Selective thyroid hormone receptor beta agonist, GC-1, is capable to reduce growth of colorectal tumor in syngeneic mouse models.

OBJECTIVE: The effect of thyroid hormone (TH) on cancers was proposed more than 100 years ago; however, conclusions are conflicting. THs are precisely regulated at tissue and cellular levels. It seems that this regulation is altered in cancers. Thyroid hormone receptor beta (TRß) has anti-proliferative and tumor-suppressive effects in many cancer cells. Therefore, we decided to investigate thyroid hormone receptor beta (THRB) expression and activation by the selective agonist, GC-1, on tumor growth in a syngeneic mouse model of colorectal cancer (CRC) and colon cell lines. METHODS: In vitro cell viability assay using MTT analysis, cell cycle analysis by PI staining, and FACS analysis were performed. In vivo tumor growth measurements were carried out by caliper and [18F] Fluoro-2-deoxy-2-D-glucose (FDG) - PET imaging. Gene expressions were determined using quantitative-PCR. RESULTS: Some concentrations of GC-1 had a marked negative effect on the cell viability of colorectal cell lines. Cell cycle analysis showed that the anti-proliferative effect of GC-1 may not result from cell cycle arrest or apoptosis. Tumor growth analysis in mice harboring colorectal tumor showed that GC-1 treatment for 8 d profoundly inhibited tumor growth and 18FDG uptake. THRB expression was decreased in mice tumor; however, it was upregulated following GC-1 administration. CONCLUSIONS: Our results showed that specific activation of TRß by GC-1 had negative effect on tumor growth and restored its gene expression in tumors of CRC mice model.

The Effects of Ovalbumin on Proliferation, Migration, and Stemness Properties of Chemoresistant SW480 Colon Cancer Cells.

Egg peptides are factors in the embryonic environment with many significant biological activities, such as anticancer activity. Therefore, the current study investigates the effect of egg ovalbumin (OVA) on survival, cell cycle, self-renewal ability, stemness properties, and migration in SW480 colon cancer cells and 5-fluorouracil (5FU) resistant subgroup. MTT test was performed to assess cell viability. Flow cytometry was employed to analyze the cell cycle. Clonogenic assay and spheroid formation were used to assess the effect of OVA on self-renewal and stemness properties. Wound healing assay and RT-PCR were performed to analyze migration and gene mRNA expression. We demonstrated that OVA (8 and 12 mg/ml) attenuated cell viability, induced cell-cycle arrest, inhibited colony formation, and non-significantly reduced spheroid formation and migration in both cell lines. Furthermore, OVA downregulated the expression of Nanog, c-Myc, and NDRG1 in both cells, suggesting a stemness and self-renewal attenuation by OVA. In conclusion, OVA exposure inhibited the 5FU-SW480 chemo-resistant subpopulation growth by inducing cell cycle arrest and diminishing self-renewal and partially stemness properties of colon cancer cells.

Correlation of Low Levels of α-1 Antitrypsin and Elevation of Neutrophil to Lymphocyte Ratio with Higher Mortality in Severe COVID-19 Patients.

BACKGROUND: Variations in COVID-19 prevalence, severity, and mortality rate remain ambiguous. Genetic or individual differences in immune response may be an explanation. Moreover, hyperinflammation and dysregulated immune response are involved in the etiology of severe forms of COVID-19. Therefore, the aim of the present study was to analyze serum alpha-1 antitrypsin (AAT) levels, as an acute-phase plasma protein with immunomodulatory effect and neutrophil to lymphocyte ratio (NLR) as a marker of inflammation response in severe COVID-19 illness. METHODS: In this retrospective observational cohort study, 64 polymerase chain reaction (PCR) positive COVID-19 hospitalized patients were studied for AAT, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), troponin, complete blood count (CBC), random blood sugar, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), and arterial oxygen saturation (O2sat) at admission and during hospitalization. RESULTS: The results showed that hospitalized patients with COVID-19 had low serum levels of AAT and high CRP levels at the first days of hospitalization. In particular, the percentages of individuals with low, normal, and high AAT levels were 7.80%, 82.80%, and 9.40%, respectively, while high and low values of CRP accounted for 86.70% and 13.30% of patients. Most of the patients had an upward neutrophil to lymphocyte ratio (NLR) trend, with a higher mortality rate (p < 0.05) and troponin levels (p < 0.05). However, comorbidities, CRP alterations, ESR alterations, nonfasting blood sugar, SGOT, SGPT, O2sat, RBC, and PLT values were not significantly different between the NLR downward and upward trend groups. CONCLUSIONS: The current study revealed that severe COVID-19 patients had low serum AAT levels related to CRP values. Therefore, AAT response may be considered as a new mechanism by which some COVID-19 patients show immune dysregulation and more severe symptoms.

