Osteoarthritis (OA) is now increasingly recognized as a disease that affects the entire joint, where synovial inflammation plays a key role in pain, cartilage degeneration, and structural progression. Synovial macrophages (SMs) are key regulators in this process due to their phenotypic plasticity and central roles in amplifying inflammation, disrupting immunometabolism, and interacting with other joint-resident cells. These characteristics make SMs attractive targets for disease-modifying interventions. However, conventional therapies are limited by poor intra-articular retention, low cellular selectivity, and inadequate control over complex pathogenic networks. This review summarizes the biological functions of SMs in OA and explains why they are a mechanistically important and therapeutically accessible target. Next, we provide a structured overview of nanomaterial-based strategies for SM-targeted OA therapy, covering major material platforms, receptor-guided delivery approaches, subset- and state-selective targeting, intracellular functional intervention, and multi-target combination designs. We highlight representative studies that show how nanomedicines can improve local retention, enhance macrophage-specific uptake, and modulate inflammation, metabolism, oxidative stress, and cell fate. Finally, we discuss the major barriers to clinical translation, such as macrophage heterogeneity, safety, pharmacokinetics, and chemistry, manufacturing, and controls (CMC), and outline future directions for biomarker-guided and precision nanotherapy in OA.
Immunoglobulin A nephropathy (IgAN) is a clinical and pathological syndrome with heterogenous manifestation and progression. The prognostic nutritional index (PNI) and the controlling nutritional status (CONUT) score, indicators of nutritional status and systemic inflammation, are associated with poor prognosis in dialysis patients. This study was aimed to investigate the predictive value of the objective nutritional indices (PNI and CONUT) for renal progression in IgAN patients. A multicenter retrospective study was conducted in biopsy-proven IgAN patients. Baseline characteristics were obtained within 1 week before renal biopsy. The renal composite endpoint comprised an estimated glomerular filtration rate (eGFR) decline >50%, a doubling of baseline serum creatinine, or the occurrence of end stage kidney disease (ESKD). The receiver operating characteristic curve analysis was conducted to determine the optimal cut-off value of PNI and CONUT. The Kaplan-Meier curve estimated the cumulative renal-survival rate. Univariate and multivariate Cox regression models were preformed to investigate the association between objective nutritional indices and renal outcomes. A total of 659 IgAN patients participated in this study. During a median follow-up period of 45 months, 68 patients (10.32%) achieved the composite endpoint. The Kaplan-Meier curve revealed that renal-survival rate was significantly higher in high PNI group (PNI > 46.5; p < 0.001) and low CONUT group (CONUT ≤2; p < 0.001). Even after adjustment of traditional risk factors, including sex, age, mean arterial pressure, hemoglobin, uric acid, eGFR, triglycerides, 24-h urinary protein, E score, T score, and treatment with ACEI/ARB, low PNI [hazard ratio (HR) = 2.514, 95% confidence intervals (CI) = 1.212-5.215, p = 0.013] and high CONUT (HR = 2.152, 95% CI = 1.087-4.259, p = 0.028) remained as independent risk factors for poor renal outcomes. This study suggested that low PNI and high CONUT were significantly and independently correlated with poor prognosis in patients with IgAN at CKD stages 1-4. The PNI and CONUT are inexpensive and straightforward indicators to help clinicians improve IgAN management.
Patients with acute decompensated ischemic heart failure (ADIHF) often present with severe clinical symptoms and poor quality of life. In China, Yiqi Fumai lyophilized injection (YQFM) is widely used in the treatment of ADIHF. However, high-quality evidence is still needed to support its efficacy and safety. This study aims to assess the therapeutic efficacy and safety of YQFM in patients with ADIHF. By conducting a multicenter, open-label, blinded-outcome, randomized controlled trial, we recruited patients with ADIHF from 37 hospitals in 20 regions of China from October 2015 to October 2018. Patients were allocated in a 1:1 ratio to either the YQFM group or the control group. Both groups received guideline-directed medical therapy (GDMT), with the YQFM group additionally receiving YQFM for 7 days. The primary outcome included the proportion of patients with a decrease from baseline B-type natriuretic peptide (BNP) value ≥ 30% on day 8 post-randomization. We evaluated the left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, and composite endpoints. A total of 666 patients with ADIHF (332 in the YQFM group and 334 in the control group) were enrolled. The full analysis set (FAS) analysis revealed that the proportion of patients in the YQFM group with a reduction of at least 30% in BNP value on day 8 was higher than that in the control group (175 [55.21%] vs. 135 [41.93%], one-sided p < 0.001, two-sided p < 0.001; RR, 1.32 [95% CI, 1.12-1.56]). The YQFM group showed statistically significant improvements in LVEF, NYHA functional class, and MLHFQ scores compared to controls. There was no statistically significant difference between the two groups regarding composite endpoint events and adverse events during the follow-up period. Based on GDMT, the combined use of YQFM was associated with further reductions in BNP levels, improve quality of life and cardiac function in patients with ADIHF, without increasing safety risks. However, no significant differences were observed in clinical events, such as mortality or hospitalization, during the follow-up period.
