Hypertension and metabolic syndrome, both of which increase with age, are multifactorial disorders. Their etiology is complex, making it challenging to isolate involved genes. This study aimed to characterize the hepa...Hypertension and metabolic syndrome, both of which increase with age, are multifactorial disorders. Their etiology is complex, making it challenging to isolate involved genes. This study aimed to characterize the hepatic gene expression in spontaneously hypertensive rats (SHR) at different ages. Blood pressure in SHR was determined by tail-cuff method at one and three months of age. Hepatic RNA was isolated and gene expression was compared using microarrays. Comparison between SHR and normotensive rats revealed significant variation in gene expression: 98 genes were upregulated and 122 were downregulated in SHR;while 88 genes were upregulated and 139 genes were downregulated in age-matched normotensive rats. Furthermore, within the SHR group, 110 genes were found to be upregulated and 168 genes downregulated across different ages. Analyses via the Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways revealed that several genes are potentially implicated in both, hypertension and metabolic syndrome. The results suggest that SHR display variations in gene expression due to aging, and when compared to normotensive rats. These variations could contribute to the development of hypertension and metabolic syndrome. Microarray studies involving older rats are necessary to further validate these findings.展开更多
Estrogen receptor alpha(ERα) is detected in more than 70% of the cases of breast cancer. Nuclear activity of ERα, a transcriptional regulator, is linked to the development of mammary tumors, whereas the extranuclear...Estrogen receptor alpha(ERα) is detected in more than 70% of the cases of breast cancer. Nuclear activity of ERα, a transcriptional regulator, is linked to the development of mammary tumors, whereas the extranuclear activity of ERα is related to endocrine therapy resistance. ERα polyubiquitination is induced by the estradiol hormone, and also by selective estrogen receptor degraders, resulting in ERα degradation via the ubiquitin proteasome system. Moreover, polyubiquitination is related to the ERα transcription cycle, and some E3-ubiquitin ligases also function as coactivators for ERα. Several studies have demonstrated that ERα polyubiquitination is inhibited by multiple mechanisms that include posttranslational modifica-tions, intera-ctions with coregula-tors, a-nd forma-tion of specific protein complexes with ERα. These events are responsible for an increase in ERα protein levels and deregulation of its signaling in breast cancers. Thus, ERα polyubiquitination inhibition may be a key factor in the progression of breast cancer and resistance to endocrine therapy.展开更多
Alzheimer disease(AD)is the primary form of dementia that occurs spontaneously in older adults.Interestingly,the epigenetic profile of the cells forming the central nervous system changes during aging and may contribu...Alzheimer disease(AD)is the primary form of dementia that occurs spontaneously in older adults.Interestingly,the epigenetic profile of the cells forming the central nervous system changes during aging and may contribute to the progression of some neurodegenerative diseases such as AD.In this review,we present general insights into relevant epigenetic mechanisms and their relationship with aging and AD.The data suggest that some epigenetic changes during aging could be utilized as biomarkers and target molecules for the prevention and control of AD.展开更多
Cell grafting has been considered a therapeutic approach for Parkinson's disease(PD) since the 1980 s. The classical motor symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra pars...Cell grafting has been considered a therapeutic approach for Parkinson's disease(PD) since the 1980 s. The classical motor symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrement in dopamine release in the striatum. Consequently, the therapy of celltransplantation for PD consists in grafting dopamineproducing cells directly into the brain to reestablish dopamine levels. Different cell sources have been shown to induce functional benefits on both animal models of PD and human patients. However, the observed motor improvements are highly variable between individual subjects, and the sources of this variability are not fully understood. The purpose of this review is to provide a general overview of the pioneering studies done in animal models of PD that established the basis for the first clinical trials in humans, and compare these with the latest findings to identify the most relevant aspects that remain unanswered to date. The main focus of the discussions presented here will be on the mechanisms associated with the survival and functionality of the transplants. These include the role of the dopamine released by the grafts and the capacity of the grafted cells to extend fibers and to integrate into the motor circuit. The complete understanding of these aspects will require extensive research on basic aspects of molecular and cellular physiology, together with neuronal network function, in order to uncover the real potential of cell grafting for treating PD.展开更多
