International Journal of Medical Sciences最新文献

Sjögren's disease (SjD) is traditionally viewed as an autoimmune exocrinopathy; however, renal involvement-particularly renal tubular acidosis (RTA)-is an underrecognized extraglandular manifestation that often precedes classical sicca symptoms and contributes to diagnostic delay. Distal RTA (dRTA) represents the dominant phenotype and arises from immune-mediated injury to α-intercalated cells, leading to disruption of key acidification components, including vacuolar H⁺-ATPase (V-ATPase), carbonic anhydrase II (CAII), and anion exchanger 1 (AE1). Beyond impaired distal proton secretion, systemic acidosis is proposed to induce adaptive responses in the proximal tubule, based largely on general renal physiology rather than SjD-specific data. Intracellular acidification may enhance sodium-dependent dicarboxylate cotransporter 1 (NaDC-1)-mediated citrate reabsorption and mitochondrial citrate metabolism. These processes may reduce urinary citrate excretion (hypocitraturia) and promote a lithogenic milieu characterized by calcium phosphate supersaturation. This integrated distal-proximal axis provides a plausible mechanistic link between tubular dysfunction and clinical manifestations such as nephrolithiasis, nephrocalcinosis, and hypokalemic paralysis. Incomplete dRTA further expands the disease spectrum and is frequently overlooked despite its clinical relevance. Current management is centered on alkali and potassium replacement, which correct metabolic abnormalities but do not address underlying immune-mediated injury. Treatment response is stage-dependent and often limited once fibrosis is established. This review proposes an integrated immuno-tubular framework that links clinical phenotype, pathogenesis, and therapeutic strategy, and highlights the need for early detection, biomarker-driven risk stratification-particularly using hypocitraturia-and incorporation of renal-specific endpoints to enable mechanism-based and precision-guided care.

FNDC5 has been implicated in glucose homeostasis and is associated with mitochondrial function. Its role in diabetes and diabetic nephropathy (DN) remains unclear. This study hypothesizes that FNDC5 deficiency predisposes the kidney to accelerated mitochondrial dysfunction in diabetes and DN. Systemic Fndc5 knockout (KO) C57BL/6 mice were generated using CRISPR/Cas9. DN were induced in six-week-old Fndc5 wild-type (WT) and KO mice using high-fat diet combined with streptozotocin injection. Weekly blood and urine analyses assessed glucose, cholesterol, triglycerides, blood urea nitrogen, creatinine, and proteinuria. At 15 weeks, kidneys and metabolic tissues including pancreas, muscle and adipose were collected for histological and molecular analyses. Results showed that while both Fndc5 WT and KO mice were successfully induced with hyperglycemia, the Fndc5 KO DN group exhibited a slightly lower cumulative glycemic burden compared with the WT DN group. Despite this milder metabolic stress, proteinuria remained comparable between the two groups. Furthermore, histological analysis revealed that Fndc5 KO DN mice displayed more severe mesangial expansion, glomerular basement membrane thickening, and podocyte effacement compared with WT DN mice. The elevated lipid peroxidation, reduced PGC-1α expression, and increased DNA fragmentation were also evident in Fndc5 KO DN. More swollen mitochondria with a significantly higher percentage of disrupted cristae were observed in Fndc5 KO DN mice compared with WT DN mice. This was accompanied by the upregulation of mitochondrial fission-related genes (Dnm1l and Fis1), downregulation of the fusion-related gene (Mfn1), and reduced expression of ATP synthase subunits (ATP5A1 and ATP5B). Systemic analysis of other metabolic tissues, including the pancreas and muscle and adipose tissues, revealed increased lipid peroxidation and decreased PGC-1α expression. These findings underscore FNDC5's role in maintaining mitochondrial integrity and cellular health under diabetic conditions, positioning FNDC5 as a potential therapeutic target.

