Crosstalk between the nervous system and cancer plays an important role in tumor metastasis yet is poorly understood.Recently,Padmanaban et al.demonstrated a novel mechanism for nerve-induced metastasis.Sensory nerve-...Crosstalk between the nervous system and cancer plays an important role in tumor metastasis yet is poorly understood.Recently,Padmanaban et al.demonstrated a novel mechanism for nerve-induced metastasis.Sensory nerve-derived substance P could induce apoptosis in breast cancer cells that overexpressed tachykinin receptors.Single-stranded RNAs(ssRNAs)leaking from dying cells subsequently interact with toll-like receptor 7(TLR7)on other cancer cells and finally promoted metastasis.This notable study displays a delicate loop between the nervous system and cancer and,more importantly,amplifies the conception of apoptosis-induced metastasis.Over the past years,a mass of breakthrough studies have proven the pivotal role of the nervous system in tumorigenesis and cancer progression thereby contributing to the creation of a new disciplinecancer neuroscience[1].Hanahan and Monje discussed in detail the interactions between the nervous system and tumors based on the theoretical framework of the cancer hallmarks,focused on nerve-mediated proliferation,angiogenesis,immune evasion,cell death resistance,and metastasis[2].展开更多
The published article titled“MicroRNA-98-5p Inhibits Cell Proliferation and Induces Cell Apoptosis in Hepatocellular Carcinoma via Targeting IGF2BP1”has been retracted from Oncology Research,Vol.25,No.7,2017,pp.1117...The published article titled“MicroRNA-98-5p Inhibits Cell Proliferation and Induces Cell Apoptosis in Hepatocellular Carcinoma via Targeting IGF2BP1”has been retracted from Oncology Research,Vol.25,No.7,2017,pp.1117–1127.展开更多
The aim of this study is to investigate the mechanism of magnesium isoglycyrrhizinate(MgIG)in the treatment of myocardial remodeling induced by isoproterenol(ISO)in mice.We assessed the impact of MgIG on ISO-induced m...The aim of this study is to investigate the mechanism of magnesium isoglycyrrhizinate(MgIG)in the treatment of myocardial remodeling induced by isoproterenol(ISO)in mice.We assessed the impact of MgIG on ISO-induced myocardial remodeling by activating the PI3K/AKT1 pathway.The cardiac function of mice was evaluated by echocardiography,revealing that MgIG could improve left ventricular function.Pathological staining analysis showed that MgIG could reduce the degree of myocardial injury caused by ISO.Serum data detected by ELISA demonstrated that MgIG could decrease the levels of CK-MB,MDA,and LDH while increasing the activity of GSH-Px.Western blotting analysis revealed that protein expression levels of Collagen I,BNP,Bax,cleaved caspase-3,p-PI3K,and p-AKT1 were decreased,whereas the protein expressions of Bcl-2,COX2,and SOD1 were increased upon MgIG treatment.However,the activation of the PI3K pathway reversed the cardioprotective effects of MgIG,as evidenced by the addition of PI3K activators.Taken together,our comprehensive results suggested that MgIG could improve ISO-induced myocardial remodeling,potentially through its mechanism of inhibiting the PI3K/AKT1 pathway to regulate apoptosis and oxidative stress.展开更多
Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal ste...Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal stem cells(MSCs)have shown great promise in tissue regeneration for DKD treatment and have protective effects against DKD,including decreased blood glucose and urinary protein levels and improved renal function.MSCs can directly differ-entiate into kidney cells or act via paracrine mechanisms to reduce apoptosis in DKD by modulating signaling pathways.MSC-derived extracellular vesicles(MSC-EVs)mitigate apoptosis and DKD-related symptoms by transferring miRNAs to target cells or organs.However,studies on the regulatory mechanisms of MSCs and MSC-EVs in apoptosis in DKD are insufficient.This review compre-hensively examines the mechanisms of apoptosis in DKD and research progress regarding the roles of MSCs and MSC-EVs in the disease process.展开更多
Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle p...Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle progression are inadequate.Ferroptosis and AMP-activated protein kinase(AMPK)signaling are important processes for ALL patients.However,it remains unclear whether apigenin works by affecting AMPK and apoptosis.Materials and Methods:SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin,and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,respectively.The thiobarbituric acid-reactive substances(TBARS)assay was used to evaluate lipid peroxidation.Intracellular Fe2+levels were measured using a commercial kit.Corresponding proteins were detected by western blotting.Results:Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen(PCNA)expression in a concentration-dependent manner in both types of ALL cells.Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells.Apigenin activated AMP-activated protein kinase(AMPK)signaling and induced ferroptosis,and those effects were attenuated by inhibition of AMPK.Eventually,the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.Conclusion:In summary,apigenin exerted anti-leukemia activity in ALL cells,and that effect was partially achieved by activation of AMPK signaling.Our findings suggest apigenin as a potential drug for treatment of ALL.展开更多
Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-asso...Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.展开更多
Momordica antiviral protein 30 kD(MAP30)is a type I ribosome-inactivating protein(RIP)with antibacterial,anti-HIV and antitumor activities but lacks the ability to target tumor cells.To increase its tumor-targeting ab...Momordica antiviral protein 30 kD(MAP30)is a type I ribosome-inactivating protein(RIP)with antibacterial,anti-HIV and antitumor activities but lacks the ability to target tumor cells.To increase its tumor-targeting ability,the arginine-glycine-aspartic(RGD)peptide and the epidermal growth factor receptor interference(EGFRi)peptide were fused with MAP30,which was named ELRL-MAP30.The efficiency of targeted therapy for triple-negative breast cancer(TNBC)MDA-MB-231 cells,which lack the expression of estrogen receptor(ER),Progesterone receptor(PgR)and human epidermal growth factor receptor-2(HER2),is limited.In this study,we focus on exploring the effect and mechanism of ELRL-MAP30 on TNBC MDA-MB-231 cells.First,we discovered that ELRL-MAP30 significantly inhibited the migration and invasion of MDA-MB-231 cells and induced MDA-MB-231 cell apoptosis.Moreover,ELRL-MAP30 treatment resulted in a significant increase in Bax expression and a decrease in Bcl-2 expression.Furthermore,ELRL-MAP30 triggered apoptosis via the Fak/EGFR/Erk and Ilk/Akt signaling pathways.In addition,recombinant ELRL-MAP30 can inhibit chicken embryonic angiogenesis,and also inhibit the tube formation ability of human umbilical vein endothelial cells(HUVECs),indicating its potential therapeutic effects on tumor angiogenesis.Collectively,these results indicate that ELRL-MAP30 has significant tumor-targeting properties in MDA-MB-231 cancer cells and reveals potential therapeutic effects on angiogenesis.These findings indicate the potential role of ELRL-MAP30 in the targeted treatment of the TNBC cell line MDA-MB-231.展开更多
