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关键词： Atopic dermatitis   italic>Loranthus tanakae Franch. & Sav.   ovalbumin   JAK2   STAT1  

摘要： Loranthus tanakae Franch. and Sav. is a traditional herbal remedy with anti-inflammatory and antioxidative properties, used to treat joint and respiratory inflammation. In this study, we investigated the therapeutic effects of L. tanakae ethanol extract (LTE) on atopic dermatitis (AD). An ovalbumin (OVA)-induced AD animal model and a human keratinocyte cell line, HaCaT, were used to assess LTE treatment effects on AD. An in vitro experiment showed that LTE treatment significantly decreased the production of regulated upon activation, normal T cell expressed and secreted (RANTES) cytokines and macrophage-derived chemokines (MDC) in tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma) (TNF-alpha/IFN-gamma)-stimulated HaCaT cells in a concentration-dependent manner. In addition, treatment with LTE markedly reduced the translocation of signal transducer and activator transcription 1 (STAT1) protein to the nucleus and the phosphorylation of Janus kinase 2 (JAK2) in TNF-alpha/IFN-gamma-stimulated HaCaT cells. In the in vivo experiment, administration of LTE significantly decreased the levels of immunoglobulin E (IgE) and interleukin-13 (IL-13) of OVA-induced AD mice, which was supported by histological evidence. Moreover, LTE treatment markedly reduced inflammatory cell infiltration and edema in the OVA-induced AD mice's damaged lesions. In addition, applying LTE notably inhibited the phosphorylation of JAK2 and STAT1 in the OVA-induced AD mice, supported by in vitro results. In conclusion, LTE effectively alleviated the AD-induced skin inflammation in the OVA-induced AD animal model and TNF-alpha/IFN-gamma-stimulated HaCaT cells;this was related to the suppression of JAK2 and STAT1 phosphorylation. These findings suggest that LTE has potential as a therapeutic agent for AD management.

关键词： Panaxatriol saponins   chronic kidney disease   renal fibrosis   TNF-alpha   TGF-beta 1/smad3   UUO model  

摘要： Renal fibrosis is a key pathological process in the progression of chronic kidney disease (CKD). Panaxatriol saponins (PTS), the main bioactive compounds extracted from Panax notoginseng (Burk.) F.H. Chen, have demonstrated antioxidative and anti-inflammatory activities. This study aimed to investigate the potential protective effects of PTS against renal fibrosis and explore the underlying pharmacological mechanisms. A unilateral ureteral obstruction (UUO) model was established in Sprague-Dawley (SD) rats to induce renal fibrosis. Histopathological changes were assessed using hematoxylin and eosin (HE) staining, Masson's trichrome staining, and transmission electron microscopy (TEM). Network pharmacology and molecular docking approaches were employed to identify potential signaling molecules through which PTS may mitigate renal fibrosis. Western blotting, quantitative real-time PCR (qRT-PCR), and immunohistochemistry were utilized to validate the involvement of specific signaling pathways in PTS-mediated anti-fibrotic effects. Our data demonstrated that PTS alleviated renal dysfunction and provided protective effects against renal fibrosis, primarily through the TNF-alpha and TGF-beta 1 signaling pathways. Moreover, PTS treatment significantly downregulated pro-inflammatory cytokines such as TNF-alpha, IL-6, and Smad3 activity. Additionally, PTS inhibited the expression of key fibrosis markers, including alpha-SMA, collagen I, and fibronectin. Our study suggests that PTS exert a prevention effect in renal fibrosis by blocking the TGF-beta 1/Smad3 signaling pathway.

关键词： Tumor-infiltrating lymphocytes   interleukin 2   adoptive cell therapy   checkpoint blockade   anti-PD-1   immune profiling  

