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Diabetic foot ulcer (DFU), a serious complication of diabetes, is a life-threatening disease that often leads to lower limb amputation and a shortened lifespan. Interleukin-27 (IL-27) is a member of the IL-12 family and has the potential to exert dual effects on the immune response. The role of IL-27 in diabetic skin wound healing is unknown. The aim of this study was to investigate whether there is abnormal expression of IL-27 in diabetic skin and whether supplementation with IL-27 can promote diabetic wound healing by modulating macrophage polarization. We established a streptozotocin (STZ)-induced diabetic mouse model and constructed diabetic wounds. We assessed protein expression by western blotting (WB) and immunohistochemical (IHC) staining. We also performed hematoxylin-eosin (H&E) staining and Masson's trichrome staining. In the presence of lipopolysaccharide (LPS) and high glucose (HG), we treated the mononuclear macrophage line RAW264.7 and bone marrow-derived macrophages (BMDMs) with IL-27. To assess macrophage polarization, we examined the expression of inducible nitric oxide synthase (iNOS), IL-1β and arginase-1 (Arg-1). To understand the underlying mechanisms, we used macrophage IL-27ra knockout mice to knockout macrophage IL-27 receptors. Our in vivo experiments revealed that the expression of IL-27 in the skin of diabetic mice was significantly decreased and that supplementation with IL-27 promoted diabetic wound healing. In vitro, compared with the LPS group, supplementation with IL-27 alleviated the suppression of multiple cellular functions, such as iNOS and IL-1β expression, cell migration, and phagocytosis, in macrophages after HG exposure. Mechanistically, we found that IL-27 expression was decreased and that the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation was inhibited in diabetic skin, leading to an inability of wound macrophages to polarize to an M1 phenotype effectively, which in turn blocked M1-to-M2 polarization of wound macrophages and ultimately delayed wound healing. The present study revealed that supplementation with IL-27 promoted M1-to-M2 polarization of wound macrophages and diabetic wound healing through the IL-27-IL-27Rα-p-STAT3 axis. These findings suggest that IL-27 may be a potential therapeutic target for DFU. Show less

Apolipoproteins are proposed to predict the status of CAD and its occurrence. The aim of this study was to assess the association between serum levels of apolipoproteins A-I, b100 and the ratio of Apo A-I/Apo b100 with the development and severity of premature coronary artery disease (PCAD). In this registry-based case-control study, patients under the age of 50 years with at least one coronary artery disease with stenosis ≥ 50% (PCAD group) were assessed and compared with patients without coronary artery involvement (normal group). The Gensini score considered to assess the CAD severity. The mean Apo A-I and Apo A-I/Apo b100 levels were higher in the control group, but Apo b100 was higher in the patient group (p < 0.05). Apo A-I and Apo A-I/Apo b100 ratio had a negative correlations (rho = -0.57, rho = -0.71, respectively) with the severity of PCAD based on the Gensini score. Apo b100 also had a positive correlation (rho = 0.67) with the severity of PCAD (p < 0.05). Apo A-I and Apo b100 were significantly associated with the occurrence of PCAD. Based on the results of multivariable analysis, with a 1 mg/dL increase in Apo A-I levels and Apo b100, the odds of PCAD decreased by 13% and increased by 31%, respectively. With a 1 mg/dL increase in apolipoprotein A-I and apolipoprotein b100 levels, the odds of high Gensini score decreased by 7% and increased by 8%, respectively (p = 0.001). The use of serum apolipoproteins in patients with suspected PCAD can predict the occurrence of CAD and its severity. Show less

