Aging,mitochondria,and neurodegenerative diseases:Aging is often viewed as the buildup of changes that lead to the gradual transformations associated with getting older,along with a rising likelihood of disease and mo...Aging,mitochondria,and neurodegenerative diseases:Aging is often viewed as the buildup of changes that lead to the gradual transformations associated with getting older,along with a rising likelihood of disease and mortality.Although organis m-wide deterioration is observed during aging,organs with high metabolic demand,such as the brain,are more vulnerable.展开更多
Mitochondria are central regulators of cellular energy metabolism,redox balance,and survival,and their dysfunction contributes to neurodegenerative,cardiovascular,and metabolic diseases,as well as aging.Beyond its rol...Mitochondria are central regulators of cellular energy metabolism,redox balance,and survival,and their dysfunction contributes to neurodegenerative,cardiovascular,and metabolic diseases,as well as aging.Beyond its role as a circadian hormone,melatonin is now recognized as a key modulator of mitochondrial physiology.This review provides an overview of the mechanisms by which melatonin can preserve mitochondrial function through multifaceted mechanisms.Experimental evidence shows that melatonin enhances the activity of electron transport chain(ETC)complexes,stabilizes the mitochondrial membrane potential(Δψ),and prevents cardiolipin(CL)peroxidation,thereby limiting permeability transition pore(mPTP)opening and cytochrome c release.Through its direct radical scavenging capacity and the upregulation of mitochondrial antioxidant defenses,melatonin protects against oxidative stress(OS)and preserves mitochondrial DNA integrity.Melatonin also regulates mitochondrial dynamics by promoting fusion,restraining excessive fission,and supporting quality control mechanisms such as mitophagy,unfolded protein response(UPR),and proteostasis.Moreover,melatonin influences mitochondrial biogenesis and intercellular communication through tunneling nanotubes(TNTs)and mitokine signaling.Thus,melatonin may represent a promising multifaceted therapeutic strategy for preserving mitochondrial homeostasis in a range of pathological conditions,including neurodegeneration and cardiovascular and metabolic diseases.However,a significant translational gap still remains between the promising preclinical data and the established clinical practice.Therefore,the aim of this review is to provide a comprehensive synthesis of current knowledge on the mechanisms through which melatonin modulates mitochondrial function and to discuss its potential therapeutic implications in neurodegenerative,cardiovascular,and metabolic diseases.展开更多
The development of cancer cell resistance to conventional treatments continues to be a major obstacle in the successful treatment of tumors of many types.The discovery of a highly efficient direct and indirect free ra...The development of cancer cell resistance to conventional treatments continues to be a major obstacle in the successful treatment of tumors of many types.The discovery of a highly efficient direct and indirect free radical scavenger,melatonin,in the mitochondrial matrix may be a factor in determining both the occurrence of cancer cell drug insensitivity as well as radioresistance.This relates to two of the known hallmarks of cancer,i.e.,exaggerated free radical generation in the mitochondria and the development ofWarburg type metabolism(glycolysis).The hypothesis elaborated in this report assumes that the high oxidative environment in the mitochondria contributes to a depression of local melatonin levels because of its overuse in neutralizing the massive amount of free radial produced.Moreover,Warburg typemetabolism and chemoresistance are functionally linked and supplementalmelatonin has been shown to reverse glycolysis and convert glucose processing to the type that occurs in normal cells.Since thismetabolic type is a key factor in determining chemoresistance,melatonin would predictably also negate cancer drug insensitivity.The possible mechanisms by which melatonin may interfere either directly or indirectly with drug resistance are summarized in the current review.展开更多
Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative...Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative stress,and causes pro-inflammatory cytokine release,creating a neurotoxic environment.In this context,we explore the intricate connection between hypertension,neuroinflammation,and neurodegeneration,as well as how hypertension interacts with other metabolic disorders,such as obesity and diabetes,to further worsen neuroinflammation.Additionally,we discuss the role of the reninangiotensin-aldosterone system,the impact of the microbiome,and the potential contribution of chronic infections in exacerbating neuroinflammation.It is essential to emphasize the potential of nanotechnology to transform therapeutic approaches.Nanoparticle-based drug delivery systems can enhance the bioavailability and selectivity of antihypertensive drugs,antioxidants,and neuroprotective compounds,enabling targeted delivery across the BBB.By combining effective blood pressure management with nanotechnology-enabled therapies that modulate inflammation,oxidative stress,and protein aggregation,we can explore new avenues for preventing and treating hypertension and metabolic disorder-associated neurodegenerative conditions.Ultimately,hypertension significantly contributes to neuroinflammation and neurodegeneration by promoting neuronal cell death,primarily through impaired cerebral blood flow and disruption of the BBB.The interaction of hypertension with metabolic disorders exacerbates these effects.However,advancements in our understanding and new technologies reveal promising nanopharmacological approaches for targeted drug delivery to the brain,thereby improving treatment outcomes,enhancing adherence,and reducing side effects.展开更多