Hypomethylation of NANOG promoter in colonic mucosal cells of obese patients: a possible role of NF-κB.

Obesity and particularly central obesity are the main risk factors of colon cancer. All intestinal cell populations including stem cells, their progenitors and differentiated colonocytes seem to be the origin of colorectal cancer. However, recent data support the role of differentiated cells as cancer origin especially during inflammation. Based on Yamanaka's seminal work, re-expression of few transcription factors in terminally differentiated cells creates stemness properti'es. Although these transcription factors are involved in tumorigenesis, they are epigenetically repressed in adult tissues. We proposed that obesity might regulate methylation of stemness genes in colonocytes via inflammatory signalling. Obesity-associated inflammation was analysed using Western blot analysis of phospho-IκB (inhibitor of NF-κB). Methylation-sensitive high-resolution melting analysis was performed on colonic mucosal samples of twenty obese and twenty normal-weight men to analyse promoter methylation of POU5F1 (OCT4), NANOG, MYC and CDKN2A. TNF-treated HT-29 cells were used to recapitulate the effect of NF-κB activation on stemness genes methylation. Our results showed that colonic phosphorylation of IκB, as a signal of NF-κB activation, was higher in obese subjects compared with their normal-weight counterparts. Moreover, promoter methylation of NANOG was likely to be lower in obese subjects and correlated with central obesity. HT-29 cells incubated by TNF-α showed hypomethylation of POU5F1 and MYC genes in addition to the NANOG. These results suggest that obesity-induced inflammation might be involved in the regulation of DNA methylation of oncogenic genes such as NANOG in differentiated colonocytes and thus predispose them to later oncogenic alterations.

Dietary Total Antioxidant Capacity and the Risk of Chronic Kidney Disease in Patients With Type 2 Diabetes: A Nested Case-Control Study in the Tehran Lipid Glucose Study.

OBJECTIVE: Dietary total antioxidant capacity (DTAC) has been hypothesized as being involved in health promotion and disease prevention. However, data about the association of the DTAC (as estimated by ferric reducing antioxidant power) with diabetes chronic complications are scarce. Therefore, the aim of this study was to determine the associations between the DTAC and chronic kidney disease (CKD) risk in subjects with type 2 diabetic. METHODS: The present case-control study consisted of 210 (102 cases and 108 controls) patients with type 2 diabetic who were participants of the phase 5 Tehran Lipid and Glucose Study and were classified based on their CKD status. DTAC was estimated based on the ferric reducing antioxidant power of selected foods. Dietary intake, sociodemographic data, medical history, and anthropometric measurements were collected from participants using a validated questionnaire. RESULTS: The mean DTAC value, as well as total calorie intake, did not show significant differences between cases and controls. CONCLUSION: No significant association was found between DTAC and CKD in patients with type 2 diabetic. Further studies are needed to confirm the effects of DTAC on the risk of CKD.

The Function of the Immune System, Beyond Strategies Based on Cell-Autonomous Mechanisms, Determines Cancer Development: Immune Response and Cancer Development.

Although cancer remains a challenging disease to treat, early detection and removal of primary tumors through surgery or chemotherapy/radiotherapy can offer hope for patients. The privilege paradigm in cancer biology suggests that cell-autonomous mechanisms play a central role in tumorigenesis. According to this paradigm, these cellular mechanisms are the primary focus for the prevention and treatment of cancers. However, this point of view does not present a comprehensive theory for the initiation of cancer and an effective therapeutic strategy. Having an incomplete understanding of the etiology of cancer, it is essential to re-examine previous assumptions about carcinogenesis and develop new, practical theories that can account for all available clinical and experimental evidence. This will not only help to gain a better understanding of the disease, but also offer new avenues for treatment. This review provides evidence suggesting a shift in focus from a cell-autonomous mechanism to systemic mechanisms, particularly the immune system, that are involved in cancer formation.

Effects of N-acetylcysteine on the expressions of UCP1 and factors related to thyroid function in visceral adipose tissue of obese adults: a randomized, double-blind clinical trial.

