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关键词： Fibrosis   Immunology   Nephrology   Therapeutics  

摘要： Low-intensity pulsed ultrasound stimulation (LIPUS) has become increasingly appreciated for its therapeutic effect on kidney diseases. However, its role and biological mechanism in treating chronic kidney disease remain poorly defined. Here, we revealed that LIPUS was applied in a safe range with an intensity of 25-315 mW/cm2. Daily LIPUS at an intensity of 315 mW/ cm2 ameliorated ischemia/reperfusion-induced (IR-induced) tubular injury and renal fibrosis, accompanied by the remarkable downregulation of IL-1R. Transcriptome sequencing showed that LIPUS significantly downregulated IL-1R and its downstream genes in IL-1(3-stimulated IRinjured mice. LIPUS effectively reversed IL-1(3-induced tubular injury and reduced the production of pro-fibrotic cytokines by downregulating IL-1R in vivo and in vitro. Renal proximal tubule-specific Il1r1-knockout mice exhibited milder renal tubular injury and fibrosis after IR injury. However, LIPUS did not ameliorate IR injury in proximal tubule-specific Il1r1-knockout mice. Collectively, daily LIPUS at an intensity of 315 mW/cm2 relieves IR-induced tubular injury and fibrosis, potentially by downregulating tubular IL-1R.

关键词： CD8+T cells   T cell receptors   COVID-19   severe disease   HLA-B*15:01  

摘要： Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B*15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8(+) T-cells directed against HLA-B*15:01-restricted Spike-derived S919-927 peptide (B15/S(919)(+)CD8(+) T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8(+) T-cell responses in HLA-B*15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/S(919)(+)CD8(+) T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/S(919)(+)CD8(+) T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/S(919)(+)CD8(+) T-cell responses lacking a highly expanded key public B15/S(919)(+)CD8(+) T-cell receptor (TCR;TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/S(919)(+)CD8(+) T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/S(919)(+)CD8(+) T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/S(919)(+)CD8(+) T-cells did not differ across disease severity. Moreover, B15/S(919)(+)CD8(+) T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B*15:01-positive COVID-19 patients who developed severe or critical disease in o

关键词： italic>hnRNP-FTNF alpha-NF kappa B signaling pathway  

摘要： Background Diabetic kidney disease (DKD), with its complex pathogenesis, is the most important cause of end-stage renal disease and has become an urgent public health problem worldwide. Heterogeneous nuclear ribonucleoprotein F (hnRNP-F) is a member of a subfamily of widely expressed nuclear heterogeneous ribonucleoproteins with biological roles in regulating gene expression and variable splicing. Some studies have investigated hnRNP-F in DKD. However, its potential mechanism in renal intrinsic cells has rarely been reported. Therefore, it is necessary to further investigate its potential mechanism in DKD in the search for novel ideas for new therapeutic targets for *** In this study, hnRNP-F was overexpressed in human renal proximal tubular epithelial (HK-2) cells cultured in high-glucose conditions, while an empty vector was transfected into HK-2 cells as a control group (NC). Meanwhile, to avoid any osmotic stress that might be caused by the use of high sugar, we also added mannose as a non-osmotic control. RNA-seq was utilized to generate transcriptome data following hnRNP-F overexpression, allowing for the analysis of differential gene expression and alternative splicing events influenced by hnRNP-F overexpression. Similarly, we overexpressed hnRNP-F in mouse podocyte clone 5 (MPC5) cells and verified the relevant indicators using Western blotting (WB) under high-glucose and high-mannitol conditions, respectively. We also downloaded the CLIP-seq data of hnRNP-F in human 293T cells from the Gene Expression Omnibus (GEO) database. Through integrative analysis of RNA-seq and CLIP-seq, we tried to identify a set of potential direct targets of hnRNP-F in *** In this study, RNA sequencing (RNA-seq) was utilized to demonstrate that the upregulation of hnRNP-F in HK-2 cells cultured under high-glucose conditions resulted in a substantial decrease in the expression of genes associated with the inflammatory response and suppression of the TNF alpha-NF k

关键词： span>Intracerebral hemorrhageCold-inducible RNA-binding proteinsNeuroinflammationMicroglial polarizationTat peptides  

摘要： Chordoma is a special malignant tumor that lacks effective therapeutic targets, which can lead to incomplete treatment and metastasis. Inflammation plays an important role in chordoma progression and malignant phenotype. Inflammatory factors such as NF-kappaB and STAT3 are continuously activated in many tumors and contribute to the malignant phenotype of tumors and are potential therapeutic targets. This study suggest TNF-alpha and NF-kappaB signaling pathways were consistently activated in chordomas. Long-term TNF-alpha treatment induces chordoma resistance to EGFR family inhibitors. The underlying mechanism is realized by the key molecules HS3ST3A and HS3ST3B1. These two enzymes are potential targets for chordoma treatment, as well as for combination drugs treatment. It should be emphasized that the above analysis lacks experimental verification.

