Conversion of antibacterial quinolone drug levofloxacin to potent cytotoxic agents.

Levofloxacin, the optical S-(-) isomer of ofloxacin, is a broad-spectrum antibacterial agent widely used to control various infections caused by Gram-positive and Gram-negative bacteria. While the COOH group is necessary for antibacterial activity, its modification can offer anticancer activity to the fluoroquinolone framework. Therefore, several levofloxacin carboxamides 11a-j and 12 containing 5-substituted-1,3,4-thiadiazole residue were synthesized and screened in vitro for their anticancer activity. The in vitro MTT viability assay revealed that the most compounds had significant activity against cancer cells MCF-7, A549, and SKOV3. In particular, the 3-chloro- and 4-fluoro- benzyl derivatives (11b and 11h), with IC50 values of 1.69-4.76 µM were as potent as or better than doxorubicin. It should be noted that the mother quinolone levofloxacin showed no activity on the tested cancer cell lines. The SAR analysis demonstrated that the 3-chloro or 4-fluoro substituent on the S-benzyl moiety had positive effect on the activity. Further in vitro evaluations of the most promising compounds 11b and 11h by flow cytometric analysis and comet test revealed the ability of compounds in the induction of apoptosis and blockage of the cell proliferation at the G1-phase by nuclear fragmentation and DNA degradation in cancer cells. The obtained results demonstrated that the alteration of 6-COOH functional group in the levofloxacin structure and conjugation with a proper heterocyclic pharmacophore is a good strategy to obtain new anticancer agents.

The role of ginger's extract and N-acetylcysteine against docetaxel-induced oxidative stress and genetic disorder.

Oxidative stress plays a prominent role in expanding toxicity and various diseases. This study investigated the potential protective effects of ginger (Zingiber officinale) rhizome extract and NAC on docetaxel induced genotoxicity and oxidative stress. The antioxidant power of NAC and ginger extract on the genetic toxicity induced by docetaxel was assessed by micronucleus test. The ROS test with DCFH reagent was used to assess the reactive oxygen species. The thiobarbituric acid method was used to evaluate the amount of MDA produced by docetaxel. The amounts of phenol and flavonoids in the ginger extracts were also evaluated. The amount of phenol in the ginger extract was 0.886 mg of gallic acid per gram of dry extract. The amount of flavonoids were 0.242 mg/mL of quercetin per gram of dry extract. As shown by the micronucleus results, concentrations of 100 and 500 µM NAC and all concentrations of the ginger extract significantly reduced the number of micronuclei produced by docetaxel. On the other hand, the results of oxidative stress tests (ROS and LPO) showed that docetaxel in HGF cells increased the production of ROS and LPO, and the concentrations of ginger extract and NAC decreased oxidative stress in HGF cells in a dose-dependent manner. The results indicate that using these two antioxidants helps inhibit genetic toxicity and oxidative stress caused by docetaxel.

Dexamethasone as an anti-cancer or hepatotoxic.

The linkage between inflammation and oxidative stress in liver damage has been proven and is undeniable; dexamethasone with some antioxidants can reduce the toxicity of liver tissue. Due to the importance of cancer treatment, glucocorticoids' synergistic effect in inhibiting cancer cell growth is also investigated. Dexamethasone alone and combined with etoposide were tested at concentrations of 1, 5, and 10 µM to evaluate the potency of dexamethasone in inhibiting the growth of A549 cells using oxidative stress factors and DNA damage. Also, intraperitoneal injection of dexamethasone in rats was used to induce liver toxicity. Coenzyme Q10 at different concentrations (1, 10, and 50 mg/kg) was used as an antioxidant to assess the oxidative stress factors and measure Caspase-3 activity. The results showed that dexamethasone combined with etoposide could significantly inhibit the growth of cancer cells and induce apoptosis. Treatment of A549 cells using dexamethasone also inhibits cancer cells' growth by inducing oxidative stress and DNA damage. Dexamethasone also, by inducing oxidative stress and activation of caspase 3, ultimately causes hepatotoxicity. Treatment with different concentrations of CoQ10 showed improved mitochondrial function, antioxidant defense, and liver enzyme. The best effect of coenzyme Q10 on dexamethasone-induced hepatotoxicity is 50 mg/kg. As a result, dexamethasone (alone and combined with etoposide) has an anti-cancer effect by damaging DNA and inducing oxidative stress. Also, CoQ10 has antioxidant effects against dexamethasone-induced hepatotoxicity by improving mitochondrial function and reducing caspase-3 activity.

