The aberrant use of alcohol is a major factor in cancer progression and metastasis.Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-canc...The aberrant use of alcohol is a major factor in cancer progression and metastasis.Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-cancerous cells along the brain-gut-liver axis.Such interplay leads to changes in molecular,cellular,and biological functions resulting in cancer progression.Recent investigations have examined the role of extracellular vesicles(EVs)in cancer mechanisms in addition to their contribution as diagnostic biomarkers.Also,EVs are emerging as novel cell-free mediators in pathophysiological scenarios including alcohol-mediated gut microbiome dysbiosis and the release of nanosized EVs into the circulatory system.Interestingly,EVs in cancer patients are enriched with oncogenes,miRNA,lipids,and glycoproteins whose delivery into the hepatic microenvironment may be enhanced by the detrimental effects of alcohol.Proof-of-concept studies indicate that alcohol-associated liver disease is impacted by the effects of exosomes,including altered immune responses,reprogramming of stromal cells,and remodeling of the extracellular matrix.Moreover,the culmination of alcoholrelated changes in the liver likely contributes to enhanced hepatic metastases and poor outcomes for cancer patients.This review summarizes the numerous aspects of exosome communications between organs with emphasis on the relationship of EVs in alcohol-associated diseases and cancer metastasis.The potential impact of EV cargo and release along a multi-organ axis is highly relevant to the promotion of tumorigenic mechanisms and metastatic disease.It is hypothesized that EVs target recipient tissues to initiate the formation of prometastatic niches and cancer progression.The study of alcohol-associated mechanisms in metastatic cancers is expected to reveal a better understanding of factors involved in the growth of secondary malignancies as well as novel approaches for therapeutic interventions.展开更多
The heart,an organ with a continuously high demand for energy,inherently lacks substantial reserves.The precise mechanisms that prioritize energy allocation to cardiac mitochondria,ensuring steady-state ATP production...The heart,an organ with a continuously high demand for energy,inherently lacks substantial reserves.The precise mechanisms that prioritize energy allocation to cardiac mitochondria,ensuring steady-state ATP production amidst high-energy organs,remain poorly understood.Our study sheds light on this process by identifying a two-strata flux system driven by the starvation hormone FGF21.We demonstrate that systemic disruptions in interorgan metabolite mobilization and transcardiac flux,arising from either adipose lipolysis or hepatic ketogenesis due to FGF21 deficiency,directly impair cardiac energetic performance.Locally,this impairment is linked to compromised intracardiac utilization of various metabolites via ketolysis and oxidation pathways,along with hindered mitochondrial biogenesis,TCA cycle,ETC flow,and OXPHOS.Consequently,the heart shifts to a hypometabolic,glycolytic,and hypoenergy state,with a reduced capacity to cope with physiological stressors such as fasting,starvation,strenuous exercise,endurance training,and cold exposure,leading to a diminished heart rate,contractility,and hemodynamic stability.Pharmacological or genetic restoration of FGF21 ameliorates these defects,reenergizing stress-exhausted hearts.This hierarchical energy-prioritizing mechanism is orchestrated by the LKB1-AMPK-mTOR energy stress response pathways.Disrupting cardiac LKB1 or mTOR pathways,akin to stalling mitochondrial energy conduits,obstructs the FGF21-governed cardiac energetic potential.Our findings reveal an essential two-strata energy flux system critical for cardiac energetic efficiency regulated by FGF21,which spatiotemporally optimizes interorgan and transcardiac metabolite flux and intracardiac mitochondrial energy sufficiency.This discovery informs the design of strategies for treating cardiac diseases linked to mitochondrial or energy deficiencies.展开更多
Chronic kidney disease(CKD)is a globally prevalent progressive disease characterized by complex interorgan signaling dysregulation.Fibroblast growth factor 23(FGF23)and active vitamin D3(VD3 and 1,25(OH)_(2)D_(3))play...Chronic kidney disease(CKD)is a globally prevalent progressive disease characterized by complex interorgan signaling dysregulation.Fibroblast growth factor 23(FGF23)and active vitamin D3(VD3 and 1,25(OH)_(2)D_(3))play critical roles in calcium-phosphate homeostasis.FGF23 reduces intestinal phosphate absorption by inhibiting 1,25(OH)_(2)D_(3) synthesis,whereas 1,25(OH)_(2)D_(3) negatively regulates FGF23 expression.In patients with CKD,this balance is disrupted,leading to elevated FGF23 levels,reduced 1,25(OH)_(2)D_(3) levels,and exacerbated kidney dysfunction and complications.Since the primary source of VD3 is cutaneous synthesis via ultraviolet B radiation,sunlight exposure can markedly increase VD3 production,subsequently increasing 1,25(OH)_(2)D_(3) levels.This suggests that sunlight therapy may serve as a potential intervention for modulating FGF23 and improving calcium–phosphate metabolism in patients with CKD.This review systematically summarizes the regulatory mechanisms of sunlight on VD3 synthesis,the role of FGF23 in CKD progression,and the potential applications of sunlight therapy in CKD management.Additionally,we discuss the applicability of sunlight therapy across different individuals,its limitations,and potential optimization strategies,providing insights for future research.展开更多
Extend case transfer architecture inter-organization workflow management fits the needs of Collaboration commerce. However, during the third step of extend case transfer architecture, modifications of private workflow...Extend case transfer architecture inter-organization workflow management fits the needs of Collaboration commerce. However, during the third step of extend case transfer architecture, modifications of private workflows might cause some fatal problems, such as dead locks, live locks and dead tasks. These problems could change the soundness and efficiency of overall work flow. This paper presents a Petri net based approach to protect the inheritance of public work flows in private domains, and discusses an implementation of our collaboration commerce work flow model.展开更多
基金by Biomedical Laboratory Research and Development,VA Office of Research and Development,No.BX004127(to McVicker BL and Tobi M).
