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Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.
Assuntos
Tecido Adiposo , Fígado Gorduroso , Leptina , Fígado , Omento , Humanos , Leptina/metabolismo , Feminino , Masculino , Fígado/metabolismo , Pessoa de Meia-Idade , Omento/metabolismo , Omento/patologia , Tecido Adiposo/metabolismo , Adulto , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Receptores para Leptina/metabolismo , Receptores para Leptina/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Resistência à Insulina , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/genéticaRESUMO
Chronic Non-Communicable Diseases (NCDs) have been considered a global health problem, characterized as diseases of multiple factors, which are developed throughout life, and regardless of genetics as a risk factor of important relevance, the increase in mortality attributed to the disease to environmental factors and the lifestyle one leads. Although the reactive species (ROS/RNS) are necessary for several physiological processes, their overproduction is directly related to the pathogenesis and aggravation of NCDs. In contrast, dietary polyphenols have been widely associated with minimizing oxidative stress and inflammation. In addition to their antioxidant power, polyphenols have also drawn attention for being able to modulate both gene expression and modify epigenetic alterations, suggesting an essential involvement in the prevention and/or development of some pathologies. Therefore, this review briefly explained the mechanisms in the development of some NCDs, followed by a summary of some evidence related to the interaction of polyphenols in oxidative stress, as well as the modulation of epigenetic mechanisms involved in the management of NCDs.
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BACKGROUND: The aim of the present study was to evaluate the methylation pattern in the suppressor of cytokine signaling 1 (SOCS1) gene in smokers and non-smokers with chronic periodontitis (CP). METHODS: Methylation-specific polymerase chain reaction (PCR) was performed to determine the methylation status of the SOCS1 promoter in 45 saliva samples from smokers and non-smokers with CP. RESULTS: Cells from the saliva of CP patients who smoked were 7.08 times more likely to have a methylated SOCS1 promoter than cells from the saliva of non-smoking patients. CONCLUSIONS: SOCS1 gene promoter methylation, with its potential effects on the expression of this gene, seems to be a consequence of exposure to tobacco and not to periodontal disease. Further studies are needed to elucidate the relationship between the epigenetic control of immune response gene expression, exposure to environmental factors, and the development, progression, and prognosis of CP.
Assuntos
Periodontite Crônica , Metilação de DNA , Células Epiteliais , Humanos , Regiões Promotoras Genéticas , Saliva , Proteína 1 Supressora da Sinalização de CitocinaRESUMO
Tumor suppressor gene promoter CpG island methylation is a well-recognized mechanism in cancer pathogenesis, but its role in multiple myeloma (MM) is controversial. The present study investigated the methylation status and expression of P16, suppressor of cytokine signaling 1 (SOCS-1), P73, E-cadherin and Src homology region 2 domain-containing phosphatase 1 (SHP-1), as well as global methylation in patients with MM during active disease and remission. Bone marrow samples were obtained from 43 patients at the Multiple Myeloma Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (Mexico City, Mexico) during active disease and remission. Methylation-specific polymerase chain reaction and ELISA were performed on bisulfite-treated or untreated DNA to determine promoter-specific or genomic methylation, respectively. Gene expression was measured using reverse-transcription polymerase chain reaction. The results indicated that SOCS-1 methylation occurred more frequently during active disease than remission [29 vs. 3.2% (P=0.021)] and was associated with more advanced forms of the disease [international staging system (ISS) 3, 16.67% vs. ISS 1, 8.3% (P=0.037)]. SHP-1 methylation during active disease was associated with a lower probability of survival at 39-month follow up (median), 52.5 vs. 87.5% (P=0.025). The percentage of methylation was associated with active disease at remission, but this was not significant. Global hypomethylation at remission was a negative predictor factor for overall survival (OS). The results indicated that methylated P16, SOCS-1 and SHP-1 were associated with clinical variables of poor prognosis in MM, likewise the persistence of global hypomethylation at remission. The negative impact on OS of global hypomethylation at remission must be confirmed in a larger sample. Future studies are necessary to investigate whether patients with global hypermethylation at remission should receive more aggressive treatments to improve their OS.
