Effects of 4,4′-dichloro-diphenyl diselenide (ClPhSe)2 on toxicity induced by mercuric chloride in mice: A comparative study with diphenyl diselenide (PhSe)2

The effects of 4,4′-dichloro-diphenyl diselenide (ClPhSe)₂ on the toxicity induced by mercuric chloride (HgCl₂) were investigated and compared with diphenyl diselenide (PhSe)₂. Mice received HgCl₂ for three days and, on the third day, received (PhSe)₂ or (ClPhSe)₂. The results verified that the administration of (ClPhSe)₂ in mice exposed to HgCl₂ increased renal δ-aminolevulinate dehydratase (δ-ALA-D), Na⁺, K⁺-ATPase activities and non-protein thiol (NPSH) levels and also decreased thiobarbituric acid-reactive substances (TBARS) and ascorbic acid levels, when compared to mice exposed to HgCl₂ + (PhSe)₂. Plasma and urinary protein, hemoglobin and hematocrit levels and histological parameters were also ameliorated in mice exposed to HgCl₂ + (ClPhSe)₂. In addition, the hepatic damage in mice exposed to HgCl₂ + (PhSe)₂ was reduced in animals exposed to (ClPhSe)₂. To sum up, the introduction of a functional group (chloro) in the aromatic ring of diaryl diselenide reduced the toxicity of this compound in liver and kidney of mice exposed to HgCl₂.     

Brain and lungs of rats are differently affected by cigarette smoke exposure: Antioxidant effect of an organoselenium compound

Cigarette smoke exposure has been associated with oxidative stress in several organs. Antioxidant effect of diphenyl diselenide (PhSe)₂, an organoselenium compound, on oxidative damage induced by sub-chronic cigarette smoke exposure in brain and lungs of rats was investigated. Animals were exposed 5 times/week to one, two, three and four cigarettes for exposure periods of 15 min during the first, second, third and fourth weeks. Reactive species (RS) levels, enzymatic antioxidant defenses (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) activities) and non-enzymatic antioxidant defenses (ascorbic acid and non-protein thiol (NPSH) levels) were examined in brain and lungs of rats. An increase in RS levels induced by cigarette smoke in both tissues of rats was demonstrated. Cigarette smoke altered enzymatic antioxidant defenses (GST, CAT and SOD activities) in both tissues, and reduced the non-enzymatic antioxidant defenses in lungs. (PhSe)₂ (0.5 mg/kg/day, 5 times/week) restored RS levels and antioxidant defenses in brain of rats exposed to cigarette smoke. (PhSe)₂ treatment increased NPSH levels, GST and GR activities per se in lungs of rats. In conclusion, sub-chronic exposure to cigarette smoke caused alterations in antioxidant defense system and a tissue-specific oxidative stress in brain and lungs of rats. (PhSe)₂ restored antioxidant defenses in lungs and brain of rats.     

Comparative in vitro and ex-vivo myelotoxicity of aflatoxins B1 and M1 on haematopoietic progenitors (BFU-E,CFU-E,and CFU-GM): Species-related susceptibility

Haemato- and myelotoxicity are adverse effects caused by mycotoxins. Due to the relevance of aflatoxins to human health, the present study, employing CFU-GM-, BFU-E- and CFU-E-clonogenic assays, aimed at (i) comparing, in vitro, the sensitivity of human vs. murine haematopoietic progenitors to AFB1 and AFM1 (0.001–50 μg/ml), (ii) assessing whether a single AFB1 in vivo treatment (0.3–3 mg/kg b.w.) alters the ability of murine bone marrow cells to form myeloid and erythroid colonies, and (iii) comparing the in vitro with the in vitro ex-vivo data.We demonstrated (i) species-related sensitivity to AFB1, showing higher susceptibility of human myeloid and erythroid progenitors (IC₅₀ values: about 4 times lower in human than in murine cells), (ii) higher sensitivity of CFU-GM and BFU-E colonies, both more markedly affected, particularly by AFB1 (IC₅₀: 2.45 ± 1.08 and 1.82 ± 0.8 μM for humans, and 11.08 ± 2.92 and 1.81 ± 0.20 μM for mice, respectively), than the mature CFU-E (AFB1 IC₅₀: 12.58 ± 5.4 and 40.27 ± 6.05 μM), irrespectively of animal species, (iii) regarding AFM1, a species- and lineage-related susceptibility similar to that observed for AFB1 and (iv) lack of effects after AFB1 in vivo treatment on the proliferation of haematopoietic colonies.     

