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关键词： Osteoarthritis   Mitochondria   Interleukin-1β   Senescence   Hexokinase   AP-1   activator protein-1   BSA   bovine serum albumin   CCK8   Cell Counting Kit-8   2-DG   2-deoxy   d   glucose   DMEM   Dulbecco's modified Eagle's medium   GAPDH   glyceraldehydes-3-phosphate dehydrogenase   IL-1β   interleukin-1β   IL-6   interleukin-6   JNK   c-jun N-terminal kinase   MMP3   matrix metalloproteinase 3   OA   osteoarthritis   RIPA   radioimmunoprecipitation assay   SDS   sodium dodecyl sulfate   TAK1   TGF-β-activated kinase 1   TNF   tumor necrosis factor  

摘要： Although mitochondrial dysfunction associated with aging and stress may be involved in chondrocyte abnormalities, its role in chondrocyte inflammatory responses remains largely unknown. In this study, we investigated the effects of rotenone, which triggers mitochondrial dysfunction, on the inflammatory responses induced by interleukin-1β (IL-1β) in primary cultured rat chondrocytes. Co-treatment with rotenone and IL-1β significantly increased the expression of matrix metalloproteinase 3, interleukin-6, and tumor necrosis factor, which are associated with osteoarthritis (OA) pathology, compared with treatment with each agent alone. The co-treatment with rotenone and IL-1β also increased the phosphorylation of c-Jun N-terminal kinase (JNK), p38, and c-Jun compared with treatment with each agent alone. Meanwhile, treatment with inhibitors of JNK, p38, and activator protein-1 (AP-1) prevented the potentiating effects of the co-treatment with rotenone and IL-1β on the gene expression of inflammatory factors. Regarding the shift from oxidative phosphorylation to glycolysis in response to rotenone, hexokinase was involved in the potentiated inflammatory factor expression and phosphorylation of JNK and p38 induced by the co-treatment with rotenone and IL-1β. These results suggest that rotenone-induced mitochondrial dysfunction enhances the IL-1β-induced inflammatory responses by increasing the activity of the JNK/p38-AP-1 signaling pathway in cultured chondrocytes. Taken together, the present findings suggest a possible mechanism for the exacerbated inflammatory responses observed in OA pathology, and may contribute to the available drug targets for the development of therapeutic agents for OA.

关键词： AD   Autonomic dysfunction   ARS   Antireflux surgery   BAL   Bronchoalveolar lavage   BOS   Bronchiolitis obliterans syndrome   CLAD   Chronic lung allograft dysfunction   DES   Distal esophageal spasm   DGE   Delayed gastric emptying   DSA   Donor-specific antibodies   EC-MPS   Enteric-coated mycophenolate sodium   EGJ   Esophagogastric junction   EGJOO   Esophagogastric junction outflow obstruction   FEV   Forced expiratory volume in one second   GCA   Glycocholic acid   GER   Gastroesophageal reflux   GERD   Gastroesophageal reflux disease   GI   Gastrointestinal   H2RA   Histamine-2 receptor antagonist   HOBE   Head-of-bed elevation   IEM   Ineffective esophageal motility   IL   Interleukin   LABW   Large airway bronchial wash   LARS   Laparoscopic antireflux surgery   LES   Lower esophageal sphincter   MMF   Mycophenolate mofetil   MPA   Mycophenolic acid   OIED   Opioid-induced esophageal dysfunction   PGA4   Pepsinogen A4   PGD   Primary graft dysfunction   POEM   Peroral endoscopic myotomy   PPI   Proton pump inhibitor   PsA   Pseudomonas aeruginosa   SP-A   Surfactant protein A   SP-D   Surfactant protein D   TCA   Taurocholic acid   TLESR   Transient lower esophageal sphincter relaxations   Chronic lung allograft dysfunction   Bile acids   Pepsinogen A4   Gastroesophageal reflux   Anti-reflux surgery  

