Dapagliflozin Improves Angiogenesis after Hindlimb Ischemia through the PI3K-Akt-eNOS Pathway.

Recently, the vascular protective effect of anti-diabetic agents has been receiving much attention. Sodium glucose cotransporter 2 (SGLT2) inhibitors had demonstrated reductions in cardiovascular (CV) events. However, the therapeutic effect of dapagliflozin on angiogenesis in peripheral arterial disease was unclear. This study aimed to explore the effect and mechanism of dapagliflozin on angiogenesis after hindlimb ischemia. We first evaluated the effect of dapagliflozin on post-ischemic angiogenesis in the hindlimbs of rats. Laser doppler imaging was used to detect the hindlimb blood perfusion. In addition, we used immunohistochemistry to detect the density of new capillaries after ischemia. The relevant signaling pathways of dapagliflozin affecting post-ischemic angiogenesis were screened through phosphoproteomic detection, and then the mechanism of dapagliflozin affecting post-ischemic angiogenesis was verified at the level of human umbilical vein endothelial cells (HUVECs). After subjection to excision of the left femoral artery, all rats were randomly distributed into two groups: the dapagliflozin group (left femoral artery resection, receiving intragastric feeding with dapagliflozin (1 mg/kg/d), for 21 consecutive days) and the model group, that is, the positive control group (left femoral artery resection, receiving intragastric feeding with citric acid-sodium citrate buffer solution (1 mg/kg/d), for 21 consecutive days). In addition, the control group, that is the negative control group (without left femoral artery resection, receiving intragastric feeding with citric acid-sodium citrate buffer solution (1 mg/kg/d), for 21 consecutive days) was added. At day 21 post-surgery, the dapagliflozin-treatment group had the greatest blood perfusion, accompanied by elevated capillary density. The results showed that dapagliflozin could promote angiogenesis after hindlimb ischemia. Then, the ischemic hindlimb adductor-muscle tissue samples from three rats of model group and dapagliflozin group were taken for phosphoproteomic testing. The results showed that the PI3K-Akt-eNOS signaling pathway was closely related to the effect of dapagliflozin on post-ischemic angiogenesis. Our study intended to verify this mechanism from the perspective of endothelial cells. In vitro, dapagliflozin enhanced the tube formation, migration, and proliferation of HUVECs under ischemic and hypoxic conditions. Additionally, the dapagliflozin administration upregulated the expression of angiogenic factors phosphorylated Akt (p-Akt) and phosphorylated endothelial nitric oxide synthase (p-eNOS), as well as vascular endothelial growth factor A (VEGFA), both in vivo and in vitro. These benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. dapagliflozin could promote angiogenesis after ischemia. This effect might be achieved by promoting the activation of the PI3K-Akt-eNOS signaling pathway. This study provided a new perspective, new ideas, and a theoretical basis for the treatment of peripheral arterial disease.

Vitamin D Supplementation during Intensive Care Unit Stay Is Associated with Improved Outcomes in Critically Ill Patients with Sepsis: A Cohort Study.

BACKGROUND: Vitamin D, as a common micronutrient, has been widely used in critically ill patients. However, whether supplementation of vitamin D in adult patients with sepsis can improve their prognosis remains controversial. METHODS: Data from the Mart for Intensive Care IV database was used in this retrospective cohort study, and adult patients with sepsis were enrolled. Critically ill patients, admitted to intensive care units (ICUs) between 2008 and 2019 at the Beth Israel Deaconess Medical Center (BIDMC), were divided into the vitamin D supplementation group and non-vitamin D supplementation group. The primary outcomes were defined as all-cause in-hospital, 28-day, and 90-day mortality rates after admission to the ICU. A 1:1 propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and overlap weighting (OW) analyses were used to minimize selection bias and balance the baseline demographic characteristics. Regression and survival analyses were performed to assess the association between vitamin D supplementation and clinical outcomes in patients with sepsis. RESULTS: In total, 3539 patients with sepsis were enrolled as study participants; of these, 315 were supplemented with vitamin D during their ICU stay. In-hospital, 28-day, and 90-day mortality rates were significantly lower in patients with sepsis supplemented with vitamin D. Multivariate regression analysis showed vitamin D supplementation as a potential protective factor for in-hospital mortality with an odds ratio (OR) = 0.70 (0.51-0.96) after adjusting for all confounders. The hazard ratios (HRs) for 28-day and 90-day mortality were 0.65 (0.50-0.85) and 0.70 (0.55-0.90), respectively. The survival analysis showed that the vitamin D supplementation group had a higher survival probability within 28 and 90 days (p-value < 0.05). These results remained relatively stable post PSM, IPTW, and OW. However, we found no evidence that vitamin D supplementation could shorten the length of stay in the ICU or hospital. CONCLUSIONS: Vitamin D supplementation during an ICU stay was associated with improved prognosis in patients with sepsis, as evidenced by lower in-hospital, 28-day, and 90-day mortality rates and lower disease severity-related scores, but showed no influence on the length of stay in the hospital or ICU.