Modulatory effect of amifostine (WR-1065) against genotoxicity and oxidative stress induced by methotrexate in human umbilical vein endothelial cells (HUVECs).

Amifostine is used in chemotherapy and radiotherapy as a cytoprotective adjuvant alongside DNA-binding chemotherapeutic agents. It functions by reducing free radicals and detoxifying harmful metabolites. Methotrexate, as an antimetabolite drug has been considered for treating various cancers and autoimmune diseases. However, the cytotoxic effects of methotrexate extend beyond tumor cells to crucial organs, including the heart. This study applied the HUVEC cell line as a reference in vitro model for researching the characteristics of vascular endothelium and cardiotoxicity. The current study aimed to assess amifostine's potential cytoprotective properties against methotrexate-induced cellular damage. Cytotoxicity was measured using the MTT assay. Apoptotic rates were evaluated by Annexin V-FITC/PI staining via flow cytometry. The genoprotective effect of amifostine was determined using the comet assay. Cells were exposed to various amifostine doses (10-200 µg/mL) and methotrexate (2.5 µM) in pretreatment culture condition. Methotrexate at 2.5 µM revealed cytotoxicity, apoptosis, oxidative stress and genotoxicity while highlighting amifostine's cyto/geno protective properties on HUVECs. Amifostine significantly decreased the levels of ROS and LPO while preserving the status of GSH and SOD activity. Furthermore, it inhibited genotoxicity (tail length, %DNA in tail, and tail moment) in the comet assay. Amifostine markedly attenuated methotrexate-induced apoptotic cell death (early and late apoptotic rates). These findings convey that amifostine can operate as a cytoprotectant agent.

Cellular effects of epsilon toxin on the cell viability and oxidative stress of normal and lung cancer cells.

INTRODUCTION: Clostridium perfringens is a type of gram-positive anaerobic bacilli. C.perfringens produces many toxins, of which epsilon (ε) is one of the major ones. The mechanism of epsilon's toxicity is located in the lipid of cell membrane tissues. Epsilon toxin is known as a bioterrorism agent. Inhalation of these aerosols can destroy pulmonary vascular endothelial cells and cause lung injury, which increases vascular permeability and pulmonary edema. METHODS: In this study, we investigated the toxicity of epsilon toxin by using the MTT assay, evaluated oxidative stress effects such as ROS and LPO using the DCFH and TBA reagents, and measured the GSH of the normal and lung cancer cells by using the DTNB reagent. RESULTS: The result showed that 1 µg/ml of epsilon toxin caused mitochondrial disorder and reduced the growth of the normal cell line. This toxin also induced ROS and damage to lipid membranes. Furthermore, the same effect occurred in the lung cancer cell, and the epsilon toxin inhibited cancer cell proliferation. CONCLUSION: This toxin causes toxicity by binding to lipid membranes. As the present study results have confirmed, epsilon toxin inhibits mitochondrial function and induces ROS and lipid membrane damage.

Investigation of genetic toxicity and oxidative stress of Clostridium perfringens epsilon toxin type D on human peripheral blood lymphocytes.

