The heavy metals (HMs) lead and cadmium are persistent environmental pollutants capable of inducing ill-health in exposed individuals. One of the primary sites of accumulation and potential damage from HMs is bone, and we therefore examined the acute effects of lead and cadmium on human bone osteoblasts in vitro over a concentration range of 0.1 μM to 1mM, and for 3, 6, 12, 24, and 48 hour exposures. Incubation of osteoblasts with either lead or cadmium reduced cell viability in a concentrations and exposure durations dependent manner, as measured using MTT and LDH assays. Cytotoxicity was significant from 0.1 μM concentrations after 48 hour exposures. Both HMs damaged cellular bioenergetics with reductions of ATP production, mitochondrial complex activities, and aerobic respiration. There was a concomitant elevation of reactive oxygen species, with induction of redox stress measured as increased lipid peroxidation, and depleted cellular redox defense systems via reduced superoxide dismutase and catalase activity and cellular glutathione levels. Both HMs induced nuclear activation of Nrf2, presumably to increase transcription of antioxidant responsive genes to combat oxidative stress. Incubation of osteoblasts with HMs also compromised the secretion of procollagen type 1, osteocalcin, and alkaline phosphatase. Pre-incubation of osteoblasts with reduced glutathione prior to challenge with HMs lessened the cytotoxicity of the HMs, indicative that antioxidants may be a beneficial treatment adjunct in cases of acute lead or cadmium poisoning.

L��� ���-������ RNA� ����RNA�� ��� ����� ����-L��� ���-������ RNA� ����RNA�� ��� ����� ����tified potential biological and gene regulators. Similar to other cell-free circulating cancer-related nucleic acids, lncRNAs are released in the peripheral circulation of cancer patients and allow for non-invasive gene expression assessment. lncRNAs are considered to be promising biomarkers for cancer prognosis and diagnosis. Several lncRNAs have been found to regulate developmental processes in a number of biological disorders. Recent studies indicated that lncRNAs are associated with numerous diseases, most notably cancer, as they were found to be highly expressed or silenced in a number of human cancers, including colorectal cancer (CRC). Despite advances in the current detection methods, over half of cancer patients succumb to the disease, as several CRC cases are diagnosed at an advanced stage. Due to the lack of non-invasive and low-cost prognostic and diagnostic tests for CRC, the identification of novel, potentially effective biomarkers has been attracting increasing attention in recent cancer research. The present review focused on the most widely applied lncRNAs in cancer detection, including CRC, in vitro.

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Diabetes mellitus risk is increased by prolonged usage of antidepressants (ADs). Although various mechanisms are suggested for their diabetogenic potential, whether a direct effect of ADs on pancreatic β-cells is involved is unclear. We examined this idea for three ADs:paroxetine, clomipramine and, with particular emphasis, fluoxetine, on insulin secretion, mitochondrial function, cellular bioenergetics, K ATP channel activity and caspase activity in murine and human cell-line models of pancreatic β-cells. Metabolic assays showed that these ADs decreased the redox, oxidative respiration and energetic potential of β-cells in a time and concentration dependent manner at concentrations (100 nM) well within their plasma therapeutic window. These effects were related to inhibition of mitochondrial complex I and III activity.Consistent with impaired mitochondrial function, lactate output was increased and insulin secretion decreased. Neither fluoxetine, antimycin nor rotenone could reactivate K ATP channel activity blocked by glucose unlike the mitochondrial uncoupler, FCCP. Chronic, but not acute, AD increased oxidative stress and activated caspases, 3, 8 and 9. To conclude, paroxetine, clomipramine and fluoxetine were all found to be cytotoxic at therapeutic concentrations on pancreatic beta-cells; an action suggested to arise by inhibition of mitochondrial bioenergetics, oxidative stress and induction of apoptosis. These actions may help explain the diabetogenic potential of these ADs in humans.

Antidepressants are commonly employed for the treatment of major depressive disorders and other psychiatric conditions. We investigated the relatively acute cytotoxic effects of three commonly prescribed antidepressants: fluoxetine, sertraline, and clomipramine on rat primary blood brain barrier endothelial cells over a concentration range of 0.1-100μM. At therapeutic concentrations (0.1μM) no significant cytotoxicity was observed after 4, 24, or 48h. At high therapeutic to overdose concentrations (1-100μM), antidepressants reduced cell viability in proportion to their concentration and exposure duration. At 1μM, antidepressants significantly reduced mitochondrial membrane potential. At drug concentrations producing ~50% inhibition of cell viability, all drugs significantly reduced cellular oxygen consumption rates, activities of mitochondrial complexes I and III, and triggered a significant increase of lactate production. Fluoxetine (6.5μM) and clomipramine (5.5μM) also significantly lowered transcellular transport of albumin. The mechanism of cellular cytotoxicity was evaluated and at high concentrations all drugs significantly increased the production of reactive oxygen species, and significantly increased the activity of the pro-apoptotic caspases-3, 8, and 9. Comet assays revealed that all drugs were genotoxic. Pre-incubation of cells with glutathione significantly ameliorated antidepressant-induced cytotoxicity, indicating the potential benefit of treatment of overdosed patients with antioxidants.

Background. Many epidemiological studies have shown that vitamin D deficiency is associated with various types of human cancers. The biological action of vitamin D and its metabolites is mediated by the transcription factor vitamin D receptor (VDR). The VDR gene is highly expressed in the colon and is involved in many biological functions. The aim of the current study was to assess the relationship between serum vitamin D metabolite and calcium levels with VDR polymorphisms in normal and colorectal cancer (CRC) patients. Methods. Fifty Saudi CRC patients and fifty controls were enrolled in the study. The levels of total vitamin D, 25(OH)D3, and calcium were measured in serum. Results. The homozygous genotype (aa) of the ApaI VDR polymorphism (rs7975232) was found to correlate with total serum vitamin D levels of CRC patients, while the heterozygous (Tt) TaqI VDR polymorphism (rs731236) was associated with serum calcium levels. In contrast, the BsmI and FokI VDR polymorphisms (rs1544410 and rs2228570, resp.) did not affect the serum levels of total vitamin D, 25-hydroxyvitamin D3, and calcium. Conclusion. Appropriate vitamin D levels were shown to be important in preventing the onset of CRC.

This study tested the hypothesis that oxidative stress could be an underlying mechanism for APs-induced ovarian cytotoxicity and reproductive dysfunction. Rat ovarian theca interstitial cells (TICs) were isolated and treated with four APs [chlorpromazine (CPZ), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ)]. MTT assay was used to test the effects of these antipsychotics on TICs viability and to estimate their 50% inhibitory concentrations (ICs). The effects of APs (ICs and 1μM concentrations) on the activities of caspases-3, -8 and -9, reactive oxygen species (ROS) production, total intracellular glutathione and lipid peroxidation (LPO) in TICs were assessed. The effect of antioxidants (reduced glutathione (GSH) and quercetin) on the APs-induced cytotoxicity on TICs was investigated. MTT assay showed all APs to reduce TICs viability. CPZ, HAL and CLZ significantly increased the activity of caspases-3, -8 and -9 (P<0.0001, <0.0001 and <0.01, respectively). All APs at ICs significantly (P<0.0001) increased ROS production, decreased total intracellular glutathione and increased LPO. MTT assay in the presence of antioxidants (reduced GSH (5mM) or quercetin (50mM)) showed each antioxidant to significantly inhibit the effects of APs at their ICs on TICs viability. In conclusion, oxidative stress seems to be a possible mechanism for APs-induced ovarian and reproductive toxicity.

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