Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine with multiple functions in the immune system and other tissues. Physiologically, MIF has been implicated in the regulation of the immune response, in pathogen clearance, in cell regeneration, in the regulation of insulin secretion, and in the regulation of cardio- and neuro-protective effects. Pathologically, high MIF levels have been associated with inflammatory and autoimmune diseases, diabetes mellitus, obesity and cancer. The present study assessed serum MIF levels in women by ELISA. Subsequently, the possible relationship between MIF serum levels and risk factors associated with the development of breast and other types of cancer was evaluated. MIF serum levels in the studied population ranged between 80.7 and 4,790.5 pg/ml. Notably, high MIF serum levels were related to obesity (median 1,604.0 pg/ml; P=0.0197 vs. overweight and P=0.0002 vs. normal body mass index), a high waist-to-hip ratio (WHR; median 1,542.0 pg/ml; P=0.0126 vs. moderate WHR) and hypertension (median 1,582.0 pg/ml; P=0.0234). Also, a weak correlation was observed between MIF levels and aging (P=0.0239, r=0.1558). Furthermore, MIF levels were decreased in women with Breast Imaging Reporting and Data System (BI-RADS) classification 2 (P=0.0189) and 3 (P=0.0023) when compared with the levels in women with BI-RADS classification 1, and no other association was identified with the other cancer risk factors evaluated. In conclusion, the present results indicated that, although increased levels of MIF were not associated with increased breast cancer risk as evaluated by BI-RADS classification or other cancer risk factors, elevated MIF levels were related to states of chronic inflammation such as obesity, a high WHR and aging, indicating that an increase in the serum concentration of MIF may be related to metabolic disease.
Non-small cell lung cancer (NSCLC) represents ~85% of all lung cancer and is a leading cause of cancer-related mortality worldwide. Trophoblast cell surface antigen-2 (TROP-2) and mucin-1 (MUC-1) have emerged as potential prognostic biomarkers and therapeutic targets. There are no reports of their combined impact as a biomarker in NSCLC. The present systematic review/meta-analysis aimed to evaluate the expression patterns and prognostic implications of TROP-2 and MUC-1 in NSCLC. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Population, Intervention, Comparison, and Outcome framework, 1,297 publications between 2019 and 2024 were systematically retrieved from PubMed, Scopus and EMBASE databases. A total of 12 studies (three for TROP-2 and nine for MUC-1) met the inclusion criteria and five (two for TROP-2 and three for MUC-1) were finally included in the final meta-analysis using fixed-effect models involving 1,159 patients. High TROP-2 [hazard ratio (HR) 1.43, 95% confidence interval (CI): 1.15-1.79; P=0.002] and MUC-1 (HR 2.25; 95% CI: 1.57-3.23, P<0.0001) were consistently overexpressed in NSCLC patient tissues. An exploratory pooled analysis of both biomarker groups demonstrated a significant association with poor clinical outcomes and short survival (HR 1.62; 95% CI: 1.34-1.96; P<0.00001), though this should not be interpreted as evidence of a true dual-biomarker effect. Mechanistically, both markers promote cancer cell proliferation, epithelial-mesenchymal transition, immune evasion and treatment resistance. In conclusion, TROP-2 and MUC-1 are valuable prognostic biomarkers in NSCLC. Their overexpression correlates with poor survival, supporting the development of targeted therapies in NSCLC.
Honokiol (HKL), a bioactive biphenolic lignan isolated from the bark of Magnolia officinalis, possesses diverse pharmacological properties, including neuroprotective, antitumor, anti-inflammatory and metabolic regulatory effects. Despite its therapeutic promise, the clinical application of HKL is severely restricted by its hydrophobicity and low oral bioavailability. The present review systematically summarized 99 studies (90 original articles and nine reviews) on the pharmacological profile of HKL. It detailed HKL's molecular interactions with key signaling targets, such as sirtuin 3, NOD-like receptor family pyrin domain containing 3-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes, Yes-associated protein/transcriptional coactivator with PDZ-binding motif, adenosine monophosphate-activated protein kinase and signal transducer and activator of transcription 3, which underly its efficacy against cancer (ovarian, liver, breast, colorectal, and lung), neurodegeneration (Alzheimer's and Parkinson's disease), metabolic disorders (diabetes, nonalcoholic fatty liver disease and obesity) and inflammatory and infectious diseases. Furthermore, the present review critically evaluated recently developed strategies to overcome its pharmacokinetic limitations. The present review offered an updated theoretical basis for understanding the structure-activity relationship of HKL and provided insights into its translation from bench to bedside.