Apolipoprotein B concentration reflects the number of atherogenic lipoproteins and is recognized as a key lipid risk marker. Whether the type or size of apoB particle (apoB-P) adds predictive value for coronary artery disease (CAD) remains unclear. A prospective analysis of 207 368 UK Biobank participants with comprehensive lipoprotein profiling and no prior history of atherosclerotic disease, diabetes, or active lipid-lowering therapy was conducted. Multivariable-adjusted Cox regression models were used to examine the association between each of the following lipid parameters with incident CAD: (i) nuclear magnetic resonance-measured apoB-P, (ii) concentrations of individual lipoprotein classes [very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL)], (iii) size subclasses, (iv) average particle diameter, and (v) immunoassay-measured lipoprotein(a) [Lp(a)]. A one standard deviation (SD) increase in apoB-P was associated with a 33% higher CAD risk [hazard ratio (HR): 1.33, 95% CI: 1.30-1.36]. Although VLDL particles were observed to carry a higher per-particle risk (HR per 100 nmol/L: 1.22, 1.11-1.34) compared with LDL (HR per 100 nmol/L: 1.07, 1.05-1.08), this difference was counterbalanced after considering relative particle abundance (LDL 91% vs VLDL 9% of total apoB-P). Thus the respective HR per 1-SD were 1.09 (1.05-1.14) and 1.24 (1.19-1.30). Particle diameter or size subclasses were not associated with CAD after apoB-P adjustment. The association of Lp(a) was robust even after apoB-P adjustment (HR:1.18, 1.16-1.20) and added independent prognostic value for CAD (area under curve: 0.769 vs 0.774, P < .001). Lipid-related atherosclerotic risk is most accurately reflected by the total count of apoB-P and is largely unaffected by the major particle type (VLDL, LDL) or size. Elevated count of Lp(a) adds additional risk, and thus adequate assessment of atherogenic risk from dyslipidemia is best accomplished by consideration of both apoB-P and Lp(a) concentrations. Show less

Deep Mutational Scanning (DMS) is an emerging method to systematically test the functional consequences of thousands of sequence changes to a protein target in a single experiment. Because of its utility in interpreting both human variant effects and protein structure-function relationships, it holds substantial promise to improve drug discovery and clinical development. However, applications in this domain require improved experimental and analytical methods. To address this need, we report novel DMS methods to precisely and quantitatively interrogate disease-relevant mechanisms, protein-ligand interactions, and assess predicted response to drug treatment. Using these methods, we performed a DMS of the melanocortin-4 receptor (MC4R), a G-protein-coupled receptor (GPCR) implicated in obesity and an active target of drug development efforts. We assessed the effects of >6600 single amino acid substitutions on MC4R's function across 18 distinct experimental conditions, resulting in >20 million unique measurements. From this, we identified variants that have unique effects on MC4R-mediated Gα Show less

The Objective of the Study Was to Explore the Associations between 20 Polymorphic Loci Related to Angiogenesis, Endothelial Dysfunction, Coagulation, Fibrinolysis, Lipid Metabolism, and Immune Response. These Loci Included Genes Such as PGF (rs12411), FLT1 (rs4769612), KDR (rs2071559), ACE (rs4340), FV (rs6025), FII (rs1799963), FVII (rs6046), SERPINE1 (rs1799889), ITGA2 (rs1126643), THBD (rs1042580), FTO (rs1421085), LPL (rs285), TLR4 (rs4986790), PLEKHA1 (rs2281673), PLEKHG1 (rs9478812), and Genome-Wide Association Studies (GWAS)-Associated Genes with Pre-Eclampsia (PE; MECOM, rs419076) in the Kazakh Population. The Study Aimed to Identify their Potential Role in the Development of PE and Related Complications. A case-control genetic study was conducted with 103 Kazakh female patients with acute cerebral circulatory failure in severe PE (40 [38.8%] of whom had a fatal outcome) and 104 Kazakh female patients with severe PE from the comparison group. Genotyping of polymorphism × loci was performed by real-time polymerase chain reaction. Associations of genotypes of single nucleotide polymorphisms (SNPs) with the development of acute cerebral circulatory failure (ACF) were studied using logistic regression analysis (PLINK 1.9 beta software), both unadjusted and adjusted for potential confounders. Multiple comparisons were accounted for using the Bonferroni correction. Significant associations (P < 0.05) between genotypes (heterozygote and/or unfavorable homozygote) of five polymorphisms of coagulation genes and the odds of ACF in severe PE were found-FV: GA (odds ratio [OR] 8.10, 95% confidence interval [CI] 3.01-21.98); FII: GA (OR 3.50, 95% CI 1.80-6.78); angiogenesis and endothelial dysfunction, PGF: TT (OR 8.40, 95% CI 2.83-25.20); immune response, TLR4: AG (OR 6.70, 95% CI 1.47-30.86); and PLEKHA1: TA (OR 3.90, 95% CI 1.64-9.00). The identified genetic associations can aid in predicting the development and severity of the clinical course of ACF in severe PE, forming high-risk groups, preventing its development, and personalizing therapy for the prevention of diseases in pregnant women and the fetus. Show less

