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  • Chrysin, a natural and biologically active flavonoid suppresses tumor growth of mouse B16F10 melanoma cells: In vitro and In vivo study
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-17
    Aïcha Sassi, Mouna Maatouk, Dorra El gueder, Imen Mokdad Bzéouich, Saïda Abdelkefi-Ben Hatira, Saloua Jemni-Yacoub, Kamel Ghedira, Leila Chekir-Ghedira
  • Caffeine-supplemented diet modulates oxidative stress markers and improves locomotor behavior in the lobster cockroach Nauphoeta cinerea
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-13
    Cícera Simoni da Silva, Rita de Cássia Gonçalves de Lima, Olusola Olalekan Elekofehinti, Yetunde Ogunbolude, Antonia Eliene Duarte, João Batista Teixeira Rocha, Irwin Rose Alencar de Menezes, Luiz Marivando Barros, Appolinaire Tsopmo, Kiven Erique Lukong, Jean Paul Kamdem
  • The in vitro radiosensitizer potential of resveratrol on MCF-7 breast cancer cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-12
    Isabel Cristina da Costa Araldi, Fernando Primitivo Romero Bordin, Francine Carla Cadoná, Fernanda Barbisan, Verônica Farina Azzolin, Cibele Ferreira Teixeira, Tadeu Baumhardt, Ivana Beatrice Mânica da Cruz, Marta Maria Medeiros Frescura Duarte, Liliane de Freitas Bauermann

    Radiation therapy is commonly applied in breast cancer (BC) patients. However, radioresistance and side effects are limiting factors of this practice. Therefore, studying substances that can enhance the radiation effect and, at the same time, protect normal cells is very relevant. Thus, the aim of this work was to assess the radiosensitizer effect of resveratrol (RV) on BC cells (MCF-7). A high cytotoxic and antiproliferative effect was observed in the treatment with 10 μM of RV + 3 Gy ionizing radiation (IR). Our results indicate that, 24 h after the exposition of cell cultures to RV + IR, an induction of necrosis/senescence has occurred. Furthermore, was observed the activation of extrinsic apoptosis pathway through a decrease of the Bax/Bcl-2 ratio and a high activity of caspase 8. Moreover, our data show that this treatment affected the oxidative cell metabolism, increasing oxidative protein, lipid and membrane damage and also acted to decrease the antioxidant enzymes activity. The antiproliferative effect on 72 h cultures may be associated with a high expression of p53 and an interruption of cell cycle in the S phase. Therefore, our results suggest that RV is a potential radiosensitizer of MCF-7 BC cells.

  • Effects of rutin on the physicochemical properties of skin fibroblasts membrane disruption following UV radiation
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-12
    Izabela Dobrzyńska, Agnieszka Gęgotek, Ewelina Gajko, Elżbieta Skrzydlewska, Zbigniew A. Figaszewski

    Human skin provides the body's first line of defense against physical and environmental assaults. This study sought to determine how rutin affects the membrane electrical properties, sialic acid content, and lipid peroxidation levels of fibroblast membranes after disruption by ultraviolet (UV) radiation. Changes in cell function may affect the basal electrical surface properties of cell membranes, and changes can be detected by electrokinetic measurements. The charge density of the fibroblast membrane surface was measured as a function of pH. A four-component equilibrium model was used to describe the interaction between ions in solution and ions on the membrane surface. Agreement was found between experimental and theoretical charge variation curves of fibroblast cells between pH 2.5 and 8. Sialic acid content was determined by Svennerholm's resorcinol method, and lipid peroxidation was estimated by measuring the malondialdehyde level. Compared to untreated cells, ultraviolet A (UVA)- or ultraviolet B (UVB)-treated skin cell membranes exhibited higher concentrations of acidic functional groups and higher average association constants with hydroxyl ions, but lower average association constants with hydrogen ions. Moreover, our results showed that UVA and UVB radiation is associated with increased levels of sialic acid and lipid peroxidation products in fibroblasts. Rutin protected cells from some deleterious UV-associated membrane changes, including changes in electrical properties, oxidative state, and biological functions.

