age, lymphocyte count, and adequacy of medical resources should be fully considered.

Clinical value of blood markers to assess the severity of coronavirus disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is threatening the world with the symptoms of seasonal influenza. This study was conducted to investigate the patient characteristics and clinical value of blood markers to assess the severity of coronavirus disease 2019 (COVID-19). METHODS: 187 patients, diagnosed with COVID-19 (non-severe and severe cases) and admitted to hospital between January 27th and March 8th of 2020, were enrolled in the present study. RESULTS: A higher proportion of clinical symptoms, including cough, expectoration, myalgia, and fatigue were observed in the non-severe group. The level of white blood cell count, neutrophils, CRP, IL-6 and IL-8 were significantly increased, while the platelet count was remarkedly decreased in the severe group. The risk model based on lymphocyte, IL-6, IL-8, CRP and platelet counts had the highest area under the receiver operator characteristic curve (AUROC). The baseline of IL-6, IL-8 and CRP was positively correlated with other parameters except in the cases of lymphocyte, hemoglobin and platelet counts. The baseline of the platelet count was negatively correlated with other parameters except in the lymphocyte and hemoglobin counts. Additionally, there was no connection between the severity of COVID-19 and cultures of blood, sputum or catheter secretion. CONCLUSIONS: The present study suggested that high leucocyte and low platelets counts were independent predictive markers of the severity of COVID-19.

Proteomic characteristics of bronchoalveolar lavage fluid in critical COVID-19 patients.

Up to 10-20% of patients with coronavirus disease 2019 (COVID-19) develop a severe pulmonary disease due to immune dysfunction and cytokine dysregulation. However, the extracellular proteomic characteristics in respiratory tract of these critical COVID-19 patients still remain to be investigated. In the present study, we performed a quantitative proteomic analysis of the bronchoalveolar lavage fluid (BALF) from patients with critical COVID-19 and from non-COVID-19 controls. Our study identified 358 differentially expressed BALF proteins (P < 0.05), among which 41 were significantly changed after using the Benjamini-Hochberg correction (q < 0.05). The up-regulated signaling was found to be mainly involved in inflammatory signaling and response to oxidative stress. A series of increased extracellular factors including Tenascin-C (TNC), Mucin-1 (KL-6 or MUC1), Lipocalin-2 (LCN2), periostin (POSTN), Chitinase 3-like 1 (CHI3L1 or YKL40), and S100A12, and the antigens including lymphocyte antigen 6D/E48 antigen (LY6D), CD9 antigen, CD177 antigen, and prostate stem cell antigen (PSCA) were identified, among which the proinflammatory factors TNC and KL-6 were further validated in serum of another thirty-nine COVID-19 patients and healthy controls, showing high potentials of being biomarkers or therapeutic candidates for COVID-19. This BALF proteome associated with COVID-19 would also be a valuable resource for researches on anti-inflammatory medication and understanding the molecular mechanisms of host response. DATABASE: Proteomic raw data are available in ProteomeXchange (http://proteomecentral.proteomexchange.org) under the accession number PXD022085, and in iProX (www.iprox.org) under the accession number IPX0002429000.

