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1.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675160

RESUMO

Diabetes Mellitus is a multifactorial disease with a critical impact worldwide. During prediabetes, the presence of various inflammatory cytokines and oxidative stress will lead to the pathogenesis of type 2 diabetes. Furthermore, insulin resistance and chronic hyperglycemia will lead to micro- and macrovascular complications (cardiovascular disease, heart failure, hypertension, chronic kidney disease, and atherosclerosis). The development through the years of pharmacological options allowed us to reduce the persistence of chronic hyperglycemia and reduce diabetic complications. This review aims to highlight the specific mechanisms with which the new treatments for type 2 diabetes reduce oxidative stress and insulin resistance and improve cardiovascular outcomes.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hiperglicemia , Resistência à Insulina , Estado Pré-Diabético , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/complicações , Hiperglicemia/complicações , Estado Pré-Diabético/complicações
2.
Int J Mol Sci ; 23(6)2022 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-35328530

RESUMO

Parkinson's disease (PD) is second-most common disabling neurological disorder worldwide, and unfortunately, there is not yet a definitive way to prevent it. Polyphenols have been widely shown protective efficacy against various PD symptoms. However, data on their effect on physio-pathological mechanisms underlying this disease are still lacking. In the present work, we evaluated the activity of a mixture of polyphenols and micronutrients, named A5+, in the murine neuroblastoma cell line N1E115 treated with 6-Hydroxydopamine (6-OHDA), an established neurotoxic stimulus used to induce an in vitro PD model. We demonstrate that a pretreatment of these cells with A5+ causes significant reduction of inflammation, resulting in a decrease in pro-inflammatory cytokines (IFN-γ, IL-6, TNF-α, and CXCL1), a reduction in ROS production and activation of extracellular signal-regulated kinases (ERK)1/2, and a decrease in apoptotic mechanisms with the related increase in cell viability. Intriguingly, A5+ treatment promoted cellular differentiation into dopaminergic neurons, as evident by the enhancement in the expression of tyrosine hydroxylase, a well-established dopaminergic neuronal marker. Overall, these results demonstrate the synergic and innovative efficacy of A5+ mixture against PD cellular pathological processes, although further studies are needed to clarify the mechanisms underlying its beneficial effect.


Assuntos
Doença de Parkinson , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Camundongos , Micronutrientes/metabolismo , Micronutrientes/farmacologia , Micronutrientes/uso terapêutico , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Polifenóis/metabolismo , Polifenóis/farmacologia , Polifenóis/uso terapêutico
3.
Cardiovasc Diabetol ; 20(1): 98, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33957931

RESUMO

BACKGROUND: Metabolic syndrome certainly favors growth of carotid plaque; however, it is uncertain if it determines plaque destabilization. Furthermore, it is likely that only some components of metabolic syndrome are associated with increased risk of plaque destabilization. Therefore, we evaluated the effect of different elements of metabolic syndrome, individually and in association, on carotid plaques destabilization. METHODS: A total of 186 carotid endarterectomies from symptomatic and asymptomatic patients were histologically analysed and correlated with major cardiovascular risk factors. RESULTS: Metabolic syndrome, regardless of the cluster of its components, is not associated with a significant increase in risk of plaque destabilization, rather with the presence of stable plaques. The incidence of unstable plaques in patients with metabolic syndrome is quite low (43.9 %), when compared with that seen in the presence of some risk factors, but significantly increases in the subgroup of female patients with hypertriglyceridemia, showing an odds ratio of 3.01 (95% CI, 0.25-36.30). CONCLUSIONS: Our data may help to identify patients with real increased risk of acute cerebrovascular diseases thus supporting the hypothesis that the control of hypertriglyceridemia should be a key point on prevention of carotid atherosclerotic plaque destabilization, especially in post-menopausal female patients.