  • Protective effect of patchoulene epoxide against ethanol-induced gastric ulcer in rats: Influence on oxidative stress, inflammation and apoptosis
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-12
    Jiali Liang, Yaoxing Dou, Xue Wu, Huilin Li, Jiazhen Wu, Qionghui Huang, Dandan Luo, Tiegang Yi, Yuhong Liu, Ziren Su, Jianping Chen

    Patchoulene epoxide (PAO), a tricyclic sesquiterpene isolated from the long-strored patchouli oil, has been demonstrated the anti-inflammatory activity in vivo based on our previous study. However, the gastroprotective effect of PAO still remains unknown. Therefore, in the present study, ethanol-induced gastric ulcer in rats was carried out to evaluate the anti-ulcerogenic activity of PAO and to elucidate the potential mechanisms that involved. According to our results, macroscopic examination revealed that pre-treatment with PAO signficantly reduced ethanol-induced gastric ulcer areas as compared with the vehicle group, which was also supported by histological evaluation. In addition, PAO was able to enhance the expressions of antioxidant enzymes including glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) as well as suppress lipid peroxidation indicated by down-regulation of malonaldehyde (MDA). Besides, the anti-inflammatory activity of PAO also contributed to gastroprotection characterized by reversing the imbalance between pro- and anti-inflammatory cytokines and modulating the expressions of NF-κB pathway-related proteins including p-IκBα, IκBα, p-p65 and p65. Furthermore, immunohistochemistry analysis exhibited potent anti-apoptosis effect of PAO as well, which appeared as down-regulation of caspase-3, Fas and Fasl protein expression. In conclusion, these findings suggested that PAO has gastroprotective activity against ethanol and this might be related to its positive influence on oxidative stress, inflammatory response and apoptosis cascade.

  • In vitro and in vivo metabolic activation of rhein and characterization of glutathione conjugates derived from rhein
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-11
    Yang Xu, Xu Mao, Boyang Qin, Ying Peng, Jiang Zheng

    Rhein (RH), 4,5-dihydroxyanthrauinone-2-carboxylic acid, is found in rhubarb (Dahuang), a traditional herbal medicine. RH has reportedly demonstrated multiple pharmacologic properties. Previous studies have also shown that RH induced hepatotoxicity, but the mechanisms of the adverse effect remain unknown. The major objective of the present study was to study the metabolic pathways of RH in order to identify potential reactive metabolites. One mono-hydroxylation metabolite (M1) was detected in urine and bile of rats given RH. M1 was also observed in rat and human liver microsomal incubations after exposure to RH. A total of three (GSH) conjugates (M2, M3 and M5) were detected in bile of rats treated with RH. We concluded that M2-M3 were directly derived from parent compound RH through spontaneous reaction with GSH. M5 was derived from M1 by reaction with GSH, which required cytoslic GSTs. M5 was further metabolized to the corresponding NAC conjugate (mercapturic acid) and was excreted in urine. P450 2C9 was mainly involved in the oxidation of RH.

  • Gallic acid attenuates type I diabetic nephropathy in rats
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-10
    Mayuresh Sudamrao Garud, Yogesh Anant Kulkarni