Pancreatic cancer (PC) remains one of the most lethal malignancies, with pain being a prevalent and debilitating symptom that severely impairs patients' quality of life and independently predicts poorer survival. While historically attributed to tumor mass effects, the mechanisms driving PC pain are far more complex. This review aims to synthesize the current understanding of the intricate biological underpinnings of PC-associated pain and discuss the paradigm shift towards mechanism-based therapeutic strategies. The pathogenesis of PC pain is fundamentally driven by dynamic tumor-nerve interactions. A central mechanism is perineural invasion (PNI), a pathologic hallmark wherein cancer cells infiltrate the perineural space, establishing a specialized "neural niche." Within this niche, bidirectional crosstalk involving cancer cells, Schwann cells, immune cells, and stromal components, which is mediated by neurotrophins, chemokines, and neurotransmitters, drives neural remodeling, neuroinflammation, and peripheral nociceptor sensitization. These peripheral signals subsequently induce central sensitization within the spinal cord and brain, perpetuating chronic, refractory pain. While conventional analgesics and interventions like celiac plexus neurolysis remain the mainstay, their relief is often incomplete and transient, as they fail to address these underlying biological drivers. A therapeutic paradigm shift is underway, moving from symptomatic palliation towards mechanism-based interventions. Emerging strategies, including molecularly targeted inhibitors, neuromodulation, and precision nanomedicine platforms, aim to directly disrupt the fundamental neurobiological pathways of pain. By targeting tumor-nerve crosstalk, neuroinflammation, and pathological neural plasticity, these approaches hold the potential to achieve more effective and durable analgesia, ultimately improving the lives of patients suffering from pancreatic cancer.

Background: Chemoresistance remains a major limitation in the treatment of colorectal cancer (CRC), particularly in tumors harboring TP53 mutations. Although aldehyde dehydrogenase 2 (ALDH2) has been implicated in cancer biology, its role in regulating platinum sensitivity and the underlying molecular context remain incompletely understood.

Methods: Public transcriptomic and proteomic datasets (TCGA, GEO, CPTAC) were analyzed to evaluate ALDH2 expression patterns, prognostic relevance, and associations with chemotherapy response in CRC. Functional studies were performed in p53-mutant and p53-wild-type CRC cell lines using pharmacological inhibition and genetic silencing of ALDH2, complemented by p53 knockout and reconstitution approaches. Downstream signaling was interrogated by gene set enrichment analysis, quantitative PCR, and pharmacological inhibition of phosphodiesterase 4B (PDE4B). Oxaliplatin sensitivity was assessed using cell viability and apoptosis assays.

Results: ALDH2 expression was significantly reduced in CRC tissues and was associated with unfavorable clinical outcomes and diminished oxaliplatin responsiveness. Functional experiments revealed that inhibition or knockdown of ALDH2 selectively induced oxaliplatin resistance in p53-mutant CRC cells, while p53-wild-type cells were largely unaffected. Mechanistically, loss of ALDH2 led to upregulation of PDE4B in a p53 status-dependent manner. Elevated PDE4B expression correlated with chemoresistance and poor recurrence-free survival in patients with p53-mutant CRC. Importantly, pharmacological inhibition of PDE4B using the clinically approved drug roflumilast effectively restored oxaliplatin-induced apoptosis and reversed chemoresistance in ALDH2-deficient, p53-mutant CRC cells.

Conclusions: This study identifies a previously unrecognized, p53 status-dependent ALDH2-PDE4B regulatory axis that governs oxaliplatin sensitivity in colorectal cancer. Our findings highlight ALDH2 as a potential predictive biomarker for oxaliplatin response in p53-mutant CRC and suggest that targeting PDE4B may represent a promising strategy to overcome chemoresistance in this molecular context.

