Role of Transcription Factor 7 like 2 and Silent Information Regulator 1 Genes in the Development of Cardiovascular Complications in a Group of Egyptian Patients with Chronic Kidney Disease

BACKGROUND: Sirtuins silent information regulator 1 (SIRT) is histone deacetylases that act as antioxidants and involved in the pathogenesis of cardiovascular diseases (CVD) which are the major complications of chronic kidney disease (CKD). Transcription factor 7-like 2 (TCF7L2) genetic polymorphisms could contribute to the risk of CVD as TCF7L2 proteins regulate vascular remodeling. AIM: We tried to demonstrate the role of genetic polymorphisms: rs7069102 and rs10823108 in SIRT1 gene and rs7903146 in TCF7L2 gene in the development of CVD in CKD Egyptian patients. METHODS: This study included 120 CKD patients (60 with CVD and 60 without CVD) and 60 age and sex-matched healthy subjects as a control group. Routine laboratory investigations were performed and genotyping for candidate single nucleotide polymorphisms was done by Taqman-real-time polymerase chain reaction. RESULTS: The frequency of the C allele of rs7069102 was significantly higher in CKD patients with CVD as compared to the normal control group (p < 0.001) and as compared to CKD patients without CVD (p < 0.001). Percentages of AG and GG genotypes of rs10823108 were significantly higher in CKD patients with CVD as compared to the normal control group (p = 0.002, 0.035, respectively). The frequency of the T allele of rs7903146 was significantly higher in CKD patients with CVD as compared to the normal control group (p < 0.001). CONCLUSION: We found that C allele of rs7069102, GG and AG genotypes of rs10823108 in the SIRT1 gene and T allele of rs7903146 in TCF7L2 gene have a potential role in the pathogenesis and the risk of CVD development in CKD Egyptian patients.

circ-Sirt1 Decelerates Senescence by Inhibiting p53 Activation in Vascular Smooth Muscle Cells, Ameliorating Neointima Formation

Vascular smooth muscle cell (VSMC) senescence is a major driver of neointimal formation. We have demonstrated that circ-Sirt1 derived from the SIRT1 gene suppressed VSMC inflammation and neointimal formation. However, the effect of circ-Sirt1 inhibiting inflammation on VSMC senescence during neointimal hyperplasia remains to be elucidated. Here, we showed that circ-Sirt1 was highly expressed in young and healthy arteries, which was decreased in aged arteries and neointima of humans and mice. Overexpression of circ-Sirt1 delayed Ang II-induced VSMC senescence in vitro and ameliorated neointimal hyperplasia in vivo. Mechanically, circ-Sirt1 inhibited p53 activity at the levels of transcription and post-translation modulation. In detail, circ-Sirt1, on the one hand, interacted with and held p53 to block its nuclear translocation, and on the other hand, promoted SIRT1-mediated p53 deacetylation and inactivation. In conclusion, our data suggest that circ-Sirt1 is a novel p53 repressor in response senescence-inducing stimuli, and targeting circ-Sirt1 may be a promising approach to ameliorating aging-related vascular disease.

MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression

The growth hormone (GH)–insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH–IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation.

circ-SIRT1 Promotes Colorectal Cancer Proliferation and EMT by Recruiting and Binding to eIF4A3

