The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the th...The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment(TME).In this study,we constructed a manganese-based nano drug delivery system(NDDS)loaded with hydroxychloroquine(HCQ)for synergistic autophagy inhibition and STING activation-based immunotherapy.Hyaluronic acid(HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis.Subsequently,it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn^(2+)and HCQ simultaneously.As a kind of STING agonist,Mn^(2+)can bind to cGAS in tumor cells,activating the cGAS-STING pathway and generating typeⅠ-interferons(IFN-Ⅰ),which helped alleviate the immunosuppressive TME.Meanwhile,HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation,further sensitizing the cGAS-STING signal.Benefiting from this synergistic mechanism,HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment.Moreover,HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis.This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy.展开更多
Worldwide prevalence of diabetes mellitus has become an issue of great concern in current decades. This life threatening disease is associated with worsening of glycemic control and progressive metabolic dysfunctions....Worldwide prevalence of diabetes mellitus has become an issue of great concern in current decades. This life threatening disease is associated with worsening of glycemic control and progressive metabolic dysfunctions. Objective: Current study aimed to investigate the effect of hydroxychloroquine (HCQ) as an adjunct to glibenclamide or metformin on glycemic control in alloxan induced diabetic rats. Methods: HCQ was combined separately with two conventional anti-diabetic drugs;glibenclamide and metformin. At first, alloxan (120 mg/kg) induced diabetic rats were treated with single dose of metformin (850 mg/70 kg BW), glibenclamide (10 mg/70 kg BW) and HCQ (300 mg/70 kg BW) intraperitoneally once daily for two weeks. Then non fixed dose combinations of glibenclamide (5 mg/70 kg BW) with HCQ (150 mg/70 kg BW) and metformin (425 mg/70 kg BW) with HCQ (150 mg/70 kg BW) were injected along with those of the three drugs alone once daily for four weeks. Results: In alloxan induced diabetic rats, glibenclamide, metformin and their combination therapies reduced blood glucose level significantly but combination therapies are the most effective. Glibenclamide or metformin in combination with HCQ also significantly (P < 0.05) reduced the elevated levels of total cholesterol, triglycerides, and low density lipoprotein cholesterol (LDL-C) level and increased high density lipoprotein cholesterol (HDL-C) level. Moreover, HCQ potentiates the liver glycogen synthesis of metformin or glibenclamide. Conclusion: Outcomes of this investigation indicate that combination of glibenclamide or metformin with HCQ improves glycemic control and provides additional metabolic benefits, not achieved with either glibenclamide or metformin alone.展开更多
Burkina Faso is a malaria-endemic country, with a high incidence of G6PD deficiency (G6PDd), which recorded its first case of COVID-19 in March 2020. G6PDd leads to a decrease in the efficiency of erythrocytes to comb...Burkina Faso is a malaria-endemic country, with a high incidence of G6PD deficiency (G6PDd), which recorded its first case of COVID-19 in March 2020. G6PDd leads to a decrease in the efficiency of erythrocytes to combat oxidative stress, while SARS-CoV-2 infection induces massive production of Reactive Oxygen Species (ROS) in patients. In the present review, we discuss a possible link between G6PDd and SARS-CoV-2 infection. The mean prevalence of G6PDd in Burkina Faso is estimated at 16.6% among males and 6.5% among females. A total of 21,128 cases of COVID-19 have been recorded in Burkina Faso with 387 deaths reported (with a mortality rate of 1.15% among diagnosed cases) as of August 30, 2022. To our knowledge, no association study between G6PDd and SARS-CoV-2 infection has been conducted to date in Burkina Faso. However, several case reports around the world have described elevated risks of hemolysis and thrombosis, and other complications among G6PD-deficient patients infected with SARS-CoV-2. The use of Hydroxychloroquine (HCQ) has also been deemed unsafe by some authors for the treatment of COVID-19 among patients with G6PDd. Although HCQ has been shown to be well tolerated in COVID-19 patients in Burkina Faso, the drug could induce hemolytic crises in people with G6PD deficiency. G6PD is important in regulating ROS and maintaining erythrocyte homeostasis. In view of its high prevalence in Burkina Faso, determination of the G6PD status is required in COVID-19 patients for adequate management such as identifying a subset of COVID-19 patients for whom close monitoring and supportive care may be essential and to restrict treatment with HCQ.展开更多