Morusin is a flavonoid compound isolated and extracted from the root bark of Morus alba L.Studies have reported that morusin exerts anti-tumor effects by inhibiting cancer cell invasion and proliferation,as well as in...Morusin is a flavonoid compound isolated and extracted from the root bark of Morus alba L.Studies have reported that morusin exerts anti-tumor effects by inhibiting cancer cell invasion and proliferation,as well as inducing tumor cell apoptosis.This article comprehensively reviews recent research on the anti-tumor effects of morusin and its related molecular mechanisms,aiming to provide theoretical support for further studies and new drug development of morusin.展开更多
Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows...Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows:the sham control group,the CP group(CP 100 mg/kg i.p.on days 1,7,14,21,28,and 35),the CP groups treated with L.draba extract(100,200 and 400 mg/kg of L.draba extract for 28 d),and the L.draba extract alone group(400 mg/kg of L.draba extract for 28 d).Serum parameters of renal and hepatic function,as well as pro-inflammatory and anti-inflammatory cytokines associated with liver and kidney damage were measured.Moreover,Bax,Bcl-2,and caspase-3 gene expression and histopathological changes were assessed.Results:L.draba extract alleviated CP-induced hepatotoxicity and nephrotoxicity by decreasing nitric oxide,TBARS,IL-6,TNF-α,and IL-1βlevels,as well as increasing superoxide dismutase,catalase and glutathione peroxidase activities,and FRAP,MIF,and TGF-βlevels.In addition,the extract downregulated the expression of pro-apoptotic genes(Bax and caspase-3)and mitigated the destruction of glomeruli and renal tubules as well as the degeneration of hepatocytes.Conclusions:L.draba extract can protect hepatic and renal structure and function against CP-induced toxicities,and may be used as a therapeutic agent for CP-induced hepatotoxicity and nephrotoxicity.展开更多
Ferroptosis, an iron-dependent type of cell death, is being considered for new clinical treatments of malignant tumors that are difficult to treat with apoptosis inducers. Although several reports have attempted to in...Ferroptosis, an iron-dependent type of cell death, is being considered for new clinical treatments of malignant tumors that are difficult to treat with apoptosis inducers. Although several reports have attempted to increase the sensitivity of cells to cell death by combining ferroptosis and apoptosis inducers using a single treatment, detailed elucidation of the respective mechanisms of ferroptosis and apoptosis during cell death remains unclear. Here, we evaluated combined treatment effectiveness using the apoptosis-sensitive rat insulinoma INS-1 cell lines. DNA laddering, an indicator of camptothecin (CPT)-induced apoptosis, was abolished by adding RSL3 and ML-162, but not erastin. We found that when the cells were treated with the apoptosis inducer CPT or the ferroptosis inducer RSL3, respectively, the degree of cytotoxicity observed increased dose-dependently. However, a combined CPT and RSL3 treatment did not show a synergistic decrease in cell viability. Camptothecin did not significantly affect increases in intracellular lipid peroxidation and reactive oxygen species or increases in mitochondrial and cytoplasmic free iron levels that were induced by treatment with RSL3 alone. Moreover, deferoxamine and α-tocopherol were found to inhibit RSL3-induced cytotoxicity but did not protect against CPT or CPT and RSL3-induced cytotoxicity. Finally, the exogenous addition of tert-butyl hydroperoxide inhibited DNA ladder formation that is induced by CPT, while the addition of hydrogen peroxide or ferrous ammonium sulfate had no effect. Taken together, these results suggest that lipid peroxides generated during ferroptosis may suppress cell death induced by apoptotic mechanisms.展开更多
D-D’-A type aza-borondipyrromethenes(aza-BODIPYs)were prepared by Suzuki cross-coupling reaction.Photothermal conversion efficiency of self-assemble aza-BODIPY-based nanoparticles(DA-azaBDP-NPs)with NIR-Ⅱ emission(...D-D’-A type aza-borondipyrromethenes(aza-BODIPYs)were prepared by Suzuki cross-coupling reaction.Photothermal conversion efficiency of self-assemble aza-BODIPY-based nanoparticles(DA-azaBDP-NPs)with NIR-Ⅱ emission(λ_(em)=1065 nm)was 37.2%under near infrared(NIR)irradiation,and the outstanding cytotoxicity was triggered by coexistence of DA-azaBDP-NPs and the NIR irradiation,with the decrease of glioblastoma migration and the inhibition of glioblastoma proliferation.DA-azaBDP-NPs could promote glioblastoma autophagy and accelerate the process of cell death.The photothermal therapy(PTT)of DAazaBDP-NPs can effectively induce glioblastoma death by apoptosis under the NIR irradiation,which is highly promising to be applied in vivo experiments of brain.展开更多
Background Ochratoxin A(OTA)is a toxin widely found in aquafeed ingredients,and hypoxia is a common prob-lem in fish farming.In practice,aquatic animals tend to be more sensitive to hypoxia while feeds are contaminate...Background Ochratoxin A(OTA)is a toxin widely found in aquafeed ingredients,and hypoxia is a common prob-lem in fish farming.In practice,aquatic animals tend to be more sensitive to hypoxia while feeds are contaminated with OTA,but no studies exist in this area.This research investigated the multiple biotoxicities of OTA and hypoxia combined on the liver of grass carp and explored the mitigating effect of curcumin(CUR).Methods A total of 720 healthy juvenile grass carp(11.06±0.05 g)were selected and assigned randomly to 4 experi-mental groups:control group(without OTA and CUR),1.2 mg/kg OTA group,400 mg/kg CUR group,and 1.2 mg/kg OTA+400 mg/kg CUR group with three replicates each for 60 d.Subsequently,32 fish were selected,divided into nor-moxia(18 fish)and hypoxia(18 fish)groups,and subjected to hypoxia stress for 96 h.Results CUR can attenuate histopathological damage caused by coming to OTA and hypoxia by reducing vacu-olation and nuclear excursion.The alleviation of this damage was associated with the attenuation of apoptosis in the mitochondrial pathway by decreasing the expression of the pro-apoptotic proteins Caspase 3,8,9,Bax,and Apaf1 while increasing the expression of the anti-apoptotic protein Bcl-2,and attenuation of endoplasmic reticulum stress(ERS)by reducing Grp78 expression and chop levels.This may be attributed to the fact that the addi-tion of CUR increased the levels of catalase(CAT)and glutathione reductase(GSH),increased antioxidant capacity,and ensured the proper functioning of respiratory chain complexes I and II,which in turn reduced the high produc-tion of reactive oxygen species(ROS),thus alleviating apoptosis and ERS.Conclusions In conclusion,our data demonstrate the effectiveness of CUR in attenuating liver injury caused by the combination of OTA and hypoxia.This study confirms the feasibility and efficacy of adding natural products to mitigate toxic damage to aquatic animals.展开更多