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Abstract This study aimed to characterize the dynamics of suppressor of cytokine signaling (SOCS1) expression in a rat model of lipopolysaccharide-induced periodontitis. Wistar rats in the experimental groups were injected three times/week with LPS from Escherichia coli on the palatal aspect of the first molars, and control animals were injected with vehicle (phosphate-buffered saline). Animals were sacrificed 7, 15, and 30 days after the first injection to analyze inflammation (stereometric analysis), bone loss (macroscopic analysis), gene expression (qRT-PCR), and protein expression/activation (Western blotting). The severity of inflammation and bone loss associated with LPS-induced periodontitis increased from day 7 to day 15, and it was sustained through day 30. Significant (p < 0.05) increases in SOCS1, RANKL, OPG, and IFN-γ gene expression were observed in the experimental group versus the control group at day 15. SOCS1 protein expression and STAT1 and NF-κB activation were increased throughout the 30-day experimental period. Gingival tissues affected by experimental periodontitis express SOCS1, indicating that this protein may potentially downregulate signaling events involved in inflammatory reactions and bone loss and thus may play a relevant role in the development and progression of periodontal disease.
Assuntos
Animais , Masculino , Periodontite/patologia , Perda do Osso Alveolar/patologia , Proteína 1 Supressora da Sinalização de Citocina/análise , Periodontite/etiologia , Periodontite/metabolismo , Fatores de Tempo , Imuno-Histoquímica , Distribuição Aleatória , Lipopolissacarídeos , Western Blotting , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/metabolismo , NF-kappa B/análise , Interferon gama/análise , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/análise , Ligante RANK/análiseRESUMO
OBJECTIVES: DNA methylation plays a critical role in the regulation of the transcription of the suppressors of cytokine signaling (SOCS) 1 and SOCS3, which are modulators in the inflammation. We hypothesized that the methylation status of SOCS1, SOCS3, and long interspersed nuclear element (LINE)-1 in gingival tissues previously inflamed would be similar to that found in gingival tissues without clinical inflammation in the period studied. MATERIALS AND METHODS: Laser capture microdissection was performed to isolate epithelial and connective gingival tissues. The groups were comprised by ten patients without history of periodontitis and absence of clinical signs of inflammation in the gingiva during the study (healthy group) and ten patients with history of periodontitis, presenting inflammation in the gingival tissue at the first examination of the study (controlled chronic periodontitis group). The gingival biopsies from the controlled chronic periodontitis group were collected after controlling the inflammation. DNA methylation patterns were analyzed using methylation-specific high-resolution melting and combined bisulfite restriction analysis. RESULTS: DNA methylation levels for SOCS1 and SOCS3 did not differ between groups or tissues; likewise, no differences were observed in total LINE-1 methylation or at specific loci. CONCLUSION: At 3 months following control of inflammation in gingival tissues, the methylation profile of SOCS1, SOCS3, and LINE-1 is similar between connective and epithelial tissues from patients that were previously affected or not by chronic inflammation. CLINICAL RELEVANCE: Clinical results of a successful treatment are observed after inflammation control and the molecular findings illustrate local and general methylation patterns in recovering tissues toward health conditions and might help to understand events that are occurring in oral cells.
Assuntos
Metilação de DNA , Desoxirribonuclease I/metabolismo , Gengiva/metabolismo , Periodontite/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Biópsia , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: During pregnancy, women normally increase their food intake and body fat mass, and exhibit insulin resistance. However, an increasing number of women are developing metabolic imbalances during pregnancy, including excessive gestational weight gain and gestational diabetes mellitus. Despite the negative health impacts of pregnancy-induced metabolic imbalances, their molecular causes remain unclear. Therefore, the present study investigated the molecular mechanisms responsible for orchestrating the metabolic changes observed during pregnancy. METHODS: Initially, we investigated the hypothalamic expression of key genes that could influence the energy balance and glucose homeostasis during pregnancy. Based on these results, we generated a conditional knockout mouse that lacks the suppressor of cytokine signaling-3 (SOCS3) only in leptin receptor-expressing cells and studied these animals during pregnancy. RESULTS: Among several genes involved in leptin resistance, only SOCS3 was increased in the hypothalamus of pregnant mice. Remarkably, SOCS3 deletion from leptin receptor-expressing cells prevented pregnancy-induced hyperphagia, body fat accumulation as well as leptin and insulin resistance without affecting the ability of the females to carry their gestation to term. Additionally, we found that SOCS3 conditional deletion protected females against long-term postpartum fat retention and streptozotocin-induced gestational diabetes. CONCLUSIONS: Our study identified the increased hypothalamic expression of SOCS3 as a key mechanism responsible for triggering pregnancy-induced leptin resistance and metabolic adaptations. These findings not only help to explain a common phenomenon of the mammalian physiology, but it may also aid in the development of approaches to prevent and treat gestational metabolic imbalances.
