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关键词： aggregates   IL-6   cadherin   mesenchymal stromal cells   systemic sclerosis  

摘要： Umbilical cord-derived mesenchymal stromal cells (MSCs) transplantation is a promising therapy for systemic sclerosis (SSc) because of their distinctive antifibrotic and immunomodulatory properties. To enhance the effects of MSCs transplantation, novel engineered MSC aggregates preconditioned with human E/N-cadherin fusion protein (hE/N-cad-Fc) and interleukin-6 (IL-6) for SSc treatment are fabricated and named 3D-Cad/IL6-MSCs. These novel-engineered MSC aggregates possess tighter cellular cohesion and exhibit enhanced antiapoptotic, immunosuppressive, and proangiogenic capabilities according to transcriptomic analyses. Moreover, 3D-Cad/IL6-MSCs have improved immunoregulatory effects on peripheral blood mononuclear cells (PBMCs), CD4+ T cells, and CD8+ T cells in vitro because of the synergistic preconditioning from IL-6 and bioactive hE/N-cad-Fc. Upon intravenous injection, 3D-Cad/IL6-MSCs significantly mitigate skin and lung fibrosis and prolong the retention duration in bleomycin (BLM)-induced SSc mouse model. In detail, they suppress excessive infiltration of macrophages and T cells in the injured skin and lungs and reestablish the immune equilibrium of circulating CD4+ T-cell subsets in vivo. These results suggest that 3D-Cad/IL6-MSCs are ideal candidates for SSc therapy and optimize the clinical utilization of MSCs.

关键词： Avian reovirus   Toll like receptor 3   Autophagy   B16-F10 melanoma cells   IRF3   NF-kappa B   IFN-gamma  

摘要： Oncolytic avian reovirus (ARV) has been identified as a virus capable of selectively infecting and inducing cell death in various cancer cell lines. This study investigates the role of ARV in activating innate immune responses in B16-F10 murine melanoma cells, focusing on the TLR3-IRF3-IFN-gamma-JAK-STAT1 and TLR3-NF-kappa B-IFN-gamma-JAK-STAT1 pathways. Our results revealed that the 6C protein of ARV interacts with toll-like receptor 3 (TLR3) in the cytoplasm, leading to nuclear translocation of IRF3 and NF-kappa B as well as the upregulation of IFN-gamma, as confirmed by quantitative real-time reverse transcription and polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), proximity ligation assay (PLA), and Western blot. Inhibition assays targeting TLR3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B), and interferon regulatory factor 3 (IRF3) further validated the involvement of the TLR3-IRF3 and TLR3-NF-kappa B pathways in IFN-gamma activation. Additionally, cells treated with signal transducer and activator of transcription 1 (STAT1) shRNA and Janus kinase (JAK) inhibitor revealed that ARV promotes autophagy via the IFN-gamma-JAK-STAT1 pathway. Immunofluorescence staining and LC3-mCherry transfection further confirm ARV's role in triggering autophagy via TLR3-IRF3-IFN-gamma-JAK-STAT1 and TLR3-NF-kappa B-IFN-gamma-JAK-STAT1 pathways. Our results revealed that oncolytic ARV induces autophagy and apoptosis in middle to late stages of virus life cycle in murine melanoma cells. These findings highlight the potential of ARV as a novel oncolytic virotherapy through immune pathway activation in cancer cells.

关键词： IL-17 | immune sex bias | immune sex dimorphism | psoriasis | testosterone | Th17  

摘要： Th17 cells play a crucial role in autoimmune disease pathogenesis. However, the mechanisms behind the sex differences in immune responses, particularly women's higher susceptibility to autoimmune diseases, remain unclear. This study investigated the role of testosterone in modulating the IL-17 response. IL-17 levels and IL-17-expressing cells were compared between males and females, and testosterone's effect on Th17 differentiation was evaluated. In an imiquimod-induced psoriasis mouse model, testosterone supplementation reduced psoriasis severity in female mice, whereas castration of male mice exacerbated psoriasis. Testosterone inhibited both in vitro Th17 differentiation and in vivo IL-17 expression, correlating with reduced psoriasis severity. Molecular studies indicated that testosterone is an inverse agonist of related orphan receptor gamma (ROR gamma t), a key transcription factor for IL-17 expression. These findings offer mechanistic insights into how testosterone limits tissue inflammation in psoriasis and suggest a basis for developing novel testosterone derivatives to target ROR gamma t and suppress Th17-mediated inflammation.

摘要： Abatacept reduces the risk of acute graft versus host disease (GVHD) in matched unrelated donor hematopoietic stem cell transplant (HSCT) for Sickle Cell Disease (SCD). We conducted a retrospective review of patients who underwent matched sibling donor (MSD) HSCT for SCD with and without adding abatacept to standard acute GVHD prophylaxis. Twenty-one patients, median age 7 years (range 2.0-14.8) received MSD HSCT with addition of 4 doses of abatacept to standard calcineurin inhibitor based acute GVHD prophylaxis while six patients, median age 9.8 years (range 1.9-14.4) underwent MSD HSCT with standard prophylaxis. One patient (4.5%) in the abatacept group developed grade II acute skin GVHD, while 3 patients (50%) in standard group developed grade II-III acute skin and gut GVHD (p = 0.022). Grade III-IV GVHD was 0% in abatacept group compared to 33% in standard group (p = 0.043). Disease-free survival was 83% in standard group at a median follow up of 11 years (IQR:9.5-13.25 years), and 100% in the abatacept group at a median follow up of 5 years (IQR:3-8 years). Our data show that addition of abatacept to calcineurin inhibitor based acute GVHD prophylaxis reduces the risk of severe acute GVHD in patients with SCD undergoing MSD HSCT without impacting disease-free survival.