Neurodegenerative diseases(NDs)such as Alzheimer’s disease(AD),Parkinson’s disease(PD),Huntington’s disease(HD),and amyotrophic lateral sclerosis(ALS)are characterized by progressive neuronal loss,which is closely ...Neurodegenerative diseases(NDs)such as Alzheimer’s disease(AD),Parkinson’s disease(PD),Huntington’s disease(HD),and amyotrophic lateral sclerosis(ALS)are characterized by progressive neuronal loss,which is closely linked to mitochondrial dysfunction.These pathologies involve a complex interplay of genetics,protein misfolding,and cellular stress,culminating in impaired energy metabolism,an increase in reactive oxygen species(ROS),and defective mitochondrial quality control.The accumulation of damaged mitochondria and dysregulation of pathways such as the Integrated Stress Response(ISR)are central to the pathogenesis of these conditions.This review explores the critical relationship between mitochondrial stress and neurodegeneration,highlighting the molecular mechanisms and biomarkers involved.It delves into the multifaceted role of melatonin as a potent neuroprotective agent.Melatonin,a lipophilic indoleamine,is produced both in the pineal gland and locally within mitochondria,where it exerts powerful antioxidant,anti-inflammatory,and anti-apoptotic effects.Its unique ability to neutralize multiple free radicals and its cascade-based antioxidant action make it superior to conventional antioxidants.Its mechanisms of action are discussed,including signaling pathway modulation and enhancement of the brain’s clearance system(the glymphatic system).Despite its potential,melatonin’s low bioavailability and rapid metabolism limit its therapeutic efficacy.In this context,nanopharmacology emerges as a promising strategy.Nanoparticles such as liposomes,polymers,and solid lipids can encapsulate melatonin and protect it from degradation,facilitating its transport across the blood-brain barrier.Preclinical evidence has shown that melatonin-loaded nanoparticles significantly improve cognitive function,reduce oxidative stress,and restore mitochondrial homeostasis in models of AD,PD,and ALS.In conclusion,the synergistic combination of melatonin and nanopharmacology offers a multimodal and highly targeted approach formitigatingmitochondrial dysfunction in NDs.While challenges remain in optimizing the formulation and safety of these nanocarriers,this combination represents a crucial frontier for developing more effective and specific treatments in the future.展开更多
The interplay between mitochondria,epigenetics,and the microbiota is intricately linked to both health and disease.Within our cells,a complex molecular dance occurs,where these components intertwine in a mesmerizing b...The interplay between mitochondria,epigenetics,and the microbiota is intricately linked to both health and disease.Within our cells,a complex molecular dance occurs,where these components intertwine in a mesmerizing ballet that plays a decisive role in our health.Mitochondria,beyond being energy powerhouses,modulate nuclear gene expression through messengers like reactive oxidative stress(ROS)and calcium.Epigenetics,acting as the molecular conductor,regulates the expression of both nuclear and mitochondrial genes through modifications like DNA methylation.The intestinal microbiota itself produces short-chain fatty acids(SCFAs)that influence mitochondrial activity.SCFA-induced epigenetic modifications,like histone acetylation,impact mitochondrial function which may lead to disease.Mitochondrial dysfunction generates retrograde signals that alter nuclear gene expression,as evidenced by increased histone H3 lysine 27 acetylation(H3K27ac)in genes essential for neuronal differentiation and mitochondrial reprogramming.Alterations in the mitochondrial-nuclear-microbiota axis are associated with diseases including diabetes,neurodegeneration,and cancer.Modulating the intestinal microbiota with probiotics or prebiotics can restore balance while intervening in mitochondrial pathways,which can be a therapeutic strategy.Additionally,using epigenetic agents like histone deacetylase(HDAC)inhibitors can reprogram gene expression and improve mitochondrial function.Finally,the present review aims to explore the central interplay between mitochondria,epigenetics modifications,and microbiota in a complex and dynamic molecular context that plays a fundamental role in human health.Specifically,it will examine the impact of microbiome components and metabolites generated from normobiosis and dysbiosis on mitochondria and epigenetic modifications across different diseases and metabolic conditions.This integrated understanding of the molecular players and their interactions provides a deeper perspective on how to promote health and potentially combat disease.展开更多