    Literatures suggest that TGF-β1 have a central role in the progression of diabetic nephropathy and its down regulation can improve the disease condition. Oxidative stress, generation of advanced glycation end products and activation of renin angiotensin system are the connecting links between hyperglycemia and TGF-β1 over expression. Gallic acid is a phytochemical having wide range of biological activities. Gallic acid is reported to have antioxidant and advanced glycation inhibitory activity. It has also shown inhibitory effects on angiotensin converting enzyme. Gallic acid qualifies as a drug candidate to be tested in the diabetic nephropathy, one of the important complication of diabetes. Streptozotocin (55 mg/kg body weight, i.p.) induced diabetic nephropathy was used as an experimental model. Gallic acid was evaluated for its possible effect at the dose of 20 and 40 mg/kg body weight. Gallic acid treatment significantly lowered plasma levels of the creatinine and blood urea nitrogen and elevated the levels of the protein and albumin. Gallic acid also improved creatinine clearance. Determination of oxidative stress parameters showed that the oxidative stress in kidney tissues was reduced significantly in gallic acid treated animals. Results of the Plasma, urine and oxidative stress parameters were also reflected in the histo-pathological evaluation showing improvement in kidney patho-physiology. ELISA assay for circulating TGF-β1 evaluation and immunohistochemical study for determination of kidney expression of TGF-β1 revealed that gallic acid significantly lowered both the circulating and tissue levels of TGF-β1. Results supports the hypothesis that gallic acid can be effectively used in the treatment of diabetic nephropathy.

  • Salinomycin induces primary chicken cardiomyocytes death via mitochondria mediated apoptosis
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-10
    Xiuge Gao, Yani Zheng, Xiangchun Ruan, Hui Ji, Lin Peng, Dawei Guo, Shanxiang Jiang

    Salinomycin, as a polyether ionophore antibiotic, is extensively used as a feed additive against coccidiosis in poultry and as a growth promoter of ruminants worldwide. Owing to its narrow therapeutic index, numerous intoxication have been reported in target/non-target animals by overdosage, misuse or drug interactions as well as human who consumed salinomycin accidently. Salinomycin-induced cardiotoxicity in chicken and non-target animals is considered as a major contributor to animal death. In the current study, we aim to elucidate the underlying mechanism of its myocardial toxicity using primary chicken myocardial cell as an in vitro model. The results showed that salinomycin altered cellular morphology and induced cell death in a concentration-dependent manner. Salinomycin treatment elevated the permeability of the cell membrane and leaded to the efflux of enzymes, including creatine kinase (CK) and lactate dehydrogenase (LDH). Flow cytometry analysis indicated the number of apoptotic cells increased significantly by salinomycin exposure. Furthermore, caspase-3 and caspase-9 were activated at gene and protein level rather than caspase-8, along with the up-regulation of apoptosis genes Bax, Cytochrome C, Apoptotic peptidase activating factor 1 (Apaf-1) and the down-regulation of Bcl-2. Salinomycin-induced mitochondrial dysfunction was accompanied by the significant decrease of mitochondrial membrane potential (MMP) and the severe ultrastructure damage. In conclusion, these findings suggest that the toxic dose of salinomycin induces severe cardiomyocytes death through mitochondria mediated apoptosis pathway.

  • Activation of p62-keap1-Nrf2 antioxidant pathway in the early stage of acetaminophen-induced acute liver injury in mice
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-10
    Zhenyu Shen, Yu Wang, Zhenhui Su, Ruirui Kou, Keqin Xie, Fuyong Song

    Acetaminophen (APAP) overdose can cause severe liver failure even death. Nearly half of drug-induced liver injury is attributed to APAP in the US and many European countries. Oxidative stress has been validated as a critical event involved in APAP-induced liver failure. p62/SQSTM1, a selective autophagy adaptor protein, is reported to regulate Nrf2-ARE antioxidant pathway in response to oxidative stress. However, the exact role of p62-keap1-Nrf2 antioxidant pathway in APAP-induced hepatotoxicity remains unknown. In the present study, the dose-response and time-course model in C57/BL6 mice were established by intraperitoneal injection of APAP. The results of serum alanine/aspartate aminotransferases (ALT/AST) and histological examination demonstrated that APAP overdose resulted in the severe liver injury. In the meantime, the levels of p62, phospho-p62 and nuclear Nrf2 were significantly increased by APAP in mice liver, suggesting an activation of p62-keap1-Nrf2 pathway. In addition, the expression of GSTA1 mRNA was increased in a dose-dependent manner, while the mRNA levels of HO-1 and GCLC were decreased with the increase of APAP dose. Our further investigation found that expression of HO-1 and GCLC peaked at 3 h∼6 h, and then were decreased gradually. Taken together, these results indicated that p62-keap1-Nrf2 antioxidant pathway was primarily activated in the early stage of APAP hepatotoxicity, which might play a protective role in the process of APAP-induced acute liver injury.

