Impacts of Nutlin-3a and exercise on murine double minute 2-enriched glioma treatment

Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients,with evidence suggesting exercise may reduce mortality risks and aid neural regeneration.The role of the small ubiquitin-like modifier(SUMO)protein,especially post-exercise,in cancer progression,is gaining attention,as are the potential anti-cancer effects of SUMOylation.We used machine learning to create the exercise and SUMO-related gene signature(ESLRS).This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers.We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers,specifically highlighting how murine double minute 2(MDM2),a component of the ESLRS,can be targeted by nutlin-3.This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation.Using comprehensive CRISPR screening,we validated the effects of specific ESLRS genes on low-grade glioma progression.We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation.Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway.Its efficacy decreased with MDM2 overexpression,and this was reversed by Nutlin-3a or exercise.Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation.Notably,both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells.These results suggest the potential for Nutlin-3a,an MDM2 inhibitor,with physical exercise as a therapeutic approach for glioma management.Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise,natural products,and immune regulation in cancer treatment.

Conserved immuno-collagenic subtypes predict response to immune checkpoint blockade

Background:Immune checkpoint blockade(ICB)has revolutionized the treatment of various cancer types.Despite significant preclinical advancements in understanding mechanisms,identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging.Recent evidence,both preclinical and clinical,underscores the pivotal role of the extracellular matrix(ECM)in modulating immune cell infiltration and behaviors.This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy.Methods:We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy.This analysis led to the identification of three distinct immuno-collagenic subtypes predictive of ICB responses.We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas(TCGA)dataset and 1,084 inhouse samples.Additionally,novel therapeutic targets were identified based on these established immuno-collagenic subtypes.Results:Our categorization divided tumors into three subtypes:“soft&hot”(low collagen activity and high immune infiltration),“armored&cold”(high collagen activity and low immune infiltration),and“quiescent”(low collagen activity and immune infiltration).Notably,“soft&hot”tumors exhibited the most robust response to ICB therapy across various cancer types.Mechanistically,inhibiting collagen augmented the response to ICB in preclinical models.Furthermore,these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types.Additionally,an unbiased approach identified B7 homolog 3(B7-H3),an available drug target,as strongly expressed in“armored&cold”tumors,relating with poor prognosis.Conclusion:This study introduces histopathology-based universal immunocollagenic subtypes capable of predicting ICB responses across diverse cancer types.These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.

Human bone marrow mesenchymal stem cell-derived extracellular vesicles inhibit shoulder stiffness via let-7a/Tgfbr1 axis

Shoulder stiffness(SS)is a common shoulder disease characterized by increasing pain and limited range of motion.SS is considered to be an inflammatory and fibrotic disorder pathologically.However,there is no consensus on the most effective conservative treatment for fibrosis.Given that human Bone Marrow Mesen-chymal Stem Cell-derived extracellular vesicles(BMSC-EVs)displayed promising therapeutic effects for various tissues,we investigated the therapeutic effect of BMSC-EVs on fibrosis in a mice immobilization model and two cell models.By conducting a series of experiments,we found that BMSC-EVs can significantly inhibit the fibrogenic process both in vitro and in vivo.In detail,BMSC-EVs suppressed the aberrant proliferation,high collagen production capacity,and activation of fibrotic pathways in TGF-β-stimulated fibroblasts in vitro.Besides,in vivo,BMSC-EVs reduced cell infiltration,reduced fibrotic tissue in the shoulder capsule,and improved shoulder mobility.In addition,via exosomal small RNA sequencing and qPCR analysis,let-7a-5p was verified to be the highest expressed miRNA with predicted antifibrotic capability in BMSC-EVs.The antifibrotic capacity of BMSC-EVs was significantly impaired after the knockdown of let-7a-5p.Moreover,we discovered that the mRNA of TGFBR1(the membrane receptor of transforming growth factorβ)was the target of let-7a-5p.Together,these findings elucidated the antifibrotic role of BMSC-EVs in shoulder capsular fibrosis.This study clarifies a new approach using stem cell-derived EVs therapy as an alternative to cell therapy,which may clinically benefit patients with SS in the future.