查看更多>>摘要：TP53,functioning as the keeper of the genome,assumes a pivotal function in the inhibition of tumorigenesis.Recent studies have revealed that p53 regulates ferroptosis pathways within tumor cells and is closely related to tumorigenesis.Therefore,we summarize the pathways and mechanisms by which p53 regulates ferroptosis and identify a series of upstream and downstream molecules involved in this process.Furthermore,we construct a p53-ferroptosis net-work centered on p53.Finally,we present the progress of drugs to prevent wild-type p53(wtp53)degeneration and restore wtp53,highlighting the deficiencies of drug development and the prospects for p53 in cancer treatment.These findings provide novel strategies and directions for future cancer therapy.
查看更多>>摘要：One potential cause of cancer is genomic instability that arises in normal cells due to years of DNA damage in the body.The clinical application of radiotherapy and cytotoxic drugs to treat cancer is based on the principle of damaging the DNA of cancer cells.However,the benefits of these treatments also have negative effects on normal tissue.While there have been notable advancements in molecular-driven therapy and immunotherapy for color-ectal cancer(CRC),a considerable portion of patients with advanced CRC do not experience any benefits from these treatments,leading to a poor prognosis.In recent years,targeted therapy aimed at suppressing the DNA damage response(DDR)in cancer cells has emerged as a potential treatment option for CRC patients,offering them more choices for treatment.Currently,the integration of DDR and clinical intervention remains in the exploratory phase.This review primarily elucidates the fundamental principles of DDR inhibitors,provides an overview of their current clinical application status in CRC,and discusses the advancements as well as limitations observed in relevant studies.
查看更多>>摘要：Neural tube defects(NTDs)represent a developmental disorder of the nervous system that can lead to significant disability in children and impose substantial social burdens.Valproic acid(VPA),a widely prescribed first-line antiepileptic drug for epilepsy and various neurological conditions,has been associated with a 4-fold increase in the risk of NTDs when used during pregnancy.Consequently,urgent efforts are required to identify innovative pre-vention and treatment approaches for VPA-induced NTDs.Studies have demonstrated that the disruption in the delicate balance between cell proliferation and apoptosis is a crucial factor contributing to NTDs induced by VPA.Encouragingly,our current data reveal that melatonin(MT)significantly inhibits apoptosis while promoting the restoration of neuroepithelial cell proliferation impaired by VPA.Moreover,further investigations demonstrate that MT substantially reduces the incidence of neural tube malformations resulted from VPA exposure,primarily by suppressing apoptosis through the modulation of intracellular reactive oxygen species levels.In addition,the Src/PI3K/ERK signaling pathway appears to play a pivotal role in VPA-induced NTDs,with significant inhibition ob-served in the affected samples.Notably,MT treatment successfully reinstates Src/PI3K/ERK signaling,thereby offering a potential underlying mechanism for the protective effects of MT against VPA-induced NTDs.In summary,our current study substantiates the considerable protective potential of MT in mitigating VPA-triggered NTDs,thereby offering valuable strategies for the clinical management of VPA-related birth defects.
查看更多>>摘要：Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer(NSCLC).p32 and OPA1 are the key regulators of mitochondrial morphology and function.This study aims to investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC and its underlying mechanism.The levels of p32 protein and mitochondrial fusion protein OPA1 are higher in cisplatin-resistant A549/DDP cells than in cisplatin-sensitive A549 cells,which facilitates mitochondrial fusion in A549/DDP cells.In addition,the expression of p32 and OPA1 protein is also upregulated in A549 cells during the development of cisplatin resistance.Moreover,p32 knockdown effectively downregulates the expression of OPA1,stimulates mitochondrial fission,decreases ATP generation and sensitizes A549/DDP cells to cisplatin-induced apoptosis.Furthermore,metformin significantly downregulates the expres-sions of p32 and OPA1 and induces mitochondrial fission and a decrease in ATP level in A549/DDP cells.The co-administration of metformin and cisplatin shows a significantly greater decrease in A549/DDP cell viability than cisplatin treatment alone.Moreover,D-erythro-Sphingosine,a potent p32 kinase activator,counteracts the met-formin-induced downregulation of OPA1 and mitochondrial fission in A549/DDP cells.Taken together,these find-ings indicate that p32/OPA1 axis-mediated mitochondrial dynamics contributes to the acquired cisplatin resistance in NSCLC and that metformin resensitizes NSCLC to cisplatin,suggesting that targeting p32 and mitochondrial dynamics is an effective strategy for the prevention of cisplatin resistance.