Impact of Shenfu injection on a composite of organ dysfunction development in critically ill patients with coronavirus disease 2019 (COVID-19): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: This study aims to determine the protection provided by Shenfu injection (a traditional Chinese medicine) against development of organ dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19). TRIAL DESIGN: This study is a multicenter, randomized, controlled, open-label, two-arm ratio 1:1, parallel group clinical trial. PARTICIPANTS: The patients, who are aged from 18 to 75 years old, with a confirmed or suspected diagnosis of severe or critical COVID-19, will be consecutively recruited in the study, according to the guideline on diagnosis and treatment of COVID-19 (the 7th version) issued by National Health Commission of the People's Republic of China. Exclusion criteria include pregnant and breastfeeding women, atopy or allergies to Shenfu Injection (SFI), severe underlying disease (malignant tumor with multiple metastases, uncontrolled hemopathy, cachexia, severe malnutrition, HIV), active bleeding, obstructive pneumonia caused by lung tumor, severe pulmonary interstitial fibrosis, alveolar proteinosis and allergic alveolitis, continuous use of immunosuppressive drugs in last 6 months, organ transplantation, expected death within 48 hours, the patients considered unsuitable for this study by researchers. The study is conducted in 11 ICUs of designated hospitals for COVID-19, located in 5 cities of China. INTERVENTION AND COMPARATOR: The enrolled patients will randomly receive 100 ml SFI (study group) or identical volume of saline (control group) twice a day for seven consecutive days. Patients in the both groups will be given usual care and the necessary supportive therapies as recommended by the latest edition of the management guidelines for COVID-19 (the 7th version so far). MAIN OUTCOMES: The primary endpoint is a composite of newly developed or exacerbated organ dysfunction. This is defined as an increase in the sequential organ failure assessment (SOFA) score of two or more, indicating sepsis and involvement of at least one organ. The SOFA score will be measured for the 14 days after enrolment from the baseline (the score at randomization). The secondary endpoints are shown below: • SOFA score in total • Pneumonia severity index score • Dosage of vasoactive drugs • Ventilation free days within 28 days • Length of stay in intensive care unit • Total hospital costs to treat the patient • 28-day mortality • The incidence of adverse drug events related to SFI RANDOMISATION: The block randomization codes were generated by SAS V.9.1 for allocation of participants in this study. The ratio of random distribution is 1:1. The sealed envelope method is used for allocation concealment. BLINDING (MASKING): The patients and statistical personnel analyzing study data are both blinded. The blinding of group assignment is not adopted for the medical staff. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study is expected to recruit 300 patients with COVID-19, (150 in each group). TRIAL STATUS: Protocol version 2.0, February 15, 2020. Patient recruitment started on February 25, and will end on August 31, 2020. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000030043. Registered February 21, 2020, http://www.chictr.org.cn/showprojen.aspx?proj=49866 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Does training improve diagnostic accuracy and inter-rater agreement in applying the Berlin radiographic definition of acute respiratory distress syndrome? A multicenter prospective study.

BACKGROUND: Poor inter-rater reliability in chest radiograph interpretation has been reported in the context of acute respiratory distress syndrome (ARDS), although not for the Berlin definition of ARDS. We sought to examine the effect of training material on the accuracy and consistency of intensivists' chest radiograph interpretations for ARDS diagnosis. METHODS: We conducted a rater agreement study in which 286 intensivists (residents 41.3%, junior attending physicians 35.3%, and senior attending physician 23.4%) independently reviewed the same 12 chest radiographs developed by the ARDS Definition Task Force ("the panel") before and after training. Radiographic diagnoses by the panel were classified into the consistent (n = 4), equivocal (n = 4), and inconsistent (n = 4) categories and were used as a reference. The 1.5-hour training course attended by all 286 intensivists included introduction of the diagnostic rationale, and a subsequent in-depth discussion to reach consensus for all 12 radiographs. RESULTS: Overall diagnostic accuracy, which was defined as the percentage of chest radiographs that were interpreted correctly, improved but remained poor after training (42.0 ± 14.8% before training vs. 55.3 ± 23.4% after training, p < 0.001). Diagnostic sensitivity and specificity improved after training for all diagnostic categories (p < 0.001), with the exception of specificity for the equivocal category (p = 0.883). Diagnostic accuracy was higher for the consistent category than for the inconsistent and equivocal categories (p < 0.001). Comparisons of pre-training and post-training results revealed that inter-rater agreement was poor and did not improve after training, as assessed by overall agreement (0.450 ± 0.406 vs. 0.461 ± 0.575, p = 0.792), Fleiss's kappa (0.133 ± 0.575 vs. 0.178 ± 0.710, p = 0.405), and intraclass correlation coefficient (ICC; 0.219 vs. 0.276, p = 0.470). CONCLUSIONS: The radiographic diagnostic accuracy and inter-rater agreement were poor when the Berlin radiographic definition was used, and were not significantly improved by the training set of chest radiographs developed by the ARDS Definition Task Force. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (registration number NCT01704066 ) on 6 October 2012.

