Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are inv...Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.展开更多
BACKGROUND Vitamin D population status may have possible unappreciated consequences to the coronavirus disease 2019(COVID-19)pandemic.Αsignificant association between vitamin D sufficiency and reduction in clinical s...BACKGROUND Vitamin D population status may have possible unappreciated consequences to the coronavirus disease 2019(COVID-19)pandemic.Αsignificant association between vitamin D sufficiency and reduction in clinical severity and inpatient mortality from COVID-19 disease has recently been shown,while a recent study has claimed lower COVID-19 cases in European countries with a better vitamin D status.Low serum 25-hydroxyvitamin-D[25(OH)D]was identified as an independent risk factor for COVID-19 infection and hospitalization,and administration of 0.532 mg(21280 IU)of calcifediol or 25(OH)D,followed by 0.266 mg on days 3 and 7 and then weekly until discharge or intensive care unit admission significantly reduced the need for intensive care unit treatment.AIM To elucidate the role of vitamin D European population status in the COVID-19 pandemic,data from the Worldometer were analyzed.METHODS Linear regression explored the correlation between published representativestandardized population vitamin D concentrations and the number of total cases/million(M),recovered/M,deaths/M and serious-critically ill/M from COVID-19 for 26 European countries populated>4 M(Worldometer).Life expectancy was analyzed with semi-parametric regression.Weighted analysis of variance/analysis of covariance evaluated serious-critical/M and deaths/M by the vitamin D population status:Deficient<50,insufficient:50-62.5,mildly insufficient>62.5-75 and sufficient>75 nmol/L,while controlling for life expectancy for deaths/M.Statistical analyses were performed in XLSTAT LIFE SCIENCE and R(SemiPar Library).RESULTS Linear regression found no correlation between population vitamin D concentrations and the total cases-recovered/M,but negative correlations predicting a reduction of 47%-64%-80%in serious-critical illnesses/M and of 61%-82%-102.4%in deaths/M further enhanced when adapting for life expectancy by 133-177-221%if 25(OH)D concentrations reach 100-125-150 nmol/L,sustained on August 15,2020,indicating a truthful association.Weighted analysis of variance was performed to evaluate serious-critical/M(r2=0.22)by the vitamin D population status and analysis of covariance the deaths/M(r2=0.629)controlling for life expectancy(r2=0.47).Serious-critical showed a decreasing trend(P<0.001)from population status deficient(P<0.001)to insufficient by 9.2%(P<0.001),to mildly insufficient by 47.6%(P<0.044)and to sufficient by 100%(reference,P<0.001).For deaths/M the respective decreasing trend(P<0.001)was 62.9%from deficient(P<0.001)to insufficient(P<0.001),65.15%to mildly insufficient(P<0.001)and 78.8%to sufficient(P=0.041).CONCLUSION Achieving serum 25(OH)D 100-150 nmol/L(40-60 ng/mL)(upper tolerable daily doses followed by maintenance proposed doses not requiring medical supervision,Endocrine Society)may protect from serious-critical illness/death from COVID-19 disease.展开更多
Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,d...Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,dizziness,impaired consciousness,ageusia,anosmia,radicular pain,and headache,as well as others.Based on the high number of series of cases reported,there is evidence for the implication of the immune system in the pathological mechanism of COVID-19.Although the exact role of the immunological mechanism is not elucidated,two main mechanisms are suggested which implicate the direct effect of severe acute respiratory syndrome coronavirus 2 infection in the central nervous system and neuroinflammation.In the context of neurological manifestations associated with COVID-19,neuropsychiatric disorders show an exacerbation and are described by symptoms and signs such as depression,anxiety,mood alterations,psychosis,post-traumatic stress disorder,delirium,and cognitive impairment,which appear to be common in COVID-19 survivors.A worsened score on psychopathological measures is seen in those with a history of psychiatric comorbidities.We review the neuropsychiatric manifestations associated with COVID-19 and some critical aspects of the innate and adaptive immune system involved in mental health disorders occurring in COVID-19.展开更多