BACKGROUND: Evidences have shown that obesity is influenced by various factors, including various hormones such as thyroid hormones and the body's metabolism rate. It seems that practical solutions such as weight loss diets and common drugs can affect these potential disorders. In this study, we investigate one of these common drugs, N-Acetylcysteine (NAC), on expressions of UCP1 and factors related to thyroid function in adults with obesity. METHODS AND ANALYSIS: The current investigation was carried out as a randomized clinical trial (RCT) including 43 adults with obesity who were potential candidates for bariatric surgery. These individuals were randomly divided into two groups: 600 mg of NAC (n = 22) or placebo (n = 21) for a duration of 8 weeks. Visceral adipose tissue was utilized in the context of bariatric surgery to investigate the gene expression of UCP1 and thyroid function. Polymerase chain reaction (PCR) was performed in duplicate for UCP1, DIO2, DIO3, THRα and ß, and 18s RNA (as an internal control) using the provided instructions to investigate the expression of the respective genes. RESULTS: Our findings revealed that after 8 weeks compared to placebo, NAC caused a significant decrease in the expression of the DIO3 gene as one of the genes related to thyroid function and metabolism. However, regarding other related genes, no statistically significant was found (despite the increase in UCP1, DIO2, and THRα expression and decrease in THRß expression). In addition, after adjustment of possible confounders, no significant effect was observed on anthropometric factors and serum levels of thyroid hormones. CONCLUSION: The results of this study indicate that, following an 8-week period, NAC effectively decreases the expression of the DIO3 gene in the visceral fat tissue, in comparison to the placebo.

Isoproterenol Alters Metabolism, Promotes Survival and Migration in 5-Fluorouracil-Treated SW480 Cells with and without Beta-hydroxybutyrate.

People with cancer often experience long-term physical and psychological stress, which can have a significant impact on tumor metabolism and treatment. The effects of adrenergic signaling on metabolic pathways are well known, but only a few studies have looked into the connection between this signaling and tumor metabolism. This study examined the effects of treatment with isoproterenol (Iso) alone and in combination with ß-hydroxybutyrate (ßHB), a mitochondrial fuel, on the metabolism, survival, and migration of SW480 colon cancer cells treated with 5-fluorouracil (5FU). The researchers measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to determine the metabolic profile of these cells. They also analyzed the gene expression of PGC-1α, c-MYC, and NANOG to investigate the relationship between metabolic phenotype and stemness status. Scratch assays were used to assess cell migration. The results showed that Iso treatment increased cell viability in both SW480 and 5FU-treated SW480 cells. There was a significant decrease in ECAR and an increase in OCR after Iso treatment in both cell types. The expression of c-MYC and NANOG, genes associated with stemness, increased, while the expression of PGC-1α, a gene related to oxidative phosphorylation, decreased following Iso treatment. Iso treatment also increased the migration potential of both SW480 and 5FU-treated SW480 cells. These findings suggest that under stressful conditions, 5FU-treated colon cancer cells can utilize the oxidative phosphorylation pathway for growth and migration.

Thyroid Hormones Imbalances and Risk of Colorectal Cancer: a Meta-analysis.

PURPOSE: No conclusive information is available about the association between hypothyroidism or hyperthyroidism and risk of colorectal cancer (CRC). We therefore aimed to summarize the findings of observational studies on the relation between hypothyroidism or hyperthyroidism and risk of CRC. METHODS: A literature search was conducted using relevant keywords in online databases for appropriate publications through July 2023. Random effects model was used to calculate combined effect sizes (ESs) and 95% confidence intervals (CIs) to investigate relationship between hypothyroidism or hyperthyroidism and CRC risk. RESULTS: Totally, we included 13 studies in the current systematic review and meta-analysis, with a total sample size of 33,557,450 individuals and 25,363 cases of CRC. Pooling 13 effect sizes revealed no significant association between hypothyroidism and risk of CRC (combined effect size: 1.13, 95% CI 0.87-1.48, P = 0.343). There was also no significant association between hyperthyroidism and risk of CRC (combined effect size: 1.09, 95% CI 0.75-1.57, P = 0.638). Additionally, there were significant associations between hypothyroidism and risk of CRC in the Far Eastern studies, between hyperthyroidism and risk of CRC in the Middle East, along with small sample size studies. CONCLUSIONS: This meta-analysis did not reveal any association between hypothyroidism or hyperthyroidism and risk of CRC. TRIAL REGISTRATION: PROSPERO CRD42022331089.

Alterations of DNA methylation and expression of genes related to thyroid hormone metabolism in colon epithelium of obese patients.

