Low-intensity exercise training improves systolic function of heart during metastatic melanoma-induced cachexia in mice.

Cardiac dysfunction frequently emerges in the initial stages of cancer cachexia, posing a significant complication of the disease. Physical fitness is commonly recommended in these early stages of cancer cachexia due to its beneficial impacts on various aspects of the condition, including cardiac dysfunction. However, the direct functional impacts of exercise on the heart during cancer cachexia largely remain unexplored. In this study, we induced cancer cachexia in mice using a metastatic B16F10 melanoma model. Concurrently, these mice underwent a low-intensity exercise regimen to investigate its potential role in cardiac function during cachexia. Our findings indicate that exercise training can help prevent metastatic melanoma-induced muscle loss without significant alterations to body and fat weight. Moreover, exercise improved the melanoma-induced decline in left ventricular ejection fraction and fractional shortening, while also mitigating the increase in high-sensitive cardiac troponin T levels caused by metastatic melanoma in mice. Transcriptome analysis revealed that exercise significantly reversed the transcriptional alterations in the heart induced by melanoma, which were primarily enriched in pathways related to heart contraction. These results suggest that exercise can improve systolic heart function and directly influence the transcriptome of the heart during metastatic melanoma-induced cachexia.

CD163 protein inhibits lipopolysaccharide-induced macrophage transformation from M2 to M1 involved in disruption of the TWEAK-Fn14 interaction.

Macrophages play a crucial role in regulating inflammation and innate immune responses, and their polarization into distinct phenotypes, such as M1 and M2, is involved in various diseases. However, the specific role of CD163, a scavenger receptor expressed by macrophages, in the transformation of M2 to M1 macrophages remains unclear. Here, dexamethasone-induced M2 macrophages were treated with lipopolysaccharide (LPS) to induce the transformation of M2 to M1 macrophages. We found that treatment with lipopolysaccharide (LPS) induced the transformation of M2-like macrophages to an M1-like phenotype, as evidenced by increased mRNA levels of Il1b and Tnf, decreased mRNA levels of Cd206 and Il10, and increased TNF-α secretion. Knockdown of CD163 enhanced the phenotypic features of M1 macrophages, while treatment with recombinant CD163 protein (rmCD163) inhibited the LPS-induced M2-to-M1 transformation. Furthermore, LPS stimulation resulted in the activation of P38, ERK, JNK, and NF-κB P65 signaling pathways, and this activation was increased after CD163 knockdown and suppressed after rmCD163 treatment during macrophage transformation. Additionally, we observed that LPS treatment reduced the expression of CD163 in dexamethasone-induced M2 macrophages, leading to a decrease in the CD163-TWEAK complex and an increase in the interaction between TWEAK and Fn14. Overall, our findings suggest that rmCD163 can inhibit the LPS-induced transformation of M2 macrophages to M1 by disrupting the TWEAK-Fn14 interaction and modulating the MAPK-NF-κB pathway.

San-wei-tan-xiang capsule attenuates atherosclerosis by increasing lysosomal activity in adipose tissue macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Dyslipidemia is the leading risk factor of atherosclerosis (AS). Adipose tissue macrophages (ATMs) can regulate postprandial cholesterol levels via uptake and hydrolyzation of lipids and regulation of macrophage cholesterol efflux (MCE). San-wei-tan-xiang (SWTX) capsule, a Traditional Chinese medicine, exerts clinical benefits in patients with atherosclerotic cardiovascular diseases. AIM OF THE STUDY: This work is aimed to evaluate the chemical ingredients and mechanisms of SWTX in anti-AS. MATERIALS AND METHODS: The chemical ingredients of SWTX identified by liquid chromatography coupled with tandem mass spectrometry were used for network pharmacological analysis. The atheroprotective function of SWTX was evaluated in ApoE-/- mice fed a cholesterol-enriched diet. RESULTS: The chemical ingredients identified in SWTX were predicated to be important for lipid metabolism and AS. Animals studies suggested that SWTX effectively attenuated the atherosclerotic plaque growth, elevated postprandial HDL cholesterol levels, elevated the proportion of Tim4 and CD36-expressed ATMs, and upregulated the uptake of lipid and lysosomal activity in ATMs. SWTX-induced elevation of postprandial HDL cholesterol levels was dependent on increased lysosomal activity, since chloroquine, an inhibitor of lysosomal function, blocked the effect of SWTX. Lastly, some predicated bioactive compounds in SWTX can elevate lysosomal activity in vitro. CONCLUSION: SWTX could attenuate atherosclerotic plaque formation by elevating lysosomal activity and enhancing MCE in ATMs.

Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction.

High levels of lactate are positively associated with the prognosis and mortality in patients with heart attack. Endothelial-to-mesenchymal transition (EndoMT) plays an important role in cardiac fibrosis. Here, we report that lactate exerts a previously unknown function that increases cardiac fibrosis and exacerbates cardiac dysfunction by promoting EndoMT following myocardial infarction (MI). Treatment of endothelial cells with lactate disrupts endothelial cell function and induces mesenchymal-like function following hypoxia by activating the TGF-ß/Smad2 pathway. Mechanistically, lactate induces an association between CBP/p300 and Snail1, leading to lactylation of Snail1, a TGF-ß transcription factor, through lactate transporter monocarboxylate transporter (MCT)-dependent signaling. Inhibiting Snail1 diminishes lactate-induced EndoMT and TGF-ß/Smad2 activation after hypoxia/MI. The MCT inhibitor CHC mitigates lactate-induced EndoMT and Snail1 lactylation. Silence of MCT1 compromises lactate-promoted cardiac dysfunction and EndoMT after MI. We conclude that lactate acts as an important molecule that up-regulates cardiac EndoMT after MI via induction of Snail1 lactylation.

Association Between Serum Uric Acid Levels and Traditional Cardiovascular Risk Factors in Xiamen Residents of China: A Real-World Study.

Background: Serum uric acid (SUA) levels was associated with cardiovascular diseases and cardiovascular events. However, the relationship between SUA levels and traditional cardiovascular risk factors has not been well-established among Xiamen residents. Our study aimed to estimate the relationship between SUA levels and cardiovascular risk factors among Xiamen residents using real-world data. Methods: Participants were enrolled from eight community health service centers in Xiamen, China. Participants were divided into four groups according to quartiles of the SUA levels. The history of diseases, the use of medications and the levels of laboratory parameters were collected. The China-PAR equation was used to evaluate the 10-year atherosclerotic cardiovascular disease (ASCVD) risk. Results: A total of 1,322 participants were enrolled. About 568 (43.0%) were men and 754 (57.0%) were women. The prevalences of hypertension, elderly, current smokers, and obesity were higher in the quartile 4 (Q4) group than the quartile 1 (Q1) group (all p < 0.001). Multivariable logistic regression analysis showed the OR for hypertension was 2.671 (95% CI 1.777-4.015, p < 0.001) in the Q4 group compared with that in the Q1 group. Further logistic regression showed the OR for hypertension was 3.254 (95% CI 1.756-6.031, p < 0.001) in men and 2.314 (95% CI 1.354-3.955, p = 0.002) in women in the Q4 group compared with that in the Q1 group, respectively. In addition, the percentage of participants with low 10-year ASCVD risk calculated by China-PAR was higher in the Q1 group than that in the Q4 group (55.86 vs. 31.82%, p < 0.001). The percentage of participants with high 10-year ASCVD risk was lower in the Q1 group compared with the Q4 group (15.32 vs. 25.45%, p < 0.001). Multiple linear logistic regression showed the 10-year China-PAR ASCVD risk scores was positively correlated with SUA after adjusting for various factors (ß = 0.135, p = 0.001). Conclusion: Serum uric acid was associated with several cardiovascular risk factors in Xiamen residents. The percentage of high 10-year ASDVD risk was higher in participants with hyperuricemia. Participants with hyperuricemia may experience cardiovascular benefit from uric acid-lowering therapy.

The Efficacy and Safety of Phase I Cardiac Rehabilitation in Patients Hospitalized in Cardiac Intensive Care Unit With Acute Decompensated Heart Failure: A Study Protocol for a Randomized, Controlled, Clinical Trial.

