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关键词： Olfactory receptors   MHC   SLA   Pigs   And mate selection  

摘要： Background Olfactory receptor (OR) genes are highly polymorphic and form extensive families that recognize a wide range of vertebrate odorants. To explore the genetic diversity of MHC-linked OR genes and their connection to MHC genes, we conducted a combined haplotype analysis of MHC-linked OR and MHC class I genes to determine the influence of MHC on OR diversity, which could be associated with MHC-based mate selection. Results We selected nine MHC-linked OR genes based on their expression levels in pig testes and developed a sequence-based typing method for these genes. We then performed high-resolution typing of these OR genes, along with three major classical MHC class I genes (SLA-1, -2, and - 3), in 48 pigs across six breeds. We observed significantly higher allelic diversity (P < 0.01) in ORs with strong linkage disequilibrium (LD) to SLA compared to those with weak or no LD, and we identified 48 SLA class I-OR haplotypes using the expectation-maximization algorithm. The genetic diversity of SLA-linked ORs was positively correlated with their expression levels in the testis. Specifically, SLA-linked ORs with higher testicular expression (FPKM >= 0.1) exhibited an increase in the number of codons under mutually diversifying selection with SLA compared to those with lower expression (FPKM < 0.1). Conclusions The presence of evolutionary interactions between MHC and linked OR genes supports the potential involvement of MHC-linked ORs in MHC-based mate selection. The use of combined haplotype information for MHC and linked ORs could provide new insights into the reproductive biology of animals.

关键词： difficult-to-treat rheumatoid arthritis   regulatory T cells   T helper 17 cells   low-dose interleukin-2   cytokines  

摘要： Objective Circulating regulatory T cells (Tregs) are closely related to immune tolerance and maintenance of immune homeostasis. Perhaps, there is a unique immune cell phenotype for difficult-to-treat rheumatoid arthritis (D2T RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of autoimmune diseases. This study focused on the uniqueness of D2T RA lymphocyte subsets and the feasibility of low-dose IL-2 *** Participants included 1,042 RA patients who were divided into three groups according to the presence or absence of treatment and their response to treatment in the last 6 months-new group, treated group, and D2T group-and 339 healthy controls (HCs). A total of 381 patients-107, 151, and 123 in each of the three experimental groups-received low-dose IL-2 treatment [0.5 million international units (MIU) per day, subcutaneous injection from day 1 to day 5]. The absolute numbers of peripheral blood lymphocyte subsets were detected by flow cytometry (FCM) and serum cytokine levels were detected by flow cytometry bead array (CBA).Results The absolute number of T, CD4+ T, and Treg cells in the D2T RA group was lower than that in the HC, new, and treated RA groups. Compared with the HC and new RA group, the ratio of Th17/Treg cells in the D2T RA group increased. The new, treated, and D2T RA groups had higher cytokine levels than the HC. The number of Treg cells in RA patients was negatively correlated with the disease activity index. Treg cells in the new, treated, and D2T RA groups could be increased by low-dose IL-2 therapy without any side *** The number of lymphocytes and subsets in D2T RA patients was reduced, especially Treg cells, resulting in a shift in the balance of effector T cells/Treg cells toward effector T cells, which is ameliorated by low-dose IL-2 without obvious side effects.

关键词： Keloid   Pruritus   Superficial dermis   IL-31   IL-31 receptor   M2 macrophages  

摘要： BackgroundThe exact pathogenesis of keloid (KD) associated pruritus is still unknown and responds poorly to current antipruritic therapies. Pruritogenic role of interleukin-31 (IL-31) has been studied extensively and was proven in a variety of pruritus associated diseases, while its role in KD is still rather *** aim of this study is to explore the pathophysiological mechanism of KD-associated pruritus by detecting the correlation between the severity of pruritus and the expression of pruritogenic cytokines IL -31 and its receptor complex components, IL-31 receptor alpha (IL-31RA) and Onstostatin M receptor beta (OSMR beta), and the number of their source *** total of 46 keloid tissue samples were included in this study and clinical data were recorded, of which 24 were available with both lesional and clinically adjacent uninvolved perilesional skin ( AUPS, taken at least 0.5 cm away from the keloid edge ), and 22 were available with lesional skin only. In this study, immunofluorescence detection was used to detect and compare the expression differences of IL-31 and its receptors (IL-31RA and OSMR beta) in different layers (epidermis, superficial dermis, and deep dermis) between keloid lesions and AUPS and the correlation between the IL-31 expression level and the severity of KD-associated pruritus was explored. In addition, immunofluorescence co-localization was used to explore the cell source of IL-31, and the correlation between the number of source cells and the severity of KD-associated pruritus was explored. The fluorescence intensity in epidermis and number of infiltrating cells in the dermis was quantified and normalized by ImageJ *** this study, the KD and AUPS groups were matched for age and gender, which were not statistically different and, there was no significant difference in the sample causes and distribution between two groups. Compared with the AUPS, the number of IL-31(+) cells in the superficial and deep d