Proteus mirabilis, a motile Gram-negative bacterium, represents a common cause of complicated urinary tract infections. Autotransporters are a family of secreted proteins from Gram-negative bacteria that direct their ...Proteus mirabilis, a motile Gram-negative bacterium, represents a common cause of complicated urinary tract infections. Autotransporters are a family of secreted proteins from Gram-negative bacteria that direct their own secretion across the outer membrane (type V autotransporter secretion mechanism). Serine protease autotransporters of Enterobacteriaceae (SPATEs) include adhesins, toxins, and proteases that can contribute to the virulence. Plasmid-encoded toxin (Pet) is the predominant protein in culture supernatants of enteroaggregative E. coli prototype strain 042 and has been extensively studied. Pet toxin is encoded on the 65-MDa adherence-related plasmid of EAEC 042 strain. In this work, Pet protein was found in the supernatant obtained from Proteus mirabilis RTX339 strain isolated from a psychiatric patient suffering complicated urinary tract infections (UTIs). The nucleotide sequence of pet gene was obtained using primers designed from E. coli 042 pet gene reported. The alignment of the sequence showed 100% identity with the pet gene reported. Is important to note that Proteus mirabilis RTX339 pet gene has chromosomal location. The chromosomal location of the gene was established since no plasmids were harbored by this strain.展开更多
Alzheimer’s disease(AD)is an irreversible neurodegenerat i ve disorder that i s responsible for around 60-80%of all dementia cases and currently affects around 50 million people worldwide.As the population’s life sp...Alzheimer’s disease(AD)is an irreversible neurodegenerat i ve disorder that i s responsible for around 60-80%of all dementia cases and currently affects around 50 million people worldwide.As the population’s life span tends to increase,current predictions suggest that by 2050,152 million people worldwide will suffer from dementia(Balsinha,2019).While the exact cause of AD remains obscure,various hypotheses regarding AD etiology have been described in the last decades.According to the amyloid hypothesis,the pathogenic changes related to AD start with the accumulation of amyloid-beta(Aβ)in the brain.These Aβpeptides form oligomers and insoluble amyloid plaques which are neurotoxic and trigger harmful downstream events such as the aggregation of the microtubule-associated protein Tau into neurofibrillary tangles,chronic inflammation,and brain atrophy.展开更多
TRIM25 is emerging as a central factor in breast cancer due to its regulation and function.In particular,it has been shown that:(1)Estrogens modulate TRIM25 gene expression;(2)TRIM25 has activity as an E3-ligase enzym...TRIM25 is emerging as a central factor in breast cancer due to its regulation and function.In particular,it has been shown that:(1)Estrogens modulate TRIM25 gene expression;(2)TRIM25 has activity as an E3-ligase enzyme for ubiquitin;and(3)TRIM25 is also an E3 ligase for interferon-stimulated gene 15 protein in the ISGylation system.Consequently,the proteome of mammary tissue is affected by TRIM25-associated pathways,involved in tumor development and metastasis.Here,we discuss the findings on the mechanisms involved in regulating TRIM25 expression and its functional relevance in breast cancer progression.These studies suggest that TRIM25 may be a biomarker and a therapeutic target for breast cancer.展开更多
Background:Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders.Effective therapeutic strategies are an unmet need for these disorder...Background:Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders.Effective therapeutic strategies are an unmet need for these disorders.Polyphenols,such as quercetin and resveratrol,are plant-derived compounds that activate sirtuins(SIRTs)and have shown promising results in some models of neuronal death,although their effects have been scarcely tested in models of motor neuron degeneration.Methods:In this work we investigated the effects of quercetin and resveratrol in an in vivo model of excitotoxic motor neuron death induced by the chronic infusion ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)into the rat spinal cord tissue.Quercetin and resveratrol were co-infused with AMPA and motor behavior and muscle strength were assessed daily for up to ten days.Then,animals were fixed and lumbar spinal cord tissue was analyzed by histological and immunocytological procedures.Results:We found that the chronic infusion of AMPA[1 mM]caused a progressive motor neuron degeneration,accompanied by astrogliosis and microgliosis,and motor deficits and paralysis of the rear limbs.Quercetin infusion ameliorated AMPA-induced paralysis,rescued motor neurons,and prevented both astrogliosis and microgliosis,and these protective effects were prevented by EX527,a very selective SIRT1 inhibitor.In contrast,neither resveratrol nor EX527 alone improved motor behavior deficits or reduced motor neuron degeneration,albeit both reduced gliosis.Conclusions:These results suggest that quercetin exerts its beneficial effects through a SIRT1-mediated mechanism,and thus SIRT1 plays an important role in excitotoxic neurodegeneration and therefore its pharmacological modulation might provide opportunities for therapy in motor neuron disorders.展开更多
