A new nomogram to predict in-hospital mortality in patients with acute decompensated chronic heart failure and diabetes after 48 Hours of Intensive Care Unit.

BACKGROUND: The study set out to develop an accurate and clinically valuable prognostic nomogram to assess the risk of in-hospital death in patients with acute decompensated chronic heart failure (ADCHF) and diabetes. METHODS: We extracted clinical data of patients diagnosed with ADCHF and diabetes from the Medical Information Mart for Intensive Care III database. Risk variables were selected utilizing least absolute shrinkage and selection operator regression analysis, and were included in multivariate logistic regression and presented in nomogram. bootstrap was used for internal validation. The discriminative power and predictive accuracy of the nomogram were estimated using the area under the receiver operating characteristic curve (AUC), calibration curve and decision curve analysis (DCA). RESULTS: Among 867 patients with ADCHF and diabetes, In-hospital death occurred in 81 (9.3%) patients. Age, heart rate, systolic blood pressure, red blood cell distribution width, shock, ß-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, assisted ventilation, and blood urea nitrogen were brought into the nomogram model. The calibration curves suggested that the nomogram was well calibrated. The AUC of the nomogram was 0.873 (95% CI: 0.834-0.911), which was higher that of the Simplified Acute Physiology Score II [0.761 (95% CI: 0.711-0.810)] and sequential organ failure assessment score [0.699 (95% CI: 0.642-0.756)], and Guidelines-Heart Failure score [0.782 (95% CI: 0.731-0.835)], indicating that the nomogram had better ability to predict in-hospital mortality. In addition, the internally validated C-index was 0.857 (95% CI: 0.825-0.891), which again verified the validity of this model. CONCLUSIONS: This study constructed a simple and accurate nomogram for predicting in-hospital mortality in patients with ADCHF and diabetes, especially in those who admitted to the intensive care unit for more than 48 hours, which contributed clinicians to assess the risk and individualize the treatment of patients, thereby reducing in-hospital mortality.

Echinacoside ameliorates doxorubicin­induced cardiac injury by regulating GPX4 inhibition­induced ferroptosis.

Echinacoside (ECH) is a compound derived from the natural herbs Cistanche and Echinacea, which has considerable protective effects on heart failure (HF). HF is characterized by myocardial damage and abnormal ferroptosis. Glutathione peroxidase 4 (GPX4) is an important regulator of ferroptosis, which plays a role in ferroptosis-related diseases. Despite this, the therapeutic mechanisms of ECH against HF remain unknown. Therefore, the aim of the present study was to investigate the cardioprotective effect and underlying mechanisms of ECH in the treatment of doxorubicin (DOX)-induced chronic HF (CHF). Cell proliferation was assessed using a CCK-8 assay. Furthermore, cardiac cell injury and oxidative stress were determined by measuring the lactate dehydrogenase (LDH), malondialdehyde (MDA), and glutathione (GSH) levels. The levels of Fe2+ and lipid reactive oxygen species (ROS), and expression of the biomarkers of ferroptosis, including GPX4 and prostaglandin-endoperoxide synthase 2 (PTGS2), were measured to examine cardiomyocyte ferroptosis. Additionally, RNA interference was used to silence Gpx4. In vitro and in vivo, ECH considerably reduced the MDA and LDH levels and increased the GSH level, thereby attenuating DOX-induced cardiac injury and oxidative stress. Meanwhile, ECH treatment decreased the lipid ROS levels and PTGS2 expression while increasing GPX4 expression, thereby alleviating DOX-induced cardiomyocyte ferroptosis. Moreover, knockdown of Gpx4 inhibited the protective effects of ECH on DOX-induced accumulation of lipid ROS in cardiomyocytes. These findings indicate that ECH can reduce DOX-induced cardiac injury by inhibiting ferroptosis via GPX4, highlighting its value as a potentially valuable therapeutic target in the management of CHF.

Mechanism of new coronavirus pneumonia agreement prescription on 2019 novel coronavirus-infected pneumonia based on network pharmacology analysis and the validation.