We describe a challenging case of a woman with Pseudomonas aeruginosa pneumonia and bloodstream infections following cardiothoracic surgery. This strain exhibited a pan-drug resistance phenotype belonging to the high-risk clone ST244. Finally, she was successfully treated by antibiotic therapy with ceftazidime/avibactam (CAZ/AVI) and meropenem (MEPM). This case suggests that the combination of CAZ/AVI and MEPM may represent a potential therapeutic option for severe infections caused by pan-drug-resistant Pseudomonas aeruginosa (PDR-PA).
Selegiline, rasagiline, safinamide, and zonisamide are commonly used with levodopa to manage motor fluctuations in Parkinson's disease (PD). This study compared the efficacy and safety of these agents as adjuncts to levodopa in Asian PD patients with motor fluctuations. A Bayesian network meta-analysis (NMA) was conducted. Randomized controlled trials (RCTs) published from database inception to August 31, 2025 were identified through PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP, Wanfang, and ClinicalTrials.gov. Eligible studies enrolled PD patients treated with levodopa plus any of the four agents. Primary outcomes included changes in daily OFF-time and Unified Parkinson's Disease Rating Scale (UPDRS) Part III score. This study is registered in PROSPERO (CRD42024627701). Eleven RCTs involving 2824 patients were included, no eligible RCTs evaluating selegiline in Asian PD patients were identified for inclusion in the analysis. All combination therapies, except for zonisamide 25 mg, were more effective than levodopa plus placebo. NMA indicated that safinamide 100 mg was significantly superior to both rasagiline 1 mg and zonisamide 25 mg in reducing OFF-time (safinamide 100 mg vs. rasagiline 1 mg: MD = - 0·52, 95% CI - 0·97 to - 0·07; safinamide 100 mg vs. zonisamide 25 mg: MD = - 0·84, 95% CI - 1·46 to - 0·22) and improving UPDRS III score (safinamide 100 mg vs. rasagiline 1 mg: MD = - 2·00, 95% CI - 3·30 to - 0·67; safinamide 100 mg vs. zonisamide 25 mg: MD = - 2·50, 95% CI - 4·10 to - 0·94). Compared with zonisamide 50 mg, safinamide 100 mg showed a trend toward a reduction in OFF-time (MD = - 0·56, 95% CI - 1·18 to 0·08) and UPDRS III score (MD = - 1·40, 95% CI - 2·90 to 0·08). Safinamide 100 mg ranked first in SUCRA ranking for reducing OFF-time and UPDRS III score. These findings were robust in sensitivity analyses. The findings suggest that levodopa in combination with safinamide 100 mg is more efficacious than combinations with rasagiline 1 mg or zonisamide 25 mg for alleviating motor fluctuations and improving motor symptoms in Asian PD patients, and shows a more favourable (though not statistically significant) trend compared with zonisamide 50 mg.