The compound cis-(dichloro)tetrammineruthenium(III) chloride induces caspase-mediated apoptosis in K562 cells

Ruthenium(III) complexes are increasingly attracting the interest of researchers due to their promising pharmacological properties. In the present study, we investigated the ability of cis-(dichloro)tetrammineruthenium(III) chloride to produce lethal effects in human chronic myelogenous leukemia K562 cells. The MTT tetrazolium reduction test and the trypan blue exclusion assay revealed that the IC₅₀ for the compound after 48 h of incubation with K562 cells was approximately 10.74 and 73.45 μM, respectively. Interestingly, it was observed that this compound exhibits mild cytotoxicity towards MRC-5 human fibroblast cells (IC₅₀ > 383 μM). Flow cytometric analysis revealed that cis-(dichloro)tetrammineruthenium(III) chloride was capable of change cell cycle distribution since the percentage of cells in the G1, S and G2 phases decreased. In addition, treatment with this compound induced apoptotic cell death in K562 cells, demonstrated by increased DNA content in the sub-G1-peak and a significant increase in caspase-3 activity. Assay using cyclosporin A, an inhibitor of the mitochondrial permeability transition pore (MPT) showed that the preincubation of K562 cells with this inhibitor had not effect on cis-(dichloro)tetrammineruthenium(III) chloride induced caspase-3 activation. In summary, cis-(dichloro)tetrammineruthenium(III) chloride displayed a significant cytotoxic effect through cell cycle arrest and apoptotic induction in K562 cells, which suggests that cis-(dichloro)tetrammineruthenium(III) chloride might have therapeutic potential against leukemia.     

Synthetic polysulfane derivatives induce cell cycle arrest and apoptotic cell death in human hematopoietic cancer cells

Natural polysulfanes including diallyltrisulfide (DATS) and diallyltetrasulfide (DATTS) from garlic possess antimicrobial, chemopreventive and anticancer properties. However these compounds exhibit chemical instability and reduced solubility, which prevents their potential clinical applicability. We synthesized six DATS and DATTS derivatives, based on the polysulfane motif, expected to exhibit improved physical and chemical properties and verified their biological activity on human leukemia cells.We identified four novel cytotoxic compounds (IC₅₀ values: compound 1, 24.96 ± 12.37 μM; compound 2, 22.82 ± 4.20 μM; compound 3, 3.86 ± 1.64 μM and compound 5, 40.62 ± 10.07 μM, compared to DATTS: IC₅₀: 9.33 ± 3.86 μM). These polysulfanes possess excellent differential toxicity, as they did not affect proliferating mononuclear blood cells from healthy donors.We further demonstrated ability of active compounds to induce apoptosis in leukemia cells by analysis of nuclear fragmentation and of cleavage of effector and executioner caspases. Apoptosis was preceded by accumulation of cells in G2/M phase with a pro-metaphase-like nuclear pattern as well as microtubular alterations. Prolonged and persistent arrest of cancer cells in early mitosis by the benzyl derivative identifies this compound as the most stable and effective one for further mechanistic and in vivo studies.     

Taxifolin mitigates oxidative DNA damage in vitro and protects zebrafish (Danio rerio) embryos against cadmium toxicity