PURPOSE: To investigate the mechanism of action underlying the effective treatment of New Coronavirus Pneumonia Agreement Prescription (NCPAP) on 2019 Novel Coronavirus-Infected Pneumonia (2019-NCIP) using network pharmacology. METHODS: In this retrospective study, 50 patients with 2019-NCIP were recruited, including 16 who received symptomatic treatment and 34 that received NCPAP formula treatment on the basis of symptomatic treatment. Hospitalization and lymphocyte percentages were served as efficacy evaluation indicators. Moreover, pharmacological analysis was performed to identify the target disease of NCPAP. Active ingredients in herbs were screened using the Traditional Chinese Medications Systems Pharmacology (TCMSP) database, and related target genes were identified. We then queried therapeutic target data for coronavirus-associated genes. The protein-protein interaction network was constructed to examine the relationships between these targets. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) network enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. RESULTS: NCPAP significantly reduced hospitalization time and increased both the absolute value and percentage of lymphocytes. Bioinformatics and cytokine analysis suggested that preventing cytokine storm syndrome and regulating immune response are the key mechanisms of NCPAP in treating 2019-NCIP. CONCLUSIONS: The possible mechanisms of NCPAP in the treatment of 2019-NCIP are reduction of cytokine storms and regulation of the immune response.

Tongxinluo promotes endothelium-dependent arteriogenesis to attenuate diabetic peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) has become one of the leading causes of disa-bility and death in diabetic patients. Restoring blood supply to the hindlimbs, especially by promoting arteriogenesis, is currently the most effective strategy, in which endothelial cells play an important role. Tongxinluo (TXL) has been widely used for the treatment of cardio-cerebrovascular diseases and extended for diabetes-related vascular disease. AIM: To investigate the effect of TXL on diabetic PAD and its underlying mechanisms. METHODS: An animal model of diabetic PAD was established by ligating the femoral artery of db/db mice. Laser Doppler imaging and micro-computed tomography (micro-CT) were performed to assess the recovery of blood flow and arteriogenesis. Endothelial cell function related to arteriogenesis and cellular pyroptosis was assessed using histopathology, Western blot analysis, enzyme-linked immuno-sorbent assay and real-time polymerase chain reaction assays. In vitro, human vascular endothelial cells (HUVECs) and human vascular smooth muscle cells (VSMCs) were pretreated with TXL for 4 h, followed by incubation in high glucose and hypoxia conditions to induce cell injury. Then, indicators of HUVEC pyroptosis and function, HUVEC-VSMC interactions and the migration of VSMCs were measured. RESULTS: Laser Doppler imaging and micro-CT showed that TXL restored blood flow to the hindlimbs and enhanced arteriogenesis. TXL also inhibited endothelial cell pyroptosis via the reactive oxygen species/nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3/Caspase-1/GSDMD signaling pathway. In addition, TXL restored endothelial cell functions, including maintaining the balance of vasodilation, acting as a barrier to reduce inflammation, and enhancing endothelial-smooth muscle cell interactions through the Jagged-1/Notch-1/ephrin-B2 signaling pathway. Similar results were observed in vitro. CONCLUSION: TXL has a pro-arteriogenic effect in the treatment of diabetic PAD, and the mechanism may be related to the inhibition of endothelial cell pyroptosis, restoration of endothelial cell function and promotion of endothelial cell-smooth muscle cell interactions.

Estrogen-Like Effect of Bazi Bushen Capsule in Ovariectomized Rats.

This study aims to show the estrogen-like effect of Bazi Bushen capsule (BZBS), a Chinese herbal compound, in ovariectomized mice. Female Sprague-Dawley (SD) rats were randomly divided into six groups: a sham-operated group, a model group (OVX), a progynova group, and BZBS groups (1, 2, and 4 d/kg/d). An ovariectomy was performed on all rats except those in the sham-operated group. Micro-computed tomography (micro-CT) scanning, hematoxylin and eosin (H&E) staining, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) detection were performed after 4 months of BZBS treatment. As a result, compared with the OVX group, rats treated with BZBS showed an increased number and area of trabecular bone and bone marrow cells, and a decreased number of adipose cells. The bone volume, trabecular number, and trabecular thickness of the right tibia in the medication groups increased and the trabecular space decreased. The 17ß-estradiol and serum calcium levels in the medication groups were elevated, but the levels of serum phosphorus, sclerostin, ß-CTX, and TRACP-5b were decreased. In the medication groups, the RANKL and sclerostin levels were decreased, while the osteoprotegerin (OPG) level was increased. In conclusion, this protocol systematically evaluated the therapeutic effects and potential molecular mechanisms of Chinese herbal compounds in ovariectomized rats with a variety of techniques.

Shensong Yangxin Capsule Reduces the Susceptibility of Arrhythmia in db/db Mice via Inhibiting the Inflammatory Response Induced by Endothelium Dysfunction.