To investigate the impact of the Panax notoginseng saponin extract on hyperlipidaemic mice. We developed a hyperlipidemia model in mouse through the administration of a high-fat diet. We conducted weekly measurements of body weight, serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and highdensity lipoprotein cholesterol (HDL-C). Additionally, serum levels of Apolipoprotein A (APOA) and Apolipoprotein B (APOB) were determined post-feeding. We assessed pathological liver tissue damage in mice, as well as examined malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity in liver tissue. Immunohistochemical analysis was conducted to detect the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) proteins within liver tissues. Administration of Panax notoginseng saponin extract led to a reduction in body weight, liver index, and histopathological scores among mice. Additionally, there was a significant reduction in TC, TG and LDL-C levels, accompanied by an increase in HDL-C levels. Additionally, an increase in hepatic SOD activity and a decrease in MDA content were observed in the liver homogenates of mice. Furthermore, the expression levels of HO-1 and Nrf2 proteins were upregulated in liver tissue. These findings suggest that Panax notoginseng saponin extracts may ameliorate high-fat diet-induced hyperlipidemia. Show less

Apolipoprotein C-III (apoC-III) is an important regulator of triglyceride (TG) metabolism and a target for intervention. The present study examined the effects of gain-of-function (GOF) variants in APOC3 on apolipoprotein B kinetics to understand further how changes in the synthesis of this apolipoprotein impact triglyceride-rich lipoprotein (TRL) metabolism. Two groups of subjects were recruited by population screening, 9 carriers of known APOC3 GOF variants and 9 age-, sex- and BMI-matched non-carriers. The kinetics of TRL were determined using stable isotope tracers of apoprotein and triglyceride metabolism in a non-steady-state protocol involving administration of a fat-rich meal. APOC3 GOF carriers had 47 % higher plasma apoC-III levels compared to non-carriers (P = 0.022) and higher production rates for the apolipoprotein. Post-prandial response (total area-under-curve) for plasma TG was 108 % greater in GOF carriers compared to non-carriers (P = 0.002) due specifically to higher levels of VLDL APOC3 GOF carriers showed specific alterations in TRL metabolism (compared to matched non-carriers), namely slower lipolysis and delayed clearance of VLDL Show less

Perfluorooctanoic acid and perfluorooctane sulfonate are well-known eight-carbon per- and polyfluoroalkyl substances (8C-PFAS) potentially toxic for the human liver. However, direct experimental evidence demonstrating their toxicity on the human liver remains limited. Consequently, this study aimed to extrapolate the 8C-PFAS liver toxicity mechanisms by leveraging omics data to integrate mouse and human findings. Through integration analyses of nine datasets (one human, six murine, and two rat), we identified 199 genes with known biological functions that are commonly affected by 8C-PFAS across species. We delineated a comprehensive regulatory network of 8C-PFAS toxicity, demonstrating that 8C-PFAS may trigger fatty liver disease by up-regulating CD36 and PPARα pathway; dysregulate xenobiotic metabolism by disrupting CAR and CYP family genes; and induce cancer by dysregulating WNT, TGFβ, FGF21, and P53 pathways. We also identified ATF3, EGR1, ESR1, NFATC4, SNAI2, TP53, and EZH2 as transcriptionally regulated by 8C-PFAS, along with PPARα, RXRα, FGFR1, TCF3, and SMAD3 as potentially functionally impacted. Collectively, these factors account for over 90 % of 8C-PFAS-affected key genes. This study not only developed a novel method for extrapolating human toxicity risks by integrating scattered toxicity evidence based on transcriptomics data, but also proposes new mechanisms by which 8C-PFAS contributes to fatty liver disease and cancer. Show less