Osteoarthritis (OA) is a heterogeneous degenerative joint disease involving cartilage degradation, subchondral bone remodeling, and chronic inflammation, which collectively lead to pain and disability. Current therapeutic strategies remain insufficient to effectively halt disease progression. To address this, we engineered a multifunctional injectable hydrogel based on hydroxybutyl chitosan (HBC) coloaded with strontium acetate (Sr) and nanosized chondroprogenitor cell-derived exosomes (CPC-EXOs) (HBC@Sr@CPC-EXOs) to modulate the inflammatory joint microenvironment and drive cartilage regeneration. The hydrogel underwent a sol-gel transition at ∼17 °C (gelling at body temperature) and swelled to equilibrium in ∼16 h, forming a water-rich matrix. Release profiling showed ∼50% cumulative Sr release at 36 h and exosome release at 60 h, yielding a functionally sequential (time-staggered) exposure, where Sr mediates early attenuation of inflammatory mediators, while CPC-EXOs sustain late-phase immunoprogramming. Under inflammatory conditions in vitro, HBC@Sr@CPC-EXOs enhanced chondrocyte viability, increased extracellular matrix anabolism, and polarized macrophages toward M2. Time-resolved assays revealed early suppression of pro-inflammatory cytokines (0-12 h), followed by later enhancement of immunoregulatory cytokines (24-48 h) (p < 0.05). Mechanistically, HBC@Sr@CPC-EXOs activated TGF-β1/Smad2/3 while suppressing Notch, driving bone marrow stromal cell (BMSC) chondrogenic differentiation. In a Sprague-Dawley (S-D) rat osteochondral defect model, HBC@Sr@CPC-EXOs achieved superior osteochondral repair, including higher International Cartilage Repair Society (ICRS) scores and greater subchondral bone regeneration than the Control (p < 0.05). Collectively, HBC@Sr@CPC-EXOs integrate immunomodulatory and regenerative cues, offering a promising strategy for attenuating OA progression and fostering cartilage repair.
The molecular mechanisms underlying non-small cell lung cancer (NSCLC) metastasis remain incompletely understood, limiting the identification of potential therapeutic targets. Here, integrating clinical data, we identify ovarian tumor domain-containing protein 5 (OTUD5), an OTU family member of deubiquitinases, as a potential metastasis suppressor in NSCLC. Reduced OTUD5 expression is observed in metastatic NSCLC specimens and correlates with poor patient survival. Using human NSCLC cell lines, we find that OTUD5 directly interacts with and deubiquitinates transcriptional intermediary factor 1 γ (TIF1γ). The latter attenuates TGF-β-induced SMAD3/4 complex formation, thereby impeding TGF-β-induced repression of OTUD5 transcription. Upon TGF-β stimulation, OTUD5 overexpression dramatically suppresses SMAD3/SMAD4 complex formation; however, this effect is abrogated when TIF1γ is silenced. OTUD5 overexpression inhibits TGF-β-induced epithelial-mesenchymal transition (EMT) and metastasis of NSCLC cells, whereas these effects are largely abrogated by TIF1γ knockdown. Notably, targeting OTUD5 with nilotinib, an FDA-approved drug for chronic myeloid leukemia (CML), enhances the OTUD5-TIF1γ interaction, reduces the ubiquitination of TIF1γ, and exerts significant anti-metastatic effects on NSCLC cells. Taken together, our findings indicate that OTUD5 inhibits TGF-β-induced EMT and NSCLC cell metastasis in a partially TIF1γ-dependent manner and reveal an OTUD5-TIF1γ-SMAD3/4 positive feedback loop for preventing TGF-β-induced EMT. These findings provide new insights into the molecular basis of NSCLC metastasis and suggest that nilotinib may be repositioned as an anti-metastatic drug by targeting OTUD5 in NSCLC treatment.
It remains unclear for the role of microtubule-associated proteins or signaling in necroptosis. Here, we conducted high-throughput screening using a cytoskeleton compound library and identified that release of guanine nucleotide exchange factor-H1 (GEF-H1) upon microtubule destabilization triggers necroptosis. Immunoprecipitation and mass spectrometry revealed that GEF-H1 interacts with DExH-Box helicase 9 (DHX9) and protein-protein interaction network analysis indicated DHX9 is associated with necroptosis. Deficiency of either GEF-H1 or DHX9 significantly inhibits necroptosis. Mechanistically, upon microtubule destabilization, GEF-H1 is translocated to the nucleus and recruits DHX9 and RNA Pol II to the Z-DNA binding protein 1 (ZBP1) promoter region. Subsequently, increasing expression of ZBP1 drives necroptosis. In addition, GEF-H1 signaling upon microtubule destabilization also plays a positive role in lipopolysaccharide-induced cell death and inflammation. Collectively, these findings uncover an important role for GEF-H1 signaling in necroptosis and inflammation.
