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Ischemic stroke in humans imposes a substantial burden on health care organizations and personal care providers due to the absence of effective therapy that can prevent or halt the development of post-ischemic dementia. As a result, many patients become bedridden and require 24-hour care. Thus, the progressive and irreversible neurodegeneration following ischemia leads to severe long-term outcomes. For this reason, there is great emphasis on better understanding the neuropathogenesis of the post-ischemic brain. Experimental and clinical studies have shown that ischemia leads to progressive neurodegeneration of the brain, which results in impaired cognitive functions and the development of full-blown Alzheimer's disease-type dementia. Elevated levels of tau protein and amyloid have been found in post-ischemic brains, which transform into amyloid plaques and neurofibrillary tangles, respectively. Furthermore, other pathological phenomena have been identified, such as calcium accumulation, decreased acetylcholine levels, excitotoxicity, blood-brain barrier permeability and inflammation. These processes lead to massive neuronal cell death and brain atrophy. Moreover, it has been noted that post-ischemic neurodegenerative processes continue well beyond the acute stage and are irreversible. Previous studies indicate that protein misfolding, aggregation, and damage to multiple organelles are the main pathological phenomena in neurons after ischemia. Autophagy is a key process for the large-scale degradation of protein aggregates and damaged organelles, and existing data indicate that autophagy plays a dual role after ischemia (pro-survival and pro-death). In this review, we focus on the importance of autophagy and mitophagy gene expression at the onset of clinical symptoms (acute phase), during disease progression, and at lesion maturation (chronic phase) after cerebral ischemia. We present the current knowledge on alterations in autophagy genes and the function of autophagy in post-ischemic cerebral neurodegeneration.
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Targeted therapies have revolutionized the treatment landscape of genitourinary (GU) malignancies, offering significant clinical benefits, particularly in renal cell carcinoma (RCC). However, the efficacy of these agents is frequently undermined by the inevitable development of therapy resistance. This review provides a critical analysis of the molecular mechanisms driving resistance in prostate, bladder, and kidney cancers and evaluates emerging clinical strategies to overcome them. We dissect the complex interplay between on-target genomic alterations (e.g., androgen receptor (AR) splice variants, fibroblast growth factor receptor (FGFR) gatekeeper mutations), the activation of compensatory bypass signaling pathways (e.g., phosphoinositide 3-kinase [PI3K]/protein kinase B [AKT] and mitogen-activated protein kinase [MAPK]), and the phenomenon of epigenetic lineage plasticity, such as the neuroendocrine transdifferentiation observed in prostate cancer. Furthermore, we examine the active role of the tumor microenvironment—mediated by cancer-associated fibroblasts and hypoxia—in sheltering tumor cells from therapeutic insults. Beyond defining these mechanisms, this review evaluates the rationale for next-generation therapeutic approaches, including proteolysis targeting chimeras (PROTACs), covalent inhibitors, and epigenetic modifiers. We also address the translational challenges of rational combination therapies, specifically the limitations imposed by cumulative toxicities. Finally, we discuss the pivotal but complex role of biomarkers, such as circulating tumor DNA (ctDNA), in guiding dynamic treatment sequencing and realizing the promise of precision oncology.
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Gynecological cancers (GCs), which primarily encompass cervical cancer (CESC), ovarian cancer (OC), and endometrial cancer (EC), represent a group of malignancies that pose a severe threat to women's health. The advancement of precision medicine holds profound significance for enhancing the diagnosis and treatment of gynecological cancers. The application of molecular-targeted drugs, coupled with progress in surgical concepts and techniques, has substantially improved the survival outcomes of patients with ovarian cancer. Neuropilin-1 (NRP1) was initially identified as a neuronal guidance protein. Recent studies have revealed multifaceted roles of NRP1 in cancers, including its regulatory effects on tumor cell proliferation, growth, metastasis, and angiogenesis. NRP1 functions as a potent modulator of immune cells in the tumor microenvironment. Suppressing NRP1 results in antitumor immune responses and affects the efficacy of cancer immunotherapy. Alterations in NRP1 expression are associated with poor prognosis across a spectrum of malignancies, indicating its potential as a biomarker for evaluating the prognosis of cancer patients. In the present review, we first aim to summarize the expression characteristics and clinical associations of NRP1 in gynecological cancers; second, we elaborate on the role and molecular mechanisms of NRP1 in the progression of these cancers. Therapeutic strategies targeting NRP1 to prevent the development of gynecological cancers will also be discussed. In conclusion, this review highlights the pivotal role of NRP1 in the progression of gynecological cancers and the development of targeted therapeutic strategies, suggesting that NRP1 is a key target for personalized treatment.
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In recent years, the incidence of metabolic diseases, such as obesity and diabetes, has steadily increased with continuous social development. These diseases substantially compromise individuals' quality of life and impose a significant socioeconomic burden. Furthermore, chronic metabolic dysregulation readily triggers various life-threatening cardiovascular complications. As the core of energy metabolism, mitochondria are closely associated with metabolic diseases and related cardiovascular complications. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, regulates the majority of mitochondrial proteins through deacetylation modifications. This process enables it to be involved in various mitochondrial functions and modulate the pathological processes of metabolic diseases such as obesity and diabetes, as well as their cardiovascular complications. This review therefore focuses on SIRT3, summarizing the latest research on its relationship with metabolic diseases and related cardiovascular complications, with the aim of providing a reference for future studies.
