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ObjectiveOur previous results have shown that obesity-induced excessive palmitic acid (PA) can promote the expression of KLF7, which plays a vital role in regulation of inflammation, glucose metabolism. But the exact mechanism of PA up-regulating the expression of KLF7 is not clear yet. This study is intend to explore whether PA promoting KLF7 expression through GPRs/NF-κB signaling pathway, causing inflammation and glucose metabolism disorders.MethodsCells were blocked GPRs/NF-κB under PA stimulation in vitro to demonstrate the molecular mechanism of PA up-regulates KLF7 expression. The regulatory effect of p65 on KLF7 was detected by luciferase reporter gene assay. Blocking GPRs/NF-κB in diet-induced obesity mice to detect the expression of KLF7, inflammatory cytokines and glucose metabolism related factors, clarifying the effects of GPRs/NF-κB on KLF7 in vivo.ResultsIn 3T3-L1 adipocytes and HepG2 cells, PA could up-regulate the expression of KLF7 by promoting the GPR40/120-NF-κB signaling pathway, leading to inflammation and reduced glucose consumption (p < 0.05 for both). Luciferase reporter gene assay and ChIP assay showed that p65 could transcriptionally up-regulates the expression of KLF7. In high-fat diet (HFD) mice, after intraperitoneal injection of GPR40 or GPR120 blocker, the levels of p-p65 and KLF7 in epididymal white adipose tissue and liver were significantly decreased (p < 0.05 for both). Pharmacological inhibition of p-p65 significantly attenuated KLF7 expression and improved glucose tolerant and insulin sensitive (p < 0.05 for both).ConclusionsOur results indicate that obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 signaling pathway.

Prostate cancer (PCa) continues to be the most common, noncutaneous cancer in men. Bone is the most frequent site of PCa metastases, and up to 90% of patients with advanced PCa develop bone metastases. An altered bone marrow microenvironment, induced by obesity, is a significant mediator for the bone tropism of PCa. However, the specific molecular mechanisms by which obesity causes changes in the bone marrow microenvironment, leading to PCa bone metastasis, are not fully understood. Our results demonstrate that a high‐fat diet (HFD) leads to dyslipidemia and changes in bone marrow of nude mice: an increase in the area and number of adipocytes and a reduction in the area and number of osteoblasts. Moreover, a HFD promoted cyclooxygenase 2 (COX2) expression and inhibited osteoprotegerin (OPG) expression in the bone microenvironment. Additionally, the total level of free fatty acids (FFAs) and caprylic acid (C8:0) was significantly higher in PCa patients with bone metastases. In vitro, caprylic acid (C8:0) promoted bone mesenchymal stem cell (MSC)‐derived adipocytic differentiation, COX2 expression, and prostaglandin E2 (PGE2) secretion, whereas osteoblastic differentiation and OPG expression were reduced. Furthermore, caprylic acid (C8:0)‐treated adipocytes promoted the invasion and migration of PCa cells. Taken together, our findings suggest caprylic acid (C8:0) promotes bone metastasis of PCa by dysregulated adipo‐osteogenic balance of bone marrow. Obesity‐induced high level of free fatty acids could change the bone marrow microenvironment that provides \"fertile soil\" for bone metastasis of prostate cancer. It was found for the first time that increased caprylic acid (C8:0) could promote the area and number of adipocytes and the level of cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) in the bone marrow cavity, which causes prostate cancer bone metastasis.

