The proteasomal system is responsible for the turnover of damaged proteins. Because of its important functions in oncogenesis, inhibiting the proteasomal system is a promising therapeutic approach for cancer treatment. Bortezomib (BTZ) is the first proteasome inhibitor approved by FDA for clinical applications. However neuropathic side effects are dose limiting for BTZ as many other chemotherapeutic agents. Therefore second-generation proteasome inhibitors have been developed including carfilzomib (CFZ). Aim of the present work was investigating the mechanisms of peripheral neuropathy triggered by the proteasome inhibitor BTZ and comparing the pathways affected by BTZ and CFZ, respectively. Neural stem cells, isolated from the cortex of E14 mouse embryos, were treated with BTZ and CFZ and mass spectrometry was used to compare the global protein pool of treated cells. BTZ was shown to cause more severe cytoskeletal damage, which is crucial in neural cell integrity. Excessive protein carbonylation and actin filament destabilization were also detected following BTZ treatment that was lower following CFZ treatment. Our data on cytoskeletal proteins, chaperone system, and protein oxidation may explain the milder neurotoxic effects of CFZ in clinical applications.

Background: JWH-018 was the first synthetic cannabinoid introduced as a legal high and the first of the new generation of novel psychoactive substances that flooded worldwide drug markets. JWH-018 was marketed as “spice,” “herbal incense,” or “herbal blend,” as a popular and legal (at the time) alternative to cannabis (marijuana). JWH-018 is a potent synthetic cannabinoid with considerable toxicity associated with its use. JWH-018 has qualitatively similar but quantitatively greater pharmacological effects than cannabis, leading to intoxications and even deaths. The mechanisms of action of the drug’s toxicity require research, and thus, the aim of the present study was to investigate the toxicological profile of JWH-018 in human SH-SY5Y neuronal cells. Methods: SH-SY5Y neuronal cells were exposed to increasing concentrations from 5 to 150 μM JWH-018 over 24 h. Cytotoxicity, DNA damage, the apoptotic/necrotic rate, and oxidative stress were assessed following SH-SY5Y exposure. Results: JWH-018 did not produce a significant decrease in SH-SY5Y cell viability, did not alter apoptotic/necrotic rate, and did not cause genotoxicity in SH-SY5Y cells with 24-h exposure. Glutathione reductase and catalase activities were significantly reduced; however, there was no significant change in glutathione peroxidase activity. Also, JWH-018 treatment significantly decreased glutathione concentrations, significantly increased protein carbonylation, and significantly increased malondialdehyde (MDA) concentrations. For significance, all P < 0.05. Discussion/Conclusion: JWH-018 produced oxidative stress in SH-SY5Y cells that could be an underlying mechanism of JWH-018 neurotoxicity. Additional in vivo animal and human-based studies are needed to confirm our findings.

Tribulus terrestris L. (Zygophyllaceae) has been commonly used to energize, vitalize, and improve sexual function and physical performance in men. This study investigates the potential cytotoxic and genotoxic, and endocrine disrupting activities of T. terrestris in vitro. The whole T. terrestris plant was extracted with water, methanol, and chloroform. The genotoxic potential of T. terrestris extracts at 3-2400 µg/mL was assessed by Comet assay in a rat kidney cell line (NRK-52E) and by Ames assay in Salmonella typhimurium TA98 and TA100 strains. Endocrine disrupting effects of the extracts at concentrations of 0.22-25 000 µg/mL were assessed by YES/YAS assay in Saccharomyces cerevisiae. Cytotoxic activity of the extracts was determined by the MTT test in NRK-52E cells. The different exposure times were used for four tests (3-48 h). The methanol extract of T. terrestris IC50 value was 160 µg/mL. The other extracts did not show cytotoxic effects. In the Comet and Ames genotoxicity assays, none of the extracts possessed genotoxic activities at concentrations of 0-2400 µg/mL. Only the water extract of T. terrestris induced frame shift mutations after metabolic activation. The water extract also showed estrogenic activity by YES/YAS assay in S. cerevisiae at concentrations ≥27 µg/mL (≥2.6-fold), while the other T. terrestris extracts had anti-estrogenic properties. Tribulus terrestris had estrogenic and genotoxic activities. The study was useful in determining its toxicological effects and the precautions regarding consumption.

