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关键词： Intervertebral disc degeneration   BQU57   Inflammation   Apoptosis   NF-kappa B signaling pathways  

摘要： Background: Intervertebral disc degeneration (IVDD) is a significant contributor to lower back pain (LBP), affecting approximately 80 % of the global population. The RalA inhibitor BQU57 plays a role in various cellular functions;however, its impact on nucleus pulposus cell (NPC) degeneration remains unclear. Methods: This study employed a combination of bioinformatics analysis and experimental validation to investigate the role of RalA in IVDD and its inhibitor BQU57 in its therapeutic potential. Gene expression datasets from the GEO database were analyzed to identify genes associated with IVDD, and clinical intervertebral disc samples were collected to validate the upregulation of RalA in degenerated discs. In vivo and in vitro assessments were conducted to evaluate the effects of BQU57 on the extracellular matrix (ECM) metabolism and apoptosis of nucleus pulposus (NP) cells. Results: Elevated expression of RalA was observed in degenerated intervertebral discs from IVDD patients, and its expression was correlated with disease severity. Further mechanistic studies revealed that the RalA inhibitor BQU57 could balance ECM metabolism and apoptosis, potentially through the activation of the NF-kappa B signaling pathway. Conclusion: RalA plays a significant role in the pathogenesis of IVDD, and it may serve as a novel therapeutic target for IVDD. BQU57 demonstrates potential as an effective small molecule drug for the prevention and treatment of IVDD.

关键词： Achilles tendon regeneration   Piezoelectric PCL/BTO nanofilm   Macrophage and T cells   Immunomodulation   IL-17A/NF-kappa B signaling pathway  

摘要： Tendon injuries are often exacerbated by persistent inflammation, which hampers tissue regeneration. In this study, we developed a noninvasive, wirelessly controlled, and self-powered piezoelectric nanofilm fabricated by coaxial electrospinning of polycaprolactone (PCL) and tetragonal barium titanate nanoparticles (BTO), and investigated its roles in modulating inflammation and repairing Achilles tendon defects as well as the mechanism in a rat model. In vitro study and in vivo study upon subcutaneous implantation showed that the piezoelectric PCL/BTO nanofilms could inhibit M1 macrophage polarization and reduce the secretion of inflammatory factors. Moreover, when bridging an Achilles tendon defect, the nanofilms could promote tenogenic gene expression including collagen deposition, and collagen remodeling, facilitate functional tendon recovery and significantly reduce tissue inflammation by suppressing M1 macrophage polarization and promoting M2 polarization. Moreover, the piezoelectric stimulation could also enhance tendon regeneration by inhibiting angiogenesis, reducing lipid deposition, and decreasing ectopic ossification. Mechanistically, the piezoelectric nanofilms reduced tissue inflammation mainly via inhibiting the nuclear factor (NF)-kappa B signaling pathway that is mediated by interleukin (IL)-17A secreted from CD3+ T cells, and thus to reduce proinflammatory factors, such as IL-1 beta and IL-6, inducible nitric oxide synthase, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. These findings indicate the potential of piezoelectric stimulation in immunomodulation, and in promoting tendon regeneration via IL-17A/NF-kappa B-mediated pathway.

关键词： Psoriasis   Interleukin 17   IL17RA genetic variant   PASI   Psoriatic arthritis  

摘要： Background: Genetic variants that can play an important role in psoriasis (PsO) ethiology and pathophysiology. Objective: To evaluate the association between the IL17RA genetic variants with the susceptibility and severity of PsO. Methods: This study included 154 patients with PsO and 154 healthy controls. The severity of PsO was determined using Psoriatic Activity and Severity Index (PASI). The IL17RA single nucleotide variants T > C rs2241043, A > G rs2241049, and G > A rs6518661 were genotyped. Results: The IL17RA A > G (rs2241049) GG genotype was associated with protection against PsO [odds ratio (OR): 0.391, 95 % confidence interval (CI):0.199-0.768, p = 0.006)] while the IL17RA T > C (rs2241043) CC genotype and the IL17RA G > A (rs6518661) AA genotype were associated with the PsO severity (OR = 0.30, 95 % CI 0.10-0.093, p = 0.020 and OR = 0.22, 95 % CI 0.05-0.99, p = 0.020, respectively). Conclusion: The results demonstrated that the IL17RA A > G (rs2241049) GG genotype may be a protective factor against the development of PsO and the CC genotype of the IL17RA T > C (rs2241043) and the AA genotype of the IL17RA G > A (rs6518661) variants were associated with protection against the severity of PsO. Considering that these variants are located in intronic regions of the IL17RA, other genetic and epigenetic mechanisms involved in these associations should be investigated.