The ancestral cultures have described many therapeutic properties of garlic,therefore,it is of central interest to elucidate the molecular basis explaining this millenary empirical knowledge.Indeed,it has been demonst...The ancestral cultures have described many therapeutic properties of garlic,therefore,it is of central interest to elucidate the molecular basis explaining this millenary empirical knowledge.Indeed,it has been demonstrated a neuroprotective effect of allicin–a phytochemical present in garlic-linked to oxidative-inflammatory modulation.Allicin improved neuronal injury by heat shock protein 70(Hsp70)and inducible nitric oxide synthase(iNOS)regulation.Also,allicin exerts renal protection involving a possible angiotensin type 1 receptor(AT1)interaction.In connection,AT1 overexpression has been recognized as a central deleterious factor in many brain diseases.However,there are no studies that evaluate AT1-Hsp70-iNOS interaction as a mechanism linked to neuroinflammation.Thus,our central aim is to evaluate if the allicin protective effect is associated with an AT1-Hsp70-iNOS counterbalance axis.For this study,a murine microglial cell line(BV-2)was injured with lipopolysaccharides and treated or not with allicin.Then,it was evaluated cell viability,proinflammatory cytokine levels,cellular oxidative stress,iNOS,Hsp70,and AT1 protein expression(cellular and mitochondrial fractions),nitrite levels,and protein-protein interactions.The results demonstrated that allicin could prevent neuronal injury due to a reduction in oxidative stress and inflammatory status mediated by an AT1-Hsp70-iNOS counterbalance axis linked to direct protein-protein interaction.展开更多
Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and infl...Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and inflammation.Angiotensin II,the main mediator of the renin-angiotensin-aldosterone system,also contributes to CVD by promoting ROS production.Reduced activity of sirtuins(SIRTs),a family of proteins that regulate cellular metabolism,also worsens oxidative stress.Reduction of energy production by mitochondria is a common feature of all metabolic disorders.High SIRT levels and 5’adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta,which promotes ketosis.Ketosis,in turn,increases autophagy and mitophagy,processes that clear cells of debris and protect against damage.Sodiumglucose cotransporter-2 inhibitors(SGLT2i),a class of drugs used to treat type 2 diabetes,have a beneficial effect on these mechanisms.Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events.SGLT2i also increase mitochondrial efficiency,reduce oxidative stress and inflammation,and strengthen tissues.These findings suggest that SGLT2i hold great potential for the treatment of CVD.Furthermore,they are proposed as anti-aging drugs;however,rigorous research is needed to validate these preliminary findings.展开更多
文摘Aging,mitochondria,and neurodegenerative diseases:Aging is often viewed as the buildup of changes that lead to the gradual transformations associated with getting older,along with a rising likelihood of disease and mortality.Although organis m-wide deterioration is observed during aging,organs with high metabolic demand,such as the brain,are more vulnerable.
文摘Mitochondria are central regulators of cellular energy metabolism,redox balance,and survival,and their dysfunction contributes to neurodegenerative,cardiovascular,and metabolic diseases,as well as aging.Beyond its role as a circadian hormone,melatonin is now recognized as a key modulator of mitochondrial physiology.This review provides an overview of the mechanisms by which melatonin can preserve mitochondrial function through multifaceted mechanisms.Experimental evidence shows that melatonin enhances the activity of electron transport chain(ETC)complexes,stabilizes the mitochondrial membrane potential(Δψ),and prevents cardiolipin(CL)peroxidation,thereby limiting permeability transition pore(mPTP)opening and cytochrome c release.Through its direct radical scavenging capacity and the upregulation of mitochondrial antioxidant defenses,melatonin protects against oxidative stress(OS)and preserves mitochondrial DNA integrity.Melatonin also regulates mitochondrial dynamics by promoting fusion,restraining excessive fission,and supporting quality control mechanisms such as mitophagy,unfolded protein response(UPR),and proteostasis.Moreover,melatonin influences mitochondrial biogenesis and intercellular communication through tunneling nanotubes(TNTs)and mitokine signaling.Thus,melatonin may represent a promising multifaceted therapeutic strategy for preserving mitochondrial homeostasis in a range of pathological conditions,including neurodegeneration and cardiovascular and metabolic diseases.However,a significant translational gap still remains between the promising preclinical data and the established clinical practice.Therefore,the aim of this review is to provide a comprehensive synthesis of current knowledge on the mechanisms through which melatonin modulates mitochondrial function and to discuss its potential therapeutic implications in neurodegenerative,cardiovascular,and metabolic diseases.