The present study aimed to develop a Justicia gendarussa Burm.f. leaf extract enriched with flavonoids and to investigate its antidiabetic mechanisms, particularly its ability to enhance pancreatic β-cell function and prevent β-cell death under hyperglycemic conditions. The extract, prepared using ethanol via the Soxhlet extraction method, yielded 15.06% dry extract by weight and exhibited a dark green, viscous appearance. Phytochemical analysis revealed a high flavonoid content (172.10 mg quercetin equivalents/g extract) and a moderate phenolic content (23.47 mg gallic acid equivalents/g extract). Antioxidant activity, evaluated using 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid assays, demonstrated potent radical scavenging capacity, with IC50 values of 1.15±0.14 and 0.42±0.07 mg/ml, respectively. High-performance liquid chromatography analysis identified vitexin as the one bioactive flavonoid in the extract with amount of 0.19±0.02 mg/g extract. In vitro studies using INS-1 pancreatic β-cells exposed to high glucose concentrations showed that the extract at concentrations of 50 and 100 µg/ml markedly increased cell viability and reduced intracellular reactive oxygen species levels comparable with those of normal-glucose controls. The antioxidant effect of the JG extract was mediated through the upregulation of key antioxidant genes, Nrf2 and Trx. Furthermore, the extract reduced apoptosis by 25.59%, an effect comparable with that of 10 µM vitexin. Gene expression analysis revealed that the extract markedly upregulated pancreatic and duodenal homeobox 1 mRNA levels compared with the high-glucose group, suggesting enhanced insulin synthesis via activation of key transcriptional regulators. In conclusion, the cytoprotective effects of JG extract are mediated through antioxidant activity, inhibition of apoptosis and stimulation of insulin gene expression. Further molecular and in vivo studies, along with clinical validation, are warranted to support the development of this herbal extract as a complementary therapeutic strategy for managing type 2 diabetes.
Shoulder rotator cuff tears are a common condition, which under specific indications is treated with arthroscopic repair. The optimal treatment aims at alleviating shoulder pain, the return of shoulder functionality and the prevention of recurrence of symptoms. The aim of the present study was to investigate and describe the augmentation of arthroscopic repair of rotator cuff tears with platelet-rich-plasma (PRP) treatment postoperatively, and its effects on pain, shoulder functionality and risk of retear. A total of 51 patients were divided into two groups. The treatment group received a subacromial PRP injection in the direct postoperative period after arthroscopic repair of rotator cuff tears, while the control group underwent arthroscopic treatment alone. There was no statistically significant difference in the verbal numeric rating score at 30 days postoperatively and the Constant-Murley and American Shoulder and Elbow Surgeons shoulder scores at 3, 6 and 12 months postoperatively between the two groups. However, the patients in the treatment group exhibited a statistically significant improvement of both scores between the 3- and 6-month timepoints, which was not observed in the control group. A smaller portion of the treatment group had rotator cuff retears compared with the control group (42.86 vs. 75.00%), although this was not statistically significant. It has not yet been adequately established that PRP treatment can provide additional benefits when combined with surgical treatment of rotator cuff tears. Further research with larger sample sizes may provide sufficient data concerning a possible protective effect on the postoperative retear risk. The trial has been registered on ClinicalTrials.gov under number NCT07689383 (submission date, July 1, 2026) and can be accessed at: clinicaltrials.gov/study/NCT07689383?term=NCT07689383&viewType=Card&rank=1.