In a phase II study, letrozole/abemaciclib demonstrated an objective response rate of 30% and a median progression-free survival (PFS) of 9.1 months in recurrent estrogen receptor-positive endometrial cancer (EC). While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response, circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. Serial plasma specimens were obtained at baseline, C2D1, C3D1, C8D1, the time of objective response, and the time of progression. Samples were analyzed using the Guardant Reveal assay to assess methylation-based tumor fraction (TF), with the Guardant360 assay providing genotyping of >700 genes in samples with detectable ctDNA. Treatment response was assessed using a measure of the relative change in TF pre- versus on-treatment. A total of 99 of 102 (97%) samples from 28 patients were successfully analyzed. Patients with above median baseline TF exhibited worse median PFS (2.0 months Baseline and on-treatment ctDNA dynamics may provide an early indication of benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify resistance alterations that may inform subsequent therapy. Show less

Xenopus embryo is an ideal model for teratogenesis assays to assess the effects of any compounds on the cellular processes crucial for early development and adult tissue homeostasis. In our screening of a chemical library with frog embryo to identify novel compounds that exert specific effects on key cellular signaling pathways, perillic acid (PA) was found to disrupt germ layer specification in early development. Thus, the mechanism underlying this effect was investigated. Embryos were exposed to PA during a specific period of early development to observe stage-specific morphological alterations induced by this compound. Whole-mount in situ hybridization was performed to examine its effects on ectodermal and mesodermal differentiation and the anterior-posterior patterning of neural tissue. Western blotting analysis was employed to identify the signaling pathways through which PA influences germ layer formation in Xenopus development. PA-treated embryos exhibited the shortening of the anterior-posterior body axis, truncation of craniofacial structures and malformation of neural crest (NC). These severe morphological defects occurred when embryos became exposed to PA during the gastrula stages. Consistent with these phenotypes, treatment with PA caused significant expansion of neural tissue concomitant with a reduction of epidermal and NC cell fates. Furthermore, PA induced the caudalization of neural fate and expressions of paraxial mesodermal genes, recapitulating the activity of the FGF/MAPK signals in germ layer specification. In line with this, ERK activation could be induced by PA treatment, which was mediated by the FGFR1 pathway. PA affects the anterior-posterior neural patterning and mesodermal specification by activating the FGF/MAPK signaling pathway. Show less

The refrigeration (cold storage) of platelet components provides several benefits over room-temperature (RT) storage, extending the shelf-life up to 21 days. However, the effect of storage conditions on platelet activation in response to stimulation remains unclear. A paired study was conducted where buffy-coat platelet concentrates were pooled, split, and allocated to RT or cold storage (n = 6 in each group). Platelet samples were taken on days 1, 7, 14, and 21, which were tested without stimulation or following activation with TRAP-6, A23187, lipopolysaccharides, or Histone-H4. Imaging flow cytometry was used to assess the surface characteristics of platelets and extracellular vesicles (EVs). The supernatant concentration of EGF, RANTES, PF4, CD62P, IL-27, CD40L, TNF-α, and OX40L was examined using ELISA. Cold-stored platelets generated a greater proportion of procoagulant platelets and EVs than RT-stored platelets in response to stimulation. The supernatant of cold-stored components contained lower concentrations of soluble factors under basal conditions, suggesting that platelet granules were better retained. Cold-stored platelets released higher concentrations of soluble factors following stimulation with TRAP-6, A23187, or Histone-H4. Only cold-stored platelets responded to lipopolysaccharides. These data demonstrate that cold-stored platelets retain the capacity to respond to stimuli after 21 days of storage, which may facilitate improved functional post-transfusion. Show less