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Cholangiocarcinoma (CCA) is a highly aggressive malignancy of the biliary tract with limited therapeutic options and a dismal prognosis. Although immune checkpoint inhibitors (ICIs) have transformed treatment paradigms for several solid tumors, their impact on CCA remains minimal. The unique immunobiology of CCA, including its immune excluded phenotype, low tumor mutational burden, and paucity of actionable biomarkers, has constrained meaningful immunotherapy responses. This review outlines the key immunologic barriers that define the tumor microenvironment in CCA, including the abundance of myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells, metabolic reprogramming, and immune checkpoint overexpression. Given the modest clinical outcomes of ICI monotherapy in CCA, we highlight the rationale for combination strategies incorporating chemotherapy, anti-angiogenic agents, epigenetic modulators, and metabolic inhibitors. Additionally, we assessed the emerging roles of adoptive cell therapy, tumor vaccines, and gut microbiome modulation as novel immunologic interventions. We also discussed how adaptive trial designs and real-time circulating tumor DNA monitoring support dynamic therapy optimization. Although the immunologic silence of CCA has historically limited the efficacy of immunotherapy, growing insights into the tumor microenvironment (TME) and advances in biomarker-guided, personalized strategies offer a compelling roadmap forward. Overcoming immune resistance in CCA will require multidimensional innovation combining biology, technology, and trial design to shift this malignancy from immune evasion to immune engagement.
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Radiation-induced morphea (RIM) is a rare, potentially debilitating complication of breast radiotherapy, characterized by localized dermal fibrosis that may extend beyond irradiated fields. It typically arises within 3–12 months after radiation exposure, but can appear years after treatment completion. Aromatase inhibitors (AIs) are frequently prescribed in postmenopausal breast cancer survivors. These agents significantly reduce estrogen levels and may amplify profibrotic pathways, potentially contributing to RIM development. This review examines the relationship between the use of AIs and RIM development, focusing on the clinical presentation, diagnostic challenges, treatment options, and knowledge gaps. RIM can mimic many dermatologic disorders, causing it to be often misdiagnosed as cellulitis, mastitis, post-radiation fibrosis, or recurrent cancer. Misdiagnosis delays initiation of treatment and can lead to poor outcomes, including breast induration, chronic pain, and disfigurement. A skin biopsy is needed for diagnostic confirmation. There are several reported treatment options for RIM, including topical or systemic corticosteroids, mesalazine, phototherapy, and many others. Current treatments provide predominantly symptomatic relief, and there is no standardized treatment at this time. As this condition can appear several years after radiation, it is recommended that breast cancer patients, especially those who currently or previously received AIs, receive periodic skin examinations after completing radiation. Incorporating dermatologic exams into long-term care allows for close monitoring of irradiated skin, facilitating earlier recognition of cutaneous changes and timely management.
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Background: Gallbladder cancer (GBC) is a highly aggressive malignancy with a notoriously poor prognosis and limited treatment options. Intriguingly, beyond its established perioperative applications, the inhalational anesthetic Sevoflurane has garnered attention for its potential anti-tumor effects, demonstrating the ability to inhibit progression in various cancers. However, its specific impact and the underlying molecular mechanisms in GBC remain largely unexplored. This study systematically investigated the anti-cancer property of Sevoflurane in GBC and associated signaling pathways.
Methods: Sevoflurane at 1.7%, 3.4% and 5.1% concentrations was separately employed to treat human intestinal biliary epithelial cells (HIBEpic) and GBC-SD cells. GBC-SD cells were also pretreated with an endoplasmic reticulum (ER) stress inhibitor Salubrinal, or transfected with Rho-associated coiled-coil containing protein kinase 1 (ROCK1)-overexpressing vectors/short hairpin RNA against ROCK1. Cell viability, migration and invasion, colony formation, and apoptosis were determined using Cell Counting Kit-8, Transwell, colony formation, and flow cytometry assays, respectively. Special kits were used to detect levels of glucose uptake, lactate and adenosine triphosphate (ATP) in GBC-SD cells. ROCK1 expression and levels of ROCK1, activating transcription factor 4 (ATF4) and C/EBP-homologous protein 10 (CHOP) were quantified by quantitative real-time reverse transcription polymerase chain reaction and Western blot analyses, respectively.
Results: Sevoflurane exposure inhibited malignant phenotypes, promoted apoptosis and expressions of ATF4 and CHOP, and reduced ROCK1 expression and levels of glucose uptake, lactate and ATP in GBC-SD cells, while Salubrinal pretreatment reversed the upregulated trends of ATF4 and CHOP (p < 0.05). ROCK1 was highly expressed in different GBC cell lines (p < 0.05). ROCK1 overexpression enhanced malignant phenotypes, promoted levels of glucose uptake, lactate and ATP, and suppressed apoptosis in GBC-SD cells, while ROCK1 silencing reversed these alterations (p < 0.05). Meanwhile, ROCK1 overexpression reversed the effects of Sevoflurane on GBC-SD cells (p < 0.05).
Conclusion: Sevoflurane suppresses GBC progression by activating ER stress and reducing glycolysis via ROCK1 downregulation.
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Background: According to the 2017 classification of periodontal and peri-implant diseases, Stage III and IV periodontitis are defined as severe and advanced forms, respectively. However, current diagnostic differentiation relies largely on clinical probing and lacks objective biomarkers that reflect the systemic inflammatory burden. The Systemic Immune-Inflammation Index (SII)—integrating neutrophil, lymphocyte, and platelet counts—comprehensively reflects the balance of the host “inflammation-immunity-thrombosis” network. Previous studies, however, often failed to adequately control for systemic confounders such as age, smoking status, and metabolic syndrome. Therefore, this study aims to apply Propensity Score Matching (PSM) to rigorously adjust for confounding variables and to evaluate the clinical utility of SII as a novel biomarker for differentiating Stage IV from Stage III periodontitis.
