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
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
Rationale:American tegumentary leishmaniasis comprises cutaneous and mucocutaneous manifestations caused by parasitic infections by various Leishmania species.This report details the clinical interventions for a patie...Rationale:American tegumentary leishmaniasis comprises cutaneous and mucocutaneous manifestations caused by parasitic infections by various Leishmania species.This report details the clinical interventions for a patient with American tegumentary leishmaniasis in Mendoza,Argentina,a non-endemic region.Patient concerns:A 43-year-old male was admitted to a tertiary care hospital in Mendoza,Argentina Republic with a history of progressive nasal discharge,septal perforation,facial pain,and pruritus.Despite treatment for presumed nasal myiasis and vasculitis with granulomatosis,symptoms persisted.Diagnosis:American tegumentary leishmaniasis.Interventions:Intravenous liposomal amphotericin B.Outcomes:Follow-up at 30 days showed no recurrence of symptoms with a remarkable clinical improvement of the nasal lesion.Lessons:This case sheds light on the necessity of accurate identification for timely intervention and the need to recognize the diverse manifestations of American tegumentary leishmaniasis to avoid misdiagnosis.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
Living organisms live in continuous interaction with its environment.During this process changes in one can induce adaptive responses on the other.Many factors in the environment have been studied with the notorious d...Living organisms live in continuous interaction with its environment.During this process changes in one can induce adaptive responses on the other.Many factors in the environment have been studied with the notorious distinction of been rare or to be of high intensity strength in its interaction with living organisms.However,little attention has been put on some factors that have constant interaction with organisms but usually have low intensity strength,such as the case of the inorganic chemical environment that surrounds us.In this review,the interaction between the chemical element and living organisms is discussed under a theoretical model of interaction between compartments,giving attention to tellurium(Te),zinc(Zn)and selenium(Se)on some cognitive functions in human and animals.After studies in our laboratory of the phenotypic expression of the HSR(Hand Skill Relative)gene in school children community living in geographic zone rich in minerals and mines of La Rioja province,Argentine,where Te was found to be in higher non-toxic concentrations,a translational experimental model to maturing rats exposed to this trace element was made.Te was found to increase some parameters related to locomotion in an open field induced by novelty and exploratory motivation.At the same time,inhibition of lateralized responses,survival responses and social activity was also observed.Some of these changes,particularly those related to lateralization had similarity with that found previously in children of La Rioja province.Discussion of similarities and discrepancies of biologic effects between animals and humans,about the possible meaning of Te and its interaction with Zn and Se with relevance to humans was analyzed.展开更多
In studies from this laboratory,the chronic administration of ZnTe during pregnancy,lactation,and prepuberal stages of litter(F_(1)generation)modified the behavioral patterns of motivated exploration,lateralized explo...In studies from this laboratory,the chronic administration of ZnTe during pregnancy,lactation,and prepuberal stages of litter(F_(1)generation)modified the behavioral patterns of motivated exploration,lateralized exploration,social activity,and survival responses of maturing rats.To determine whether these affected behaviors would extend to the next generation,F_(1)litter rats previously exposed to tellurium(Te)up to 30-day-old were left at rest with no further treatment up to 90-day-old.Then,F1 female rats were mated with normal untreated male rats,and in the next generation(F_(2)),the litter rats at 30-day-old preserved the modified behaviors previously observed in their parents.The study revealed that Te effects were intergenerational.Here,considering that ZnTe was used in the previous study and that Zn ion has many physiological functions in the cell,experiments were conducted to elucidate if Zn would have an intergenerational effect similar to Te.Working with the same experimental setup as in the previous study but using ZnCl_(2)instead of ZnTe,results revealed that none of the behavioral responses studied were affected by the F_(1) generation.However,in the F_(2)generation,lateralized exploration and survival behavior were inhibited,suggesting that Zn also has an intergenerational effect.展开更多
Connexin 43 (CX43) is one of the major components of gap junctions, the structures responsible for the intercellular communication and transmission of the electrical impulse in the left ventricle. There is limited inf...Connexin 43 (CX43) is one of the major components of gap junctions, the structures responsible for the intercellular communication and transmission of the electrical impulse in the left ventricle. There is limited information on the histological changes of CX43 with age and their effect on electrophysiology, especially in humans. Here, we analyzed left ventricular biopsies from living donors starting at midlife to characterize age-related CX43 remodeling. We assessed its quantity, degree of lateralization, and spatial heterogeneity together with fibrotic deposition. We observed no significant age-related remodeling of CX43. Only spatial heterogeneity increased slightly with age, and this increase was better