查看更多>>摘要：The incidence and related death of hepatocellular carcinoma(HCC)have increased over the past decades.However,the molecular mechanisms underlying HCC pathogenesis are not fully understood.Long noncoding RNA(IncRNA)RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer,but its role and specific mechanism in HCC are still unknown.Here,we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells.Moreover,this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3(NR4A3).Glycometabolism reprogramming is one of the main characteristics of tumor cells.In this study,we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1(PDK1)and pyruvate dehydrogenase(PDH),thus contributing to the pro-liferation of HCC cells.Furthermore,knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the pro-moter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA,which leads to the increased transcription of NR4A3.Altogether,RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogram-ming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis,which provides an IncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.
查看更多>>摘要：Long noncoding RNAs(lncRNAs)are important regulators of bone metabolism.In this study,lncRNA microarray analysis was used to identify differentially expressed lncRNAs in differentiated osteoclasts.lncRNA-Gm5532 is highly expressed during osteoclast differentiation.lncRNA-Gm5532 knockdown impairs osteoclast formation and bone resorption.Mechanistic experiments show that lncRNA-Gm5532 functions as a competing endogenous RNA(ceRNA)and acts as a sponge for miR-125a-3p,which promotes TNF receptor-associated factor 6(TRAF6)ex-pression.miR-125a-3p mimics suppress osteoclast differentiation and TAK1/NF-κB/MAPK signaling.The miR-125a-3p inhibitor reverses the negative effects of siGm5532 on osteoclast differentiation.In summary,our study reveals that lncRNA-Gm5532 functions as an activator in osteoclast differentiation by targeting the miR-125a-3p/TRAF6 axis,making it a novel biomarker and potential therapeutic target for osteoporosis.
查看更多>>摘要：Invasion and metastasis are the leading causes of death in individuals with malignant tumors,including gastric cancer.In this study,we aim to explore the effect and related mechanisms of methionine restriction(MR)on gastric carcinoma metastasis.In the MR cell model,gastric carcinoma cells are cultured in the MR medium,and in the animal model,BALB/c nude rodents are administered with a methionine-free diet after receiving injections of MKN45 cells into the caudal vein.Transwell assay is used to detect cell invasion and migration.Chromatin im-munoprecipitation is performed to investigate the levels of H3K9me2,H3K27Ac,and H3K27me3 in the E-cadherin promoter.The results show that MR inhibits gastric carcinoma cell migration,invasion,and lung metastasis.MR increases E-cadherin while reducing the H3K27me3 level in the E-cadherin promoter.E-cadherin expression in gastric carcinoma cells is adversely regulated by HDAC2.Overexpressing HDAC2 reduces the H3K27Ac level in the E-cadherin promoter,while interfering with HDAC2 increases the H3K27Ac level.HDAC2 interference under MR conditions further upregulates E-cadherin expression and inhibits gastric carcinoma cell migration,invasion,and lung metastasis.MR combined with HDAC2 interference promotes E-cadherin expression by mediating the me-thylation and acetylation of E-cadherin,thus inhibiting the invasion,migration,and lung metastasis of gastric carcinoma cells.Our study provides a new theoretical basis for the inhibitory effect of MR on gastric cancer.
