A genetic variant study of bortezomib-induced peripheral neuropathy in Chinese multiple myeloma patients.

Background: Bortezomib results in peripheral neuropathy (PN) in approximately 50% of patients, during multiple myeloma (MM) treatment, a complication known as Bortezomib-induced peripheral neuropathy (BIPN). The drug response varies among individuals. Genetic factor may play an important role in BIPN. Methods: A next-generation sequencing (NGS) panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy. mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR (RT-qPCR). Serum homocysteine (Hcy) levels were detected in 40 samples by chemiluminescent microparticle immunoassay (CMIA). Results: Compared with the non-BIPN group (n = 89), a total of 8 significantly associated single nucleotide polymorphisms (SNPs) were identified in the BIPN group (n = 115): MTHFR (rs1801131, rs1801133, rs17421511), EPHX1 (rs1051740), MME (rs2016848), ALDH1A1 (rs6151031), HTR7 (rs1935349) and CYP2A6 (rs8192720). The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment (NP group) was lower than that of newly diagnosed patients without peripheral neuritis after treatment (NnP group) (1.70 ± 0.77 vs. 2.81 ± 0.97, p= 0.009). Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group (11.66 ± 1.79 µmol/L vs. 8.52 ± 3.29 µmol/L, p= 0.016) and healthy controls (11.66 ± 1.79 µmol/L vs. 8.55 ± 2.13 µmol/L, p≤ 0.001). Conclusion: CYP2A6, EPHX1, MTHFR, ALDH1A1, HTR7, MME and BIPN are linked in Chinese MM patients. BIPN is more likely to occur in patients with lower MTHFR mRNA expression, which might result in higher serum Hcy levels.

Grape seed proanthocyanidin extract protects the retina against early diabetic injury by activating the Nrf2 pathway.

The present study aimed to investigate whether grape seed proanthocyanidin extract (GSPE) has a protective effect on diabetic retinal function. A total of 30 Wistar rats were randomly divided into three equal groups, including the control, diabetic and GSPE-treated diabetic groups. Retinal tissue was harvested and subsequently stained with hematoxylin and eosin. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and methane dicarboxylic aldehyde (MDA) levels were evaluated using respective assay kits; whereas nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1 expression levels were assessed by immunohistochemical and western blot analysis. Cell apoptosis in the retina was determined using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method. The results showed that the structure of the retina was damaged in diabetic rats, as compared with the control rats. Notably, the structure of the retina improved in the GSPE-treated diabetic group, as compared with the diabetic group. SOD and GSH-Px activities were significantly increased in the retina of rats in the GSPE-treated diabetic group, as compared with the diabetic group (P=0.011 and P=0.001, respectively). Furthermore, a significant reduction in MDA was detected (P=0.013) and the expression levels of Nrf2 and HO-1 in the bladders of rats in the GSPE-treated diabetic group were significantly increased, as compared with the diabetic group (P=0.038 and P=0.043, respectively). Apoptosis of retinal cells was significantly increased in the diabetic group, as compared with the control group (P<0.001); a significant reduction was also detected in the GSPE-treated diabetic group, as compared with the diabetic group (P=0.014). These results demonstrate that GSPE administration may protect the retina against hyperglycemic damage, possibly by ameliorating oxidative stress-mediated injury via the activation of the Nrf2 pathway.