explained by biological age than by chronological age. Importantly, we found that CX43 features varied considerably among individuals in our population with no relevant relationship to age or fibrosis content, in contrast to animal species. We used our experimental results to feed computational models of human ventricular electrophysiology and to assess the effects of interindividual differences in specific features of CX43 and fibrosis on conduction velocity, action potential duration, and arrhythmogenicity. We found that larger amounts of fibrosis were associated with the highest arrhythmic risk, with this risk being increased when fibrosis deposition was combined with a reduction in CX43 amount and/or with an increase in CX43 spatial heterogeneity. These mechanisms underlying high arrhythmic risk in some individuals were not associated with age in our study population. In conclusion, our data rule out CX43 remodeling as an age-related arrhythmic substrate in the population beyond midlife, but highlight its potential as a proarrhythmic factor at the individual level, especially when combined with increased fibrosis.展开更多
Functional laterality is known as an intrinsic property of the brain.Since several studies have shown the presence of laterality in many species other than humans,it has been suggested that this is an adaptive mechani...Functional laterality is known as an intrinsic property of the brain.Since several studies have shown the presence of laterality in many species other than humans,it has been suggested that this is an adaptive mechanism to aid survival.Previous studies have shown that lateralized behavior observed during exposure to different environmental stimuli is not constant in normal animals,depending on the geometrical form of the exploratory field.In these exploratory fields,animals showed right-or left-biased exploratory behavior,according to the nature of the geometrical properties of the environment.Previously,it was found that tellurium(Te)was able to block spontaneous left-biased exploration in one defined geometrical environment.In the present work,the influence of Te and selenium(Se)in animals exposed to novel geometrically different environments were studied.Three geometrically different testing fields(square,rectangle,and T-shaped)were presented to Se-and Te-treated groups of rats.The results show that in the square field,only the Se treatment was able to block spontaneous right-biased exploratory responses;in the rectangular field,both Se and Te treatments blocked right-biased exploratory responses,and in the T-shaped field,only Te was able to block spontaneous left-biased exploratory responses.Data suggest that trace elements modify lateralized behavioral responses independently of the form of the novel exploratory field,suggesting the presence of a specific action in the brain.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 the Consejo Nacional de Investigaciones Cientıfícas y Técnicas(CONICET)(PIP 2021-2023/11220200102779CO).
文摘Rationale:American tegumentary leishmaniasis comprises cutaneous and mucocutaneous manifestations caused by parasitic infections by various Leishmania species.This report details the clinical interventions for a patient with American tegumentary leishmaniasis in Mendoza,Argentina,a non-endemic region.Patient concerns:A 43-year-old male was admitted to a tertiary care hospital in Mendoza,Argentina Republic with a history of progressive nasal discharge,septal perforation,facial pain,and pruritus.Despite treatment for presumed nasal myiasis and vasculitis with granulomatosis,symptoms persisted.Diagnosis:American tegumentary leishmaniasis.Interventions:Intravenous liposomal amphotericin B.Outcomes:Follow-up at 30 days showed no recurrence of symptoms with a remarkable clinical improvement of the nasal lesion.Lessons:This case sheds light on the necessity of accurate identification for timely intervention and the need to recognize the diverse manifestations of American tegumentary leishmaniasis to avoid misdiagnosis.
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Living organisms live in continuous interaction with its environment.During this process changes in one can induce adaptive responses on the other.Many factors in the environment have been studied with the notorious distinction of been rare or to be of high intensity strength in its interaction with living organisms.However,little attention has been put on some factors that have constant interaction with organisms but usually have low intensity strength,such as the case of the inorganic chemical environment that surrounds us.In this review,the interaction between the chemical element and living organisms is discussed under a theoretical model of interaction between compartments,giving attention to tellurium(Te),zinc(Zn)and selenium(Se)on some cognitive functions in human and animals.After studies in our laboratory of the phenotypic expression of the HSR(Hand Skill Relative)gene in school children community living in geographic zone rich in minerals and mines of La Rioja province,Argentine,where Te was found to be in higher non-toxic concentrations,a translational experimental model to maturing rats exposed to this trace element was made.Te was found to increase some parameters related to locomotion in an open field induced by novelty and exploratory motivation.At the same time,inhibition of lateralized responses,survival responses and social activity was also observed.Some of these changes,particularly those related to lateralization had similarity with that found previously in children of La Rioja province.Discussion of similarities and discrepancies of biologic effects between animals and humans,about the possible meaning of Te and its interaction with Zn and Se with relevance to humans was analyzed.
