Anlotinib,a novel multitarget tyrosine kinase inhibitor,has shown promising results in the management of various carcinomas.This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell car...Anlotinib,a novel multitarget tyrosine kinase inhibitor,has shown promising results in the management of various carcinomas.This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma(OSCC)and the underlying molecular mechanism.A retrospective clinical study revealed that anlotinib improved the median progression-free survival(m PFS)and median overall survival(m OS)of patients with recurrent and metastatic(R/M)OSCC,respectively.Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patientderived xenograft models.Mechanistically,RNA-sequencing identified that oxidative stress,oxidative phosphorylation and AKT/m TOR signaling were involved in anlotinib-treated OSCC cells.Anlotinib upregulated NADPH oxidase 5(NOX5)expression,elevated reactive oxygen species(ROS)production,impaired mitochondrial respiration,and promoted apoptosis.Moreover,anlotinb also inhibited phosphoAkt(p-AKT)expression and elevated p-e IF2αexpression in OSCC cells.NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells.Collectively,we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC.The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/e IF2αpathway.展开更多
The porcine intestinal mucosa require large amounts of energy for nutrient processing and cellular functions and is vulnerable to injury by weaning stress involving bioenergetics failure. The mitochondrial bioenergeti...The porcine intestinal mucosa require large amounts of energy for nutrient processing and cellular functions and is vulnerable to injury by weaning stress involving bioenergetics failure. The mitochondrial bioenergetic measurement in porcine enterocytes have not been defined. The present study was to establish a method to measure mitochondrial respiratory function and profile mitochondrial function of IPEC-J2 using cell mito stress test and glycolysis stress test assay by XF24 extracellular flux analyzer. The optimal seeding density and concentrations of the injection compounds were determined to be 40,000 cells/well as well as 0.5 μ M oligomycin, 1 μM carbonyl cyanide p-trifluoromethoxy-phenylhydrazone(FCCP) and 1 μM rotenone & antimycin A, respectively. The profiles of mitochondrial respiration and glycolysis confirmed that porcine enterocyte preferentially derived much more energy from glutamine than glucose. These results will provide a basis for further study of mitochondrial function and bioenergetics of the porcine small intestine.展开更多
Background:The survival of pancreatic cancer cells,particularly cancer stem cells which are responsible for tumor relapse,depends on mitochondrial function.Mitochondrial transcription factor A(TFAM)is critical for the...Background:The survival of pancreatic cancer cells,particularly cancer stem cells which are responsible for tumor relapse,depends on mitochondrial function.Mitochondrial transcription factor A(TFAM)is critical for the regulation of mitochondrial DNA and thus mitochondrial function.However,the possible involvement of TFAM in pancreatic cancer is unknown.Methods:Human samples were obtained from pancreatic cancers and their adjacent tissues;human pancreatic cell lines were cultured in RPMI1640 medium.TFAM expressions in pancreatic tissues and cultured cells were determined using immunohistochemistry,ELISA,and reverse transcription polymerase chain reaction(RT-PCR).The effect of TFAM on cell growth,migration,colony formation and apoptosis were evaluated.Mitochondrial biogenesis in pancreatic cancer and normal cells were examined.Results:The majority of pancreatic cancer tissues exhibited higher TFAM expression compared to the adjacent counterparts.Consistently,TFAM mRNA and protein levels were higher in pancreatic cancer cell lines than in immortalized normal pancreatic epithelial cells.There was no difference on TFAM level between gemcitabine-sensitive and resistant pancreatic cancer cells.Functional analysis demonstrated that TFAM overexpression activated pancreatic normal and tumor cells whereas TFAM inhibition effectively inhibited the growth of pancreatic cancer cells.TFAM inhibition enhanced gemcitabine’s cytotoxicity and suppressed growth,anchorage-independent colony formation and survival of gemcitabine-resistant pancreatic cancer cells.Mechanistic studies showed that TFAM inhibition resulted in remarkable mitochondrial dysfunction and energy crisis followed by oxidative stress.The basal mitochondrial biogenesis level correlated well with TFAM level in pancreatic cancer cells.Conclusions:TFAM played essential roles in pancreatic cancer via regulating mitochondrial functions which highlighted the therapeutic value of inhibiting TFAM to overcome gemcitabine resistance.展开更多
Prevalence of type 2 diabetes has been increased worldwide following the high incidence of obesity and growing population of aging, which are two conditions for absolute energy excess with accumulation of TAG in the b...Prevalence of type 2 diabetes has been increased worldwide following the high incidence of obesity and growing population of aging, which are two conditions for absolute energy excess with accumulation of TAG in the body and relative energy excess due to reduced energy expense, respectively. It appears that type 2 diabetes is a compensatory mechanism of body to energy excess through urine discharge of glucose.展开更多
基金supported by funding from the National Natural Science Foundation of China(NSFC 81672659)。
文摘Anlotinib,a novel multitarget tyrosine kinase inhibitor,has shown promising results in the management of various carcinomas.This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma(OSCC)and the underlying molecular mechanism.A retrospective clinical study revealed that anlotinib improved the median progression-free survival(m PFS)and median overall survival(m OS)of patients with recurrent and metastatic(R/M)OSCC,respectively.Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patientderived xenograft models.Mechanistically,RNA-sequencing identified that oxidative stress,oxidative phosphorylation and AKT/m TOR signaling were involved in anlotinib-treated OSCC cells.Anlotinib upregulated NADPH oxidase 5(NOX5)expression,elevated reactive oxygen species(ROS)production,impaired mitochondrial respiration,and promoted apoptosis.Moreover,anlotinb also inhibited phosphoAkt(p-AKT)expression and elevated p-e IF2αexpression in OSCC cells.NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells.Collectively,we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC.The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/e IF2αpathway.