关键词： Severe asthma   Biologics   Clinical remission   Exacerbation  

摘要： Background: The optimal selection of biologics is critical for achieving clinical remission (CR) in patients with severe asthma. This real-world study examined baseline prebiologic factors associated with CR in patients with severe asthma receiving anti-IL-4R alpha, anti-IL-5/5R, or anti-IgE treatment. Methods: This Japanese multicenter retrospective observational study included consecutive patients with severe asthma whose spirometry and asthma control test (ACT) data were available after at least 1 year of anti-IL-4R alpha, anti-IL-5/5R, or anti-IgE treatment. The 3-domain CR was defined based on no maintenance oral corticosteroid (OCS) use, no exacerbation in the previous year, and ACT >= 23. The 4-domain CR was defined based on no OCS, no exacerbation, ACT >= 20, and percentage-predicted forced expiratory volume in 1 s >= 80 %. Results: A total of 236 patients with severe asthma were included (n = 81, 104, and 51 for the anti-IL-4R alpha, anti-IL-5/5R, and anti-IgE treatment groups, respectively). The rates of 3-and 4-domain CR were 28-47 % and 22-36 %, respectively. In the multivariate models, the presence of chronic rhinosinusitis and higher FeNO levels were associated with 3-domain CR in patients receiving anti-IL-4R alpha treatment but not in those receiving anti-IL-5/5R or anti-IgE treatment after adjusting for baseline OCS use, past-year exacerbation history, body mass index, sex, and disease duration. Moreover, higher FeNO levels were associated with 4-domain CR in patients receiving anti-IL-4R alpha treatment after adjustment for the same variables. Conclusion: Anti-IL-4R alpha treatment may be effective for patients with severe asthma who have chronic rhinosinusitis or high FeNO levels at baseline.

关键词： nephrotic syndrome   idiopathic nephrotic syndrome   minimal change disease   focal segmental glomerulosclerosis   pediatric   children   pathogenesis   immune mechanisms   FSGS   Focal segmental glomerulosclerosis   GWAS   Genome-wide association studies   HLA   Human leukocyte antigen   IL   Interleukin   INS   Idiopathic nephrotic syndrome   MCD   Minimal change disease   NS   Nephrotic syndrome   PSMA1   Proteasome subunit alpha type 1   SSNS   Steroid sensitive nephrotic syndrome   suPAR   Soluble urokinase plasminogen activator receptor   Th   T-helper   TNF-⍺   Tumor necrosis factor alpha   Treg   T-regulatory   UCHL1   Ubiquitin C-terminal hydrolase L1  

关键词： Gastrodia elata Blume extract   Sepsis-induced lung injury   IL-23/IL-17 A axis   Neutrophil infiltration  