Taxifolin (TAX) is a natural source of bioflavonoid found in various conifers. In this study, initially we investigated the antioxidant potential of TAX under in vitro assays such as 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), ferric-ion reducing power (FRAP) and hydroxyl radical (OH). The activities of DPPH, ABTS, FRAP and OH radical levels were significantly inhibited by TAX with an IC₅₀ values of 16.48, 66.34, 18.17 and 11.42 μg/ml, respectively. Secondly, TAX exhibited a strong protection against OH mediated DNA damage on pUC19 plasmid DNA at 1.0 μg/ml. Finally, we evaluated the protective mechanism of TAX against cadmium intoxicated zebrafish embryos (Danio rerio). We found that embryos exposed to 100 μM Cd exhibited significantly reduced survival, delayed hatching and phenotypic abnormalities at 24, 48, 72 and 96 hours post fertilization (hpf). Similarly, Cd intoxicated embryos showed significantly increased cardiac function (131 beats/min) at 60 hpf. Conversely, treatment with TAX (0.1, 1.0 and 10 μM) significantly enhanced the antioxidant enzyme levels (SOD, CAT, GPx and GR) by reducing the lipid peroxidation (MDA) in zebrafish embryos. Collectively, our results concluded that TAX could act as a potent redox scavenger against oxidative DNA damage and also functions as a crucial suppressor of Cd toxicity in zebrafish embryos.     

Mitochondrial toxicity of selective COX-2 inhibitors via inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria

Cyclooxygenase-2 (COX-2) inhibitors (coxibs) are non-steroidal anti-inflammatory drugs (NSAIDs) designed to selectively inhibit COX-2. However, drugs of this therapeutic class are associated with drug induced liver injury (DILI) and mitochondrial injury is likely to play a role. The effects of selective COX-2 inhibitors on inhibition of oxidative phosphorylation (ATP synthesis) in rat liver mitochondria were investigated. The order of potency of inhibition of ATP synthesis was: lumiracoxib (IC₅₀: 6.48 ± 2.74 μM) > celecoxib (IC₅₀: 14.92 ± 6.40 μM) > valdecoxib (IC₅₀: 161.4 ± 28.6 μM) > rofecoxib (IC₅₀: 238.4 ± 79.2 μM) > etoricoxib (IC₅₀: 405.1 ± 116.3 μM). Mechanism based inhibition of ATP synthesis (K_inact 0.078 min^− 1 and K_I 21.46 μM and K_inact/K_I ratio 0.0036 min^− 1 μM^− 1) was shown by lumiracoxib and data suggest that the opening of the MPT pore may not be the mechanism of toxicity. A positive correlation (with r² = 0.921) was observed between the potency of inhibition of ATP synthesis and the log P values. The in vitro metabolism of coxibs in rat liver mitochondria yielded for each drug substance a major single metabolite and identified a hydroxy metabolite with each of the coxibs and these metabolites did not alter the inhibition profile of ATP synthesis of the parent compound. The results suggest that coxibs themselves could be involved in the hepatotoxic action through inhibition of ATP synthesis.     

Toxicity of the synthetic polymeric 3-alkylpyridinium salt (APS3) is due to specific block of nicotinic acetylcholine receptors

The in vivo and in vitro toxic effects of the synthetic polymeric 3-alkylpyridinium salt (APS3), from the Mediterranean marine sponge Reniera sarai, were evaluated on mammals, with emphasis to determine its mode of action. The median lethal doses of APS3 were 7.25 and higher that 20 mg/kg in mouse and rat, respectively. Intravenous administration of 7.25 and 20 mg/kg APS3 to rat caused a significant fall followed by an increase in mean arterial blood pressure accompanied by tachycardia. In addition, cumulative doses of APS3 (up to 60 mg/kg) inhibited rat nerve-evoked skeletal muscle contraction in vivo, with a median inhibitory dose (ID₅₀) of 37.25 mg/kg. When administrated locally by intramuscular injection to mouse, APS3 decreased the compound muscle action potential recorded in response to in vivo nerve stimulation, with an ID₅₀ of 0.5 mg/kg. In vitro experiments confirmed the inhibitory effect of APS3 on mouse hemidiaphragm nerve-evoked muscle contraction with a median inhibitory concentration (IC₅₀) of 20.3 μM, without affecting directly elicited muscle contraction. The compound inhibited also miniature endplate potentials and nerve-evoked endplate potentials with an IC₅₀ of 7.28 μM in mouse hemidiaphragm. Finally, APS3 efficiently blocked acetylcholine-activated membrane inward currents flowing through Torpedo nicotinic acetylcholine receptors (nAChRs) incorporated to Xenopus oocytes, with an IC₅₀ of 0.19 μM. In conclusion, our results strongly suggest that APS3 blocks muscle-type nAChRs, and show for the first time that in vivo toxicity of APS3 is likely to occur through an antagonist action of the compound on these receptors.     