Based on genetic studies, lysosome dysfunction is thought to play a pathogenetic role in Parkinson's disease. Here we show that VPS13C, a bridge-like lipid-transport protein and a Parkinson's disease gene, is a sensor of lysosome stress or damage. Following lysosome membrane perturbation, VPS13C rapidly relocates from the cytosol to the surface of lysosomes where it tethers their membranes to the ER. This recruitment depends on Rab7 and requires a signal at the damaged lysosome surface that releases an inhibited state of VPS13C, which hinders access of its VAB domain to lysosome-bound Rab7. Although another Parkinson's disease protein, LRRK2, is also recruited to stressed or damaged lysosomes, its recruitment occurs at much later stages and by different mechanisms. Given the role of VPS13 proteins in bulk lipid transport, these findings suggest that lipid delivery to lysosomes by VPS13C is part of an early protective response to lysosome damage. Show less

The causal relationships between the gut microbiota and prostate cancer, prostatitis, and benign prostatic hyperplasia remain uncertain. We intend to identify the causal connections between the gut microbiota and prostatic diseases and investigate the potential mechanisms involved. A two-sample Mendelian randomization (MR) analysis was conducted to elucidate the impact of 196 gut microbiota on prostatic diseases risk. Reverse MR, linkage disequilibrium regression score (LDSC), and colocalization analyses were performed to strengthen causal evidence. Phenome-wide MR (Phe-MR) analysis was used to evaluate the potential side effects of targeting the detected gut microbiota. We designed a two-step MR study to assess the mediating effects of sex hormones, blood metabolites, and proteins. According to the MR analyses, 31 bacterial taxa were causally associated with prostatic diseases, of which 23 types were newly identified. In addition, Our study represents the first comprehensive exploration of the causal effects of the gut microbiota on prostatic diseases and reveals the mediating effects of sex hormones and blood metabolites on the "gut-prostate axis." Show less

Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat. Milk-derived exosomes, particularly those from sheep milk (SM-Exo), have shown potential in treating gastrointestinal disorders, though their efficacy in Cd-induced colitis remains unclear. In this study, we investigated the therapeutic potential of SM-Exo in a Cd-induced colitis model. Hu sheep were exposed to Cd, and their fecal microbiota were collected to prepare bacterial solutions for fecal microbiota transplantation (FMT) in mice. The changes in gut microbiota and gene expression were analyzed through microbiome and transcriptomics. Our results showed that prior to treatment, harmful bacteria (e.g., Show less

Phytochemicals possess diverse therapeutic potential; however, the impact of arene substitutions on the pharmacological properties of the bibenzyl compounds batatasin III and gigantol, derived from This study examines how structural differences between these compounds affect cellular glucose uptake and lipid metabolism during adipocyte differentiation. The effects of both bibenzyl compounds on cytotoxicity and glucose uptake were assessed in mouse and human pre-adipocytes and rat skeletal muscle myoblasts using colorimetric assays. Lipid metabolism was evaluated through Oil Red O staining and quantification of triglyceride and glycerol levels, while protein and gene expression during adipocyte differentiation were analyzed via western blotting and RT-qPCR. At the highest non-cytotoxic concentration (25 µM), gigantol significantly enhanced glucose uptake (up to 2-fold) under both basal and insulin-stimulated conditions, whereas batatasin III showed a similar effect only under basal conditions. Gigantol upregulated GLUT1 and GLUT4 in myotubes but downregulated them in adipocytes, whereas batatasin III had minimal impact on these transporters. Both compounds suppressed lipid accumulation in mouse and human adipocytes by decreasing intracellular triglyceride content and promoting extracellular glycerol release. However, batatasin III did not affect extracellular glycerol release during early adipocyte differentiation, as evidenced by the marked downregulation of key lipogenic proteins (PLIN1, LPL, FABP4) observed only with gigantol. Molecular docking analyses suggest that gigantol's greater bioactivity may result from its higher number of arene substitutions. This study provides the first evidence that differences in arene substitutions among orchid-derived bibenzyls influence their pharmacological properties. Our findings support the strategic modification of natural products as a potential approach for managing metabolic disorders. Show less