Achromobacter xylosoxidans is an emerging non-fermenting gram-negative bacillus that is increasingly associated with multidrug-resistant infections, particularly among vulnerable patient populations, such as patients with cystic fibrosis and lung transplant recipients. The intrinsic and acquired resistance mechanisms of A. xylosoxidans, including efflux pumps, β-lactamase production and altered membrane permeability, limit the effectiveness of standard antimicrobial regimens. Notably, cefiderocol, a siderophore cephalosporin with activity against resistant gram-negative pathogens, has been considered as a potential therapeutic option for A. xylosoxidans infections. In the present narrative review, current evidence on the in vitro activity and clinical use of cefiderocol against A. xylosoxidans is summarised. A structured literature search was conducted using PubMed, Web of Science and Google Scholar to identify relevant studies reporting susceptibility data and clinical outcomes. In conclusion, available in vitro and in vivo studies generally support the activity of cefiderocol against A. xylosoxidans, although some heterogeneity in susceptibility has been observed.
KBG syndrome (KBGS) is a neurodevelopmental disorder caused by ANKRD11 (ankyrin repeat domain-containing protein 11) haploinsufficiency. Its broad phenotypic variability and overlap with other types of chromatinopathies frequently hinder clinical recognition, and genotype-phenotype associations remain limited. The present study aimed to characterize the clinical and molecular features of individuals with KBGS and expand the craniofacial phenotype using two-dimensional (2D) facial morphometry. The present retrospective study involved patients with molecularly confirmed KBGS evaluated between January 2017 and February 2025 at Fundación Valle del Lili (Cali, Colombia). Detailed developmental, craniofacial, skeletal, neurological and behavioral features were documented. Molecular diagnoses were established using clinical exome sequencing. Craniofacial differences were quantified using 2D morphometric analysis. A systematic review of the literature was performed to compare the prevalence of clinical manifestations observed in the present cohort with previously reported cohorts. All 10 individuals carried pathogenic or likely pathogenic ANKRD11 variants, including multiple novel frameshift mutations. Developmental delay and intellectual disability were universal. Recurrent clinical findings included facial asymmetry, low hair implantation, bulbous nasal tip, synophrys, scoliosis, seizures, behavioral disturbance and hearing impairment. Morphometric analysis identified distinctive craniofacial patterns differentiating patients from controls, mainly involving facial asymmetry, increased forehead height, nasal prominence, increased lower lip thickness and reduced chin prominence. The literature review confirmed shared chromatinopathy-related features, including developmental delay, intellectual disability, craniofacial dysmorphism, skeletal anomalies and behavioral disturbances, as well as under-recognized findings such as facial asymmetry, low anterior hairline, hypotonia and hearing impairment. The present study broadens the phenotypic and genotypic landscape of KBGS, providing quantitative craniofacial characterization, and refines genotype-phenotype associations to support improved diagnostic accuracy.
The integration of artificial intelligence (AI) into digital pathology is perhaps the most revolutionary leap forward in modern diagnostic medicine. The present review analyzes the existing context of AI pathology systems, particularly diagnostic precision, clinical validation, and technical systems such as convolutional neural networks and transformers and discusses the integration challenge in clinical workflows for these systems. AI systems have achieved pathologist-level performance in controlled settings, including diagnostic accuracy >99% and area under the receiver operating characteristic curve values exceeding 0.97. However, translating research into clinical adoption is riddled with several challenges attributable to computational requirements, data standardization issues, regulatory hurdles and limitations in generalizability. Moreover, Vision Transformers are widely popular as powerful alternatives to conventional convolutional models, delivering high performance in certain domains while also imposing a novel computational burden. Overcoming these challenges is a prerequisite for the successful integration of AI into pathology practice and the realization of its full diagnostic potential.