The most prevalent illness in men is prostate cancer, which risk increases with age and obesity. The precursor NUCB2 gene produces the adipokine nesfatin-1, which was first found in hypothalamic neurons. It is currently unclear how NUCB2 polymorphisms, cancer-promoting lifestyle factors, and prostate cancer are related. We investigated the relationship between clinicopathological features and 4 NUCB2 gene polymorphisms in prostate cancer when compared to healthy individuals. Compared with the wild-type T/T genotype, carriage of at least one G allele (T/G or G/G genotypes) at the NUCB2 SNP rs10766383 was linked with a declined risk of clinical T3+T4 stage, pathologic T3+T4 stage, and perineural invasion. In addition, the TG/GG genotypes at rs10766383 were also associated to a lower risk of clinical T3+T4 stage and perineural invasion in patients with biochemical recurrence. Importantly, GTEx data indicated that the wild-type TT homozygous genotype was linked with markedly higher NUCB2 levels compared to the GG allele of variant rs10766383 variant in mucosa and whole blood tissues. Thus, the NUCB2 SNP rs10766383 may play a protective function against prostate cancer progression.

Background: Emergence agitation is a clinically relevant phenomenon during recovery from general anesthesia. This study aimed to compare the effects of remimazolam and propofol as anesthetic induction agents on emergence agitation.

Methods: This retrospective propensity score-matched study included adult patients undergoing elective transurethral endoscopic urologic surgery under general anesthesia. Patients were divided into remimazolam- or propofol-based induction groups. The primary outcome was the incidence of emergence agitation, defined as a Ricker Sedation-Agitation Scale (RSAS) score ≥ 5 during emergence. Secondary outcomes included the severity of emergence agitation, extubation time, postoperative pain scores, use of analgesics or antiemetics in the post-anesthesia care unit (PACU) and risk factor identification.

Results: A total of 239 patients were analyzed before matching, and 99 matched pairs were generated. After matching, the incidence of emergence agitation was significantly lower in the remimazolam group compared with the propofol group (13.1% vs. 36.4%; P = 0.001). Remimazolam-based induction was independently associated with a reduced risk of emergence agitation (odds ratio 0.23, 95% confidence interval 0.09-0.56; P < 0.001). The distribution of RSAS scores demonstrated reduced severity of agitation in the remimazolam group. Extubation time, postoperative pain scores, and PACU medication did not differ between groups. Younger age and male sex were identified as independent risk factors.

Conclusions: Remimazolam-based anesthetic induction reduced incidence and severity of emergence agitation compared with propofol, without delaying extubation or impairing early postoperative recovery. Remimazolam may represent a favorable induction agent for adult patients at risk for emergence agitation.

Background: C-type lectin domain family 3 member B (CLEC3B), also known as tetranectin, is a secreted protein associated with extracellular matrix remodeling and tumor microenvironment regulation. However, its expression pattern and clinical significance in breast cancer tissues remain unclear. This study aimed to investigate CLEC3B expression in breast cancer tissues and its associations with clinicopathological characteristics and the tumor microenvironment.

Methods: Ninety-eight women with newly diagnosed breast cancer who underwent surgical treatment at our hospital between September 2023 and December 2024 were included in this study. Tumor and adjacent non-tumorous tissues, including vascular regions, were obtained from the enrolled patients and processed for immunohistochemical analysis. CLEC3B expression was semiquantitatively graded from 1 to 4. Associations between CLEC3B expression, clinicopathological and biochemical variables were analyzed using the chi-square test, Spearman correlation, and multivariable logistic regression. Double immunofluorescence staining was performed to assess colocalization of CLEC3B with CD68 (macrophages) and CD31 (endothelial cells).