Guanosine and synthetic organoselenium compounds modulate methylmercury-induced oxidative stress in rat brain cortical slices: Involvement of oxidative stress and glutamatergic system

Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been pointed as two key mechanisms in methylmercury-toxicity. Thus, here we investigate the involvement of glutamatergic system in methylmercury (MeHg) neurotoxicity and whether diphenyl diselenide, ebselen and guanosine could protect cortical rat brain slices from MeHg-induced ROS generation. MeHg (100 and 200 μM) increased 2′,7′-dichlorodihydrofluorescin (DCFH) oxidation after 2 h of exposure. At 50 μM, MeHg increased DCFH oxidation only after 5 h of exposure. Guanosine (1 and 5 μM) did not caused any effect per se; however, it blocked the increase in DCFH caused by 200 or 50 μM MeHg. Ebselen (5 and 10 μM) decreased significantly the DCFH oxidation after 2 and 5 h of exposure to MeHg. Diphenyl diselenide (5 μM) did not change the basal DCFH oxidation, but abolished the pro-oxidant effect of MeHg. MK-801 also abolished the pro-oxidant effect of MeHg. These results demonstrate for the first time the potential antioxidant properties of organoseleniun compounds and guanosine against MeHg-induced ROS generation after short-term exposure in a simple in vitro model. In conclusion, endogenous purine (guanosine) and two synthetic organoselenium compounds can modulate the pro-oxidant effect of MeHg in cortical brain slices.     

Phenolic constituents of Pulicaria undulata (L.) C.A. Mey. sub sp. undulata (Asteraceae): Antioxidant protective effects and chemosystematic significances

One new naturally isoflavone compound, 5,7,2′,3′,4′ penta hydroxyl isoflavone-4′-O-β-glucopyranoside (1) was isolated from the aqueous methanol extract (AME) of Pulicaria undulata subsp. undulata, together with seven known compounds: kaempferol (2), kaempferol 3-O-β-glucoside (3), quercetin (4), quercetin 3-O-β-glucoside (5), quercetin 3-O-β-galactoside (6), quercetin 3,7-di OCH₃ (7), and caffeic acid (8). Their structures were established through chemical (acid hydrolysis) and spectral analysis (UV, NMR, and ESIM). The AME and some isolated compounds were evaluated as protective agents. Free radical scavenging using a microscaled 2,2-diphenyl-1-picrylhydrazyl assay was used to assess the direct antioxidant properties that were evaluated by the ability to protect murine Hepa1c1c7 liver cells against damage induced by the organic peroxide tert-butyl hydroperoxide. The neutral red uptake assay (NRU) was used to record the activity. Results of the 2,2-diphenyl-1-picrylhydrazyl assay recorded differential scavenging properties in ascending order: 5,7,2′,3′,4′ penta hydroxyl isoflavone-4′-O-β-glucopyranoside > quercetin > quercetin 3-O-galactoside > caffeic acid > quercetin 3,7-di-OCH₃ > kaempferol with 50% inhibitory concentrations of 3.9 μM, 7.5 μM, 11.4 μM, 12.2 μM, 78.1 μM, and 252.3 μM, respectively. The antioxidative potential reveals the potency of AME, quercetin, and quercetin 3,7-di-OCH₃. The latter compound showed full protection at 100 μM (33 μg/mL) against the induced toxicant effect where the 50% effective concentration was calculated as 33.6 ± 1.7 μM (11.1 μg/mL). In addition to quercetin, which was extensively shown previously as a cytoprotective agent, AME was less potent; it was capable of protecting 75% at 100 μg/mL with 50% effective concentration of 92.3 ± 4 μg/mL. Moreover, the isolated flavonoids were found to be significantly chemosystematic markers.     

