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1.
Pharmacol Res ; 204: 107207, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734193

RESUMO

In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis. Indole-3-propionic acid (IPA), a Tryptophan catabolic product mainly produced by C. Sporogenes, has been recently shown to exert either favorable or unfavorable effects in the context of metabolic and cardiovascular diseases. We performed a study to delineate clinical and multiomics characteristics of human subjects characterized by low and high IPA levels. Subjects with low IPA blood levels showed insulin resistance, overweight, low-grade inflammation, and features of metabolic syndrome compared to those with high IPA. Metabolomics analysis revealed that IPA was negatively correlated with leucine, isoleucine, and valine metabolism. Transcriptomics analysis in colon tissue revealed the enrichment of several signaling, regulatory, and metabolic processes. Metagenomics revealed several OTU of ruminococcus, alistipes, blautia, butyrivibrio and akkermansia were significantly enriched in highIPA group while in lowIPA group Escherichia-Shigella, megasphera, and Desulfovibrio genus were more abundant. Next, we tested the hypothesis that treatment with IPA in a mouse model may recapitulate the observations of human subjects, at least in part. We found that a short treatment with IPA (4 days at 20/mg/kg) improved glucose tolerance and Akt phosphorylation in the skeletal muscle level, while regulating blood BCAA levels and gene expression in colon tissue, all consistent with results observed in human subjects stratified for IPA levels. Our results suggest that treatment with IPA may be considered a potential strategy to improve insulin resistance in subjects with dysbiosis.


Assuntos
Microbioma Gastrointestinal , Humanos , Masculino , Animais , Feminino , Pessoa de Meia-Idade , Resistência à Insulina , Indóis , Camundongos Endogâmicos C57BL , Metabolômica , Camundongos , Adulto , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Síndrome Metabólica/microbiologia , Comorbidade , Músculo Esquelético/metabolismo , Músculo Esquelético/microbiologia , Multiômica
2.
Acta Diabetol ; 60(11): 1441-1448, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37401947

RESUMO

Hyperglycemia strongly affects endothelial function and activation, which in turn increases the risk of atherosclerotic cardiovascular disease. Among pharmacotherapies aimed at lowering blood glucose levels, glucagon-like peptide 1 receptor agonists (GLP-1RA) represent a class of drugs involved in the improvement of the endothelium damage and the progression of cardiovascular diseases. They show antihypertensive and antiatherosclerotic actions due at least in part to direct favorable actions on the coronary vascular endothelium, such as oxidative stress reduction and nitric oxide increase. However, cumulative peripheral indirect actions could also contribute to the antiatherosclerotic functions of GLP-1/GLP-1R agonists, including metabolism and gut microbiome regulation. Therefore, further research is necessary to clarify the specific role of this drug class in the management of cardiovascular disease and to identify specific cellular targets involved in the protective signal transduction. In the present review, we provide an overview of the effects of GLP-1RAs treatment on cardiovascular disease with particular attention on potential molecular mechanisms involving endothelium function on formation and progression of atherosclerotic plaque.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Hipoglicemiantes/uso terapêutico , Endotélio Vascular/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
3.
Aging Dis ; 14(2): 319-324, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37008061

RESUMO

In elderly Type 2 Diabetes (T2D) patients the relationship between the destabilization of gut microbiome and reversal of dysbiosis via glucose lowering drugs has not been explored. We investigated the effect of 6 months therapy with a fixed combination of Liraglutide and Degludec on the composition of the gut microbiome and its relationship with Quality of Life, glucose metabolism, depression, cognitive function, and markers of inflammation in a group of very old T2D subjects (n=24, 5 women, 19 men, mean age=82 years). While we observed no significant differences in microbiome biodiversity or community among study participants (N = 24, 19 men, mean age 82 years) who responded with decreased HbA1c (n=13) versus those who did not (n=11), our results revealed a significant increase in Gram-negative Alistipes among the former group (p=0.013). Among the responders, changes in the Alistipes content were associated directly with cognitive improvement (r=0.545, p=0.062) and inversely with TNFα levels (r=-0.608, p=0.036). Our results suggest that this combination drug may have a significant impact on both gastrointestinal microbes and cognitive function in elderly T2D individuals.