Methods: This retrospective case-control study enrolled patients diagnosed with Stage III and IV periodontitis. To mitigate selection bias, a 1:1 PSM analysis was performed to balance baseline covariates, including age, gender, smoking status, diabetes mellitus, hypertension, body mass index (BMI), and educational level. Differences in SII levels between groups were analyzed using the Mann-Whitney U test. A multivariate logistic regression model was constructed to assess the association between SII and the risk of Stage IV periodontitis. Additionally, Restricted Cubic Spline (RCS) modeling was employed to explore potential non-linear dose-response relationships.
Results: After PSM, a total of 212 patients with balanced baseline characteristics were included (106 each for Stage III and IV). Analysis revealed that SII levels were significantly higher in patients with Stage IV periodontitis compared to those with Stage III [Median: 577.23 vs. 529.06, p = 0.003]. Multivariate logistic regression confirmed that, even after adjusting for all confounding factors, elevated SII levels remained an independent risk factor for progression to Stage IV periodontitis (p < 0.001). Furthermore, RCS analysis demonstrated a significant linear dose-response relationship between SII levels and the risk of Stage IV periodontitis (poverall = 0.009), with no evidence of a non-linear threshold effect (pnon-linearity = 0.069).
Conclusion: Even after rigorous adjustment for systemic confounders, elevated SII levels are significantly associated with Stage IV periodontitis and exhibit a linear cumulative trend. As a cost-effective and accessible objective indicator, SII not only aids in the precise grading of Stage III and Stage IV periodontitis but also highlights the heightened systemic inflammatory burden in severe cases, thereby supporting the implementation of multidisciplinary management strategies.
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Background: Tooth wear (TW) typically requires occlusal reconstruction as an effective treatment. Progression of TW into a pathological state may cause various symptoms, including temporomandibular joint (TMJ) pain, occlusal disorders, and aesthetic concerns. Previous studies mainly focused on oral and facial tissues and electromyographic activity of masticatory muscles rather than the nervous system. This study aims to investigate the effects of bite reconstruction following TW on the peripheral and central nervous systems (CNS).
Methods: The bilateral maxillary molars of 60 Sprague-Dawley rats were examined, and a subgroup of 20 rats was selected to establish an occlusal reconstruction model. Subsequently, four time points were designated for general observation and measurement of pressure pain threshold (PPT). Immunofluorescence was employed to evaluate the expression of substance P (SP), calcitonin gene-related peptide (CGRP), and phosphorylated extracellular signal-regulated kinase (p-ERK) in trigeminal ganglion and medulla oblongata tissues. quantitative real-time polymerase chain reaction (qPCR) was performed to measure expression of tachykinin precursor 1 (Tac1), calcitonin-related polypeptide alpha (CALCA), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and brain-derived neurotrophic factor (BDNF). Additionally, Western blot (WB) was conducted to analyze expression of mitogen-activated protein kinase p38 (p38), phosphorylated p38 (p-p38), extracellular signal-regulated kinase (ERK), and p-ERK proteins.
Results: No bleeding or ulceration was observed in any rat group following each operation. Additionally, no significant tooth loosening or loss occurred, and facial symmetry during chewing and stable body weight were maintained in all groups. In the occlusal reconstruction group, PPT values significantly decreased on the third day post-modeling (p < 0.001) but gradually returned to baseline levels by day 28. SP levels significantly increased over time following occlusal reconstruction (p < 0.001) and returned to normal levels by day 28. The expression of p-ERK increased significantly 3 days after reconstruction (p < 0.001); although the number of positive cells decreased at day 14, it remained significantly higher than the control group (p < 0.01) before returning to baseline levels by day 28. Similarly, the expression of Tac1, CALCA, TNF-α, IL-1β, and BDNF genes exhibited a consistent downward trend on days 3, 7, and 14 post-reconstruction (p < 0.01). WB analysis revealed that expression of p-p38 and p-ERK proteins peaked on day 3 in the occlusal reconstruction group (p < 0.001) and gradually decreased thereafter.
Conclusions: Occlusal reconstruction may alleviate pain perception and nerve injury through activation of the p38 mitogen-activated protein kinase (MAPK)/ERK signaling pathway and regulation of factors such as SP, CGRP, and BDNF.
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Background: Myocardial ischemia/reperfusion injury (MIRI) remains a leading cause of morbidity and mortality in patients with cardiovascular disease. Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly implicated in cardiomyocyte damage during MIRI. Heat shock factor 1 (HSF1) and heme oxygenase-1 (HMOX1) are stress-responsive proteins, but their interplay in regulating ferroptosis during myocardial injury has not been fully elucidated. This study aimed to investigate the role of the HSF1–HMOX1 axis in modulating ferroptosis and myocardial injury after ischemia/reperfusion (I/R).
Methods: An I/R rat model was established by transient ligation of the left anterior descending coronary artery, with sham-operated rats serving as controls. H9c2 cardiomyocytes subjected to hypoxia/reoxygenation (H/R) and co-cultured with RAW 264.7 macrophages were used for in vitro experiments. HSF1 overexpression and knockdown, as well as HMOX1 knockdown via siRNA, were performed. Myocardial injury was assessed by measurement of serum creatine kinase–myocardial band (CK-MB) and cardiac troponin I (cTn-I), as well as histologic and immunohistochemical means. Ferroptosis was evaluated using cell viability assays, reactive oxygen species (ROS) detection, and protein detection of glutathione peroxidase 4 (GPX4), SLC7A11, and ACSL4 by means of Western blotting. Inflammatory responses and macrophage polarization were analyzed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry.
Results: HSF1 and HMOX1 expression were transiently upregulated in myocardial tissues during early I/R but decreased at 24 h. HSF1 overexpression further increased ROS accumulation and exacerbated ferroptosis, as reflected by GPX4 downregulation and ACSL4 upregulation. Conversely, HSF1 knockdown attenuated ferroptosis and injury. HMOX1 knockdown reversed the pro-ferroptotic effects of HSF1 overexpression, indicating that HMOX1 mediates HSF1-induced ferroptosis. Furthermore, the HSF1–HMOX1 axis promoted macrophage polarization toward the pro-inflammatory M1 phenotype, enhancing tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 secretion.