Assessment of the chemopreventive effect of casearin B,a clerodane diterpene extracted from Casearia sylvestris (Salicaceae)

Studies have shown that Casearia sylvestris compounds protect DNA from damage both in vitro and in vivo. Complementarily, the aim of the present study was to assess the chemopreventive effect of casearin B (CASB) against DNA damage using the Ames test, the comet assay and the DCFDA antioxidant assay. The genotoxicity was assessed by the comet assay in HepG2 cells. CASB was genotoxic at concentrations higher than 0.30 μM when incubated with the FPG (formamidopyrimidine-DNA glycosylase) enzyme. For the antigenotoxicity comet assay, CASB protected the DNA from damage caused by H₂O₂ in the HepG2 cell line in concentrations above 0.04 μM with post-treatment, and above 0.08 μM with pre-treatment. CASB was not mutagenic (Ames test) in TA 98 and TA 102. In the antimutagenicity assays, the compound was a strong inhibitor against aflatoxin B1 (AFB) in TA 98 (>88.8%), whereas it was moderate (42.7–59.4%) inhibitor against mytomicin C (MMC) in TA 102. Additionally, in the antioxidant assay using DCFDA, CASB reduced reactive oxygen species (ROS) generated by H₂O₂. In conclusion, CASB was genotoxic to HepG2 cells at high concentrations; was protective of DNA at low concentrations, as shown by the Ames test and comet assay; and was also antioxidant.     

Effects of phenyl saligenin phosphate on cell viability and transglutaminase activity in N2a neuroblastoma and HepG2 hepatoma cell lines

The main aim of this study was to determine whether sub-lethal concentrations of the organophosphate compound phenyl saligenin phosphate (PSP) could disrupt the activity of the Ca²⁺-activated enzyme tissue transglutaminase (TGase 2) from cultured cell lines of neuronal (N2a) and hepatic (HepG2) origin.The results indicated that PSP added directly to cytosol extracts from healthy cells was able to inhibit TGase 2 activity by 40–60% of control levels at sub-lethal concentrations (?0.1 μM) that were approximately 100-fold lower than their IC₅₀ values in cytotoxicity assays. Following 24 h exposure of N2a cells to 0.3 and 3 μM PSP in situ, a similar reduction in activity was observed in subsequent assays of TGase 2 activity. However, significantly increased activity was observed following in situ exposure of HepG2 cells to PSP (ca. 4-fold at 3 μM). Western blotting analysis indicated slightly reduced levels of TGase 2 in N2a cells compared to the control, whereas an increase was observed in the level of TGase 2 in HepG2 cells. We suggest that TGase 2 represents a potential target of organophosphate toxicity and that its response may vary in different cellular environments, possibly affected by its expression pattern.     

Apoptosis induction by 4-nerolidylcatechol in melanoma cell lines

Pothomorphe umbellata, a native Brazilian plant, is popularly known to be effective in the treatment of skin lesions. This benefit is attributed to 4-nerolidylcatechol (4-NC), a compound extracted from P. umbellata. Since melanomas show prominent resistance to apoptosis and exhibit extreme chemoresistance to multiple forms of therapy, novel compounds addressing induction of cell death are worth investigating. Here, we evaluated effects on cell cycle progression and possible cytotoxic activity of 4-NC in melanoma cell lines as well as human dermal fibroblasts. Inhibitory effects on cell invasion and MMP activity were also investigated. 4-NC showed cytotoxic activity for all melanoma cell lines tested (IC₅₀ = 20–40 μM, 24 h for tumoral cell lines; IC₅₀ = 50 μM for fibroblast cell line) associated with its capacity to induce apoptosis. Furthermore, this is the first time that 4-NC is described as an inhibitor of cell invasiveness, due mainly to a G1 cell cycle arrest and inhibition of MMP-2 activity in melanoma cell lines.     

