The Kaohsiung journal of medical sciences最新文献

Although environmental enrichment (EE) promotes post-stroke motor recovery, the mechanisms underlying its regulation of cerebellar dentate nucleus (DN) plasticity remain unclear; this study therefore investigated how EE coordinates autophagy, mitochondrial homeostasis, and synaptic remodeling in the contralateral DN to facilitate functional restoration. Using a permanent middle cerebral artery occlusion (pMCAO) mouse model, we combined behavioral tests (rotarod and ladder rung) with electron microscopy, Western blotting (LC3B, p62, mTOR/p-mTOR), and ELISA (TNF-α, IL-1β, IL-6) to assess motor function, ultrastructural changes, autophagy, and neuroinflammation. Results demonstrated that EE significantly improved cerebellar-mediated motor coordination, reduced neuronal degeneration, and preserved mitochondrial integrity, while enhancing autophagic activity via increased LC3B expression and decreased p62 accumulation. Ultrastructural analysis revealed elevated synaptic density and a shift toward mitochondrial rejuvenation, paralleled by attenuated neuroinflammatory responses and suppressed pro-inflammatory cytokine levels, consistent with mTOR pathway inhibition. These findings indicate that EE promotes motor recovery by activating a self-reinforcing repair loop in the DN, wherein autophagy-mediated mitochondrial clearance and neuroinflammation suppression create a permissive microenvironment for synaptic remodeling, thereby establishing the DN as a pivotal hub for EE's therapeutic effects and supporting combinatory strategies targeting autophagy-mitochondrial pathways to optimize rehabilitation.

Colorectal cancer (CRC) has raised considerable health concerns worldwide, with increasing incidence rates, specifically among younger populations. Despite remarkable progress in diagnosing and treating various diseases, the genetic basis of CRC remains only partially understood. This paper aims to examine novel genetic variants associated with CRC in Iranian patients. We performed whole-exome sequencing (WES) in two Iranian families with a history of early-onset CRC. Candidate variants were validated by Sanger sequencing and assessed for segregation. Pathogenicity was evaluated through comprehensive in silico analysis and the application of ACMG/AMP guidelines. Analysis revealed two clinically significant variants. In Family 1, we identified a heterozygous stop-gain variant in MLH1 (c.1043T>A, p.Leu348), a known pathogenic mutation consistent with Lynch syndrome. In Family 2, we discovered a previously undocumented heterozygous missense variant in ERBB2 (c.2268G>T, p.Arg756Ser). Through a detailed ACMG assessment, this ERBB2 variant was classified as Likely Pathogenic based on its location in a critical tyrosine kinase domain, absence from population databases, and concordant deleterious in silico predictions. WES offers a deeper understanding of CRC genetics, suggesting potential biomarkers with promising applications for early diagnosis and targeted treatments, eventually improving patient-related outcomes. The results of this study underscore the significant contribution of genetic screening to the well-being of high-risk families and offer valuable insights for targeted therapeutic approaches.

Ferroptosis resistance is a key player in cervical cancer (CC) development. Hypoxia is a negative factor affecting CC treatment by inducing ferroptosis resistance. Our study aimed to investigate the detailed mechanisms of hypoxia-induced ferroptosis resistance in CC cells. The mRNA and protein levels were assessed using RT-qPCR and western blot. Immunofluorescence staining was used to analyze the co-localization of Budding uninhibited by benzimidazole 1 (BUB1) and Kinesin family member 20A (KIF20A) in CC cells. Fe²⁺, MDA, and GSH levels were measured by commercial kits. Cell viability was determined by CCK-8. The molecular interactions were analyzed by RIP or Co-IP. MeRIP was adopted to measure the m⁵C level of KIF20A. We found that hypoxia facilitated ferroptosis resistance in CC cells. Hypoxia led to the upregulation of KIF20A, and KIF20A knockdown weakened hypoxia-mediated ferroptosis resistance in CC cells. Mechanistically, Aly/REF export factor (ALYREF) stabilized KIF20A mRNA stability via m⁵C modification. In addition, KIF20A upregulated BUB1 in CC cells by directly interacting with BUB1. Rescue experiments indicated that BUB1 overexpression partially reversed the inhibitory effect of KIF20A knockdown on hypoxia-mediated ferroptosis resistance in CC cells. In conclusion, hypoxia triggers ALYREF-mediated m⁵C methylation of KIF20A to activate the KIF20A/BUB1 axis, thereby inducing ferroptosis resistance in CC cells.

