Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without co...Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore,overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment.Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicininduced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice.These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.展开更多
I present herewith a concise historic account of our development of the new technique for cancer therapy: Reversal of Cancer by Dual Strategy. This new method is based on the possible correction of the mitochondrial f...I present herewith a concise historic account of our development of the new technique for cancer therapy: Reversal of Cancer by Dual Strategy. This new method is based on the possible correction of the mitochondrial filamentation defect of tumors plus minor cytotoxicity addressed to the anoxic and fagocitic tumor’s redoubts, using the administration of the anticancer agents with a chrono-therapeutic emphasis on the patient’s mobility. Such methods probably will reach patients in the near future with the collaboration of private clinical trials mainly at least in the USA, Europe and Japan. Only the more essential references of this effort are provided.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
The contribution of the author’s groups on the control of energy metabolism of cancer cells has been concisely reviewed. It is proposed that Otto Warburg’s “respiratory defect” of tumoral cells resides in an alter...The contribution of the author’s groups on the control of energy metabolism of cancer cells has been concisely reviewed. It is proposed that Otto Warburg’s “respiratory defect” of tumoral cells resides in an alteration of the recurrent filamentation cycle of mitochondria. These give those organelles an affinity lower for ADP than the affinity of the tumor cell isoenzyme of pyruvate kinase. These two findings may explain the essentials of the intimate mechanism of the aerobic glycolysis of cancer cells.展开更多
It is well known that malignant cells have accelerated glucose uptake and metabolism in order to maintain their fast proliferation rates. With the increased influx of glucose into cancer cells, glycolysis is facilitat...It is well known that malignant cells have accelerated glucose uptake and metabolism in order to maintain their fast proliferation rates. With the increased influx of glucose into cancer cells, glycolysis is facilitated through a coordinated regulation of metabolic enzymes and pyruvate consumption. Shiftting from mitochondrial oxidative phosphorylation to glycolysis and other pathways such as pentose phosphate pathway (PPP) and de novo fatty acid synthesis in the breast tumor provides not only energy but also the materials needed for cell proliferation. Glucose augmentation in tumor cells can be due to the elevated level of glucose transporter (GLUT) proteins, such as the over-expression of GLUT1 and expression of GLUT5 in breast cancers. Moreover, other factors such as hypoxia-inducible factor-1 (HIF-1), estrogen and growth factors are important modulators of glucose metabolism in the progression of breast carcinomas. Therapies targeting at the glycolytic pathway, fatty acid synthesis and GLUTs expression are currently being investigated. Restoring tumor cells to its normal glucose metabolic state would endow tumor specific and accessible treatment that targets glucose metabolism.展开更多
Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from sa...Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from satisfactory,mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis.Herein,we construct a cancer cell membrane camouflaged nano-inhibitor,mTPPa-Sy nanoparticle(NP),which co-encapsulates OXPHOS inhibitor(mitochondrial-targeting photosensitizers:TPPa)and glycolysis inhibitor(syrosingopine(Sy))for synergistically blocking the two different energy pathways.The mTPPa-Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells.Under laser irradiation,the mitochondrial-targeting TPPa,which is synthesized by conjugating pyropheophorbide a(PPa)with triphenylphosphin,produces excessive reactive oxygen species(ROS)and further disrupts the OXPHOS.Interestingly,OXPHOS inhibition reduces O_(2) consumption and improves ROS production,further constructing a closed-loop OXPHOS inhibition system.Moreover,TPPa-initiated OXPHOS inhibition in combination with the Sytriggered glycolysis inhibition results in lethal energy depletion,significantly suppressing tumor growth even after a single treatment.Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion,providing a prospective strategy for efficient cancer therapy.展开更多