文摘The development of cancer cell resistance to conventional treatments continues to be a major obstacle in the successful treatment of tumors of many types.The discovery of a highly efficient direct and indirect free radical scavenger,melatonin,in the mitochondrial matrix may be a factor in determining both the occurrence of cancer cell drug insensitivity as well as radioresistance.This relates to two of the known hallmarks of cancer,i.e.,exaggerated free radical generation in the mitochondria and the development ofWarburg type metabolism(glycolysis).The hypothesis elaborated in this report assumes that the high oxidative environment in the mitochondria contributes to a depression of local melatonin levels because of its overuse in neutralizing the massive amount of free radial produced.Moreover,Warburg typemetabolism and chemoresistance are functionally linked and supplementalmelatonin has been shown to reverse glycolysis and convert glucose processing to the type that occurs in normal cells.Since thismetabolic type is a key factor in determining chemoresistance,melatonin would predictably also negate cancer drug insensitivity.The possible mechanisms by which melatonin may interfere either directly or indirectly with drug resistance are summarized in the current review.
基金Supported by Agencia Nacional de Promoción de la Investigación,el Desarrollo Tecnológico y la Innovación,No.PICT 2020 Serie A 4000.
文摘Hypertension disrupts cerebral blood flow,leading to endothelial dysfunction,breakdown of the blood-brain barrier(BBB),and inflammatory cell infiltration.This cascade triggers glial cell activation,increases oxidative stress,and causes pro-inflammatory cytokine release,creating a neurotoxic environment.In this context,we explore the intricate connection between hypertension,neuroinflammation,and neurodegeneration,as well as how hypertension interacts with other metabolic disorders,such as obesity and diabetes,to further worsen neuroinflammation.Additionally,we discuss the role of the reninangiotensin-aldosterone system,the impact of the microbiome,and the potential contribution of chronic infections in exacerbating neuroinflammation.It is essential to emphasize the potential of nanotechnology to transform therapeutic approaches.Nanoparticle-based drug delivery systems can enhance the bioavailability and selectivity of antihypertensive drugs,antioxidants,and neuroprotective compounds,enabling targeted delivery across the BBB.By combining effective blood pressure management with nanotechnology-enabled therapies that modulate inflammation,oxidative stress,and protein aggregation,we can explore new avenues for preventing and treating hypertension and metabolic disorder-associated neurodegenerative conditions.Ultimately,hypertension significantly contributes to neuroinflammation and neurodegeneration by promoting neuronal cell death,primarily through impaired cerebral blood flow and disruption of the BBB.The interaction of hypertension with metabolic disorders exacerbates these effects.However,advancements in our understanding and new technologies reveal promising nanopharmacological approaches for targeted drug delivery to the brain,thereby improving treatment outcomes,enhancing adherence,and reducing side effects.
文摘Neurodegenerative diseases(NDs)such as Alzheimer’s disease(AD),Parkinson’s disease(PD),Huntington’s disease(HD),and amyotrophic lateral sclerosis(ALS)are characterized by progressive neuronal loss,which is closely linked to mitochondrial dysfunction.These pathologies involve a complex interplay of genetics,protein misfolding,and cellular stress,culminating in impaired energy metabolism,an increase in reactive oxygen species(ROS),and defective mitochondrial quality control.The accumulation of damaged mitochondria and dysregulation of pathways such as the Integrated Stress Response(ISR)are central to the pathogenesis of these conditions.This review explores the critical relationship between mitochondrial stress and neurodegeneration,highlighting the molecular mechanisms and biomarkers involved.It delves into the multifaceted role of melatonin as a potent neuroprotective agent.Melatonin,a lipophilic indoleamine,is produced both in the pineal gland and locally within mitochondria,where it exerts powerful antioxidant,anti-inflammatory,and anti-apoptotic effects.Its unique ability to neutralize multiple free radicals and its cascade-based antioxidant action make it superior to conventional antioxidants.Its mechanisms of action are discussed,including signaling pathway modulation and enhancement of the brain’s clearance system(the glymphatic system).Despite its potential,melatonin’s low bioavailability and rapid metabolism limit its therapeutic efficacy.In this context,nanopharmacology emerges as a promising strategy.Nanoparticles such as liposomes,polymers,and solid lipids can encapsulate melatonin and protect it from degradation,facilitating its transport across the blood-brain barrier.Preclinical evidence has shown that melatonin-loaded nanoparticles significantly improve cognitive function,reduce oxidative stress,and restore mitochondrial homeostasis in models of AD,PD,and ALS.In conclusion,the synergistic combination of melatonin and nanopharmacology offers a multimodal and highly targeted approach formitigatingmitochondrial dysfunction in NDs.While challenges remain in optimizing the formulation and safety of these nanocarriers,this combination represents a crucial frontier for developing more effective and specific treatments in the future.