文摘The aberrant use of alcohol is a major factor in cancer progression and metastasis.Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-cancerous cells along the brain-gut-liver axis.Such interplay leads to changes in molecular,cellular,and biological functions resulting in cancer progression.Recent investigations have examined the role of extracellular vesicles(EVs)in cancer mechanisms in addition to their contribution as diagnostic biomarkers.Also,EVs are emerging as novel cell-free mediators in pathophysiological scenarios including alcohol-mediated gut microbiome dysbiosis and the release of nanosized EVs into the circulatory system.Interestingly,EVs in cancer patients are enriched with oncogenes,miRNA,lipids,and glycoproteins whose delivery into the hepatic microenvironment may be enhanced by the detrimental effects of alcohol.Proof-of-concept studies indicate that alcohol-associated liver disease is impacted by the effects of exosomes,including altered immune responses,reprogramming of stromal cells,and remodeling of the extracellular matrix.Moreover,the culmination of alcoholrelated changes in the liver likely contributes to enhanced hepatic metastases and poor outcomes for cancer patients.This review summarizes the numerous aspects of exosome communications between organs with emphasis on the relationship of EVs in alcohol-associated diseases and cancer metastasis.The potential impact of EV cargo and release along a multi-organ axis is highly relevant to the promotion of tumorigenic mechanisms and metastatic disease.It is hypothesized that EVs target recipient tissues to initiate the formation of prometastatic niches and cancer progression.The study of alcohol-associated mechanisms in metastatic cancers is expected to reveal a better understanding of factors involved in the growth of secondary malignancies as well as novel approaches for therapeutic interventions.
基金funded by Startup Funds from Wenzhou Medical University and The First Affiliated Hospital(to Y.L.)the National Natural Science Foundation of China(U22A20385 to X.L.,92357304 to Z.H.)the Natural Science Foundation of Zhejiang Province(LDQ24H310001 to Z.H.).
文摘The heart,an organ with a continuously high demand for energy,inherently lacks substantial reserves.The precise mechanisms that prioritize energy allocation to cardiac mitochondria,ensuring steady-state ATP production amidst high-energy organs,remain poorly understood.Our study sheds light on this process by identifying a two-strata flux system driven by the starvation hormone FGF21.We demonstrate that systemic disruptions in interorgan metabolite mobilization and transcardiac flux,arising from either adipose lipolysis or hepatic ketogenesis due to FGF21 deficiency,directly impair cardiac energetic performance.Locally,this impairment is linked to compromised intracardiac utilization of various metabolites via ketolysis and oxidation pathways,along with hindered mitochondrial biogenesis,TCA cycle,ETC flow,and OXPHOS.Consequently,the heart shifts to a hypometabolic,glycolytic,and hypoenergy state,with a reduced capacity to cope with physiological stressors such as fasting,starvation,strenuous exercise,endurance training,and cold exposure,leading to a diminished heart rate,contractility,and hemodynamic stability.Pharmacological or genetic restoration of FGF21 ameliorates these defects,reenergizing stress-exhausted hearts.This hierarchical energy-prioritizing mechanism is orchestrated by the LKB1-AMPK-mTOR energy stress response pathways.Disrupting cardiac LKB1 or mTOR pathways,akin to stalling mitochondrial energy conduits,obstructs the FGF21-governed cardiac energetic potential.Our findings reveal an essential two-strata energy flux system critical for cardiac energetic efficiency regulated by FGF21,which spatiotemporally optimizes interorgan and transcardiac metabolite flux and intracardiac mitochondrial energy sufficiency.This discovery informs the design of strategies for treating cardiac diseases linked to mitochondrial or energy deficiencies.
基金financially supported by the National Natural Science Foundation of China(No.22177030).
文摘Chronic kidney disease(CKD)is a globally prevalent progressive disease characterized by complex interorgan signaling dysregulation.Fibroblast growth factor 23(FGF23)and active vitamin D3(VD3 and 1,25(OH)_(2)D_(3))play critical roles in calcium-phosphate homeostasis.FGF23 reduces intestinal phosphate absorption by inhibiting 1,25(OH)_(2)D_(3) synthesis,whereas 1,25(OH)_(2)D_(3) negatively regulates FGF23 expression.In patients with CKD,this balance is disrupted,leading to elevated FGF23 levels,reduced 1,25(OH)_(2)D_(3) levels,and exacerbated kidney dysfunction and complications.Since the primary source of VD3 is cutaneous synthesis via ultraviolet B radiation,sunlight exposure can markedly increase VD3 production,subsequently increasing 1,25(OH)_(2)D_(3) levels.This suggests that sunlight therapy may serve as a potential intervention for modulating FGF23 and improving calcium–phosphate metabolism in patients with CKD.This review systematically summarizes the regulatory mechanisms of sunlight on VD3 synthesis,the role of FGF23 in CKD progression,and the potential applications of sunlight therapy in CKD management.Additionally,we discuss the applicability of sunlight therapy across different individuals,its limitations,and potential optimization strategies,providing insights for future research.
文摘Extend case transfer architecture inter-organization workflow management fits the needs of Collaboration commerce. However, during the third step of extend case transfer architecture, modifications of private workflows might cause some fatal problems, such as dead locks, live locks and dead tasks. These problems could change the soundness and efficiency of overall work flow. This paper presents a Petri net based approach to protect the inheritance of public work flows in private domains, and discusses an implementation of our collaboration commerce work flow model.
