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关键词： orthodontics   monocyte   macrophage activation   mechanotransduction   periodontal ligament  

摘要： Orthodontic root resorption (ORR) is a common yet significant complication of orthodontic treatment, largely driven by interactions between periodontal ligament cells (PDLCs) and M1 macrophages. Despite the clinical relevance of ORR, the role of mechanosensitive ion channels in PDLC-mediated ORR and the underlying mechanisms regulating inflammatory cell recruitment remain poorly understood. Here, we identified PIEZO1 as a critical mechanosensitive ion channel that modulates monocyte recruitment and ORR. Using in vivo models treated with the PIEZO1 activator Yoda1 and inhibitor AAV-shPiezo1, we demonstrated that PIEZO1 activation promoted the recruitment of Ly6Chi inflammatory monocytes and exacerbated ORR. In contrast, PIEZO1 inhibition attenuated ORR and the accumulation of M1 macrophages. Mechanistically, PIEZO1 positively regulated the C-X-C motif chemokine 12 (CXCL12) and its receptor, C-X-C chemokine receptor type 4 (CXCR4). Blocking the CXCL12/CXCR4 axis using the CXCR4 antagonist AMD3100 significantly alleviated ORR, reversed M1 macrophage accumulation, and mitigated the recruitment of CD11b+Ly6Chi monocytes. Transwell migration assays with application of the PIEZO1 activator Yoda1 and PIEZO1 inhibitor GsMTX4 consistently confirmed the PIEZO1/CXCL12/CXCR4 axis as a key driver of PDLC-monocyte interactions. Notably, PIEZO1 overactivation was linked to excessive IL-6 production, and IL-6 deficiency inhibited the activation of PIEZO1 induced by Yoda1, leading to attenuation of ORR, M1 macrophage accumulation, and CXCL12/CXCR4 axis activation. Collectively, these findings reveal PIEZO1 in PDLCs as a pivotal modulator of inflammatory monocyte recruitment via the CXCL12/CXCR4 axis in ORR, with IL-6 playing an essential role in PIEZO1 activation. This study provides new insights into the molecular crosstalk between PDLCs and macrophages, offering potential therapeutic targets for mitigating ORR in orthodontic patients.

关键词： Eosinophilia   tumor necrosis factor-alpha inhibitors   etanercept   golimumab   hematologic side effects   biological  

摘要： Introduction We present an unusual case of a 28-year-old rheumatologic male patient who developed eosinophilia while he was on etanercept therapy first and then on *** Representation Although eosinophilia is rarely reported in the literature as a side-effect of various Tumor Necrosis Factor-alpha [TNF-alpha] antagonists, it represents a riddle about the future treatments of these patients since the persistence of therapy might lead to the onset of dermatologic or visceral eosinophilic complications in such *** Furthermore, the pathogenesis of eosinophilia is still unknown, and all the proposed hypotheses do not explain the eosinophilic proliferation in certain subjects.

关键词： Psoriasis   Bimekizumab   Gender   Treatment   Real world evidence  

摘要： Introduction Several studies have demonstrated that psoriasis severity is generally greater in male patients, but it is unclear whether this gender difference may affect short-term therapeutic response. Notably, no studies have specifically investigated bimekizumab, a humanized, full-length IgG1 monoclonal antibody that acts as a dual inhibitor of interleukin (IL)-17A and IL-17F. Methods This was a cross-sectional, observational, retrospective, multicenter analysis. A cohort of 318 patients with moderate to severe psoriasis, 229 male patients (median [IQR] age 35 [23-67] years) and 89 female patients (median [IQR] age 33 [20-68] years), were retrospectively evaluated for short-term response (16 weeks) to bimekizumab according to standard dosage (320 mg at weeks 0, 4, 8, 12, and 16, and every 8 weeks thereafter). Patients were assessed to evaluate whether gender differences in demographic and clinical characteristics can affect treatment response to standard dose of bimekizumab, during the first 16 weeks of treatment. Therapeutic outcomes were evaluated by analyzing Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores recorded in each patient at three consecutive time points: baseline (T0), after 4 weeks (T4), and after 16 weeks of treatment (T16). Results Male patients showed more severe disease at baseline, compared to female patients (p = 0.01). A significant reduction in disease severity was observed in both male and female patients after 16 weeks of treatment, but male patients showed a faster decrease in PASI score between baseline and week 4 of treatment compared to female patients (p < 0.001). Nevertheless, by week 16, difference in PASI response and DLQI reduction between genders became less pronounced. Conclusion Although male patients exhibit greater disease severity at baseline compared to female patients, this does not result in a differential response to bimekizumab over the short term. Both male and female patients