Background Glucocorticoids (GCs) are the most important and frequently used class of anti‐inflammatory drugs. However, the mechanisms underlying excessive glucocorticoid‐mediated induction of muscle atrophy remain incompletely understood. Methods We generated skeletal muscle‐specific Klf9 transgenic mice (mKlf9TG) and skeletal muscle‐specific Klf9 knockout mice (Klf9mlc−/−). The body weight, tissue weight, body composition, grip strength, running distance and muscle fibre cross section of mKlf9TG, Klf9mlc−/− mice and their littermate controls were examined. Expression of genes related to muscle protein synthesis and degradation pathways were also tested in the mKlf9TG mice, Klf9mlc−/− mice and their littermate controls. We performed Klf9 gain‐ or loss‐of‐function studies in differentiated C2C12 myotubes using lentiviruses encoding Klf9 or the shRNA specific to Klf9 in vitro. Luciferase reporter gene assay and ChIP assay were performed to explore the molecular mechanism of Klf9 action. Klf9mlc−/− and Klf9fl/fl mice were treated with dexamethasone (Dex). Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the Dex/Klf9‐ediated skeletal muscle wasting. Results Skeletal muscle Klf9 gene expression was significantly upregulated by Dex (p < 0.05 or p < 0.01 vs. vehicle group). Compared with littermate control mice (R‐loxP), mKlf9TG mice exhibited decreased skeletal muscle mass (TA 0.101 ± 0.018 vs. 0.040 ± 0.007 g, p < 0.001) and impaired grip strength (forelimb 157.4 ± 3.7 vs. 93.45 ± 9.8 and four limbs 255.3 ± 23.1 vs. 170.1 ± 36.2, p < 0.001). Conversely, compared with Klf9fl/fl, Klf9mlc−/− mice exhibited increased skeletal muscle mass (TA 0.103 ± 0.012 vs. 0.123 ± 0.005 g, p < 0.001) and enhanced grip strength (forelimb 110.3 ± 5.8 vs. 156.8 ± 10.0 and four limbs 155.5 ± 6.3 vs. 226.5 ± 19.7, p < 0.001). Skeletal muscle Klf9 deficiency alleviated muscle atrophy induced by acute high‐dose Dex treatment (p < 0.001). Mechanistically, Klf9 induces the expression of myostatin (Mstn) and muscle atrophy F‐box (MAFbx) by directly binding to and activating the transcription of their promoters. Treatment of AAV‐MSTN reduced the increased grip strength of Klf9mlc−/− mice (forelimb 143.5 ± 22.3 vs. 118.8 ± 3.1 and four limbs 249.8 ± 24.7 vs. 208.7 ± 9.0, p < 0.001). Conclusions In summary, our study provides novel insights into the mechanisms underlying GC‐induced muscular atrophy and reveals that skeletal muscle induction of Klf9 expression is a mechanism underlying GC therapy‐induced muscle loss. Thus, targeting Klf9 may offer novel approaches to the treatment of skeletal muscle wasting diseases.

Background Leishmaniasis is a neglected tropical disease with significant global public health implications, leading to diverse clinical manifestations. It disproportionately affects impoverished populations in over 90 countries, making it a major health concern worldwide. Methods This study provides a comprehensive analysis of the global burden of leishmaniasis from 1990 to 2021 across 204 countries and territories, using data from the Global Burden of Disease Study 2021. It estimates the disability-adjusted life years (DALYs) associated with leishmaniasis, assessing its impact across different age groups, sexes, and sociodemographic index (SDI) categories. Results The findings show a decline in the global age-standardized DALY rate for visceral leishmaniasis, from 75.73 to 5.39 per 100,000 population (a reduction of 92.9%). However, the DALY rate for cutaneous and mucocutaneous leishmaniasis has increased from 3.86 to 4.88 per 100,000 (a 26.4% rise), particularly in low- and middle-SDI countries. The study also reveals significant sex disparities in occupational risk factors, with men being more vulnerable to environmental and industrial exposures. Additionally, nutritional deficiencies, particularly calcium and zinc deficiencies, are identified as significant global risk factors. Conclusion The results underscore the need for targeted public health interventions, particularly those addressing nutritional deficiencies and occupational exposures. Region-specific health strategies should be developed to account for local risk factors, sex differences, and the varying impacts of environmental and industrial exposures, especially in less developed regions.

