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摘要： Profiling the HLA diversity at the population level benefits multiple clinical and anthropological applications, such as tracing population migration, identifying genetic relationships between different groups, quantifying the added diversity in a global donor pool and matching for solid organ and stem cell transplantation. We calculated nine-locus HLA-A similar to C similar to B similar to DRB1 similar to DRB3/4/5 similar to DQA1 similar to DQB1 similar to DPA1 similar to DPB1 allele and haplotype frequencies in about 170,000 volunteer donor genotypes from the NMDP Mexico (NMDP MX, previously Be The Match Mexico) donor center. These donors are predominantly of Mexican ancestry recruited from multiple regions in Mexico. The goal of the study was to describe the HLA genetic profiles of the Mexican population and investigate the contribution of these donors' HLA in serving Mexican, US and international patients in need of hematopoietic cell transplants. Additionally, we estimated that almost all Mexican patients will have an available 5 of 8 or better matched donor in the NMDP MX donor center with matches also available for some of the Latino patients in the U.S. We demonstrate that Mexican populations clustered genetically and shared multiple frequent alleles and haplotypes with populations from the US Mexican or Chicano, US South/Central American Hispanic, and some Latino populations. Operationally, 78 % of NMDP Mexico donors contributed genotypes that were observed a total of three times or less on the registry, increasing the diversity of the overall NMDP registry. More than 300 donor collections were facilitated through the NMDP MX donor center serving mostly Hispanic/Latino patients in the US and abroad. This study highlights the importance of adding the NMDP MX donors to the worldwide donor pool and paves the way for a data-driven strategy for future planning and donor recruitment.

关键词： IL-17 inhibitors   inflammatory bowel disease   Secukinumab  

摘要： IL-17 inhibitors effectively treat psoriasis and psoriatic arthritis but may increase the risk of inflammatory bowel disease (IBD). We assessed their association with IBD compared to apremilast. Utilising the TriNetX database, we analysed patients with psoriasis or ankylosing spondylitis initiating IL-17 inhibitors or apremilast. We used propensity score matching and Cox models to estimate IBD risk. Among 13,216 matched patients per group, 142 developed IBD with IL-17 inhibitors versus 60 with apremilast (aHR = 2.50, 95% CI: 1.85-3.39). IL-17 inhibitors increase IBD risk, necessitating careful patient selection and monitoring.

关键词： Pharmacokinetics   Population pharmacokinetic model   Safety   TQH2722   IL-4Ra monoclonal antibody   Phase I  

摘要： The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics (PK) of TQH2722, an Interleukin-4 receptor alpha (IL-4Ra) monoclonal antibody, in healthy subjects. In this randomized, doubleblind and placebo-controlled trial, TQH2722 was subcutaneously injected as single-ascending dose (n = 46;50, 150, 300, 600 and 1200 mg) or multiple-ascending dose (n = 20;150 and 600 mg;four doses every 2 weeks). Subjects were monitored for adverse events and blood samples were collected for pharmacokinetics. A population pharmacokinetic model was developed and validated. TQH2722 was well tolerated with no serious or severe adverse events observed. After a single dose, the maximum concentration occurred at 3-7 days, with t1/2 ranged from 2.65 to 17.43 days. Four repeated dosing caused about 3-fold degree of accumulation for Cmax and AUC. Regardless of single or multiple doses, the exposure showed a nonlinear and greater than dose proportional increase. A two-compartment model taking into account the mechanistic target-mediated drug disposition process with parallel linear and nonlinear Michaelis-Menten (MM) elimination and first-order absorption well described the pharmacokinetics of TQH2722. In conclusion, TQH2722 was safe and well tolerated, and its PK profiles were well characterized, supporting its further clinical development in patients. (c) 2025 Published by Elsevier Inc. on behalf of American Pharmacists Association.

关键词： Actinobacillus pleuropneumoniae   CpxAR   Lipopolysaccharide   Amyloid precursor protein   beta-Amyloid   IL-1 beta   Porcine alveolar macrophage  

摘要： Actinobacillus pleuropneumoniae (A. pleuropneumoniae), a porcine respiratory tract pathogen, causes porcine pleuropneumonia. Porcine alveolar macrophages (PAMs) play a crucial role during A. pleuropneumoniae infection. Amyloid precursor protein (APP) can be cleaved by beta- and gamma-secretase to produce beta-amyloid (A beta). APP and A beta are associated with the inflammatory response. They activate microglia and astrocytes to secrete IL-1 beta, IL-6, and other cytokines. In this study, we found that during the interaction between A. pleuropneumoniae and PAMs, the two-component system CpxAR upregulates wecA expression, increasing lipopolysaccharide (LPS) production. LPS promotes APP production and cleavage to generate A beta. The A beta activates NF-kappa B, leading to increased IL-1 beta expression. We hypothesize that A. pleuropneumoniae infection of PAMs regulates APP production and cleavage to control A beta levels. Different quantities of A beta induce PAMs to produce varying amounts of cytokines, leading to different pathological processes in porcine pleuropneumonia.