Epsilon toxin (Etx) is an enormously potent pore-forming toxin and a category B biological agent. Etx is the main virulence determinant of Clostridiumperfringens types B and D toxin. It has a cytotoxic effect on distal and collecting kidney tubules. Also, Etx crosses the blood-brain barrier, binds to myelin structures, and destroys oligodendrocytes. The main purpose of this study was to investigate the toxic effects of Etx on human blood lymphocytes, which we examined for the first time for the genetic toxicity of this bacterial toxin. In this study, after taking blood and dividing into nine groups and putting in contact with different dilutions of Etx (1,5,10,25,50,100 and 200 µM), methotrexate (750 µM), and normal saline by Cytokinesis blocked micronucleus (CBMN) assay, we looked at genetic toxicity and the level of oxidative stress created in the under study lymphocytes. The results of this study showed that Etx has significant oxidative stress effects on human lymphocytes at doses above 25 µM, and also this bacterial toxin significantly increases the number of micronuclei formed in lymphocytes. The results of this study indicate that Etx has toxic effects it is genetic and interferes with cell division processes. Thus, human lymphocytes can be used extensively in future studies on Etx.

Synthesis, computational study and cytotoxicity of 4-hydroxycoumarin-derived imines/enamines.

In this study, we applied a direct condensation between 3-acetyl-4-hydroxy-2H-chromen-2-one and different amines (anilines and benzyl amines) in order to synthesize some coumarin-based imines/enamines (3a-o) as cytotoxic agents. All the compounds were characterized by means of FT-IR, NMR, mass spectroscopy and elemental analyses. Since the title compounds can exist as different forms including (s-cis)-imine and (s-trans)-imine or (E and Z)-enamines, their conformational and geometrical aspects were investigated computationally by DFT method. The optimized geometry parameters, ΔE, ΔG, ΔH, Mulliken atomic charge, HOMO and LUMO energy, and NBO analysis suggested that these compounds can exist predominantly in (E)-enamine form. All the synthesized compounds (3a-o) were evaluated in vitro for their cytotoxic activities against cancer cell lines (MCF-7 and A549) and normal cell line (BEAS-2B) using the MTT assay. The 4-hydroxybenzyl derivative 3k was found to be the most potent cytotoxic agent with no selectivity, similar to doxorubicin. However, the 4-chlorobenzyl analog 3o could be considered as an equipotent compound respect to doxorubicin with higher selectivity.

Physio-chemical responses of exogenous calcium nanoparticle and putrescine polyamine in Saffron (Crocus sativus L.).

The aim of this study was to investigate the effect of calcium nanoparticles (CaNP) and putrescine polyamine on some physiological and biochemical properties of saffron (Crocus sativus L.) under the control condition. Saffron corm was treated by different concentrations of putrescine (0, 0.25, 0.5, 1, 2 mM) and CaNP (0, 0.25, 0.5, 1, 1.5 g/l). The treatment of corm with putrescine and CaNP separately caused a significant increase in morphological parameters. Changes in biochemical parameters were also significant. Compared to other concentrations, the highest concentration of putrescine (1 mM) and CaNP (1 g/l) treatment in the plant showed the greatest effect. The combined effect of putrescine and CaNP treatment on morphological parameters was significant. The results of HPLC analysis showed that CaNP treatment alone is more effective on crocin, picrocrocin, and safranal content than the combined effect of CaNP and putrescine. The present study reported the functional potential of CaNP and putrescine combination to increase growth and phytochemical properties in Crocus sativus.

Ginkgo biloba attenuated hepatotoxicity induced by combined exposure to cadmium and fluoride via modulating the redox imbalance, Bax/Bcl-2 and NF-kB signaling pathways in male rats.

Aim of this study was to investigate the efficacy of Ginkgo Biloba (G.B) hydro-ethanolic extract against hepatotoxicity induced by combined exposure to cadmium (Cd) and fluoride (F) in Wistar rats. Animals were exposed to F (30 mg/L) + Cd (40 mg/L), F + Cd plus G.B (50,100 and 200 mg/kg), G.B (200 mg/kg), F + Cd plus Vit C(1000 mg/L) in drinking water for 42 days. Significant raise in liver enzymes and histopathological changes were observed in F + Cd treated rats. F + Cd exposure enhanced protein and glutathione oxidation, lipid peroxidation and decreased superoxide dismutase activity. F and Cd combination also caused mitochondrial dysfunction, swelling and mitochondrial membrane potential collapse in liver isolated mitochondria. Up-regulation of inflammatory genes (TNF-α, IL-1ß and NF-kB) and pro-apoptotic Bax as well as down-regulation of anti-apoptotic Bcl-2 were detected after co-exposure to F and Cd. Interestingly, G.B alleviated F + Cd induced liver oxidative stress, mitochondrial damage and prevented inflammation and apoptosis. Furthermore, decrease in serum liver enzymes and improvement of histopathologic lesions were observed in G.B treated rats. This study explored the potential beneficial role of G.B on F + Cd combined hepatotoxic effects via considering its possible antioxidant, anti-inflammatory, mitochondrial protection and anti-apoptotic effects.