The MC4R gene plays a critical role in regulating food intake, making it an important model for studying genetic mutations that impact the protein function. This study aimed to identify the most deleterious functional and structural variants in individuals with obesity by analyzing SNPs from the NCBI dbSNP database and selecting pathogenic variants from ClinVar. Bioinformatics tools were employed to predict deleterious SNPs, and conservation analysis was performed using ConSurf. Stability predictions were made with MUpro, I-Mutant2.0, and iStable. The 3D structure of the MC4R protein was examined using YASARA view. A total of 20 out of 348 missense mutations were associated with obesity. Fifteen of these variants were predicted to be the most deleterious. Eight variants located in conserved regions were found to significantly reduce protein stability and cause structural changes (S58C, E61K, N62S, I69R, D90N, R165Q, P299H, and I316S), indicating their potential as obesity biomarkers and therapeutic targets. Show less

Although it has been shown that the tumor extracellular matrix (ECM) may sustain the cancer stem cell (CSC) niche, its role in the modulation of CSC properties remains poorly characterized. To elucidate this, paired tumor and adjacent normal mucosa, derived from colon cancer patients' surgical resections, were decellularized and recellularized with two distinct colon cancer cells, HT-29 or HCT-15. Methods: The matrix impact on cancer stem cell marker expression was evaluated by flow cytometry and qRT-PCR, while transforming growth factor-β (TGF-β) secretion and matrix metalloprotease (MMP) activity were quantified by ELISA and zymography. Results: In contrast to their paired normal counterparts, the tumor decellularized matrices enhanced HT-29 expression of the pluripotency and stemness genes Show less

Genetic testing of patients with severe hypertriglyceridemia often identifies a single heterozygous pathogenic variant in the LPL gene. The complex and variable phenotype associated with this genotype is the topic of this review. Previous research showed that heterozygosity for lipoprotein lipase deficiency is associated with reduced but variable post heparin lipolytic activity alongside inconsistent plasma lipid phenotypes ranging from normal to mild-to-moderate to severe hypertriglyceridemia. Recent research confirms and extends these observations, showing that a heterozygous individual can express a highly variable phenotype over time, depending on the presence of secondary factors. About 10% (range 8-20%) of patients with severe hypertriglyceridemia or multifactorial chylomicronemia syndrome are heterozygous for a rare pathogenic LPL variant, and a clinically relevant minority of these has recalcitrant or sustained hypertriglyceridemia. Heterozygosity for lipoprotein lipase deficiency predisposes to hypertriglyceridemia, which is sometimes severe depending on secondary factors, but is typically quite responsive to routine interventions such as diet, lifestyle and existing lipid-lowering therapies. However, many heterozygotes for pathogenic variants in LPL have completely normal plasma lipids. Show less

Lung squamous cell carcinoma (LUSC) is one of the most common subtype of lung cancer and is associated with the poor prognoses. The fibroblast growth factor receptor (FGFR) family is known to be activated through fusions with various partners across multiple cancer types, including nonsmall cell lung cancer (NSCLC). FGFR inhibitors are currently undergoing clinical evaluation for the treatment of tumors harboring these fusions. While FGFR1 amplification has been well-documented in numerous NSCLC datasets, the characterization of specific FGFR fusion variants remains limited. In this study, we identified a novel PLPP5-FGFR1 fusion in a 65-year-old male patient with lung squamous cell carcinoma through targeted RNA sequencing. The fusion junction was located between exon 1 of PLPP5 and exon 5 of FGFR1, and the result was validated by Sanger sequencing. To our knowledge, this is the first reported case of a PLPP5-FGFR1 fusion coexisting with a TP53 mutation in LUSC. These findings broaden the spectrum of potential translocation partners in FGFR1 fusions, and the clinical implications of this novel fusion on treatment outcomes and prognosis warrant further investigation and long-term follow-up. Show less

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with complex etiology, often associated with histological markers of oxidative stress, inflammation, and disturbances in calcium homeostasis. Traditionally, amyloid Show less