Objective To investigate the mechanism of benzyl isothiocyanate(BITC)in the treatment of anaplastic thyroid cancer(ATC).Methods Using network pharmacological analysis,key targets of BITC and ATC were screened,followed...Objective To investigate the mechanism of benzyl isothiocyanate(BITC)in the treatment of anaplastic thyroid cancer(ATC).Methods Using network pharmacological analysis,key targets of BITC and ATC were screened,followed by CO and KEGG enrichment analysis.In order to validate the findings,AutoDock software was used to dock BITC and ATC key targets.BITC was applied to two ATC cell lines(8505C and CAL-62).Flow cytometry was used to analyze cell apoptosis.Autophagy inhibitors hydroxychloroquine sulfate(HCQ)and 3-methyladenine(3MA)were used in combination with BITC.Real-time quantitative PCR was conducted to detect the gene level of LC3B,while Western blotting was utilized to examine the expression of NF-kB,LC3B I,Beclin-1,and Bcl-2.In animal experiments,a mouse tumor model was constructed using CAL-62 cells,treated with intraperitoneal injections of BITC(100 mg/kg)and normal saline respectively,administered every other day for a total of 21 days.Immunoblotting of tumor tissue was performed to detect the expression of LC3B II,Bcl-2,Beclin-1,and NFkB.Results A total of 10 key targets with binding energies≤-4.0 kcal/mol were identified.KECG analysis showed that these genes are mainly involved in NF-kB signaling pathway and apoptosis.BITC inhibited ATC cells with IC50 values of 27.56μmol/L for 8505C and 28.30μmol/L for CAL-62.The expression levels of NF-kB,Beclin-1,and Bcl-2 decreased,while LC3B I and LC3B gene expression increased.Combining 3MA with BITC enhanced cell inhibition LC3B II expression.HCQ increased LC3B II expression without enhancing cell and viability inhibition.In the mouse tumor model,compared to the control group,the treatment group had higher LC3B II and lower Bcl-2,Beclin-1,and NF-kB levels.Conclusion BITC could inhibit the growth of ATC cells in vitro and in vivo,disrupt the autophagy degradation,and inhibit the NF-kB pathway.展开更多
Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT....Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82172719,82102918)Joint Funds of Henan Province Foundation for Science and Technology(No.232301420011).
文摘The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment(TME).In this study,we constructed a manganese-based nano drug delivery system(NDDS)loaded with hydroxychloroquine(HCQ)for synergistic autophagy inhibition and STING activation-based immunotherapy.Hyaluronic acid(HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis.Subsequently,it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn^(2+)and HCQ simultaneously.As a kind of STING agonist,Mn^(2+)can bind to cGAS in tumor cells,activating the cGAS-STING pathway and generating typeⅠ-interferons(IFN-Ⅰ),which helped alleviate the immunosuppressive TME.Meanwhile,HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation,further sensitizing the cGAS-STING signal.Benefiting from this synergistic mechanism,HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment.Moreover,HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis.This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy.
文摘Worldwide prevalence of diabetes mellitus has become an issue of great concern in current decades. This life threatening disease is associated with worsening of glycemic control and progressive metabolic dysfunctions. Objective: Current study aimed to investigate the effect of hydroxychloroquine (HCQ) as an adjunct to glibenclamide or metformin on glycemic control in alloxan induced diabetic rats. Methods: HCQ was combined separately with two conventional anti-diabetic drugs;glibenclamide and metformin. At first, alloxan (120 mg/kg) induced diabetic rats were treated with single dose of metformin (850 mg/70 kg BW), glibenclamide (10 mg/70 kg BW) and HCQ (300 mg/70 kg BW) intraperitoneally once daily for two weeks. Then non fixed dose combinations of glibenclamide (5 mg/70 kg BW) with HCQ (150 mg/70 kg BW) and metformin (425 mg/70 kg BW) with HCQ (150 mg/70 kg BW) were injected along with those of the three drugs alone once daily for four weeks. Results: In alloxan induced diabetic rats, glibenclamide, metformin and their combination therapies reduced blood glucose level significantly but combination therapies are the most effective. Glibenclamide or metformin in combination with HCQ also significantly (P < 0.05) reduced the elevated levels of total cholesterol, triglycerides, and low density lipoprotein cholesterol (LDL-C) level and increased high density lipoprotein cholesterol (HDL-C) level. Moreover, HCQ potentiates the liver glycogen synthesis of metformin or glibenclamide. Conclusion: Outcomes of this investigation indicate that combination of glibenclamide or metformin with HCQ improves glycemic control and provides additional metabolic benefits, not achieved with either glibenclamide or metformin alone.