摘要： Background Chronic Lung Allograft Dysfunction (CLAD) is the leading cause of late morbidity and mortality following lung transplantation. Increasing evidence implicates microaspiration, often secondary to gastroesophageal reflux disease (GERD) and gastrointestinal (GI) dysfunction, as a critical non-alloimmune driver of CLAD. However, its often silent presentation, diagnostic complexity, and heterogeneous management contribute to persistent knowledge and treatment gaps. Methods This narrative review synthesizes recent literature on the pathophysiology, diagnosis, and clinical impact of microaspiration and GI dysfunction in lung transplant recipients. We focus on emerging biomarkers (e.g., conjugated bile acids and pepsinogen A4), diagnostic modalities, and both medical and surgical treatment strategies aimed at mitigating aspiration-induced graft injury. Key Content and Findings Microaspiration leads to epithelial damage, surfactant disruption, immune activation, and microbial dysbiosis, collectively promoting allograft dysfunction. Conjugated bile acids in large airway bronchial wash fluid and pepsinogen A4 have shown superior specificity as aspiration biomarkers compared to pepsin alone. Gastrointestinal disorders, such as GERD, gastroparesis, and esophageal dysmotility, frequently co-exist post-transplant and contribute to aspiration risk. Pharmacologic interventions provide limited benefit, while anti-reflux surgery significantly improves graft outcomes, particularly when performed early. Conservative measures such as head-of-bed elevation also reduce reflux burden and may complement therapeutic strategies. Conclusions Microaspiration is a modifiable and underrecognized contributor to allograft injury. Integration of aspiration biomarkers, early reflux evaluation, and personalized stepwise management, including surgical intervention when indicated, may improve long-term transplant outcomes. This review provides clinicians with a structured framework for diagnosi

关键词： 盐酸青藤碱   急性T淋巴细胞白血病   CEM细胞   细胞凋亡   RNA-seq测序   增殖抑制   工程化细胞  

摘要： 背景:盐酸青藤碱有抗多种肿瘤的作用,但目前尚不清楚盐酸青藤碱对急性T淋巴细胞白血病的作用。目的:探讨盐酸青藤碱对急性T淋巴细胞白血病CEM细胞的抑制作用。方法:应用不同浓度(0.5,1,2,4 mmol/L)盐酸青藤碱处理CEM细胞,CCK-8检测细胞增殖抑制率并计算IC50;倒置显微镜和吉姆萨染色观察CEM细胞形态变化;利用RNA-Seq测序分析差异基因表达并进行生物信息学分析。结合转录组测序结果,流式细胞术检测不同浓度(1,2,4 mmol/L)盐酸青藤碱作用后CEM细胞凋亡率;Western blot检测不同浓度(1,2,4 mmol/L)盐酸青藤碱作用后CEM细胞中Bcl-2、Bax、Caspase-9蛋白的表达。结果与结论:①盐酸青藤碱呈剂量和时间依赖性地抑制CEM细胞生长;②盐酸青藤碱干预后CEM细胞数量下降,核固缩;③RNA-seq测序筛出53个异常表达基因,基因本体分析主要富集在细胞过程、细胞解剖实体与粘连关系等,信号通路分析与肿瘤相关的是细胞凋亡;④盐酸青藤碱呈剂量依赖性地促进CEM细胞凋亡;⑤盐酸青藤碱上调CEM细胞中Bax、Caspase-9蛋白表达,下调Bcl-2蛋白表达。由此可见,盐酸青藤碱可诱导CEM细胞凋亡从而抑制细胞增殖,可能与其上调Bax和Caspase-9蛋白表达,以及下调Bcl-2蛋白表达有关。

关键词： Diabetic retinopathy   OTUD3   Oxidative stress   PPARγ   TNF-α  

摘要： Aims Diabetic retinopathy (DR) is one of the major complications of diabetes. In addition to hyperglycemia, various mechanisms contribute to the development of microvascular damage to the retina, which have not been fully elucidated. The aim of this study was to investigate Ovarian tumor domain-containing protein 3 (OTUD3)'s protection against DR by targeting peroxisome proliferator-activated receptor γ (PPARγ)-mediated dysfunction and identifying therapeutic strategies. Materials and methods We conducted clinical analysis of 208 type 2 diabetes mellitus (T2DM) patients with OTUD3 genotyping, combined with diabetic homozygous mutated ( Otud3 −/− ) mouse models and retinal pigment epithelium (RPE) cell lines (OTUD3 knockdown/mutation). Key findings We found increased hyperreflective foci (HRF) associated with an increased immune activation in diabetic Otud3 −/− mice compared to Otud3 wild-type ( Otud3 +/+ ) mice. OTUD3 knockdown or mutated cells showed increased cell dysfunction and oxidative stress markers under inflammatory conditions. Further upstream transcription factors predict analysis suggest PPARγ as the potential target of OTUD3. Finally, we found PPARγ agonist could rescue the phenotype in RPE cells characterized by increased ROS levels, enhanced migration, and elevated apoptosis resulting from OTUD3 loss of function through knockdown or mutation. Significance Our study offers novel insights into how deubiquitylase OTUD3 maintains the normal function of the retina by deubiquitylating PPARγ and provides a novel therapeutic target for this vision-threatening diabetic complications.