Synthesis and biological assessment of ciprofloxacin-derived 1,3,4-thiadiazoles as anticancer agents.

The quinolone-3-carboxylic acid scaffold is essential structure for antibacterial activity of fluoroquinolones such as ciprofloxacin. Modification of 3-carboxylic functionality in this structure can be used for switching its activity from antibacterial to anticancer. Accordingly, a series of C-3 modified ciprofloxacin derivatives containing N-(5-(benzylthio)-1,3,4-thiadiazol-2-yl)-carboxamide moiety was synthesized as novel anticancer agents. Most of compounds showed significant activity against MCF-7, A549 and SKOV-3 cancer cells in the MTT assay. In particular, compounds 13a-e and 13g were found to be as potent as standard drug doxorubicin against MCF-7 cell line (IC50s = 3.26-3.90 µM). Furthermore, the 4-fluorobenzyl derivatives 13h and 14b with IC50 values of 3.58 and 2.79 µM exhibited the highest activity against SKOV-3 and A549 cells, being as potent as doxorubicin. Two promising compounds 13e and 13g were further tested for their apoptosis inducing activity and cell cycle arrest. Both compounds could significantly induce apoptosis in MCF-7 cells, while compound 13e was more potent apoptosis inducer resulting in an 18-fold increase in the proportion of apoptotic cells at the IC50 concentration in MCF-7 cells. The cell cycle analysis revealed that compounds 13e and 13g could increase cell portions in the sub-G1 phase, inducing oligonucleosomal DNA fragmentation and apoptosis confirmed by comet assay.

The implication of mitochondrial dysfunction and mitochondrial oxidative damage in di (2-ethylhexyl) phthalate induced nephrotoxicity in both in vivo and in vitro models.

Di-(2-ethylhexyl) phthalate (DEHP) and its main metabolite, monoethylhexyl phthalic acid (MEHP), are a serious threat to human and animals' health in the current century. However, their exact mechanism to induce nephrotoxicity is not clear. In the current study, we addressed toxic effects of MEHP and DEHP on embryonic human kidney cells (HEK-293 cell line) and kidney tissue of rats, respectively. In the HEK-293, MTT assay and oxidative stress parameters were measured after treatment with different concentrations of MEHP. For in vivo study, rats were treated with different doses of DEHP (50, 100, 200, 400 mg/kg) via gavage administration for 45 days. The renal function biomarkers (BUN and creatinine) were determined in serum of rats. Mitochondrial toxic parameters including MTT, mitochondrial membrane potential (MMP), mitochondrial swelling, and also oxidative stress parameters were measured in isolated kidney mitochondria. Histopathological effects of DEHP were also evaluated in rats' kidneys. We demonstrated that MEHP induced oxidative stress and cytotoxicity in HEK-293 cells in a concentration dependent manner. The administration of DEHP led to histopathological changes in kidney tissue, which concurred with BUN and creatinine alternations in serum of rats. The results of present study showed a significant mitochondrial dysfunction and oxidative stress confirmed by enhancement of mitochondrial swelling, mitochondrial reactive oxygen species (ROS) and malondialdehyde (MDA), and reduction of MMP and mitochondrial glutathione (GSH). Taken together, this study showed that DEHP/MEHP resulted in mitochondrial dysfunction and oxidative damage, which suggest a vital role of mitochondria in DEHP/MEHP-induced nephrotoxicity.

Design, synthesis and biological evaluation of flexible and rigid analogs of 4H-1,2,4-triazoles bearing 3,4,5-trimethoxyphenyl moiety as new antiproliferative agents.