BACKGROUND: Colorectal cancer is common among obese individuals. The purpose of the current study was to determine changes in DNA methylation status and mRNA expression of thyroid hormone receptor beta (THRB), as a tumor suppressor, and thyroid hormone inactivating enzyme, type 3 deiodinase (DIO3) genes, in human epithelial colon tissues of healthy obese individuals. METHODS: Colon biopsies were analyzed by methylation sensitive-high resolution melting (MS-HRM) to investigate promoter methylation of DIO3 and THRB, and by quantitative real-time polymerase chain reaction to assay expression of DIO3 and THRB mRNA on eighteen obese and twenty-one normal-weight healthy men. RESULTS: There was no significant difference in mean methylation levels at the THRB promoter region between the two groups. Nevertheless, obesity decreased THRB expression levels, significantly (P < 0.05; fold change: 0.19). Furthermore, obesity attenuated DNA methylation (P < 0.001) and enhanced mRNA expression of DIO3 (P < 0.05; fold change: 3). CONCLUSIONS: Our findings suggest that obesity may alter expression of THRB and DIO3 genes through epigenetic mechanism. Alterations of THRB and DIO3 expressions may predispose colon epithelium of obese patients to neoplastic transformation.

Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling.

Hepcidin negatively regulates systemic iron homeostasis in response to inflammation and elevated serum iron. Conversely, hepcidin expression is diminished in response to hypoxia, oxidative stress, and increased erythropoietic demand, though the molecular intermediates involved are incompletely understood. To address this, we have investigated hypoxic hepcidin regulation in HuH7 hepatoma cells either cultured alone or cocultured with activated THP-1 macrophages. HuH7 hepcidin mRNA expression was determined using quantitative polymerase chain reaction (Q-PCR). Hepcidin promoter activity was measured using luciferase reporter constructs containing a 0.9 kb fragment of the wild-type human hepcidin promoter, and constructs containing mutations in bone morphogenetic protein (BMP)/SMAD4, signal transducer and activator of transcription 3 (STAT3), CCAAT/enhancer-binding protein (C/EBP), and E-box-responsive elements. Hepatic expression of bone morphogenetic proteins BMP2 and BMP6 and the BMP inhibitor noggin was determined using Q-PCR, and the protein expression of hemojuvelin (HJV), pSMAD 1/5/8, and SMAD4 was determined by western blotting. Following exposure to hypoxia or H(2)O(2), hepcidin mRNA expression and promoter activity increased in HuH7 cells monocultures but were decreased in HuH7 cells cocultured with THP-1 macrophages. This repression was attenuated by mutation of the BMP/SMAD4-response element, suggesting that modulation of SMAD signaling mediated the response to hypoxia. No changes in hepatocyte BMP2, BMP6 or noggin mRNA, or protein expression of HJV or pSMAD 1/5/8 were detected. However, treatment with hypoxia caused a marked decrease in nuclear and cytosolic SMAD4 protein and SMAD4 mRNA expression in cocultured HuH7 cells. Together these data indicate that hypoxia represses hepcidin expression through inhibition of BMP/SMAD signaling.

Obesity and intestinal stem cell susceptibility to carcinogenesis.

BACKGROUND: Obesity is a top public health problem associated with an increase in colorectal cancer incidence. Stem cells are the chief cells in tissue homeostasis that self-renew and differentiate into other cells to regenerate the organ. It is speculated that an increase in stem cell pool makes cells susceptible to carcinogenesis. In this review, we looked at the recent investigations linking obesity/high-fat diet-induced obesity to intestinal carcinogenesis with regard to intestinal stem cells and their niche. FINDINGS: High-fat diet-induced obesity may rise intestinal carcinogenesis by increased Intestinal stem cells (ISC)/progenitor's population, stemness, and niche independence through activation of PPAR-δ with fatty acids, hormonal alterations related to obesity, and low-grade inflammation. However, these effects may possibly relate to the interaction between fats and carbohydrates, and not a fatty acid per se. Nonetheless, literature studies are inconsistency in their results, probably due to the differences in the diet components and limitations of genetic models used. CONCLUSION: High-fat diet-induced obesity affects carcinogenesis by changing ISC proliferation and function. However, a well-matched diet and the reliable colorectal cancer models that mimic human carcinogenesis is necessary to clearly elucidate the influence of high-fat diet-induced obesity on ISC behavior.

Colorectal cancer causes alteration of thyroid hormone profile in newly diagnosed patients.