Acetaminophen (APAP) is the most commonly used analgesic and antipyretic drug in the world. However, hepatotoxicity caused by APAP overdose is the most frequent cause of acute liver failure worldwide and oxidative stress involved in the pathogenesis of APAP hepatotoxicity. Celastrol is a natural triterpenoid derived from Tripterygium wilfordii Hook F. that exhibits antioxidant, anti-inflammatory, and antitumor activities. In this study, we aimed to investigate the potential ameliorative effects of celastrol against APAP-induced cytotoxicity and oxidative stress. Human hepatocellular carcinoma cells (HepG2) were incubated with 20 mM of APAP for 24 h and posttreated with 50 nM, 100 nM, or 200 nM of celastrol for a further 24 h. The methylthiazolyldiphenyl-tetrazolium bromide, lactate dehydrogenase, and neutral red uptake assays showed celastrol posttreatments recovered cell viability and cell membrane integrity in a concentration-dependent manner. Celastrol posttreatments exerted a significant increase in the glutathione content and a decrease in the malondialdehyde and protein carbonylation levels. Also, celastrol posttreatments attenuated the APAP-induced oxidative stress by raising glutathione peroxidase, glutathione reductase, and catalase activities. However, superoxide dismutase activity did not change. In conclusion, celastrol treatment may improve cell viability and increase cellular antioxidant defense in HepG2 cells. These results suggest that celastrol may have the potential to ameliorate the APAP-induced oxidative stress and cytotoxicity.

Colorectal cancer (CRC) is the third most common cancer in the world and its etiology involves the interaction of genetic and environmental factors. New blood vessels form through a process called angiogenesis and have an essential role in tumor growth, progression, and metastasis of malignant tumors. The vascular endothelial growth factor (VEGF), one of the most important angiogenic factors, is a specific mitogen for vascular endothelial cells. In the present case-control study, we carried out the study to evaluate whether the VEGF single-nucleotide polymorphisms play a role in modulating susceptibility to CRC. We evaluated the VEGF -2578A>C, +936C>T, and -460C>T genotypes obtained from 103 patients with CRC and 129 healthy controls by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Also, haplotype analysis was determined. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated. -2578A>C was significantly associated with CRC risk (OR 1.81; 95% CI 0.94-3.47; p=0.0495), while distribution of +936C>T and -460C>T genotypes in cases and controls did not significantly differ. The VEGF A2578-T936-T460 haplotype might be associated with the development of CRC (OR 8.77; 95% CI 1.05-73.36; p=0.0434). There was significant haplotype effect for all eight haplotypes (p=0.02). These results suggest that the VEGF polymorphisms might play a role in the development of CRC. Therefore, the VEGF polymorphisms might be further investigated to use in the determination of risk factors for CRC and to have a predictive value for anti-VEGF-targeted cancer therapies.

Aim: Colorectal cancer is the third most common cause of cancer-related mortality. Previous studies demonstrated increased telomerase activity in colorectal cancer tissue and suggested a prognostic value for patients with colorectal carcinoma. Telomerase reverse transcriptase (TERT), one of the main functional subunits of the telomerase, is an important factor in modulating telomerase activity, telomere length, and genomic stability. However, there are few studies that have addressed the association between genetic variation at TERT and the risk of colorectal cancer. Method: We evaluated the influence of three common single-nucleotide polymorphisms (SNPs) of the TERT gene (rs2853669, rs2736100, rs2736098) on susceptibility to colorectal cancer in 104 patients and 135 controls in a Turkish population. Results: We observed that rs2736098 was significantly associated with increased risk of colorectal cancer (OR = 2.53; 95% CI = 1.26–5.10; p = 0.008). On the other hand, rs2736100 and rs2853669 showed no association with colorectal cancer (p ≥ 0.128). Conclusion: These findings are the first results of TERT allele distributions in the Turkish population and also provide increased understanding with respect to colorectal cancer etiology.