Migraine is the leading cause of years lived with disability (YLDs) in young and middle-aged populations globally. Despite strategic initiatives to standardize headache care in China, large-scale real-world evidence regarding clinical management patterns remains sparse. The China Migraine Registry (CHIME) was established to bridge this gap. This study aims to delineate the CHIME methodology and report the baseline clinical characteristics, diagnostic accuracy, and therapeutic patterns of its initial cohort. CHIME is a nationwide, multi-center, prospective, longitudinal cohort study involving over 100 specialized headache centers across 28 provinces in China. Initiated in May 2024, the study utilizes a proprietary digital health platform integrated with a clinical decision support system (CDSS 2.0) for headache disorders. Data collection encompasses structured clinical profiles, patient-reported outcomes, and specialized sub-study cores. This baseline analysis details the cross-sectional characteristics of patients enrolled through February 15, 2026. Among 11,814 participants (79.43% female; mean age 37.42 ± 10.94 years), 10,123 (85.7%) had episodic migraine (EM), 1,019 (8.6%) had chronic migraine (CM), and 672 (5.7%) had probable migraine. A profound diagnostic-therapeutic gap was identified: only 31.0% of patients had received a correct prior diagnosis. Paradoxically, 91.43% had undergone auxiliary investigations, primarily cranial imaging (87.36%). Acute treatment relied heavily on non-specific analgesics (NSAIDs: 59.77% EM, 51.03% CM). Among patients meeting clinical criteria for prophylaxis, only 26.59% were receiving preventive therapy, and the treatment maintenance rate was critically low (12.56% for ≥3 months). CM patients exhibited significantly higher disability (MIDAS Grade IV: 52.2% vs. 26.9%) and psychiatric comorbidities compared to EM patients (p < 0.001). The CHIME study reveals a paradoxical "treatment odyssey" in China characterized by a low correct diagnosis rate, pervasive diagnostic over-investigation, alongside a systemic under-utilization of evidence-based therapies. These findings highlight the urgent need for standardized diagnostic implementation and improved prophylactic maintenance in China's headache care system.
Uterine infertility is a substantial global health challenge, imposing profound physical and emotional burdens on affected individuals, with endometrial injury being a key contributing factor. In this study, we report that platelet-derived extracellular vesicles (PEVs) exhibit remarkable regenerative potential, facilitating effective endometrial repair and improving pregnancy outcomes in both preclinical and preliminary clinical settings. Leveraging their nanoscale size and biological functionality, PEVs accumulate effectively at inflammation sites within the injured endometrium following intrauterine perfusion. Mechanistic studies showed that PEVs activate the AMPK-ULK1 pathway in macrophages, enhancing mitophagy to modulate their phenotype and reduce inflammatory secretion. This fostered an immunomodulatory microenvironment conducive to endometrial regeneration. We first provide preliminary evidence from a small-scale clinical trial on the potential of PEVs for treating infertility. Our findings, which show improved pregnancy outcomes in patients with endometrial injury, support the feasibility of this approach and justify larger studies. These findings provide critical insights into the mechanisms of PEV-driven regeneration and pave the way for the development of PEV-based therapies for endometrial repair and infertility treatment.
To further investigate the prognostic value of advanced cervical lymph node (CLN) extranodal extension (ENE) involving different structures and its potential synergistic effects with other nodal features in nasopharyngeal carcinoma (NPC). A total of 1,373 non-metastatic NPC patients from three centers between 2011 and 2021 were enrolled. For advanced CLN ENE, involved structures, maximum axial diameter (MAD), necrosis, and bilaterality were recorded. Adjusted hazard ratios (AHRs) and random survival forests were used to identify the high-risk structure group. Kaplan-Meier analysis and multivariable Cox models were applied to evaluate overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS). CLN metastasis was identified in 1135/1373 patients (82.7 %), including 169 (14.9 %) with advanced CLN ENE. The high-risk structure group comprised the hyoid muscles, scalene muscles, longissimus cervicis muscle, interval muscles, internal/external/common carotid artery, lower cranial nerves region, and skin; all other involved structures were classified as intermediate risk. Advanced CLN ENE involving high-risk structures was the only independent adverse prognostic factor after adjustment. Survival differed significantly between high-risk and intermediate-risk CLN ENE. Among N1/N2 patients, high-risk CLN ENE showed survival similar to N3 disease (AHRs > 1), whereas intermediate-risk CLN ENE showed better OS than N3, with comparable PFS and DMFS (AHRs < 1). Compared with necrosis, MAD, or bilaterality, structure-based stratification more effectively distinguished prognostic differences in advanced CLN ENE. N1/N2 patients with high-risk or intermediate-risk CLN ENE had outcomes close to N3 disease but with marked heterogeneity.