Background: Cardiac rehabilitation (CR) improves outcomes in patients with heart failure. However, data on CR efficacy in patients with acute decompensated heart failure is limited. This study is designed to assess the efficacy and safety of CR in patients hospitalized in cardiac intensive care unit (CICU) with acute decompensated heart failure (ADHF). Methods: This is a single-center, randomized controlled, single-blind clinical trial. A total of 120 participants hospitalized in CICU with ADHF will be randomly allocated in the ratio of 1:1 to two groups: CR group and control group. Participants will receive tailored and progressive CR intervention or attention control. The CR intervention include personalized breathing training, small muscle group resistance training, and aerobic endurance training based on the physical fitness assessment results. The subjects will receive the CR training for 5 days and will be followed up for 6 months. The primary endpoints are the score of the short physical performance battery (SPPB) and 6-month all-cause rehospitalization. The secondary endpoints include cardio-pulmonary function, activities of daily living (ADL), in-hospital mortality rate and 6-month all-cause mortality rate. Discussion: This randomized, controlled, clinical trial will assess whether CR improves physical function and reduces rehospitalization in patients hospitalized in CICU with ADHF. The results will provide further research-based evidence for the clinical application of CR in patients with ADHF. Trial Registration: Chinese Clinical Trial Registry ChiCTR2100050151. Registered on 19 August 2021.

A Novel Nomogram for Predicting Morbidity Risk in Patients with Secondary Malignant Neoplasm of Bone and Bone Marrow: An Analysis Based on the Large MIMIC-III Clinical Database.

Objective: Bone and bone marrow are the third most frequent sites of metastases from many cancers and are associated with low survival and high morbidity rates. Currently, there are no effective bedside tools to predict the morbidity risk of these patients in general intensive care units (ICUs). The main objective of this study was to establish and validate a nomogram to predict the morbidity risk of patients with bone and bone marrow metastases. Methods: Data on patients with bone and bone marrow metastases were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The patients were divided into training and validation cohorts. The data were analyzed using univariate and multivariate Cox regression methods. Factors significantly and independently prognostic of survival were used to construct a nomogram predicting 30-day morbidity. The nomogram was validated by various methods, including Harrell's concordance index (C-index), area under the receiver operating characteristic curve (AUC), calibration curve, integrated discrimination improvement (IDI), net reclassification index (NRI), and decision curve analysis (DCA). Results: The study included 610 patients in the training cohort and 262 in the validation cohort. Multivariate Cox regression analysis showed that temperature, SpO2, Sequential Organ Failure Assessment (SOFA) score, Oxford Acute Severity of Illness Score (OASIS), comorbidities with coagulopathy, white blood cell count, heart rate, and respiratory rate were independent predictors of patient survival. The resulting nomogram had good discriminative ability, as shown by high AUCs, and was well calibrated, as demonstrated by calibration curves. Improvements in NRI and IDI values suggested that the nomogram was superior to the SOFA scoring system. DCA curves revealed that the nomogram showed good value in clinical applications. Conclusion: This prognostic nomogram, based on demographic and laboratory parameters, was predictive of the 30-day morbidity rate in patients with secondary malignant neoplasms of the bone and bone marrow, suggesting its applicability in clinical practice.

Emerging roles of sortilin in affecting the metabolism of glucose and lipid profiles.

Dyslipidemia has recently been identified as an important factor in modulating the progression of several health conditions, grouped as cardio-metabolic syndrome and including obesity,insulin resistance, and atherosclerosis. Among multiple factors which regulate the development of cardio-metabolic syndrome, sortilin has been found in multiple cell types, such as adipocyte, hepatocyte, and macrophage, suggesting that sortilin is correlated to the development and the severity of cardio-metabolic syndrome. Consistently, several genome-wide association  (GWAS) and basic experimental research studies are being conducted to find novel gene loci involved in regulating the pathological progression of cardio-metabolic syndrome. According to these data, both SORT1 gene and sortilin protein have an important function in regulating the circulating lipid and glucose metabolism resulting in modulation of disease progression. In this comprehensive review, we summarize the recent research results in regards to sortilin function in modulating the circulating lipid and glucose metabolism. Moreover, we also discuss and analyze the emerging evidence elucidating the potential mechanisms by which sortilin affects synthesis and secretion of lipid and glucose.