文摘Hypertension and metabolic syndrome, both of which increase with age, are multifactorial disorders. Their etiology is complex, making it challenging to isolate involved genes. This study aimed to characterize the hepatic gene expression in spontaneously hypertensive rats (SHR) at different ages. Blood pressure in SHR was determined by tail-cuff method at one and three months of age. Hepatic RNA was isolated and gene expression was compared using microarrays. Comparison between SHR and normotensive rats revealed significant variation in gene expression: 98 genes were upregulated and 122 were downregulated in SHR;while 88 genes were upregulated and 139 genes were downregulated in age-matched normotensive rats. Furthermore, within the SHR group, 110 genes were found to be upregulated and 168 genes downregulated across different ages. Analyses via the Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways revealed that several genes are potentially implicated in both, hypertension and metabolic syndrome. The results suggest that SHR display variations in gene expression due to aging, and when compared to normotensive rats. These variations could contribute to the development of hypertension and metabolic syndrome. Microarray studies involving older rats are necessary to further validate these findings.
基金Supported by the DGAPA-UNAM,Nos.PAPIIT–IA200916 and PAPIIT–IA201618
文摘Estrogen receptor alpha(ERα) is detected in more than 70% of the cases of breast cancer. Nuclear activity of ERα, a transcriptional regulator, is linked to the development of mammary tumors, whereas the extranuclear activity of ERα is related to endocrine therapy resistance. ERα polyubiquitination is induced by the estradiol hormone, and also by selective estrogen receptor degraders, resulting in ERα degradation via the ubiquitin proteasome system. Moreover, polyubiquitination is related to the ERα transcription cycle, and some E3-ubiquitin ligases also function as coactivators for ERα. Several studies have demonstrated that ERα polyubiquitination is inhibited by multiple mechanisms that include posttranslational modifica-tions, intera-ctions with coregula-tors, a-nd forma-tion of specific protein complexes with ERα. These events are responsible for an increase in ERα protein levels and deregulation of its signaling in breast cancers. Thus, ERα polyubiquitination inhibition may be a key factor in the progression of breast cancer and resistance to endocrine therapy.
文摘Alzheimer disease(AD)is the primary form of dementia that occurs spontaneously in older adults.Interestingly,the epigenetic profile of the cells forming the central nervous system changes during aging and may contribute to the progression of some neurodegenerative diseases such as AD.In this review,we present general insights into relevant epigenetic mechanisms and their relationship with aging and AD.The data suggest that some epigenetic changes during aging could be utilized as biomarkers and target molecules for the prevention and control of AD.
基金Supported by DGAPA-PAPIIT,No.IN207116CONACyT,No.179927
文摘Cell grafting has been considered a therapeutic approach for Parkinson's disease(PD) since the 1980 s. The classical motor symptoms of PD are caused by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrement in dopamine release in the striatum. Consequently, the therapy of celltransplantation for PD consists in grafting dopamineproducing cells directly into the brain to reestablish dopamine levels. Different cell sources have been shown to induce functional benefits on both animal models of PD and human patients. However, the observed motor improvements are highly variable between individual subjects, and the sources of this variability are not fully understood. The purpose of this review is to provide a general overview of the pioneering studies done in animal models of PD that established the basis for the first clinical trials in humans, and compare these with the latest findings to identify the most relevant aspects that remain unanswered to date. The main focus of the discussions presented here will be on the mechanisms associated with the survival and functionality of the transplants. These include the role of the dopamine released by the grafts and the capacity of the grafted cells to extend fibers and to integrate into the motor circuit. The complete understanding of these aspects will require extensive research on basic aspects of molecular and cellular physiology, together with neuronal network function, in order to uncover the real potential of cell grafting for treating PD.
