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关键词： Osteoarthritis   polyphyllin I   TWIST1   chondrocytes   MMP-3   PPI  

摘要： Background Osteoarthritis (OA) is a chronic joint disease characterized by the degradation of articular cartilage. Polyphyllin I (PPI) has anti-inflammatory effects in many diseases. However, the mechanism of PPI in OA remains *** HC-a cells treated with IL-1 beta were identified by immunofluorescence staining and microscopic observation. The expression of collagen II and DAPI in HC-a cells was detected by immunofluorescence. The effects of gradient concentration of PPI on IL-1 beta-induced cell viability, apoptosis, senescence, and inflammatory factor release were detected by MTT, flow cytometry, SA-beta-Gal assay and ELISA, respectively. Expressions of apoptosis-related genes, extracellular matrix (ECM)-related genes, and TWIST1 were determined by qRT-PCR and western blot as needed. The above-mentioned experiments were conducted again after TWIST1 overexpression in IL-1 beta-induced *** IL-1 beta reduced the number of chondrocytes and the density of collagen II. PPI (0.25, 0.5, 1 mu mol/L) had no effect on cell viability, but it dose-dependently elevated the inhibition of cell viability regulated by IL-1 beta. The elevation of cell apoptosis, senescence and expression of IL-6 and TNF-alpha were suppressed by PPI in a dose-dependent manner. Additionally, PPI reduced the expression of cleaved caspase-3, bax, MMP-3, and MMP-13 and promoted the expression of collagen II. TWIST1 expression was diminished by PPI. TWIST1 overexpression reversed the above-mentioned effects of PPI on *** PPI suppressed apoptosis, senescence, inflammation, and ECM degradation of OA chondrocytes by downregulating the expression of TWIST1.

关键词： NGS   Read length   Sample number   Flow cell  

摘要： Two NGS-based assays, HLA typing (HLA-A, B, C, DRB1/3/4/5, DQA1/B1, DPA1/B1) and chimerism testing (202 single nucleotide polymorphisms) were combined and sequenced together, using the MiSeq V2 reagent kit. The HLA typing library pool (sample number: X, 1.42 nM) and the chimerism library pool (sample number: Y, 1.33 nM) were combined at the volume ratio X:2Y (X + 2Y <= 100). Chimerism MiSeq sample sheets (dual index) were edited to support 150 bp read length and uploaded to the BaseSpace Sequence Hub. After NGS, chimerism FASTQ files were downloaded and analyzed. An HLA typing MiSeq sample sheet was then uploaded to requeue indices for FASTQ file generation. Both the combined and the separate NGS achieved sufficient read numbers, sequence quality, chimerism assay sensitivity of 0.1 %, and comparable test results on clinical samples (HLA typing, N = 44;chimerism genotyping, N = 24, % recipient chimerism, N = 95). Potential benefits and considerations in combining NGS-based tests are discussed.

关键词： Non-HLA antibody   Donor-specific antibody   Human leukocyte antigen   Liver transplantation   Rejection  

摘要： Antibodies to HLA or non-HLA antigens are associated with detrimental outcomes in organ transplants. Here, we aim to examine whether donor-specific antibodies (DSA) and non-HLA antibodies are associated with rejection in a single-center cohort of 101 pediatric liver transplant (PLTx) recipients. Rejection was found in 50/101 biopsies (49.5 %). DSA was positive in 32 paired sera and associated with rejection (HR = 2.63[1.10-6.30]). Antibodies to 3 non-HLA antigens, SNRPB (small nuclear ribonucleoprotein polypeptides B), GSTT1 (Glutathione S-transferase theta-1), and Actin were associated with rejection. Rejection was found in 22/35 cases positive for any of the three non-HLA antibodies. The presence of DSA and non-HLA antibodies was associated with an augmented risk of rejection (HR = 6.32[1.57-25.30], p < 0.01]. In conclusion, DSA or non-HLA antibodies were associated with a higher risk for rejection in PLTx recipients. When they were detected concomitantly, the risk for rejection increased significantly, indicating the synergistic effect of actions.