Assuntos
Doenças das Artérias Carótidas/epidemiologia , Hipertrigliceridemia/epidemiologia , Síndrome Metabólica/epidemiologia , Placa Aterosclerótica , Triglicerídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/diagnóstico , Incidência , Itália/epidemiologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Ruptura Espontânea , Fatores Sexuais , Fatores de Tempo
4.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360753

RESUMO

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1ß from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proteína HMGB1/farmacologia , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Interleucina-2/farmacologia , Leptina/metabolismo , Leucócitos Mononucleares/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/patologia , Hiperinsulinismo/patologia , Leucócitos Mononucleares/patologia
5.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525692

RESUMO

Flavonoids display a broad range of structures and are responsible for the major organoleptic characteristics of plant-derived foods and beverages. Recent data showed their activity, and in particular of luteolin-7-O-glucoside (LUT-7G), in reduction of oxidative stress and inflammatory mechanisms in different physiological systems. In this paper, we tried to elucidate how LUT-7G could exert both antioxidant and anti-inflammatory effects in endothelial cells cultured in vitro. Here, we showed that LUT-7G is able to inhibit the STAT3 pathway, to have an antiproliferative action, and an important antioxidant property in HUVEC cells. These properties are exerted by the flavone in endothelial through the transcriptional repression of a number of inflammatory cytokines and their receptors, and by the inhibition of ROS generation. ROS and STAT3 activation has been correlated with the production of oxysterols and other hydroxylated fatty acids, and they have been recognized important as players of atherogenesis and cardiocirculatory system diseases. The analysis of the general production pathway of these hydroxylated species, showed a strong decrease of cholesterol hydroxylated species such as 7-alpha-hydroxicholesterol, 7-beta-hydroxicholesterol by the treatment with LUT-7G. This confirms the anti-inflammatory properties of LUT-7G also in the endothelial district, showing for the first time the molecular pathway that verify previous postulated cardiovascular benefits of this flavone.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Flavonas/farmacologia , Glucosídeos/farmacologia , Queratinócitos/citologia , Sialiltransferases/metabolismo , Linhagem Celular , Proliferação de Células , Células Endoteliais/química , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Ácidos Graxos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidroxilação , Queratinócitos/química , Queratinócitos/efeitos dos fármacos , Metabolômica , Oxisteróis/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Medicina (Kaunas) ; 57(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34356993

RESUMO

Background and Objectives: Glycated hemoglobin (HbA1c) dosage is considered the gold standard in glycol-metabolic monitoring, but it presents limits, which can underestimate the glycemia trend. In this regard, it was introduced the glycated albumin (GA). The aim of the study is to verify the predictivity of the GA compared to HbA1c in identifying glyco-metabolic alterations in non-diabetic and diabetic hemodialysis (HD) patients. Materials and Methods: For this purpose, we conducted a multicenter study involving one analysis laboratory and six dialysis centers in the Lazio region (Rome, Italy). Both diabetic and non-diabetic HD patients represent the study population, and the protocol included five time points. Results: The analyzed data highlighted the ability of GA to predict changes in glycemic metabolism in HD patients, and GA values are not significantly influenced, like HbA1c, by dialysis therapy itself and by comorbidities of the uremic state, such as normochromic and normocytic anemia. Thus, GA seems to reflect early glyco-metabolic alterations, both in patients with a previous diagnosis of diabetes and in subjects without diabetes mellitus. As part of this study, we analyzed two HD patients (one diabetic and one non-diabetic) in which GA was more predictive of glycol-metabolic alterations compared to HbA1c. Our study confirms the need to compare classical biomarkers used for the monitoring of glyco-metabolic alterations with new ones, likely more reliable and effective in specific subgroups of patients in which the classic biomarkers can be influenced by the preexisting pathological conditions. Conclusions: In conclusion, our evidence highlights that in uremic patients, GA shows a better ability to predict glyco-metabolic alterations allowing both an earlier diagnosis of DM and a prompt modulation of the hypoglycemic therapy, thus improving the clinical management of these patients.


Assuntos
Diabetes Mellitus Tipo 2 , Biomarcadores , Glicemia , Diabetes Mellitus Tipo 2/complicações , Hemoglobinas Glicadas/análise , Produtos Finais de Glicação Avançada , Humanos , Diálise Renal , Albumina Sérica , Albumina Sérica Glicada
7.
Molecules ; 25(20)2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33081292