文摘Proteus mirabilis, a motile Gram-negative bacterium, represents a common cause of complicated urinary tract infections. Autotransporters are a family of secreted proteins from Gram-negative bacteria that direct their own secretion across the outer membrane (type V autotransporter secretion mechanism). Serine protease autotransporters of Enterobacteriaceae (SPATEs) include adhesins, toxins, and proteases that can contribute to the virulence. Plasmid-encoded toxin (Pet) is the predominant protein in culture supernatants of enteroaggregative E. coli prototype strain 042 and has been extensively studied. Pet toxin is encoded on the 65-MDa adherence-related plasmid of EAEC 042 strain. In this work, Pet protein was found in the supernatant obtained from Proteus mirabilis RTX339 strain isolated from a psychiatric patient suffering complicated urinary tract infections (UTIs). The nucleotide sequence of pet gene was obtained using primers designed from E. coli 042 pet gene reported. The alignment of the sequence showed 100% identity with the pet gene reported. Is important to note that Proteus mirabilis RTX339 pet gene has chromosomal location. The chromosomal location of the gene was established since no plasmids were harbored by this strain.
基金supported by grant UNAM-PAPIIT IN209221MH was a Feodor Lynen Fellow,awarded by the Alexander von Humboldt Foundation.
文摘Alzheimer’s disease(AD)is an irreversible neurodegenerat i ve disorder that i s responsible for around 60-80%of all dementia cases and currently affects around 50 million people worldwide.As the population’s life span tends to increase,current predictions suggest that by 2050,152 million people worldwide will suffer from dementia(Balsinha,2019).While the exact cause of AD remains obscure,various hypotheses regarding AD etiology have been described in the last decades.According to the amyloid hypothesis,the pathogenic changes related to AD start with the accumulation of amyloid-beta(Aβ)in the brain.These Aβpeptides form oligomers and insoluble amyloid plaques which are neurotoxic and trigger harmful downstream events such as the aggregation of the microtubule-associated protein Tau into neurofibrillary tangles,chronic inflammation,and brain atrophy.
文摘TRIM25 is emerging as a central factor in breast cancer due to its regulation and function.In particular,it has been shown that:(1)Estrogens modulate TRIM25 gene expression;(2)TRIM25 has activity as an E3-ligase enzyme for ubiquitin;and(3)TRIM25 is also an E3 ligase for interferon-stimulated gene 15 protein in the ISGylation system.Consequently,the proteome of mammary tissue is affected by TRIM25-associated pathways,involved in tumor development and metastasis.Here,we discuss the findings on the mechanisms involved in regulating TRIM25 expression and its functional relevance in breast cancer progression.These studies suggest that TRIM25 may be a biomarker and a therapeutic target for breast cancer.
基金This work was done under the auspice of Consejo Nacional de Ciencia y Tecnología(CONACyT,protocol approval number 240817)of Dirección General de Asuntos del Personal Académico(DGAPA),UNAM(protocol approval number IN204516).RLG is recipient of a CONACyT doctoral scholarship.
文摘Background:Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders.Effective therapeutic strategies are an unmet need for these disorders.Polyphenols,such as quercetin and resveratrol,are plant-derived compounds that activate sirtuins(SIRTs)and have shown promising results in some models of neuronal death,although their effects have been scarcely tested in models of motor neuron degeneration.Methods:In this work we investigated the effects of quercetin and resveratrol in an in vivo model of excitotoxic motor neuron death induced by the chronic infusion ofα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)into the rat spinal cord tissue.Quercetin and resveratrol were co-infused with AMPA and motor behavior and muscle strength were assessed daily for up to ten days.Then,animals were fixed and lumbar spinal cord tissue was analyzed by histological and immunocytological procedures.Results:We found that the chronic infusion of AMPA[1 mM]caused a progressive motor neuron degeneration,accompanied by astrogliosis and microgliosis,and motor deficits and paralysis of the rear limbs.Quercetin infusion ameliorated AMPA-induced paralysis,rescued motor neurons,and prevented both astrogliosis and microgliosis,and these protective effects were prevented by EX527,a very selective SIRT1 inhibitor.In contrast,neither resveratrol nor EX527 alone improved motor behavior deficits or reduced motor neuron degeneration,albeit both reduced gliosis.Conclusions:These results suggest that quercetin exerts its beneficial effects through a SIRT1-mediated mechanism,and thus SIRT1 plays an important role in excitotoxic neurodegeneration and therefore its pharmacological modulation might provide opportunities for therapy in motor neuron disorders.