As a discipline,comparative immunology enhances zoology and has gained wide acceptance in the biological sciences.It is an offshoot of the parent field,immunology,and is an amalgam of immunology and zoology.All animal...As a discipline,comparative immunology enhances zoology and has gained wide acceptance in the biological sciences.It is an offshoot of the parent field,immunology,and is an amalgam of immunology and zoology.All animals from protozoans to humans have solved the threat of extinction by having evolved an immune-defense strategy that ensures the capacity to react against foreign,non-self microorganisms and cancers that disturb the homeostatic self.Invertebrate-type innate immune responses evolved first and they characterize the metazoans.These rapid natural responses act immediately and are often essential for the occurrence of slower,more specific,adaptive vertebratetype immune responses.As components of the innate immune system,there is an emphasis on several major steps in the evolutionary process:(i)recognition;(ii)the phagocytic cell;and(iii)the natural killer cell.When vertebrates evolved,beginning with fish,thymus-controlled T cells first appeared,as did bone marrow-derived B cells(first found in amphibians with long bones).These were the precursors of the plasma cells that synthesize and secrete antibodies.Confirming the concept of self/non-self,invertebrates possess natural,non-adaptive,innate,non-clonal,non-anticipatory immune responses,whereas vertebrates possess adaptive,acquired,clonal,and anticipatory responses.This symposium concerns:(i)aspects of the immune spectrum in representative groups;(ii)specific findings(in particular models;e.g.earthworms);(iii)clues as to the possible biomedical application of relevant molecules derived from animals,notably invertebrates;and(iv)some views on the more practical applications of understanding immune systems of invertebrates and ectotherms,and their possible role in survival.展开更多
Although cell-cycle arrest,senescence,and apoptosis are well accepted as the classic barriers in tumorigenesis,recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer dev...Although cell-cycle arrest,senescence,and apoptosis are well accepted as the classic barriers in tumorigenesis,recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer development.It is well accepted that ferroptosis,an iron-dependent programmed cell death,acts as a new type of tumor suppression mechanism tightly linked with numerous metabolic pathways.SLC7A11 is a transmembrane cystine/glutamate transporter protein that plays a vital role in controlling ferroptosis in vivo.The levels of SLC7A11 are dynamically regulated by various types of stresses,such as oxidative stress,nutrient deprivation,endoplasmic reticulum stress,radiation,oncogenic stress,DNA damage,and immune stress.SLC7A11 can be transcriptionally regulated by both activators such as ATF4,NRF2,and ETS1,and repressors including BACH1,p53,ATF3,and STAT1 during stress responses.Moreover,SLC7A11 activity and its protein stability and cellular localization are also modulated upon stress.Patients’data show that SLC7A11 is overexpressed in various types of human cancers,and higher levels of SLC7A11 predict poorer overall survival.Growing evidence also suggests that targeting SLC7A11 is a promising approach in cancer therapy by effectively inhibiting tumor proliferation,invasion,and metastasis,as well as counteracting cancer stem cells and overcoming chemoresistance.This review highlights the regulation of SLC7A11 as an unconventional checkpoint in tumorigenesis through modulating ferroptotic responses under various types of stress.展开更多
Main text The disruption of protein folding homeostasis in motoneurons(MNs)and the accumulation of protein aggregates are some of the main molecular hallmarks of amyotrophic lateral sclerosis(ALS).Evidence from sporad...Main text The disruption of protein folding homeostasis in motoneurons(MNs)and the accumulation of protein aggregates are some of the main molecular hallmarks of amyotrophic lateral sclerosis(ALS).Evidence from sporadic and familial ALS(fALS)patients and from ALS models suggests that protein aggregation directly participates in neurodegeneration.In turn,the loss of MN homeostasis triggers a coping mechanism,the integrated stress response(ISR)[1].The ISR is initiated by four independent stress-sensing kinases,each of them activated by distinct stresses:protein kinase R(PKR)by double-strand RNA,protein kinase RNA-like endoplasmic reticulum kinase(PERK)by protein misfolding at the endoplasmic reticulum(ER),general control nonderepressible 2(GCN2)by nutrient starvation,and heme-regulated inhibitor(HRI)by heme deprivation.展开更多
基金supported by the Ministerio de Economía,Industria y Competitividad(Agencia Estatal de Investigación,AEI,to CGF and MP)Fondo Europeo de Desarrollo Regional(MINECO-FEDER)(PID2022-139016OA-I00,PDC2022-133441-I00,to CGF and MP),Generalitat de Catalunya(2021 SGR 00357+3 种基金to CGF and MP)co-financed by Secretaria d’Universitats i Recerca del Departament d’Empresai Coneixement de la Generalitat de Catalunya 2021(Llavor 00086,to CGF)the recipient of an Alzheimer’s Association Research Fellowship(AARF-21-848511)the Agència de Gestiód’Ajuts Universitaris i de Recerca(AGAUR)for her FI-SDUR fellowship(2021FISDU 00182).