Dual role of resveratrol in modulation of genotoxicity induced by sodium arsenite via oxidative stress and apoptosis

The potential benefits of resveratrol as an anticancer (proapoptosis) and antioxidant (pro-survival) compound have been studied extensively. However, the role of resveratrol in modulation of the toxicity induced by sodium arsenite (NaAsO₂) is still unclear. In the present study, we examined the effects of resveratrol on NaAsO₂-induced cytotoxicity, DNA and chromosomal damage, cell cycle progression, apoptosis and oxidative stress in human lung adenocarcinoma epithelial (A549) cell line at concentrations from 1 to 20 μM after 24 h exposure. Our results revealed that at 1 and 5 μM, resveratrol was found to exert benefit effects, promoting cell viability and proliferation over 24 h NaAsO₂ exposure, whereas, resveratrol was showed to inhibit cell survival under the same condition at 20 μM. Corresponding to the opposing effect of resveratrol at low vs. high concentrations, DNA and chromosomal damage, cell apoptotic rate and level of oxidative stress were also alleviated by lower concentrations (1, 5 μM) of resveratrol, but exacerbated by higher concentration (20 μM) resveratrol. Our study implicates that resveratrol is the most beneficial to cells at 1 and 5 μM and caution should be taken in applying resveratrol as an anticancer therapeutic agent or nutraceutical supplement due to its concentration dependent effect.     

Inhibition of sphingosine kinase-2 ablates androgen resistant prostate cancer proliferation and survival

BackgroundEndogenous sphingolipid signaling has been shown to play an important role in prostate cancer endocrine resistance.MethodsThe novel SphK2 inhibitor, ABC294640, was used to explore SphK signaling in androgen resistant prostate cancer cell death signaling.ResultsIt dose-dependently decreased PC-3 and LNCaP cell viability, IC₅₀ of 28 ± 6.1 μM (p < 0.05) and 25 ± 4.0 μM (p < 0.05), respectively. ABC294640 was more potent in long-term clonogenic survival assays; IC₅₀ of 14 ± 0.4 μM (p < 0.05) in PC-3 cells and 12 ± 0.9 μM (p < 0.05) in LNCaP cells. Intrinsic apoptotic assays failed to demonstrate increased caspase-9 activity. Ki-67 staining demonstrated decreased proliferation by 50 ± 8.4% (p < 0.01) in PC-3 cells.ConclusionsSphK2 inhibition decreases androgen resistant prostate cancer viability, survival, and proliferation independently of the intrinsic apoptotic pathway. Findings are in contrast to recent observations of ABC29460 acting dependently on the intrinsic pathway in other endocrine resistant cancer cell lines.     

Toxic effects of xylazine on endothelial cells in combination with cocaine and 6-monoacetylmorphine

The use of xylazine as a drug of abuse has emerged worldwide in the last 7 years, including Puerto Rico. Clinical findings reported that xylazine users present greater physiological deterioration, than heroin users. The aim of this study was to assess the xylazine toxicity on endothelial cells, as this is one of the first tissues impact upon administration. Human umbilical vein endothelial cells in culture were treated with xylazine, cocaine, 6-monoacetylmorphine (heroin metabolite) and its combinations, at concentrations of 0.10–400 μM, for periods of 24, 48 and 72 h. IC₅₀ were calculated and the Annexin V assay implemented to determine the cell death mechanism. Results indicated IC₅₀ values at 24 h as follow: xylazine 62 μM, cocaine 210 μM, 6-monoacetylmorphine 300 μM. When these drugs were combined the IC₅₀ value was 57 μM. Annexin V results indicated cell death by an apoptosis mechanism in cells treated with xylazine or in combination. Results demonstrated that xylazine use inhibits the endothelial cell proliferation, at lower concentrations than cocaine and 6-monoacetylmorphine. These findings contribute to the understanding of the toxicity mechanisms induced by xylazine on endothelial cells.     