OBJECTIVES: Subcellular alteration of thyroid hormones (THs) signaling is proposed in many types of cancers. Some studies show deiodinase type 3, as an oncofetal protein, re-expresses in some cancer types. Therefore, we aimed to investigate the product of this enzyme, reverse triiodothyronine (rT3) in serum of newly diagnosed colorectal cancer (CRC) patients. METHODS: In this cross-sectional study, blood from 38 laboratory-confirmed cases was taken, and serum levels of rT3, total T3 (triiodothyronine), total T4 (thyroxine), free T3, free T4, and thyroid-stimulating hormone (TSH) were detected by using an enzyme-linked immunosorbent assay. RESULTS: The results illustrated that rT3 and free T3 levels increased in patients with early stages of colorectal cancer, despite normal levels of total T3, total T4, free T4, and TSH. CONCLUSION: The elevation of rT3 in CRC patients can probably be due to the re-expression of deiodinase type 3 in CRC. Further research is needed to study the role of intracellular THs modulation in CRC and its impact on CRC treatment.

Anti-mullerian hormone attenuates insulin resistance and systemic inflammation in old obese C57BL/6 male mice.

PURPOSE: Epidemiological studies show that Anti-mullerian hormone (AMH) is inversely correlated with age, obesity-related diseases, and all-cause mortality in men. To further investigate the role of AMH in aging and obesity, we studied the effect of AMH treatment on the inflammatory and metabolic parameters and weight in old male C57BL/6 mice. METHOD: Thirty-six old male C57BL/6 mice (18 month-old) were either on the High-Fat Diet (HFD) or Normal Diet (ND). When obesity occurred in the HFD group, each group was divided into two subgroups; AMH-treated (ND+AMH and HFD+AMH) or controls (ND and HFD). The AMH subgroup received 15 ng/gbw of recombinant AMH injection every 48 h in four weeks. Then, serum AMH, CRP, fasting glucose, fasting insulin, and HOMA-IR were measured and analyzed. RESULTS: AMH injection decreased CRP level (HFD =622.86±25.73, HFD+AMH =543.2±24.99 ng/ml, p= 0.003), fasting insulin (HFD=1.50± 0.34, HFD+AMH =0.8±0.25 ng/ml, p=0.006) and HOMA-IR (HFD=12.76± 2.88, HFD+AMH =7.06±2.31, p=0.008) in the obese old mice comparison with control. In ND group, just CRP levels dropped following AMH injection (ND=451.24±20.61, ND+AMH= 326.8±23.76 ng/ml; p=0.001). Accelerated weight gain was observed in HFD+AMH compared with the HFD subgroup (p<0.05). CONCLUSIONS: In conclusion, increasing the circulating level of AMH could subside the systemic inflammation through decreasing CRP levels regardless of diet type and enhance insulin sensitivity in old obese mice. It can also lead to higher weight gain, without inflammation, in old obese male mice who are on an HFD.

Erythropoietin regulates intestinal iron absorption in a rat model of chronic renal failure.

Erythropoietin is produced by the kidney and stimulates erythropoiesis; however, in chronic renal disease its levels are reduced and patients develop anemia that is treatable with iron and recombinant hormone. The mechanism by which erythropoietin improves iron homeostasis is still unclear, but it may involve suppression of the iron regulatory peptide hepcidin and/or a direct effect on intestinal iron absorption. To investigate these possibilities, we used the well-established 5/6th nephrectomy rat model of chronic renal failure with or without human recombinant erythropoietin treatment. Monolayers of human intestinal Caco-2 cells were also treated with erythropoietin to measure any direct effects of this hormone on intestinal iron transport. Nephrectomy increased hepatic hepcidin expression and decreased intestinal iron absorption; these effects were restored to levels found in sham-operated rats on erythropoietin treatment of the rats with renal failure. In Caco-2 cells, the addition of erythropoietin significantly increased the expression of apical divalent metal transporter 1 (DMT1) and basolateral ferroportin and, consequently, iron transport across the monolayer. Taken together, our results show that erythropoietin not only exerts a powerful inhibitory action on the expression of hepcidin, thus permitting the release of iron from reticuloendothelial macrophages and intestinal enterocytes, but also acts directly on enterocytes to increase iron absorption.

New Insight into Diabetes Management: From Glycemic Index to Dietary Insulin Index.