Objective To study the effect of glutamate on metabolism, shifts in glycolysis and lactate release in rat astrocytes. Methods After 10 days, secondary cultured astrocytes were treated with 1 mmol/L glutamate for 1 h, ...Objective To study the effect of glutamate on metabolism, shifts in glycolysis and lactate release in rat astrocytes. Methods After 10 days, secondary cultured astrocytes were treated with 1 mmol/L glutamate for 1 h, and the oxygen consumption rates （OCR） and extra cellular acidification rate （ECAR） was analyzed using a Seahorse XF 24 Extracellular Flux Analyzer. Cell viability was then evaluated by MTT assay. Moreover, changes in extracellular lactate concentration induced by glutamate were tested with a lactate detection kit. Results Compared with the control group, treatment with 1 mmol/L glutamate decreased the astrocytes’ maximal respiration and spare respiratory capacity but increased their glycolytic capacity and glycolytic reserve. Further analysis found that 1-h treatment with different concentrations of glutamate （0.1-1 mmol/L） increased lactate release from astrocytes, however the cell viability was not affected by the glutamate treatment. Conclusion The current study provided direct evidence that exogenous glutamate treatment impaired the mitochondrial respiration capacity of astrocytes and enhanced aerobic glycolysis, which could be involved in glutamate injury or protection mechanisms in response to neurological disorders.展开更多
目的探讨线粒体动力相关蛋白1(dynamic-related protein 1,DRP1)在肝癌细胞糖代谢重编程中的作用。方法(1)siRNA下调肝癌细胞SNU-739中DRP1表达后,检测对肝癌细胞葡萄糖摄取与乳酸产生的影响,以明确DRP1对肝癌细胞糖酵解的调控作用。(2)...目的探讨线粒体动力相关蛋白1(dynamic-related protein 1,DRP1)在肝癌细胞糖代谢重编程中的作用。方法(1)siRNA下调肝癌细胞SNU-739中DRP1表达后,检测对肝癌细胞葡萄糖摄取与乳酸产生的影响,以明确DRP1对肝癌细胞糖酵解的调控作用。(2)siRNA下调肝癌细胞SNU-739中DRP1表达后,检测对肝癌细胞氧耗速率与ATP产生的影响,以明确DRP1对肝癌细胞氧化磷酸化的调控作用。(3)siRNA下调肝癌细胞SNU-739中DRP1表达后,利用质谱检测对糖酵解与线粒体三羧酸循环代谢产物的影响。结果(1)下调DRP1可显著抑制肝癌SNU-739细胞的葡萄糖摄取(siCtrl:si-DRP1#1:si-DRP1#2=1.000±0.069:0.417±0.032:0.400±0.040;F=141.400,P<0.001)与乳酸产生(siCtrl:si-DRP1#1:si-DRP1#2=1.000±0.050:0.327±0.040:0.310±0.036;F=256.700,P<0.001)。(2)下调DRP1可激活肝癌SNU-739细胞的氧耗速率(siCtrl:si-DRP1#1:si-DRP1#2=1.000±0.069:1.623±0.081:1.591±0.046;F=81.720,P<0.001)与ATP产生(siCtrl:si-DRP1#1:si-DRP1#2=1.000±0.062:1.813±0.093:1.850±0.070;F=119.200,P<0.001)。(3)下调DRP1后,肝癌SNU-739细胞中糖酵解中间产物葡萄糖、丙酮酸与乳酸的水平均显著降低(均P<0.001),而三羧酸循环关键产物柠檬酸、延胡索酸与苹果酸的水平均显著升高(均P<0.001)。结论线粒体动力相关蛋白DRP1通过激活糖酵解并抑制氧化磷酸化而促进肝癌细胞的糖代谢重编程。展开更多
基金supported by the National Natural Science Foundation of China (81871095 and 82170873)the National Key R&D Program of China (2018YFC2000304)+1 种基金the Tsinghua Precision Medicine Foundation (10001020132, China)the Tsinghua University Spring Breeze Fund (20211080005, China)。
文摘Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore,overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment.Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicininduced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice.These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.
文摘I present herewith a concise historic account of our development of the new technique for cancer therapy: Reversal of Cancer by Dual Strategy. This new method is based on the possible correction of the mitochondrial filamentation defect of tumors plus minor cytotoxicity addressed to the anoxic and fagocitic tumor’s redoubts, using the administration of the anticancer agents with a chrono-therapeutic emphasis on the patient’s mobility. Such methods probably will reach patients in the near future with the collaboration of private clinical trials mainly at least in the USA, Europe and Japan. Only the more essential references of this effort are provided.
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.
文摘The contribution of the author’s groups on the control of energy metabolism of cancer cells has been concisely reviewed. It is proposed that Otto Warburg’s “respiratory defect” of tumoral cells resides in an alteration of the recurrent filamentation cycle of mitochondria. These give those organelles an affinity lower for ADP than the affinity of the tumor cell isoenzyme of pyruvate kinase. These two findings may explain the essentials of the intimate mechanism of the aerobic glycolysis of cancer cells.
文摘It is well known that malignant cells have accelerated glucose uptake and metabolism in order to maintain their fast proliferation rates. With the increased influx of glucose into cancer cells, glycolysis is facilitated through a coordinated regulation of metabolic enzymes and pyruvate consumption. Shiftting from mitochondrial oxidative phosphorylation to glycolysis and other pathways such as pentose phosphate pathway (PPP) and de novo fatty acid synthesis in the breast tumor provides not only energy but also the materials needed for cell proliferation. Glucose augmentation in tumor cells can be due to the elevated level of glucose transporter (GLUT) proteins, such as the over-expression of GLUT1 and expression of GLUT5 in breast cancers. Moreover, other factors such as hypoxia-inducible factor-1 (HIF-1), estrogen and growth factors are important modulators of glucose metabolism in the progression of breast carcinomas. Therapies targeting at the glycolytic pathway, fatty acid synthesis and GLUTs expression are currently being investigated. Restoring tumor cells to its normal glucose metabolic state would endow tumor specific and accessible treatment that targets glucose metabolism.