Value of Kidney Disease Improving Global Outcomes Urine Output Criteria in Critically Ill Patients: A Secondary Analysis of a Multicenter Prospective Cohort Study.

BACKGROUND: Urine output (UO) is an essential criterion of the Kidney Disease Improving Global Outcomes (KDIGO) definition and classification system for acute kidney injury (AKI), of which the diagnostic value has not been extensively studied. We aimed to determine whether AKI based on KDIGO UO criteria (KDIGOUO) could improve the diagnostic and prognostic accuracy, compared with KDIGO serum creatinine criteria (KDIGOSCr). METHODS: We conducted a secondary analysis of the database of a previous study conducted by China Critical Care Clinical Trial Group (CCCCTG), which was a 2-month prospective cohort study (July 1, 2009 to August 31, 2009) involving 3063 patients in 22 tertiary Intensive Care Units in Mainland of China. AKI was diagnosed and classified separately based on KDIGOUOand KDIGOSCr. Hospital mortality of patients with more severe AKI classification based on KDIGOUOwas compared with other patients by univariate and multivariate regression analyses. RESULTS: The prevalence of AKI increased from 52.4% based on KDIGOSCrto 55.4% based on KDIGOSCrcombined with KDIGOUO. KDIGOUOalso resulted in an upgrade of AKI classification in 7.3% of patients, representing those with more severe AKI classification based on KDIGOUO. Compared with non-AKI patients or those with maximum AKI classification by KDIGOSCr, those with maximum AKI classification by KDIGOUOhad a significantly higher hospital mortality of 58.4% (odds ratio [OR]: 7.580, 95% confidence interval [CI]: 4.141-13.873, P< 0.001). In a multivariate logistic regression analysis, AKI based on KDIGOUO (OR: 2.891, 95% CI: 1.964-4.254, P< 0.001), but not based on KDIGOSCr (OR: 1.322, 95% CI: 0.902-1.939, P = 0.152), was an independent risk factor for hospital mortality. CONCLUSION: UO was a criterion with additional value beyond creatinine criterion for AKI diagnosis and classification, which can help identify a group of patients with high risk of death.

Alpinetin inhibits lipopolysaccharide-induced acute kidney injury in mice.

Alpinetin, a novel plant flavonoid isolated from Alpinia katsumadai Hayata, has been demonstrated to have anti-inflammatory and antioxidant effects. However, the effects of alpinetin on lipopolysaccharide (LPS)-induced acute kidney injury have not been reported. In the present study, we investigated the protective effects and the underlying mechanism of alpinetin against LPS-induced acute kidney injury in mice. The results showed that alpinetin inhibited LPS-induced kidney histopathologic changes, blood urea nitrogen (BUN) and creatinine levels. Alpinetin also inhibited LPS-induced ROS, MDA, and inflammatory cytokines TNF-α, IL-6 and IL-1ß production in kidney tissues. Meanwhile, Western blot analysis showed that alpinetin suppressed LPS-induced TLR4 expression and NF-κB activation in kidney tissues. In addition, alpinetin was found to up-regulate the expression of Nrf2 and HO-1 in a dose-dependent manner. In conclusion, alpinetin protected LPS-induced kidney injury through activating Nrf2 and inhibiting TLR4 expression.

Cardiac arrest: a case-based review.

BACKGROUND: Coffee is commonly consumed among young people in China. However, consumers are rarely aware of physically adverse effects as a result of excessive consumption of caffeine. DATA SOURCES: A literature search using multiple databases was performed for articles published with concentration on meta-analyses, systematic reviews, and randomized controlled trials. RESULTS: Excess coffee consumption is also a risk of primary cardiac arrest especially in young people. Treatment modalities include activated charcoals, beta-blockers, vasopressin and hemodialysis when necessary. CONCLUSION: Coffee consumers should be advised not to routinely take more than moderate coffee.

Prevalence, risk factors, clinical course, and outcome of acute kidney injury in Chinese intensive care units: a prospective cohort study.