关键词： Sepsis   IL-33   Myocardial injury   Inflammation   Oxidative stress   Apoptosis  

摘要： Septic myocardial injury, a severe sepsis complication linked to high morbidity and mortality, remains a major global clinical challenge. Interleukin-33 (IL-33), a damage-associated pro-inflammatory factor, has been implicated in regulating immune responses and inflammation, but its specific role in septic myocardial injury has not been fully elucidated. This study examined IL-33's role in septic myocardial injury using Gene Expression Omnibus (GEO) database datasets, alongside in vitro and in vivo experiments. Our results indicated a significant upregulation of IL-33 in septic myocardial injury, as demonstrated in both clinical and experimental settings. Blocking IL-33 significantly enhanced cardiac function and alleviated cardiomyocyte damage. Mechanistic investigations revealed that neutralizing IL-33 mitigates inflammation, oxidative stress, and apoptosis in cardiomyocytes by regulating the nuclear factor kappa B (NF-kappa B)/signal transducer and activator of transcription 3 (STAT3)/suppressors of cytokine signaling 3 (SOCS3) signaling pathway. Peritoneal macrophages are recognized as a potential origin of IL-33, and targeting IL-33 derived from these cells further reduced cardiomyocyte injury. The study underscores IL-33's crucial involvement in septic myocardial injury pathogenesis, indicating that IL-33 may serve as a promising therapeutic target.

关键词： Immunomodulatory activity   Lycopodium complanatum ssp. chamaecyparissus   TNF-alpha   IL-6   Lycopodine  

摘要： In the current work, the results of in vivo bioactivities of the petroleum ether (PE), chloroform (CHL), and methanol (MET) extracts of Lycopodium complanatum L. ssp. chamaecyparissus (***.) Doll (LCC, Lycopodiaceae) were assessed in a dose-dependent manner on tumor necrosis factor (TNF-a), and interleukin-6 (IL-6) in specific pathogen-free (6-8 weeks SPF) mice. The levels of proinflammatory cytokines, e.g. TNF-a and IL-6 secreted from murine peritoneal macrophages, were assayed and determined following exposure to varying doses (50 and 100 mg kg-1) of LCC-PE, LCC--CHL, and LCC-MET using anti-mouse ELISA kits. The samples with or without control lipopolysaccharide (LPS, Escherichia coli 026: B6) were collected from SPF mice on the treatment days. The cytopathogenic effect was not observed in the samples at the tested doses times. According to our data, at 100 mg kg-1 dose of PE, CHL, and MET extracts of LCC, moderate activities were observed, where significant differences were found between the doses of the samples (p < 0.05). The antimicrobial and antiviral data we obtained from our previous research and the current data obtained have been consistent with the immunomodulatory activity of LCC-PE in particular. The immunomodulatory activity of the extracts might be due to their alkaloidal content such as lycopodine as the major alkaloid, along with dihydrolycopodine and lycodine. (c) 2025 SAAB. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Radiation-induced lymphopenia   Animal models   Precise irradiation   Lymphocyte-rich organs   Lung cancer  

