Diffuse axonal injury and oxidative stress: A comprehensive review

Traumatic brain injury (TBI) is one of the worldâ\u80\u99s leading causes of morbidity and mortality among young individuals. TBI applies powerful rotational and translational forces to the brain parenchyma, which results in a traumatic diffuse axonal injury (DAI) responsible for brain swelling and neuronal death. Following TBI, axonal degeneration has been identified as a progressive process that starts with disrupted axonal transport causing axonal swelling, followed by secondary axonal disconnection and Wallerian degeneration. These modifications in the axonal cytoskeleton interrupt the axoplasmic transport mechanisms, causing the gradual gathering of transport products so as to generate axonal swellings and modifications in neuronal homeostasis. Oxidative stress with consequent impairment of endogenous antioxidant defense mechanisms plays a significant role in the secondary events leading to neuronal death. Studies support the role of an altered axonal calcium homeostasis as a mechanism in the secondary damage of axon, and suggest that calcium channel blocker can alleviate the secondary damage, as well as other mechanisms implied in the secondary injury, and could be targeted as a candidate for therapeutic approaches. Reactive oxygen species (ROS)-mediated axonal degeneration is mainly caused by extracellular Ca2+. Increases in the defense mechanisms through the use of exogenous antioxidants may be neuroprotective, particularly if they are given within the neuroprotective time window. A promising potential therapeutic target for DAI is to directly address mitochondria-related injury or to modulate energetic axonal energy failure

Apatinib for the treatment of gastric cancer

Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2, has demonstrated encouraging anti-cancer activity in gastric cancer within both in vitro and in vivo models. AREAS COVERED: Apatinib's efficacy, tolerability and safety have been evaluated in one Phase II and one Phase III study in metastatic/advanced gastric cancer. In this review, we focus on the mechanism of action of apatinib, its pharmacokinetic profile and its clinical activity in the treatment of advanced/metastatic gastric cancer. Expert commentary: Unfortunately, as yet, there is no definitive biomarker data for apatinib in gastric cance

Nitric oxide, malondialdheyde and non-enzymatic antioxidants assessed in viable spermatozoa from selected infertile men

There are growing evidences that the semen of infertile male population shows higher reactive oxygen species (ROS) levels concomitant with lower antioxidant capacity compared to those detected in semen of fertile population. The plasma membrane of the sperm cell, which has high levels of polyunsaturated fatty acids, renders it particularly sensitive to ROS. The aim of this study was to compare the sperm parameters (concentration, motility, morphology and vitality) and the levels of malondialdehyde (MDA), as marker of lipid peroxidation (LPO), nitric oxide (NO), ascorbic acid (AA), total (GSHt) and oxidized glutathione (GSSG) in viable sperm in a group of 38 infertile patients and in a group of 55 control subjects with unknown reproductive potential. The comparison between variables in infertile patients and controls revealed that the sperm quality was reduced in the infertile group, whereas the levels of NO, AA and GSH were significantly increased in viable spermatozoa from infertile men; however, the endogenous levels of MDA were similar in infertile and control groups. Based on our results, we could speculate that the rise of GSHt and AA levels in viable sperm of infertile group help partially to counteract the damaging effect of ROS and partly prevent a substantial LPO. The observation of the concomitant increase of NO and antioxidant indices in viable spermatozoa of infertile subjects is a novel finding and we think that these results can be useful since the viable sperm population is conceivably used in assisted reproductive technology

Role of chemotherapy in the treatment of metastatic castration-resistant prostate cancer patients who have progressed after abiraterone acetate

Abiraterone acetate is a novel irreversible inhibitor of CYP17 that was recently approved for men with post-chemotherapy or chemo-naive castration-resistant prostate cancer. Unfortunately, this agent is not curative, and patients often ultimately develop resistance. However, men who progress after treatment with this new hormonal agent may be considered for another line of chemotherapy-based treatment. In 2004, docetaxel (D) and prednisone were found to improve survival compared with older regimens. More recently, cabazitaxel (C), a novel taxane chemotherapy, has been found to prolong survival in patients who exhibit disease progression during or after D chemotherapy. Here, we review the first clinical studies in which castration-resistant prostate cancer patients received chemotherapy with D or C after progression during abiraterone acetate treatment

Efficacy and Safety of Regorafenib With 2/1 Schedule for Patients ≥ 75 Years With Metastatic Colorectal Cancer (mCRC) After Failure of 2 Lines of Chemotherapy