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To systematically summarize domestic and international evidence on self-management education for patients with non-alcoholic fatty liver disease (NAFLD), and to provide an evidence base for nurses to deliver health education and guide patient self-management. The evidence summary adhered to the standards issued by the Fudan University Center for Evidence-based Nursing.Guided by the "6s" evidence pyramid, a top-down search was conducted of evidence related to self-management education in patients with NAFLD. Sources included clinical decision-support tools, guidelines, best practice documents, systematic reviews, evidence summaries, expert consensus statements and randomized controlled trials. The following databases and resources were systematically searched: BMJ Best Practice, Up To Date, PubMed, Web of Science, the Cochrane Library, CINAHL, CNKI, the Wanfang Database and relevant guideline websites. The search period covered the time from the beginning of the database up to August 2025. 19 articles met the inclusion criteria, comprising 6 guidelines, 4 systematic reviews, 5 expert consensus statements, 2 randomized controlled trials and 2 evidence summaries. Thirty pieces of evidence were generated in five domains: (1) disease monitoring and assessment; (2) weight and nutritional management; (3) exercise and physical activity management; (4) self-monitoring and health education; and (5) social support systems. Most evidence was of moderate-to-high quality and showed good consistency. The synthesized evidence on self-management education for patients with NAFLD provides a reference for clinical practice. It can support nurses in developing scientific, individualized self-management education plans according to patients' characteristics, thereby improving the quality of long-term disease management and health outcomes.
Multidrug-resistant organisms (MDROs) pose a serious threat to global public health, particularly in intensive care units (ICU). Few studies have employed machine learning (ML) to capture complex clinical interactions. This study aimed to develop an explainable ML model for early risk stratification of MDRO colonization or infection by integrating patient-specific clinical features with environmental exposure factors. We analyzed the data of 420 ICU patients (210 MDRO-positive cases and 210 matched controls) admitted between January 2020 and October 2023. Predictors were selected using least absolute shrinkage and selection operator (LASSO) regression. Six ML models-Logistic Regression, Random Forest, Gradient Boosting, AdaBoost, XGBoost, and LightGBM-were developed and evaluated using internal validation on a randomly split test set. The best performing model was interpreted using SHapley Additive exPlanations (SHAP), and a web-based tool was developed for clinical applications. Five predictors were identified through LASSO regression and were independently associated with the composite endpoint in subsequent multivariable logistic regression, including residence in a long-term care facility, MDRO-positive status of the prior bed occupant, central venous catheterization, surgery prior to infection, and duration of arterial catheterization. The XGBoost model demonstrated the highest performance, with an area under the curve of 0.926 for the training set and 0.862 for the validation set. SHAP analysis improved interpretability by quantifying feature contributions and illustrating the rationale behind individual predictions. A web-based tool was developed to facilitate real-time clinical risk assessment. This study demonstrates the utility of integrating environmental risk factors into a ML framework for improved MDRO prediction, resulting in a web-based tool with the potential for clinical decision support and enhancing infection control workflows.
Cellular senescence, which is a hallmark of cancer, has been gaining increasing attention in recent years. However, its role in immunosuppressive microenvironment of intrahepatic cholangiocarcinoma (iCCA) remains poorly understood. We utilized publicly available bulk and single-cell transcriptomic datasets of iCCA to identify senescent tumor cells and the cell type composition within the immunosuppressive microenvironment. Then, the roles of senescent tumor cells and immunosuppressive cell types were verified through in vitro and in vivo experiments. We defined a 101 iCCA senescence-related gene signature (ISG) to assess cellular senescence in iCCA. Higher ISG levels indicate a poorer prognosis and increased infiltration of immunosuppressive cell types. We observed that the ISG-high malignant subgroup exhibits low proliferation but high stemness. Meanwhile, the ISG-high malignant cells upregulated the hypoxia and glycolysis pathways. Furthermore, we identified the key transcriptional factor EGR1 and demonstrated its regulatory role in the expression of CDKN1A. Mechanistically, the K422 site of EGR1 undergoes lactylation, which promotes its nuclear translocation and further regulates the transcription of CDKN1A, ultimately leading to the induction of the senescence phenotype. Moreover, cell-cell interaction analysis revealed that ISG-high malignant cells recruited and regulated immunosuppressive MACRO+ tumor-associated macrophages through the LGALS9-CD44/THBS1-CD47 axis, and the immunosuppressive MACRO+ TAMs could also recruit Tregs through the CXCL12-CXCR4 axis, thereby forming an immunosuppressive microenvironment. We defined a novel ISG signature in iCCA and identified EGR1 as a critical driver of senescent tumor cells in iCCA.These findings offer new insights into senescent tumor cells and the immunosuppressive microenvironment.
