Regulation of renal ischemia-reperfusion injury and tubular epithelial cell ferroptosis by pparγ m6a methylation: mechanisms and therapeutic implications.

This study aimed to elucidate the role and underlying mechanisms of Peroxisome proliferator-activated receptor gamma (PPARγ) and its m6A methylation in renal ischemia-reperfusion (I/R) injury and ferroptosis of tubular epithelial cells (TECs). High-throughput transcriptome sequencing was performed on renal tissue samples from I/R injury models and sham-operated mice, complemented by in vivo and in vitro experiments focusing on the PPARγ activator Rosiglitazone and the manipulation of METTL14 and IGF2BP2 expression. Key evaluations included renal injury assessment, ferroptosis indicator measurement, and m6A methylation analysis of PPARγ. Our findings highlight the critical role of the PPARγ pathway and ferroptosis in renal I/R injury, with Rosiglitazone ameliorating renal damage and TEC ferroptosis. METTL14-mediated m6A methylation of PPARγ, dependent on IGF2BP2, emerged as a pivotal regulator of PPARγ expression, renal injury, and ferroptosis. This study reveals that PPARγ m6A methylation, orchestrated by METTL14 through an IGF2BP2-dependent mechanism, plays a crucial role in mitigating renal I/R injury and TEC ferroptosis. These insights offer promising avenues for therapeutic strategies targeting acute kidney injury.

Tanshinone IIA relieves arthritis by inhibiting autophagy of fibroblast-like synoviocytes via matrix metalloproteinase9/receptor for advanced glycation end product/toll-like receptor 9 signal axis in mice with collagen-induced arthritis.

In this study, we probed into the related mechanism underlying the role of Tanshinone IIA (TIIA) in RA fibroblast-like synoviocytes (RA-FLSs). We constructed a mouse model of RA using the collagen-induced arthritis (CIA) method. Gain- or loss-of-function approaches were used to manipulate matrix metalloproteinase9 (MMP9), receptor for advanced glycation end product (RAGE), and toll-like receptor 9 (TLR9) in both CIA mice and RA-FLSs following treatment with TIIA to study the in vivo and in vitro effect of TIIA through analysis of cell viability, and measurement of autophagy and inflammatory proteins as well as severity of RA. In vitro and in vivo animal experiments results showed that TIIA could inhibit the proliferation of RA-FLSs and affect autophagy, thereby improving the symptoms of RA in mice. Mechanically, TIIA could inhibit the expression of MMP9 in RA-FLSs, thereby inhibiting the shedding of RAGE and thus inhibiting the activation of TLR9. Finally, animal experiments confirmed that TIIA affected autophagy by regulating the MMP9/RAGE/TLR9 axis, and finally improve the symptoms of RA in mice. Conclusively, TIIA may inhibit expression of MMP9 to suppress the combination of RAGE and TLR9, thereby inhibiting RA-FLS proliferation and affecting autophagy, eventually improve the RA.

Polymorphonuclear neutrophil activation by Src phosphorylation contributes to HLA-A2 antibody-induced transfusion-related acute lung injury.

Human leukocyte antigen (HLA)-A2 antibody contributes to the pathogenesis of transfusion-related acute lung injury (TRALI) via polymorphonuclear neutrophil (PMN) activation, but the signaling pathways involved this process remain largely undefined. In this study, we sought to study the signaling pathways involved in the pathogenesis of HLA-A2-induced TRALI. Lipopolysaccharide (LPS), and the plasma from the HLA-A2 antibody-positive donors were utilized to establish a rat model of TRALI. Human pulmonary endothelial cells (HPMECs) were in vitro co-cultured with HLA-A2 antibody-treated PMNs and then treated with LPS to induce a cytotoxicity model. The effects of HLA-A2 antibody on HPMEC injury were evaluated in this model. Besides, dasatinib was used to block the Src phosphorylation to explore whether Src involved in the TRALI or HPMEC injury induced by HLA-A2 antibody. The HLA-A2 antibody plus LPS induced TRALI and stimulated PMN activation in rats. HLA-A2 antibody-induced TRALI could be attenuated via depletion of PMN. HLA-A2 antibody activated NF-κB and NLRP3 inflammasome. In addition, HLA-A2 antibody aggravated the HPMEC injuries and the release of PMN surfaces makers, but dasatinib treatment reversed this effect, indicating that HLA-A2 antibody activated PMNs and exacerbated TRALI by stimulating phosphorylation of Src followed by activation of NF-κB and NLRP3 inflammasome, which was validated in vivo. In summary, HLA-A2 induced PMNs by activating NF-κB/NLRP3 inflammasome via phosphorylated-Src elevation, thereby exacerbating TRALI. This study highlights promising target for the treatment of antibody-mediated TRALI.