关键词： Parkinson   Carvacrol   Inflammasome   Thalidomide   Oxidative stress   Haloperidol  

摘要： BackgroundParkinson's disease is a debilitating and the second most common neurodegenerative disorder with a high prevalence. Parkinson's disease has a multifaceted etiology characterized by an altered redox state and an excessive inflammatory response. In this study, we investigated the potential neuroprotective properties of carvacrol in a haloperidol-induced Parkinson's model. In female Sprague-Dawley rats, the animal Parkinson model was induced by intraperitoneally administering 1 mg / kg of haloperidol once daily for fifteen days. Carvacrol was administered at a dose of 25 and 50 mg / kg once daily for fifteen days before haloperidol administration. In order to further illustrate the vital role of the tumor necrosis factor (TNF-alpha) pathway, we administered 50 mg / kg of the TNF-alpha inhibitor thalidomide once daily for 15 *** results showed that haloperidol-induced motor deficits, changed endogenous antioxidant enzymes, along with higher levels of inflammasome (NLRP3) and other inflammatory mediators. Moreover, increased levels of lipid peroxidase (LPO) indicated a significant rise in oxidative stress due to haloperidol. Moreover, carvacrol reduced these effects by preventing pyroptosis mediated by the inflammasome (NLRP3) and TNF-alpha. The administration of thalidomide mitigated oxidative stress and suppresses inflammatory pathways through the augmentation of the intrinsic antioxidant system. Further, co-treatment of carvacrol with thalidomide synergized the neuroprotective effect of carvacrol as demonstrated by various immunoassays and histology *** together, our findings suggest that carvacrol mitigated haloperidol-induced Parkinson-like symptoms, partially through the downregulation of TNF-alpha and NLRP3.

摘要： L’ormone ipotalamico growth hormone-releasing hormone (GHRH), oltre a promuovere il rilascio di GH da parte dell’adenoipofisi, esercita numerosi effetti a livello periferico. Diversi studi hanno infatti dimostrato importanti azioni extra-ipofisarie del GHRH e dei suoi analoghi agonisti sintetici, suggerendo il loro possibile sviluppo clinico nelle patologie cardiovascolari, neurodegenerative, nel diabete e nelle malattie metaboliche.

关键词： Antioxidant   Cubebin   Diabetic nephropathy   Streptozotocin   Diabetes  

摘要： Cubebin, a dibenzyl butyrolactone lignan belonging to several distinct families, including Aristolochiaceae, Myristicaceae, Piperaceae, and Rutaceae, and possesses several pharmacological activities, including analgesic, anti-inflammatory, antioxidant, and vasodilatory. The current study aimed to evaluate the effect of cubebin on streptozotocin (STZ)-evoked diabetic nephropathy (DN). DN is a well-identified complication of diabetes mellitus (DM) characterized by renal hypertrophy that progressively declines kidney function. Wistar rats were randomly divided into groups- normal, STZ control (65 mg/kg/body weight), and STZ + cubebin (10 and 20 mg/kg). Biochemical parameters such as glucose levels, kidney parameters, lipid profile, oxidative stress, endogenous antioxidant markers, inflammatory cytokines and histopathology were performed. Molecular docking [(PDB ID: TNF-alpha (7JRA), NF-kappa B (1SVC), TGF-beta 1 (3TZM)] and dynamic simulation (MDS) were also performed with the selected target. STZ-induced DN was changes in these parameters. In contrast, DN + cubebin at 10 and 20 mg/kg doses improved the biochemical parameters and histological changes. Furthermore, molecular docking and simulation studies showed a binding affinity with negative binding energy with TNF-alpha (7jra, - 11.342 kcal/mol), TGF-beta 1 (3tzm, - 9.162 kcal/mol) and NF-kappa B (1svc, - 6.665 kcal/mol). The results of MDS provided insight into the mechanisms that associate proteins TNF-alpha, NF-kappa B, and TGF-beta 1 in conformational dynamics upon binding to cubebin. In conclusion, these findings exhibit a potential effect of cubebin in STZ-evoked DN rats.