Circular RNA (circRNA), a recently identified type of endogenous noncoding RNA, has been implicated in the occurrence and development of a variety of tumors; however, whether circ-SIRT1, derived from pre-mRNA of the parental SIRT1 gene, is involved in colorectal cancer (CRC) remains unknown, as do the potential underlying mechanisms. The expression of circ-SIRT1 in CRC cells and tissue was detected by RT-qPCR. Colony formation and Cell Counting Kit-8 assays were used to evaluate the effect of circ-SIRT1 knockdown on the proliferative ability of CRC cells. Wound healing and Transwell assays were used to assess the effect of circ-SIRT1 knockdown on the migratory and invasive capacity of CRC cells. RNA immunoprecipitation and RNA pull-down assays were employed to validate the binding of circ-SIRT1 to EIF4A3. Western blot was used to identify the changes in the expression of EIF4A3 and EMT-related proteins. The RT-qPCR results showed that circ-SIRT1 was highly expressed in CRC cells and tissue and was positively correlated with the depth of tumor invasion. Knocking down circ-SIRT1 inhibited the proliferation and invasion of CRC cells and EMT. We further found that EIF4A3 could bind to circ-SIRT1, and that overexpressing circ-SIRT1 decreased the abundance of EIF4A3 at the mRNAs of the EMT marker proteins N-cadherin and vimentin. Combined, our findings suggested that circ-SIRT1 regulates the expression of EMT-related proteins by preventing EIF4A3 recruitment to the respective mRNAs. Our results further indicate that circ-SIRT1 functions as an oncogene in CRC by promoting the proliferation, invasion, and EMT of CRC cells through the circ-SIRT1/EIF4A3/N-cadherin/vimentin pathway.

The Association between Silent Mating Type Information Regulator 2 Homolog 1 (SIRT1) Gene Polymorphism and Systemic Lupus Erythromatosis (SLE)

ABSTRACT Background Systemic lupus erythematosus (SLE) is a chronic severe multisystem autoimmune disease that affects multiple organs being characterized by heterogeneous manifestations that may affect the skin, joint, heart, brain, kidney, hematopoietic and central nervous systems. It is characterized by autoantibody production for a variety of self-antigens, but it is specifically associated with anti-double stranded DNA (anti-dsDNA), and immune complex deposition. The Silent Mating Type Information Regulator 2 Homolog 1 (SIRT1) is a NAD-dependent deacetylase enzyme that plays an important role in regulating a variety of cellular processes, such as energy metabolism, cell-cycle progression, apoptosis, aging, immune system regulation and inflammation. Aim of the Work The aim of the present study is to investigate the association of SIRT1 rs3758391 gene polymorphism with SLE and to study its impact on disease progression to lupus nephritis. Subjects and Methods This is a case control study conducted at Ain Shams University Hospital, with a total of 50 participants including 34 patients diagnosed with SLE in addition to 16 age and sex matched individuals serving as a healthy control group. Results The results revealed no significant difference between the SLE patients and the controls as regards CC, CT and TT genotypes, yet there was a statistical significant difference between both groups as regards the C and T alleles. Conclusion The present study highlights that SIRT1 gene rs3753891 does not seem to influence lupus nephritis susceptibility and disease activity as indicated by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scoring. However, T allele may be a risk factor for lupus susceptibility.

Effect of Reynoutria Japonica and its Extract on Sirt1 in Cisplatin-Induced Renal Injury

Background: Mechanisms of drug-induced kidney injury include mitochondrial dysfunction and oxidative stress. Resveratrol is a natural activator of sirt1 that is related to oxidative stress.Aim: To explore the mechanism of treating drug-induced kidney injury with Reynoutria japonica and its extract (Resveratrol).Design: Fifty adult male SD rats were randomly divided into five groups: blank group, model group, Reynoutria japonica group, resveratrol group and lotensin group. Each group was given the corresponding drug. ACR was measured on the seventh day every week. Creatinine and urea nitrogen were measured on the fourth weekend. All rats were sacrificed on the fourth weekend to detect the relevant indicators in the kidney.Results: At the fourth week, the ACR, Scr and BUN of the Resveratrol group were higher than those of the lotensin group and Reynoutria japonica group (P<0.05). The values of Scr and BUN were lower in the Reynoutria japonica group than in the lotensin group (P<0.05). The levels of SOD, NO, and sirt1 gene and protein expression in the model group and treatment group were lower than those in the blank group, and those in the model group were lower than those in the treatment group (P<0.05). The levels of SOD, NO, and sirt1 gene and protein expression in the Reynoutria japonica group were higher than the lotensin group (P<0.05).Conclusions: The therapeutic effect of the Reynoutria japonica group was better than that of the lotensin group and resveratrol group.