文摘Dysregulation of G9a,a histone-lysine N-methyltransferase,has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress.Likewise,microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis,especially in multifactorial diseases such as Alzheimer’s disease.Therefore,our aim has been to provide partial insights into the interconnection between G9a,microRNAs,oxidative stress,and neuroinflammation.To better understand the biology of G9a,we compared the global microRNA expression between senescence-accelerated mouse-prone 8(SAMP8)control mice and SAMP8 treated with G9a inhibitor UNC0642.We found a downregulation of miR-128 after a G9a inhibition treatment,which interestingly binds to the 3′untranslated region(3′-UTR)of peroxisome-proliferator activator receptor γ(PPARG)mRNA.Accordingly,Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group.We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor.To confirm these antioxidant effects,we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult.In this setting,treatment with G9a inhibitor increases both cell survival and antioxidant enzymes.Moreover,up-regulation of PPARγby G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis.In addition,we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression.Finally,PPARγ/GADD45αpotentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition.Altogether,we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due,at least in part,by the modulation of PPARγ-dependent pathways by miR-128.
文摘BACKGROUND Vitamin D population status may have possible unappreciated consequences to the coronavirus disease 2019(COVID-19)pandemic.Αsignificant association between vitamin D sufficiency and reduction in clinical severity and inpatient mortality from COVID-19 disease has recently been shown,while a recent study has claimed lower COVID-19 cases in European countries with a better vitamin D status.Low serum 25-hydroxyvitamin-D[25(OH)D]was identified as an independent risk factor for COVID-19 infection and hospitalization,and administration of 0.532 mg(21280 IU)of calcifediol or 25(OH)D,followed by 0.266 mg on days 3 and 7 and then weekly until discharge or intensive care unit admission significantly reduced the need for intensive care unit treatment.AIM To elucidate the role of vitamin D European population status in the COVID-19 pandemic,data from the Worldometer were analyzed.METHODS Linear regression explored the correlation between published representativestandardized population vitamin D concentrations and the number of total cases/million(M),recovered/M,deaths/M and serious-critically ill/M from COVID-19 for 26 European countries populated>4 M(Worldometer).Life expectancy was analyzed with semi-parametric regression.Weighted analysis of variance/analysis of covariance evaluated serious-critical/M and deaths/M by the vitamin D population status:Deficient<50,insufficient:50-62.5,mildly insufficient>62.5-75 and sufficient>75 nmol/L,while controlling for life expectancy for deaths/M.Statistical analyses were performed in XLSTAT LIFE SCIENCE and R(SemiPar Library).RESULTS Linear regression found no correlation between population vitamin D concentrations and the total cases-recovered/M,but negative correlations predicting a reduction of 47%-64%-80%in serious-critical illnesses/M and of 61%-82%-102.4%in deaths/M further enhanced when adapting for life expectancy by 133-177-221%if 25(OH)D concentrations reach 100-125-150 nmol/L,sustained on August 15,2020,indicating a truthful association.Weighted analysis of variance was performed to evaluate serious-critical/M(r2=0.22)by the vitamin D population status and analysis of covariance the deaths/M(r2=0.629)controlling for life expectancy(r2=0.47).Serious-critical showed a decreasing trend(P<0.001)from population status deficient(P<0.001)to insufficient by 9.2%(P<0.001),to mildly insufficient by 47.6%(P<0.044)and to sufficient by 100%(reference,P<0.001).For deaths/M the respective decreasing trend(P<0.001)was 62.9%from deficient(P<0.001)to insufficient(P<0.001),65.15%to mildly insufficient(P<0.001)and 78.8%to sufficient(P=0.041).CONCLUSION Achieving serum 25(OH)D 100-150 nmol/L(40-60 ng/mL)(upper tolerable daily doses followed by maintenance proposed doses not requiring medical supervision,Endocrine Society)may protect from serious-critical illness/death from COVID-19 disease.
文摘Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,dizziness,impaired consciousness,ageusia,anosmia,radicular pain,and headache,as well as others.Based on the high number of series of cases reported,there is evidence for the implication of the immune system in the pathological mechanism of COVID-19.Although the exact role of the immunological mechanism is not elucidated,two main mechanisms are suggested which implicate the direct effect of severe acute respiratory syndrome coronavirus 2 infection in the central nervous system and neuroinflammation.In the context of neurological manifestations associated with COVID-19,neuropsychiatric disorders show an exacerbation and are described by symptoms and signs such as depression,anxiety,mood alterations,psychosis,post-traumatic stress disorder,delirium,and cognitive impairment,which appear to be common in COVID-19 survivors.A worsened score on psychopathological measures is seen in those with a history of psychiatric comorbidities.We review the neuropsychiatric manifestations associated with COVID-19 and some critical aspects of the innate and adaptive immune system involved in mental health disorders occurring in COVID-19.