Inhibition of cuproptosis contributes to the development of non-small cell lung cancer (NSCLC). The expression of RNA-binding motif protein 15 (RBM15) is upregulated in NSCLC. Nonetheless, its relationship with cuproptosis remains unclear. This study aimed to explore the role of RBM15 in regulating cuproptosis in NSCLC. A549 cells were treated with elesclomol (ES-Cu) and tetrathiomolybdate (TTM) to induce or inhibit cellular cuproptosis. EdU, CCK-8, Transwell assays, and flow cytometry were used to detect cellular phenotypes. The expression levels of relevant genes and proteins were analyzed using RT-qPCR and western blotting. RIP and MeRIP were utilized to investigate the interaction of RBM15 and YT521-B homology domain family-3 (YTHDF3) with serine/arginine splicing factor 1 (SRSF1). The effect of the RBM15/m6A/SRSF1/ATP7B axis on tumor growth was evaluated using tumor xenografts in nude mice. Copper levels were assessed using commercially available kits. In NSCLC cells, RBM15 suppression inhibited proliferation and invasion while promoting cuproptosis; however, treatment with TTM (copper chelators) reversed the effect of sh-RBM15. ES-Cu treatment inhibited cell proliferation and invasion, and RBM15 knockdown further promoted the effect of ES-Cu, but upregulated RBM15 reversed the regulatory effect of ES-Cu. Mechanistically, RBM15 promoted the m6A modification of SRSF1 by recruiting YTHDF3. Increased SRSF1 enhanced ATPase copper-transporting beta (ATP7B) exon 21 splicing. Furthermore, SRSF1 promoted cell proliferation and invasion and inhibited cuproptosis by regulating ATP7B alternative splicing. Finally, we verified that RBM15 promoted tumor growth by mediating SRSF1 in vivo. In short, RBM15-mediated m6A modification enhanced SRSF1 stability, and SRSF1 promoted ATP7B alternative splicing to inhibit cuproptosis, thereby promoting NSCLC cell proliferation and tumor growth.

Radiofrequency ablation is an effective treatment for benign thyroid nodules. Since initial nodule volume may impact the efficacy of radiofrequency ablation, this study evaluated its long-term outcomes across varying nodule sizes, focusing on regrowth, new growth, and clinical management implications. This retrospective study included 160 patients who underwent thyroid radiofrequency ablation for benign thyroid nodules at a Taiwanese tertiary center between July 2016 and April 2018. Patients were classified into three groups based on nodule size: small (< 10 mL), medium (10-30 mL), and large (> 30 mL). Treatment efficacy was assessed over a period of up to 5 years, focusing on volume reduction rate, regrowth, residual volume, and new growth. The initial ablation rate of all benign thyroid nodules was 99.46%. After the 5-year follow-up, the volume reduction rate was 92.96%. The small nodule group demonstrated the highest volume reduction rate. The incidence of increased residual vital volume was 3.57%. The overall regrowth rate was 9.82%, with a mean time to regrowth of 2.8 years. No nodules required retreatment due to regrowth. New growth was observed in 22.32% of patients, with the highest incidence in the large nodule group (34.29%). Radiofrequency ablation is effective in the long-term management of benign thyroid nodules across various sizes, achieving substantial volume reduction rate with minimal complications. For larger nodules, monitoring for new growth warrants increased attention and may serve as a critical parameter indicative of recurrence and the potential need for retreatment.

Inflammation is a common mediator of pancreatic cancer and depression. This study investigated the predictive value and clinical associations of inflammatory markers and depression in cancer patients using machine learning (ML) and statistical modeling. Pancreatic cancer patients (n = 328; mean age, 65 years; majority with stage IV disease) were assessed using the Patient Health Questionnaire-9 (PHQ-9; depression defined as PHQ-9 ≥ 10). Clinically significant depression was present in 35% of subjects at baseline, and the rate declined at follow-up. Four ML models (logistic regression, random forest, support vector machine, and extreme gradient boosting; XGBoost) were trained using routinely collected clinical data and showed comparable performances with moderate but consistent discriminative capacity (AUC: 0.70-0.72). Permutation importance analysis revealed C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and albumin as key predictors of depression. Generalized estimating equations further confirmed that elevated CRP (OR = 1.32, p = 0.001) and NLR (OR = 1.55, p = 0.001) were independently associated with depression. These findings suggest that inflammatory markers can not only help to identify patients at risk for depression but also underscore the linkage between inflammation and depression. ML models incorporating these markers may therefore support early detection and intervention in pancreatic cancer care.

