查看更多>>摘要：Exosomes are small membrane vesicles containing microRNA,RNA,DNA fragments,and proteins that are transferred from donor cells to recipient cells.Tumor cells release exo-somes to reprogram the factors associated with the tumor microenvironment(TME)causing tu-mor metastasis and immune escape.Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1(PD-L1)that binds with re-ceptor program death protein 1(PD-1)and promote tumor progression by escaping immune response.Currently,some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction.Despite notable treatment outcomes,some pa-tients show poor drug response.Exosomal PD-L1 plays a vital role in lowering the treatment response,showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the ef-fect of cell surface PD-L1.To enhance therapeutic response,inhibition of exosomal PD-L1 is required.Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors.Im-mune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine,nifedipine,lercanidipine,diltiazem,and verapamil were also reported to suppress cellular PD-L1 expression.Therefore,to enhance the PD-1/PD-L1 blockage therapy response,the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consider-ation.In this review,we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.
查看更多>>摘要：N6-methyladenosine(m6A)is the most prevalent modification in the eukaryotic transcriptome and has a wide range of functions in coding and noncoding RNAs.It affects the fate of the modified RNA,including its stability,splicing,and translation,and plays an important role in post-transcriptional regulation.Bones play a key role in supporting and pro-tecting muscles and other organs,facilitating the movement of the organism,ensuring blood production,etc.Bone diseases such as osteoarthritis,osteoporosis,and bone tumors are serious public health problems.The processes of bone development and osteogenic differen-tiation require the precise regulation of gene expression through epigenetic mechanisms including histone,DNA,and RNA modifications.As a reversible dynamic epigenetic mark,m6A modifications affect nearly every important biological process,cellular component,and molecular function,including skeletal development and homeostasis.In recent years,studies have shown that m6A modification is involved in osteogenesis and bone-related diseases.In this review,we summarized the proteins involved in RNA m6A modification and the latest progress in elucidating the regulatory role of m6A modification in bone formation and stem cell direc-tional differentiation.We also discussed the pathological roles and potential molecular mech-anisms of m6A modification in bone-related diseases like osteoporosis and osteosarcoma and suggested potential areas for new strategies that could be used to prevent or treat bone de-fects and bone diseases.
查看更多>>摘要：Extracellular vesicles(EVs)are nano-size vesicles secreted naturally by all cells into the extracellular space and have been recognized as important cell-cell mediators in multicel-lular organisms.EVs contain nucleic acids,proteins,lipids,and other cellular components,regulating many basic biological processes and playing an important role in regenerative med-icine and diseases.EVs can be traced to their cells of origin and exhibit a similar function.Moreover,EVs demonstrate low immunogenicity,good biocompatibility,and fewer side ef-fects,compared to their parent cells.Mesenchymal stem cells(MSCs)are one of the most important resource cells for EVs,with a great capacity for self-renewal and multipotent differ-entiation,and play an essential role in stem cell therapy.The mechanism of MSC therapy was thought to be attributed to the differentiation of MSCs after targeted migration,as previously noted.However,emerging evidence shows the previously unknown role of MSC-derived para-crine factors in stem cell therapy.Especially EVs derived from oral tissue MSCs(OMSC-EVs),show more advantages than those of all other MSCs in tissue repair and regeneration,due to their lower invasiveness and easier accessibility for sample collection.Here,we systematically review the biogenesis and biological characteristics of OMSC-EVs,as well as the role of OMSC-EVs in intercellular communication.Furthermore,we discuss the potential therapeutic roles of OMSC-EVs in oral and systemic diseases.We highlight the current challenges and future direc-tions of OMSC-EVs to focus more attention on clinical translation.We aim to provide valuable insights for the explorative clinical application of OMSC-EVs.