关键词： Foodborne Diseases   Notification of Infectious Diseases   COVID-19 pandemic  

摘要： Background. Foodborne diseases are a major global public health concern, causing significant morbidity and mortality worldwide. The COVID-19 pandemic has had widespread effects on various aspects of life, including the food supply chain, potentially impacting the incidence of foodborne diseases. This study aims to analyze the differences between notified and diagnosed cases and investigate the potential impact of the COVID-19 pandemic on foodborne diseases in the metropolitan area of Bologna, Italy. Study Design. A retrospective time trend analysis from two databases was conducted. Methods. The Local Health Authority of Bologna collected data re/Emilia-Romagna Region on the infectious disease reporting system over a six-year period (2017-2022), which included three years of the COVID-19 pandemic. This data was compared with information collected during the same period at the microbiology laboratory serving the entire metropolitan area of Bologna. Statistical methods included percent change calculations, binomial tests, annual averages, gender and age stratification, and trend analysis with regression. Results. An increase (+34.4%, P-value <= 0.01) in notified cases during the pandemic-compared to the pre-pandemic period-was found. However, no differences were observed in diagnosed cases when comparing the two periods. The year 2021 saw a significant increase in reported cases of foodborne diseases among schoolers (+300.0%) and workers (+133.3%) compared to 2020. On the other hand, diagnosed cases decreased significantly in 2020 (-19.1%, P<0.01) and increased in 2021 (+21.9%, P<0.01). In absolute terms, a stark difference was observed between notified and diagnosed cases across all the study years (2017-2022). Conclusions. This study highlights the discrepancy between notified and diagnosed cases of foodborne diseases and how the COVID-19 pandemic has increased reporting without affecting transmission. These findings contribute to the ongoing discussion on improving

关键词： Loteprednol etabonate   NLRP3 inflammasome   IL-1 beta   Pyroptosis   Sepsis   Colitis  

摘要： Excessive activation of the NLRP3 inflammasome leads to cellular inflammation and tissue damage. Finding an inhibitor of its activation is urgent need for NLRP3 inflammasome-associated inflammatory diseases. In this study, we identified Loteprednol etabonate (LE), a well-known anti-inflammatory drug for ocular conditions, as a potent inhibitor of NLRP3 inflammasome activation through screening an FDA-approved drug library. In cellular models, LE significantly reduced IL-1f) transcription, suppressed NLRP3 inflammasome activation, and finally inhibited the maturation and secretion of IL-1 beta and GSDMD-mediated pyroptosis. Mechanistic investigations showed that LE might inhibit IL-1f) transcription by blocking both NF-kappa B and AP-1 signaling pathways. Furthermore, in mouse models of NLRP3 inflammasome-associated inflammatory diseases, including LPSinduced sepsis and DSS-induced colitis, intraperitoneal injection of LE significantly suppressed inflammatory response and improved mice survival rate. Collectively, these findings identify LE as a novel inhibitor of NLRP3 inflammasome activation, offering a promising therapeutic strategy for the treatment of NLRP3 inflammasomeassociated inflammatory diseases.

关键词： Autoimmune   HLA   IgLON5   Progressive supranuclear palsy   Peptide modelling   Tau  

摘要： Objectives: Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen (HLA) locus on chromosome 6 is a polymorphic region with complex linkage patterns that has been implicated in several autoimmune and neurological disorders. The HLA locus has not been systematically examined in PSP. It is unclear whether tau and HLA can interact to induce an autoimmune disease mechanism. Methods: We evaluated an autopsy confirmed PSP cohort (n = 44) and compared allele/haplotype frequencies to those of the reference group of a local deceased Canadian donor pool. We performed HLA-Tau peptide binding prediction and modelling of HLA Class II - Tau Peptide interactions. Findings: Odds ratio was 2.94(95% CI 1.01 to 8.55;p = 0.047) for DQB1*06:01 allele, and 2.59(95% CI 1.39 to 4.83;p = 0.0025) for the narcolepsy-associated haplotype (DRB1*15:01-DQB1*06:02). One patient with 4-repeat tau PSP-type pathology was a carrier of the IgLON5-associated haplotype (DRB1*10:01-DQB1*05:01). HLA-Tau peptide binding prediction and modelling of HLA Class II - Tau Peptide interactions revealed strong-binding tau peptides but not the PSP-protofilament fold for alleles DQA1*01:02-DQB1*06:02 and DQA1*01:03-DQB1*06:01. Conclusion: Our study suggests that epitopes within the tau peptide may bind to HLA alleles that are found in a subset of PSP patients supporting the notion of an autoimmune pathophysiological component. These findings have implications for subtyping and stratifying patients for therapies, including those targeting immune modulation.