Stress causes depression and cognitive decline. With limitations in pharmacotherapy, sciatic nerve stimulation (SNS) offers a promising nondrug alternative. This study aimed to explore the therapeutic efficacy of SNS in mitigating stress-induced depressive behaviors and memory deficits by focusing on astrocytic dysfunction and cellular senescence in the hippocampus. C57BL/6 mice were subjected to the water immersion restraint stress (WIRS) paradigm to induce stress-related behavioral deficits. Behavioral tests assessed locomotion, anxiety, depression-like behavior, and memory. Astrocytic disruption and cellular senescence in the hippocampus were assessed using glial fibrillary acidic protein (GFAP) immunostaining and senescence-associated β-galactosidase (SA-β-gal) staining. SNS at 20 Hz significantly improved cognitive function and reduced depression-like behavior in WIRS-treated mice. It also restored hippocampal GFAP expression and decreased both SA-β-gal-positive cell accumulation and the expression of senescence markers p16 and p21, suggesting an attenuation of cellular senescence. To further explore the link between cellular senescence and SNS-mediated effects, we administered the anti-senescence agent vitamin C to WIRS mice. While vitamin C alleviated stress-induced hippocampal senescence and depressive behavior, it failed to reverse memory deficits or restore GFAP expression, indicating that the benefits of SNS extend beyond its anti-senescent actions. In summary, SNS effectively counteracts the neurobehavioral consequences of chronic stress by targeting astrocytic dysfunction and cellular senescence. These findings support SNS as a promising, nonpharmacological strategy for treating stress-related depression and cognitive decline. Future studies should explore its clinical translation and broader therapeutic potential.

Skin cancer, encompassing melanoma and non-melanoma types, remains a significant public health concern globally. Conventional therapies-such as surgery, radiotherapy, chemotherapy, and immunotherapy-are constrained by poor skin penetration, systemic toxicity, and high recurrence rates. Nanotechnology has emerged as a promising strategy to address these limitations through enhanced drug delivery, targeted tumor accumulation, and reduced off-target effects. This review summarizes recent advances in nanocarrier-based approaches for skin cancer therapy. Key platforms include liposomes, polymeric nanoparticles, dendrimers, metallic nanoparticles, and biomimetic systems. These nanocarriers facilitate passive, active, and stimuli-responsive targeting, thereby improving drug distribution within tumors and enhancing therapeutic precision. Applications include chemotherapy, photothermal and photodynamic therapy, gene and RNA delivery, and immunotherapy. Despite substantial preclinical success, challenges persist in translating findings to the clinic. These include limited dermal penetration, tumor heterogeneity, immune clearance, and regulatory barriers. Innovative solutions-such as multifunctional nanocarriers, personalized formulations, and non-invasive delivery devices-are being investigated to address these issues. In conclusion, nanotechnology holds considerable potential to transform skin cancer treatment. Continued interdisciplinary efforts are crucial for translating laboratory innovations into clinically viable therapies, ensuring safer and more effective outcomes for patients.

Osimertinib (OSI) resistance in non-small cell lung cancer (NSCLC) remains a significant challenge. This report explored the precise role of USP28 on OSI resistance in NSCLC and identified a functional downstream effector. OSI-resistant H1975 cells (H1975/OSI) were established by long-term OSI exposure. USP28 and SIRT1 expression levels were analyzed by quantitative PCR, immunoblotting, and immunohistochemistry. Functional assays included cell viability, colony formation, EdU incorporation, apoptosis analysis, and glycolysis assays. The interaction between USP28 and SIRT1 was confirmed by co-immunoprecipitation (Co-IP) assay and SIRT1 protein stability analysis. In vivo validation was performed using H1975/OSI xenograft models. USP28 and SIRT1 were upregulated in H1975/OSI cells and OSI-resistant NSCLC tissues. USP28 overexpression enhanced cell proliferation and glycolysis, suppressed apoptosis, and conferred OSI resistance in H1975 cells, while its depletion exerted opposite effects in H1975/OSI cells. Mechanistically, USP28 stabilized SIRT1 by deubiquitination. SIRT1 knockdown attenuated the effects of USP28 overexpression, while SIRT1 restoration reversed the phenotype alterations upon USP28 depletion. In vivo, USP28 depletion sensitized H1975/OSI xenografts to OSI treatment. Our study indicates that USP28 promotes OSI resistance in NSCLC by deubiquitinating SIRT1. Targeting the USP28/SIRT1 axis may represent a novel therapeutic approach to overcome OSI resistance in EGFR-mutant NSCLC.