β-Sitosterol (BS), is a significant bioactive component of phytosterols found in plants, foods, and dietary supplements. Its nutritional benefits include lowering of cholesterol levels, boost immune system as well as reduce inflammation. Previous studies have demonstrated its significant anticancer effects across various human cancers. However, the specific mechanisms of action of BS in lung cancer remain unclear. This study aimed to investigate the mechanisms through which BS exerts its anticancer properties in human lung cancer cells, focusing on its anti-proliferative, apoptotic, cytotoxic, and anti-migratory effects. We conducted an in vitro study to assess the effects of BS on lung cancer cell lines A549 and H1975. We used a range of assays, including MTT, western blot, wound healing, transwell migration, immunofluorescence, TUNEL, and cell survival assays, to evaluate the impact of BS on cell proliferation, apoptosis, cytotoxicity, and migration. Our findings indicate that BS inhibits the proliferation of lung cancer cells in a time- and dose-dependent manner. It significantly promotes apoptosis and impairs both cancer cell migration and survival. Additionally, BS suppresses the expression of both fibroblast growth factor receptor-1 (FGFR1) and epidermal growth factor (EGFR), leading to the downregulation of the PI3K/AKT/mTOR/CD1 signaling pathway. BS demonstrates significant anticancer potential in lung cancer cells by inhibiting proliferation, inducing apoptosis, and reducing cell migration. These effects are likely mediated by the concurrent downregulation of FGFR1 and EGFR, leading to the inhibition of the PI3K/AKT/mTOR/CD1 signaling pathway, thereby warranting further investigation of BS as a potential therapeutic agent for lung cancer. Show less

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta, and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations. Show less

Abnormal lipid accumulation is an important cause of metabolic dysfunction-associated fatty liver disease (MAFLD) progression and can induce several stress responses within cells. This study is the first to explore the role and molecular mechanism of stress granules (SGs) in MAFLD. A gene knock-down model of G3BP1, a core SG molecule in mice and HepG2 cells, was constructed to explore the role of SGs in MAFLD induced in vivo by a high-fat diet or in vitro by palmitic acid (PA). Methods included metabolic phenotyping; western blotting; qPCR; and immunofluorescence, haematoxylin/eosin and masson staining. The downstream molecules of G3BP1 and its specific molecular mechanism were screened using RNA sequencing (RNA-seq). G3BP1 and TIA1 expression were upregulated in high-fat diet-fed mouse liver tissues and PA-induced HepG2 cells, and the two molecules showed significantly increased colocalisation. G3BP1 knock-down slightly increased TIA1 expression in the livers of obese mice but not in lean mice. G3BP1 deficiency aggravated liver lipid deposition and insulin resistance in obese mice, and this phenotype was confirmed in vitro in PA-induced hepatocytes. RNA-seq demonstrated that G3BP1 slowed down MAFLD progression by inhibiting APOC3, possibly through a mechanistic suppression of APOC3 entry into the nucleus. This study reveals for the first time a protective role for SGs in MAFLD. Specifically, knocking down the core G3BP1 molecule in SGs aggravated the progression of fatty acid-induced MAFLD through a mechanism that may involve the nuclear entry of APOC3. These findings provide a new therapeutic direction for MAFLD. Show less

Monogenic obesity caused by mutations in the melanocortin-4 receptor (MC4R) gene remains a significant health challenge, despite numerous efforts to discover effective treatments. The MC4R has emerged as a promising target for drug development due to its role in energy homeostasis and adipose tissue formation. Show less

Breast cancer, a major threat to women's health worldwide, has mechanisms of onset that remain unclear. Within the human lysosomal system, a class of enzymes known as cathepsins exhibit elevated expression levels in various malignant tumors, suggesting that they may play key roles in cancer progression. This study employed the two-sample Mendelian randomization (MR) approach to investigate the potential causal relationship between cathepsin levels and the risk of developing breast cancer. Furthermore, we conducted MR analysis using eQTL data to investigate how gene expression, mediated by cathepsins, affects the occurrence of different types of breast cancer and assessed the regulatory effects of cathepsins. MR analysis revealed that increased levels of cathepsin E are associated with a greater risk of malignant breast tumors (IVW: p = 0.006, OR = 1.103, 95% CI = 1.028-1.184), and increased levels of cathepsin F are associated with an increased risk of These findings highlight the dual roles of cathepsins as potential risk and protective factors for breast cancer, underscoring their potential in diagnostic and therapeutic strategies. Show less