关键词： Crystallography   Human leukocyte antigen   Micropolymorphism  

摘要： Micropolymorphisms in human leukocyte antigen class I (HLA–I) molecules critically influence antigen presentation and immune recognition. Most studies have focused on variations within the peptide-binding groove (PBG), neglecting the potential impact of residues located outside this region. HLA-C*14:02 and HLA-C*14:03 differ only at position 21 (R21 and H21, respectively), which is situated outside the PBG, yet these two allotypes exhibit distinct clinical associations with HIV control in the context of KIR2DL2, an inhibitory killer cell immunoglobulin-like receptor that modulates natural killer (NK) cell activity. Here, we investigated the molecular mechanisms by which the R21H micropolymorphism shapes immune responses. Structural and biochemical analyses revealed that position 21 indirectly regulates the conformation of the B pocket within the PBG, significantly affecting HLA-C*14 stability and altering the composition of its peptide repertoire, while preserving core peptide motifs and recognition by KIR2DL2. Notably, the R21H variation is evolutionarily conserved across various HLA-I molecules and exhibits similar interactions with neighboring residues, suggesting a broadly conserved role in structural stability and immune regulation. These findings suggest that the stability differences between HLA-C*14 allotypes may influence their differential clinical associations, highlighting the previously underappreciated role of micropolymorphisms outside the PBG in modulating immune responses. © 2025 Elsevier B.V.

关键词： ADME/T characteristics   drug-like properties   Matricaria chamomilla L   molecular dynamics simulation   rheumatoid arthritis  

摘要： Chamomile, emphasized as an herbal remedy with healing potential for human health, is used in traditional medicine. In this study, the potential of compounds derived from Matricaria chamomilla L. against IL-6, JAK-1 and TNF-alpha target proteins associated with rheumatoid arthritis (RA) was compared with known inhibitors. The drug-likeness and ADME/T properties of these compounds were investigated using online tools, and molecular docking and molecular dynamics simulations of the selected structures were examined. IL-6, JAK-1 and TNF-alpha formed stable complexes with apigenin, quercetin and galaxolide, respectively, demonstrating that these compounds exhibit potential inhibitory activity against RA.

关键词： Foot rot   F.necrophorum   Skin explant   TNF-alpha   TNFR1   NF-kappa B  

摘要： Foot rot is a contagious disease caused by ***. It is responsible for economic losses in dairy farming. Studies on foot rot in dairy cows are focused on the isolation and identification of pathogens and treatment methods. Few studies have reported inflammatory changes in tissues and regulatory mechanisms following infection. Here, the effects of *** infection on the skin explants and skin fibroblasts between the toes of cattle were analyzed using histopathology and other techniques. *** infection increased the epidermal thickness and number of hair follicles and sebaceous glands. Other skin appendages exhibited varying degrees of necrosis, and a significant infiltration of inflammatory cells was noted in the interdigital skin explants. The expressions of pro-inflammatory cytokines (IL-1 beta and TNF-alpha) and key genes in the inflammatory signalling pathway (TNFR1 and NF-kappa B p65) were elevated. Treatment with the TNFR1 inhibitor CAY10500 reduced inflammatory cell infiltration and alleviated TNFR1 and p65 expression. An inflammatory cell model was established using different proportions of *** to infect BDF cells. *** infection significantly inhibited the proliferation and viability of BDF cells and enhanced the expression of TRADD, TRAF2, TNF-alpha, and IL-18. CAY10500 reduced the *** infection-induced inflammatory response and induced inflammatory responses in interdigital skin explants and BDF cells by inhibiting the TNF-alpha/TNFR1/NF-kappa B signaling pathway. In summary, these findings provide new insights into the mechanism of inflammatory responses in dairy cows with foot rot.

关键词： Bone inflammation   Lipopolysaccharide   TLR4   IFN gamma   IL-10   M-CSF   RANKL  

摘要： The inflammatory response in bone tissue often triggered by LPS is a complex process. Since LPS through TLR4 and in presence of IFN gamma activates osteoclast differentiation and bone resorption, therefore, suppression of osteoclastogenesis through inhibition of TLR4 vs IFN gamma mediated inflammation could be a reasonable strategy for the treatment of inflammatory bone loss. Administration of anti-TLR4 (30 mg/kg) and anti-IFN gamma antibodies (6.6 mg/kg) were utilized before LPS (5 mg/kg) challenge and subsequently mice were treated with mouse IL-10 (0.02 mg/kg). Then RBMCs were isolated from different groups of mice and stimulated (in vitro) with M-CSF (10 ng/ml) and RANKL (10 ng/ml) to induce bone marrow cell differentiation in presence of LPS (100 ng/ml). The involvement of RANKL and M-CSF in the regulation of bone inflammation underlines the intricate signaling pathways. Furthermore, the study sheds light on the potential therapeutic effects of exogenous IL-10 possibly through STAT3 signaling in the RBMCs. The use of antibodies against TLR4 and IFN gamma, in conjugation with IL-10in LPS bone damage model, appears to downregulate the activation of NF-kappa B, and reduction of many proinflammatory cytokines regulating the inflammatory cascade in RBMC. This suggests a promising avenue for the development of treatments aimed at mitigating bone inflammation associated with bacterial infections. Therefore, inhibition of TLR4 and IFN gamma could be explored as potential therapeutic agents against LPS induced bone loss.