Conclusions: The HSF1–HMOX1 axis promotes ferroptosis and exacerbates myocardial damage in ischemia/reperfusion injury by integrating stress response pathways and inflammatory regulation. Inhibiting this axis may represent a promising therapeutic strategy for reducing MIRI and improving cardiac outcomes.
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Background: High-fat diet (HFD) induces neuroinflammation and oxidative stress, leading to cerebral injury and cognitive decline. Propofol, an intravenous anesthetic, exhibits anti-inflammatory and antioxidant effects. The present study aimed to evaluate its neuroprotective role in HFD-induced brain injury and to explore whether these effects may be associated with regulation of the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway.
Methods: Rats were assigned to normal diet (ND), HFD, HFD+low-dose propofol, and HFD+high-dose propofol groups. After intervention, cognitive function was tested using the Morris water maze. Brain histopathology, apoptosis, inflammatory cytokines, oxidative stress markers, and protein expression related to apoptosis, autophagy, and AMPK/mTOR signaling were analyzed.
Results: HFD-fed rats exhibited impaired learning and memory performance, neuronal damage and apoptosis, increased levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA), as well as reduced superoxide dismutase (SOD) activity and glutathione (GSH) levels (all p < 0.05), accompanied by autophagy dysregulation characterized by LC3-II accumulation and p62 upregulation, along with suppression of AMPK with activation of mTOR (p < 0.05). Propofol treatment, particularly at the higher dose, significantly improved cognitive function, attenuated neuronal injury and apoptosis, reduced inflammatory and oxidative stress markers, restored autophagy-related alterations, which were accompanied by enhanced AMPK activation and inhibited mTOR signaling (p < 0.05).
Conclusion: Propofol alleviates HFD-induced neuroinflammation, oxidative stress, apoptosis, and autophagy-related alterations, which may be associated with modulation of the AMPK/mTOR signaling pathway, supporting its potential as a therapeutic strategy for metabolic-associated neurological disorders.
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Background: The persistent expression of high-risk human papillomavirus (hrHPV) E6 oncoproteins is a critical determinant in driving and maintaining the malignant phenotype of cervical cancer, a pathogenic process where autophagy serves as a key regulatory mechanism. This study aimed to identify autophagy-related genes as potential biomarkers for prognostic evaluation in cervical cancer.
Methods: This study established an HPV 16 E6-induced C33a cervical cancer cell model, which was treated with the autophagy activator rapamycin or inhibitor 3-methyladenine to modulate autophagy. The expression of the autophagy-related gene C-X-C motif chemokine ligand 8 (CXCL8) was analyzed by reverse transcription-quantitative PCR (RT-qPCR), western blotting, and enzyme-linked immunosorbent assay. Cell viability, migration, invasion, and apoptosis were assessed using the Cell Counting Kit-8 assay, wound healing assay, Transwell assay, and Terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assays, respectively. Furthermore, CXCL8 expression levels in tumor tissues from cervical cancer patients with favorable (n = 81) and unfavorable (n = 61) prognosis were examined by immunohistochemistry and RT-qPCR. Univariate and multivariate Cox proportional hazards regression analyses were conducted to identify independent risk factors influencing disease-free survival (DFS) in cervical cancer patients. Receiver operating characteristic (ROC) curve analysis was employed to evaluate the predictive value of CXCL8 for unfavorable prognosis risk.
Results: Mechanistic studies indicated the participation of CXCL8 in HPV 16 E6–induced malignant phenotypes. The autophagy activator rapamycin or CXCL8-neutralizing antibody could neutralize the oncogenic effects of HPV 16 E6. CXCL8 was highly expressed in tumor tissues with poor prognosis. It showed correlations with poor tumor differentiation, cervical infiltration depth ≥2/3, and lymph node metastasis, independent of clinical stage. CXCL8 was identified as an independent prognostic factor in cervical cancer [hazard ratio = 3.143, 95% confidence interval (CI): 1.519–6.507, p = 0.002] and was significantly correlated with inferior DFS (χ2 = 34.905, p < 0.0001). Furthermore, a model combining CXCL8 with squamous cell carcinoma antigen and cytokeratin 19 fragment showed promising prognostic accuracy, achieving an area under the curve of 0.897 (95% CI: 0.835–0.942) with 90.16% sensitivity and 88.89% specificity.
Conclusion: The CXCL8 gene promotes cervical cancer progression by contributing to the regulation of autophagy mediated by HPV 16 E6. This functional role underpins its potential utility as a clinical prognostic biomarker.
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Background: To investigate the role and the underlying mechanisms of Calcium/calmodulin-dependent protein kinase Iα (CaMKIα) in modulating inflammatory responses during acute lung injury (ALI) via the AMPK/Sirtuin 3 (SIRT3) signaling pathway.
Methods: Neonatal rats were intratracheally administered Lipopolysaccharide (LPS) to induce ALI, while L2 alveolar epithelial cells were treated with LPS (100 ng/mL) in vitro. CaMKIα expression was silenced using siRNA in L2 cells and via AAV2/9-shRNA in rats. AMP-activated protein kinase (AMPK) activity was inhibited with Compound C (5 μM) in vitro. Pulmonary histopathology, bronchoalveolar lavage fluid cytokine levels, and key AMPK/SIRT3 pathway protein expressions were assessed.
Results: CaMKIα knockdown significantly alleviated lung injury in ALI rats, and significantly reduced lung edema, inflammatory cytokine levels, and histological injury (all p < 0.05). In vitro, CaMKIα knockdown enhanced L2 cell viability, suppressed apoptosis, and reduced pro-inflammatory cytokine production (all p < 0.05) via AMPK/SIRT3 activation. Inhibition of AMPK with Compound C abolished these protective effects (p < 0.05), confirming the involvement of this pathway.