摘要： This study evaluated the efficacy and safety of unengineered tumor-infiltrating lymphocytes (TILs) combined with pembrolizumab and either high (HD, Arm-1) or low (LD, Arm-2) doses of IL-2 in patients with metastatic melanoma (MM). Patients were lymphodepleted with cyclophosphamide and fludarabine, followed by TIL infusion and IL-2 (Arm-1: 720,000 IU/kg IV q 8 hrs up to 15 doses;Arm-2: 2 million IU SC for 14 days). Patients received pembrolizumab 200 mg IV starting 21 days post-TIL infusion, and every 3 weeks for up to 2 years. The primary endpoint was overall response rate (ORR) per RECIST 1.1. Blood samples were collected for longitudinal flow cytometry and cytokine analysis. In Arm-1 (n = 7), one patient had a partial response (PR) for 10 months, two had stable disease (SD), three had progressive disease (PD), and one was not evaluable (NE). In Arm-2 (n = 7), one patient had an ongoing PR for over 76 months, one had SD, and five had PD. The toxicity profiles were comparable;however, patients in Arm-2 had lower grade 3 febrile neutropenia (57% vs. 71%) and shorter hospitalization (median 16 days vs. 18 days). No correlation was observed between TIL phenotype and clinical response, although PR patients received high numbers of TIL with a high CD8+/CD4+ T cell ratio. IL-2 dose did not affect the frequency, phenotype, or proliferation of circulating T cell subsets, and anti-PD-1 did not boost T-cell proliferation. No significant differences were observed between IL-2 doses, suggesting low-dose IL-2 as an alternative to high-dose IL-2 after TIL administration.

关键词： Respiratory syncytial virus   multiepitope   in silico   recombinant subunit vaccine  

摘要： Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infections in infants and the elderly. The burden of RSV-related hospitalizations and deaths is significantly increasing. Recently, RSV vaccines targeting F protein have been approved, but their long-term efficacy is yet to be evaluated. This study aimed to design a polyvalent multi-epitope RSV subunit vaccine tailored to Korean HLA types using in silico methods. Nine prevalent HLA allele types in Korea were used to predict vaccine epitopes. Combinations of selected epitopes were created, and stable combinations were selected and conjugated with human beta-defensin and PADRE. Fifty-five multi-epitope combinations were selected for vaccine construction, and 33 vaccine constructs induced strong immune responses in silico. The final vaccine candidate is a 228-amino acid construct weighing 23,957 Da and effectively induces humoral and cellular immune responses with high population coverage, suggesting potential for further development.

关键词： Infectious agents   allergic rhinitis   IL   TLR   IFNs  

摘要： Allergic rhinitis (AR) is increasingly prevalent, yet diagnostic and therapeutic approaches remain inadequate. Recent studies show links between infectious diseases and noninfectious disorders, but the underlying mechanisms are largely unknown. We used bidirectional Mendelian randomization (MR) to investigate the impact of antibodies against infectious diseases on AR. Our results indicate that CMV IgG+, human herpesvirus 7 U14 antibodies, anti-varicella zoster virus IgG (VZV IgG+), and varicella zoster virus glycoproteins E/I antibodies are positively correlated with AR, while Epstein-Barr virus EBNA-1, ZEBRA, Merkel cell polyomavirus VP1, BK polyomavirus VP1, anti-human herpesvirus 6 E1A IgG, and human herpesvirus 6 IE1A antibodies are negatively correlated. Reverse MR analysis shows AR increases VZV IgG+ likelihood. These findings suggest a bidirectional causal relationship between infectious disease immune responses and AR, advancing understanding and potential diagnostics.

关键词： Da-Yuan-Yin decoction   damp-heat syndrome   neutrophil extracellular traps   faecal metabolites   gut microbiota   inflammation  

摘要： BackgroundDa-Yuan-Yin Decoction (DYY), used since the early Qing Dynasty in China for damp-heat syndrome, was evaluated for its comprehensive protective *** and methodsRats received a high-fat/high-sugar diet for 14 days, then daily exposure to high temperature/humidity (31.0 +/- 0.5 degrees C, 85%-95%) for 10 hours over 14 days. Damp-heat syndrome was induced on day 29 via intraperitoneal lipopolysaccharide (LPS) injections (1 mg/kg and 0.5 mg/kg after 4 hours). Two hours post-modeling, rats received DYY (400 or 800 mg/kg/day) orally for 5 days. Symptoms were scored. On day 33, kidney, spleen, tongue, lung, liver, stomach, and colon tissues underwent histopathological and immunochemical/immunofluorescence analysis. Serum levels of inflammation factors, C-reactive protein (CRP), cell-free DNA (cfDNA), myeloperoxidase (MPO), and superoxide dismutase (SOD) were quantified. Complete blood count (CBC), blood biochemistry, short-chain fatty acids (SCFAs), gut microbiota composition in the colon, and metabolites in the cecum were *** significantly reduced symptom scores and decreased CRP level, while also regulating parameters in CBC and biochemical profiles. The treatment ameliorated tissue damage in the kidney, spleen, tongue, lung, liver, stomach, and colon. DYY downregulated citrullinated histone H3 (Cit H3), polyclonal peptidylarginine deiminase 4 (PADI4), and MPO expressions in the lung, stomach, and colon. Furthermore, it modulated inflammatory responses, suppressed the interleukin-23 (IL-23)/janus kinase-2 (JAK2)/signal transduction and transcription activator-3 (STAT3) signaling pathway and enhanced antioxidant activity. DYY administration significantly increased total SCFA content. The intervention restored gut microbiota diversity and abundance, while ameliorating metabolic *** pathophysiological alterations were observed in rats with damp-heat syndrome. The comprehensive protective effects of DYY invol