摘要： Purpose: Over half of radiotherapy-treated cancer patients develop radiation-induced lymphopenia (RIL). Severe RIL has been associated with worse prognosis and survival, and recent studies suggested that RIL also affects immunotherapy efficacy. We aimed to develop murine grade 2 (>= 20 % decrease in absolute lymphocyte counts (ALC)) RIL models and to examine the effects of RIL on progression-free survival upon radiotherapy-immunotherapy treatment. Materials and methods: C57BL6/J mice received heart, large blood vessels (LBV) or thoracic vertebrae irradiation (10 Gy) and ALC were monitored weekly. In tumour-bearing animals, Lewis Lung Carcinoma cells were injected subcutaneously one day prior to RIL induction. When tumours reached 212 +/- 45 mm(3), tumours were locally irradiated (10 Gy), and animals were injected with L19-IL2 (1 mg/kg, 3 times QOD) or vehicle intravenously. Tumour growth was monitored until reaching > 4 times treatment starting volume. Flow cytometry-based immune cell profiling was performed on blood collected 2 weeks post-tumour cell injection. Results: Radiation treatment plans targeting lymphocyte-rich organs were optimized to achieve maximal target coverage while minimal dose to normal tissues. In na & iuml;ve animals, LBV and vertebrae irradiation led to grade 2 RIL, however heart irradiation induced only grade 1 RIL. In tumour-bearing animals, RIL induction was confirmed by a 16 % and 20 % drop in ALC upon LBV and vertebrae irradiation, respectively. Grade 2 RIL did not negatively influence progression-free survival upon radiotherapy. Radiation combined with L19-IL2 induced a tumour growth delay compared to radiotherapy only (p < 0.0005). LBV or vertebrae irradiation did not affect radiotherapy-immunotherapy outcome, explained by the restored and increased lymphocyte and eosinophil counts upon L19-IL2 administration (p < 0.05). L19-IL2 increased inducible regulatory and CD8(+) T cells, especially in vertebrae (p < 0.01) and LBV (p = 0.07) irra

关键词： Coenzyme Q 10   FCA-Salt rat   Cardiac fibrosis   Renal fibrosis   Inflammation  

摘要： Hypertension is one of the most common factors contributing to cardiac remodeling that links to changes in both heart and kidney functions. Several studies have reported the beneficial effects of Coenzyme Q10 (CoQ10) in reducing oxidative stress due to its antioxidant properties. However, the cardioprotective and nephroprotective roles of CoQ10 against the toxicity induced by fludrocortisone acetate (FCA) have yet to be investigated. Therefore, we evaluated the CoQ10 effects on FCA-induced cardiotoxicity and nephrotoxicity in a rat model (FCASalt). We analyzed various oxidative stress parameters and antioxidant enzyme activities using biochemical assays. In addition, we examined inflammatory and fibrosis via histological staining of heart and kidney tissues. CoQ10 significantly reduced lipid peroxidation product-malondialdehyde (MDA) while increased nitric oxide (NO) in the FCA-Salt rats. Antioxidant enzyme activities were also enhanced by CoQ10 in these rats. Histopathological examination detected tissue damage and fibrosis in the FCA-Salt group, which was significantly reduced by CoQ10. Furthermore, enzyme-linked immunosorbent assay (ELISA) indicated the activation of Transforming growth factor-(31/Tumor necrosis factor-alpha (TGF-(31/TNF-alpha) by CoQ10. Consequently, our study suggests that CoQ10 can effectively protect heart and kidney health against cardiotoxicity and nephrotoxicity in FCA-Salt hypertensive rats via TGF-(31/TNF-alpha pathway.

关键词： Asthma   Ma-Xing-Shi-Gan decoction   Gut microbiota   Treg cells   histone deacetylation  

摘要： Background: Gut microbiota imbalance is well-known as one important trigger of allergic asthma. Ma-Xing-ShiGan decoction (MXSG) is a traditional Chinese medicine prescription with ideal clinical efficacy on asthma. However, whether and how MXSG exerts its efficacy on asthma through gut microbiota remains unclear. Purpose: To investigate the underlying mechanism of MXSG against asthma using multi-omics technologies. Methods: An asthma model was established using 8-week-old C57BL/6 J mice, after which they were daily administrated with high-, medium- and low-dose MXSG for 7 days. Histopathological examinations and flow cytometry were performed to evaluate the effects of MXSG on lung immune injury. Key regulatory pathways were predicted via network pharmacology and verified using 16S rRNA sequencing, metagenomics, metabolomics, and in vivo experiments including the knockout of the targeting gene. Results: MXSG alleviated asthma symptoms, elevated intestinal microbial diversities, and enriched potential beneficial microbes such as Lactococcus, Lactobacillus, and Limosilactobacillus. Network pharmacology and experimental validation highlighted the IL-17/Treg signaling as crucial for asthma treatment. IL-17 knockout experiments revealed its necessity for Treg differentiation during asthma. Moreover, IL-17-deficient asthmatic mice exhibited lower levels of Lactobacillus and significant changes in microbial genes involving histone deacetylases (HDAC) and short-chain fatty acids (SCFAs). Finally, MXSG significantly boosted SCFA production and reduced HDAC9 expression, which were correlated with Treg cell ratios. Conclusion: Our study delineates a novel mechanism where MXSG synergizes with the IL-17 family to enrich intestinal beneficial microbes (e.g. Lactobacillus) and SCFAs. This inhibits the expression of SCFA-downstream HDAC9 to promote Treg differentiation, and thus potentially alleviates asthma.