RESUMO

Extra virgin olive oil (EVOO) is a lipid food, which constitutes a pillar of the Mediterranean diet. A high number of scientific data have demonstrated that it exerts a variety of beneficial effects on human health due to its peculiar chemical composition including fatty acids (98-99%) and other active compounds even if found in a very low percentage (1-2%). Among them, minor polar compounds (MCPs), represented mainly by phenolic compounds, are relevant for their healthy properties, as stated by the European Food Safety Authority's (EFSA) claims. In this paper, we described the results obtained from a pilot in vivo study, focused for the first time on the evaluation of the possible beneficial effects of two EVOOs on chronic kidney disease (CKD) patients after the consumption of 40 mL per day for 9 weeks. The selected EVOOs, traced in the production chain, and characterized by High-Performance Liquid Chromatography (HPLC-DAD-MS) analysis, resulted rich in MCPs and satisfied the EFSA's claim for their content of hydroxytyrosol and derivatives. The results obtained by this in vivo study appear to highlight the potential beneficial role in CKD patients of these EVOOs and are promising for future studies.


Assuntos
Azeite de Oliva/administração & dosagem , Fenóis/administração & dosagem , Álcool Feniletílico/análogos & derivados , Insuficiência Renal Crônica/dietoterapia , Idoso , Cromatografia Líquida de Alta Pressão , Dieta Mediterrânea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Azeite de Oliva/química , Fenóis/química , Álcool Feniletílico/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia
8.
Genes Immun ; 20(7): 539-554, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30563970

RESUMO

Alterations in the molecular mechanisms of cell death are a common feature of cancer. These alterations enable malignant cells to survive intrinsic death signalling leading to accumulation of genetic aberrations and helping them to cope with adverse conditions. Regulated cell death has historically been exclusively associated with classical apoptosis; however, increasing evidence indicates that several alternative mechanisms orchestrate multiple death pathways, such as ferroptosis, entosis, necroptosis and immunogenic cell death, each with distinct underlying molecular mechanisms. Although pharmacological targeting of cell death pathways has been the subject of intensive efforts in recent decades with a dominant focus on targeting apoptosis, the identification of these novel death pathways has opened additional venues for intervention in cancer cells and the immune system. In this mini-review, we cover some recent progress on major recently emerged cell death modalities, emphasizing their potential clinical and therapeutic implications. We also discuss the interplay between cell death and immune response, highlighting the potential of the combination of traditional anticancer therapy and immunocheckpoint blockade. While attempting to stimulate discussion and draw attention to the possible clinical impact of these more recently emerged cell death modalities, we also cover the major progress achieved in translating strategies for manipulation of apoptotic pathways into the clinic, focusing on the attempts to target the anti-apoptotic protein BCL2 and the tumour suppressor p53.


Assuntos
Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Neoplasias/terapia , Apoptose/genética , Entose , Ferroptose , Genes bcl-2/genética , Genes p53/genética , Humanos , Sistema Imunitário , Imunoterapia , Necroptose , Neoplasias/genética , Transdução de Sinais
9.
Biochem J ; 475(5): 1019-1035, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29437994

RESUMO

Obesity represents one of the most complex public health challenges and has recently reached epidemic proportions. Obesity is also considered to be primarily responsible for the rising prevalence of metabolic syndrome, defined as the coexistence in the same individual of several risk factors for atherosclerosis, including dyslipidemia, hypertension and hyperglycemia, as well as for cancer. Additionally, the presence of three of the five risk factors (abdominal obesity, low high-density lipoprotein cholesterol, high triglycerides, high fasting glucose and high blood pressure) characterizes metabolic syndrome, which has serious clinical consequences. The current study was conducted in order to identify metabolic differences in visceral adipose tissue (VAT) collected from obese (body mass index 43-48) human subjects who were diagnosed with metabolic syndrome, obese individuals who were metabolically healthy and nonobese healthy controls. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analyses were used to obtain the untargeted VAT metabolomic profiles of 481 metabolites belonging to all biochemical pathways. Our results indicated consistent increases in oxidative stress markers from the pathologically obese samples in addition to subtle markers of elevated glucose levels that may be consistent with metabolic syndrome. In the tissue derived from the pathologically obese subjects, there were significantly elevated levels of plasmalogens, which may be increased in response to oxidative changes in addition to changes in glycerolphosphorylcholine, glycerolphosphorylethanolamine glycerolphosphorylserine, ceramides and sphingolipids. These data could be potentially helpful for recognizing new pathways that underlie the metabolic-vascular complications of obesity and may lead to the development of innovative targeted therapies.