BACKGROUND: Acute kidney injury (AKI) has been recognized as a major healthcare problem affecting millions of patients worldwide. However, epidemiologic data concerning AKI in China are still lacking. The objectives of this study were to characterize AKI defined by RIFLE criteria, assess the association with hospital mortality, and evaluate the impact of AKI in the context of other risk factors. METHODS: This prospective multicenter observational study enrolled 3,063 consecutive patients from 1 July 2009 to 31 August 2009 in 22 ICUs across mainland China. We excluded patients who were admitted for less than 24 hours (n = 1623), younger than 18 years (n = 127), receiving chronic hemodialysis (n = 29), receiving renal transplantation (n = 1) and unknown reasons (n = 28). There were 1255 patients in the final analysis. AKI was diagnosed and classified according to RIFLE criteria. RESULTS: There were 396 patients (31.6%) who had AKI, with RIFLE maximum class R, I, and F in 126 (10.0%), 91 (7.3%), and 179 (14.3%) patients, respectively. Renal function deteriorated in 206 patients (16.4%). In comparison with non AKI patients, patients in the risk class on ICU admission were more likely to progress to the injury class (odds ratio (OR) 3.564, 95% confidence interval (CI) 1.706 - 7.443, P = 0.001], while patients in the risk class (OR 5.215, 95% CI 2.798-9.719, P < 0.001) and injury class (OR 13.316, 95% CI 7.507-23.622, P < 0.001) had a significantly higher probability of deteriorating into failure class. The adjusted hazard ratios for 90-day mortality were 1.884 for the risk group, 3.401 for the injury group, and 5.306 for the failure group. CONCLUSIONS: The prevalence of AKI was high among critically ill patients in Chinese ICUs. In comparison with non-AKI patients, patients with RIFLE class R or class I on ICU admission were more susceptibility to progression to class I or class F. The RIFLE criteria were robust and correlated well with clinical deterioration and mortality.

Thirty-eight cases of acute pancreatitis in pregnancy: a 6-year single center retrospective analysis.

Thirty-eight pregnant inpatients with acute pancreatitis (AP) were retrospectively reviewed from 2006 to 2012 in our hospital. The incidence of pregnancy-associated AP was 2.27‰. Most (78.95%) of the attack occurred in the third trimester. The median of APACHE II score was 6 and severe AP accounted for 31.58% (12 cases). Primary diseases were absent in most cases (57.89%). The most common clinical presentations were abdominal pain (89.47%) and vomiting (68.42%). Pleural effusion and ascites were found only in the third trimester. Elevated white blood cell count, amylase and lipase were commonly found in biochemical examinations. Eleven cases required intensive care in ICU and 21 cases received caesarean section. There were 2 maternal deaths and 12 fetal losses including 4 abortions. It is concluded that AP is a rare entity in pregnancy. The incidence of pancreatitis increases with the gestational age. However, the severity is not necessarily related with the pregnancy trimesters. The diagnosis is based on clinical presentations, laboratory tests and imaging examinations. Although the treatment strategy of a pregnant woman with pancreatitis is similar to the general non-pregnant patient with AP, a multidisciplinary team consisting of gastroenterologist, gastrointestinal surgeon, radiologist, obstetrician, and ICU doctor should be set up.

[Effects of Tanshinone II A on the myocardial apoptosis and the miR-133 levels in rats with heart failure].

OBJECTIVE: To explore the effects of Tanshinone II A (Tan II A) on the myocardial apoptosis in rats with heart failure and its mechanisms for regulating the miR- 133 levels. METHODS: The heart failure rat model was established by thoracic aorta constriction (TAC). Tan II A Injection was applied for 12 successive weeks. Meanwhile, partial heart failure rats were subcutaneously implanted with osmotic pump of antagonist to observe its inhibition on the miR-133 level. Twelve weeks later, the hemodynamic conditions, the myocardial apoptosis (using TUENL method), myocardial pro-apoptotic genes (Bax and Caspase-3), and the expressions of anti-apoptosis genes (Bcl-2) (using Western blot and RT-PCR method) were analyzed. RESULTS: Compared with the sham-operation group, TAC operation could deteriorate the heart function (except the mean arterial pressure), elevate the myocardial apoptosis level, increase the protein and mRNA levels of Bax and Caspase-3, and down-regulate the protein and mRNA levels of miR-133 and Bcl-2. TAC rats treated by Tan II A could significantly improve all indices with statistical difference except the heart rate. Subcutaneously pumping of antagonist could partially abolish the anti-apoptosis effect of Tan II A. CONCLUSION: Tan II A could decrease the myocardial apoptosis level of heart failure rats, which was possibly realized by up-regulating the miR-133 level.