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized primarily by chronic visceral pain, with a complex pathogenesis and limited efficacy of current therapeutic interventions. Growing evidence indicates that electroacupuncture (EA) and repetitive transcranial magnetic stimulation (rTMS) exert significant analgesic effects on visceral pain. However, the underlying neural circuit mechanisms remain poorly understood. In this study, the ventral part of the lateral septal nucleus (LSV) was identified as a critical brain region mediating the analgesic effects of EA and rTMS in a mouse model of visceral pain. Visceral nociceptive stimulation significantly increased c-Fos expression in the LSV, predominantly within glutamatergic (Glu+) neurons. Optogenetic inhibition of LSV Glu+ neurons attenuated visceral pain, whereas their activation exacerbated pain-related behaviors. Both EA and rTMS individually reduced visceral pain-induced c-Fos expression and alleviated pain behaviors, with the combined EA + rTMS treatment producing a more pronounced analgesic effect than either treatment alone. Moreover, fiber photometry recordings demonstrated that EA and rTMS decreased glutamate release and concurrently increased cannabinoid signaling in the LSV, suggesting that these interventions modulate neurotransmitter dynamics to regulate neuronal excitability. In summary, our findings highlight the pivotal role of LSV Glu+ neurons in the modulation of visceral pain. EA and rTMS exert their therapeutic effects by regulating glutamate and cannabinoid release within this circuit. These insights provide a foundation for developing targeted neuromodulatory strategies for the treatment of chronic visceral pain.
Brain injury after cardiac arrest (CA) is a major cause of death and disability, with neuroinflammation increasingly recognized as a key driver. Although the sphingosine-1-phosphate receptor 3 (S1PR3)-a G protein-coupled receptor-has been linked to neurological disorders, its role in CA-induced brain injury remains unclear. We induced CA in mice via intravenous potassium chloride injection. S1PR3 expression and subcellular localization were assessed in cortex and hippocampus. Mice received intraperitoneal CAY10444 (a selective S1PR3 antagonist) alone or with Colivelin TFA (a Janus Kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) agonist). Survival after return of spontaneous circulation (ROSC) was recorded. Neurological function was evaluated using neurological deficit score, rotarod, adhesive removal, and novel object recognition tests. Brain pathology was examined by H&E, Nissl, immunohistochemistry, and Golgi staining. Microglial and astrocyte activation were quantified by immunohistochemistry; IL-1β, TNF-α, and IL-6 mRNA levels were measured; and JAK2/STAT3 pathway activity was assessed by Western blot for p-JAK2 and p-STAT3. CA/CPR upregulated S1PR3 in the brain and increased its co-localization with neurons and glia. CAY10444 improved survival and all behavioral outcomes. It reduced neuronal loss, axonal damage, dendritic spine loss, and suppressed microglial and astrocytic activation in the hippocampus. CAY10444 also lowered IL-1β, TNF-α, and IL-6 expression and decreased CA-induced JAK2/STAT3 phosphorylation. Colivelin TFA partially reversed these benefits. CAY10444 confers neuroprotection after CA/CPR by inhibiting S1PR3 and downstream JAK2/STAT3 signaling, thereby dampening neuroinflammation and neuronal death. S1PR3 is therefore a promising therapeutic target for CA-induced brain injury.