Evaluating the expression of key genes involved in resistance to oxidative stress in ALL patients

Background: Leukemia accounts for about 8% of all cancers and causes approximately 7% of mortalities due to malignancies. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and rare in older subjects. The aim of this study was to evaluate the expression of oxidative stress resistance genes including Catalase, manganese superoxide dismutase (MnSOD), Forkhead Box O3 (Foxo3a), and sirtuin-1 (SIRT1) in ALL patients that may be applied for therapeutic purposes in the future. Materials and Methods: In this observational case-control study, blood samples were drawn from 60 newly diagnosed ALL patients and 10 healthy individuals as a control group. After RNA extraction and cDNA synthesis, real-time polymerase chain reaction (RT-PCR) amplification was performed using specific primers for evaluating the expression of Catalase, MnSOD, Foxo3a, and SIRT1 genes. Results: The expression of all studied genes were significantly higher in ALL patients than in the control group; catalase gene, FOX gene, MnSOD gene, and SIRT1 gene were expressed 4 times (p =0.04), 4.5 times (p =0.001), 2.2 times (p =0.05) and 4.8 (p =0.01) times higher than healthy individuals in the control group respectively. However, no significant relationship between their expression and the stage of the disease and blast percentage was demonstrated (P>0.05). Conclusion: According to these results, the authors believe that the pathways involved in oxidative stress may be one of the most important causes of ALL disease's development and progression. In this regard, targeting the critical genes of these pathways can be considered a potential treatment with fewer side effects.

Identification of Stabilization of Malvid Anthocyanins and Antioxidant Stress Activation via the AMPK/SIRT1 Signaling Pathway

Vitis amurensis Rupr. “Beibinghong” is abundant in anthocyanins, including malvidin (Mv), malvidin-3-glucoside (Mv3G), and malvidin-3,5-diglucoside (Mv35 G). Anthocyanins offer nutritional and pharmacological effects, but their stability is poor. Interaction of malvid anthocyanins with caffeic acid through ultrahigh pressure technology produces stable anthocyanin derivatives. This study aims to identify the structure of stable mallow-like anthocyanins and to determine the effect of these stable anthocyanins on human umbilical vein endothelial cells (HUVECs) with H2O2-induced oxidative damage and the signaling pathway involved. The products of malvid anthocyanins and caffeic acid bonding were identified and analyzed using ultra-high performance liquid chromatography-quadrupole-Orbitrap mass spectrometry (UPLC-Q-Orbitrap MS/MS). The bonding products were malvidin-3-O-guaiacol (Mv3C), malvidin-3-O-(6″-O-caffeoyl)-glucoside (Mv3CG), and malvidin-3-O-(6″-O-caffeoyl)-5-diglucoside (Mv3C5G). An oxidative stress injury model in HUVECs was established using H2O2 and treated with Mv, Mv3G, Mv35 G, Mv3C, Mv3CG, and Mv3C5G at different concentrations (10, 50, and 100 μmol/L). Results showed that the above compound concentrations can significantly increase cell proliferation rate and reduce intracellular reactive oxygen species at 100 μmol/L. The effects of the most active products Mv and Mv3C on the AMP-activated protein (AMPK)/silencing information regulator-1 (SIRT1) pathway were analyzed. Results showed that Mv and Mv3C significantly increased SOD activity in the cells and significantly upregulated the expression of SIRT1 mRNA, SIRT1, and p-AMPK protein. However, they did not significantly change the expression of AMPK protein. After the silent intervention of siRNA in SIRT1 gene expression, the upregulation of SIRT1 and p-AMPK protein by Mv and Mv3C was significantly inhibited. These results indicate that stabilization malvid anthocyanins exerts an antioxidant activity via the AMPK/SIRT1 signaling pathway.