4.
Pharmacol Res ; 187: 106570, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36423788

RESUMO

Hypercholesterolemia is a major driver of atherosclerosis, thus contributing to high morbidity and mortality worldwide. Gut microbiota have been identified as modulator of blood lipids including cholesterol levels. Few studies have already linked certain bacteria and microbial mechanisms to host cholesterol. However, in particular mouse models revealed conflicting results depending on genetics and experimental protocol. To gain further insights into the relationship between intestinal bacteria and host cholesterol metabolism, we first performed fecal 16S rRNA targeted metagenomic sequencing in a human cohort (n = 24) naïve for cholesterol lowering drugs. Here, we show alterations in the gut microbiota composition of hypercholesterolemic patients with depletion of Bifidobacteria, expansion of Clostridia and increased Firmicutes/Bacteroidetes ratio. To test whether pharmacological intervention in gut microbiota impacts host serum levels of cholesterol, we treated hypercholesterolemic Apolipoprotein E knockout with oral largely non-absorbable antibiotics. Antibiotics increased serum cholesterol, but only when mice were fed normal chow diet and cholesterol was measured in the random fed state. These elevations in cholesterol already occurred few days after treatment initiation and were reversible after stopping antibiotics with re-acquisition of intestinal bacteria. Gene expression analyses pointed to increased intestinal cholesterol uptake mediated by antibiotics in the fed state. Non-targeted serum metabolomics suggested that diminished plant sterol levels and reduced bile acid cycling were involved microbial mechanisms. In conclusion, our work further enlightens the link between gut microbiota and host cholesterol metabolism. Pharmacological disruption of the gut flora by antibiotics was able to exacerbate serum cholesterol and may impact cardiovascular disease.


Assuntos
Antibacterianos , Microbioma Gastrointestinal , Hipercolesterolemia , Animais , Humanos , Camundongos , Antibacterianos/efeitos adversos , Colesterol/metabolismo , Firmicutes , Microbioma Gastrointestinal/efeitos dos fármacos , Hipercolesterolemia/microbiologia , RNA Ribossômico 16S/genética
5.
Front Endocrinol (Lausanne) ; 14: 1297847, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38313841

RESUMO

Introduction: Type 1 diabetes mellitus (T1DM) development involves a complex interplay of genetic, environmental, and immunological factors. By modulating the activity of proteases and receptors, the protein tissue inhibitor of metalloproteinase 3 (TIMP3) plays a role in limiting the expression and function of pro-inflammatory cytokines, which have been implicated in the advancement of T1DM. This study was aimed at examining the effect of TIMP3 overexpression in myeloid cells on the development of T1DM. Methods and results: Twelve weeks after multiple low doses of streptozotocin (MLDS) treatment, diabetic mice overexpressing TIMP3 specifically in myeloid cells under the CD68 promoter (MacT3 mice) showed improved insulin secretion, islet morphology and vascularization, antioxidant defense system, and regulatory factors of mitochondrial biosynthesis and function. To get mechanistic insights into the origin of this protection, the severity of insulitis and inflammatory parameters were evaluated in pancreatic tissues 11 days after MLSD treatment, showing significantly reduced insulitis and levels of the pro-inflammatory cytokine tumor necrosis factor-α, interleukin -1ß, and interferon -γ in MacT3 mice. Discussion: The results indicate that TIMP3 is involved in maintaining islet architecture and functions, at least in part, through modulation of pro-inflammatory cytokine production associated with insulitis and may represent a novel therapeutic strategy for T1DM.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Inibidor Tecidual de Metaloproteinase-3 , Animais , Camundongos , Linhagem da Célula , Citocinas/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Interferon gama , Hormônios Pancreáticos , Estreptozocina , Inibidor Tecidual de Metaloproteinase-3/genética
6.
Acta Diabetol ; 59(12): 1589-1596, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36044097