Several flexible and rigid analogs of 4H-1,2,4-triazoles (compounds 8a-g and 9a-g) bearing trimethoxyphenyl pharmacophoric unit, were designed and synthesized as potential anticancer agents. The in vitro cytotoxic assay indicated that both flexible and rigid analogs (8 and 9, respectively) can potentially inhibit the growth of cancerous cells (A549, MCF7, and SKOV3), with IC50 values less than 5.0 µM. Furthermore, compounds 10a-l as regional isomers of compounds 9 exhibited remarkable cytotoxic activity with IC50 values ranging from 0.30 to 5.0 µM. The rigid analogs 9a, 10h and 10k were significantly more potent than etoposide against MCF7, SKOV3 and A549 cells, respectively. These compounds showed high selectivity towards cancer cells over normal cells, as they had no significant cytotoxicity against L929 cells. In addition, the representative compounds 9a and 10h could inhibit the tubulin polymerization at micro-molar levels. By determining changes in the colchicine-tubulin fluorescence, it was suggested that compound 10h could bind to the tubulin at the colchicine pocket. The molecular docking study further confirmed the inhibitory activity of promising compounds 9a, 10h and 10k on tubulin polymerization through binding to the colchicine-binding site.

New potent antifungal triazole alcohols containing N-benzylpiperazine carbodithioate moiety: Synthesis, in vitro evaluation and in silico study.

A number of 1H-1,2,4-triazole alcohols containing N-(halobenzyl)piperazine carbodithioate moiety have been designed and synthesized as potent antifungal agents. In vitro bioassays against different Candida species including C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis revealed that the N-(4-chlorobenzyl) derivative (6b) with MIC values of 0.063-0.5 µg/mL had the best profile of activity, being 4-32 times more potent than fluconazole. Docking simulation studies confirmed the better fitting of compound 6b in the active site of lanosterol 14α-demethylase (CYP51) enzyme, the main target of azole antifungals. Particularly, the potential of compound 6b against fluconazole-resistant isolates along with its minimal toxicity against human erythrocytes and HepG2 cells make this prototype compound as a good lead for discovery of potent and safe antifungal agents.

Cerium oxide nanoparticles protects against acrylamide induced toxicity in HepG2 cells through modulation of oxidative stress.

Acrylamide (AA) is a toxic chemical compound found in cooked foods. Considerable evidences suggest that oxidative stress and mitochondrial dysfunction are contributed to AA toxicity. Ceric oxide (CeO2) nanoparticles (nano-ceria) have the potential to be developed as a therapeutic for oxidative stress insults due to their catalytic antioxidant properties. In this study we investigated, whether nano-ceria exerted a protective effect against AA-induced cytotoxicity and oxidative damage. HepG2 human cancer cell lines were exposed to nano-ceria (50, 100, and 200 µM) and after 30 min, AA in the half maximal inhibitory concentration (IC50) concentration (200 µM) was added to the cells. Twenty four hours later, cellular viability, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), and cellular levels of glutathione (GSH) were assayed. AA decreased cell viability and pretreatment with nano-ceria significantly decreased AA-induced cytotoxicity. In addition, nano-ceria alleviated AA-induced ROS generation and LPO and depressed GSH level. Our results suggested that nano-ceria prevented cellular and oxidative damage induced by AA.

Melatonin Loading Chitosan-Tripolyphosphate Nanoparticles: Application in Attenuating Etoposide-Induced Genotoxicity in HepG2 Cells.