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Therapies that improve leptin sensitivity have potential as an alternative treatment approach against obesity and related comorbidities. We investigated the effects of Socs3 gene ablation in different mouse models to understand the role of SOCS3 in the regulation of leptin sensitivity, diet-induced obesity (DIO) and glucose homeostasis. Neuronal deletion of SOCS3 partially prevented DIO and improved glucose homeostasis. Inactivation of SOCS3 only in LepR-expressing cells protected against leptin resistance induced by HFD, but did not prevent DIO. However, inactivation of SOCS3 in LepR-expressing cells protected mice from diet-induced insulin resistance by increasing hypothalamic expression of Katp channel subunits and c-Fos expression in POMC neurons. In summary, the regulation of leptin signaling by SOCS3 orchestrates diet-induced changes on glycemic control. These findings help to understand the molecular mechanisms linking obesity and type 2 diabetes, and highlight the potential of SOCS3 inhibitors as a promising therapeutic approach for the treatment of diabetes.
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Recent studies provide evidence on the emerging role of the SOCS1 gene in the development and progression of atherosclerotic lesions. This gene encodes for the suppressor of the cytokine signaling-1 protein that interacts directly with the Janus kinases that are essential intracellular mediators of the immune cytokine action. The aim of this study was to test for associations between SOCS1 gene single nucleotide polymorphisms (SNPs) and the risk of developing acute coronary syndromes (ACS) in a group of Mexicans patients. Four SNPs [-3969 C>T (rs243327), -1656 G>A (rs243330), -820 G>T (rs33977706) and +1125 G>C (rs33932899)] of SOCS1 gene were determined for TaqMan genotyping assays in a group of 447 patients with ACS and 622 healthy controls. Under heterozygous model, the -3969 C>T (rs243327) SNP was associated with increased risk of ACS (OR=1.45, P(Het)=0.021). On the other hand, under co-dominant and heterozygous models, the -1656 G/A (rs243330) SNP was associated with increased risk of ACS (OR=1.47, P(Co-dom)=0.038 and OR=1.50, P(Het)=0.013, respectively). Moreover, under co-dominant, dominant, and heterozygous models, the -820T/G (rs33977706) SNP was associated with increased risk of ACS (OR=1.59, P(Co-dom)=0.03, OR=1.48, P(Dom)=0.028 and OR=1.61, P(Het)=0.01). Finally, under co-dominant and heterozygous models, the +1125 G/C (rs33932899) SNP was associated with increased risk of ACS (OR=1.54, P(Co-dom)=0.006, OR=1.58, P(Het)=0.012, respectively). Models were adjusted for gender, age, body index mass, dyslipidemia, alcohol consumption, and smoking. In summary, our data suggests that the four studied polymorphisms of the SOCS1 gene play an important role as susceptibility markers for developing ACS.
Assuntos
Síndrome Coronariana Aguda/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras da Sinalização de Citocina/genética , Síndrome Coronariana Aguda/epidemiologia , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Proteína 1 Supressora da Sinalização de CitocinaRESUMO
O Trypanosoma cruzi é um parasita intracelular e agente causador da doença de Chagas, que afeta milhões de pessoas em todo o mundo. Sabe-se que durante os processos de inflamação, regeneração e fibrose desencadeados pelo T. cruzi no hospedeiro há a participação de diversos mediadores e fatores. O objetivo deste trabalho foi avaliar a associação entre polimorfismos de nucleotídeos únicos com as formas clínicas e o grau de fibrose em pacientes com doença de Chagas. Os polimorfismos foram analisados por PCR em tempo real. Foram incluídos no estudo 55 pacientes com diagnóstico de doença de Chagas e classificados de acordo com a forma clínica da doença, sendo que 17 apresentavam a forma indeterminada, 15 a forma cardíaca sem disfunção ventricular e 23 a forma cardíaca com disfunção ventricular. Os genótipos CA dos polimorfismos do gene LGALS3 (rs4644 e rs4652); AG e GG do SOCS3 (rs4969170); CT e TT do IL-28B (rs12979860 e 8099917, respectivamente); AG, AG, CC, AG e AG do CLDN-1 (rs10212165, rs3909582, rs9865082, rs9880018 e rs9848283, respectivamente); e CC do CCL5 (rs2280789) foram estatisticamente mais frequentes em pacientes com a forma cardíaca do que com a forma indeterminada da doença. Com relação ao grau de fibrose, os genótipos CC dos polimorfismos do gene LGALS3 (rs4644 e rs4652); AA do SOCS3 (rs4969170); CC do rs12979860 e TT do rs8099917 do IL-28B; AA do rs10212165, AA, AG e GG do rs3909582, CC e CT do rs9865082, AG e GG do rs9880018 e AA do rs9848283 do gene CLDN1; e CC do CCL5 (rs2280789) foram estatisticamente mais frequentes em indivíduos com fibrose cardíaca <15% quando comparados com o grupo com fibrose ≥15%. Diante do exposto concluimos que os polimorfismos analisados podem ser úteis como futuros biomarcadores para estadiamento e conduta terapêutica em pacientes com doença de Chagas.