查看更多>>摘要：Epithelial-mesenchymal transformation(EMT)plays an important role in the progression of diabetic nephropathy.Dexmedetomidine(DEX)has shown renoprotective effects against ischemic reperfusion injury;however,whether and how DEX prevents high glucose-induced EMT in renal tubular epithelial cells is incompletely known.Here,we conduct in vitro experiments using HK-2 cells,a human tubular epithelial cell line.Our results demonstrate that high glucose increases the expressions of EMT-related proteins,including Vimentin,Slug,Snail and Twist,while de-creasing the expression of E-cadherin and increasing Cdk5 expression in HK-2 cells.Both Cdk5 knockdown and inhibition by roscovitine increase the expressions of E-cadherin while decreasing the expressions of other EMT-related markers.DEX inhibits Cdk5 expression without affecting cell viability and changes the expressions of EMT-related markers,similar to effects of Cdk5 inhibition.Furthermore,Cdk5 is found to interact with Drp1 at the protein level and mediate the phosphorylation of Drp1.In addition,Drp1 inhibition with mdivi-1 could also restrain the high glucose-induced EMT process in HK-2 cells.Immunofluorescence results show that roscovitine,Mdivi-1 and DEX inhibit high glucose-induced intracellular ROS accumulation,while the oxidant H2O2 eliminates the protective effect of DEX on the EMT process.These results indicate that DEX mitigates high glucose-induced EMT progression in HK-2 cells via inhibition of the Cdk5/Drp1/ROS pathway.
查看更多>>摘要：Osteoarthritis(OA)is a prevalent and chronic joint disease that affects the aging population,causing pain and disability.Macrophages in synovium are important mediators of synovial inflammatory activity and pathological joint pain.Previous studies have demonstrated the significant involvement of κ-opioid receptor(KOR)in the reg-ulation of pain and inflammation.Our study reveals a significant reduction in synovial KOR expression among patients and mice with OA.Here,we find that KOR activation effectively inhibits the expressions of the LPS-induced-inflammatory cytokines TNF-a and IL-6 by inhibiting macrophage M1 phenotype.Mechanistically,KOR activation effectively suppresses the proinflammatory factor secretion of macrophages by inhibiting the translocation of NF-κB into the nucleus.Our animal experiments reveal that activation of KOR effectively alleviates knee pain and prevents synovitis progression in OA mice.Consistently,KOR administration suppresses the expressions of M1 macrophage markers and the NF-κB pathway in the synovium of the knee.Collectively,our study suggests that targeting KOR may be a viable strategy for treating OA by inhibiting synovitis and improving joint pain in affected patients.
查看更多>>摘要：Cardiomyocyte apoptosis is an important cause of trauma-induced secondary cardiac injury(TISCI),in which the endoplasmic reticulum stress(ERS)-mediated apoptosis signaling pathway is known to be first activated,but the mechanism remains unclear.In this study,rat models of traumatic injury are established by using the Noble-Collip trauma device.The expression of glucose-regulating protein 78(GRP78,a molecular chaperone of the cardio-myocyte ER),acetylation modification of GRP78 and apoptosis of cardiomyocytes are determined.The results show that ERS-induced GRP78 elevation does not induce cardiomyocyte apoptosis in the early stage of trauma.However,with prolonged ERS,the GRP78 acetylation level is elevated,and the apoptosis of cardiomyocytes also increases significantly.In addition,in the early stage of trauma,the expression of histone acetyl-transferase(HAT)P300 is increased and that of histone deacetylase 6(HDAC6)is decreased in cardiomyocytes.Inhibition of HDAC function could induce the apoptosis of traumatic cardiomyocytes by increasing the acetylation level of GRP78.Our present study demonstrates for the first time that post-traumatic protracted ERS can promote cardiomyocyte apoptosis by increasing the acetylation level of GRP78,which may provide an experimental basis for seeking early molecular events of TISCI.
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