Assuntos
Gordura Intra-Abdominal/metabolismo , Síndrome Metabólica/metabolismo , Metaboloma , Obesidade/metabolismo , Adulto , Biomarcadores/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/complicações , Metabolômica , Pessoa de Meia-Idade , Obesidade/complicações
10.
Int J Mol Sci ; 20(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31331067

RESUMO

Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer's Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.


Assuntos
Encéfalo/metabolismo , Neuroproteção , Proteína Quinase C/metabolismo , Fatores Etários , Envelhecimento/metabolismo , Animais , Biomarcadores , Suscetibilidade a Doenças , Desenvolvimento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/metabolismo , Proteína Quinase C/química , Proteína Quinase C/genética , Transdução de Sinais/efeitos dos fármacos
11.
Cardiovasc Diabetol ; 17(1): 46, 2018 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-29598820

RESUMO

BACKGROUND: In the last decade, several studies have reported an unexpected and seemingly paradoxical inverse correlation between BMI and incidence of cardiovascular diseases. This so called "obesity paradox effect" has been mainly investigated through imaging methods instead of histologic evaluation, which is still the best method to study the instability of carotid plaque. Therefore, the purpose of our study was to evaluate by histology the role of obesity in destabilization of carotid plaques and the interaction with age, gender and other major cerebrovascular risk factors. METHODS: A total of 390 carotid plaques from symptomatic and asymptomatic patients submitted to endarterectomy, for whom complete clinical and laboratory assessment of major cardiovascular risk factors was available, were studied by histology. Patients with a BMI ≥ 30.0 kg/m2 were considered as obese. Data were analyzed by multivariate logistic regression and for each variable in the equation the estimated odds ratio (OR) was calculated. RESULTS: Unstable carotid plaque OR for obese patients with age < 70 years was 5.91 (95% CI 1.17-29.80), thus being the highest OR compared to that of other risk factors. Unstable carotid plaque OR decreased to 4.61 (95% CI 0.54-39.19) in males ≥ 70 years, being only 0.93 (95% CI 0.25-3.52) among women. When obesity featured among metabolic syndrome risk factors, the OR for plaque destabilization was 3.97 (95% CI 1.81-6.22), a significantly higher value compared to OR in non-obese individuals with metabolic syndrome (OR = 1.48; 95% CI 0.86-2.31). Similar results were obtained when assessing the occurrence of acute cerebrovascular symptoms. CONCLUSIONS: Results from our study appear to do not confirm any paradoxical effect of obesity on the carotid artery district. Conversely, obesity is confirmed to be an independent risk factor for carotid plaque destabilization, particularly in males aged < 70 years, significantly increasing such risk among patients with metabolic syndrome.


Assuntos
Artérias Carótidas/patologia , Estenose das Carótidas/patologia , Transtornos Cerebrovasculares/etiologia , Obesidade/complicações , Placa Aterosclerótica , Fatores Etários , Idoso , Índice de Massa Corporal , Estenose das Carótidas/complicações , Transtornos Cerebrovasculares/diagnóstico por imagem , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Prognóstico , Medição de Risco , Fatores de Risco , Cidade de Roma , Ruptura Espontânea , Fatores Sexuais
12.
Biochem Biophys Res Commun ; 482(3): 440-444, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28212728

RESUMO

The transcription factor p63 belongs to the p53-family and is a master regulator of proliferative potential, lineage specification, and differentiation in epithelia during development and tissue homeostasis. In cancer, p63 contribution is isoform-specific, with both oncogenic and tumour suppressive roles attributed, for ΔNp63 and TAp63, respectively. Recently, p53 and TAp73, in line with other tumour suppressor genes, have emerged as important regulators of energy metabolism and metabolic reprogramming in cancer. To date, p63 contributions in controlling energy metabolism have been partially investigated; given the extensive interaction of the p53 family members, these studies have potential implications in tumour cells for metabolic reprogramming. Here, we review the role of p63 isoforms, TAp63 and ΔNp63, in controlling cell metabolism, focusing on their specific metabolic target genes and their physiological/functional context of action.