关键词： Pain   Extracellular vesicle   MSC   Neuron   MicroRNA  

摘要： Mesenchymal stem cell-derived extracellular vesicle (MSC-EV) has shown promise for pain relief, but its efficacy is limited. Preconditioning MSC with tumor necrosis factor-α (TNF-α) may enhance their therapeutic potential; however, the impact on analgesia and underlying mechanisms remains unclear. Here, we investigated the analgesic effects of EV from TNF-α-preconditioned MSC (T-EV) in a chronic constriction injury (CCI) mouse model and examined the molecular mechanisms involved. Following intrathecal injection, T-EV produced greater improvements in mechanical and thermal pain thresholds than control MSC-EV (C-EV), achieving enhanced pain relief for two weeks. Whole-cell patch-clamp recordings revealed that T-EV markedly decreased both the firing rate and action potential amplitude of dorsal root ganglion (DRG) neurons. RNA sequencing revealed that T-EV was enriched in miR-101b-3p. Silencing miR-101b-3p in T-EV abolished their enhanced analgesic effects and reversed DRG hyperexcitability. Moreover, miR-101b-3p was shown by luciferase assays to bind directly to the 3′UTR of Nav1.6, suppressing its expression. Engineered MSC-derived nanovesicle overexpressing miR-101b-3p replicated the increased pain relief observed with T-EV. These findings demonstrate that TNF-α preconditioning improves the analgesic potency of MSC-EV by delivering miR-101b-3p, which downregulates Nav1.6 and decreases DRG hyperexcitability. This study supports the therapeutic potential of miR-101b-3p-enriched vesicle as a novel strategy for treating neuropathic pain.

关键词： Lung transplantation   Donor   Recipient   Resection   LT   Lung transplantation   HLA   Human leukocyte antigen   pTLC   Predicted total lung capacity   PGD   Primary gtraft dysfunction   ISHLT   International Society for Heart and Lung Transplantation   CLAD   Chronic lung allograft dysfunction   LAS   Lung allocation score   ICU   Intensive care unit   ILD   Interstitial lung disease  

摘要： Background Lung transplantation (LT) is a well-established therapeutic option for patients with advanced respiratory diseases. However, the impact of size discrepancy between donor and recipient remains controversial. Objective This study aims to evaluate the impact of lung graft volume reduction due to size mismatch between donor and recipient. Methods A retrospective analysis was conducted at a single reference center, including all LT procedures performed between January 1, 2015, and July 30, 2024. Surgical protocols were reviewed, and the need for graft volume reduction was recorded. The decision to perform graft reduction was made intraoperatively by the lead surgeon. Results A total of 420 patients were included. Lung graft resection was performed in 14 cases (3.3 %). Patients requiring graft resection had longer operative times, prolonged intubation and ICU stays, and increased tracheostomy requirements. The donor-to-recipient predicted total lung capacity (pTLC) ratio was significantly higher among patients requiring resection. While 5-year survival was not significantly different, 1- and 3-year survival rates were worse for patients requiring resection. Conclusion Lung graft resection due to donor-recipient size discrepancy can be a viable option for suitable recipients, although it is associated with increased postoperative morbidity. Given the small sample size (14 patients), these findings should be interpreted cautiously, and larger studies are needed to confirm these results. Early referral to transplant centers and careful donor-recipient matching are crucial to minimize the need for graft resection and improve outcomes.

关键词： Autophagy   Immune evasion   Lumpy skin disease virus   ORF142   cGAS/STING  

摘要： Lumpy skin disease (LSD), caused by the Lumpy skin disease virus (LSDV), poses a significant threat to the global cattle farming industry. Viral proteins evolved the ability to escape host immune responses. Here, we demonstrate that LSDV infection inhibits interferon-β (IFN-β) production in Madin-Darby bovine kidney (MDBK) cells, even in the presence of Sendai virus (SEV) inducers. Through further investigation, we identify multiple genes at both ends of the LSDV genome that strongly inhibit IFN-β or NF-κB activation of the promoter. Notably, ORF142 selectively inhibits IFN-β promoter activity but fails to inhibit NF-κB promoter activity. Subsequently, we reveal that ORF142 negatively regulate the cGAS/STING-mediated IFN-I production. Overexpression of ORF142 suppresses IFN-β and interferon-stimulated response element (ISRE) activity, while the absence of ORF142 upregulates the transcription levels of IFN-β and interferon-stimulated genes (ISGs) in MDBK cells. Mechanistically, ORF142 interacts with STING to facilitate autophagy-lysosomal degradation by recruiting NBR1, thereby impeding the activation of downstream signaling molecules, such as IRF3, and inhibiting IFN-I production. In conclusion, our findings elucidate the immune evasion mechanism of ORF142 encoded by LSDV, offering insights for the development of antiviral drugs or attenuated live vaccines to mitigate LSD.