Background Heat stress(HS)poses a significant threat to male goat reproduction.Sertoli cells(SCs)provide both structural and nutritional support necessary for germ cells.HS induces physiological and biochemical change...Background Heat stress(HS)poses a significant threat to male goat reproduction.Sertoli cells(SCs)provide both structural and nutritional support necessary for germ cells.HS induces physiological and biochemical changes in SCs.Nevertheless,the molecular mechanisms involved are still not fully understood.Melatonin is a classic antioxidant that can alleviate HS-induced male reproductive damage.However,the underlying molecular mechanisms by which melatonin mitigates damage to goat testicular SCs remain unclear and require further investigation.Results In this study,an in vivo heat stress model was established in goats.The results showed that HS exposure led to testicular injury,abnormal spermatogenesis and apoptosis of SCs.To elucidate the mechanism of HS-induced SC apoptosis,primary SCs were isolated and cultured from goat testes,then exposed to HS.HS exposure increased the production of reactive oxygen species(ROS),decreased adenosine triphosphate(ATP)synthesis,and reduced mitochondrial membrane potential in SCs.Additionally,HS increased the expression of mitochondrial fission proteins 1(FIS1)and dynamin-related protein 1(DRP1)while decreasing the expression of mitochondrial fusion proteins Mitofusin 1(MFN1),Mitofusin 2(MFN2),and optic atrophy 1(OPA1).This resulted in excessive mitochondrial fission and mitochondria-dependent apoptosis.Mdivi-1(DRP1 inhibitor)reduces mitochondria-dependent apoptosis by inhibiting excessive mitochondrial fission.Mitochondrial fission is closely related to mitophagy.HS activated upstream mitophagy but inhibited autophagic flux,disrupting mitophagy and exacerbating mitochondria-dependent apoptosis.Finally,the classical antioxidant melatonin was shown to reduce mitochondria-dependent apoptosis in SCs exposed to HS by decreasing ROS levels,restoring mitochondrial homeostasis,and normalizing mitophagy.Conclusions In summary,these findings indicated that the mechanism of HS-induced mitochondria-dependent apoptosis in SCs is mediated by hyperactivation of the ROS-DRP1-mitochondrial fission axis and inhibition of mitochondrial autophagy.Melatonin inhibited HS-induced mitochondria-dependent apoptosis in SCs by restoring mitochondrial homeostasis.This study enhances the understanding of the mechanisms through which heat stress triggers apoptosis and provides a vision for the development of drugs against HS by targeting mitochondria in goats.展开更多
Premature ovarian insufficiency(POI)caused by chemotherapy is a common complication in female cancer survivors of childbearing age.Traditional methods,including mesenchymal stem cell(MSC)transplant and hormone replace...Premature ovarian insufficiency(POI)caused by chemotherapy is a common complication in female cancer survivors of childbearing age.Traditional methods,including mesenchymal stem cell(MSC)transplant and hormone replacement therapy,have limited clinical application because of their drawbacks,and more methods need to be developed.In the current study,the potential effects and underlying mechanisms of human umbilical cord MSC-derived extracellular vesicles(h UCMSC-EVs)were investigated in a cisplatin(CDDP)-induced POI mouse model and a human granulosa cell(GC)line.The results showed that h UCMSC-EVs significantly attenuated body weight loss,ovarian weight loss,ovary atrophy,and follicle loss in moderate-dose(1.5 mg/kg)CDDP-induced POI mice,similar to the effects observed with h UCMSCs.We further found that the h UCMSCEVs inhibited CDDP-induced ovarian GC apoptosis by upregulating anti-apoptotic mi RNA levels in GCs,thereby downregulating the m RNA levels of multiple pro-apoptotic genes.In general,our findings indicate that the moderate-dose chemotherapy may be a better choice for clinical oncotherapy,considering effective rescue of the oncotherapy-induced ovarian damage with h UCMSC-EVs.Additionally,multiple mi RNAs in h UCMSC-EVs may potentially be used to inhibit the chemotherapy-induced ovarian GC apoptosis,thereby restoring ovarian function and improving the life quality of female cancer patients.展开更多
Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to...Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to investigate the efficacy and mechanism of pristimerin on ESCC in vitro and in vivo.The inhibitory effect of pristimerin on cell growth was assessed using trypan blue exclusion and colony formation assays.Cell apoptosis was evaluated by flow cytometry.Gene and protein expressions were analyzed through quantitative reverse transcription-polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry.RNA sequencing(RNA-Seq)was employed to identify significantly differentially expressed genes(DEGs).Cell transfection and RNA interference assays were utilized to examine the role of key proteins in pristimerin's effect.Xenograft models were established to evaluate the antitumor efficiency of pristimerin in vivo.Pristimerin inhibited cell growth and induced apoptosis in ESCC cells.Upregulation of Noxa was crucial for pristimerin-induced apoptosis.Pristimerin activated the Forkhead box O3a(FoxO3a)signaling pathway and triggered FoxO3a recruitment to the Noxa promoter,leading to Noxa transcription.Blocking FoxO3a reversed pristimerin-induced Noxa upregulation and cell apoptosis.Pristimerin treatment suppressed xenograft tumors in nude mice,but these effects were largely negated in Noxa-KO tumors.Furthermore,the chemosensitization effects of pristimerin in vitro and in vivo were mediated by Noxa.This study demonstrates that pristimerin exerts an antitumor effect on ESCC by inducing AKT/FoxO3a-mediated Noxa upregulation.These findings suggest that pristimerin may serve as a potent anticancer agent for ESCC treatment.展开更多
In most types of erectile dysfunction,particularly in advanced stages,typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis.However,the current treatment methods h...In most types of erectile dysfunction,particularly in advanced stages,typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis.However,the current treatment methods have shown limited success in reversing these pathologic changes.Recent research has revealed that changes in autophagy levels,along with alterations in apoptosis and fibrosis-related proteins,are linked to the progression of erectile dysfunction,suggesting a significant association.Autophagy,known to significantly affect cell fate and tissue fibrosis,is currently being explored as a potential treatment modality for erectile dysfunction.However,these present studies are still in their nascent stage,and there are limited experimental data available.This review analyzes erectile dysfunction from a pathological perspective.It provides an in-depth overview of how autophagy is involved in the apoptotic processes of smooth muscle and endothelial cells and its role in the fibrotic processes occurring in the cavernosum.This study aimed to develop a theoretical framework for the potential effectiveness of autophagy in preventing and treating erectile dysfunction,thus encouraging further investigation among researchers in this area.展开更多
Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and ...Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.展开更多
BACKGROUND:The mechanisms underlying hypothermic liver injury necessitate investigation for the development of effective diagnostic and therapeutic approaches.We aim to establish a model of hypothermic liver injury to...BACKGROUND:The mechanisms underlying hypothermic liver injury necessitate investigation for the development of effective diagnostic and therapeutic approaches.We aim to establish a model of hypothermic liver injury to explore the hepatic alterations,thereby facilitating the prevention and treatment of the liver injury associated with hypothermia.METHODS:The mice were placed in a−20℃ environment,to establish a hypothermic injury model.The liver function,metabolites,and proteins expression were measured by thromboelastography,histopathology,metabolomics and western blotting,respectively.Furthermore,apoptosis and pathway changes in the liver cells conducted with target metabolites were examined and verified.RESULTS:According to the prolonged righting reflex recovery time and death occurrence,the mice with the anal temperature(AT)dropping to 20℃ or 15℃ were used to establish a model of hypothermia.The model mice showed changes in alanine aminotransferase(ALT),aspartate transaminase(AST),and coagulation indicators.HE staining results indicated that liver tissue in the AT 20℃ mice had large hemorrhagic patches,while the AT 15℃ mice displayed significant congestion,along with extensive infiltration of inflammatory cells around the central vein.Metabolomic and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses of target metabolites revealed a significant increase in 3-hydroxybutyric acid and changes in the cyclic adenosine monophosphate(cAMP)signaling pathway in the liver tissue of hypothermic mice.The hypothermic mice showed decreases in levels of cAMP,protein kinase A C-α(PKA C-α),and phosphorylated BCL-2/BCL-XL-associated death promoter(p-Bad)and an increase in BCL-2/BCLXL-associated death promoter(Bad)level in the liver.These protein changes and apoptosis were intensified by 3-hydroxybutyric acid in liver cells.CONCLUSION:Hypothermia may induce apoptosis in the liver cell which may be related to the changes of the cAMP-PKA pathway proteins expression.These findings provide a basis for the treatment of hypothermic injury.展开更多
Morin is a functional flavonoid commonly found in human diet.Compared to being used solely,it is evident that morin can be more effective as a drug adjuvant.However,research on the combined effect and its correspondin...Morin is a functional flavonoid commonly found in human diet.Compared to being used solely,it is evident that morin can be more effective as a drug adjuvant.However,research on the combined effect and its corresponding mechanism is limited.Here,we found that morin significantly potentiated the inhibitory effects of the natural compound celastrol on the proliferation of lung cancer cells.Morin and celastrol synergistically exhibit marked apoptosis induction in lung cancer cells,accompanied by changes in the abundance of apoptosis-related proteins.Transcriptome analyses revealed that the combination of morin and celastrol had a significant impact on the number of differentially expressed genes in lung cancer cells.Among these genes,BIRC3 was one of the most significantly different ones,which plays a crucial role in the process of tumor resistance to apoptosis.In addition,several genes identified are primarily associated with intracellular signal transduction pathways,specifically the NF-κB signaling pathway.Importantly,the treatment combining morin and celastrol in tumor-bearing mice results in a synergistic effect that significantly suppressed tumor growth.These findings indicate that morin could be a promising functional adjuvant,and the combination of morin and celastrol has potential for the treating lung cancer.展开更多
Due to the discharge of industrialwastewater,urban domestic sewage,and intensive marine aquaculture tailwater,nitrate(NO_(3)^(−))pollution has emerged as a significant issue in offshore waters.Nitrate pollution affect...Due to the discharge of industrialwastewater,urban domestic sewage,and intensive marine aquaculture tailwater,nitrate(NO_(3)^(−))pollution has emerged as a significant issue in offshore waters.Nitrate pollution affects aquatic life and may interact with other pollutants,leading to comprehensive toxicity.Cadmium(Cd^(2+))is the most widespread metal contaminant,adversely affecting aquatic life in the coastal waters of China.Despite this,few studies have focused on the synergistic toxicity of NO_(3)^(−)and Cd^(2+)in marine organisms.This study conducted a 30-day exposure experiment on marine Japanese flounder(Paralichthys olivaceus)to explore the synergistic toxicity of NO_(3)^(−)and Cd^(2+).Our results demonstrated that the exposure to Cd^(2+)alone induced slight histopathological changes in the liver.However,malformations such as hepatic vacuolar degeneration and sinusoid dilatationwere exacerbated under co-exposure.Moreover,co-exposure induced the downregulation of antioxidants and the upregulation of the product malonaldehyde(MDA)from lipid peroxidation,indicating potent oxidative stress in the liver.The increased mRNA expression of IL-8,TNF-α,and IL-1β,along with the decreased expression level of TGF-β,indicated a synergistic inflammatory response in the organisms.Furthermore,the co-exposure led to an abnormal expression of P53,caspase-3,caspase-9,Bcl-2,and Bax,and disturbed the apoptosis in the liver through TUNEL staining analysis.Overall,our results imply that co-exposure synergistically affects inflammation,redox status,and apoptosis in flounders.Therefore,the findings from this study provide valuable perspectives on the ecological risk assessment of marine teleosts co-exposure to NO_(3)^(−)and Cd^(2+).展开更多
文摘Crosstalk between the nervous system and cancer plays an important role in tumor metastasis yet is poorly understood.Recently,Padmanaban et al.demonstrated a novel mechanism for nerve-induced metastasis.Sensory nerve-derived substance P could induce apoptosis in breast cancer cells that overexpressed tachykinin receptors.Single-stranded RNAs(ssRNAs)leaking from dying cells subsequently interact with toll-like receptor 7(TLR7)on other cancer cells and finally promoted metastasis.This notable study displays a delicate loop between the nervous system and cancer and,more importantly,amplifies the conception of apoptosis-induced metastasis.Over the past years,a mass of breakthrough studies have proven the pivotal role of the nervous system in tumorigenesis and cancer progression thereby contributing to the creation of a new disciplinecancer neuroscience[1].Hanahan and Monje discussed in detail the interactions between the nervous system and tumors based on the theoretical framework of the cancer hallmarks,focused on nerve-mediated proliferation,angiogenesis,immune evasion,cell death resistance,and metastasis[2].
文摘The published article titled“MicroRNA-98-5p Inhibits Cell Proliferation and Induces Cell Apoptosis in Hepatocellular Carcinoma via Targeting IGF2BP1”has been retracted from Oncology Research,Vol.25,No.7,2017,pp.1117–1127.