Assuntos
Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Antioxidantes/metabolismo , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos , Redes e Vias Metabólicas , Neoplasias/etiologia , Neoplasias/metabolismo , Isoformas de Proteínas/metabolismo
13.
Biochem Biophys Res Commun ; 482(3): 498-505, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28212736

RESUMO

p73 is a transcription factor belonging to the p53 tumour suppressor family. p73-/- mice exhibit a range of phenotypes including neurological, reproductive and inflammatory defects. Although the role of p73 in the control of genomic stability explains part of these phenotypes, a clear mechanism of how p73 participates in the inflammatory response is still elusive. Interleukin-1ß (IL-1ß) has a crucial role in mediating the inflammatory response. Because of its high potency to induce inflammation, the activation and secretion of IL-1ß is tightly regulated by large protein complexes, named inflammasomes. Inflammasomes regulate activation of proinflammatory caspase-1, which in turn proteolytically processes its substrates, including pro-IL-1ß. Caspase-1 gene transcription is strongly activated by p53 protein family members including p73. Here, we have addressed whether p73 might be directly involved in IL-1ß regulation and therefore in the control of the inflammatory response. Our results show that TAp73ß upregulates pro-IL-1ß mRNA and processed IL-1ß protein. In addition, analysis of breast and lung cancer patient cohorts demonstrated that interaction between p73 and IL-1ß predicts a negative survival outcome in these human cancers.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteína Tumoral p73/metabolismo , Animais , Biomarcadores Tumorais/genética , Caspase 1/metabolismo , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Inflamassomos/metabolismo , Camundongos , Camundongos Knockout , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Proteína Tumoral p73/antagonistas & inibidores , Proteína Tumoral p73/deficiência , Proteína Tumoral p73/genética , Regulação para Cima
14.
Nephrol Dial Transplant ; 32(6): 1053-1060, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28498963

RESUMO

BACKGROUND.: Normalization of arterial pressure occurs in just a few patients with hypertensive chronic kidney disease undergoing kidney transplantation. Hypertension in kidney transplant recipients may be related to multiple factors. We aimed to assess whether hypertension in kidney-transplanted patients may be linked to reinnervation of renal arteries of the transplanted kidney. METHODS.: We investigated renal arteries innervation from native and transplanted kidneys in three patients 5 months, 2 years and 11 years after transplantation, respectively. Four transplanted kidneys from non-hypertensive patients on immunosuppressive treatment without evidence of hypertensive arteriolar damage were used as controls. RESULTS: . Evidence of nerve sprouting was observed as early as 5 months following transplantation, probably originated from ganglions of recipient patient located near the arterial anastomosis and was associated with mild hypertensive arteriolar damage. Regeneration of periadventitial nerves was already complete 2 years after transplantation. Nerve density tended to reach values observed in native kidney arteries and was associated with hypertension-related arteriolar lesions in transplanted kidneys. Control kidneys, albeit on an immunosuppressive regimen, presented only a modest regeneration of sympathetic nerves. CONCLUSIONS: . Our results suggest that the considerable increase in sympathetic nerves, as found in patients with severe arterial damage, may be correlated to hypertension rather than to immunosuppressive therapy, thus providing a morphological basis for hypertension recurrence despite renal denervation.


Assuntos
Hipertensão/fisiopatologia , Falência Renal Crônica/cirurgia , Rim/inervação , Regeneração Nervosa , Idoso , Pressão Sanguínea/fisiologia , Feminino , Humanos , Hipertensão/mortalidade , Rim/patologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/fisiopatologia , Transplante de Rim , Masculino , Artéria Renal/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia
15.
Pharmacol Res ; 111: 659-667, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27461137

RESUMO

Epsilon Protein kinase C (εPCK) is a particular kinase that, when activated, is able to protect against different stress injuries and therefore has been proposed to be a potential molecular target against acute and chronic diseases. Particular attention has been focused on εPCK for its involvement in the protective mechanism of Ischemic Preconditioning (IPC), a powerful endogenous mechanism characterized by subthreshold ischemic insults able to protect organs against ischemic injury. Therefore, in the past decades several εPCK modulators have been tested with the object to emulate εPCK mediate protection. Among these the most promising, so far, has been the ΨεRACK peptide, a homologous of RACK receptor for εPKC, that when administrated can mimic its effect in the cells. However, results from studies on εPCK indicate controversial role of this kinase in different organs and diseases, such as myocardial infarct, stroke, diabetes and cancer. Therefore, in this review we provide a discussion on the function of εPCK in acute and chronic diseases and how the different activators and inhibitors have been used to modulate its activity. A better understanding of its function is still needed to definitively target εPCK as novel therapeutic strategy.