Conclusion: CaMKIα attenuates inflammatory responses in ALI through activation of the AMPK/SIRT3 axis, indicating it may serve as a promising target for ALI therapy.
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Background: Axial spondyloarthritis (axSpA) often presents atypically in female patients, leading to prominent issues of diagnostic delay. However, the specific determinants of diagnostic delay in women and their impact on 12-month outcomes following treatment initiation remain understudied. This study aimed to identify independent factors associated with diagnostic delay in female axSpA patients and evaluate the independent effect of diagnostic delay on disease activity outcomes at 12 months post-diagnosis.
Methods: This was a single-center retrospective cohort study. We consecutively enrolled 156 female patients diagnosed with axSpA between January 1, 2020, and June 30, 2024. Demographic, clinical, and care pathway data were extracted from medical records. Diagnostic delay was defined as the interval (in years) from symptom onset to definitive diagnosis, analyzed after natural logarithmic transformation. The primary outcome was disease activity at 12 months post-diagnosis, measured by the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP). Univariate and multivariable linear regression analyses were used to identify factors influencing diagnostic delay. Multivariable linear regression (adjusted for baseline ASDAS-CRP, disease phenotype, treatment regimen, and age at onset) assessed the independent impact of diagnostic delay on the outcome.
Results: The median diagnostic delay was 5.90 years (interquartile range: 4.40–7.46). Multivariable linear regression identified that initial consultation with a non-rheumatologist [Beta coefficient (β) = 0.589, 95% confidence interval (95% CI): 0.493–0.686, p < 0.001], prior misdiagnosis (β = 0.218, 95% CI: 0.144–0.292, p < 0.001), non-radiographic axSpA (nr-axSpA) phenotype (β = 0.132, 95% CI: 0.059–0.206, p < 0.001), and concomitant uveitis (β = 0.182, 95% CI: 0.108–0.257, p < 0.001) were independent risk factors for prolonged diagnostic delay. Outcome analysis revealed that, after adjusting for confounders, longer diagnostic delay (β = 0.649, 95% CI: 0.450–0.848, p < 0.001), use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) compared to Non-Steroidal Anti-inflammatory Drugs (NSAIDs) monotherapy (β = 0.157, 95% CI: 0.011–0.302, p = 0.036), and higher baseline ASDAS-CRP score (β = 0.481, 95% CI: 0.384–0.578, p < 0.001) were independent predictors of poorer disease control (higher ASDAS-CRP score) at 12 months post-diagnosis.
Conclusion: In female axSpA patients, suboptimal care pathways, misdiagnosis, and atypical clinical manifestations are major contributors to diagnostic delay. A longer diagnostic delay independently predicts worse 12-month treatment outcomes. These findings underscore the urgent need to enhance early recognition capabilities among non-rheumatologists and optimize referral pathways to shorten diagnostic delay.
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Background: Retinoblastoma (RB) is a highly aggressive pediatric ocular malignancy whose molecular mechanisms remain unclear. Although implicated in various cancers, the amino acid transporter Solute Carrier Family 38 Member 5 (SLC38A5) remains uncharacterized in RB. Herein, we aimed to investigate the expression pattern, biological functions, and underlying mechanisms of SLC38A5 in RB.
Methods: SLC38A5 expression was analyzed in human RB cell lines using Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). Functional characterization was performed through genetic manipulation (knockdown/overexpression) followed by comprehensive phenotypic assessment. In vivo xenograft models were used to evaluate tumor growth.
Results: SLC38A5 was significantly overexpressed in RB cell lines, particularly in Y79 and WERI-Rb1 (p < 0.001). SLC38A5 knockdown suppressed cell proliferation, migration, and invasion, and induced apoptosis (p < 0.05). Conversely, SLC38A5 overexpression enhanced these malignant phenotypes (p < 0.05). Additionally, SLC38A5 modulated mitochondrial function via the mTOR signaling pathway (p < 0.05). In vivo, SLC38A5 overexpression promoted tumor growth, whereas knockdown inhibited tumor progression (p < 0.05).
Conclusion: SLC38A5 acts as a key regulator of RB progression by modulating core biological processes, including proliferation, migration, invasion, and mitochondrial function. Targeting SLC38A5 may represent a potential therapeutic strategy for RB.
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Background: Excess intramyocellular lipid induces lipotoxicity, which has been implicated in the development of insulin resistance and metabolic diseases. Although dietary capsaicin has been shown to reduce intramyocellular lipid content in mice, the underlying mechanisms remain unclear. This study aims to investigate the effects of capsaicin on lipophagy and fatty acid metabolism in skeletal muscle cells and explore the underlying mechanisms.
Methods: Wild-type and transient receptor potential vanilloid channel 1 (TRPV1) knock-out (KO) mice were fed a high-fat diet (HD) with or without capsaicin for 4 months. They underwent a fasting exercise to induce autophagy before measurement. C2C12 myotubes were cultured with palmitate and treated with or without capsaicin, specific antagonists, or transcription factor EB (TFEB) RNAi. Respiratory exchange ratio (RER), metabolic parameters and muscle mitochondrial fatty acid oxidation were assessed. Autophagic flux was detected using the Premo Autophagy Tandem Sensor. TFEB transcriptional activity was detected by luciferase assays. RNA-sequencing, Western blotting, and immunofluorescence were conducted to analyze the expression of lipophagy-related genes.