This research focused on establishing and testing a machine learning-driven predictive tool aimed at assisting in the identification of diabetic kidney disease (DKD). The prediction models were developed and internally temporally validated using single institution data. A total of 1463 patients from Shaanxi Provincial People's Hospital between March 2023 and September 2024 were incorporated in our study. Least absolute shrinkage and selection operator regression with 10-fold cross-validation was used to select the optimal features. We compared extreme gradient boosting, random forest (RF), support vector machine, and logistic regression across a range of metrics: area under the receiver operating characteristic curve (AUC-ROC), area under the precision-recall curve (AUC-PR), accuracy, precision, recall, kappa values, and F1-score. For each algorithm, a simplified model was developed using only routinely available clinical variables and was trained and evaluated on the same datasets as the full model. Decision curve analysis and calibration curve served to evaluate the clinical utility of the optimal models. Analysis and interpretation of feature importance were performed via SHapley Additive exPlanations and Local Interpretable Model-agnostic Explanations. When screening for DKD in Type 2 diabetes, the full RF model achieved superior performance (AUC-ROC = 0.906, AUC-PR = 0.902, accuracy = 0.830, F1 = 0.847, precision = 0.794, recall = 0.907, and kappa = 0.657) and significantly outperformed the simplified RF model. It also exhibited a favorable clinical net benefit and well-calibrated performance. The most influential predictors identified in the full RF model were urine α1-microglobulin, hypertension, 24-h urinary total protein, duration of Type 2 diabetes mellitus, systolic blood pressure, serum retinol-binding protein, complement C1q, and 25-hydroxyvitamin D. A RF prediction model was developed to facilitate early screening of DKD, highlighting the significant roles of specific clinical and laboratory factors in disease prediction.

Aims/Introduction Microribonucleic acid‐155 (microRNA155) and microRNA29 are reported to inhibit glucose metabolism in some cell and animal models, but no evidence from susceptible populations that examines the relationship between microRNA155 or microRNA29 and type 2 diabetes mellitus currently exists. Furthermore, target genes regulated by microRNA155 and microRNA29 that affect glucose and lipid metabolism remain unknown. Materials and Methods Human participants were divided into normal weight (n = 72), obesity (n = 120) and type 2 diabetes (n = 59) groups. The contents of microRNA155 and microRNA29 abundance in serum were measured, and candidate genes potentially related to glucose and lipid metabolism targeted by either microRNA155 or microRNA29 were screened. Overexpression of microRNA155 and microRNA29 in HepG2 cells was used to verify candidate gene expression, and measure the effects on glucose and lipid metabolism. Results Serum levels of microRNA155 and microRNA29 show a significant increase in individuals with obesity and type 2 diabetes compared with normal weight individuals. Identified target genes for microRNA155 were MAPK14, MAP3K10, DUSP14 and PRKAR2B. Identified target genes for microRNA29 were PEX11A and FADS1. Overexpression of microRNA155 or microRNA29 in HepG2 cells was found to downregulate the expression of identified target genes, and result in inhibition of triglyceride synthesis and glucose incorporation. Conclusions MicroRNA155 and microRNA29 were significantly higher in type 2 diabetes patients compared with the control patients, their levels were also positively correlated with fasting plasma glucose levels, and over‐expression of microRNA155 or microRNA29 were found to downregulate glucose and lipid metabolism target genes, and reduce lipid synthesis and glucose incorporation in HepG2 cells. We found that microribonucleic acid‐155 and microribonucleic acid‐29 promote the development of type 2 diabetes mellitus. In addition, we screened and validated its downstream target genes in vitro.

AbstractOur study is based on the establishment of a cohort of human obese omental adipose tissue and the culture of adipocytes in vitro. To observe the effect of high level of free fatty acid (FFA) on the expression of DNA methyltransferases (DNMTs) and the anti-inflammatory factor Kruppel-like factor 4 (KLF4) in adipocytes and evaluate the role of methyltransferases in FFA inhibiting KLF4 expression. A total of 20 normal patients and 20 obese patients were selected for further test. qRT-PCR and western blot were used to detect the mRNA and protein expression levels of DNMT1/DNMT3a/DNMT3b and KLF4 in human adipose tissue and 3T3-L1 adipocytes which stimulated with saturated fatty acid, palmitic acid (PA). Bisulfite sequencing PCR (BSP) detected methylation status of KLF4 gene in human adipose tissue. It was found that the mRNA and protein expression levels of DNMT1 and DNMT3a in the omental tissue of obese individuals were higher than those in normal group, but the expression of KLF4 was decreased. The positive methylation rate of KLF4 promoter region in obese individuals were significantly higher than those in normal individuals, especially at CpG_33 and CpG_34 sites. Meanwhile compared with non-methylated group at CpG_33 and CpG_34 sites of KLF4 promoter region, the DNMT3a mRNA expression in methylated group were significantly increased. A total of 200 μM PA significantly promoted DNMT1, DNMT3a, and DNMT3b and inhibited KLF4 protein expression levels in 3T3-L1 adipocytes. Our findings suggest that under obesity status, the lower expression level of KLF4 of visceral adipose tissue may correlate with palmitic acid promoted DNMTs expression in adipocytes.

