BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence ...BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival.However,the molecular mechanisms underlying that remain unclear.AIM To investigate the role and mechanisms of MXS in ameliorating hepatic injury,steatosis and inflammation.METHODS A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis(NASH)model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes.Liver tissues were collected for western blotting and immunohisto chemistry(IHC)assays.Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining.The serum samples were collected for biochemical assays and NMR-based metabonomics analysis.The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH.RESULTS MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress.The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation,inflammation and hepatic fibrosis in the pathogenesis of NASH.The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis.Mechanistically,we found that MXS protected against NASH by attenuating the sex hormone-related metabolism,especially the metabolism of male hormones.CONCLUSION MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones.Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.展开更多
Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by provi...Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by providing NAD+ precursors and/or intermediates, thus promoting their survival rate and potentially driving uncontrollable proliferation. Here, a synergistic intervention NAD+/NADH homeostasis and mitochondrial metabolism strategy with magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) are developed to address grand challenge of metabolic reprogramming for antitumor bioenergetic therapy. A mitochondrial-targeted cascade amplification nanoplatform ([β-MQ]TRL), triggered by NAD(P)H: quinone oxidoreductase-1 (NQO1), can enable a continuous depletion of cytosol NADH until cell death. The end-product, hydrogen peroxide (H_(2)O_(2)), can be further catalytically converted to higher toxic ·OH in proximity to mitochondria based on [β-MQ]TRL mediated Fenton-like reaction, hijacking tumorigenic energy sources and leading to mitochondrial dysfunction. Additionally, the mild thermal ablation enabled by [β-MQ]TRL further amplifies this cascade reaction to effectively prevent tumor metastasis and recurrence. This synchronous intervention strategy with MRI/PAI establishes unprecedented efficiency in antitumor bioenergetic therapy in vivo, which shows excellent promise for clinical application.展开更多
Cancer is a major threat to human health.Among various treatment methods,precision therapy has received significant attention since the inception,due to its ability to efficiently inhibit tumor growth,while curtailing...Cancer is a major threat to human health.Among various treatment methods,precision therapy has received significant attention since the inception,due to its ability to efficiently inhibit tumor growth,while curtailing common shortcomings from conventional cancer treatment,leading towards enhanced survival rates.Particularly,organelle-targeted strategies enable precise accumulation of therapeutic agents in organelles,locally triggering organelle-mediated cell death signals which can greatly reduce the therapeutic threshold dosage and minimize side-effects.In this review,we comprehensively discuss history and recent advances in targeted therapies on organelles,specifically including nucleus,mitochondria,lysosomes and endoplasmic reticulum,while focusing on organelle structures,organelle-mediated cell death signal pathways,and design guidelines of organelle-targeted nanomedicines based on intervention mechanisms.Furthermore,a perspective on future research and clinical opportunities and potential challenges in precision oncology is presented.Through demonstrating recent developments in organelle-targeted therapies,we believe this article can further stimulate broader interests in multidisciplinary research and technology development for enabling advanced organelle-targeted nanomedicines and their corresponding clinic translations.展开更多
基金Supported by Chongqing Fundamental Research Funds,No.jbky20210001Key Programs of Technological Innovation and Application Development of Chongqing,China,No.cstc2021jscx-dxwtBX0016+2 种基金Natural Science Foundation of Chongqing,No.cstc2021jcyjmsxmX0793Science and Technology Project in Social Livelihood of Bishan District,Chongqing,China,No.BSKJ0078 and No.BSKJ0075Performance Incentive-oriented Project of Chongqing,No.jxjl20220007。
文摘BACKGROUND The modified Xiaoyao San(MXS)formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer,which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival.However,the molecular mechanisms underlying that remain unclear.AIM To investigate the role and mechanisms of MXS in ameliorating hepatic injury,steatosis and inflammation.METHODS A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis(NASH)model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes.Liver tissues were collected for western blotting and immunohisto chemistry(IHC)assays.Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining.The serum samples were collected for biochemical assays and NMR-based metabonomics analysis.The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH.RESULTS MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress.The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation,inflammation and hepatic fibrosis in the pathogenesis of NASH.The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis.Mechanistically,we found that MXS protected against NASH by attenuating the sex hormone-related metabolism,especially the metabolism of male hormones.CONCLUSION MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones.Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.
基金financially supported by the Shanghai 2020 “Science and Technology Innovation Action Plan” Social Development Science and Technology Research Project(No.20dz1203600)the Fundamental Research Funds for the Central Universities,and the Open Funds for Characterization of Tongji University.
文摘Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by providing NAD+ precursors and/or intermediates, thus promoting their survival rate and potentially driving uncontrollable proliferation. Here, a synergistic intervention NAD+/NADH homeostasis and mitochondrial metabolism strategy with magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) are developed to address grand challenge of metabolic reprogramming for antitumor bioenergetic therapy. A mitochondrial-targeted cascade amplification nanoplatform ([β-MQ]TRL), triggered by NAD(P)H: quinone oxidoreductase-1 (NQO1), can enable a continuous depletion of cytosol NADH until cell death. The end-product, hydrogen peroxide (H_(2)O_(2)), can be further catalytically converted to higher toxic ·OH in proximity to mitochondria based on [β-MQ]TRL mediated Fenton-like reaction, hijacking tumorigenic energy sources and leading to mitochondrial dysfunction. Additionally, the mild thermal ablation enabled by [β-MQ]TRL further amplifies this cascade reaction to effectively prevent tumor metastasis and recurrence. This synchronous intervention strategy with MRI/PAI establishes unprecedented efficiency in antitumor bioenergetic therapy in vivo, which shows excellent promise for clinical application.
基金National High Technology Research and Development Program of China(Program863,No.2013AA032202).
文摘Cancer is a major threat to human health.Among various treatment methods,precision therapy has received significant attention since the inception,due to its ability to efficiently inhibit tumor growth,while curtailing common shortcomings from conventional cancer treatment,leading towards enhanced survival rates.Particularly,organelle-targeted strategies enable precise accumulation of therapeutic agents in organelles,locally triggering organelle-mediated cell death signals which can greatly reduce the therapeutic threshold dosage and minimize side-effects.In this review,we comprehensively discuss history and recent advances in targeted therapies on organelles,specifically including nucleus,mitochondria,lysosomes and endoplasmic reticulum,while focusing on organelle structures,organelle-mediated cell death signal pathways,and design guidelines of organelle-targeted nanomedicines based on intervention mechanisms.Furthermore,a perspective on future research and clinical opportunities and potential challenges in precision oncology is presented.Through demonstrating recent developments in organelle-targeted therapies,we believe this article can further stimulate broader interests in multidisciplinary research and technology development for enabling advanced organelle-targeted nanomedicines and their corresponding clinic translations.