RESUMO

AIMS: Disturbances in circadian rhythms may promote cardiometabolic disorders in rotating night shift workers (r-NSWs). We hypothesized that timed light therapy might reverse disrupted circadian rhythms and glucose intolerance observed among r-NSWs). METHODS: R-NSWs were randomly assigned to a protocol that included 12 weeks on followed by 12 weeks off light therapy (n = 13; 6 men; mean age, 39.5 ± 7.3 years) or a no-treatment control group (n = 9; 3 men; mean age 41.7 ± 6.3 years). Experimental and control participants underwent identical metabolic evaluations that included anthropometric, metabolic (including oral glucose tolerance tests), lipid, and inflammation-associated parameters together with an assessment of sleep quality and expression of circadian transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs) at baseline, 12 weeks, and 24 weeks of the protocol. RESULTS: Twelve weeks of warm white-light exposure (10,000 lx at 35 cm for 30 min per day) had no impact on sleep, metabolic, or inflammation-associated parameters among r-NSWs in the experimental group. However, our findings revealed significant decreases in REV-ERBα gene expression (p = 0.048) and increases in the REV-ERBα/BMAL1 ratio (p = 0.040) compared to baseline in PBMCs isolated from this cohort. Diminished expression of REV-ERBα persisted, although the REV-ERBα/BMAL1 ratio returned to baseline levels after the subsequent 12-day wash-out period. CONCLUSIONS: Our results revealed that intermittent light therapy had no impact on inflammatory parameters or glucose tolerance in a defined cohort of r-NSWs. However, significant changes in the expression of circadian clock genes were detected in PBMCs of these subjects undergoing light therapy.


Assuntos
Fatores de Transcrição ARNTL , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Fatores de Transcrição ARNTL/genética , Leucócitos Mononucleares/metabolismo , Ritmo Circadiano/genética , Fototerapia , Inflamação , Glucose , Lipídeos
7.
Card Electrophysiol Clin ; 14(1): 21-28, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35221082

RESUMO

Coronavirus-19 disease (COVID-19) affects more people than previous coronavirus infections and has a higher mortality. Higher incidence and mortality can probably be explained by COVID-19 causative agent's greater affinity (about 10-20 times) for angiotensin-converting enzyme 2 (ACE2) receptor compared with other coronaviruses. Here, the authors first summarize clinical manifestations, then present symptoms of COVID-19 and the pathophysiological mechanisms underlying specific organ/system disease. The worse clinical outcome observed in COVID-19 patients with diabetes may be in part related to the increased ADAM17 activity and its unbalanced interplay with ACE2. Therefore, strategies aimed to inhibit ADAM17 activity may be explored to develop new effective therapeutic approaches.


Assuntos
COVID-19 , Doenças Vasculares , Humanos , SARS-CoV-2
8.
Mol Metab ; 59: 101454, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35150905

RESUMO

OBJECTIVE: Metabolic syndrome, obesity, and steatosis are characterized by a range of dysregulations including defects in ubiquitin ligase tagging proteins for degradation. The identification of novel hepatic genes associated with fatty liver disease and metabolic dysregulation may be relevant to unravelling new mechanisms involved in liver disease progression METHODS: Through integrative analysis of liver transcriptomic and metabolomic obtained from obese subjects with steatosis, we identified itchy E ubiquitin protein ligase (ITCH) as a gene downregulated in human hepatic tissue in relation to steatosis grade. Wild-type or ITCH knockout mouse models of non-alcoholic fatty liver disease (NAFLD) and obesity-related hepatocellular carcinoma were analyzed to dissect the causal role of ITCH in steatosis RESULTS: We show that ITCH regulation of branched-chain amino acids (BCAAs) degradation enzymes is impaired in obese women with grade 3 compared with grade 0 steatosis, and that ITCH acts as a gatekeeper whose loss results in elevation of circulating BCAAs associated with hepatic steatosis. When ITCH expression was specifically restored in the liver of ITCH knockout mice, ACADSB mRNA and protein are restored, and BCAA levels are normalized both in liver and plasma CONCLUSIONS: Our data support a novel functional role for ITCH in the hepatic regulation of BCAA metabolism and suggest that targeting ITCH in a liver-specific manner might help delay the progression of metabolic hepatic diseases and insulin resistance.