关键词： Infection   Inflammation   Autoimmunity   Immunogenetics   MHC   TLR   Psychiatric disorder  

摘要： The spectrum of infectious risk organisms showing associations with psychiatric traits is expanding. Infectious agents can modulate the risk of psychiatric disorders at different stages of life, such as gestational, childhood, adolescent, and adult periods. Prenatal infection appears to 'prime' the developing brain, whereas infection during childhood or later periods may act as a 'second hit', and these may have synergistic effects on the risk of developing psychiatric diseases. However, neither all the individuals with antecedent infection develop psychiatric disorders, nor do infectious organisms alone lead to psychiatric phenotypes. This suggests modulatory effects of additional host factors. The host genetic background crucially determines differential susceptibility to infection and serves as an important gateway for immune activation and signalling, as well as homeostatic brain functions. Despite the presence of several immune checkpoints and effectors, the infectious organisms disrupt the balance between immune-activating and immune-compensatory mechanisms and contribute to immune dysregulation. This depends substantially on genetic loci encoding immune molecules such as Toll-like receptors, Major Histocompatibility Complex, cytokines/ chemokines and their receptors, complement proteins, and other molecules and elements such as human endogenous retroviruses and gut microbiome that have distinct roles in immune regulation and immune effector functions. Genetic variations within these loci not only influence differential susceptibility to infection but also confer risk to psychiatric disorders. This article highlights a comprehensive overview of the nexus between infections and immune function-related genes and their impact on psychiatric traits. Understanding such interactions will lead to the identification of genetic markers of susceptibility to infection and psychiatric diseases.

关键词： 5-MTHF   5-methyl THF   AA   arachidonic acid   ADHD   attention-deficit hyperactivity disorder   AIMS   Abnormal Involuntary Movement Scale   ALA   α   -lipoic acid   AMPK   AMP-activated protein kinase   AP   antipsychotic   ASD   autism spectrum disorder   BARS   Barnes Akathisia Rating Scale   BDNF   brain-derived neurotrophic factor   BPRS   Brief Psychiatric Rating Scale   CDSS   Calgary Depression Scale for Schizophrenia   CGI-S   Clinical Global Impression–Severity   CI   confidence interval   DHA   docosahexaenoic acid   DSHEA   Dietary Supplement Health and Education Act   EMA   European Medicines Agency   EPA   eicosapentaenoic acid   EPS   extrapyramidal symptoms   FDA   US Food and Drug Administration   FGA   first-generation antipsychotic   GAF   Global Assessment of Functioning   GSH   glutathione   HDRS   Hamilton Depression Rating Scale   IL   interleukin   LDL   low-density lipoprotein   LTP   long-term potentiation   MCCB   MATRICS Cognitive Consensus Battery   mGluR   2   metabotropic glutamate receptor 2   NAC   N-Acetylcysteine   NbN   neuroscience-based nomenclature   Nf-kB   nuclear factor kappa-light-chain-enhancer   NMDA   N-methyl-D-aspartic acid   Nrf-2   nuclear factor erythroid 2-related factor   OR   odds ratio   PANSS   Positive and Negative Symptoms of Schizophrenia   PI3K   phosphatidylinositol-3 kinase   PPAR   γ   peroxisome proliferator-activated receptor gamma   PUFA   polyunsaturated fatty acid   UGT   UDP-glucuronosyltransferase   RCT   randomized controlled trial   SANS   Scale for the Assessment of Negative Symptoms   SAS   Simpson-Angus Scale   SCFA   short-chain fatty acids   SGA   second-generation antipsychotic   THF   tetrahydrofolate   TNF-   α   tumor necrosis factor-   α   UKU   Udvalg for Kliniske Undersøgelser   VDR   vitamin D receptor  