Assuntos
Proteína Quinase C-épsilon/metabolismo , Doença Aguda , Animais , Doença Crônica , Cardiopatias/metabolismo , Cardiopatias/prevenção & controle , Humanos , Doenças Metabólicas/metabolismo , Neoplasias/metabolismo , Neuroproteção
16.
Am J Physiol Endocrinol Metab ; 309(9): E787-92, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26374766

RESUMO

Patients with metabolically healthy obesity (MHO) do not present the cluster of metabolic abnormalities that define the metabolic syndrome (MetS). Whether MHO is associated with lower impairment of vasoreactivity than the MetS is unknown. For this purpose, forearm blood flow (FBF) responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and/or the selective endothelin type A (ETA) receptor blocker BQ-123 in 119 obese individuals with MHO (n = 34) or with the MetS (n = 85) and in healthy lean controls (n = 56). ACh and SNP caused a significant vasodilation in both obese and lean participants (all P < 0.001). However, the response to both agents was significantly lower in the obese than in the control group (both P < 0.001). Among the obese participants, the reactivity to ACh was higher in MHO than in MetS patients, whereas the responsiveness to SNP was equally impaired in both groups (P = 0.45). Infusion of BQ-123 significantly increased FBF in obese patients (P < 0001), but not in the lean participants; hence, FBF following ETA receptor blockade was higher in both obese groups than in controls (both P < 0.001). FBF response to BQ-123 was significantly higher in patients with the MetS than in those with MHO (P = 0.007). In conclusion, patients with MHO have abnormal vascular reactivity, although their endothelial dysfunction is less pronounced than in patients with the MetS. These findings indicate that obesity is associated with vascular damage independent of those metabolic abnormalities underlying the MetS.


Assuntos
Endotelina-1/fisiologia , Síndrome Metabólica/fisiopatologia , Obesidade Metabolicamente Benigna/fisiopatologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Acetilcolina/farmacologia , Adulto , Endotelina-1/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Feminino , Antebraço/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Nitroprussiato/farmacologia , Peptídeos Cíclicos/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/fisiologia
17.
Am J Physiol Endocrinol Metab ; 308(9): E744-55, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25714671

RESUMO

Liver has a principal role in glucose regulation and lipids homeostasis. It is under a complex control by substrates such as hormones, nutrients, and neuronal impulses. Insulin promotes glycogen synthesis, lipogenesis, and lipoprotein synthesis and inhibits gluconeogenesis, glycogenolysis, and VLDL secretion by modifying the expression and enzymatic activity of specific molecules. To understand the pathophysiological mechanisms leading to metabolic liver disease, we analyzed liver protein patterns expressed in a mouse model of diabetes by proteomic approaches. We used insulin receptor-knockout (IR(-/-)) and heterozygous (IR(+/-)) mice as a murine model of liver metabolic dysfunction associated with diabetic ketoacidosis and insulin resistance. We evaluated liver fatty acid levels by microscopic examination and protein expression profiles by orthogonal experimental strategies using protein 2-DE MALDI-TOF/TOF and peptic nLC-MS/MS shotgun profiling. Identified proteins were then loaded into Ingenuity Pathways Analysis to find possible molecular networks. Twenty-eight proteins identified by 2-DE analysis and 24 identified by nLC-MS/MS shotgun were differentially expressed among the three genotypes. Bioinformatic analysis revealed a central role of high-mobility group box 1/2 and huntigtin never reported before in association with metabolic and related liver disease. A different modulation of these proteins in both blood and hepatic tissue further suggests their role in these processes. These results provide new insight into pathophysiology of insulin resistance and hepatic steatosis and could be useful in identifying novel biomarkers to predict risk for diabetes and its complications.