Nutrition can affect gut dysbiosis and low-grade inflammation in type 1 diabetes (T1D). The present cross-sectional study aimed to explore the association between dietary factors and inflammatory and endotoxemia markers in patients with T1D. Participants completed a 24-h dietary recall, a 3-day food record and a food frequency questionnaire, and serum levels of inflammatory and endotoxemia markers, and fecal calprotectin levels were measured. In the T1D group, higher high-sensitivity C-reactive protein levels were associated with a higher intake of hot drinks (such as coffee, tea and cocoa) [OR, 3.95 (95% CI, 1.41-11.08), P=0.009] and legumes [OR, 4.91 (95% CI,1.38-17.41), P=0.014], and a lower intake of protein [OR, 0.27 (95% CI, 0.08-0.87), P=0.028], fat [OR, 0.29 (95% CI, 0.09-0.93), P=0.037], energy [OR, 0.26 (95% CI, 0.09-0.77), P=0.015] and fiber [OR, 0.34 (95% CI, 0.12-0.99), P=0.047]. Higher lipopolysaccharide (LPS) levels [OR, 2.07 (95% CI, 1.17-8.02), P=0.022]) and LPS/high-density lipoprotein ratio [OR, 2.71 (95% CI, 1.06-6.95), P=0.038] were associated with an increased consumption of red meat. In addition, fecal calprotectin levels were positively associated with higher protein consumption [OR, 3.37 (95% CI, 1.14-9.95), P=0.028]. In conclusion, the present exploratory study identified several associations between dietary choices and markers of intestinal permeability and inflammation in T1D, highlighting the need for further intervention studies investigating intestinal permeability.
Mutations in the filaggrin (FLG) gene are recognized as major genetic predispositions for atopic dermatitis (AD), yet characterization of FLG protein expression in human subjects remains limited due to the invasive nature of skin biopsies. The present study aimed to evaluate buccal cells as a non-invasive alternative for assessing FLG protein expression and degradation profiles in AD. Buccal cells were collected from 36 patients with AD and 36 healthy controls (aged 20-40 years). FLG gene expression was evaluated using reverse transcription quantitative PCR, while FLG protein expression was assessed by immunoblotting. Although FLG gene expression exhibited substantial variability, FLG protein levels remained relatively stable across samples. Notably, distinct FLG degradation profiles were observed in patients with AD, particularly involving low-molecular-weight fragments. Mild palmar hyperlinearity was identified in 11% of controls and 33% of patients with AD. In addition, buccal cell pellets from patients with AD exhibited increased viscosity compared with those from controls, which was not explained by mucin expression. These findings suggest that buccal cells provide a feasible, non-invasive epithelial model for investigating FLG protein dynamics, offering a complementary approach to skin-based studies. The observed alterations in degradation profiles and pellet viscosity offer new insights into epithelial barrier dysfunction and support the potential of protein-level approaches in AD research.
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally. Chenodeoxycholic acid (CDCA), a key component of bile acids, improves hepatic lipid metabolism. The present study aimed to investigate whether CDCA regulates hepatic lipid metabolism by interacting with pyruvate kinase (PK), and to elucidate the underlying molecular mechanism. High-fat cell and murine models were generated. The levels of total cholesterol (TC), triglycerides (TG), superoxide dismutase (SOD) and malondialdehyde (MDA) in cells and animal livers were measured. BODIPY and Oil Red staining were employed to detect the lipid droplet content. Reverse transcription-quantitative PCR was used to assess the expression of the lipid-related genes. Immunoprecipitation and molecular docking were used to examine the interaction between CDCA and PK, as well as their interaction sites. The effects of their binding on PK activity and pyruvate synthesis were investigated. Both in vitro and in vivo experiments demonstrated that compared with the high-fat group, the TG, TC and MDA levels in the CDCA-treated group were markedly reduced. In addition, lipid droplet count was markedly decreased and SOD activity was increased. The mRNA expression levels of lipid synthesis genes (such as fatty acid synthase and sterol regulatory element-binding transcription factor 1) were notably decreased, whereas those of lipid metabolism genes (CTP synthase 1 and peroxisome proliferator-activated receptor α) exhibited the opposite trend. CDCA specifically bound to the PK-M2 subtype, which promoted PK activity and pyruvate production. Pretreatment with a PK inhibitor completely reversed lipid synthesis inhibition and β-oxidation enhancement induced by CDCA. CDCA notably ameliorated hepatic lipid deposition, and its underlying mechanism was revealed to be closely associated with the direct binding of CDCA to PK and subsequent enhancement of PK activity.
