Toxicology and Environmental Health Sciences最新文献

Objective: During cyanide poisoning, the rescue of vital organs like the brain is urgent. However, due to the presence of the blood-brain barrier (BBB), the currently available cyanide antidotes cannot reach the brain. Dimethyl trisulfide (DMTS) is a potent cyanide antidote and has excellent BBB permeability. Nonetheless, its formulation and application are challenging due to its highly lipophilic profile. In this work, a novel DMTS formulation, called FF-DMTS, was investigated. Its effect on in vitro DMTS permeability through BBB models, cellular viability, and in vivo absorption were tested.

Methods: The particle size was measured in FF-DMTS formulation. The permeability of DMTS in this new formulation was tested in BBB-PAMPA and in primary triple co-culture models of BBB. The effect of FF-DMTS on cellular viability was determined. To test the membrane and barrier integrity transendothelial electrical resistance (TEER) and cell layer impedance measurements, immunofluorescent stainings and the fluorescein permeability technique were applied. The pharmacokinetics of DMTS were revealed in blood and brain tissue.

Results: The average size of micelles in FF-DMTS was 16 nm. The permeability of DMTS through BBB-PAMPA and cell culture model was 7.68 × 10^-6 and 23.81 × 10^-6 cm/s, respectively. The FF-DMTS disturbed the barrier integrity of brain endothelial cells without causing any alteration in cellular viability until 300 µg/ml DMTS concentration. After administration of 150 mg/kg DMTS to mice, its absorption into the blood was rapid (5 min) and the plasma concentration of DMTS reached 5.2 µg/ml. The DMTS was also detected in brain, where its peak concentration was 495 ng/g brain tissue after 10 min of intramuscular administration. Furthermore, even 2 h later, DMTS was detected in brain.

Conclusions: Here, we showed that the novel FF-DMTS formulation has good permeability through BBB and a remarkable pharmacokinetic profile. Therefore, further investigation of the efficacy of FF-DMTS for treating cyanide intoxication is important.

Breast cancer is the most frequent type of cancer in women, many patients experience recurrences and metastasis. miR-21 (microRNA-21) as biomarker is under investigation for breast cancer. At present, there is very limited information available regarding effect of chemotherapy on miR-21 expression in breast cancer and its correlation with the clinical improvement. Hence, this study was planned to evaluate the effect of chemotherapy on miR-21 in metastatic breast cancer and its relationship with the clinical outcome. Females, aged-18-90 years diagnosed with Invasive Ductal Carcinoma of breast and candidate of neoadjuvant chemotherapy including Adriamycin (60 mg/m²), Cyclophosphamide (600 mg/m²) with or without Taxane (75-175 mg/m²) were included in the study. Before and after 42 days of staring of chemotherapy sample was collected for circulatory miR-21 and RECIST 1.1 criteria was applied to assess the clinical status. Blood samples for routine clinical biomarkers including liver function test and renal function tests was also collected. miR-21 expression before and after chemotherapy was assessed using standard method based on real time PCR. Expression of miR-21, RECIST criteria and other liver and kidney related biomarkers were compared before and after chemotherapy. After neoadjuvant chemotherapy expression of miR-21 was significantly increased by 5.65-fold. There was significant improvement in clinical scores based on RECIST criteria (0.046). No significant correlation was observed between miR-21 expression and difference in RECIST score (r = - 0.122, p = 0.570). Neoadjuvant chemotherapy causes clinical improvement in breast cancer patients however it is not correlated with the miR-21 expression which significantly increased after chemotherapy.