Assuntos
Aminoácidos de Cadeia Ramificada , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Obesidade , Ubiquitina-Proteína Ligases , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Regulação para Baixo , Feminino , Humanos , Camundongos , Camundongos Knockout , Obesidade/complicações , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
9.
iScience ; 25(1): 103707, 2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35036884

RESUMO

Compelling evidence support an involvement of oxidative stress and intestinal inflammation as early events in the predisposition and development of obesity and its related comorbidities. Here, we show that deficiency of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) in the gastrointestinal tract drives spontaneous obesity. Intestinal epithelium-specific Sod2 ablation in mice induced adiposity and inflammation via phospholipase A2 (PLA2) activation and increased release of omega-6 polyunsaturated fatty acid arachidonic acid. Remarkably, this obese phenotype was rescued when fed an essential fatty acid-deficient diet, which abrogates de novo biosynthesis of arachidonic acid. Data from clinical samples revealed that the negative correlation between intestinal Sod2 mRNA levels and obesity features appears to be conserved between mice and humans. Collectively, our findings suggest a role of intestinal Sod2 levels, PLA2 activity, and arachidonic acid in obesity presenting new potential targets of therapeutic interest in the context of this metabolic disorder.

10.
Diagnostics (Basel) ; 11(11)2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34829465

RESUMO

BACKGROUND: The aim of this study was to evaluate how the high sensitivity C-reactive protein (hs-CRP) values influence the risk of carotid plaque instability in association with other cardiovascular risk factors. METHODS: One hundred and fifty-six carotid plaques from both symptomatic and asymptomatic patients requiring surgical carotid endarterectomy were retrospectively collected. According to the modified American Heart Association, atherosclerosis plaques have been histologically distinguished into unstable and stable. The following anamnestic and hematochemical data were also considered: age, gender, hypertension, diabetes mellitus, smoking habit, therapy, low-density lipoprotein (LDL)-C, kidney failure and hs-CRP. RESULTS: The results of our study clearly show that high levels of hs-CRP significantly increase the carotid plaque instability in dyslipidemic patients. Specifically, a 67% increase of the risk of carotid plaque instability was observed in patients with high LDL-C. Therefore, the highest risk was observed in male dyslipidemic patients 2333 (95% CI 0.73-7.48) and in aged female patients 2713 (95% CI 0.14-53.27). DISCUSSION: These data strongly suggest a biological relationship between the hs-CRP values and the alteration of lipidic metabolism mostly in male patients affected by carotid atherosclerosis. The measurement of hs-CRP might be useful as a potential screening tool in the prevention of atheroscletotic disease.