  • Bioactivation of 1-chloro-2-hydroxy-3-butene, an in vitro metabolite of 1,3-butadiene, by rat liver microsomes
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-10
    Ye Wang, Ying-Xin Yu, Yang Luan, Jing An, Dong-Guang Yin, Xin-Yu Zhang
  • Coagonist of GLP-1 and glucagon decreases liver inflammation and atherosclerosis in dyslipidemic condition
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-08
    Vishal Patel, Amit Joharapurkar, Samadhan Kshirsagar, Brijesh Sutariya, Maulik Patel, Dhreerendra Pandey, Hiren Patel, Ramchandra Ranvir, Shekhar Kadam, Dipam Patel, Rajesh Bahekar, Mukul Jain

    Dyslipidemia enhances progression of atherosclerosis. Coagonist of GLP-1 and glucagon are under clinical investigation for the treatment of obesity and diabetes. Earlier, we have observed that coagonist reduced circulating and hepatic lipids, independent of its anorexic effects. Here, we investigated the role of coagonist of GLP-1 and glucagon receptors in complications of diet-induced dyslipidemia in hamsters and humanized double transgenic mice. Hamsters fed on high fat high cholesterol diet were treated for 8 weeks with coagonist of GLP-1 and glucagon receptors (75 and 150 μg/kg). Pair-fed control was maintained. Cholesterol fed transgenic mice overexpressing hApoB100 and hCETP with coagonist (300 μg/kg) for 4 weeks. After the completion of treatment, biochemical estimations were done. Coagonist treatment reduced triglycerides in plasma, liver and aorta, plasma cholesterol and hepatic triglyceride secretion rate. Expressions of HMG-CoA reductase and SBREBP-1C were reduced and expressions of LDLR, CYP7A1, ABCA1 and ABCB11 were increased in liver, due to coagonist treatment. Coagonist treatment increased bile flow rate and biliary cholesterol excretion. IL-6 and TNF-α were reduced in plasma and expression of TNF-α, MCP-1, MMP-9 and TIMP-1 decreased in liver. Treatment with coagonist reduced oxidative stress in liver and aorta. Energy expenditure was increased and respiratory quotient was reduced by coagonist treatment. These changes were correlated with reduced hepatic inflammation and lipids in liver and aorta in coagonist treated hamsters. Coagonist treatment also reduced lipids in cholesterol-fed transgenic mice. These changes were independent of glycaemia and anorexia observed after coagonist treatment. Long term treatment with coagonist of GLP-1 and glucagon receptor ameliorated diet-induced dyslipidemia and atherosclerosis by regulating bile homeostasis, liver inflammation and energy expenditure.

  • Interaction of DNA with water soluble complex of Nickle and formation of DNA cross-links
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-08
    Maryam Nejat Dehkordi, Bjorn Akerman

    Interaction of double stranded DNA with bulky and hydrophobic Salen type Schiff base complex: [N, N′ Bis [3- tert-butyl-5-[triphenyl-phosphonium – methyl] - salicylidene] 1,2 ethylene-diamine nickel(III) acetate (refer to Ni Salen complex) was extensively investigated using the spectroscopic techniques and gel electrophoresis. Absorption titration experiment showed the hypochromic effect and the significant red shift of the complex absorption. In competition experiments with ethidium bromide (EB), Ni Salen complex exhibited non-competitive binding at high concentrations. UV-vis absorption and fluorescence emission data agreed on a binding constant of (1.64 ± 0.01) μM−1, thereby showing the strong interaction of the complex with DNA; also, a binding site size of 2.33 ± 0.01 base pairs per complex was achieved.Thermal denaturation experiment showed that Tm of calf thymus-DNA was increased by approximately 10 °C at a molar ratio of the dye/base of 0.2. The CD spectra of DNA exhibited an increase in both positive and negative peaks without any shift in the position of bands upon addition of the complex. The amplitude of the LD spectra of DNA was decreased in the presence of the complex. Reduced linear dichroism (LDred) revealed that the transition moment of complex was parallel to the DNA helix axis. Gel electrophoresis experiments confirmed that Ni Salen complex had no nuclease/DNA cleaving activity; also, DNA-DNA cross links were formed at high concentrations of complex, leading to the aggregation of DNA.