基金Jiangxi Provincial Department of Education Science and Technology Project(Grant No.GJJ2401615)Jiangxi Provincial Department of Education Teaching Reform Project(Grant No.JXJG-24-15-15).
文摘The aim of this study is to investigate the mechanism of magnesium isoglycyrrhizinate(MgIG)in the treatment of myocardial remodeling induced by isoproterenol(ISO)in mice.We assessed the impact of MgIG on ISO-induced myocardial remodeling by activating the PI3K/AKT1 pathway.The cardiac function of mice was evaluated by echocardiography,revealing that MgIG could improve left ventricular function.Pathological staining analysis showed that MgIG could reduce the degree of myocardial injury caused by ISO.Serum data detected by ELISA demonstrated that MgIG could decrease the levels of CK-MB,MDA,and LDH while increasing the activity of GSH-Px.Western blotting analysis revealed that protein expression levels of Collagen I,BNP,Bax,cleaved caspase-3,p-PI3K,and p-AKT1 were decreased,whereas the protein expressions of Bcl-2,COX2,and SOD1 were increased upon MgIG treatment.However,the activation of the PI3K pathway reversed the cardioprotective effects of MgIG,as evidenced by the addition of PI3K activators.Taken together,our comprehensive results suggested that MgIG could improve ISO-induced myocardial remodeling,potentially through its mechanism of inhibiting the PI3K/AKT1 pathway to regulate apoptosis and oxidative stress.
基金Supported by Science and Technology Research Program of Jilin Provincial Department of Education,No.JJKH20231218KJProject of the Jilin Provincial Administration of Traditional Chinese Medicine,No.2024111.
文摘Diabetic kidney disease(DKD)has a high incidence and mortality rate and lacks effective preventive and therapeutic methods.Apoptosis is one of the main reasons for the occurrence and development of DKD.Mesenchymal stem cells(MSCs)have shown great promise in tissue regeneration for DKD treatment and have protective effects against DKD,including decreased blood glucose and urinary protein levels and improved renal function.MSCs can directly differ-entiate into kidney cells or act via paracrine mechanisms to reduce apoptosis in DKD by modulating signaling pathways.MSC-derived extracellular vesicles(MSC-EVs)mitigate apoptosis and DKD-related symptoms by transferring miRNAs to target cells or organs.However,studies on the regulatory mechanisms of MSCs and MSC-EVs in apoptosis in DKD are insufficient.This review compre-hensively examines the mechanisms of apoptosis in DKD and research progress regarding the roles of MSCs and MSC-EVs in the disease process.
基金supported by The National Natural Science Foundation of China(No.31902283)Research Foundation for Master students at the Affiliated Hospital of Zunyi Medical College(No.22-2018).
文摘Background:The outcomes of pediatric patients with acute lymphoblastic leukemia(ALL)remain far less than favorable.While apigenin is an anti-cancer agent,studies on the mechanism by which it regulates ALL cell cycle progression are inadequate.Ferroptosis and AMP-activated protein kinase(AMPK)signaling are important processes for ALL patients.However,it remains unclear whether apigenin works by affecting AMPK and apoptosis.Materials and Methods:SUP-B15 and T-cell Jurkat ALL cells were treated with apigenin,and cell viability and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)and terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)assays,respectively.The thiobarbituric acid-reactive substances(TBARS)assay was used to evaluate lipid peroxidation.Intracellular Fe2+levels were measured using a commercial kit.Corresponding proteins were detected by western blotting.Results:Results showed that apigenin reduced cell viability and the levels of Ki67 and proliferating cell nuclear antigen(PCNA)expression in a concentration-dependent manner in both types of ALL cells.Apigenin also exerted anti-apoptotic effects on SUP-B15 and Jurkat cells.Apigenin activated AMP-activated protein kinase(AMPK)signaling and induced ferroptosis,and those effects were attenuated by inhibition of AMPK.Eventually,the reduced cell proliferation and increased cell apoptosis caused by apigenin in ALL cells were partly abolished by AMPK inhibition.Conclusion:In summary,apigenin exerted anti-leukemia activity in ALL cells,and that effect was partially achieved by activation of AMPK signaling.Our findings suggest apigenin as a potential drug for treatment of ALL.
基金supported by the National Natural Science Foundation of China,Nos.82071008(to BL)and 82004001(to XJ)Medical Science and Technology Program of Health Commission of Henan Province,No.LHGJ20210072(to RQ)Science and Technology Department of Henan Province,No.212102310307(to XJ)。
文摘Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.
文摘Momordica antiviral protein 30 kD(MAP30)is a type I ribosome-inactivating protein(RIP)with antibacterial,anti-HIV and antitumor activities but lacks the ability to target tumor cells.To increase its tumor-targeting ability,the arginine-glycine-aspartic(RGD)peptide and the epidermal growth factor receptor interference(EGFRi)peptide were fused with MAP30,which was named ELRL-MAP30.The efficiency of targeted therapy for triple-negative breast cancer(TNBC)MDA-MB-231 cells,which lack the expression of estrogen receptor(ER),Progesterone receptor(PgR)and human epidermal growth factor receptor-2(HER2),is limited.In this study,we focus on exploring the effect and mechanism of ELRL-MAP30 on TNBC MDA-MB-231 cells.First,we discovered that ELRL-MAP30 significantly inhibited the migration and invasion of MDA-MB-231 cells and induced MDA-MB-231 cell apoptosis.Moreover,ELRL-MAP30 treatment resulted in a significant increase in Bax expression and a decrease in Bcl-2 expression.Furthermore,ELRL-MAP30 triggered apoptosis via the Fak/EGFR/Erk and Ilk/Akt signaling pathways.In addition,recombinant ELRL-MAP30 can inhibit chicken embryonic angiogenesis,and also inhibit the tube formation ability of human umbilical vein endothelial cells(HUVECs),indicating its potential therapeutic effects on tumor angiogenesis.Collectively,these results indicate that ELRL-MAP30 has significant tumor-targeting properties in MDA-MB-231 cancer cells and reveals potential therapeutic effects on angiogenesis.These findings indicate the potential role of ELRL-MAP30 in the targeted treatment of the TNBC cell line MDA-MB-231.
基金Supported by Heilongjiang Provincial Key Research and Development Program(Guided Category)(GZ20220039)Central Government Funds for Local University Reform and Development(Talent Cultivation Program)(2020GSP16).