11.
Br J Pharmacol ; 178(24): 4891-4906, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34411281

RESUMO

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) patients exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour in ALS has not been studied in detail. We here investigated if microglial KCa 3.1 is linked to hypothalamic neuroinflammation and affects feeding behaviours in ALS mouse models. EXPERIMENTAL APPROACH: hSOD1G93A and TDP43A315T mice were treated daily with 120 mg·kg-1 of TRAM-34 or vehicle by intraperitoneal injection from the presymptomatic until the disease onset phase. Body weight and food intake were measured weekly. The later by weighing food provided minus that left in the cage. RT-PCR and immunofluorescence analysis were used to characterize microglia phenotype and the main populations of melanocortin neurons in the hypothalamus of hSOD1G93A and age-matched non-tg mice. The cannabinoid-opioid interactions in feeding behaviour of hSOD1G93A mice were studied using an inverse agonist and an antagonist of the cannabinoid receptor CB1 (rimonabant) and µ-opioid receptors (naloxone), respectively. KEY RESULTS: We found that treatment of hSOD1G93A mice with the KCa 3.1 inhibitor TRAM-34 (i), attenuates the pro-inflammatory phenotype of hypothalamic microglia, (ii) increases food intake and promotes weight gain, (iii) increases the number of healthy pro-opiomelanocortin (POMC) neurons and (iv), changes the expression of cannabinoid receptors involved in energy homeostasis. CONCLUSION AND IMPLICATIONS: Using ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for KCa 3.1 to counteract weight loss in ALS.


Assuntos
Esclerose Lateral Amiotrófica , Comportamento Alimentar , Canais de Potássio Cálcio-Ativados/metabolismo , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/metabolismo , Animais , Modelos Animais de Doenças , Metabolismo Energético , Homeostase , Melanocortinas , Camundongos , Camundongos Transgênicos , Microglia/citologia , Pirazóis/farmacologia , Receptores de Canabinoides , Medula Espinal/metabolismo , Superóxido Dismutase-1/metabolismo , Aumento de Peso
12.
Acta Diabetol ; 58(12): 1587-1594, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34181080

RESUMO

Diabetic kidney disease, one of the most severe complications associated with diabetes, is characterized by albuminuria, glomerulosclerosis and progressive loss of renal function. Loss of TIMP3, an Extracellular matrix-bound protein, is a hallmark of diabetic nephropathy in human and mouse models, suggesting its pivotal role in renal diseases associated to diabetes. There is currently no specific therapy for diabetic nephropathy, and the ability to restore high TIMP3 activity specifically in the kidney may represent a potential therapeutic strategy for the amelioration of renal injury under conditions in which its reduction is directly related to the disease. Increasing evidence shows that diabetic nephropathy is also regulated by epigenetic mechanisms, including noncoding RNA. This review recapitulates the pathological, diagnostic and therapeutic potential roles of TIMP3 and the noncoding RNA (microRNA, long noncoding RNA) related to its expression, in the progression of diabetic nephropathy.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , MicroRNAs , Albuminúria , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Humanos , Rim , Camundongos , Prognóstico , Inibidor Tecidual de Metaloproteinase-3
13.
J Clin Endocrinol Metab ; 106(11): e4350-e4359, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34192323

RESUMO

CONTEXT: Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1ß, IL-6, IL-8, and TNF-α, that is associated with cardiovascular disease. OBJECTIVE: We investigated whether REMAP is associated with and improves the prediction of mortality in T2D. METHODS: A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification. RESULTS: REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase = 1.34, P < .001). In CEA patients, REMAP was associated with mortality (HR = 1.64, P = .04) and a modest change was observed when plaque stability was taken into account (HR = 1.58; P = .07). REMAP improved discrimination and reclassification measures of both Estimation of Mortality Risk in Type 2 Diabetic Patients and Risk Equations for Complications of Type 2 Diabetes, well-established prediction models of mortality in T2D (P < .05-< .001). CONCLUSION: REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1ß monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested.


Assuntos
Citocinas/sangue , Complicações do Diabetes/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/mortalidade , Inflamação/sangue , Resistina/sangue , Idoso , Aterosclerose/sangue , Aterosclerose/complicações , Aterosclerose/terapia , Biomarcadores/sangue , Estudos de Coortes , Complicações do Diabetes/terapia , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Inflamação/complicações , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/sangue , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/patologia , Estudos Prospectivos , Fatores de Risco , Fator de Necrose Tumoral alfa/sangue
14.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068941