Chronic kidney disease (CKD) is a medical condition affecting >800 million patients globally, with end-stage kidney disease representing the most severe stage, usually requiring dialysis as a form of renal replacement therapy. As these patients have an increased risk of sepsis-associated mortality, and due to the limitations that arise from the use of traditional methods, prompt and accurate approaches in pathogen identification are required to ensure appropriate clinical management. The present study aimed to identify and analyze the bacterial profile of hemodialysis (HD) catheters obtained from patients with CKD who were undergoing hemodialysis using 16S ribosomal DNA (rDNA) amplicon sequencing. The present study proposed the use of the metagenomic approach in clinical laboratory settings. The results obtained in the present study revealed that the bacterial profile between site A (from the patient to the dialysis machine) and site V (from the machine back into the patient) had notable differences, with α- and β-diversity indices suggesting an increased diversity at site V. In addition, analyses of the relative abundance and linear discriminant analysis effect size revealed the presence of known pathogens, including Klebsiella pneumoniae, Gardnerella vaginalis, Escherichia coli, Staphylococcus epidermidis, Acinetobacter baumannii, Corynebacterium striatum and Stenotrophomonas maltophilia. In summary, the findings of the present study highlighted the potential use of 16S rDNA amplicon sequencing as a culture-independent alternative for determining pathogens in patients undergoing HD.
Primary pulmonary tumors in pediatric patients are rare; however, they are frequently malignant, posing significant diagnostic challenges. Therefore, the present study aimed to systematically investigate the clinical, imaging and pathological characteristics of primary pulmonary tumors in children. A total of 36 pediatric patients diagnosed with primary pulmonary tumors were included. Clinical data were collected, including clinical manifestations, imaging findings, pathological analysis, diagnosis and therapy. Among 36 pediatric patients with primary pulmonary tumors, 19 were girls and 17 were boys. The age at diagnosis was 2.0-9.8 years with a median of 4 years. A total of 11 histopathologic tumor types were identified, with pleuropulmonary blastoma (PPB) being the most prevalent. The clinical manifestations were nonspecific, primarily presenting as respiratory symptoms, including cough and fever. These symptoms were frequently associated with complications, including pleural effusion and atelectasis. The maximum tumor diameter ranged from 2.0 to 7.0 cm (median: 4.0 cm), with a predominance of unilateral and unifocal lesions. Furthermore, younger age at diagnosis, solitary lesions and larger non-cystic tumors are indicative of a higher likelihood of PPB. The surgical treatment of thirty-five patients was primarily comprised of open thoracotomy and thoracoscopic surgery. Chemotherapy was administered to 16 patients, while two received a combination of chemotherapy and radiotherapy. Follow-up data were available for 33 patients, with a median follow-up time of 15.0 months and three patients experienced tumor recurrence. The clinical manifestations of primary pulmonary tumors in children are not specific. Imaging and pathological characteristics are valuable in the differential diagnosis of benign and malignant tumors. Younger age at diagnosis, solitary lesions and larger non-cystic tumors are indicative of a higher likelihood of PPB. Integrating molecular diagnostics is an important direction for future research to improve early detection and treatment outcomes.
The high metabolic demand of the liver renders it dependent on mitophagy for mitochondrial quality control. While exercise and nutritional interventions are known to influence hepatic mitophagy, the precise regulatory mechanisms remain incompletely understood. Mitophagy in the liver is influenced by a combination of exercise-related parameters, dietary factors and sex-specific biological factors. Drawing from 19 animal studies published between 2016 and 2026, the present narrative review examines how different exercise modalities and dietary interventions regulate hepatic mitophagy. Among models of obesity and metabolic dysfunction, structured endurance training and higher-intensity exercise protocols yield better capacity to re-establish coordinated mitochondrial quality control than voluntary or low-intensity physical activity protocols. Notably, a single bout of exercise can produce a transient elevation in mitophagic flux, whereas sustained training over time expands mitophagy capacity without necessarily maintaining heightened flux at rest. Moderate-intensity continuous training more effectively restores canonical PTEN-induced kinase 1/Parkin-dependent flux, whereas high-intensity interval training favors structural mitochondrial recovery and upstream energetic signaling, although the relative efficacy depends on the model, disease severity and readout assessed. In high-fat or Western dietary settings, mitophagy is often compromised, with exercise producing incomplete recovery unless paired with improved diet or weight loss. These responses are also influenced by sex differences: Females tend to maintain higher intrinsic mitochondrial quality with less inducible mitophagy, whereas males exhibit a greater reliance on exercise-induced activation of mitophagy. Paternal and maternal developmental programming has also emerged as an important modulator of mitophagy induction. In conclusion, mitophagy in the liver is modified by different exercise and dietary interventions in a manner that is further conditioned by sex and developmental history.