文摘Morusin is a flavonoid compound isolated and extracted from the root bark of Morus alba L.Studies have reported that morusin exerts anti-tumor effects by inhibiting cancer cell invasion and proliferation,as well as inducing tumor cell apoptosis.This article comprehensively reviews recent research on the anti-tumor effects of morusin and its related molecular mechanisms,aiming to provide theoretical support for further studies and new drug development of morusin.
基金supported by the Basic Research Joint Special General Project of Yunnan Provincial Local Universities(part)(No:202301BA070001-029,202301BA070001-044)Yunnan Province High-level Scientific and Technological Talents and Innovation Team Selection Special Young and Middle-aged Academic and Technical Leaders Reserve Talent Project(No:202405AC350067).
文摘Objective:To investigate the protective effects of Lepidium draba L.(L.draba)on cyclophosphamide(CP)-induced hepatotoxicity and nephrotoxicity in rats.Methods:A total of 36 rats were divided into six groups as follows:the sham control group,the CP group(CP 100 mg/kg i.p.on days 1,7,14,21,28,and 35),the CP groups treated with L.draba extract(100,200 and 400 mg/kg of L.draba extract for 28 d),and the L.draba extract alone group(400 mg/kg of L.draba extract for 28 d).Serum parameters of renal and hepatic function,as well as pro-inflammatory and anti-inflammatory cytokines associated with liver and kidney damage were measured.Moreover,Bax,Bcl-2,and caspase-3 gene expression and histopathological changes were assessed.Results:L.draba extract alleviated CP-induced hepatotoxicity and nephrotoxicity by decreasing nitric oxide,TBARS,IL-6,TNF-α,and IL-1βlevels,as well as increasing superoxide dismutase,catalase and glutathione peroxidase activities,and FRAP,MIF,and TGF-βlevels.In addition,the extract downregulated the expression of pro-apoptotic genes(Bax and caspase-3)and mitigated the destruction of glomeruli and renal tubules as well as the degeneration of hepatocytes.Conclusions:L.draba extract can protect hepatic and renal structure and function against CP-induced toxicities,and may be used as a therapeutic agent for CP-induced hepatotoxicity and nephrotoxicity.
文摘Ferroptosis, an iron-dependent type of cell death, is being considered for new clinical treatments of malignant tumors that are difficult to treat with apoptosis inducers. Although several reports have attempted to increase the sensitivity of cells to cell death by combining ferroptosis and apoptosis inducers using a single treatment, detailed elucidation of the respective mechanisms of ferroptosis and apoptosis during cell death remains unclear. Here, we evaluated combined treatment effectiveness using the apoptosis-sensitive rat insulinoma INS-1 cell lines. DNA laddering, an indicator of camptothecin (CPT)-induced apoptosis, was abolished by adding RSL3 and ML-162, but not erastin. We found that when the cells were treated with the apoptosis inducer CPT or the ferroptosis inducer RSL3, respectively, the degree of cytotoxicity observed increased dose-dependently. However, a combined CPT and RSL3 treatment did not show a synergistic decrease in cell viability. Camptothecin did not significantly affect increases in intracellular lipid peroxidation and reactive oxygen species or increases in mitochondrial and cytoplasmic free iron levels that were induced by treatment with RSL3 alone. Moreover, deferoxamine and α-tocopherol were found to inhibit RSL3-induced cytotoxicity but did not protect against CPT or CPT and RSL3-induced cytotoxicity. Finally, the exogenous addition of tert-butyl hydroperoxide inhibited DNA ladder formation that is induced by CPT, while the addition of hydrogen peroxide or ferrous ammonium sulfate had no effect. Taken together, these results suggest that lipid peroxides generated during ferroptosis may suppress cell death induced by apoptotic mechanisms.
基金supported by the National Natural Science Foundation of China(Nos.22078201,U1908202)Liaoning&Shenyang Key Laboratory of Functional Dye and Pigment(Nos.2021JH13/10200018,21-104-0-23).
文摘D-D’-A type aza-borondipyrromethenes(aza-BODIPYs)were prepared by Suzuki cross-coupling reaction.Photothermal conversion efficiency of self-assemble aza-BODIPY-based nanoparticles(DA-azaBDP-NPs)with NIR-Ⅱ emission(λ_(em)=1065 nm)was 37.2%under near infrared(NIR)irradiation,and the outstanding cytotoxicity was triggered by coexistence of DA-azaBDP-NPs and the NIR irradiation,with the decrease of glioblastoma migration and the inhibition of glioblastoma proliferation.DA-azaBDP-NPs could promote glioblastoma autophagy and accelerate the process of cell death.The photothermal therapy(PTT)of DAazaBDP-NPs can effectively induce glioblastoma death by apoptosis under the NIR irradiation,which is highly promising to be applied in vivo experiments of brain.
基金financially supported by the earmarked fund for CARS(CARS-45)National Natural Science Foundation of China(32273144,32072985)National Key R&D Program of China(2019YFD0900200).
文摘Background Ochratoxin A(OTA)is a toxin widely found in aquafeed ingredients,and hypoxia is a common prob-lem in fish farming.In practice,aquatic animals tend to be more sensitive to hypoxia while feeds are contaminated with OTA,but no studies exist in this area.This research investigated the multiple biotoxicities of OTA and hypoxia combined on the liver of grass carp and explored the mitigating effect of curcumin(CUR).Methods A total of 720 healthy juvenile grass carp(11.06±0.05 g)were selected and assigned randomly to 4 experi-mental groups:control group(without OTA and CUR),1.2 mg/kg OTA group,400 mg/kg CUR group,and 1.2 mg/kg OTA+400 mg/kg CUR group with three replicates each for 60 d.Subsequently,32 fish were selected,divided into nor-moxia(18 fish)and hypoxia(18 fish)groups,and subjected to hypoxia stress for 96 h.Results CUR can attenuate histopathological damage caused by coming to OTA and hypoxia by reducing vacu-olation and nuclear excursion.The alleviation of this damage was associated with the attenuation of apoptosis in the mitochondrial pathway by decreasing the expression of the pro-apoptotic proteins Caspase 3,8,9,Bax,and Apaf1 while increasing the expression of the anti-apoptotic protein Bcl-2,and attenuation of endoplasmic reticulum stress(ERS)by reducing Grp78 expression and chop levels.This may be attributed to the fact that the addi-tion of CUR increased the levels of catalase(CAT)and glutathione reductase(GSH),increased antioxidant capacity,and ensured the proper functioning of respiratory chain complexes I and II,which in turn reduced the high produc-tion of reactive oxygen species(ROS),thus alleviating apoptosis and ERS.Conclusions In conclusion,our data demonstrate the effectiveness of CUR in attenuating liver injury caused by the combination of OTA and hypoxia.This study confirms the feasibility and efficacy of adding natural products to mitigate toxic damage to aquatic animals.