关键词： Interleukin-6   Neuroinflammation   Ethanol   Alcohol use disorder   Mechanical allodynia   Spinal cord  

摘要： Alcohol use disorder (AUD) is defined by the emergence of negative affective symptoms during withdrawal. Neuroinflammation is a key contributor to AUD, and it is well known to play an essential role in the pathogenesis of pain states. The chronic-intermittent ethanol two-bottle choice (CIE-2BC) paradigm is well-established to generate alcohol-dependent (Dep) and non-dependent (Non-Dep) mice. Our recent work demonstrated that the CIE-2BC model promotes mechanical allodynia in Dep mice, with these mice developing mechanical allodynia during withdrawal. In this study, we examined the role of interleukin-6 (IL-6) in the development of mechanical allodynia by adapting the CIE-2BC mouse model and employing the von Frey test, in situ hybridization (RNAscope), and Multiplex protein analysis of the spinal cord, examining changes in this target including an array of cytokines associated with IL-6 signaling. CIE-2BC escalated alcohol drinking and enhanced mechanical allodynia in Dep versus Non-Dep mice, with Dep females displaying greater alcohol intake. Dep mice displayed increased IL-6 protein in the spinal cord while males additionally had increased Il6+ cell expression versus Non-Dep controls. Systemic treatment of an IL-6 receptor antibody (IL-6R Ab) did not decrease mechanical allodynia during abstinence. Collectively, these data suggest that alcohol exerts sex-dependent effects on spinal IL-6 levels. However, in our study, blocking IL-6 signaling did not reduce alcohol-associated pain sensitivity in a mouse model of comorbid pain and alcohol dependence.

关键词： AEBP1   IL-32   Mycobacterium tuberculosis   RNA-Seq   TNF pathway   macrophage  

摘要： Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, survives in host macrophages, the primary effector and antigen-presenting cells involved in the host immune response. We previously showed that Interleukin-32 (IL-32) is significantly increased in the peripheral blood plasma of tuberculosis patients, can act as an anti-MTB agent. However, the underlying molecular mechanism for its effect remains unknown. Here, we showed that inhibiting IL-32 with monoclonal antibody increases MTB loads that was positively correlated with higher antibody concentrations and longer exposure times. RNA-Sequencing result indicated that 3797 genes were shown to be up-regulated in response to IL-32 inhibition, while 1365 genes were down-regulated. GO and KEGG analysis indicated that classical signaling pathways, including TNF, cell cycle, and Wnt were significantly enriched. Consistent expression trends were observed in NF-κB pathway-related antibacterial factors that are functionally capable of inhibiting MTB. Using differentially expressed gene and protein-protein interaction analysis, AEBP1 was the gene with the most significant difference in expression and regulated by IL-32. These findings suggest a dynamic molecular and cellular mechanism by which IL-32 positively regulates the AEBP1-IκBα-NF-κB-TNF-α axis to inhibit MTB infection in human macrophages.

关键词： Methamphetamine   IL-17A   IL-17RC   Methamphetamine use disorder   Mice  

摘要： We demonstrated previously that blocking IL-17A, a proinflammatory cytokine, prevents oxycodone-induced depression-like effects and anxiety-like effects during abstinence from MDPV (a psychostimulant) in rats. Here, we tested the hypothesis that eliminating IL-17A signaling (pharmacological antagonism using IL-17A Ab or genetic deletion of IL-17RC) would inhibit behavioral and neurochemical effects elicited by methamphetamine (METH) exposure and abstinence in adult mice. We investigated rewarding and locomotor-activating effects of METH and withdrawal-induced anxiety- and depression-like effects during METH abstinence. Mice received saline or METH (5 mg/kg, IP) once daily for 18 d. Locomotion was measured on days 1 and 15. Anxietyand depression-like effects were investigated 72 and 96 h after the last METH injection using the elevated plus maze and forced swim test, respectively. IL-17A antibody (Ab, 60 mu g/100 mu l, IP) was injected every 3rd day of METH exposure. METH-induced hyperlocomotion was significantly reduced in IL-17RC knockout mice or by treatment with the IL-17A Ab (100 mu g/100 mu l). Neutralization of IL-17A or genetic deletion of IL-17RC prevented development of depression-like effects during METH abstinence. Also, mRNA levels of IL-17RC, but not IL-17RA, in the NAC were enhanced during METH abstinence. Development of METH conditioned place preference (CPP) was prevented by IL-17A Ab but was not affected by IL-17RC deletion in mice conditioned with METH (3 mg/kg) for 4 d. Our data show that abolishing IL-17A signaling reduces METH-induced hyperlocomotion and CPP and attenuates depression-like effects during METH abstinence. These results highlight studying IL-17A blockade as a neuroimmune-based approach to mitigate METH adverse effects.