摘要： Antipsychotic (AP) medications are the primary treatment for severe mental illnesses, including schizophrenia and severe mood disorders. APs are currently categorized into typical or first-generation APs and atypical or second-generation APs. Although both first-generation and second-generation APs are considered effective in treating psychotic symptoms in severe mental disorders, they differ in their mechanisms, treatment strategies, and side effect profiles. Because of their potential motor and metabolic side effects, which often compromise patient adherence and clinical outcomes, whether and how to use APs remains controversial. The use of dietary interventions in combination with APs is emerging as a viable strategy to reduce AP adverse effects while maintaining their efficacy and enhance patient adherence to treatment. In contrast to drugs that possess a well defined molecular mechanism of action, dietary interventions act in pleiotropic ways by nature. While providing a holistic approach to patient care this pleiotropy needs to be analyzed and systematized to enhance the efficacy and safety of the combination of them with APs. Guidelines for this type of treatment are still needed. In this review, we explore the pharmacological properties, therapeutic applications, and limitations of APs, and discuss the potential benefits and limitations of those dietary interventions that are employed to improve the efficacy and counteract side effects of APs discussing also their mechanisms of action. Finally, we critically discuss the main results of clinical studies combining APs and dietary interventions and provide a view on future directions in terms of research and clinical use of these combinations. Significance Statement: Antipsychotic drugs are useful in a variety of psychiatric conditions, yet their use is hampered by issues of efficacy and safety. An important step toward therapy optimization is their use in combination with dietary interventions (ie, dietary sup

关键词： Preformed DSA   Imlifidase   Kidney transplantation   Highly sensitized patients   HLA delisting   Pretransplant desensitization  

摘要： Highly sensitized patients awaiting kidney transplantation face substantial challenges due to the presence of potential donor-specific anti-HLA antibodies (DSA). These antibodies increase the risk of antibody-mediated rejection (ABMR), but also complicate their access to HLA compatible transplantation. Although advancements in allocation priority programs, such as the Spanish Program for the Access of Highly Sensitized Patients to Kidney Transplantation (PATHI), have introduced virtual crossmatching (v-XM) to streamline compatibility assessments, patients with >99,5 % virtual panel reactive antibodies (vPRA) often remain on waiting lists for extended periods with minimal chances of receiving a transplant. This article summarizes Spanish guidelines for a harmonized and comprehensive framework for the management of highly sensitized patients. These guidelines focus on strategies to facilitate transplantation in the presence of DSA, including a stepwise approach to delist HLA antigens, prioritizing those recognized as "less deleterious" antibodies, to expand transplant options while minimizing immunological risks. Conventional desensitization techniques are discussed, alongside the innovative use of imlifidase to enable transplants in particularly complex cases. Post-transplant monitoring protocols are also exposed, with a focus on early detection of antibody rebound and effective management of ABMR. Ultimately, this resource offers clinicians a structured framework to navigate the intricate challenges of kidney transplantation in high-risk populations, aiming to enhance access to life-saving procedures and improve patient outcomes.

关键词： pIgRL4.2   IFN   SVCV   CRISPR/Cas9   Zebrafish  

摘要： The mucosal immune system plays a critical role in defending the body against external pathogens and preserving homeostasis. The polymeric immunoglobulin receptor (PIGR) is a critical component of this system, responsible for facilitating the transport and secretion of soluble polymeric immunoglobulins across epithelial cells, thereby contributing to immune defense. In zebrafish, a pIgR-like (pIgRL) family exists, among which pIgRL4.2 is highly expressed in multiple immune organs, suggesting its potential role in immunity. In this study, spring viremia of carp virus (SVCV) infection significantly downregulates pIgRL4.2 expression. Conversely, overexpression of pIgRL4.2 in EPC cells markedly delays SVCV-induced cytopathic effects and effectively suppresses SVCV replication. Additionally, overexpression of pIgRL4.2 enhances IFN activation induced by both poly (I:C) treatment and SVCV infection. Furthermore, CRISPR/Cas9 was used to generate pIgRL4.2-null zebrafish, and disruption of pIgRL4.2 in zebrafish has been demonstrated to result in a reduction in survival rates following SVCV challenge. This is accompanied by a consistent downregulation of antiviral responsive genes, concomitant with an increase in SVCV replication in pIgRL4.2-deficient zebrafish. Therefore, this study demonstrates that pIgRL4.2 inhibits viral replication by positively regulating the IFN signaling pathway.