RESUMO

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Fibrose/prevenção & controle , Lisina/química , Nitrofuranos/farmacologia , Ramipril/farmacologia , Sulfonas/farmacologia , Ubiquitinação , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Quimioterapia Combinada , Feminino , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Camundongos , Camundongos Endogâmicos DBA
15.
Acta Diabetol ; 58(8): 1111-1117, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33788000

RESUMO

OBJECTIVE: To detect premature gluco-metabolic defects among night shift workers with disturbances in circadian rhythms. DESIGN AND METHODS: We performed a hypothesis-generating, cross-sectional analysis of anthropometric, metabolic, lipid, and inflammation parameters, comparing active (a-NSW, n = 111) and former (f-NSW, n = 98) rotating night shift workers with diurnal workers (controls, n = 69). All participants were hospital nurses. We also evaluated the Pittsburgh Sleep Quality Index (PSQI) and assessed expression of transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs), as indicators of the molecular clock. RESULTS: Both a-NSW and f-NSW participants had significantly higher glycated hemoglobin (HbA1c) and white blood cell counts (WBC) (p < 0.001 for both), PSQI global score (p = 0.001) and diastolic blood pressure levels (p = 0.024) compared with controls. Expression of REV-ERBα/BMAL1 RNA in PBMC was significantly higher in a-NSW (p = 0.05) than in f-NSW or control participants. Multivariate regression analysis showed that working status and PSQI were independent determinants of higher HbA1c levels (p < 0.001). CONCLUSIONS: We demonstrated that young, healthy night shift workers show subclinical abnormalities in HbA1c and changes in peripheral clock gene expression.


Assuntos
Fatores de Transcrição ARNTL/genética , Expressão Gênica , Hemoglobinas Glicadas/análise , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Jornada de Trabalho em Turnos , Fatores de Transcrição ARNTL/sangue , Adulto , Pressão Sanguínea , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Estudos Transversais , Feminino , Hospitais , Humanos , Inflamação , Contagem de Leucócitos , Leucócitos Mononucleares/química , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/sangue , Enfermeiras e Enfermeiros , RNA/sangue , Sono/fisiologia
16.
Clin Transl Med ; 11(2): e305, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33634991

RESUMO

BACKGROUND: Diabetic nephropathy (DN), one of the major complications of diabetes, is characterized by albuminuria, glomerulosclerosis, and progressive loss of renal function. Loss of TIMP3, an Extracellular Matrix bound protein affecting both inflammation and fibrosis, is a hallmark of DN in human subjects and mouse models. METHODS: This study was designed to provide evidences that the modulation of the system involving TIMP3 and its target A Disintegrin And Metalloproteinase 17 (ADAM17), may rescue kidney pathology in diabetic mice. Mice with cell-targeted overexpression of TIMP3 in myeloid cells (MacT3), podocyte-specific ADAM17 knockout mice (∆PodA17), and DBA/2J mice, were rendered diabetic at 8 weeks of age with a low-dose streptozotocin protocol. DBA/2J mice were administered new peptides based on the human TIMP3 N-terminal domain, specifically conjugated with G3C12, a carrier peptide highly selective and efficient for transport to the kidney. Twelve weeks after Streptozotocin injections, 24-hour albuminuria was determined by ELISA, kidney morphometry was analyzed by periodic acid-shift staining, and Real Time-PCR and western blot analysis were performed on mRNA and protein extracted from kidney cortex. RESULTS: Our results showed that both genetic modifications and peptides treatment positively affect renal function and structure in diabetic mice, as indicated by a significant and consistent decline in albuminuria along with reduction in glomerular lesions, as indicated by reduced mesangial expansion and glomerular hypertrophy, decreased deposition of extracellular matrix in the mesangium, diminished protein expression of the NADPH oxidases 4 (NOX4), and the improvement of podocyte structural markers such as WT1, nephrin, and podocin. Moreover, the positive effects were exerted through a mechanism independent from glycemic control. CONCLUSIONS: In diabetic mice the targeting of TIMP3 system improved kidney structure and function, representing a valid approach to develop new avenues to treat this severe complication of diabetes.