  • Arctigenin protects against ultraviolet-A-induced damage to stemness through inhibition of the NF-κB/MAPK pathway
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-06
    See-Hyoung Park, Jae Youl Cho, Sae Woong Oh, Mingyeong Kang, Seung Eun Lee, Ju Ah Yoo, Kwangseon Jung, Jienny Lee, Sang Yeol Lee, Jongsung Lee
  • Mechanisms of 2,3,7,8-tetrachlorodibenzo-p-dioxin- induced cardiovascular toxicity: An overview
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-06
    Mahdieh Sadat Mohsenzadeh, Bamdad Riahi Zanjani, Gholamreza Karimi

    2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant and its toxicity is mediated by the aryl hydrocarbon receptor (AHR). Mechanisms of TCDD cardiovascular toxicity consist of oxidative stress, growth factor modulation, and ionic current alteration. It is indicated that the rodent cardiovascular system is a target for TCDD cardiomyopathy. Here, our understanding of TCDD cardiovascular toxicity is reviewed.

  • Organoselenium group is critical for antioxidant activity of 7-chloro-4-phenylselenyl-quinoline
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-01-06
    Ane G. Vogt, Guilherme T. Voss, Renata L. de Oliveira, Jaini J. Paltian, Luis F.B. Duarte, Diego Alves, Cristiano R. Jesse, Silvane S. Roman, Juliano A. Roehrs, Ethel A. Wilhelm, Cristiane Luchese

    The quinolone compounds have been reported for many biological properties, especially as potent antioxidants. This study investigated the antioxidant effect of 7-chloro-4-phenylselenyl-quinoline (PSQ), a quinolone derivative with organoselenium group, against oxidative stress induced by sodium nitroprusside (SNP) in brains of mice. A second objective was to verify the importance of phenylselenyl group presents at position 4 of the quinoline structure to antioxidant effect of compound. So, it was compared the antioxidant effect of PSQ with a quinoline without organoseleniun group (7-chloroquinoline [QN]). Swiss mice were used and received SNP (0.335 μmol/site, intracerebroventricular) 30 min after treatment with PSQ or QN, at the doses of 50 mg/kg (intragastrically). After 1 h, animals were sacrificed and the brains were removed to biochemistry analysis. Thiobarbituric acid reactive species (TBARS), protein carbonyl (PC) and non-protein thiol (NPSH) levels, as well as catalase (CAT), glutathione S transferase (GST) and δ -aminolevulinic acid (δ-ALA-D) activities were determined. SNP increased TBARS and PC levels, and reduced the enzymatic (CAT and GST activity) and non-enzymatic (NPSH levels) antioxidant defenses and inhibited the δ-ALA-D activity. PSQ avoided the increase in the lipid peroxidation and PC levels, as well as the decrease in the NPSH levels, CAT, GST and δ-ALA-D activities QN partially avoided the increase in lipid peroxidation, but it not protected against alterations induced by SNP. In conclusion, phenylselenyl group present in quinoline structure is critical for antioxidant activity of PSQ.