Effects of ondansetron exposure during ICU stay on outcomes of critically ill patients with sepsis: a cohort study.

Background: Sepsis is a life-threatening disease with high morbidity and mortality, characterized by an inadequate systemic immune response to an initial stimulus. Whether the use of ondansetron (OND) during intensive care unit (ICU) stay is associated with the prognosis of sepsis patients remains unclear. Methods: Critically ill patients with sepsis were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Multivariate logistic regression and Cox regression analyses were used to explore the association between OND use and clinical outcomes after adjusting for confounders. Kaplan-Meier survival curve was used for survival analysis. Propensity score matching (PSM) and subgroup analysis were performed to further confirm the results. Results: The OND-medication group showed reduced in-hospital mortality, 28-day and 90-day mortalities. The OR for in-hospital mortality was 0.80 (0.64-0.99) and HRs for 28-day mortality and 90-day mortality were 0.77 (0.64-0.92) and 0.83 (0.70-0.98), respectively. After PSM, the clinical outcomes remained consistent. In-hospital mortality was lower in the OND-medication group (28.1% vs. 35.8%, P= 0.044), as well as 28-day mortality (23.4% vs. 32.1%, P=0.022) and 90-day mortality (27.4% vs. 35.8%, P=0.035). The protective effect of OND in sepsis patients was relatively robust, independent of age, septic shock, vasopressin and mechanical ventilation. Additionally, the OND users had longer lengths of stay in ICU (6.9(3.1-13.2) vs. 5.1(2.5-11.0), P = 0.026) while no statistical differences were found in lengths of stay in hospital (P = 0.333). Conclusion: OND exposure might be associated with lower in-hospital, 28-day, and 90-day mortality rates in critically ill patients with sepsis. This study indicated that OND might help improve the prognosis of patients with sepsis.

A Novel Composite Indicator of Predicting Mortality Risk for Heart Failure Patients With Diabetes Admitted to Intensive Care Unit Based on Machine Learning.

Background: Patients with heart failure (HF) with diabetes may face a poorer prognosis and higher mortality than patients with either disease alone, especially for those in intensive care unit. So far, there is no precise mortality risk prediction indicator for this kind of patient. Method: Two high-quality critically ill databases, the Medical Information Mart for Intensive Care IV (MIMIC-IV) database and the Telehealth Intensive Care Unit (eICU) Collaborative Research Database (eICU-CRD) Collaborative Research Database, were used for study participants' screening as well as internal and external validation. Nine machine learning models were compared, and the best one was selected to define indicators associated with hospital mortality for patients with HF with diabetes. Existing attributes most related to hospital mortality were identified using a visualization method developed for machine learning, namely, Shapley Additive Explanations (SHAP) method. A new composite indicator ASL was established using logistics regression for patients with HF with diabetes based on major existing indicators. Then, the new index was compared with existing indicators to confirm its discrimination ability and clinical value using the receiver operating characteristic (ROC) curve, decision curve, and calibration curve. Results: The random forest model outperformed among nine models with the area under the ROC curve (AUC) = 0.92 after hyper-parameter optimization. By using this model, the top 20 attributes associated with hospital mortality in these patients were identified among all the attributes based on SHAP method. Acute Physiology Score (APS) III, Sepsis-related Organ Failure Assessment (SOFA), and Max lactate were selected as major attributes related to mortality risk, and a new composite indicator was developed by combining these three indicators, which was named as ASL. Both in the initial and external cohort, the new indicator, ASL, had greater risk discrimination ability with AUC higher than 0.80 in both low- and high-risk groups compared with existing attributes. The decision curve and calibration curve indicated that this indicator also had a respectable clinical value compared with APS III and SOFA. In addition, this indicator had a good risk stratification ability when the patients were divided into three risk levels. Conclusion: A new composite indicator for predicting mortality risk in patients with HF with diabetes admitted to intensive care unit was developed on the basis of attributes identified by the random forest model. Compared with existing attributes such as APS III and SOFA, the new indicator had better discrimination ability and clinical value, which had potential value in reducing the mortality risk of these patients.

Beetroot as a functional food with huge health benefits: Antioxidant, antitumor, physical function, and chronic metabolomics activity.

Previously, beetroot is mainly consumed as a food additive. In recent years, the beetroot, especially the betalains (betanin) and nitrates it contains, now has received increasing attention for their effective biological activity. Betalains have been proven to eliminate oxidative and nitrative stress by scavenging DPPH, preventing DNA damage, and reducing LDL. It also has been found to exert antitumor activity by inhibiting cell proliferation, angiogenesis, inducing cell apoptosis, and autophagy. In some chronic diseases, nitrate is the main component for lowing blood lipids, glucose, and pressure, while its role in treating hypertension and hyperglycemia has not been clearly stated. Moreover, the intake of nitrate-rich beetroot could enhance athletic performance and attenuate muscle soreness in certain types of exercise. The objective of this review is to provide sufficient evidence for the clarification of health benefits of beetroot, especially in the aspect of biooxidation, neoplastic diseases, some chronic diseases, and energy supplementation.