Results: Lipid overload inhibited fatty acid oxidation and impaired autophagy flux in muscles of HD-fed wild-type mice and myotubes cultured with palmitate. Although capsaicin significantly attenuated this inhibition (p < 0.05), the effect was not replicated in the TRPV1 KO mice (p > 0.05). In cultured myotubes, capsaicin dose-dependently promoted the expression of TFEB and also enhanced TFEB transcriptional activity (p < 0.05). This led to increased acidic lysosomes, degradation of p62 and perilipin 2, and improved fatty acid oxidation (p < 0.05). The TRPV1 antagonist, the calcineurin inhibitor, or TFEB siRNA significantly inhibited the effects of capsaicin (p < 0.05).
Conclusions: Capsaicin ameliorates impaired lipophagy and fatty acid oxidation in lipid-overloaded skeletal muscle cells through a TRPV1/TFEB-dependent pathway.
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Background: Cardiac hypertrophy is a major risk factor for heart failure, and accumulating evidence suggests that ferroptosis—a form of regulated cell death driven by iron—dependent lipid peroxidation-contributes to its progression. However, the regulatory mechanisms linking cardiac hypertrophy and ferroptosis remain incompletely understood. This study, therefore, aimed to investigate the role of anoctamin 1 (ANO1), a calcium-activated chloride channel, in cardiac hypertrophy and ferroptosis.
Methods: A transverse aortic constriction (TAC) mouse model and angiotensin II (AngII)-stimulated H9c2 cardiomyocytes were used to evaluate ANO1 expression. Loss- and gain-of-function experiments were performed in vitro and in vivo. Ferroptosis-related markers, oxidative stress indicators, histological changes, and cardiac hypertrophy parameters were assessed by qPCR, Western blotting, immunohistochemistry, and functional assays.
Results: ANO1 expression was significantly elevated in hypertrophic hearts and AngII-treated cardiomyocytes (p < 0.05). Silencing ANO1 reduced the expression of the ferroptosis-promoting enzyme Acyl-CoA synthetase long-chain family member 4 (ACSL4), restored solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) levels (p < 0.05), and mitigated oxidative stress and lipid peroxidation, thus leading to improved cell viability and reduced hypertrophy. Conversely, ANO1 overexpression aggravated ferroptosis and oxidative injury (p < 0.05), which could be reversed by the ferroptosis inhibitor ferrostatin-1 (p < 0.05). In vivo, AAV9-mediated ANO1 knockdown attenuated TAC-induced cardiac hypertrophy and ferroptosis (p < 0.05), indicating its pathological role.
Conclusion: ANO1 promotes cardiac hypertrophy by enhancing ferroptosis and oxidative stress. Targeting ANO1 may represent a promising therapeutic strategy for preventing or treating pathological cardiac remodeling.
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Background: Over the past 50 years, the consumption of ultra-processed food (UPF) has increased significantly, paralleling the rising trend in obesity. UPF has been shown to have numerous adverse health outcomes and is associated with various lifestyle-related diseases. Although the relationship between UPF and visceral adipose tissue has been explored, comprehensive analyses of UPF in relation to abdominal ultrasound parameters and glycemic parameters in patients with abdominal obesity and type 2 diabetes mellitus (T2DM) remain limited. Therefore, this study was conducted to investigate the aforementioned relationship in this specific patient population.
Methods: A retrospective study was conducted on 286 T2DM patients admitted to our hospital from January 2021 to December 2024, consisting of 172 patients with abdominal obesity. The T2DM patients with abdominal obesity were divided into two groups: low UPF intake group (n = 74) and high UPF intake group (n = 98). Spearman's rank correlation was used to assess associations between variables. The receiver operating characteristic (ROC) curve was employed to evaluate the predictive value of relevant indicators in T2DM patients with or without abdominal obesity.
Results: There were no statistically significant differences in age, gender, hypertension, smoking status, alcohol consumption, Triglycerides (TG). Glycosylated hemoglobin (HbA1c), and interleukin-6 (IL-6) between the low UPF intake group and the high UPF intake group (p > 0.05). However, differences in Body Mass Index (BMI); Glucose (GLU); Total Cholesterol (TC), Hypersensitive C-reactive Protein (hsCRP), Subcutaneous Adipose Tissue (SAT), and visceral adipose tissue (VAT) were statistically significant (p < 0.05). Correlation analysis indicated that UPF intake was positively correlated with Glucose (GLU), TC, hsCRP, SAT, and VAT (r = 0.437, 0.287, 0.192, 0.372, 0.447; p < 0.05). Furthermore, BMI, SAT, VAT, and UPF intake significantly differed between patients with and without abdominal obesity (p < 0.05). Binary Logistics regression analysis revealed that SAT, VAT, and UPF intake were independent influencing factors for abdominal obesity in T2DM patients (p < 0.05). ROC analysis demonstrated that the area under the curve of the composite index was 0.799, with a standard error of 0.027 (95% CI: 0.747–0.852), a Youden index of 0.53, sensitivity of 70.35%, and specificity of 82.46%.
Conclusion: UPF intake is positively correlated with GLU, TC, hsCRP, SAT, and VAT, and the combination of UPF intake with SAT and VAT has a high predictive value for abdominal obesity in T2DM patients.
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Background: Sepsis-induced acute kidney injury (AKI) is a severe clinical complication characterized by tubular epithelial cell damage and mitochondrial dysfunction. This study aims to elucidate the mechanism by which methylation of CCCTC-binding factor (CTCF) regulates the E1A binding protein p300 (EP300)/methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 (MTHFD2) axis and, as a result, impacts mitochondrial function during septic tubular injury.
Methods: Human renal proximal tubular epithelial HK-2 cells were treated with lipopolysaccharide (LPS) to mimic septic conditions. The regulatory relationship between CTCF methylation and the EP300/MTHFD2 axis was analyzed using luciferase reporter assays, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and methylation-specific PCR (MSP). Cell viability, apoptosis, reactive oxygen species (ROS) levels, and mitochondrial membrane potential were assessed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, flow cytometry, and JC-1 staining, respectively.