Assuntos
Diabetes Mellitus/metabolismo , Fígado/metabolismo , Proteoma/metabolismo , Receptor de Insulina/genética , Animais , Diabetes Mellitus/genética , Modelos Animais de Doenças , Inflamação/genética , Inflamação/metabolismo , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas/metabolismo , Proteômica
18.
Pulm Pharmacol Ther ; 35: 1-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26363278

RESUMO

The concomitant presence of systemic arterial hypertension and chronic obstructive pulmonary disease (COPD) is frequent. Indeed, arterial hypertension is the most common comorbid disease in COPD patients. Since many antihypertensive drugs can act on airway function the treatment of arterial hypertension in COPD patients appears complex. Moreover, in these patients, a combined therapy is required for the adequate control of blood pressure. Currently, available data are inconsistent and not always comparable. Therefore the aim of this review is to analyze how antihypertensive drugs can affect airway function in order to improve the clinical management of hypertensive patients with COPD. Thiazide diuretics and calcium channel blockers appear the first-choice pharmacological treatment for these patients.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/complicações , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Humanos
19.
Clin Exp Nephrol ; 19(1): 140-5, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24652221

RESUMO

BACKGROUND: Treatment with folic acid and vitamin B12 appears capable of reducing total plasma homocysteine levels (tHcy), but it is unknown whether vitamin B12 alone reduces tHcy values. In this study we investigate the effects of alternate vitamins supplementation on homocysteine levels in patients treated by diffusive and convective dialysis techniques. METHODS: 74 patients were randomized blindly into two groups of 37 subjects each. The first group was treated initially with vitamin B12 for 2 months and with folic acid for the following 2 months. The second group was treated initially with folic acid. A wash out period of 2 months followed the treatment in both groups. RESULTS: Total homocysteine levels decreased in both groups following the alternate vitamins therapy and dialysis, without significant difference between diffusive and convective techniques. Surprisingly, after the wash-out period, tHcy increased remarkably, regardless of the dialysis procedure used. At the end of the study, folate levels showed a higher reduction with haemodialysis compared to haemodiafiltration. In contrast, vitamin B12 levels showed a significant increase using diffusive haemodialysis, confirming a decisive role of membrane performance. CONCLUSIONS: In conclusion we show for the first time that, even if total homocysteine levels decreased in both dialysis procedures, the convective techniques demonstrate a superior capacity on the reduction of tHcy levels compared to the diffusive method. Moreover, the lower depletion of vitamin B12 by diffusive techniques could determine a higher reduction of folate levels, demonstrating the decisive role of the membrane performance in the treatment of this patients.


Assuntos
Suplementos Nutricionais , Homocisteína/sangue , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Diálise Renal/métodos , Vitaminas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Ácido Fólico/uso terapêutico , Genótipo , Hemodiafiltração , Humanos , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Vitamina B 12/uso terapêutico , Adulto Jovem
20.
Lipids Health Dis ; 13: 54, 2014 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-24655786

RESUMO

BACKGROUND: Dyslipidemia and abnormal phospholipid metabolism are frequent in uremic patients and increase their risk of cardiovascular disease (CVD): ω-3 polyunsaturated fatty acids (PUFAs) may reduce this risk in the general population. In this study we compared the plasma and erythrocyte cell membrane composition of PUFAs in a group of Caucasian hemodialysis (HD) patients and in a control group of healthy subjects and evaluated the erythrocyte/cell membrane fatty acid ratio as a marker of the dietary intake of phospholipids. The relationship between ω-3 and ω-6 fatty acids and the possible differences in PUFAs concentrations were also investigated. METHODS AND RESULTS: After obtaining a fully informed consent, a total of ninety-nine HD patients and 160 non uremic control subjects from "Tor Vergata" University Hospital were enrolled into the study. None of them took antioxidant drugs or dietary supplements for at least 90 days prior to the observation. Blood samples were analysed by gas-chromatographic coupled to a mass spectrometric detector.The daily intake of total calories, proteins, lipids and carbohydrates is significantly lower in HD patients than in controls (p < 0.001). Most plasma and erythrocyte PUFA were also reduced significantly in HD patients (p < 0.001). CONCLUSIONS: Our results suggest that many classes of PUFAs are lacking in HD patients, due to the removal of nutrients during the dialysis and to persistent malnutrition. A dietary treatment addressed to increase plasma ω-3 PUFAs and to optimize ω-6/ω-3 ratio may exert a protective action and reduce the risk of CVD in HD patient.


Assuntos
Membrana Eritrocítica/metabolismo , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Fosfolipídeos/sangue , Fosfolipídeos/metabolismo , Adulto , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/sangue , Ácidos Graxos Ômega-6/metabolismo , Feminino , Humanos , Masculino , Diálise Renal , Triglicerídeos/sangue , Triglicerídeos/metabolismo
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