关键词： HLA   BCR   NK cells   CDC   ADCC   AMR  

摘要： Donor-specific anti-HLA antibodies (DSAs) bind to donor vascular endothelial cells and mediate allograft rejection (AMR), but a clinical challenge for which targeted therapeutic options remain limited. We used a multiplexed single-antigen bead (SAB) assay to detect anti-human leukocyte antigen (HLA) antibodies. Based on the antigens which patient's antibodies aganist to, we developed bivalent HLA-Fc fusion proteins composed of HLA-derived antigenic domains and human IgG1-Fc effector regions (rA24-Fc and rB13-Fc). Specific binding and functional activity of the HLA-Fc proteins were further validated by flow cytometry, ELISA, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays. Our findings demonstrate that the fusion proteins rA24-Fc and rB13-Fc significantly reduced HLA-specific antibody reactivity in vitro. Notably, rA24-Fc and rB13-Fc selectively bound to B-cell hybridomas (e.g., mouse W6/32 cells) expressing membrane immunoglobulins (BCR) which bound to the most HLA class I antigens. Importantly, rA24-Fc and rB13-Fc elicited antigen-specific, Fc-dependent elimination of the specific B-cell hybridomas. This study highlights HLA-Fc fusion proteins as a promising therapeutic strategy for the antigen-specific suppression of depletion of alloreactive B cells through dual cytotoxic mechanisms. This precision targeted to BCR of B cells approach is used to apply to the treatment of antibody-mediated rejection.

关键词： biologics   clinical trial   il-17 inhibitor   off-label   psoriasis  

摘要： In this issue of Blood Advances, Wynn et al demonstrate that, in the setting of double cord blood transplant (DCBT), shared human leukocyte antigen (HLA) mismatches between the patient and the losing cord blood unit (LU) when mismatched with the w...

摘要： BACKGROUND & AIMS:Anti-tumor necrosis factor (anti-TNF) is a mainstay of inflammatory bowel disease (IBD) therapy but fails in many patients. Although TNF has pro-inflammatory effects, depletion of TNF receptor 1 (TNFR1) paradoxically exacerbates chronic colitis. Because colitis induces remodeling of mesenchymal cell populations, which provide a niche for epithelial stem cells involved in mucosal healing, we hypothesized that TNFR1 promotes colonic mesenchymal cell diversity and stem cell niche function. METHODS:Mesenchymal TNFR1 function was studied using TNFR1 , platelet derived growth factor receptor alpha (PDGFRα)-Cre;TNFR1 mice, and mixed-genotype mesenchymal-epithelial co-cultures. Mesenchymal cell diversity and gene function were assessed using single-cell RNA-Seq of primary colonic myofibroblasts (CMFs) and via anti-integrin A6 (ITGA6) antibody treatment and exogenous R-spondin 3 (RSPO3) supplementation. RESULTS:TNFR1 mesenchyme exhibits reduced cell diversity, with specific depletion of specialized TNF- and interferon-signaling pericryptal cell-type. Deletion of TNFR1 in the pericryptal mesenchyme diminished the (PDGFRα)+ CMF population and reduced RSPO3 expression, but increased ITGA6 expression relative to controls (TNFR1 ). Moreover, inhibition of ITGA6 reversed the proliferative and migratory phenotype of TNFR1 CMFs and restored expression of PDGFRα and RSPO3. Co-cultures of colonoids with TNFR1 CMFs resulted in downregulation of stem cell marker expression; this was rescued by supplementation with RSPO3. Supporting the role for mesenchymal TNFR1 in regulating colonic epithelial stem cells, mice deficient for TNFR1 in PDGFRα+ cells showed a 40% loss of Lgr5+ stem cells, consistent with the global TNFR1-deficient mouse. CONCLUSION:TNFR1-mediated signaling regulates specification and function of colonic mesenchyme, performing an integral role in the maintenance of the crypt stem cell population.

摘要： MiR-34a is implicated in aging, cell senescence, inflammation, and neurodegenerative diseases. In order to investigate the role of miR-34a in Alzheimer's disease (AD), we produced an AD mouse model, Tg-SwDI mice, with whole body/constitutive miR-34a knockout (KO). MiR-34a KO improved long-term memory in Tg-SwDI mice, which was associated with decreases in the ratio of insoluble Aβ42 to Aβ40 and with increases in soluble and insoluble Aβ40 in the cerebral cortex. Anti-Iba1 immunofluorescence revealed increases in activated microglia. Bulk RNA-sequencing of the hippocampus followed by a gene set enrichment analysis (Enrichr) identified "cellular response to type I interferon" and "type I interferon signaling pathway" as the most prominent gene sets in miR-34a KO Tg-SwDI mice compared to miR-34a wild-type Tg-SwDI mice. Many interferon-stimulated genes (ISGs) that characterize interferon responsive microglia (IRM) were upregulated in miR-34a KO Tg-SwDI mice. MiR-34a knockdown strongly enhanced ISGs expression in TLR7 ligand-stimulated BV2 microglia. These results suggest that miR-34a inhibits the transition of microglia to the IRM state that may modulate synaptic and cognitive functions in neurodegenerative diseases and aging.