基金supported by the National Key Research and Development Program of China(No.2022YFD1300200)Basic Research Program of Jiangsu Province(BK20220315)+1 种基金Key Research and Development Project in Shaanxi Province(No.2022QCY-LL-52,No.2024NC-ZDCYL-03-02)Core and Key technological breakthroughs Project in agriculture of Shanxi Province(No.2023NYGG005).
文摘Background Heat stress(HS)poses a significant threat to male goat reproduction.Sertoli cells(SCs)provide both structural and nutritional support necessary for germ cells.HS induces physiological and biochemical changes in SCs.Nevertheless,the molecular mechanisms involved are still not fully understood.Melatonin is a classic antioxidant that can alleviate HS-induced male reproductive damage.However,the underlying molecular mechanisms by which melatonin mitigates damage to goat testicular SCs remain unclear and require further investigation.Results In this study,an in vivo heat stress model was established in goats.The results showed that HS exposure led to testicular injury,abnormal spermatogenesis and apoptosis of SCs.To elucidate the mechanism of HS-induced SC apoptosis,primary SCs were isolated and cultured from goat testes,then exposed to HS.HS exposure increased the production of reactive oxygen species(ROS),decreased adenosine triphosphate(ATP)synthesis,and reduced mitochondrial membrane potential in SCs.Additionally,HS increased the expression of mitochondrial fission proteins 1(FIS1)and dynamin-related protein 1(DRP1)while decreasing the expression of mitochondrial fusion proteins Mitofusin 1(MFN1),Mitofusin 2(MFN2),and optic atrophy 1(OPA1).This resulted in excessive mitochondrial fission and mitochondria-dependent apoptosis.Mdivi-1(DRP1 inhibitor)reduces mitochondria-dependent apoptosis by inhibiting excessive mitochondrial fission.Mitochondrial fission is closely related to mitophagy.HS activated upstream mitophagy but inhibited autophagic flux,disrupting mitophagy and exacerbating mitochondria-dependent apoptosis.Finally,the classical antioxidant melatonin was shown to reduce mitochondria-dependent apoptosis in SCs exposed to HS by decreasing ROS levels,restoring mitochondrial homeostasis,and normalizing mitophagy.Conclusions In summary,these findings indicated that the mechanism of HS-induced mitochondria-dependent apoptosis in SCs is mediated by hyperactivation of the ROS-DRP1-mitochondrial fission axis and inhibition of mitochondrial autophagy.Melatonin inhibited HS-induced mitochondria-dependent apoptosis in SCs by restoring mitochondrial homeostasis.This study enhances the understanding of the mechanisms through which heat stress triggers apoptosis and provides a vision for the development of drugs against HS by targeting mitochondria in goats.
基金Financial support for the current study was provided by the grant from"Blue Engineering"Excellent Young Teacher Foundation in Colleges and Universities of Jiangsu Province(Grant No.KY101R202207 to Xiaojun Chen)。
文摘Premature ovarian insufficiency(POI)caused by chemotherapy is a common complication in female cancer survivors of childbearing age.Traditional methods,including mesenchymal stem cell(MSC)transplant and hormone replacement therapy,have limited clinical application because of their drawbacks,and more methods need to be developed.In the current study,the potential effects and underlying mechanisms of human umbilical cord MSC-derived extracellular vesicles(h UCMSC-EVs)were investigated in a cisplatin(CDDP)-induced POI mouse model and a human granulosa cell(GC)line.The results showed that h UCMSC-EVs significantly attenuated body weight loss,ovarian weight loss,ovary atrophy,and follicle loss in moderate-dose(1.5 mg/kg)CDDP-induced POI mice,similar to the effects observed with h UCMSCs.We further found that the h UCMSCEVs inhibited CDDP-induced ovarian GC apoptosis by upregulating anti-apoptotic mi RNA levels in GCs,thereby downregulating the m RNA levels of multiple pro-apoptotic genes.In general,our findings indicate that the moderate-dose chemotherapy may be a better choice for clinical oncotherapy,considering effective rescue of the oncotherapy-induced ovarian damage with h UCMSC-EVs.Additionally,multiple mi RNAs in h UCMSC-EVs may potentially be used to inhibit the chemotherapy-induced ovarian GC apoptosis,thereby restoring ovarian function and improving the life quality of female cancer patients.
基金supported by the Projects of International Cooperation and Exchanges(Nos.G2022027004L,G2022027012L)the Hubei Province Natural Science Foundation of China(No.2022CFB481)+3 种基金the Natural Science Foundation of Hubei Provincial Department of Education(No.T2022021)the Advantages Discipline Group(Biology and Medicine)Project in Higher Education of Hubei Province(2021-2025)(Nos.2025BMXKQY2,2024XKQY26)the Innovative Research Program for Graduates of Hubei University of Medicine(No.YC2024003,YC2022033)the Student's Platform for Innovation and Entrepreneurship Training Program(Nos.202410929010,202210929005)。
文摘Pristimerin,which is one of the compounds present in Celastraceae and Hippocrateaceae,has antitumor effects.However,its mechanism of action in esophageal squamous cell carcinoma(ESCC)remains unclear.This study aims to investigate the efficacy and mechanism of pristimerin on ESCC in vitro and in vivo.The inhibitory effect of pristimerin on cell growth was assessed using trypan blue exclusion and colony formation assays.Cell apoptosis was evaluated by flow cytometry.Gene and protein expressions were analyzed through quantitative reverse transcription-polymerase chain reaction(qRT-PCR),Western blotting,and immunohistochemistry.RNA sequencing(RNA-Seq)was employed to identify significantly differentially expressed genes(DEGs).Cell transfection and RNA interference assays were utilized to examine the role of key proteins in pristimerin's effect.Xenograft models were established to evaluate the antitumor efficiency of pristimerin in vivo.Pristimerin inhibited cell growth and induced apoptosis in ESCC cells.Upregulation of Noxa was crucial for pristimerin-induced apoptosis.Pristimerin activated the Forkhead box O3a(FoxO3a)signaling pathway and triggered FoxO3a recruitment to the Noxa promoter,leading to Noxa transcription.Blocking FoxO3a reversed pristimerin-induced Noxa upregulation and cell apoptosis.Pristimerin treatment suppressed xenograft tumors in nude mice,but these effects were largely negated in Noxa-KO tumors.Furthermore,the chemosensitization effects of pristimerin in vitro and in vivo were mediated by Noxa.This study demonstrates that pristimerin exerts an antitumor effect on ESCC by inducing AKT/FoxO3a-mediated Noxa upregulation.These findings suggest that pristimerin may serve as a potent anticancer agent for ESCC treatment.