摘要： The Compendium of Materia Medica recorded that the traditional Chinese medicine Gastrodia elata Blume (G. elata) has applications in antibacterial and antiviral. GE05 was prepared from the rhizome of G. elata and its active ingredients have been proven to alleviate inflammatory response. However, the protective effect and the underlying mechanism of G. elata in sepsis remain unclear. Our study aims to uncover the efficacy and molecular mechanisms of GE05 in ameliorating sepsis-induced lung injury. Here, we have shown that GE05 could inhibit the expression of inflammatory cytokines in peritoneal macrophages. Bioinformatics analysis showed the activation of interleukin (IL)-17 signaling pathway in acute lung injury (ALI) mice. We established septicemia models and showed that GE05 improves survival rates and protects against sepsis-induced lung injury by downregulating the IL-23/IL-17 A axis. Quantitative real- time PCR (qPCR) analysis and immunohistochemistry have indicated that IL-17 A inhibition reduces the release of chemokine ligand (Cxcl) 1, Cxcl2, granulocytemacrophage colony stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF), mitigating neutrophil infiltration-induced lung tissue damage. Meanwhile, GE05 could inhibit the activation of the IL-17 Arelated phosphatidylinositol 3-kinase/ c-Jun N-terminal kinase (PI3K/JNK) signaling pathway, suppressing the expression of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, and IL-6. These results demonstrated that GE05 is a promising agent that targets the IL-23/IL-17 A axis, providing new way for preventing and treating sepsisinduced lung injury.

关键词： Leiomyoma   Uterin fibroid   Polymorphism   ERS-1   IL-8   ICAM-1   TNFAIP2  

摘要： Objective: In this study, we aimed to investigate the difference between ICAM-1, IL-8, and ER-alpha gene polymorphisms and the effects of the formation of leiomyomas by measuring serum levels of IL-8 and ICAM-1 in uterine leiomyoma and control patients. Study Design. The roles of ERS-1, TNSFIP2, ICAM-1, and IL-8 gene polymorphisms in leiomyoma development were investigated using TaqMan SNP genotyping assay. In addition, serum IL-8 and ICAM-1 levels of leiomyoma and control group individuals were measured using the ELISA method. The sample included in the study consisted of 75 people diagnosed with uterine leiomyoma (leiomyoma group) and 75 healthy volunteers without ovarian pathology (control group) who came to Sivas Cumhuriyet University Medical Faculty Gynaecology and Obstetrics Clinic. Results: TNFAIP2 rs8126, ICAM-1 rs5498 and ESR-1 rs17847075 polymorphisms were not associated with leiomyoma disease. In addition, individuals carrying heterozygous genotypes of ESR-1 rs9322331 (p = 0.01, OR = 2.4), IL-8 rs4073 (p = 0.02, OR = 2.4) and IL-8 rs2227306 (p = 0.01, OR = 2.246) polymorphisms may be at risk for leiomyoma. Similarly, mutant alleles of ESR-1 rs9322331 (p = 0.005, OR = 2.172), IL-8 rs4073 (p = 0.01, OR = 2.204) and IL-8 rs2227306 (p = 0.004, OR = 2.2) polymorphisms were found to be risk alleles. Furthermore, it was observed that IL-8 serum levels increased more in the leiomyoma group (1.83 f 0.4 pg/mL) compared to the control group (1.02 f 0.2 pg/mL). Likewise, a significant decrease in ICAM-1 levels was found in the leiomyoma group (1595.5 f 80 ng/mL) compared to the control group (2939.3 f 104 ng/mL). Conclusion: In this context, it was concluded that polymorphisms of IL-8 and ESR-1 genes, which are thought to be risk factors in leiomyoma harvests, and factors affecting IL-8 and ICAM-1 expression should be further investigated.

关键词： Diabetic kidney disease   Hypoxia   Sirt1   Hif-1(   Morusin  

摘要： Background and Purpose: Hypoxia is generally considered the major cause of renal tubular injury. The interaction between sirtuin 1 (SIRT1) and hypoxia inducible factor 1 subunit alpha (HIF-1 alpha) is a key mediator of hypoxiainduced renal tubular damage. In this study, we identified morusin from a screen of SIRT1 inducers and reported its potential for the treatment of diabetic kidney disease (DKD). Experimental Approach: Intraperitoneal injection of morusin in db/db and STZ-induced diabetic mice was assessed for its effect on tubulointerstitial damage. The expression and acetylation level of HIF-1 alpha were analyzed by immunoblotting or immunostaining. The effects of morusin treatment on hypoxia-induced extracellular matrix (ECM) accumulation, apoptosis and IL-16 production in HK2 cells were evaluated by immunoblotting. Luciferase reporter gene and ChIP analysis was used to determine whether IL-16 was the target genes of HIF-1 alpha. Key Results: In db/db and STZ-induced mice, morusin treatment alleviated kidney injury and inhibited renal inflammation and fibrosis. Mechanistic analysis using animal models and HK2 cells revealed that morusin treatment upregulated SIRT1 expression by enhancing its stability, and reduced the expression and acetylation levels of HIF-1 alpha as well as expression of its regulated genes, thereby inhibiting ECM accumulation, apoptosis and IL-16 production. Furthermore, morusin decreased expression of the IL-16 through inhibited HIF-1 alpha binding to the IL-16 promoter. Conclusion and Implications: Our study is the first to demonstrate that morusin ameliorated tubulointerstitial damage in diabetic mice by regulating SIRT1/HIF-1 alpha/IL-16 signaling pathway. Taken together, our findings suggest that morusin is a clinical candidate compound to prevent DKD.

