Background: Chronic pain poses a significant public health challenge. We present the global and regional data on Prevalence, Incidence and Years Lived with Disability (YLDs) for Chronic pain from the Global burden of disease (GBD) study 2019 data and analyze their associations with Socio-demographic index (SDI), age, and gender, and the future trends from 2020 to 2035. Methods: Regional trends in the burden of chronic pain and its association with age, gender, and SDI were assessed from 1990 to 2019. Joinpoint analysis was employed to describe trends in chronic pain burden across different SDI regions. Additionally, the Bayesian Age-Period-Cohort model (BAPC) was used for predicting future trends. Age-standardized rates (ASRs) of prevalence, incidence, and YLDs were employed to quantify the burden of chronic pain. Results: Between 1990 and 2019, a significant increase was observed in global prevalence and YLDs rates of chronic pain. Higher rates were found among females, whereas a faster rise was noted among males. Notably, Low Back Pain (LBP) and Migraine accounted for predominant YLDs globally, particularly among those aged 75 and above. A notable prevalence of Tension-type Headache (TTH) was observed among younger populations. Furthermore, ASRs for chronic pain were highest in high-SDI regions. Projections suggest an increase in headache ASRs globally for both genders from 2020 to 2035. Conclusion: From 1990 to 2019, the global burden of chronic pain increased significantly, with projections indicating a continued rise in headache burden over the next 15 years, underscoring the need for heightened attention to these issues.

The death and disability caused by myocardial infarction is a health problem that needs to be addressed worldwide, and poor cardiac repair and fibrosis after myocardial infarction seriously affect patient recovery. Postmyocardial infarction repair by M2 macrophages is of great significance for ventricular remodeling. Quercitrin (Que) is a common flavonoid in fruits and vegetables that has antioxidant, anti-inflammatory, antitumor and other effects, but whether it has a role in the treatment of myocardial infarction is unclear. In this study, we constructed a mouse myocardial infarction model and administered Que. We found through cardiac ultrasound that Que administration improved cardiac ejection fraction and reduced ventricular remodeling. Staining of heart sections and detection of fibrosis marker protein levels revealed that Que administration slowed fibrosis after myocardial infarction. Flow cytometry showed that the proportion of M2 macrophages in the mouse heart was increased and that the expression levels of M2 macrophage markers were increased in the Que-treated group. Finally, we identified by metabolomics that Que reduces glycolysis, increases aerobic phosphorylation, and alters arginine metabolic pathways, polarizing macrophages toward the M2 phenotype. Our research lays the foundation for the future application of Que in myocardial infarction and other cardiovascular diseases.

Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T‐regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria‐associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4⁺CD25⁺Foxp3⁺ cells in whole blood cells and serum levels of IL‐4 and IL‐10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4⁺ T cells. Cultured medium from KB‐treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL‐4 and IL‐10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L‐carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L⁺ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL‐33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL‐4 and IL‐10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL‐33/ST2L signaling.

Background.: The aim of the present study was to investigate the therapeutic potential of metformin in preventing cyclosporine A (CsA)-induced nephrotoxicity. Methods.: Three groups of adult male Sprague-Dawley rats were treated with vehicle, CsA, and CsA + metformin for 4 weeks following 1 week on low sodium diet, respectively. At the end of treatment, all animals were euthanized, and the samples of kidney, urine, and blood were collected for functional, morphological, and molecular biological evaluation. Results.: Metformin effectively prevented CsA-induced renal dysfunction with increased creatinine clearance rate and reduced blood urea nitrogen and serum creatinine, as well as less proteinuria in comparison to the CsA group. Morphologically, metformin ameliorated CsA-induced renal fibrosis and tissue collapse in the areas of arteries, glomeruli, and proximal tubules. We further demonstrated that the antifibrotic effects of metformin in kidneys treated with CsA were associated with decreased phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). Conclusions.: In conclusion, our study revealed new therapeutic potential of metformin to attenuate calcineurin inhibitor-induced renal fibrosis, which was closely related to the suppression of MEK/ERK1/2 pathway.

Atherosclerosis (AS) is one of the most serious and common cardiovascular diseases affecting human health. AS is featured by the accumulation of plaques in vessel walls. The pathophysiology of AS is relevant in the low‐density lipoprotein (LDL) uptake by macrophages, as well as the conversion of macrophages to foam cells. However, the mechanisms about how macrophages regulate AS have not been fully elucidated. In this study, we aimed to illuminate the roles of ZBTB20 and to excavate the underlying regulative mechanisms of ZBTB20 in AS. The microarray analysis revealed that ZBTB20 was a hub gene in the oxidative stress and inflammatory responses induced by oxidized LDL (ox‐LDL) in AS. Correspondingly, our validation studies showed that ZBTB20 increased in either the human atherosclerotic lesion or the ox‐LDL‐stimulated macrophages. Moreover, the knockdown of ZBTB20 decreased M1 polarization, suppressed the proinflammatory factors, inhibited mitochondrial fission, and reduced the oxidative stress level of macrophages induced by ox‐LDL. The mechanistic studies revealed that the ZBTB20 knockdown suppressed NF‐κB/MAPK activation and attenuated the mitochondrial fission possibly via regulating the nucleus translocation of NRF2, a pivotal transcription factor on redox homeostasis. Our in vivo studies showed that the sh‐ZBTB20 adenovirus injection could reduce the progression of AS in apolipoprotein E‐deficient (ApoE^-/-) mice. All in all, these results suggested that ZBTB20 positively regulated the oxidative stress level, mitochondrial fission, and inflammatory responses of macrophages induced by ox‐LDL, and the knockdown of ZBTB20 could attenuate the development of AS in ApoE^-/- mice.

Background: Prevention is highly involved in reducing the incidence of post-thrombotic syndrome (PTS). We aimed to develop accurate models with machine learning (ML) algorithms to predict whether PTS would occur within 24 months.Materials and methods: The clinical data used for model building were obtained from the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis study and the external validation cohort was acquired from the Sun Yat-sen Memorial Hospital in China. The main outcome was defined as the occurrence of PTS events (Villalta score ≥5). Twenty-three clinical variables were included, and four ML algorithms were applied to build the models. For discrimination and calibration, F scores were used to evaluate the prediction ability of the models. The external validation cohort was divided into ten groups based on the risk estimate deciles to identify the hazard threshold.Results: In total, 555 patients with deep vein thrombosis (DVT) were included to build models using ML algorithms, and the models were further validated in a Chinese cohort comprising 117 patients. When predicting PTS within 2 years after acute DVT, logistic regression based on gradient descent and L1 regularization got the highest area under the curve (AUC) of 0.83 (95% CI:0.76–0.89) in external validation. When considering model performance in both the derivation and external validation cohorts, the eXtreme gradient boosting and gradient boosting decision tree models had similar results and presented better stability and generalization. The external validation cohort was divided into low, intermediate, and high-risk groups with the prediction probability of 0.3 and 0.4 as critical points.Conclusion: Machine learning models built for PTS had accurate prediction ability and stable generalization, which can further facilitate clinical decision-making, with potentially important implications for selecting patients who will benefit from endovascular surgery.