Results: The expression of CLEC3B was identified in both tumor cell membrane and cytoplasm, and was significantly higher in breast cancer tissues than in adjacent non-tumorous tissues. CLEC3B expression was also significantly higher in blood vessels than in tumor parenchyma (p < 0.0001), indicating predominant vascular localization. High CLEC3B expression (grade 3-4) was associated with a tumor size of 2-5 cm, Ki-67 ≥14%, and the luminal B HER2-positive subtype. Spearman analysis showed that a high CLEC3B expression was correlated with larger tumor size, higher Ki-67 index, higher carcinoembryonic antigen level, and shorter prothrombin time. Multivariable logistic regression analysis further demonstrated that tumor size ≥2 cm and high Ki-67 (≥14%) were independently associated with high CLEC3B expression, whereas molecular subtype was not. CLEC3B was colocalized with CD68 and CD31, confirming its expression in macrophages and endothelial cells. CD4⁺ and CD8⁺ T-cell infiltration was abundant regardless of CLEC3B expression level.

Conclusion: The expression of CLEC3B was upregulated in breast cancer tissues and predominantly localized to the tumor vasculature and macrophages. Its expression was associated with aggressive clinicopathological features and certain biochemical parameters. No apparent differences in CD4⁺ or CD8⁺ T-cell infiltration were observed across different levels of CLEC3B expression. These findings suggest that CLEC3B expression may be associated with vascular and microenvironment-related characteristics of breast cancer.

Background: The relationship between Neuromyelitis optica spectrum disorder (NMOSD) and specific cardiovascular outcomes, particularly macrovascular events such as peripheral artery disease (PAD) and venous thromboembolism (VTE), has not been examined in a population-based study. The current study investigated the association between NMOSD and the risks of PAD and VTE.

Materials and methods: This retrospective cohort study used data from the Taiwan National Health Insurance Research Database. Patients with new-onset NMOSD between 2003 and 2020. Patients with previous PAD or VTE were excluded. Each patient was matched to five general patients for comparison using propensity score matching. In total, the study included 2,027 patients with NMOSD and 10,135 matched general population controls. A Cox proportional hazards model was used to investigate PAD and VTE risk, with relevant variables controlled for. NMOSD was stratified by severity to further verify the association between disease severity and macrovascular event risk. The control variables considered in this study were sex, age, insured salary, urbanization, Charlson comorbidity index (CCI), and related comorbidities.

Results: The average follow-up of all participants was 7.01 person-years. After adjustments for relevant variables, patients with NMOSD had significantly higher risks of PAD (adjusted hazard ratio [aHR] = 1.40; 95% confidence interval [CI]: 1.02-1.92) and VTE (aHR = 4.81; 95% CI: 3.08-7.52). The risk of vascular events was strongly associated with disease severity. Severe NMOSD was associated with markedly increased risks of PAD (aHR = 2.26; 95% CI: 1.41-3.61) and VTE (aHR = 11.69; 95% CI: 6.86-19.90), whereas mild and moderate disease did not significantly increase PAD risk.

Conclusion: NMOSD is a significant risk factor for PAD and VTE. These findings highlight the importance of proactive vascular risk assessment and preventive management in patients with NMOSD.

Oral squamous cell carcinoma (OSCC) is associated with aggressive clinical behavior and poor outcomes. In this study, we investigated the anticancer efficacy and underlying mechanisms of Stellettin B, an isomalabaricane triterpene isolated from the marine sponge Jaspis stellifera, in OSCC cells. Our results demonstrate that Stellettin B significantly inhibited the proliferation of HSC-3 and OC-2 cells while sparing normal oral keratinocytes. Mechanistically, Stellettin B triggers a predominantly caspase-independent apoptotic program, evidenced by the pronounced mitochondrial-to-nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) following DNA damage, whereas classical caspase activation functions as a dispensable, secondary event. Furthermore, Stellettin B suppressed migration and invasion by reversing epithelial-mesenchymal transition (EMT), characterized by E-cadherin upregulation and downregulation of Vimentin, Snail, Slug, and β-catenin. Transcriptomic profiling further revealed significant suppression of mTORC1 signaling and EDIL3 expression. In conclusion, these findings demonstrate that Stellettin B exerts multimodal antitumor activity in OSCC and highlight its therapeutic potential as a marine-derived anticancer agent.