We report a case of a primary cutaneous spindle cell sarcoma (SCS) with FN1::FGFR1 fusion. The tumor lacked the typical histologic and immunohistochemical features associated with other FN1-rearranged neoplasms, such as phosphaturic mesenchymal tumors (PMT) and calcified chondroid mesenchymal neoplasms (CCMN). Unlike PMTs, which often feature a cartilaginous matrix and are associated with tumor-induced osteomalacia (TIO), the present case lacked these characteristics and did not show FGF23 mRNA expression. Immunohistochemically, the tumor cells showed patchy staining for CD34 but were negative for markers such as ERG, desmin, S100, and pan-TRK. The fusion event in this case involves the loss of the FGFR1 Ig1 (D1) domain, a mechanism proposed to drive oncogenesis by releasing FGFR1 from autoinhibition. Despite the preservation of other FGFR1 domains, no evidence of FGF23 signaling was detected, and the patient had no clinical history of TIO. This case underscores the complexity of oncogenesis in FN1::FGFR1-rearranged neoplasms, a form of "promiscuous" gene fusion, where similar fusions lead to diverse tumor phenotypes. It emphasizes the importance of incorporating molecular testing in diagnosing spindle cell sarcomas, particularly those occurring in acral sites, to identify this underrecognized entity. Show less

This study investigated the effects of periodontitis (P) and non-surgical periodontal therapy (NSPT) on behavior, neurodegeneration, and neuroinflammation in rats with Alzheimer's disease (AD)-like pathology. AD-like pathology was induced in rats (n = 28) using STZ neurodegeneration model. Periodontitis was experimentally induced (n = 32), and half of which received NSPT with Chlorhexidine (CHX) gel. Behavioral assessment included the passive avoidance task (PA) and Morris water maze (MWM). Levels of NLRP3, phosphorylated tau (p-tau), and tau in the hippocampus, cerebrospinal fluid (CSF), and serum were measured by ELISA, while BACE1, IL1β, iNOS, and NF-κβ proteins were assessed by Western blotting. Rats in the AD and AD + P groups performed worse in behavioral tests compared to controls (p < 0.05), whereas the NSPT group showed similar performance to controls (p > 0.05). CSF p-tau levels were comparable between AD and AD + P groups, but the hippocampal p-tau/tau ratio was significantly higher in the AD + P group (p < 0.05). BACE1 levels were similar in P and AD groups. NLRP3 and iNOS levels did not show significant differences across groups. Notably, the NSPT group exhibited reduced NF-κβ levels (p < 0.05). Periodontitis may exacerbate AD-like molecular pathology, particularly by promoting tau hyperphosphorylation, while NSPT appears to mitigate disease progression and improve behavioral outcomes. Show less

Lymphoplasmacytic lymphoma (LPL) is a type of low-grade B-cell lymphoma, with 90-95% of cases associated with Waldenström macroglobulinemia, characterized by the presence of IgM-type M-protein. We report, for the first time, a case of LPL-producing Bence Jones (BJ) protein kappa. The patient was a 78-year-old woman admitted to our department due to general fatigue and proteinuria that had persisted for 2 months. No M-protein was detected by blood immunofixation, but kappa-type BJ protein was detected in the urine. Light microscopy of a kidney biopsy sample revealed infiltration of lymphocytes and plasma cells into the perirenal adipose tissue and renal interstitium. The infiltrating cells exhibited kappa light chain restriction. Bone marrow examination revealed clusters of immature plasmacytoid lymphocytes that were CD20 positive, CD5 negative, and exhibited light chain restriction. Genetic analysis detected a MYD88 mutation, leading to the diagnosis of LPL in the patient. Six months after starting treatment with tirabrutinib, urinary protein levels improved to 0.2 g/gCr. Renal infiltration was identified due to urinary protein, and currently, no extramedullary lesions outside the kidneys are observed. Tirabrutinib has been extremely effective, but careful follow-up is still required. Show less