Etoposide is one of the most effective chemotherapeutic agents used in the treatment of various types of cancers. However, as a Topoisomerase II inhibitor, during clinical use, several side effects may occur. In addition, in several in vivo and in vitro studies, etoposide has been shown to have a range of genotoxic effects including single and double strand breaks. Melatonin is an anti-aging and antioxidant hormone synthesized from the pineal gland. The genoprotective, antioxidant, and free radical scavenger properties of melatonin have been well explained in various studies. The aim of this study was to explore whether melatonin nanoparticles protects against etoposide-induced genotoxicity in the HepG2 cell line. HepG2 cells (25 × 104 cells/well) were cultured in 24-well plates: a control group and 3 melatonin and its nanoparticles + etoposide groups (pre- and cotreatment conditions). Our results show that etoposide induced a noticeable genotoxic effect in HepG2 cells. Melatonin reduced the effects of etoposide significantly in both types of experiment conditions, through the reduction of the level of DNA damage measured via comet assay. Furthermore, melatonin decreased the intracellular reactive oxygen species generation. It also increased the intracellular glutathione levels in HepG2 cells. Nano melatonin is more effective than regular melatonin. The most protective effect was observed with melatonin when it was administrated 24 h before etoposide treatment.

Biomonitoring-based exposure assessment of benzene, toluene, ethylbenzene and xylene among workers at petroleum distribution facilities.

Elevated emissions of volatile organic compounds, including benzene, toluene, ethylbenzene, and o, p, and m-xylenes (BTEX), are an occupational health concern at oil transfer stations. This exploratory study investigated personal exposure to BTEX through environmental air and urine samples collected from 50 male workers at a major oil distribution company in Iran. Airborne BTEX exposures were evaluated over 8h periods during work-shift by using personal passive samplers. Urinary BTEX levels were determined using solid-phase microextraction with gas chromatography mass spectrometry for separation and detection. Mean exposure to ambient concentrations of benzene differed by workers' job type: tanker loading workers (5390µg/m3), tank-gauging workers (830µg/m3), drivers (81.9µg/m3), firefighters (71.2µg/m3) and office workers (19.8µg/m3). Exposure across job type was similarly stratified across all personal exposures to BTEX measured in air samples with maximum concentrations found for tanker loading workers. Average exposures concentrations of BTEX measured in urine were 11.83 ppb benzene, 1.87 ppb toluene, 0.43 ppb ethylebenzene, and 3.76 ppb xylene. Personal air exposure to benzene was found to be positively associated with benzene concentrations measured in urine; however, a relationship was not observed to the other BTEX compounds. Urinary exposure profiles are a potentially useful, noninvasive, and rapid method for assessing exposure to benzene in a developing and relatively remote production region.

Expression of MT1 receptor in patients with gastric adenocarcinoma and its relationship with clinicopathological features.

Gastric cancer accounts 8% of the total cancer cases leading to 10% of total cancer deaths worldwide. The indoleamine N-acetyl-5-methoxytryptamine, better known as melatonin, is the principal hormone produced by the pineal gland. Recently, it has been well documented some anti-cancer roles of melatonin in some malignancies as breast and colon cancer; as well as some its protective roles in the GI tract that have been known as free radical scavenger, antimitogenic and apoptotic properties. According to the anti-cancer effects of melatonin, wide distribution of this neurohormone in GI tract and some proposed physiologic and pharmacologic roles for this neurohormone and following our previous study which has shown expression of MT2 receptor in gastric adenocarcinoma, this study initially scheduled to determine the expression of melatonin receptor MT1 in tissue samples of adenocarcinoma cancer patients. A total of 10 gastric adenocarcinoma patients and 10 normal individuals were examined for MT1 gene expression by real-time PCR. Additionally, for screening of different alleles of MT1 in our samples, the SSCP-PCR procedure was developed. Our results have shown interestingly high expression for MT1 receptor in cancer and marginal cancer groups comparing with normal group. Our findings also have shown that a remarkable association between MT1 receptor mRNA levels and grade in individuals over age 50. PCR-SSCP analysis results showed a variation between individuals which may be effective on their gene expression patterns. According to our knowledge, for the first time this study evaluated the expression of MT1 receptor gene in gastric adenocarcinoma tissues which consistent with our previous study but with some difference in comparisons between kind of tissue expression and difference in polymorphisms. Moreover, these results show the defending role of melatonin in the GI system.

Mitochondrial dysfunction contribute to diabetic neurotoxicity induced by streptozocin in mice: protective effect of Urtica dioica and pioglitazone.