Liver cancer is one of the most common and aggressive malignancies worldwide, with high rates of proliferation, migration and invasion contributing to poor patient outcomes. Ozonated water has potential anti-tumor effects. However, the underlying mechanisms, particularly its interaction with key signaling pathways such as IL-6/STAT3, remain poorly understood. The IL-6/STAT3 pathway serves a critical role in cancer progression, regulating processes such as cell survival and metastasis. To the best of our knowledge, however, the association between ozonated water and this pathway in liver cancer cells has not been thoroughly investigated. Therefore, the objective of the present study was to explore the effects of ozonated water on the proliferation, migration and invasion of HepG2 and Huh-7 liver cancer cells and determine the relationship between ozone and the IL-6/STAT3 signaling pathway, and the potential mechanism of this pathway in HepG2 cells. Proliferation was evaluated using the Cell Counting Kit-8 assay. Wound healing assay was used to evaluate migration ability. Transwell assay with Matrigel was used to evaluate invasion ability. Flow cytometry was used for cell apoptosis analysis. Protein expression was estimated by western blot analysis. Treatment with ozone at a concentration of 20 µg for 24 h inhibited liver cancer cell proliferation, migration and invasion capacities. Flow cytometric analysis revealed a marked increase in apoptosis rate in ozone-treated HepG2 cells (25.15±0.72 vs. 12.90±0.83% in control treated with MEM). Western blotting indicated downregulation of IL-6/STAT3 pathway components in ozone-treated HepG2 cells, with IL-6 and phosphorylated (p-)STAT3 expression levels showing the most pronounced reduction. Concurrently, Bcl-2 protein expression significantly decreased in the ozone-treated cells, whereas cleaved caspase-3 exhibited upregulated expression in treated cells. Ozone inhibited the proliferation, migration and invasion of and induced the apoptosis of liver cancer cells. Medical ozone water may induce liver cancer cell apoptosis by downregulating the IL-6/STAT3 signaling pathway, as evidenced by decreased expression of p-STAT3 and downstream anti-apoptotic proteins (Bcl-2) alongside apoptotic induction.
Baicalin has protective effects against a range of cardiovascular conditions, such as myocardial ischemia-reperfusion injury, cardiac dysfunction, and apoptosis in cardiomyocytes. However, the underlying protective mechanisms in diabetic cardiomyopathy (DCM) remain unclear. The present study aimed to investigate the specific molecular mechanism activated by baicalin to ameliorate DCM. The effects of baicalin were investigated in vitro and its potential targets and pathways were identified using network pharmacology, molecular docking, echocardiography, reverse transcription PCR, ELISA, histopathology, immunofluorescence staining and western blotting. Baicalin significantly alleviated high-glucose (HG)-induced injury in H9c2 cells by inhibiting fibrotic markers, inflammatory factors and pyroptosis. Moreover, protein tyrosine phosphatase non-receptor type 22 (PTPN22) and tumor necrosis factor (TNF) were identified as crucial targets for baicalin. Molecular docking indicated that baicalin exhibited a strong binding affinity for PTPN22 and TNF. Baicalin successfully suppressed HG-induced pyroptosis, inflammation and fibrotic markers in addition to inhibiting the activation of TNF-α and PTPN22 signaling pathways. In addition, PTPN22-small interfering RNA treatment modulated pyroptosis in vitro. The present study offers insight into the key therapeutic mechanisms activated by baicalin, and its potential therapeutic targets, PTPN22 and TNF-α.