Trypanosoma cruzi is an intracellular parasite and the agent that causes Chagas disease, which affects millions of people worldwide. Several factors and mediators are known to actively participate in the inflammation, fibrosis and tissue regeneration, which is triggered by T. cruzi within the host. The aim of this study was to evaluate the association of single nucleotide polymorphisms with clinical forms and rate of fibrosis in Chagas disease patients. The polymorphisms were analyzed by real-time PCR. The study consisted of 55 Chagas disease patients that were classified according to the clinical form of the disease, including 17 patients presenting the indeterminate form, 15 patients presenting the cardiac form without ventricular dysfunction and 23 patients presenting the cardiac form with ventricular dysfunction. The genotypes of CA of LGALS3 gene polymorphisms (rs4644 and rs4652); AG and GG of SOCS3 (rs4969170); CT and TT of IL-28B (rs12979860 and 8099917, respectively); AG, AG, CC, AG and AG of CLDN-1 (rs10212165, rs3909582, rs9865082, rs9880018 and rs9848283, respectively); and CC of CCL5 (rs2280789) were significantly more frequent in patients presenting the cardiac form compared to patients presenting the indeterminate form. Regarding the degree of fibrosis, the CC genotype of polymorphisms of the genes LGALS3 (rs4644 and rs4652); AA of SOCS3 (rs4969170); CC of rs12979860 and TT of rs8099917 of the IL-28B; AA of rs10212165 and AA, AG and GG of rs3909582, CC and CT of rs9865082, AG and GG of rs9880018 and AA of rs9848283 of the gene CLDN1; and CC of CCL5 (rs2280789) were statistically more frequent in patients presenting <15% cardiac fibrosis when compared to patients presenting fibrosis ≥15%. Taken together, our results suggest that the polymorphisms analyzed may be useful biomarkers for therapeutic management of patients with Chagas disease.
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Humanos , Doença de Chagas/complicações , Doença de Chagas/diagnóstico , Doença de Chagas/mortalidade , Doença de Chagas/parasitologia , Doença de Chagas/patologia , Doença de Chagas/prevenção & controle , Doença de Chagas/terapia , Trypanosoma cruzi , Trypanosoma cruzi/crescimento & desenvolvimentoRESUMO
Maternal exposure to nicotine during lactation causes hyperleptinemia in the pups and, at adulthood, these animals are overweight and hyperleptinemic, while, in their hypothalamus, the leptin signaling pathway is reduced, evidencing a central leptin resistance. Then, we evaluated the expression of pro-opiomelanocortin (POMC), alpha-melanocyte stimulating hormone (α-MSH), cocaine and amphetamine-regulated transcript (CART), neuropeptide Y (NPY), agouti-related peptide (AgRP) and others in different hypothalamic nuclei in order to better understand the mechanisms underlying the obese phenotype observed in these animals at adulthood. On the 2nd postnatal day (P2), dams were subcutaneously implanted with osmotic minipumps releasing nicotine (NIC-6 mg/kg/day) or saline for 14 days. Offspring were killed in P180 and immunohistochemistry and Western blot analysis were carried out. Significance data had p<0.05. Adult NIC offspring showed more intense NPY staining in the paraventricular nucleus (PVN) (+21%) and increased number of POMC-positive cells in the: arcuate nucleus (+33%), as an increase in fiber density of α-MSH in PVN (+85%). However, the number of CART-positive cells was reduced in the PVN (-25%). CRH staining was more intense in NIC offspring (+136%). Orexins and AgRP were not altered. Thus, maternal nicotine exposure changes hypothalamic neuropeptides in the adult progeny that is partially compatible with leptin resistance.