Assuntos
Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/prevenção & controle , Expressão Gênica/genética , Rim/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-3/genética , Animais , Antibióticos Antineoplásicos/administração & dosagem , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Estreptozocina/administração & dosagem
17.
Eur Radiol ; 31(4): 1923-1931, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32965572

RESUMO

OBJECTIVES: To evaluate the diagnostic accuracy of venous-phase dual-energy computed tomography (VP-DECT) in the identification of PE compared with standard CT pulmonary angiography (CTPA). METHODS: This prospective IRB-approved study included 61 consecutive oncology patients (35 females, 26 males, mean age 66.91 years) examined by CTPA and VP-DECT. DECT data were post-processed on a SyngoVia workstation to obtain monoenergetic images (MEI+). The diagnosis of PE was based on the presence of any vascular perfusion defects. DECT images were evaluated independently by two radiologists (8 and 16 years of experience). A consensus reading of CTPA images (two senior radiologists, 18 and 24 years of experience) represented the reference for diagnosis. The diagnostic accuracy values of VP-DECT on a per-patient and per-lobe basis were assessed. Interobserver agreement was calculated using k-statistics. A value of p < 0.05 was considered statistically significant. RESULTS: Thirty of 61 patients (49.18%) were diagnosed with PE by CTPA, with 57/366 lobes being involved (15.57%). The sensitivity and specificity of the per-patient analysis of VP-DECT images were 90.0% (27/30) and 100% (31/31) respectively, for both readers. As concerns the per-lobe analysis, the sensitivity ranged from 100% for the right lower lobe to 50% for the left upper lobe for reader 1, and from 100% for the left upper lobe to 69.23% for the lingula for reader 2. The interobserver agreement ranged from 0.8671 (patients' analysis) to 0.6419 (lobes' analysis). CONCLUSION: VP-DECT could be considered an accurate imaging tool for diagnosing PE in a selected, high-prevalence population, compared with CTPA. KEY POINTS: • With regard to the patients' analysis, venous-phase DECT sensitivity and specificity in diagnosing pulmonary embolism were 90% and 100%, respectively, for both readers. • With regard to the lobes' analysis, the sensitivity ranged from 100 to 50%, for reader 1, and from 100 to 69.23%, for reader 2, respectively. • The sensitivity and specificity of lung perfusion maps obtained from venous DECT were 73.33% and 67.74% as concerns the patients' analysis and 71.92% and 75.72% as regards the lobes' analysis, respectively.


Assuntos
Artéria Pulmonar , Embolia Pulmonar , Idoso , Angiografia , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Masculino , Estudos Prospectivos , Artéria Pulmonar/diagnóstico por imagem , Embolia Pulmonar/diagnóstico por imagem , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
18.
Mol Metab ; 36: 100976, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251665

RESUMO

OBJECTIVE: The metabolic influence of gut microbiota plays a pivotal role in the pathogenesis of cardiometabolic diseases. Antibiotics affect intestinal bacterial diversity, and long-term usage has been identified as an independent risk factor for atherosclerosis-driven events. The aim of this study was to explore the interaction between gut dysbiosis by antibiotics and metabolic pathways with the impact on atherosclerosis development. METHODS: We combined oral antibiotics with different diets in an Apolipoprotein E-knockout mouse model linking gut microbiota to atherosclerotic lesion development via an integrative cross-omics approach including serum metabolomics and cecal 16S rRNA targeted metagenomic sequencing. We further investigated patients with carotid atherosclerosis compared to control subjects with comparable cardiovascular risk. RESULTS: Here, we show that increased atherosclerosis by antibiotics was connected to a loss of intestinal diversity and alterations of microbial metabolic functional capacity with a major impact on the host serum metabolome. Pathways that were modulated by antibiotics and connected to atherosclerosis included diminished tryptophan and disturbed lipid metabolism. These pathways were related to the reduction of certain members of Bacteroidetes and Clostridia by antibiotics in the gut. Patients with atherosclerosis presented a similar metabolic signature as those induced by antibiotics in our mouse model. CONCLUSION: Taken together, this work provides insights into the complex interaction between intestinal microbiota and host metabolism. Our data highlight that detrimental effects of antibiotics on the gut flora are connected to a pro-atherogenic metabolic phenotype beyond classical risk factors.