基金supported by the Health Commission Research Project of China(No.HDSL202001057)the Jiangxi Provincial Health Commission Research Project(No.SKJP20203656)the Doctoral Start-up Fund of the First Affiliated Hospital of Gannan Medical University(No.QD063).
文摘In most types of erectile dysfunction,particularly in advanced stages,typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis.However,the current treatment methods have shown limited success in reversing these pathologic changes.Recent research has revealed that changes in autophagy levels,along with alterations in apoptosis and fibrosis-related proteins,are linked to the progression of erectile dysfunction,suggesting a significant association.Autophagy,known to significantly affect cell fate and tissue fibrosis,is currently being explored as a potential treatment modality for erectile dysfunction.However,these present studies are still in their nascent stage,and there are limited experimental data available.This review analyzes erectile dysfunction from a pathological perspective.It provides an in-depth overview of how autophagy is involved in the apoptotic processes of smooth muscle and endothelial cells and its role in the fibrotic processes occurring in the cavernosum.This study aimed to develop a theoretical framework for the potential effectiveness of autophagy in preventing and treating erectile dysfunction,thus encouraging further investigation among researchers in this area.
基金financially supported by the National Natural Science Foundation of China(3226058782060598)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of China(202210661140)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021110).
文摘Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.
基金supported by a grant from the Liaoning Provincial Science&Technology Committee(2023-BS-032,2021JH2/10300024).
文摘BACKGROUND:The mechanisms underlying hypothermic liver injury necessitate investigation for the development of effective diagnostic and therapeutic approaches.We aim to establish a model of hypothermic liver injury to explore the hepatic alterations,thereby facilitating the prevention and treatment of the liver injury associated with hypothermia.METHODS:The mice were placed in a−20℃ environment,to establish a hypothermic injury model.The liver function,metabolites,and proteins expression were measured by thromboelastography,histopathology,metabolomics and western blotting,respectively.Furthermore,apoptosis and pathway changes in the liver cells conducted with target metabolites were examined and verified.RESULTS:According to the prolonged righting reflex recovery time and death occurrence,the mice with the anal temperature(AT)dropping to 20℃ or 15℃ were used to establish a model of hypothermia.The model mice showed changes in alanine aminotransferase(ALT),aspartate transaminase(AST),and coagulation indicators.HE staining results indicated that liver tissue in the AT 20℃ mice had large hemorrhagic patches,while the AT 15℃ mice displayed significant congestion,along with extensive infiltration of inflammatory cells around the central vein.Metabolomic and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses of target metabolites revealed a significant increase in 3-hydroxybutyric acid and changes in the cyclic adenosine monophosphate(cAMP)signaling pathway in the liver tissue of hypothermic mice.The hypothermic mice showed decreases in levels of cAMP,protein kinase A C-α(PKA C-α),and phosphorylated BCL-2/BCL-XL-associated death promoter(p-Bad)and an increase in BCL-2/BCLXL-associated death promoter(Bad)level in the liver.These protein changes and apoptosis were intensified by 3-hydroxybutyric acid in liver cells.CONCLUSION:Hypothermia may induce apoptosis in the liver cell which may be related to the changes of the cAMP-PKA pathway proteins expression.These findings provide a basis for the treatment of hypothermic injury.
基金supported by the National Nature Science Foundation Project(32202067)the Young Talent Fund of Association for Science and Technology in Shaanxi,China(20230203)。
文摘Morin is a functional flavonoid commonly found in human diet.Compared to being used solely,it is evident that morin can be more effective as a drug adjuvant.However,research on the combined effect and its corresponding mechanism is limited.Here,we found that morin significantly potentiated the inhibitory effects of the natural compound celastrol on the proliferation of lung cancer cells.Morin and celastrol synergistically exhibit marked apoptosis induction in lung cancer cells,accompanied by changes in the abundance of apoptosis-related proteins.Transcriptome analyses revealed that the combination of morin and celastrol had a significant impact on the number of differentially expressed genes in lung cancer cells.Among these genes,BIRC3 was one of the most significantly different ones,which plays a crucial role in the process of tumor resistance to apoptosis.In addition,several genes identified are primarily associated with intracellular signal transduction pathways,specifically the NF-κB signaling pathway.Importantly,the treatment combining morin and celastrol in tumor-bearing mice results in a synergistic effect that significantly suppressed tumor growth.These findings indicate that morin could be a promising functional adjuvant,and the combination of morin and celastrol has potential for the treating lung cancer.
基金supported by the National Natural Science Foundation of China(No.32202963)the Natural Science Foundation of Jiangsu Province(No.BK20220681)+3 种基金the Doctoral Program of Entrepreneurship and Innovation in Jiangsu Province(No.JSSCBS20221625)the Scientific Research Foundation Program of Jiangsu Ocean University(No.KQ22009)the Undergraduate Innovation&Entrepreneurship Training Program of Jiangsu Province,China(No.SY202411641631001)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX2023-112).
文摘Due to the discharge of industrialwastewater,urban domestic sewage,and intensive marine aquaculture tailwater,nitrate(NO_(3)^(−))pollution has emerged as a significant issue in offshore waters.Nitrate pollution affects aquatic life and may interact with other pollutants,leading to comprehensive toxicity.Cadmium(Cd^(2+))is the most widespread metal contaminant,adversely affecting aquatic life in the coastal waters of China.Despite this,few studies have focused on the synergistic toxicity of NO_(3)^(−)and Cd^(2+)in marine organisms.This study conducted a 30-day exposure experiment on marine Japanese flounder(Paralichthys olivaceus)to explore the synergistic toxicity of NO_(3)^(−)and Cd^(2+).Our results demonstrated that the exposure to Cd^(2+)alone induced slight histopathological changes in the liver.However,malformations such as hepatic vacuolar degeneration and sinusoid dilatationwere exacerbated under co-exposure.Moreover,co-exposure induced the downregulation of antioxidants and the upregulation of the product malonaldehyde(MDA)from lipid peroxidation,indicating potent oxidative stress in the liver.The increased mRNA expression of IL-8,TNF-α,and IL-1β,along with the decreased expression level of TGF-β,indicated a synergistic inflammatory response in the organisms.Furthermore,the co-exposure led to an abnormal expression of P53,caspase-3,caspase-9,Bcl-2,and Bax,and disturbed the apoptosis in the liver through TUNEL staining analysis.Overall,our results imply that co-exposure synergistically affects inflammation,redox status,and apoptosis in flounders.Therefore,the findings from this study provide valuable perspectives on the ecological risk assessment of marine teleosts co-exposure to NO_(3)^(−)and Cd^(2+).