Effects of andrographolide on the activation of mitogen activated protein kinases and nuclear factor-κB in mouse peritoneal macrophage-derived foam cells.

OBJECTIVE: To observe the effect of andrographolide on the activation of mitogen-activated protein kinases (MAPKs) and expression of nuclear factor-κB (NF-κB) in macrophage foam cells. METHODS: The mouse peritoneal macrophages were cultured in the media in the presence of oxidized low-density lipoprotein (ox-LDL), ox-LDL+andrographolide, or neither (control). The phosphorylation of MAPK molecules (p38MAPK, JNK, ERK1/2) and the expressions of NK-κB p65 were examined by Western blot. RESULTS: As compared with cells in the control group, the expressions of phospho-p38 and NF-κB p65 were increased in the cells cultured with either ox-LDL or ox-LDL+andrographolide (P<0.01), but attenuated significantly in the presence of ox-LDL+ andrographolide when compared with ox-LDL (P<0.05). The phospho-JNK increased in the presence of either ox-LDL or ox-LDL+andrographolide when compared with control cells (P<0.01), but no significant difference existed between ox-LDL and ox-LDL+andrographolide (P>0.05). The expression of phospho-ERK1/2 was increased in the presence of ox-LDL compared with the control cells (P<0.01), but no significant differences existed between the cells cultured in the presence of ox-LDL+andrographolide and the control medium (P>0.05). CONCLUSIONS: Andrographolide could inhibit the activation of ERK1/2, p38MAPK and NK-κB induced by ox-LDL in macrophage foam cells, which might be one of its mechanisms in preventing atherosclerosis.

Effect of sodium tanshinone II A sulfonate on phosphorylation of extracellular signal-regulated kinase 1/2 in angiotensin II-induced hypertrophy of myocardial cells.

OBJECTIVE: To observe the effects of sodium tanshinone II A sulfonate (STS) on angiotensin II (Ang II)-induced hypertrophy of myocardial cells through the expression of phosphorylated extracellular signal-regulated kinase (p-ERK1/2). METHODS: In the primary culture of neonatal rat myocardial cells, the total protein content in myocardial cells was determined by coomassie brilliant blue and the protein synthesis rate was measured by [3H]-Leucine incorporation as indexes for hypertrophy of myocardial cells. The expression of p-ERK1/2 was determined using Western blot and immunofluorescence labeling. RESULTS: (1) The total protein and protein synthesis rate increased significantly in contrast to the control group after the myocardial cells were stimulated by Ang II (1 micromol/L) for 24 h; STS markedly inhibited the increment of the total protein level induced by Ang II and the syntheses of protein. (2) After pretreatment of myocardial cells with Ang II (1 micromol/L) for 5 min, the p-ERK1/2 protein expression was increased, with the most obvious effect shown at about 10 min; pretreatment of myocardial cells with STS at different doses (2, 10, 50 micromol/L) for 30 min resulted in obvious inhibition of the expression of p-ERK1/2 stimulated by Ang II in a dose-dependent manner. (3) After the myocardial cells were stimulated by Ang II (1 micromol/L), the immunofluorescence of ERK1/2 rapidly appeared in the nucleus. The activation and translocation process of ERK1/2 induced by Ang II was blocked distinctly by STS. CONCLUSION: STS inhibited the myocardial cell hypertrophy induced by Ang II, and the mechanism may be associated with the inhibition of p-ERK1/2 expression.