文摘Burkina Faso is a malaria-endemic country, with a high incidence of G6PD deficiency (G6PDd), which recorded its first case of COVID-19 in March 2020. G6PDd leads to a decrease in the efficiency of erythrocytes to combat oxidative stress, while SARS-CoV-2 infection induces massive production of Reactive Oxygen Species (ROS) in patients. In the present review, we discuss a possible link between G6PDd and SARS-CoV-2 infection. The mean prevalence of G6PDd in Burkina Faso is estimated at 16.6% among males and 6.5% among females. A total of 21,128 cases of COVID-19 have been recorded in Burkina Faso with 387 deaths reported (with a mortality rate of 1.15% among diagnosed cases) as of August 30, 2022. To our knowledge, no association study between G6PDd and SARS-CoV-2 infection has been conducted to date in Burkina Faso. However, several case reports around the world have described elevated risks of hemolysis and thrombosis, and other complications among G6PD-deficient patients infected with SARS-CoV-2. The use of Hydroxychloroquine (HCQ) has also been deemed unsafe by some authors for the treatment of COVID-19 among patients with G6PDd. Although HCQ has been shown to be well tolerated in COVID-19 patients in Burkina Faso, the drug could induce hemolytic crises in people with G6PD deficiency. G6PD is important in regulating ROS and maintaining erythrocyte homeostasis. In view of its high prevalence in Burkina Faso, determination of the G6PD status is required in COVID-19 patients for adequate management such as identifying a subset of COVID-19 patients for whom close monitoring and supportive care may be essential and to restrict treatment with HCQ.
文摘Objective To investigate the mechanism of benzyl isothiocyanate(BITC)in the treatment of anaplastic thyroid cancer(ATC).Methods Using network pharmacological analysis,key targets of BITC and ATC were screened,followed by CO and KEGG enrichment analysis.In order to validate the findings,AutoDock software was used to dock BITC and ATC key targets.BITC was applied to two ATC cell lines(8505C and CAL-62).Flow cytometry was used to analyze cell apoptosis.Autophagy inhibitors hydroxychloroquine sulfate(HCQ)and 3-methyladenine(3MA)were used in combination with BITC.Real-time quantitative PCR was conducted to detect the gene level of LC3B,while Western blotting was utilized to examine the expression of NF-kB,LC3B I,Beclin-1,and Bcl-2.In animal experiments,a mouse tumor model was constructed using CAL-62 cells,treated with intraperitoneal injections of BITC(100 mg/kg)and normal saline respectively,administered every other day for a total of 21 days.Immunoblotting of tumor tissue was performed to detect the expression of LC3B II,Bcl-2,Beclin-1,and NFkB.Results A total of 10 key targets with binding energies≤-4.0 kcal/mol were identified.KECG analysis showed that these genes are mainly involved in NF-kB signaling pathway and apoptosis.BITC inhibited ATC cells with IC50 values of 27.56μmol/L for 8505C and 28.30μmol/L for CAL-62.The expression levels of NF-kB,Beclin-1,and Bcl-2 decreased,while LC3B I and LC3B gene expression increased.Combining 3MA with BITC enhanced cell inhibition LC3B II expression.HCQ increased LC3B II expression without enhancing cell and viability inhibition.In the mouse tumor model,compared to the control group,the treatment group had higher LC3B II and lower Bcl-2,Beclin-1,and NF-kB levels.Conclusion BITC could inhibit the growth of ATC cells in vitro and in vivo,disrupt the autophagy degradation,and inhibit the NF-kB pathway.
基金This work was supported by the National Natural Science Foundation of China(Nos.82102918,81972893 and 82172719)the Key Program for Science and Technology Research in Henan Province(No.232102311093,China)the Training Plan for Young Backbone Teachers in Higher Education Institutions of Henan Province(No.2021ZDGGJS054,China).
文摘Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.