文摘As a discipline,comparative immunology enhances zoology and has gained wide acceptance in the biological sciences.It is an offshoot of the parent field,immunology,and is an amalgam of immunology and zoology.All animals from protozoans to humans have solved the threat of extinction by having evolved an immune-defense strategy that ensures the capacity to react against foreign,non-self microorganisms and cancers that disturb the homeostatic self.Invertebrate-type innate immune responses evolved first and they characterize the metazoans.These rapid natural responses act immediately and are often essential for the occurrence of slower,more specific,adaptive vertebratetype immune responses.As components of the innate immune system,there is an emphasis on several major steps in the evolutionary process:(i)recognition;(ii)the phagocytic cell;and(iii)the natural killer cell.When vertebrates evolved,beginning with fish,thymus-controlled T cells first appeared,as did bone marrow-derived B cells(first found in amphibians with long bones).These were the precursors of the plasma cells that synthesize and secrete antibodies.Confirming the concept of self/non-self,invertebrates possess natural,non-adaptive,innate,non-clonal,non-anticipatory immune responses,whereas vertebrates possess adaptive,acquired,clonal,and anticipatory responses.This symposium concerns:(i)aspects of the immune spectrum in representative groups;(ii)specific findings(in particular models;e.g.earthworms);(iii)clues as to the possible biomedical application of relevant molecules derived from animals,notably invertebrates;and(iv)some views on the more practical applications of understanding immune systems of invertebrates and ectotherms,and their possible role in survival.
基金supported by the National Cancer Institute of the National Institutes of Health(USA)(No.R35CA253059,RO1CA258390,RO1CA254970 to W.G.).
文摘Although cell-cycle arrest,senescence,and apoptosis are well accepted as the classic barriers in tumorigenesis,recent studies indicate that metabolic regulation is equally important as a major checkpoint in cancer development.It is well accepted that ferroptosis,an iron-dependent programmed cell death,acts as a new type of tumor suppression mechanism tightly linked with numerous metabolic pathways.SLC7A11 is a transmembrane cystine/glutamate transporter protein that plays a vital role in controlling ferroptosis in vivo.The levels of SLC7A11 are dynamically regulated by various types of stresses,such as oxidative stress,nutrient deprivation,endoplasmic reticulum stress,radiation,oncogenic stress,DNA damage,and immune stress.SLC7A11 can be transcriptionally regulated by both activators such as ATF4,NRF2,and ETS1,and repressors including BACH1,p53,ATF3,and STAT1 during stress responses.Moreover,SLC7A11 activity and its protein stability and cellular localization are also modulated upon stress.Patients’data show that SLC7A11 is overexpressed in various types of human cancers,and higher levels of SLC7A11 predict poorer overall survival.Growing evidence also suggests that targeting SLC7A11 is a promising approach in cancer therapy by effectively inhibiting tumor proliferation,invasion,and metastasis,as well as counteracting cancer stem cells and overcoming chemoresistance.This review highlights the regulation of SLC7A11 as an unconventional checkpoint in tumorigenesis through modulating ferroptotic responses under various types of stress.
基金supported by PID2020-120497RB-I00 MCIU/AEI/https://doi.org/10.13039/501100011033,BFU2017-90043-P MCINN/AEI/https://doi.org/10.13039/501100011033/by FEDER“Una manera de hacer Europa”(MA and TA),Proyecto Intramural IdisNa 2022(MA),Fundación para la Investigación Médica Aplicada(FIMA)Proyectos I+D,2017(TA)and Fundación Occident and DalecandELA Association(MA)supported by República de Panamá,Programa de Becas IFARHU-SENACYT(reference number 270-2018-922),NP by AC FIMA pre-doctoral fellowship.
文摘Main text The disruption of protein folding homeostasis in motoneurons(MNs)and the accumulation of protein aggregates are some of the main molecular hallmarks of amyotrophic lateral sclerosis(ALS).Evidence from sporadic and familial ALS(fALS)patients and from ALS models suggests that protein aggregation directly participates in neurodegeneration.In turn,the loss of MN homeostasis triggers a coping mechanism,the integrated stress response(ISR)[1].The ISR is initiated by four independent stress-sensing kinases,each of them activated by distinct stresses:protein kinase R(PKR)by double-strand RNA,protein kinase RNA-like endoplasmic reticulum kinase(PERK)by protein misfolding at the endoplasmic reticulum(ER),general control nonderepressible 2(GCN2)by nutrient starvation,and heme-regulated inhibitor(HRI)by heme deprivation.