基金supported by the National Key Basic Research Program of China (2013CB127302)National Natural Science Foundation of China (31330075, 31372326, 31301988, 31301989)the State Key Laboratory of Animal Nutrition (2004DA125184F1401)
文摘The porcine intestinal mucosa require large amounts of energy for nutrient processing and cellular functions and is vulnerable to injury by weaning stress involving bioenergetics failure. The mitochondrial bioenergetic measurement in porcine enterocytes have not been defined. The present study was to establish a method to measure mitochondrial respiratory function and profile mitochondrial function of IPEC-J2 using cell mito stress test and glycolysis stress test assay by XF24 extracellular flux analyzer. The optimal seeding density and concentrations of the injection compounds were determined to be 40,000 cells/well as well as 0.5 μ M oligomycin, 1 μM carbonyl cyanide p-trifluoromethoxy-phenylhydrazone(FCCP) and 1 μM rotenone & antimycin A, respectively. The profiles of mitochondrial respiration and glycolysis confirmed that porcine enterocyte preferentially derived much more energy from glutamine than glucose. These results will provide a basis for further study of mitochondrial function and bioenergetics of the porcine small intestine.
基金This work was supported by the grant from Science and Technology Project of Hubei Provincial Department of Education(B2020139).
文摘Background:The survival of pancreatic cancer cells,particularly cancer stem cells which are responsible for tumor relapse,depends on mitochondrial function.Mitochondrial transcription factor A(TFAM)is critical for the regulation of mitochondrial DNA and thus mitochondrial function.However,the possible involvement of TFAM in pancreatic cancer is unknown.Methods:Human samples were obtained from pancreatic cancers and their adjacent tissues;human pancreatic cell lines were cultured in RPMI1640 medium.TFAM expressions in pancreatic tissues and cultured cells were determined using immunohistochemistry,ELISA,and reverse transcription polymerase chain reaction(RT-PCR).The effect of TFAM on cell growth,migration,colony formation and apoptosis were evaluated.Mitochondrial biogenesis in pancreatic cancer and normal cells were examined.Results:The majority of pancreatic cancer tissues exhibited higher TFAM expression compared to the adjacent counterparts.Consistently,TFAM mRNA and protein levels were higher in pancreatic cancer cell lines than in immortalized normal pancreatic epithelial cells.There was no difference on TFAM level between gemcitabine-sensitive and resistant pancreatic cancer cells.Functional analysis demonstrated that TFAM overexpression activated pancreatic normal and tumor cells whereas TFAM inhibition effectively inhibited the growth of pancreatic cancer cells.TFAM inhibition enhanced gemcitabine’s cytotoxicity and suppressed growth,anchorage-independent colony formation and survival of gemcitabine-resistant pancreatic cancer cells.Mechanistic studies showed that TFAM inhibition resulted in remarkable mitochondrial dysfunction and energy crisis followed by oxidative stress.The basal mitochondrial biogenesis level correlated well with TFAM level in pancreatic cancer cells.Conclusions:TFAM played essential roles in pancreatic cancer via regulating mitochondrial functions which highlighted the therapeutic value of inhibiting TFAM to overcome gemcitabine resistance.
基金supported by a project(32271220)of the National Science Foundation of China to Jianping Ye.
文摘Prevalence of type 2 diabetes has been increased worldwide following the high incidence of obesity and growing population of aging, which are two conditions for absolute energy excess with accumulation of TAG in the body and relative energy excess due to reduced energy expense, respectively. It appears that type 2 diabetes is a compensatory mechanism of body to energy excess through urine discharge of glucose.