Assuntos
Aterosclerose/metabolismo , Aterosclerose/microbiologia , Microbioma Gastrointestinal/genética , Idoso , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Bactérias/genética , Ceco/microbiologia , Progressão da Doença , Fezes , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Redes e Vias Metabólicas , Metaboloma , Metabolômica/métodos , Camundongos , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Soro/química
19.
Int J Biochem Cell Biol ; 118: 105659, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31765819

RESUMO

The O subfamily of forkhead (FoxO) 1 is a crucial regulator of cell metabolism in several tissues, including the heart, where it is involved in cardiac regulation of glucose and lipid metabolic pathways, and endothelium, controlling the levels of some relevant biomarkers in atherosclerotic process. Despite the growing understanding of FoxO1 biology, the metabolic consequences of FoxO1 modifications and its implication in CVD, atherosclerosis and T2DM are still not incompletely described. In this review we discuss how FoxO1 affects cardiovascular pathophysiology and which of its effects should be restrained or enhanced to preserve endothelial and heart functions.


Assuntos
Aterosclerose/genética , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Proteína Forkhead Box O1/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Proteína Forkhead Box O1/metabolismo , Glucose/genética , Glucose/metabolismo , Coração/fisiopatologia , Humanos , Metabolismo dos Lipídeos/genética , Miocárdio/metabolismo , Transdução de Sinais/genética
20.
Acta Diabetol ; 56(12): 1265-1274, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31292722

RESUMO

AIM: Obesity and low-grade inflammation are associated with an increased risk of hepatocellular carcinoma (HCC), a leading cause of cancer-related death worldwide. The tissue inhibitor of metalloproteinase (TIMP) 3, an endogenous inhibitor of protease activity that represents a key mediator of inflammation, is reduced in inflammatory metabolic disorders and cancer. In contrast, Timp3-deficient mice (Timp3-/-) are highly resistant to developing HCC in response to a diethylnitrosamine (DEN); therefore, we aimed to elucidate the biological role of genetic loss of Timp3 in obesity-related hepatocarcinogenesis. METHODS: Fourteen-day-old male wild-type (wt) and Timp3-/- mice were injected with 25 mg/kg DEN or an equal volume of saline. After 4 weeks, mice were randomized into two dietary groups and fed either normal or high-fat diet and allowed to grow until 32 weeks of age. Liver histological features were analyzed, and differentially expressed genes in the liver were quantified. RESULTS: In Timp3-/- mice fed with the obesogenic diet, despite the increase in liver steatosis and inflammation, both the number of tumors and the total tumor size are significantly reduced 30 weeks post-DEN injection, compared to control mice. Moreover, Timp3 deletion in hepatocarcinogenesis during obesity is associated with a reduction in FoxM1 transcriptional activity through H19/miR-675/p53 pathway. CONCLUSIONS: This study suggests that Timp3 ablation leads to cell cycle perturbation, at least in part by repressing FoxM1 transcriptional activity through H19/miR-675/p53 pathway.


Assuntos
Carcinoma Hepatocelular/patologia , Dieta Hiperlipídica/efeitos adversos , Neoplasias Hepáticas/patologia , Obesidade/etiologia , Inibidor Tecidual de Metaloproteinase-3/genética , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Dietilnitrosamina , Progressão da Doença , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Proteína Forkhead Box M1/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/patologia , Transdução de Sinais/genética
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