查看更多>>摘要：Ferroptosis is a novel form of regulated cell death characterized by iron-dependent excessive lipid peroxidation.The core organelle involved in ferroptosis is mitochondria.Mito-chondria undergoing ferroptosis are distinct from normal mitochondria in terms of morphology,biochemistry,gene expression,and energy metabolism.An increasing number of studies have shown that mitochondria and their associated metabolic pathways mediate ferroptosis in the development and progression of breast cancer.In this review,we discuss the relevant research about ferroptosis in breast cancer and provide a comprehensive summary of mitochondrial regulation in ferroptosis from the perspective of lipid metabolism,oxidative phosphorylation,ion metabolism,glycometabolism,and nucleotide metabolism.We also summarize the appli-cation of mitochondrial metabolism-related pathways as ferroptosis treatment targets.Here we provide new insights into the relationship between mitochondria,ferroptosis,and breast cancer treatment.
查看更多>>摘要：The incidence and mortality rates of cancer are increasing every year worldwide but the survival rate of cancer patients is still unsatisfactory.Therefore,it is necessary to further elucidate the molecular mechanisms involved in tumor development and drug resis-tance to improve cancer cure or survival rates.In recent years,autophagy has become a hot topic in the field of oncology research,which plays a double-edged role in tumorigenesis,pro-gression,and drug resistance.Meanwhile,long non-coding RNA(lncRNA)has also been shown to regulate autophagy,and the two-sided nature of autophagy determines the dual regulatory role of autophagy-related lncRNAs(ARlncRNAs).Therefore,ARlncRNAs can be effective ther-apeutic targets for various cancers.Furthermore,the high abundance and stability of ARlncR-NAs in tumor tissues make them promising biomarkers.In this review,we summarized the roles and mechanisms of ARlncRNAs in tumor cell proliferation,apoptosis,migration,invasion,drug resistance,angiogenesis,radiation resistance,and immune regulation.In addition,we described the clinical significance of these ARlncRNAs,including as biomarkers/therapeutic targets and their association with clinical drugs.
查看更多>>摘要：As the most common internal modification of mRNA,N6-methyladenosine(m6A)and its regulators modulate gene expression and play critical roles in various biological and patholog-ical processes including tumorigenesis.It was reported previously that m6A methyltransferase(writer),methyltransferase-like 3(METTL3)adds m6A in primary microRNAs(pri-miRNAs)and fa-cilitates its processing into precursor miRNAs(pre-miRNAs).However,it is unknown whether m6A modification also plays a role in the maturation process of pre-miRNAs and(if so)whether such a function contributes to tumorigenesis.Here,we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia(AML)patients,especially in relapsed patients,and plays an onco-genic role in AML.Moreover,YTHDF2 promotes expression of miR-126-3p(also known as miR-126,as it is the main product of precursor miR-126(pre-miR-126)),a miRNA that was reported as an oncomiRNA in AML,through facilitating the processing of pre-miR-126 into mature miR-126.Mechanistically,YTHDF2 recognizes m6A modification in pre-miR-126 and recruits AGO2,a regulator of pre-miRNA processing,to promote the maturation of pre-miR-126.YTHDF2 posi-tively and negatively correlates with miR-126 and miR-126's downstream target genes,respec-tively,in AML patients,and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis,indi-cating that miR-126 is a functionally important target of YTHDF2 in AML.Overall,our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the ther-apeutic potential of targeting this axis for AML treatment,but also suggest that m6A plays a role in pre-miRNA processing that contributes to tumorigenesis.
查看更多>>摘要：Therapeutic targeting FOX03A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells.Here,we show that FOXO3A deficiency induces a compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance.Mitochondrial metabolism acts downstream of mTOR to provoke activa-tion of JNK/c-JUN via reactive oxygen species(ROS).At the molecular level,FOXO3A directly binds to the promoter of G protein gamma subunit 7(GNG7)and preserves its expression,while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR.Consequently,combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML.Through a structure-based virtual screening,we report one potent small-molecule FOXO3A inhibitor(Gardenoside)that exhibits a strong effect of anti-FOXO3A DNA binding.Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model.These re-sults demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and vali-date a combinatorial approach for treating AML.
