Association of genetic polymorphism of glutathione S-transferases with colorectal cancer susceptibility in snuff (Naswar) addicts.

The current study aimed to investigate the relationship between polymorphisms in detoxifying (GSTM1, GSTT1, and GSTP1) genes and their association with colorectal cancer (CRC) in tobacco addicts of Pashtun ethnicity. Polymorphisms in the selected genes were genotyped in a case-control study consisting of 100 histologically confirmed male CRC patients and 100 birth-year and gender-matched healthy controls using the PCR-RFLP method. The GSTM1 null, and GSTT1 null genotypes were significantly contributed to the risk of CRC in the cases (OR= 3.131, 95% CI: 1.451-6.758, P = 0.004, and OR= 3.541, 95% CI: 1.716-7.306, P = 0.001, respectively), whereas the association observed for GSTP1 Val/Val (1.139, 95% CI: 0.356-3.644, P = 0.826) did not show statistical significance. The combined GSTM1 null and GSTT1 null showed a 41-fold increased risk (95% CI: 4.945-351.950, P = 0.001), while, the combined GSTM1 null and GSTP1 Ile/Val or Val/Val variant genotypes exhibited about 3-fold (95% CI: 1.196-7.414, P = 0.019) increased risk to CRC. Similarly, the combined GSTT1 null and GSTP1 Ile/Val or Val/Val variant genotypes showed about a 3-fold (95% CI: 1.285-8.101, P = 0.013) increased risk of CRC. In the combination of three GST genotypes, the GSTM1 null, GSTT1 null, and GSTP1 Ile/Val or Val/Val variant genotypes demonstrated a more than a 22-fold (95% CI: 2.441-212.106, P = 0.006) increased risk of CRC. Our findings suggest that GSTM1 and GSTT1 polymorphism and its combination with GSTP1 may be associated with CRC susceptibility in the Naswar addicted Pashtun population of Khyber Pakhtunkhwa, Pakistan.

Kaempferol protects against streptozotocin-induced diabetic cardiomyopathy in rats by a hypoglycemic effect and upregulating SIRT1.

This study investigated if kaempferol could attenuate the oxidative, inflammatory, and fibrotic damage of the left ventricles (LVs) in streptozotocin (STZ)-diabetic rats by modulating silent mating type information regulation 2 homolog 1 (SIRT1) signaling. Adult male rats were divided into 5 groups (n = 12/each) as control, control + kaempferol, STZ-induced diabetes mellitus (STZ-DM), STZ-DM + kaempferol, and STZ-DM + kaempferol + EX-527, a sirtuin 1 (SIRT1) inhibitor. Administration of kaempferol to diabetic rats significantly preserved the systolic and diastolic functions of the LVs that was associated with a significant reduction in ventricular collagen deposition, infiltration of inflammatory cells, and protein expression of Bcl2-associated X protein (Bax), cleaved caspase-3, and cytochrome-C. In both the control and diabetic rats, kaempferol attenuated the loss in body weights, reduced fasting glucose levels, and increased fasting insulin levels and HOMA-ß. Besides, kaempferol lowered the levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), downregulated the transforming growth factor-ß1 (TGF-ß1) and reduced the nuclear levels of NF-κB p65. In concomitant, kaempferol increased the LV levels of manganese superoxide dismutase (MnSOD) and glutathione (GSH) and stimulated the total protein levels of Bcl2, the nuclear activity of SIRT1, and nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2). These events were associated with increased deacetylase activity and total levels of SIRT1 and a parallel decrease in the acetylation of Nrf2, NF-κB, smad2, and FOXO1. In conclusion: kaempferol attenuate diabetic cardiomyopathy in STZ-treated rats through its hypoglycaemic and insulin-releasing effects, as well as a cardiac independent mechanism that involves activation of SIRT1.

Quercetin protects against experimentally-induced myocardial infarction in rats by an antioxidant potential and concomitant activation of signal transducer and activator of transcription 3.

This study tested if the protective effect of quercetin (QUR) against experimentally-induced acute myocardial infarction (AMI) in rats involves modulating the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Rats were divided into 6 groups as sham-operated (control), control + QUR, AMI, AMI + QUR, AMI + S3I-210 (a STAT3 inhibitor), and AMI + QUR + S31-201. QUR (50 mg/kg/orally) and S3I-201 (a STAT3 inhibitor) (5 mg/kg/i.p.) were administered for 7 days before the induction of AMI and the experiment was ended 24 h post-AMI. Pre-treatment with QUR reduced the infarct size, improved the left ventricular (LV) functions and the structure of the myofibrils and the mitochondria, and reduced circulatory levels of lactate dehydrogenase (LDH), creatinine-kinase MB (CKMB), and troponin-I. QUR also reduced LV levels of reactive oxygen species (ROS) and malondialdehyde (MDA), inhibited the opening of the mitochondria transition pores (mtPTP), and reduced protein levels of cytochrome-C, cleaved caspase-3 and p-JAK2 (Tyr1007/1008) in the LVs of AMI rats. In the LV of both the control and AMI rats, QUR didn't affect the levels of p-JAK2 but significantly increased the levels of total glutathione (GSH) and manganese superoxide dismutase (MnSOD), reduced the levels of Bax and the nuclear levels and activity of NF-κB p65, tumor necrosis-factors-α (TNF-α), interleukin-6 (IL-6), and p-STAT1 (Ser727) but further increased the levels of p-STAT3 (Ser727). All these effects exerted by QUR were partially reversed but the decrease in nuclear protein levels and activity of NFκB, levels of TNF-α and IL-6, and pSTAT3 were completely prevented by co-administration of S3I-201. In conclusion, QUR protects against MI by upregulation of antioxidants and activation of STAT3.