Aims/Introduction Type 2 diabetes mellitus is closely linked to increased levels of free fatty acids (FFAs) in obese individuals, although which FFA is most associated with type 2 diabetes mellitus is unclear. This study aimed to identify the specific FFAs that best predict the occurrence of type 2 diabetes mellitus in obese individuals, and assess their potential application value. Materials and Methods Participants were divided into three groups: a normal weight group (n = 20), an obese group (n = 10) and a type 2 diabetes mellitus group (n = 10). FFAs in serum samples were determined by ultra‐high‐pressure liquid chromatography–mass spectrometry, and orthogonal partial least squares discriminant analysis models were used to study the FFA profile among the three groups. Results Compared with the normal weight group, 14 FFAs (C8:0/10:0/14:0/16:1/18:1/20:2/ 20:3 /20:4/ 20:5/ 22:6/7:0/9:0/11:0 and C13:0) were significantly increased in the obese group, and nine FFAs (C14:0, C18:1, C20:1, C 18:2, C20:2, C20:3, C18:3, C20:5 and C22:6) were significantly increased in the type 2 diabetes mellitus group. Subsequently, the Venn diagram results showed that six FFAs (C14:0, C18:1, C20:2, C20:3, C20:5 and C22:6) were significantly increased in both the obese and type 2 diabetes mellitus groups. Among these six, C22:6 was finally identified as an independent risk factor for type 2 diabetes mellitus, and had a great potential to predict the susceptibility to type 2 diabetes mellitus (area under the curve 0.803). Conclusions C22:6 can be an independent risk factor for type 2 diabetes mellitus, and it has a great potential to predict the susceptibility to type 2 diabetes mellitus. Our aim was to identify the different free fatty acids among the normal weight group, obese group and type 2 diabetes mellitus group. We finally found that C22:6 has a better ability to predict the susceptibility to type 2 diabetes mellitus, which is the key risk factor for type 2 diabetes mellitus caused by obesity.

Background Obesity-induced elevated serum free fatty acids (FFAs) levels result in the occurrence of type 2 diabetes mellitus (T2DM). However, the molecular mechanism remains largely enigmatic. This study was to explore the effect and mechanism of KLF15 on FFAs-induced abnormal glucose metabolism. Methods Levels of TG, TC, HDL-C, LDL-C, and glucose were measured by different assay kits. qRT-PCR and Western Blot were used to detect the levels of GPR120, GPR40, phosphorylation of p38 MAPK, KLF15, and downstream factors. Results KLF15 was decreased in visceral adipose tissue of obesity subjects and high-fat diet (HFD) mice. In HFD mice, GPR120 antagonist significantly promoted KLF15 protein expression level and phosphorylation of p38 MAPK, meanwhile reduced the blood glucose levels. While, blocking GPR40 inhibited the KLF15 expression. In 3T3-L1 adipocytes, 1500 μM PA inhibited KLF15 through a GPR120/P-p38 MAPK signal pathway, and 750 μM OA inhibited KLF15 mainly through GPR120 while not dependent on P-p38 MAPK, ultimately resulting in abnormal glucose metabolism. Unfortunately, GPR40 didn’t contribute to PA or OA-induced KLF15 reduction. Conclusions Both PA and OA inhibit KLF15 expression through GPR120, leading to abnormal glucose metabolism in adipocytes. Notably, the inhibition of KLF15 expression by PA depends on phosphorylation of p38 MAPK.

Ha X, Wang J, Chen K, et al. Cancer Manag Res. 2020;12:1355-1369. We, the Editors and Publisher of the journal Cancer Management and Research have retracted the published article. Following publication, concerns have been raised in 2025 by a third party about the integrity of the data in Figures 2 and 3 of the article. Further investigation conducted by the Journal and Publisher confirmed significant integrity concerns, including unexpected similarities in the image panels representative of different treatment conditions in Figures 2 and 3. When approached for an explanation, the authors have cooperated with the investigation and provided the requested raw data. Upon further review, the Journal and Publisher identified additional image integrity concerns present in the original raw data provided for Figures 2 and 3. Further data integrity concerns were identified in the raw data provided for Figure 1. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article. The corresponding author listed in this publication has been informed. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as 'Retracted'.