关键词： induced pluripotent stem cells   neuroinflammation   gene therapy   microglia   motor neurons  

摘要： Spinal muscular atrophy (SMA) is a pediatric genetic disorder characterized by the loss of spinal cord motor neurons (MNs). Although the mechanisms underlying MN loss are not clear, current data suggest that glial cells contribute to disease pathology. We have previously found that SMA astrocytes drive microglial activation and MN loss potentially through the upregulation of NF-KB-mediated pro-inflammatory cytokines. In this study, we tested the ability of neutralizing C-C motif chemokine ligand 5 (CCL5) while increasing either interleukin-10 (IL-10) or IL-1 receptor antagonist (IL-1ra) to reduce the pro-inflammatory phenotype of SMA astrocytes. While IL-10 was ineffective, IL-1ra ameliorated SMA astrocyte-driven glial activation and MN loss in induced pluripotent stem cell- derived cultures in vitro. In vivo AAV5 delivered IL-1ra overexpression, and miR-30 small hairpin RNA knockdown of CCL5 made modest but significant improvements in lifespan, weight gain, MN number, and motor function of SMND7 mice. These data identify IL-1ra and CCL5 as possible therapeutic targets for SMA and highlight the importance of glial-targeted therapeutics for neurodegenerative disease.

关键词： renal transplantation   HLA-DQ   molecular mismatch   immunogenicity   risk stratification  

摘要： Human leukocyte antigen (HLA) mismatching, particularly with HLA-DQ, significantly impacts the development of donor-specific antibodies (DSA) and transplant outcomes. HLA-DQ antibodies are highly immunogenic and detrimental, necessitating advanced high-resolution HLA typing to improve mismatch assessment and clinical risk evaluation. Traditional serological or low-resolution typing often misclassifies mismatches, leading to inaccuracies in assessing immunogenicity and predicting outcomes. Emerging molecular mismatch algorithms refine immunogenicity assessments by analyzing amino acid differences and structural interactions. These tools show promise for personalizing transplant protocols but have limitations, such as variability in predicting individual patient outcomes. Immunogenicity of mismatches also depends on evolutionary divergence and specific amino acid differences, with studies revealing that certain evolutionary lineages and polymorphisms influence T-cell alloreactivity and DSA development. Complexities in HLA-DQ protein expression, including combinatorial diversity of heterodimers and inter-isotypic heterodimers, further complicate risk evaluation. Expression levels, influenced by tissue specificity and inflammatory stimuli, and alternative splicing of HLA-DQ transcripts add additional layers of variability. Future clinical applications, enabled by high-resolution HLA typing, may include refined graft selection, improved DSA monitoring, and individualized therapy. However, understanding the precise mechanisms of HLA-DQ immunogenicity remains a priority for advancing transplantation science and enhancing patient outcomes.

摘要： La diffusione della cromatografia liquida abbinata a spettrometria di massa (LC-MS/MS) ha consolidato l’importanza delle misurazioni accurate degli ormoni steroidei nella diagnosi e nella gestione dell’iperandrogenismo femminile. Inoltre, questa tecnologia ha rinnovato l’interesse per le vie steroidee non canoniche. I moderni pannelli LC-MS/MS, che includono un gran numero di steroidi di diverse classi, offrono un grande potenziale nella caratterizzazione dell’iperandrogenismo femminile. Infatti, la posibilità di monitorare contemporaneamente i diversi pathways steroidei potrebbe aiutare a chiarire i numerosi aspetti oscuri delle varie forme di iperandrogenismo e a migliorarne la diagnosi. Stiamo assistendo ad un’evoluzione dell’attuale paradigma diagnostico, basato sulla valutazione di pochi ormoni interpretati rispetto a valori soglia rigidi e non standardizzati, a favore di una visione di sistema più adatta alla caratterizzazione di malattie complesse con un elevato grado di eterogeneità fenotipica, in linea con il moderno concetto di medicina di precisione. Altre importanti applicazioni dei pannelli LC-MS/MS multisteroidei riguardano la caratterizzazione di farmaci che agiscono sulla steroidogenesi e la medicina sportiva. Negli ultimi anni, gli androgeni 11-ossigenati-C19 stanno attirando grande attenzione. Sebbene la rilevanza di questi androgeni in alcuni deficit della steroidogenesi sia evidente, i dati finora ottenuti non mostrano un chiaro legame tra androgeni 11-ossigenati-C19, iperandrogenismo clinico e dismetabolismo in altri contesti, come la PCOS. Sono necessari ulteriori studi su popolazioni ampie e ben caratterizzate per svelare il ruolo dei percorsi non canonici nella fisiopatologia femminile, aiutati dall’uso di test funzionali e dalla definizione di opportuni intervalli di riferimento. In particolare, è necessario chiarire le traiettorie del flusso degli steroidi attraverso le diverse vie durante il complesso periodo della maturazione sessuale, al