文摘In studies from this laboratory,the chronic administration of ZnTe during pregnancy,lactation,and prepuberal stages of litter(F_(1)generation)modified the behavioral patterns of motivated exploration,lateralized exploration,social activity,and survival responses of maturing rats.To determine whether these affected behaviors would extend to the next generation,F_(1)litter rats previously exposed to tellurium(Te)up to 30-day-old were left at rest with no further treatment up to 90-day-old.Then,F1 female rats were mated with normal untreated male rats,and in the next generation(F_(2)),the litter rats at 30-day-old preserved the modified behaviors previously observed in their parents.The study revealed that Te effects were intergenerational.Here,considering that ZnTe was used in the previous study and that Zn ion has many physiological functions in the cell,experiments were conducted to elucidate if Zn would have an intergenerational effect similar to Te.Working with the same experimental setup as in the previous study but using ZnCl_(2)instead of ZnTe,results revealed that none of the behavioral responses studied were affected by the F_(1) generation.However,in the F_(2)generation,lateralized exploration and survival behavior were inhibited,suggesting that Zn also has an intergenerational effect.
基金AEI-Ministerio de Ciencia e Innovación through projects PID2019-105674RB-I00,TED2021-130459B-I00,PID2022-140556OB-I00PID2022-139859OB-I00 funded by MCIN/AEI/10.13039/501100011033+2 种基金“ERDF A way of making Europe”,by Gobierno de Aragón through projects LMP94_21,LMP128_21,and BSICoS group T39_23Rthe European Research Council through project ERC G.A.638284.Computations were performed using ICTS NANBIOSIS(HPC Unit,U.Zaragoza)L.G.-M.was supported by a predoctoral fellowship from the Departamento de Ciencia,Universidad y Sociedad del Conocimiento from the Gobierno de Aragón 2016-2020 cofounded by Programa Operativo del Fondo Social Europeo Aragón(C150/2016),EMBO Short-Term fellowship(7710),and Ibercaja-CAI Estancias de Investigación(IT18/18).
文摘Connexin 43 (CX43) is one of the major components of gap junctions, the structures responsible for the intercellular communication and transmission of the electrical impulse in the left ventricle. There is limited information on the histological changes of CX43 with age and their effect on electrophysiology, especially in humans. Here, we analyzed left ventricular biopsies from living donors starting at midlife to characterize age-related CX43 remodeling. We assessed its quantity, degree of lateralization, and spatial heterogeneity together with fibrotic deposition. We observed no significant age-related remodeling of CX43. Only spatial heterogeneity increased slightly with age, and this increase was better explained by biological age than by chronological age. Importantly, we found that CX43 features varied considerably among individuals in our population with no relevant relationship to age or fibrosis content, in contrast to animal species. We used our experimental results to feed computational models of human ventricular electrophysiology and to assess the effects of interindividual differences in specific features of CX43 and fibrosis on conduction velocity, action potential duration, and arrhythmogenicity. We found that larger amounts of fibrosis were associated with the highest arrhythmic risk, with this risk being increased when fibrosis deposition was combined with a reduction in CX43 amount and/or with an increase in CX43 spatial heterogeneity. These mechanisms underlying high arrhythmic risk in some individuals were not associated with age in our study population. In conclusion, our data rule out CX43 remodeling as an age-related arrhythmic substrate in the population beyond midlife, but highlight its potential as a proarrhythmic factor at the individual level, especially when combined with increased fibrosis.
基金supported by Secretaría de Ciencia,Técnica y Postgrado of Universidad Nacional de Cuyo,and Consejo de Investigaciones de la Universidad del Aconcagua,Mendoza,Argentina.
文摘Functional laterality is known as an intrinsic property of the brain.Since several studies have shown the presence of laterality in many species other than humans,it has been suggested that this is an adaptive mechanism to aid survival.Previous studies have shown that lateralized behavior observed during exposure to different environmental stimuli is not constant in normal animals,depending on the geometrical form of the exploratory field.In these exploratory fields,animals showed right-or left-biased exploratory behavior,according to the nature of the geometrical properties of the environment.Previously,it was found that tellurium(Te)was able to block spontaneous left-biased exploration in one defined geometrical environment.In the present work,the influence of Te and selenium(Se)in animals exposed to novel geometrically different environments were studied.Three geometrically different testing fields(square,rectangle,and T-shaped)were presented to Se-and Te-treated groups of rats.The results show that in the square field,only the Se treatment was able to block spontaneous right-biased exploratory responses;in the rectangular field,both Se and Te treatments blocked right-biased exploratory responses,and in the T-shaped field,only Te was able to block spontaneous left-biased exploratory responses.Data suggest that trace elements modify lateralized behavioral responses independently of the form of the novel exploratory field,suggesting the presence of a specific action in the brain.