  • Nifuroxazide, a STAT3 inhibitor, mitigates inflammatory burden and protects against diabetes-induced nephropathy in rats
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-30
    Eman Said, Sawsan A. Zaitone, Mohamed Eldosoky, Nehal M. Elsherbiny

    Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. Moreover,it is amongst the most common causes of end-stage renal failure. Inflammation is a crucial player in both development and progression of DN. JAK2/STA3 is a pleotropic cascade reported to regulate diverse inflammatory events. Previous studies reported involvement of JAK2/STA3 signal transduction pathway in diabetes-associated renal injury. In the current study, the inhibitory effect of nifuroxazide (25 mg/kg/day, orally) against inflammatory condition associating diabetic kidney progression in rats was evaluated. The underlying hypothesis is mainly via the inhibitory effect of nifuroxazide on STAT3 signaling. Results revealed that nifuroxazide effectively inhibited STAT3 activation in diabetic male rats, improved glomerular filtration function, protected against diabetes-induced histopathological and ultramicroscopic structural alterations. Further, nifuroxazide treatment significantly reduced renal macrophage infiltration and fibrosis and decreased mRNA and protein levels of TNF-α and IL-18 in diabetic renal tissue. The current findings shed the light on nifuroxazide's efficacy as an alternative anti-inflammatory therapy to hinder the development and progression of DN in diabetic patients mainly via STAT3 inhibition.

  • 更新日期:2017-12-31
  • Synthesis and characterisation of arsenic nanoparticles and its interaction with DNA and cytotoxic potential on breast cancer cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-22
    A. Subastri, V. Arun, Preeti Sharma, E. Preedia babu, A. Suyavaran, S. Nithyananthan, Ghedeir M. Alshammari, B. Aristatile, V. Dharuman, C. Thirunavukkarasu
  • Gas chromatography-mass spectrometry metabolomic study of lipopolysaccharides toxicity on rat basophilic leukemia cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-22
    Fangchao Cui, Pei Zhu, Jian Ji, Ivana Blaženović, Morteza Gholami, Yinzhi Zhang, Xiulan Sun

    Lipopolysaccharide (LPS) can lead to uncontrollable cytokine production, fatal sepsis syndrome and depression/multiple organ failure, as pathophysiologic demonstration. Various toxic effects of LPS have been extensively reported, mainly on the toxicity of LPS in cellular level, macrophages or tumor cells, etc. This work aimed on the impact of LPS on mast cell metabolism, which focused on LPS-induced cellular metabolic profiles. Gas chromatography-mass spectrometry (GC-MS) based metabolomics strategy was implemented for the endo-metabolites detection in rat basophilic leukemia (RBL-2H3) cells, treated with 10 μg/mL LPS for 24 h, along with multiple time-dose tests of cells viability/apoptosis. Significantly changes metabolites were mainly involved the metabolism of glycine, serine, threonine and the biosynthesis of phenylalanine, tyrosine, tryptophan and pentose phosphate pathway. The endo-metabolism results illustrated that LPS treatment led to downregulation of glycine, serine and threonine metabolism besides pentose phosphate pathway in RBL-2H3 cells. This novel insight into LPS cellular metabolism, provides some heuristic guidance for elucidating the underlying mechanism of LPS-mediated disease.

  • Apoptosis induction and inhibition of HeLa cell proliferation by alpha-naphthoflavone and resveratrol are aryl hydrocarbon receptor-independent
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-20
    Alegre Flores-Pérez, Guillermo Elizondo

    Human papilloma viruses 16 and 18 express E6 and E7 oncoproteins. E6 activates and redirects E6-associated protein (E6AP), an E3 ubiquitin ligase. E6AP interacts with Ube2l3, an E2 ubiquitin conjugating enzyme protein (also known as UbcH7), to promote p53 ubiquitination and degradation by the 26S proteasome. Therefore, blocking E6-mediated p53 degradation might be an alternative treatment for cervical cancer. In addition, activation of the aryl hydrocarbon receptor (AHR) induces Ube2l3 expression, resulting in p53 ubiquitination and degradation. The aim of the present study was to determine whether inhibition of AHR in HeLa cells resulted in an increase in p53 and apoptosis along with a decrease in cell proliferation. The results demonstrate that two AHR antagonists, α-naphthoflavone (α-NF) and resveratrol, decreased cell proliferation, arrested cells in the gap 1/synthesis (G1/S) phases, and increased p53 levels and apoptosis. However, knocking out the Ahr gene did not abrogate the effects of α-NF and resveratrol. Moreover, Ahr-null cells presented similar cell proliferation rates and apoptosis levels when compared to control HeLa cells. Taken together, the results indicate that α-NF's and resveratrol's cytostatic and cytotoxic actions, respectively, occur through an AHR-independent mechanism, and that AHR is not required for HeLa cell proliferation.