文摘The interplay between mitochondria,epigenetics,and the microbiota is intricately linked to both health and disease.Within our cells,a complex molecular dance occurs,where these components intertwine in a mesmerizing ballet that plays a decisive role in our health.Mitochondria,beyond being energy powerhouses,modulate nuclear gene expression through messengers like reactive oxidative stress(ROS)and calcium.Epigenetics,acting as the molecular conductor,regulates the expression of both nuclear and mitochondrial genes through modifications like DNA methylation.The intestinal microbiota itself produces short-chain fatty acids(SCFAs)that influence mitochondrial activity.SCFA-induced epigenetic modifications,like histone acetylation,impact mitochondrial function which may lead to disease.Mitochondrial dysfunction generates retrograde signals that alter nuclear gene expression,as evidenced by increased histone H3 lysine 27 acetylation(H3K27ac)in genes essential for neuronal differentiation and mitochondrial reprogramming.Alterations in the mitochondrial-nuclear-microbiota axis are associated with diseases including diabetes,neurodegeneration,and cancer.Modulating the intestinal microbiota with probiotics or prebiotics can restore balance while intervening in mitochondrial pathways,which can be a therapeutic strategy.Additionally,using epigenetic agents like histone deacetylase(HDAC)inhibitors can reprogram gene expression and improve mitochondrial function.Finally,the present review aims to explore the central interplay between mitochondria,epigenetics modifications,and microbiota in a complex and dynamic molecular context that plays a fundamental role in human health.Specifically,it will examine the impact of microbiome components and metabolites generated from normobiosis and dysbiosis on mitochondria and epigenetic modifications across different diseases and metabolic conditions.This integrated understanding of the molecular players and their interactions provides a deeper perspective on how to promote health and potentially combat disease.
基金Secretaría de Ciencia,Técnica y Postgrado,Universidad Nacional de Cuyo,and from ANPCyT(Agencia Nacional de Promoción de la Ciencia y la Tecnología,grant number PICT 2016-4541)both awarded to W.Manucha.
文摘The ancestral cultures have described many therapeutic properties of garlic,therefore,it is of central interest to elucidate the molecular basis explaining this millenary empirical knowledge.Indeed,it has been demonstrated a neuroprotective effect of allicin–a phytochemical present in garlic-linked to oxidative-inflammatory modulation.Allicin improved neuronal injury by heat shock protein 70(Hsp70)and inducible nitric oxide synthase(iNOS)regulation.Also,allicin exerts renal protection involving a possible angiotensin type 1 receptor(AT1)interaction.In connection,AT1 overexpression has been recognized as a central deleterious factor in many brain diseases.However,there are no studies that evaluate AT1-Hsp70-iNOS interaction as a mechanism linked to neuroinflammation.Thus,our central aim is to evaluate if the allicin protective effect is associated with an AT1-Hsp70-iNOS counterbalance axis.For this study,a murine microglial cell line(BV-2)was injured with lipopolysaccharides and treated or not with allicin.Then,it was evaluated cell viability,proinflammatory cytokine levels,cellular oxidative stress,iNOS,Hsp70,and AT1 protein expression(cellular and mitochondrial fractions),nitrite levels,and protein-protein interactions.The results demonstrated that allicin could prevent neuronal injury due to a reduction in oxidative stress and inflammatory status mediated by an AT1-Hsp70-iNOS counterbalance axis linked to direct protein-protein interaction.
文摘Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and inflammation.Angiotensin II,the main mediator of the renin-angiotensin-aldosterone system,also contributes to CVD by promoting ROS production.Reduced activity of sirtuins(SIRTs),a family of proteins that regulate cellular metabolism,also worsens oxidative stress.Reduction of energy production by mitochondria is a common feature of all metabolic disorders.High SIRT levels and 5’adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta,which promotes ketosis.Ketosis,in turn,increases autophagy and mitophagy,processes that clear cells of debris and protect against damage.Sodiumglucose cotransporter-2 inhibitors(SGLT2i),a class of drugs used to treat type 2 diabetes,have a beneficial effect on these mechanisms.Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events.SGLT2i also increase mitochondrial efficiency,reduce oxidative stress and inflammation,and strengthen tissues.These findings suggest that SGLT2i hold great potential for the treatment of CVD.Furthermore,they are proposed as anti-aging drugs;however,rigorous research is needed to validate these preliminary findings.