Perioperative neurocognitive disorder (PND) is a common postoperative complication, although its pathophysiological mechanisms remain incompletely understood. Inositol-requiring enzyme 1α (IRE1α) is an endoplasmic reticulum (ER) membrane sensor that participates in the pathogenesis of cognitive disorders through ER stress. However, its relationship with PND remains unclear. This study aimed to investigate whether IRE1α contributes to PND through surgery-induced ER stress. An abdominal surgery model was used to investigate the postoperative effects of surgery on the mouse hippocampus. Behavioral tests, mRNA sequencing of hippocampal tissue, protein detection, Nissl staining, immunohistochemistry, immunofluorescence staining, and electron microscopy were performed. Aged mice in the surgery group received intraperitoneal injection of an IRE1α inhibitor. Surgery-induced cognitive impairment was mainly observed in aged mice. Surgery-induced ER stress was associated with activation of the IRE1α/ASK1/JNK pathway, increased microglial activation, enhanced release of inflammatory factors, and mitochondrial damage. Treatment with the IRE1α inhibitor improved these outcomes. Surgery-induced ER stress was associated with IRE1α overactivation and postoperative cognitive impairment in aged mice. Suppression of the IRE1α/ASK1/JNK pathway ameliorated postoperative neuroinflammation, mitochondrial pathology, and microglial activation, thereby improving postoperative cognitive function in aged mice.
To report 30-day results from an ongoing 5-year study of intraoperative pancreatoscopy (IOP) in patients undergoing pancreatic surgery for main pancreatic duct (MPD) intraductal papillary mucinous neoplasm (IPMN). IOP may detect skip lesions and objectify disease extent during surgery for IPMN with MPD involvement, but prospective multicenter data are lacking. Prospective international study including patients with IPMN and MPD diameter >5 mm on preoperative imaging, scheduled for surgery at 8 centers in 6 countries. Primary endpoint was the rate of detection by IOP of discontinuous (skip) lesions along the MPD. Secondary endpoints included IOP technical success, influence of IOP findings on surgical plan, and related serious adverse events (SAEs). Among 100 patients undergoing IOP, skip lesions were documented in 13 (13.0%). IOP was technically successful in 91 (91.0%). In 41 patients (41.0%), IOP findings were reported by the surgeon to be impactful by confirming the absence of lesions in a dilated MPD and hence sparing parenchyma in 26 (26%), extending the initial resection in 12 (12%), or changing the type of partial pancreatectomy in 3 (3%). There were no IOP-related SAEs. Surgery-related SAEs were reported in 27 (27%) patients. IOP identified skip lesions in 13% of patients undergoing surgery for IPMN with MPD involvement. IOP influenced the surgical plan in 41% of patients. There were no IOP-related SAEs. Longer follow-up is ongoing. ClinicalTrials.gov number NCT03729453.
Gestational diabetes mellitus (GDM) causes APOs. The diagnostic OGTT has a lag, and the role of lncRNA EGFR-AS1 in GDM has potential. This study evaluated the potential of EGFR-AS1 for the GDM clinical application and explored the role of the EGFR-AS1/miR-142-5p/ROCK2 axis in placental endothelial injury. Serum EGFR-AS1, miR-142-5p and ROCK2 levels were detected via qPCR in 135 GDM patients and 110 healthy pregnant women. The clinic value of EGFR-AS1 was analyzed using ROC and logistic regression. A high glucose (HG)-induced model was established, in which EGFR-AS1 was silenced alone or co-silenced with miR-142-5p. The regulatory mechanism of EGFR-AS1/miR-142-5p/ROCK2 axis on placental endothelial injury was then analyzed via CCK-8, ELISA, qPCR, and WB. In GDM patients, serum EGFR-AS1 and ROCK2 were elevated, whereas miR-142-5p was reduced. Serum EGFR-AS1 showed high diagnostic efficiency for GDM and acted as an independent predictor of APOs occurrence. Silencing EGFR-AS1 reversed HG-induced HPVECs injury-evidenced by inhibited inflammatory factor release, balanced oxidative stress, up-regulated pro-angiogenic factors mRNA expression, and down-regulated proteins expression related to apoptosis and endothelial injury. Dual-luciferase reporter assays confirmed binding between EGFR-AS1 and miR-142-5p, as well as between miR-142-5p and ROCK2. Notably, co-inhibiting EGFR-AS1 and miR-142-5p abolished the protective effect of EGFR-AS1 silencing. EGFR-AS1 is a clinical auxiliary biomarker for GDM diagnosis and prediction. It aggravates HPVECs injury via EGFR-AS1/miR-142-5p/ROCK2 axis, which impairs placental function and triggers APOs, providing a new target for GDM intervention.