Purpose: The aim of our study was to investigate the mechanism by which the Chinese compound Shensong Yangxin Capsule (SSYX) reduces susceptibility to arrhythmia in db/db mice. Methods: The db/db mice without drug treatment served as the model group. Other-treated db/db mice were administered SSYX for 8 weeks. Electrocardiogram (ECG), electrical mapping, pathological changes, immunofluorescence staining, real-time quantitative PCR, and Western blot analyses were then conducted. Results: SSYX decreased arrhythmia susceptibility and shortened the abnormal ECG parameters of db/db mice. Meanwhile, SSYX restored irregular conduction direction and shortened the conduction time of the isolated heart. HE and Masson staining showed that SSYX alleviated inflammatory infiltration and collagen fiber deposition. Western blot showed that SSYX decreased the protein expression of ICAM-1, VCAM-1, and MCP-1 and increased the protein expression of occludin, ZO-1, eNOS, and Cx43. SSYX also increased the content of NO, decreased ET-1, TNF-α, IL-1ß, IL-6, MCP-1, and CCR-2 mRNA expression, and increased Kv 4.2, Kv 4.3, Cav 1.2, and Nav 1.5 mRNA expression. Furthermore, SSYX decreased the fluorescence intensity of F4/80 and iNOS, increased the fluorescence intensity of CD31 and eNOS, and improved the Cx43 and α-actinin connection structure in cardiac tissues. The above therapeutic effects of SSYX were inhibited by L-NAME. Conclusion: SSYX reduced the susceptibility of db/db mice to arrhythmia by inhibiting the inflammatory response and macrophage polarization, and this effect of SSYX occurred through protection of endothelial cell function.

METTL14 promotes doxorubicin-induced cardiomyocyte ferroptosis by regulating the KCNQ1OT1-miR-7-5p-TFRC axis.

Doxorubicin (DOX) has toxic effects on the heart, causing cardiomyopathy and heart injury, but the underlying mechanisms of these effects require further investigation. This study investigated the role of DOX in promoting ferroptosis to induce myocardial injury. AC16 cardiomyocyte and neonatal rat ventricle cardiomyocytes were used as an in vitro model to study the molecules involved in myocardial injury using gene silencing, ectopic expression, and RNA immunoprecipitation. Messenger RNA and protein level analyses showed that DOX treatment resulted in the upregulation of methyltransferase-like 14 (METTL14), which catalyzes the m6A modification of the long non-coding RNA KCNQ1OT1, a miR-7-5p sponge. The RNA-binding protein IGF2BP1 is associated with KCNQ1OT1 to increase its stability and robustly inhibit miR-7-5p activity. Furthermore, a lack of miR-7-5p expression led to increased levels of transferrin receptor, promoting the uptake of iron and production of lipid reactive oxygen species and demonstrating that DOX-induced ferroptosis occurs in AC16 cells. Additionally, we found that miR-7-5p targets METTL14 in AC16 cells. Meanwhile, the role of METTL14/KCNQ1OT1/miR-7-5p axis in regulating ferroptosis in neonatal rat ventricle cardiomyocytes was also confirmed. Our results indicate that selectively inhibiting ferroptosis mediated by a METTL14/KCNQ1OT1/miR-7-5p positive feedback loop in cardiomyocytes could provide a new therapeutic approach to control DOX-induced cardiac injury.

Research on the Influence of Combustion Methods on NO x Emissions from Co-combustion of Various Tannery Wastes.

To further increase combustion efficiency and reduce nitrogen oxide pollution caused by tannery wastes, three raw materials, including tannery sludge, chrome-tanned buffing dust, and chrome shavings, were burned together in a dual-bed model reactor under various conditions. In addition, a thermogravimetric analysis of co-combustion of three tannery wastes was studied in this study, which was conducive to understanding the combustion characteristics and positive effects. The comprehensive combustibility index S, the flammability index K r, and the stable combustion characteristic index G b all increased when the tannery sludge was blended with chrome-tanned buffing dust and chrome shavings, indicating that the combustion behavior was improved by co-combustion. For normal combustion, decreasing the gas volume flow and temperature resulted in a decrease in the oxidation of nitrogen compounds, consequently lowering the NO x emission. During air staged combustion, at an appropriate secondary gas ratio of about 10-40%, the NO x reduction would be increased from 10.9 to 19.3%. By increasing the tertiary gas volume flow from 0.2 to 1.1 L/min in decoupling combustion, an average relative NO x reduction efficiency of 47% was attained compared with normal combustion. The results offered a viable technology that resulted in a lower NO x emission and realized the application of decoupling combustion.

SYVN1/GPX5 axis affects ischemia/reperfusion induced apoptosis of AC16 cells by regulating ROS generation.