Curcumin activates NLRC4, AIM2, and IFI16 inflammasomes and induces pyroptosis by up-regulated ISG3 transcript factor in acute myeloid leukemia cell lines.

Curcumin, the primary bioactive component isolated from turmeric, has been found to possess a variety of biological functions, including anti-leukemia activity. However, the effect of curcumin in different leukemia cells vary. In this study, we demonstrated that curcumin induced the expression of AIM2, IFI16, and NLRC4 inflammasomes in leukemia cells U937 by increasing the expression levels of ISG3 transcription factor complex, which activated caspase 1, promoted cleavage of GSDMD, and induced pyroptosis. We also found that pyroptosis executor GSDMD was not expressed in two curcumin-insensitive cells HL60 and K562 cells. In addition, exogenous overexpression of GSDMD by lentiviral transduction in K562 cells increased the anti-cancer activity of curcumin, and inhibiting the expression of GSDMD by shRNA enhanced U937 cells to resist curcumin. The results showed that inducing pyroptosis is a novel mechanism underlying the anti-leukemia effects of curcumin.

CREM Is Correlated With Immune-Suppressive Microenvironment and Predicts Poor Prognosis in Gastric Adenocarcinoma.

The transcriptional repressor cAMP response element modulator (CREM) has an important role in T-cell development. In this study, we used the integrated Bioinformatics Methods to explore the role of CREM in gastric adenocarcinoma (GAC). Our results showed that high CREM expression was closely related with poorer overall survival in GAC. By GSEA cluster analysis, we found that the high expression of CREM was associated with the cancer-associated pathway in GAC. Moreover, single-cell sequencing data showed that CREM is mainly localized in exhausted CD8+ T cells. Its prognostic value and the potential function lead to T-cell exhaustion in the tumor microenvironment (TME). Similar results were also obtained in glioma and lung cancer. High expression of CREM, correlated with clinical relevance of GAC, was associated with T-cell exhaustion and M2 polarization in GAC. These findings suggest that CREM can be used as a prognostic biomarker in GAC, which might provide a novel direction to explore the pathogenesis of GAC.

MiR-144-induced KLF2 inhibition and NF-kappaB/CXCR1 activation promote neutrophil extracellular trap-induced transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is a clinical syndrome which is associated with the formation of neutrophil extracellular trap (NET). Recent studies have demonstrated the roles of microRNAs (miRNAs) in the pathophysiological process of TRALI. Here, the study focused on the role of miR-144 and the molecular mechanisms in NET-induced TRALI. Up-regulated miR-144 and under-expressed KLF2 were determined in patients with TRALI. In the mouse model of a two-event TRALI induced by intraperitoneal injections with lipopolysaccharide and anti-H-2Kd mAb, we determined expression patterns of miR-144, Krüppel-like factor 2 (KLF2), chemokine (C-X-C motif) receptor 1 (CXCR1) and nuclear factor kappa-B (NF-kappaB) p65. The results confirmed that miR-144 was highly expressed, while KLF2 was poorly expressed in mice with TRALI. Dual-luciferase reporter gene assay identified that miR-144 could target KLF2. Using gain- and loss-of-function approaches, we analysed the effects of miR-144 and its interaction with KLF2 on TRALI. Enforced expression of miR-144 was found to aggravate NET-induced TRALI by down-regulating KLF2 and activating the NF-kappaB/CXCR1 signalling pathway in TRALI mice. Collectively, miR-144-targeted inhibition of KLF2 and activation of NF-kappaB/CXCR1 are possible mechanisms responsible for NET-caused TRALI. These findings aid in the development of therapeutic modalities for the treatment of TRALI.