关键词： Interleukin-6   Circadian rhythms   Metabolic cycles   Energy balance   Sexual dimorphism  

摘要： Objective: Interleukin-6 (IL-6) is a pleiotropic cytokine involved in immune regulation and energy metabolism. Its diurnal secretion influences core circadian components, emphasizing its critical role in circadian biology. Despite known sex differences in immune, circadian, and metabolic processes, how IL-6 integrates these processes remains poorly understood. Methods: IL6 knockout (KO) and control mice of both sexes were phenotyped for circadian and metabolic traits under standard (STD) and high-fat diet (HFD), fasting, and time-restricted feeding. Molecular analyses in muscle, liver, and hypothalamus assessed clock gene expression and IL-6 signaling pathway. Circulating sex steroid hormones were quantified to examine their contribution to the observed sex-specific phenotypes. Results: IL-6 deficiency disrupts circadian locomotor and metabolic rhythms in a sex-and diet-dependent manner. Males exhibit impaired light-driven circadian rhythms under STD conditions and metabolic misalignment under HFD, whereas females display greater circadian resilience under STD conditions but increased vulnerability to circadian disruption during HFD. Additionally, IL-6 emerges as a novel regulator of the foodentrainable oscillator (FEO), linking food anticipatory activity and metabolic cycles under both STD and HFD in a sex-dependent manner. Conclusions: These findings identify IL-6 as a critical mediator of circadian-metabolic plasticity, shaping sex-and diet-specific trade-offs between circadian stability and metabolic homeostasis. Our study highlights IL-6 as a potential therapeutic target for mitigating circadian misalignment-associated metabolic disorders, with implications for the timed modulation of IL-6 signaling. (c) 2025 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://***/licenses/by-nc-nd/4.0/).

关键词： cell contact   chemokines   mesenchymal stem/stromal cells   paracrine factor   type 1 diabetes mellitus  

摘要： Interferon-gamma (IFNγ) plays a crucial role in the pathogenesis of type 1 diabetes (T1D) and is widely utilized to license mesenchymal stem/stromal cells (MSCs) to enhance their immunosuppressive properties through a process known as preconditioning or priming. This study investigates the interaction of MSCs preconditioned with (IFNγ) or without (IFNγ) IFNγ, with peripheral blood mononuclear cells (PBMCs) from healthy controls (HC) and T1D patients. We assessed the effects of these interactions on anti-inflammatory gene expression, chemokine and receptor profiles, and the induction of regulatory T (Treg) cells. Our findings reveal contrasting responses in HC and T1D PBMCs when exposed to IFNγ and IFNγ MSCs, particularly in the expression of key genes such as CXCR3 and its ligands (CXCL9, CXCL10), CXCR6, CCR5, and its ligands (CCL3 and CCL4). Pathway enrichment analysis further showed that IFNγ preconditioning tailors MSC responses to specific immune microenvironments. These differential gene expression patterns were also reflected in the proportions of Treg cells, which varied depending on whether paracrine signaling or direct cell contact was involved. Collectively, our results demonstrate that IFNγ and IFNγ MSCs create distinct immunomodulatory microenvironments in T1D PBMCs compared to HC PBMCs, emphasizing the potential for tailored MSC-based therapies in T1D treatment.