Results: CTCF interacted with EP300 and impacted the expression of MTHFD2 (p < 0.01). Knockdown of CTCF resulted in MTHFD2 downregulation and decreased H3K27ac enrichment at the MTHFD2 promoter (p < 0.001). EP300 regulated MTHFD2 transcription by promoting histone H3 lysine 27 acetylation (H3K27ac) at its promoter (p < 0.05). Functional experiments demonstrated that CTCF silencing exacerbated LPS-induced weakened viability, increased apoptosis, elevated ROS production, and decreased mitochondrial membrane potential (p < 0.001). Notably, EP300 overexpression reversed these pathological changes (p < 0.001). Furthermore, the methylation status of the CTCF promoter was influenced by MTHFD2 expression (p < 0.05).
Conclusion: This in vitro study reveals a novel regulatory axis in which methylation of CTCF modulates the EP300/MTHFD2 pathway, which may contribute to mitochondrial dysfunction in tubular epithelial cells (HK-2) under septic conditions.
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Background: Gastric cancer has a poor prognosis and remains a major public health challenge. Therefore, identifying reliable biomarkers is essential to enhance early detection and improve patient survival.
Methods: We integrated gene expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to identify markedly dysregulated genes, and performed Mendelian randomization analyses using MR-Base to evaluate potential causal relationships. Colocalization analysis was subsequently conducted to refine candidate loci. Functional enrichment analyses, including Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), were performed to explore the underlying biological processes, followed by construction of a regulatory network and development of a prognostic model. We further established and validated a risk model for predicting overall survival. Single-cell RNA sequencing data (GSE163558) were analyzed to characterize gene expression across specific cell types. Finally, immunohistochemistry (IHC) was used to verify protein-level differences between gastric cancer tissues and adjacent normal tissues.
Results: Pyruvate dehydrogenase kinase 4 (PDK4) and repulsive guidance molecule A (RGMA) were identified as biomarkers. These genes play active roles in key biological processes, including cellular transformation and angiogenesis. By integrating PDK4 and RGMA expression with clinical parameters, we constructed a prognostic model that accurately predicted 3- and 5-year survival outcomes in the TCGA-STAD cohort. Single-cell analysis further revealed cell–type–specific expression patterns of these genes. In addition, immunohistochemical assays demonstrated higher protein levels in tumor tissues compared with adjacent normal tissues.
Conclusions: This comprehensive study suggests that PDK4 and RGMA are promising biomarkers that may facilitate the early detection of gastric cancer and improve prognostic assessment. These findings provide new insights into the disease's pathogenesis and may further inform future clinical decision-making.
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Background: Gastric cancer (GC) has a poor response to current chemo-immunotherapy. Ferroptosis is a newly recognised form of iron-dependent cell death that can enhance drug efficacy; however, the key regulator factors and mechanisms governing ferroptosis in gastric cancer remain unclear. This study aimed to investigate the synergistic antitumor effect of oxaliplatin combined with a programmed death-1 (PD-1) inhibitor in gastric cancer and elucidate the regulatory role of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in ferroptosis.
Methods: Subcutaneous mouse forestomach carcinoma (MFC) gastric cancer xenograft models were successfully developed using immunodeficient BALB/c nude mice and randomized into control, oxaliplatin, PD-1 inhibitor, and combination groups for in vivo efficacy assessment. In vitro, STEAP4 was silenced in MFC cells via siRNA to evaluate its impact on drug sensitivity. Western blotting, qRT-PCR (Quantitative Reverse Transcription Polymerase Chain Reaction), transmission electron microscopy, and biochemical assays were used to detect STEAP4 expression and ferroptosis-related markers.
Results: The combination treatment significantly suppressed tumor growth compared with monotherapies (p < 0.01). Mechanistically, it induced ferroptosis, characterized by mitochondrial shrinkage, increased Fe2+ and ROS (Reactive Oxygen Species) levels, upregulation of ACSL4, and downregulation of glutathione peroxidase 4 (GPX4) and SLC7A11. STEAP4 expression was markedly elevated in tumor tissues after combination therapy (p < 0.01). STEAP4 knockdown reduced the sensitivity of MFC cells to the combination and reversed ferroptosis induction by suppressing ACSL4 and restoring GPX4 and SLC7A11 expression.
Conclusion: The combination of oxaliplatin and a PD-1 inhibitor exerts potent synergistic effects in gastric cancer through STEAP4 upregulation, which promotes ferroptosis and enhances treatment sensitivity. STEAP4 may serve as a potential biomarker and therapeutic target for optimizing combination therapy in gastric cancer.
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Background: Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors with significant variations in prognosis and sensitivity to imatinib. Traditional detection of the DEL 557–558 mutation requires invasive procedures and is costly. Radiogenomics, by analyzing imaging, can predict tumor mutations and provide diagnostic and prognostic insight. Based on this, this study constructs and validates a radiomics-based prediction framework to preoperatively identify the KIT exon 11 codon 557–558 deletion mutation (DEL 557–558) in GISTs using contrast-enhanced CT (CE-CT).
Methods: The CE-CT images and medical record data were examined for 126 GIST patients who underwent surgical resection and gene mutation testing between 2019 and 2021 at the medical center. Optimal radiomic features were extracted from the selected region of interest (ROI) on the CE-CT images. Two logistic regression (LR) models were established to forecast DEL 557–558: one utilized solely radiomic features, while the other incorporated both radiomic and clinicopathological parameters. The effectiveness of the LR models' predictions was assessed through receiver operating characteristic (ROC) curve analysis, with the mean area under the curve (AUC) value calculated via a five-fold cross-validation protocol.