Background: In the CORRECT (patients with metastatic COloRectal Cancer treated with REgorafenib or plaCebo after failure of standard Therapy) trial, regorafenib was proven to extend survival of patients with metastatic colorectal cancer (mCRC) that progressed after all available therapies. Grade 3 to 4 toxicity occurred in 54% of patients, and data on the activity and tolerability of regorafenib in elderly patients were scarce. The aim of this study was to evaluate the efficacy and safety of an alternative schedule, 2-week-on treatment and 1 week-off (2/1 schedule), of regorafenib for elderly patients with mCRC. Patients and Methods: Patients â\u89¥ 75 years with mCRC who progressed after oxaliplatin- and irinotecan-based chemotherapy received regorafenib on a 2/1 schedule. Potentially frail subjects were identified by G8 screening tool and excluded. The 2-month disease-control rate was the primary endpoint, and the secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and objective response rate. Results: Between February 2014 and May 2017, 23 patients with mCRC were recruited at our institution. No partial or complete responses were observed, and the stable disease and disease-control rate were 52.2%. The median PFS was 4.8 months (95% confidence interval, 3.8-6.3 months), and the median OS was 8.9 months (95% confidence interval, 6.9-10.6 months). Adverse events were uncommon, and the most frequent grade 3 toxicity adverse events were hand-foot skin reaction (9%) and fatigue (9%). Toxicity-related dose reductions and discontinuations occurred in 5 and 2 patients, respectively. Conclusion: Regorafenib administered with a modified 2/1 schedule to patients who were aged â\u89¥ 75 years and non-frail with treatment-refractory mCRC seems to be tolerable and achieve encouraging results in terms of PFS and OS

Gemcitabine, oxaliplatin, and capecitabine (GEMOXEL) compared with gemcitabine alone in metastatic pancreatic cancer: a randomized phase II study

Background: Single-agent gemcitabine (GEM) has been considered for many years as the standard first-line treatment for advanced pancreatic cancer. However, recently, several studies reported encouraging activity and good tolerability for some combination regimens. Considering the apparently non-overlapping toxicity and the proved individual efficacy of GEM, oxaliplatin (l-OHP), and capecitabine (CAP), this randomized phase II study compared the activity and safety of the combination GEM, l-OHP, and CAP (GEMOXEL) versus GEM alone, in patients with metastatic pancreatic cancer. Materials and methods: The treatment in GEMOXEL arm consisted of GEM 1,000 mg/m2 as a 30-min intravenous infusion on days 1, 8, 15, 22, l-OHP 100 mg/m2 i.v. on day 2, and CAP 1,500 mg/m2/day in two divided doses on days 1-14, every 21 days (one cycle). In both treatment groups, GEM was administered weekly for seven consecutive weeks followed by 1-week rest for the first 8 weeks, and thereafter, GEM was continued on days 1, 8, 15, every 28 days. Chemotherapy was administered until disease progression or unacceptable toxicity. Results: Sixty-seven patients were enrolled in the study. Thirty-four were randomly assigned to GEMOXEL and 33 to GEM. At 4 months, disease control rate was 79.4 % with GEMOXEL versus 45.4 % with GEM (p = 0.004). The median progression-free survival was 6.8 months (95 % CI 5.3-7.3 months) in GEMOXEL arm and 3.7 months (95 % CI 2.9-4.7 months) in GEM arm (p < 0.001). The median OS was 11.9 months (95 % CI 10.6-12.9 months) in GEMOXEL arm and 7.1 months (95 % CI 5.5-9.1 months) in GEM arm (p < 0.001). Hematologic and non-hematologic toxicity was more severe with combination chemotherapy, yet still tolerable. No grade 4 adverse events were observed with either regimen. Conclusion: GEMOXEL regimen seemed to be safe and more efficient than the standard therapy with GEM alone in the treatment of metastatic pancreatic cancer

Cytotoxic Effects of Cannabinoids on Human HT-29 Colorectal Adenocarcinoma Cells: Different Mechanisms of THC, CBD, and CB83

In this study, we investigated the effects of exposition to IC50 dose for 24 h of a new synthetic cannabinoid (CB83) and of phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on HT-29 colorectal carcinoma cells. Cell viability and proliferative activity evaluated using the MTT, lactate dehydrogenase (LDH), and CyQUANT assays showed that cell viability was significantly affected when CB83, THC, and CBD were administered to cells. The results obtained showed that the reduced glutathione/oxidized glutathione ratio was significantly reduced in the cells exposed to CBD and significantly increased in the cells treated with the CB83 when compared to the controls. CBD treatment causes a significant increase in malondialdehyde content. The catalase activity was significantly reduced in HT-29 cells after incubation with CB83, THC, and CBD. The activities of glutathione reductase and glutathione peroxidase were significantly increased in cells exposed to THC and significantly decreased in those treated with CBD. The ascorbic acid content was significantly reduced in cells exposed to CB83, THC, and CBD. The ultrastructural investigation by TEM highlighted a significantly increased percentage of cells apoptotic and necrotic after CB83 exposition. The Annexin V-Propidium Iodide assay showed a significantly increased percentage of cells apoptotic after CB83 exposition and necrotic cells after CBD and THC exposition. Our results proved that only CBD induced oxidative stress in HT-29 colorectal carcinoma cells via CB receptor-independent mechanisms and that CB83 caused a mainly CB2 receptor-mediated antiproliferative effect comparable to 5-Fuorouracil, which is still the mainstay drug in protocols for colorectal cancer