Summary
Ageing can be defined as the progressive failure of repair and maintenance systems with a consequent accumulation of cellular damage in nucleic acids, proteins, and lipids. These various types of damage promote ageing by driving cellular senescence and apoptosis. The nuclear factor‐kappa B (NF‐kB) pathway is one of the key mediators of ageing and this pathway is activated by genotoxic, oxidative and inflammatory stress, and regulates expression of cytokines, growth factors, and genes that regulate apoptosis, cell‐cycle progression, and inflammation. Therefore, NF‐kB is increased in a variety of tissues with ageing, thus the inhibition of NF‐kB leads to delayed onset of ageing‐related symptoms and pathologies such as diabetes, atherosclerosis, and cancer. Metformin is often used as an anti‐diabetic medication in type 2 diabetes throughout the world and appears to be a potential anti‐ageing agent. Owing to its antioxidant, anticancer, cardio‐protective and anti‐inflammatory properties, metformin has become a potential candidate drug, improving in the context of ageing and ageing‐related diseases. An inappropriate NF‐kB activation is associated with diseases and pathologic conditions which can impair the activity of genes involved in cell senescence, apoptosis, immunity, and inflammation. Metformin, inhibiting the expression of NF‐kB gene, eliminates the susceptibility to common diseases. This review underlines the pleiotropic effects of metformin in ageing and different ageing‐related diseases and attributes its effects to the modulation of NF‐kB.
Metformin is the most widely used anti-diabetic drug in the world. It reduces advanced glycation end product (AGEs)-induced ROS generation in high glucose condition. Protein glycation contributes to skin aging as it deteriorates the existing collagen by crosslinking. The progressive increase of AGE during aging not only causes oxidative damage to cellular macromolecules but also modulates the activation of transcription factors nuclear factor kappa-B(NF-kB). However, it is still unclear whether metformin can change collagen production and NF-kB activity induced by high glucose conditions in 3T3 fibroblast. The effects of metformin on proliferation, apoptosis, and collagen levels and NF-kB activity of in vitro cell aging model of 3T3 fibroblast cells in high glucose conditions. At first, we investigated the effects of 50 mM high glucose concentration, with or without metformin, on 3T3 fibroblast proliferation, by BrdU immunostaining for cell proliferation. Apoptotic levels were analyzed by flow cytometric assay. NF-kB(p65) activity was measured by transcription factor assay kit and collagen I and III levels by Collagen Estimation Assay through ELISA. We observed that metformin exposure leads to decreased apoptosis levels and increased proliferation of 3T3 fibroblast in high glucose media. We also determined that metformin exposure leads to increased production of collagen I-III and decreased activation of NF-kB(p65) activity. The data are consistent with the observation that metformin has a protective effect in this in vitro model of aging 3T3 fibroblasts under high glucose conditions inducing cell proliferation, collagen I and III production, protection from apoptosis, and reducing NF-kB(p65) activity.
Morbid obesity (MO) is associated with an increase in circulating levels of systemic acute phase proteins such as C-reactive protein (CRP). Toll-like receptor is possible candidate for inflammatory responses which is mainly mediated by NFKB1. The aim of this study was to investigate the relationship between NFKB1 and Toll-like receptor (TLR) 2 polymorphisms and the risk of MO in a Turkish population in the context of CRP serum levels which may contribute to susceptibility to the disease. We analysed the distribution of NFKB1-94 ins/del ATTG rs28362491 and TLR2 Arg753Gln rs5743708 polymorphisms using PCR-RFLP method and CRP serum levels using ELISA method in 213 MO and 200 healthy controls. The frequency of the ins/ins genotype and ins allele of rs28362491 was significantly higher in the patients compared to control group (P: 0.0309; P: 0.0421, respectively). Additionally, the frequency of GG genotype and G allele of rs5743708 was found to be statistically higher in the patient group (P: 0.0421; P < 0.0001, respectively). In addition, serum CRP levels (>20 mg/l) in MO patients with ins/ins genotype were significantly higher than in patients with del/ins genotype (P: 0.0309). Serum CRP levels were also higher in MO patients with GG genotype and G allele (P: 0.0001). According to combined analysis, the wild type of rs28362491 and rs5743708 polymorphisms (ins/ins/GG genotype) was also significantly higher in the patient group versus the control group when compared with the combined ins/ins/GA and del/ins/GA genotype (P < 0.0001). Therefore, our findings suggest that rs28362491 and rs5743708 polymorphisms were significantly associated with MO disease through acting by modulating serum CRP levels.
BackgroundBehçet disease (BD) belongs to a disease family that has a transparent borderline between autoinflammatory and autoimmune disorders. Fas and some miRNAs have revealed to display remarkable roles in both autoimmune and autoinflammatory processes, and they can play important roles in defective apoptosis in BD. We investigated the association of the susceptibility of BD with Fas, miRNA variations, and their both single and combined presence in a Turkish population as a case-control study.MethodsThe distributions of FAS-670 A>G rs1800682, mir146a rs2910164, and mir196a rs11614913 polymorphisms are analyzed with the polymerase chain reaction–restriction fragment length polymorphism method in 115 BD patients and 220 controls in 6-month period.ResultsStatistical analysis indicates that in the case of Fas-670 A/G rs1800682, AA genotype and A allele have a protective role in BD (p = 0.0004 and p = 0.0009, respectively). The dominant model (AA + AG/GG) also displays a protective effect on BD unlike the recessive model (p = 0.03). In addition, both homozygous genotype (CC) of rs2910164 of mir-146a (p = 0.04) and the dominant model (CC + CG vs. GG) have protective effects on BD unlike the recessive model (p < 0.0001). Both mir-196a2 rs1800682 polymorphism and combined genotype analysis of rs1800682-rs2910164 and rs1800682-rs11614913 gave no statistically significant differences within the groups for genotypes and either of the alleles (p > 0.05).ConclusionsThese findings indicate that both Fas rs1800682 and mir-146a rs2910164 variants might be important factors participating in the protection against BD in the Turkish population.
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