Cadmium induced pathophysiology: Prophylactic role of edible jute (Corchorus olitorius) leaves with special emphasis on oxidative stress and mitochondrial involvement

The present study was undertaken to evaluate the protective effect of aqueous extract of Corchorus olitorius leaves (AECO) against CdCl₂ intoxication. In vitro bioassay on isolated mice hepatocytes confirmed dose dependent cytoprotective effect of AECO. The CdCl₂ (30 μM) exhibited a significantly increased levels of lipid peroxidation, protein carbonylation along with the reduction of antioxidant enzymes and reduced glutathione levels in hepatocytes. AECO (200 and 400 μg/ml) + CdCl₂ (30 μM) could significantly restore the aforementioned oxidation parameters in hepatocytes. Beside this, AECO could significantly reduce Cd-induced increase in Bad/Bcl-2 ratio and the over-expression of NF-κB, caspase 3 and caspase 9. In in vivo assay, CdCl₂ (4 mg/kg body weight, for 6 days) treated rats exhibited a significantly increased intracellular Cd accumulation, oxidative stress and DNA fragmentation in the organs. In addition, the haematological parameters were significantly altered in the CdCl₂ treated rats. Simultaneous administration of AECO (50 and 100 mg/kg body weight), could significantly restore the biochemical, antioxidant and haematological parameters near to the normal status. Histological studies of the organs supported the protective role of jute leaves. Presence of substantial quantity of phenolic compounds and flavonoids in extract may be responsible for overall protective effect.     

Apoptosis in MCF-7 breast cancer cells induced by S-alkenylmercaptocysteine (CySSR) species derived from Allium tissues in combination with sodium selenite

S-Allylmercaptocysteine (CySSA) from garlic is known to exhibit anti-cancer effects. Apoptosis induction by CySSA was contrasted with S-1-propenylmercaptocysteine (CySSPe) (the major onion analog) in the presence of Na₂SeO₃ (Se) in breast cancer cells MCF-7. The dose of CySSA or CySSPe alone required to reduce viable cells by 50% was >400 μM, and this was reduced to 62 μM and 91 μM for CySSA + Se and CySSPe + Se, respectively, at molar ratios of 39:1. Synergism of the mixtures was confirmed by isobologram analysis and the treatments evoked enhanced thiol efflux from MCF-7 cells. Apoptosis was confirmed by Annexin-V and propidium iodide staining. Cell cycle arrest occurred at the G2/M and sub-G1 interphases. Both CySSR + Se mixtures reduced the levels of Akt. CySSPe + Se elevated GSK-3 protein levels, whereas CySSA + Se did not. CySSR + Se mixtures enhanced phospho-c-Jun levels, with CySSA + Se more potent than CySSPe + Se. Corresponding increases in phospho-p53, Bax and Bad levels were observed, indicating apoptosis occurred via the mitochondrial pathway. Lack of caspases 6/7 activation implicated a caspase-independent pathway for apoptosis. Reduction of imported CySSR and export of thiols by MCF-7 cells facilitates the reduction of selenite to yield H₂Se, a cytotoxic agent. This appears to be the first report of an anti-cancer effect of CySSPe.     

Diphenyl diselenide induces apoptotic cell death and modulates ERK1/2 phosphorylation in human neuroblastoma SH-SY5Y cells

Diphenyl diselenide (PhSe)₂ is a synthetic organoselenium compound displaying glutathione peroxidase-like activity. Protective and antioxidant potential of (PhSe)₂ have been extensively investigated in in vivo and in vitro studies. In spite of this, there is a lack of studies addressed to the investigation of potential cytotoxic effect and signaling pathways modulated by this compound. Herein, we aimed to analyze the effects of 24-h treatment with (PhSe)₂ on cell viability and a possible modulation of signaling pathways in human neuroblastoma cell line SH-SY5Y. For this purpose, cells were incubated with (PhSe)₂ (0.3–30 μM) for 24 h and cell viability, apoptotic cell death and modulation of MAPKs (ERK1/2 and p38^MAPK), and PKC substrates phosphorylation was determined. (PhSe)₂ treatment significantly decreased cell viability and increased the number of apoptotic cells with induction of PARP cleavage. An increase in ERK1/2 phosphorylation was observed at (PhSe)₂ 3 μM. In contrast, higher concentrations of the chalcogenide inhibited ERK1/2, p38^MAPK and PKC substrate phosphorylation. Pre-treatment with ERK1/2 inhibitor, U0126, increased cell susceptibility to (PhSe)₂. Together, these data indicate a cytotoxic potential of (PhSe)₂ in a neuronal cell line, which appears to be mediated by the ERK1/2 pathway.