INTRODUCTION: Uncontrolled chronic hyperglycemia in diabetic patients could result in various complications, including neurotoxicity. Urtica dioica L. (UD) is known for its hypoglycemic and antioxidant effects. In this study, we evaluated the efficacy of UD and pioglitazone (PIO) in reduction of neurotoxicity and oxidative stress in streptozocin-induced diabetic mice. MATERIALS AND METHODS: Male mice were divided into seven groups: control, diabetic, dimethyl sulfoxide-treated control, PIO-treated, UD-treated, UD-PIO-treated, and vitamin E-treated. For induction of diabetes, streptozocin was injected in a single dose (65 mg/kg, i.p.). All treatments were performed for 5 weeks. Neurotoxicity was evaluated through hot plate and formalin test. Then, animals were killed, brain tissue was separated and the mitochondrial fraction was isolated with different centrifuge technique. Also, oxidative stress markers (reactive oxygen species, lipid peroxidation, protein carbonyl, glutathione) were measured in brain. Mitochondrial function was evaluated by MTT test in brain isolated mitochondria. RESULTS: Elevation of oxidative stress markers and mitochondrial damage were observed in diabetic mice compared to control group. Administration of PIO and UD ameliorated the oxidative stress and mitochondrial damage (p < 0.05) in diabetic mice. Also increase in pain score was shown in diabetic mice that treatment with UD and PIO diminished elevation of pain score in diabetic mice. Interestingly, simultaneous administration of PIO and UD showed synergism effect in attenuation of oxidative stress and hyperglycemia. CONCLUSION: UD showed a therapeutic potential for the attenuation of oxidative stress and diabetes-induced hyperglycemia that can be considered as co-treatment in treatment of diabetic neurotoxicity.

New indole-based chalconoids as tubulin-targeting antiproliferative agents.

Tubulin-targeting compounds have a broad anticancer spectrum and are an important class of chemotherapeutic agents. Due to the importance of 3-bromo-3,5-dimethoxyphenyl scaffold in the anticancer activity of microtubule inhibitors such as crolibulin (EPC2407), we introduced this functionality into the indole-derived chalcones. Thus, we describe here the synthesis and biological evaluation of new indole-based chalconoids as tubulin-targeting antiproliferative agents. The best result was obtained by compound 9b against A549 cell with IC50 of 4.3µg/mL, being more potent than the reference drug etoposide. Further biological evaluations revealed that compound 9b can inhibit tubulin polymerization and decrease the mitochondrial thiol content, resulting the induction of apoptosis in cancer cells. Docking studies with tubulin indicated that compound 9b could bind to the colchicine binding site.

BTEX exposure assessment and quantitative risk assessment among petroleum product distributors.

The aim of this study was to evaluate benzene, toluene, ethylbenzene, and xylene (BTEX) exposure among workers at four stations of a major oil distribution company. Personal BTEX exposure samples were collected over working shift (8h) for 50 workers at four stations of a major oil distribution company in Iran. Measured mean values for workers across four sites were benzene (2437, 992, 584, and 2788µg/m3 respectively), toluene (4415, 2830, 1289, and 9407µg/m3), ethylbenzene (781, 522, 187, and 533µg/m3), and xylene (1134, 678, 322, and 525µg/m3). The maximum mean concentration measured across sites for benzene was 2788µg/m3 (Station 4), toluene was 9407µg/m3 (Station 4), ethylbenzene was 781µg/m3 (Station 1) and xylene was 1134µg/m3 (Station 1). The 8h averaged personal exposure benzene concentration exceeded the recommended value of 1600µg/m3 established by the Iranian Committee for Review and Collection of Occupational Exposure Limit and American Conference of Governmental Industrial Hygienists. Mean values for excess lifetime cancer risk for exposure to benzene were then calculated across workers at each site. Estimates of excess risk ranged from 1.74 ± 4.05 (Station 4) to 8.31 ± 25.81 (Station 3). Risk was assessed by calculation of hazard quotients and hazard indexes, which indicated that xylene and particularly benzene were the strongest contributors. Tanker loading was the highest risk occupation at these facilties. Risk management approaches to reducing exposures to BTEX compounds, especially benzene, will be important to the health of workers in Iran.