Neurodegenerative disorders are typically“split”based on their hallmark clinical,anatomical,and pathological features,but they can also be“lumped”by a shared feature of impaired mitochondrial biology.This leads us...Neurodegenerative disorders are typically“split”based on their hallmark clinical,anatomical,and pathological features,but they can also be“lumped”by a shared feature of impaired mitochondrial biology.This leads us to present a scientific framework that conceptualizes Alzheimer’s disease(AD),Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and Huntington’s disease(HD)as“metabolic icebergs”comprised of a tip,a bulk,and a base.The visible tip conveys the hallmark neurological symptoms,neurodegenerative regions,and neuronal protein aggregates for each disorder.The hidden bulk depicts impaired mitochondrial biology throughout the body,which is multifaceted and may be subdivided into impaired cellular metabolism,cell-specific mitotypes,and mitochondrial behaviours,functions,activities,and features.The underlying base encompasses environmental factors,especially modern industrial toxins,dietary lifestyles,and cognitive,physical,and psychosocial behaviours,but also accommodates genetic factors specific to familial forms of AD,PD,and ALS,as well as HD.Over years or decades,chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk,which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip.We propose that impaired mitochondrial biology can be repaired and recalibrated by activating“mitohormesis”,which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases.Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of,or suffering with,neurodegenerative disorders.展开更多
Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved...Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.展开更多
Occupational and environmental exposures to industrial chemicals are well known to cause hepatotoxicity and liver injury.However,despite extensive evidence showing that exposure can lead to disease,current research ap...Occupational and environmental exposures to industrial chemicals are well known to cause hepatotoxicity and liver injury.However,despite extensive evidence showing that exposure can lead to disease,current research approaches and regulatory policies fail to address the possibility that subtle changes caused by low level exposure to chemicals may also enhance preexisting conditions.In recent years,the conceptual understanding of the contribution of environmental chemicals to liver disease has progressed significantly.Mitochondria are often target of toxicity of environmental toxicants resulting in multisystem disorders involving different cells,tissues,and organs.Here,we review persistent maladaptive changes to mitochondria in response to environmental toxicant exposure as a mechanism of hepatotoxicity.With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of toxicant-induced liver disease,rational targeted therapy can be developed to better predict risk,as well as to treat or prevent this disease.展开更多
Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats...Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats,e.g.,as from olive oil.In the Mediterranean region the consumption of vegetables is elevated providing a class of compounds,the isothiocyanates(ITCs)as found in the cabbage family.The ITCs have raised great interest for their health benefits over the past few decades.Some of the key ITC compounds,sulforaphane,phenethylisothiocyanate and benzyl isothiocyanate,have been studied in vitro and in vivo and the data support their promise for cancer chemoprevention,as anti-tumor agents,and for chemoprotection of normal tissues and organs.Along with other polyphenolic compounds in the diet,in general,they also possess key anti-inflammatory properties thus satisfying the criteria for compounds that could intervene in cancer initiation and progression.In this review we provide a larger overview of the advantages of including ITCs in the diet as food or as supplements and speculate on what could constitute a valuable therapeutic strategy for improving and sustaining good health and countering cancer disease in humans.展开更多
文摘Neurodegenerative disorders are typically“split”based on their hallmark clinical,anatomical,and pathological features,but they can also be“lumped”by a shared feature of impaired mitochondrial biology.This leads us to present a scientific framework that conceptualizes Alzheimer’s disease(AD),Parkinson’s disease(PD),amyotrophic lateral sclerosis(ALS),and Huntington’s disease(HD)as“metabolic icebergs”comprised of a tip,a bulk,and a base.The visible tip conveys the hallmark neurological symptoms,neurodegenerative regions,and neuronal protein aggregates for each disorder.The hidden bulk depicts impaired mitochondrial biology throughout the body,which is multifaceted and may be subdivided into impaired cellular metabolism,cell-specific mitotypes,and mitochondrial behaviours,functions,activities,and features.The underlying base encompasses environmental factors,especially modern industrial toxins,dietary lifestyles,and cognitive,physical,and psychosocial behaviours,but also accommodates genetic factors specific to familial forms of AD,PD,and ALS,as well as HD.Over years or decades,chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk,which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip.We propose that impaired mitochondrial biology can be repaired and recalibrated by activating“mitohormesis”,which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases.Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of,or suffering with,neurodegenerative disorders.
文摘Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.
基金funded by awards from the National Institutes of Health: K01 DK096042, R03 DK107912, R21 ES031531, P30DK120531 and P20GM113226, USA。
文摘Occupational and environmental exposures to industrial chemicals are well known to cause hepatotoxicity and liver injury.However,despite extensive evidence showing that exposure can lead to disease,current research approaches and regulatory policies fail to address the possibility that subtle changes caused by low level exposure to chemicals may also enhance preexisting conditions.In recent years,the conceptual understanding of the contribution of environmental chemicals to liver disease has progressed significantly.Mitochondria are often target of toxicity of environmental toxicants resulting in multisystem disorders involving different cells,tissues,and organs.Here,we review persistent maladaptive changes to mitochondria in response to environmental toxicant exposure as a mechanism of hepatotoxicity.With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of toxicant-induced liver disease,rational targeted therapy can be developed to better predict risk,as well as to treat or prevent this disease.
文摘Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats,e.g.,as from olive oil.In the Mediterranean region the consumption of vegetables is elevated providing a class of compounds,the isothiocyanates(ITCs)as found in the cabbage family.The ITCs have raised great interest for their health benefits over the past few decades.Some of the key ITC compounds,sulforaphane,phenethylisothiocyanate and benzyl isothiocyanate,have been studied in vitro and in vivo and the data support their promise for cancer chemoprevention,as anti-tumor agents,and for chemoprotection of normal tissues and organs.Along with other polyphenolic compounds in the diet,in general,they also possess key anti-inflammatory properties thus satisfying the criteria for compounds that could intervene in cancer initiation and progression.In this review we provide a larger overview of the advantages of including ITCs in the diet as food or as supplements and speculate on what could constitute a valuable therapeutic strategy for improving and sustaining good health and countering cancer disease in humans.