关键词： Phellodendrine chloride   Gouty arthritis   Chondrocytes   STAT3   Proteoglycan  

摘要： Background: Phellodendrine, a primary bioactive constituent of Phellodendron chinense Schneid (PCS), is crucial in its pharmacological profile. Phellodendrine exhibits potent anti-nephritic properties and demonstrates a marked inhibitory effect on the cellular immune response. However, the effects of phellodendrine on proteoglycan depletion and cartilage degeneration in gouty arthritis remain insufficiently understood. Therefore, the objective of this study is to elucidate the therapeutic potential and underlying mechanisms of phellodendrine chloride (PC) in the treatment of gouty arthritis. Methods: A monosodium urate (MSU)-induced arthritis model in rats, along with a peritonitis model in mice, was developed, in combination with a chondrocyte model. Neutrophil proportions were quantified using flow cytometry. The expression levels of MMP-3, STAT3, and phosphorylated STAT3 (p-STAT3) in chondrocytes were determined by Western blot analysis. Proteoglycan levels in chondrocytes were assessed using toluidine blue staining and quantitative reverse transcription PCR (qRT-PCR). Joint swelling rates were monitored at 0-24 h in rats, and histopathological changes in joint tissues were subsequently analyzed. Results: Phellodendrine chloride mitigated the rise in neutrophil proportions within MSU-induced peritoneal lavage fluid in mice and decreased inflammatory cell infiltration in rat ankle tissues. Treatment with phellodendrine chloride led to a downregulation of MMP-3 protein levels and inhibited IL-1 beta-induced proteoglycan degradation in chondrocytes. Additionally, results from experiments combining IL-1 beta with AG490 or IL-6 demonstrated that phellodendrine chloride attenuated IL-1 beta-induced MMP-3 expression and proteoglycan degradation. Conclusion: Our findings suggest that phellodendrine chloride mitigates gouty arthritis (GA) by modulating the IL-6/STAT3 signaling pathway.

关键词： Adipocyte browning   Macrophage polarization   TNF alpha   Mitochondrial respiration   Palmitic acid   LPS  

摘要： Obesity and its associated pro-inflammatory activity contribute significantly to metabolic dysfunction. In contrast, browning of white adipose tissue (WAT) generally improves metabolic health. Our prior research suggested that macrophage-derived pro-inflammatory cytokines suppress key regulators of browning-adrenergic receptor beta 3 (Adrb3) and peroxisome proliferator-activated receptor gamma (Pparg)-as well as energy metabolism mediators-insulin receptor substrate 1 (Irs1) and hormone-sensitive lipase (Lipe)-in dietinduced obese mice. To explore this mechanism, we developed an in vitro model using RAW264.7 macrophages and 3T3-L1 adipocytes exposed to palmitic acid (PA) and/or lipopolysaccharide (LPS). PA (200 mu M) and LPS (1.0 mu g/ml) synergistically promoted M1 polarization of macrophages and secretion of pro-inflammatory cytokines, with tumor necrosis factor-alpha (TNF alpha), C-C motif chemokine ligand 2 (CCL2), CCL5, and interleukin6 (IL-6) being predominant. Conditioned media from both control and PA-treated macrophages, when exposed to LPS >= 0.01 mu g/ml, significantly downregulated Adrb3, Pparg, Irs1, and Lipe in adipocytes. At physiologically relevant LPS levels (<= 0.001 mu g/ml), PA-treated macrophage media exerted greater suppression of these genes than controls. Among the cytokines, TNF alpha emerged as the primary mediator, significantly reducing expression of the four key regulators. Furthermore, adipocytes treated with TNF alpha exhibited significant reductions in both uncoupling protein 1 (Ucp1) expression and mitochondrial respiration. These findings demonstrate that exposure to obesity-associated factors (PA and LPS) induces macrophage-derived TNF alpha, which suppresses browning and mitochondrial function in adipocytes. This mechanism may inform new therapeutic strategies targeting TNF alpha to alleviate obesity-related metabolic disorders.