关键词： Severe asthma   anti-IL-5/IL-5(R) therapy   responder   remission   biomarker  

摘要： IntroductionPrevious studies of anti-IL-5/IL-5(R) therapies in severe asthma found that response was mainly predicted by indicators of good baseline disease control. However, long-term response predictors remain *** to anti-IL-5/IL-5(R) therapy in the well-characterised, real-life, international German Asthma Net (GAN) registry were analysed using regression analyses. Response was defined by >= 50% reduction in exacerbations or corticosteroid dose, super-response by a complete stop of both, and remission additionally by controlled asthma (ACT score >= 20).ResultsSeventy-seven percent of 347 patients (55% female, 56.6 +/- 12.3 years, follow-up 20.3 +/- 13 months) were responders and showed improved exacerbation rates, asthma control, and corticosteroid treatment reduction. Response was independently predicted by inhaled corticosteroid dose (odds ratio [OR] 1.5;p = 0.014), exacerbation rate (OR 1.2;p = 0.009), and treatment duration (OR 1.05, p = 0.023). Univariately, blood eosinophil counts notably predicted response (OR 12.4;p = 0.004). Super-response was inversely associated with corticosteroid dependence and depression. Remission was associated with the absence of systemic corticosteroids, better asthma control, and FEV1 in *** results underscore that long-term anti-IL-5/IL-5(R) therapy reduces exacerbation and corticosteroid burden, especially in patients with severe disease and high type 2 inflammatory burden. Contrastingly, low baseline corticosteroid use and markers of good asthma control predicted remission and super-responder status.

关键词： Cognitive dysfunction   biomarkers   ischemic stroke   neuroinflammation therapeutic targets   TNF signaling pathway   tumor necrosis factor-alpha (TNF-alpha)  

摘要： BackgroundPost-stroke cognitive impairment (PSCI) is a prevalent complication that impairs stroke survivors' quality of life and rehabilitation. Growing evidence highlights the crucial role of inflammation in PSCI pathogenesis. The tumor necrosis factor (TNF) signaling pathway, especially tumor necrosis factor-alpha (TNF-alpha), has gained attention for its role in neuroinflammatory diseases. TNF pathway activation is strongly associated with neuronal injury and neuroinflammation in stroke, suggesting its involvement in PSCI. However, the exact mechanisms by which TNF signaling contributes to PSCI remain *** review summarizes recent evidence on the TNF signaling pathway to elucidate its molecular mechanisms, analyze its role in PSCI pathogenesis, and examine associated inflammatory responses and their functional consequences. We also explores potential therapeutic targets, offering novel perspectives for PSCI *** comprehensive literature search was conducted across electronic databases including PubMed, Web of Science, Embase, and MEDLINE to identify relevant studies. We systematically reviewed recent research investigating the role and mechanisms of the TNF signaling pathway in PSCI. Eligible studies were rigorously screened, followed by data extraction and quality assessment using standardized *** TNF signaling pathway is complex and heterogeneous in PSCI, potentially attributable to variations in study designs, samples, experimental models, and interventions. Emerging evidence supports the therapeutic potential of pharmacological and biological agents targeting this pathway. These findings highlight the need for integrated clinical and basic research to strengthen the foundation for early diagnosis, prevention, and treatment of PSCI, and to guide evidence-based clinical decisions.