关键词： CRSwNP   IL-33   KIT   mast cell   miR-221-3p  

摘要： BackgroundMast cells (MCs) are involved in type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP), which depends on interleukin (IL)-33 stimulation. MiR-221 is reported to be an important regulator of MCs, and miR-221-3p can be expressed in CRSwNP. However, the role of miR-221-3p in CRSwNP is *** tissues from control subjects (n = 12) and polyps from patients with CRSwNP (n = 40) were collected. The expression of miR-221-3p and cytokines was detected by real-time quantitative polymerase chain reaction (qPCR). The activation of P65 and ERK was determined by western blotting. The localization of miR-221-3p was detected via in situ hybridization combined with immunofluorescence (IF), and its target was identified via a luciferase reporter system. Human MCs were incubated with IL-33 or stem cell factor. MicroRNA mimics/inhibitor and lentiviral plasmids were used to determine the role of miR-221-3p in *** observed increased expression of miR-221-3p in CRSwNP, and localized its expression in MCs. The expression of miR-221-3p was negatively correlated with that of IL-4, IL-5, and IL-13 in CRSwNP. MiR-221-3p can be induced by IL-33 in MCs and plays a negative regulatory role in cytokine expression and signaling pathways in IL-33-induced MC activation. As the direct target of miR-221-3p, the receptor KIT was negatively correlated with miR-221-3p and decreased in CRSwNP. In MCs, KIT is essential for an effective response to IL-33 stimulation. We here demonstrated that miR-221-3p regulates cytokine expression by targeting KIT in IL-33-activated ***-221-3p inhibits MC-dependent type 2 inflammatory conditions, rendering it a negative regulator of CRSwNP.

关键词： NLR   PHR   PLR   Psoriasis vulgaris   SII  

摘要： Background and objective IL-17 and IL-23 inhibitors are widely used as biological agents in patients with psoriasis vulgaris to suppress inflammation and reduce disease severity. This study aimed to examine changes in inflammatory parameters, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), systemic inflammation index (SII), platelet/hemoglobin ratio (PHR), and red cell distribution width/platelet ratio (RPR), as well as the Psoriasis Area and Severity Index (PASI), in psoriasis patients receiving biological therapy (IL-17 and IL-23 inhibitors). Materials and methods This retrospective study included 110 patients with psoriasis vulgaris treated with IL-23 (risankizumab, guselkumab or IL-17 inhibitors ( secukinumab, and ixekizumab). Disease severity was assessed using the PASI score. Hematological parameters (NLR, PLR, SII, PHR, and RPR) and PASI values of the patients were recorded and analyzed at baseline (month 0) and during treatment (month 6). Results A significant decrease was observed in NLR, SII, and PHR values during treatment. NLR decreased significantly from 2.43 +/- 1.25 at baseline to 2.12 +/- 0.81 at month 6 (p = 0.002). Both IL-17 and IL-23 groups significantly reduced NLR (p = 0.044, p = 0.029, respectively). SII decreased significantly from 695 +/- 390 at baseline to 588 +/- 288 at month 6 (p = 0.002). Both groups significantly reduced SII levels (p = 0.044, p = 0.018, respectively).PHR decreased significantly from 19.8 +/- 6.60 at baseline to 19.2 +/- 6.58 at month 6 (p = 0.033).PASI score significantly decreased during treatment (p < 0.001). Conclusion The significant reduction in NLR and SII levels in both the IL-17 and IL-23 groups suggests that these markers may be used together rather than separately in treatment follow-up. The significant decrease in PHR levels may indicate that IL-17 and IL-23 inhibitors contribute to reducing cardiovascular disease risk in patients with psoriasis vulgaris and promote a favorable

关键词： Porcine epidemic diarrhea virus   Protein kinase R like endoplasmic reticulum   kinase   Eukaryotic initiation factor 2 alpha   Cellular translation   Nuclear factor kappa B   Interferon  

摘要： Porcine epidemic diarrhea virus (PEDV) is one of the most important porcine pathogens for which no preventive and antiviral treatment measures are available. A pervious study revealed that the unfolded protein response (UPR) induced by endoplasmic reticulum (ER) stress can be utilized to inhibit PEDV replication. Here, we demonstrated that the UPR suppresses the replication of multiple genotypes of PEDV in both Vero and swine testis (ST) cells, primarily through activation of the PERK-eIF2 alpha branch among the three UPR pathways. The PERK-eIF2 alpha pathway inducers CCT020312 and salubrinal efficiently inhibited the replication of multiple genotypes of PEDV in both Vero and ST cells, whereas the inhibitor AMG PERK 44 promoted PEDV replication. Furthermore, we found that PERK-eIF2 alpha arm-mediated inhibition of PEDV replication is caused by phosphorylated eIF2 alpha-induced attenuation of global protein translation. Additionally, phosphorylated eIF2 alpha promotes NF kappa B signaling activation and facilitates to the production of IFN-I, eliciting innate immunity to suppress viral replication. These data show that PERK-eIF2 alpha pathway dampens the replication of multiple genotypes of PEDV, suggesting that this target may be exploited to develop as a broad-spectrum anti-PEDV drugs.