基金This work was financially supported by National Natural Science Foundation of China(No.81773656)Liaoning Revitalization Talents Program(No.XLYC1808017)+1 种基金Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454)National Postdoctoral Foundation of China(No.2021M693868).
文摘Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from satisfactory,mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis.Herein,we construct a cancer cell membrane camouflaged nano-inhibitor,mTPPa-Sy nanoparticle(NP),which co-encapsulates OXPHOS inhibitor(mitochondrial-targeting photosensitizers:TPPa)and glycolysis inhibitor(syrosingopine(Sy))for synergistically blocking the two different energy pathways.The mTPPa-Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells.Under laser irradiation,the mitochondrial-targeting TPPa,which is synthesized by conjugating pyropheophorbide a(PPa)with triphenylphosphin,produces excessive reactive oxygen species(ROS)and further disrupts the OXPHOS.Interestingly,OXPHOS inhibition reduces O_(2) consumption and improves ROS production,further constructing a closed-loop OXPHOS inhibition system.Moreover,TPPa-initiated OXPHOS inhibition in combination with the Sytriggered glycolysis inhibition results in lethal energy depletion,significantly suppressing tumor growth even after a single treatment.Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion,providing a prospective strategy for efficient cancer therapy.
基金supported by the National Natural Science Foundation of China,No.81271286Beijing Natural Science Foundation,No.7152027 to YUAN FangInnovation Foundation of Beijing Neurosurgical Institute,No.2014-11 to YAN Xu
文摘Objective To study the effect of glutamate on metabolism, shifts in glycolysis and lactate release in rat astrocytes. Methods After 10 days, secondary cultured astrocytes were treated with 1 mmol/L glutamate for 1 h, and the oxygen consumption rates （OCR） and extra cellular acidification rate （ECAR） was analyzed using a Seahorse XF 24 Extracellular Flux Analyzer. Cell viability was then evaluated by MTT assay. Moreover, changes in extracellular lactate concentration induced by glutamate were tested with a lactate detection kit. Results Compared with the control group, treatment with 1 mmol/L glutamate decreased the astrocytes’ maximal respiration and spare respiratory capacity but increased their glycolytic capacity and glycolytic reserve. Further analysis found that 1-h treatment with different concentrations of glutamate （0.1-1 mmol/L） increased lactate release from astrocytes, however the cell viability was not affected by the glutamate treatment. Conclusion The current study provided direct evidence that exogenous glutamate treatment impaired the mitochondrial respiration capacity of astrocytes and enhanced aerobic glycolysis, which could be involved in glutamate injury or protection mechanisms in response to neurological disorders.
文摘目的探讨线粒体动力相关蛋白1(dynamic-related protein 1,DRP1)在肝癌细胞糖代谢重编程中的作用。方法(1)siRNA下调肝癌细胞SNU-739中DRP1表达后,检测对肝癌细胞葡萄糖摄取与乳酸产生的影响,以明确DRP1对肝癌细胞糖酵解的调控作用。(2)siRNA下调肝癌细胞SNU-739中DRP1表达后,检测对肝癌细胞氧耗速率与ATP产生的影响,以明确DRP1对肝癌细胞氧化磷酸化的调控作用。(3)siRNA下调肝癌细胞SNU-739中DRP1表达后,利用质谱检测对糖酵解与线粒体三羧酸循环代谢产物的影响。结果(1)下调DRP1可显著抑制肝癌SNU-739细胞的葡萄糖摄取(siCtrl:si-DRP1#1:si-DRP1#2=1.000±0.069:0.417±0.032:0.400±0.040;F=141.400,P<0.001)与乳酸产生(siCtrl:si-DRP1#1:si-DRP1#2=1.000±0.050:0.327±0.040:0.310±0.036;F=256.700,P<0.001)。(2)下调DRP1可激活肝癌SNU-739细胞的氧耗速率(siCtrl:si-DRP1#1:si-DRP1#2=1.000±0.069:1.623±0.081:1.591±0.046;F=81.720,P<0.001)与ATP产生(siCtrl:si-DRP1#1:si-DRP1#2=1.000±0.062:1.813±0.093:1.850±0.070;F=119.200,P<0.001)。(3)下调DRP1后,肝癌SNU-739细胞中糖酵解中间产物葡萄糖、丙酮酸与乳酸的水平均显著降低(均P<0.001),而三羧酸循环关键产物柠檬酸、延胡索酸与苹果酸的水平均显著升高(均P<0.001)。结论线粒体动力相关蛋白DRP1通过激活糖酵解并抑制氧化磷酸化而促进肝癌细胞的糖代谢重编程。