Results: Gastric location, higher mitotic count and higher Ki-67 expression were associated with GIST patients with DEL 557–558 mutation. The radiomic features model, incorporating 12 radiomic features, had AUCs of 0.90 ± 0.01 (95% CI: 0.87–0.94), 0.76 ± 0.04 (95% CI: 0.66–0.88), 0.892 (95% CI: 0.824–0.960) and 0.850 (95% CI: 0.720–0.980) in the prediction of DEL 557–558 in the training, validation, cross-validation and test datasets, respectively. The integrated model combining radiomic attributes with clinicopathological parameters displayed enhanced predictive performance, achieving AUC values of 0.93 ± 0.01 (95% CI: 0.90–0.96), 0.82 ± 0.04 (95% CI: 0.71–0.91), 0.916 (95% CI: 0.857–0.974) and 0.875 (95% CI: 0.745–1.000) in the training, validation, cross-validation and test datasets, respectively.
Conclusion: Radiomics models may help predict DEL 557–558 mutations, thereby enabling more effective treatment selection and prognosis assessment.
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Background: Polycystic ovary syndrome (PCOS) is a common disease that often results in miscarriage among females. The study aimed to elucidate the relationship between chromatin regulators and PCOS to explore potential biomarkers for PCOS.
Methods: Differential genes between PCOS patients and healthy controls were screened based on GSE10946 dataset. Pivotal genes were screened using LASSO (Least Absolute Shrinkage and Selection Operator), XGBoost (eXtreme Gradient Boosting) and random forest, and crossover genes of these three machine learning methods were further screened using a Venn diagram. The predictive potential of these key genes was evaluated using receiver operating characteristic (ROC) curve analysis, and functional enrichment analysis was conducted to elucidate the associated signaling pathways. To investigate their roles in PCOS and their effects on the immune microenvironment, immunity profiles between PCOS patients and healthy controls were compared; the correlations between key genes and immune cell populations were also examined, and then the associations of these genes with potential drug candidates were explored.
Results: GADD45A and TAF5 were identified as critical genes associated with PCOS, exhibiting significantly decreased expression levels in PCOS patients compared to healthy controls (both p < 0.05). Both genes showed strong predictive performance. Functional enrichment revealed their involvement in pathways such as cholesterol homeostasis and E2F targets. Immune infiltration analysis indicated distinct differences in immune cell composition between the PCOS and control groups, with gene expression levels closely correlating with specific immune cell subsets (all p < 0.05).
Conclusion: GADD45A and TAF5 have high predictive ability for PCOS and have the potential to be new biomarkers and therapeutic targets for PCOS.
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Background: Apolipoprotein O (APOO) influences the tumor microenvironment and cancer progression, but its role in macrophage regulation in breast cancer (BC) remains unclear. This study aimed to investigate APOO's effect on macrophage polarization and its molecular mechanisms in BC.
Methods: Gene expression data obtained from single-cell RNA sequencing (RNA-seq) and The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) were analyzed to identify key BC-associated genes. Clinical relevance was validated with TCGA patient data. APOO was overexpressed in tumor cells and co-cultured with macrophages. M2 polarization was assessed by cluster of differentiation 206 (CD206) flow cytometry and quantitative real-time PCR (qRT-PCR), and the role of aarF domain containing kinase 2 (ADCK2) was evaluated by co-culture with ADCK2 knockdown macrophages.
Results: Our analysis identified anti-müllerian hormone (AMH), APOO, neurexophilin 4 (NXPH4), and vascular endothelial growth factor (VEGF) as key differentially expressed genes in BC. Among these, APOO was notably upregulated in tumor tissues as well as correlated significantly with poorer clinical outcomes (p < 0.05). Immune infiltration analysis indicated that higher APOO expression was linked to enhanced macrophage infiltration, with a notable increase in M2-like macrophages. Functional assays demonstrated that APOO promotes M2 macrophage polarization via the ADCK2 signaling pathway (p < 0.05).
Conclusions: These findings suggest that APOO may serve as both a potential biomarker and a therapeutic target in BC treatment strategies.
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Background: Subarachnoid hemorrhage (SAH), particularly with intraventricular extension (Fisher grade IV), is frequently accompanied by electrocardiographic (ECG) abnormalities, which are often attributed to autonomic dysfunction. The periaqueductal gray (PAG), a midbrain structure involved in autonomic and nociceptive processing, may play a pivotal role in these cardiovascular manifestations. This systematic review aims to analyze ECG alterations in patients with SAH complicated by intraventricular hemorrhage (IVH) and examine the autonomic effects of PAG stimulation in both experimental and clinical studies.
Methods: A systematic search of PubMed, Scopus, and Web of Science was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible studies included adult or neonatal patients with SAH+IVH reporting ECG or autonomic outcomes, and human or animal studies assessing autonomic effects of PAG stimulation. Data extraction focused on ECG changes, heart rate variability (HRV), blood pressure, autonomic indices, stimulation parameters, and neuroanatomical correlations.
Results: Of 59 initially identified studies, 22 met the inclusion criteria. Among these, 10 clinical studies described ECG abnormalities in Fisher IV SAH patients, including corrected QT interval (QTc) prolongation, ST-segment changes, and T-wave inversion. The remaining 12 studies, focusing on PAG stimulation, revealed its modulatory effects on HRV, heart rate, and blood pressure. Specifically, ventral PAG stimulation enhanced parasympathetic output, whereas stimulation of lateral regions was associated with sympathetic activation.
Conclusions: The review highlights a possible pathophysiological link between intraventricular blood extension in SAH and ECG abnormalities, potentially mediated by PAG involvement. Experimental data reinforce the role of the PAG in autonomic regulation. Future studies should focus on neurocardiac monitoring strategies and targeted neuromodulation in patients with hemorrhagic brain injury.