Ischemia/reperfusion (I/R) induced injury is a major cause of coronary heart disease (CHD). Increased production of reactive oxygen species (ROS) can lead to an I/R injury in CHD, and the ROS level can be regulated by Glutathione peroxidase (GPX) enzyme family. In this study, we investigated the role and underlying molecular mechanism of GPX5 in I/R-induced AC16 cells. We found that the serum level of GPX5 was down-regulated in patients with CHD and I/R-induced AC16 cells. Overexpression of GPX5 inhibited I/R-induced apoptosis by suppressing the production of ROS. On the other hand, knock-down of GPX5 promoted apoptosis in AC16 cells by up-regulating the level of ROS. Furthermore, we found that GPX5 was regulated by synovial apoptosis inhibitor 1 (SYVN1)-mediated ubiquitination in AC16 cells. In I/R-induced AC16 cells, the expression of SYVN1 was up-regulated, and SYVN1 knock-down decreased the ROS levels and apoptotic rate but increased GPX5 levels. Moreover, GPX5 knockdown promoted ROS production and apoptosis, while its effects were attenuated by SYVN1 knockdown. Furthermore, SYVN1 was up-regulated while GPX5 was down-regulated in the myocardial tissue of I/R-injured rats. Taken together, our data demonstrate that GPX5 inhibits I/R-induced apoptosis of AC16 cells by down-regulating ROS level, and its stabilization is regulated by SYVN1-mediated ubiquitination.

Dexmedetomidine attenuates one-lung ventilation associated lung injury by suppressing inflammatory responses: A systematic review and meta-analysis.

One-lung ventilation (OLV), a common ventilation technique, is associated with perioperative lung injury, tightly connected with inflammatory responses. Dexmedetomidine has shown positive anti-inflammatory effects in lung tissues in pre-clinical models. This study investigated the efficacy of dexmedetomidine for suppressing inflammatory responses in patients requiring OLV. We searched PubMed, MEDLINE, Embase, Scopus, Ovid, and Cochrane Library for randomized controlled trials focusing on dexmedetomidine's anti-inflammatory effects on patients requiring OLV without any limitation on the year of publication or languages. 20 clinical trials were assessed with 870 patients in the dexmedetomidine group and 844 in the control group. Our meta-analysis investigated the anti-inflammatory property of dexmedetomidine perioperatively [T1 (30-min OLV), T2 (90-min OLV), T3 (end of surgery) and T4 (postoperative day 1)], demonstrating that dexmedetomidine's intraoperative administration resulted in a significant reduction in serum concentration of interleukin-6, tumor necrosis factor-α and other inflammatory cytokines perioperatively. By calculating specific I2 index, significant heterogeneity was observed on all occasions, with I2 index ranging from 95% to 99%. For IL-6 changes, sensitivity analysis showed that the exclusion of a single study led to a significant decrease of heterogeneity (96%-0%; p < 0.00001). Besides, pulmonary oxygenation was ameliorated in the dexmedetomidine group comparing with the control group. In conclusion, perioperative administration of dexmedetomidine can attenuate OLV induced inflammation, ameliorate pulmonary oxygenation, and may be conducive to a decreased occurrence of postoperative complications and better prognosis. However, the results should be prudently interpreted due to the evidence of heterogeneity and the limited number of studies.

WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA.

Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP's effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.

Preparation of Nanocomposite Peptide and Its Inhibitory Effect on Myocardial Injury in Type-II Diabetic Rats.

Complications of diabetes are the main cause of death and disability in diabetic patients. Cardiovascular diseases, especially diabetic cardiomyopathy, are one of the major complications and causes of death in type 2 diabetes. Peptide drugs have a better effect on improving cellular oxidative damage, reducing tissue inflammation and inhibiting intracellular calcium overload. The application of nanotechnology to the preparation of peptide drugs and myocardial injury can effectively improve myocardial stun, arrhythmia and myocardial systolic dysfunction in patients with type 2 diabetes. The use of nanotechnology to develop more stable Glucagon-like peptide 1 analogues or sustained-release preparations, improve patient compliance and improve the efficacy of diabetes, is of great significance for the prevention and treatment of diabetic cardiomyopathy. Therefore, this study used nanotechnology to prepare PLGA-GLP-1 nanoparticles using polyglycolic acid glycolic acid as a drug carrier, which achieved long-acting drug and its morphology by transmission electron microscopy. At the same time, this study explored the anti-cardiomyocyte injury and anti-myocardial damage of PLGA-GLP-1 nanocomposite peptide and its molecular mechanism by using animal models and cell models. Experimental studies have shown that PLGA-GLP-1 nanocomposite peptide has a protective effect on myocardial injury in diabetic rats. Its mechanism is related to the PLGA-GLP-1 nanocomposite peptide enhancing the body's antioxidant capacity, anti-cardiomyocyte apoptosis, and promoting mitochondrial DNA repair in cardiomyocytes.