查看更多>>摘要：CDC42 controls intestinal epithelial(IEC)stem cell(IESC)division.How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear.We utilized models of inflam-matory bowel diseases(IBD),colorectal cancer,aging,and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia.Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer.Cdc42 floxed mice were crossed with Villin-Cre,Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2,or Bmi 1-CreERT2 mice to generate Cdc42 deficient mice.Irradiation,colitis,aging,and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation,IESC/progenitor regenerative capacity,and IEC repair.Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival;in contrast,lower levels of CDC42 were found in the inflamed IBD colon.Colonic Cdc42 depletion significantly reduced Lgr5+IESCs,increased progenitors'hyperplasia,and induced mucosal inflammation,which led to crypt dysplasia.Colonic Cdc42 depletion markedly enhanced irra-diation-or chemical-induced colitis.Depletion or inhibition of Cdc42 reduced colonic Lgr5+IESC regeneration.In conclusion,depletion of Cdc42 reduces the IESC regeneration and IEC repair,leading to prolonged mucosal inflammation.Constitutive monogenic loss of Cdc42 in-duces mucosal inflammation,which could result in intestinal neoplasia in the context of aging.
查看更多>>摘要：Emerging evidence suggested that zinc finger protein 831(ZNF831)was associated with immune activity and stem cell regulation in breast cancer.Whereas,the roles and molec-ular mechanisms of ZNF831 in oncogenesis remain unclear.ZNF831 expression was significantly diminished in breast cancer which was associated with promoter CpG methylation but not mu-tation.Ectopic over-expression of ZNF831 suppressed breast cancer cell proliferation and col-ony formation and promoted apoptosis in vitro,while knockdown of ZNF831 resulted in an opposite phenotype.Anti-proliferation effect of ZNF831 was verified in vivo.Bioinformatic analysis of public databases and transcriptome sequencing both showed that ZNF831 could enhance apoptosis through transcriptional regulation of the JAK/STAT pathway.ChIP and lucif-erase report assays demonstrated that ZNF831 could directly bind to one specific region of STAT3 promoter and induce the transcriptional inhibition of STAT3.As a result,the attenuation of STAT3 led to a restraint of the transcription of Bcl2 and thus accelerated the apoptotic pro-gression.Augmentation of STAT3 diminished the apoptosis-promoting effect of ZNF831 in breast cancer cell lines.Furthermore,ZNF831 could ameliorate the anti-proliferation effect of capecitabine and gemcitabine in breast cancer cell lines.Our findings demonstrate for the first time that ZNF831 is a novel transcriptional suppressor through inhibiting the expres-sion of STAT3/Bcl2 and promoting the apoptosis process in breast cancer,suggesting ZNF831 as a novel biomarker and potential therapeutic target for breast cancer patients.
查看更多>>摘要：Reactive oxidative species(ROS)production-driven ferroptosis plays a role in acute kidney injury(AKI).However,its exact molecular mechanism is poorly understood.Scavenger receptor CD36 has important roles in oxidizing lipids,lipid accumulation,metabolic syndrome,and insulin resistance in chronic kidney disease,but its roles remain unexplored in AKI.The present study investigated the role and mechanism of CD36 in regulating proximal tubular cell ferroptosis and AKI.The expression of CD36 was found to be significantly up-regulated in AKI renal tissues and correlated with renal function,which might serve as an independent biomarker for AKI patients.Moreover,in adult mice subjected to AKI,deletion of CD36(CD36-/-)induced tubular cell ROS accumulation,ferroptosis activation,and renal injury.Mechanistically,combining LC-MS/MS,co-IP,and ubiquitination analyses revealed that CD36 could specifically bind to ferroptosis suppressor protein 1(FSP1)and regulate its ubiquitination at sites K16 and K24,leading to FSP1 degradation and progression of ferroptosis in AKI.The present results emphasize a novel mechanism of CD36 in cisplatin-induced AKI.The discovery of the special CD36 roles in promoting ferroptosis and AKI development by regulating the ubi-quitination of FSP1 in proximal tubular cells may be potential therapeutic targets for AKI.Moreover,CD36 may play a key role in the progression of AKI.Therefore,targeting CD36 may provide a promising treatment option for AKI.
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