BACKGROUND: Despite efforts to control hyperglycemia, diabetes management is still challenging. This may be due to focusing on reducing hyperglycemia and neglecting the importance of hyperinsulinemia; while insulin resistance and resultant hyperinsulinemia preceded diabetes onset and may contribute to disease pathogenesis. OBJECTIVE: The present narrative review attempts to provide a new insight into the management of diabetes by exploring different aspects of glycemic index and dietary insulin index. RESULTS: The current data available on this topic is limited and heterogeneous. Conventional diet therapy for diabetes management is based on reducing postprandial glycemia through carbohydrate counting, choosing foods with low-glycemic index and low-glycemic load. Since these indicators are only reliant on the carbohydrate content of foods and do not consider the effects of protein and fat on the stimulation of insulin secretion, they cannot provide a comprehensive approach to determine the insulin requirements. CONCLUSION: Selecting foods based on carbohydrate counting, glycemic index or glycemic load are common guides to control glycemia in diabetic patients, but neglect the insulin response, thus leading to failure in diabetes management. Therefore, paying attention to insulinemic response along with glycemic response seems to be more effective in managing diabetes.

Beta-Hydroxybutyrate Promotes Proliferation, Migration and Stemness in a Subpopulation of 5FU Treated SW480 Cells: Evidence for Metabolic Plasticity in Colon Cancer

Background: Beta-hydroxybutyrate (BHB) as a ketone body is the metabolic fuel in oxidative phosphorylation pathway. So far the effects of BHB on the biology of tumor cells is contradictory. Therefore, we investigated the effect of BHB on viability, metabolism, proliferation and migration of 5FU treated SW480 colon cancer cell line. Methods: we treated the SW480 cells with IC50 dose of 5-fluorouracil (5FU) for 72 h to isolate a subpopulation of 5FU treated cells that were resistant to it. Effects of BHB on cell viability was investigated by MTT assay. Measurement of oxygen consumption rate (OCR) in parallel with extracellular acidification rate (ECAR) upon BHB treatment was used for determination of metabolic profile of these cells. Investigating the relationship between metabolic phenotype and the status of differentiation and stemness was done by analyzing the expression of PGC-1α, c-MYC, NANOG, ALPi and KRT20 genes by qRT-PCR. Clonogenic and scratch assay were performed to determine the proliferation and migration abilities of incubated with BHB compared to untreated cells. Results: BHB increased cell viability in SW480 and 5FU treated SW480 cells. The results showed a significantly decreased ECAR and increased OCR in both cell types following BHB treatment reflecting the superiority of oxidative phosphorylation profile compared to glycolysis in both cell types. Also, treatment with BHB increases the expression of genes normally associated with stemness and mitochondrial biogenesis and decreases the expression of genes related to glycolytic program and differentiation in 5FU treated cells. Self-renewal and migration potential of BHB treated cells increased significantly. Conclusion: These findings suggest that BHB utilization via oxidative mitochondrial metabolism can fuel proliferation, migration and stemness in 5FU treated SW480 colon cancer cells.

The relationship between MnSOD Val16Ala gene polymorphism and the level of serum total antioxidant capacity with the risk of chronic kidney disease in type 2 diabetic patients: a nested case-control study in the Tehran lipid glucose study.

BACKGROUND: Several studies have shown significant associations between manganese superoxide dismutase (MnSOD) Val16Ala polymorphism and diabetic complications, but this association has not been explored in relation with chronic kidney disease (CKD) in Type 2 diabetes mellitus (T2DM) patients. Total antioxidant capacity (TAC) level changes in diabetic condition and may play important role in onset or progression of the disease and its complications. The present study investigated the association of MnSOD Val16Ala polymorphism and serum TAC with the risk of CKD in T2DM patients. METHODS: This nested case-control study included 280 type 2 diabetic patients with CKD and 280 age, sex and diabetes duration-matched control subjects selected from the participants of the Tehran Lipid and Glucose Study. MnSOD val16Ala (rs4880) SNP was genotyped by the Tetra-Primer ARMS-polymerase chain reaction analysis. Serum TAC was measured using ferric-reducing antioxidant power assay. Statistical analysis was performed using STATA statistical package v.12.0 or SPSS (Version 22.0). RESULTS: The Ala allele of the MnSOD Val16Ala polymorphism was associated with a lower risk of CKD (odds ratio (OR), 0.55; 95% confidence interval (CI), 0.36-0.84; P = 0.006). Median serum TAC in CKD group was 920 µmol/L and was significantly lower (p < 0.001) compared to the control group (1045 µmol/L). Using an adjusted conditional logistic regression, we didn't observe any significant interaction between MnSOD Val16Ala SNP with quartiles of serum TAC in relation to CKD. CONCLUSION: A significant association was found between the MnSOD Val16Ala polymorphism and CKD, but this association is not affected by serum TAC level in T2DM patients.