  • Identification of d-amino acid oxidase and propiverine interaction partners and their potential role in the propiverine-mediated nephropathy
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-19
    Marcia Y. Maier, Lisanne Luks, Oliver Baudendistel, Valentin Wittmann, Daniel R. Dietrich

    Propiverine, a frequently-prescribed pharmaceutical for the treatment of symptoms associated with overactive bladder syndrome, provoked massive intranuclear and cytosolic protein inclusions in rat proximal tubule epithelium, primarily consisting of the peroxisomal targeting signal 1 (PTS1) containing protein d-amino acid oxidase (DAAO). As this type of nephropathy was also observed for other drugs, the aim was to determine whether propiverine interferes with trafficking and/or import of peroxisomal proteins. To elucidate this, DAAO- and propiverine-specific interaction partners from human HEK293 and rat WKPT cell lines and rat kidney and liver homogenate were determined using co-immunoprecipitation with subsequent nano-ESI-LC-MS/MS analyses. Corroboration of the role of DAAO- and/or propiverine-specific interaction partners in the drug-induced DAAO accumulation was sought via specific immunofluorescence staining of rat kidney sections from control and propiverine-treated rats. Above analyses demonstrated the interaction of propiverine with several protein classes, foremost peroxisomal proteins (DAAO, MFE2, HAOX2) and proteins of the protein quality control system, i.e. chaperones (HSP70 and DnaJ co-chaperones), proteases and proteasomal proteins (regulatory subunits of the 26S proteasome; Rpn1/2). The immunofluorescence analysis revealed mislocalization of many PTS1-proteins (DAAO, CAT, MFE2, ACOX1, EHHADH) in rat renal sections, strongly suggesting that propiverine primarily binds to PTS1 proteins resulting in the formation of PTS1 but not PTS2 or peroxisomal membrane protein (PMP) accumulations. Moreover, chaperones involved in peroxisomal trafficking (HSC70, DnaJB1) and peroxisomal biogenesis factor proteins (PEX3, PEX5, PEX7), also presented with distinct mislocalization patterns. Concomitantly, an increased number of peroxisomes was observed, suggestive of a compensatory mechanism for the presumably suboptimally functioning peroxisomes.Overall, the data presented suggested that propiverine interacts exclusively with DAAO or with a selected number of PTS1 proteins. The consequence of this interaction is the abrogated trafficking and peroxisomal import of PTS1 proteins concomitant with their nuclear and cytosolic accumulation due to inhibited degradation and imbalanced protein homeostasis.

  • Nutritional shortage augments cisplatin-effects on murine melanoma cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-19
    F. Antunes, G.J. Pereira, M.G. Jasiuliones, C. Bincoletto, S.S. Smaili

    Melanoma incidence increases every year worldwide and is responsible for 80% of skin cancer deaths. Due to its metastatic potential and resistance to almost any treatments such as chemo, radio, immune and target-therapy, the patients still have a poor prognosis, especially at metastatic stage. Considering that, it is crucial to find new therapeutic approaches to overcome melanoma resistance. Here we investigated the effect of cisplatin (CDDP), one of the chemotherapeutic agents used for melanoma treatment, in association with nutritional deprivation in murine melanoma cell lines. Cell death and autophagy was evaluated after the treatment with cisplatin, nutritional deprivation and its association using an in vitro model of murine melanocytes malignant transformation to metastatic melanoma. Our results showed that nutritional deprivation augmented cell death induced by cisplatin in melanomas cells, especially at the metastatic subtype, with slight effects on melanocytes. Mechanistic studies revealed that although autophagy was present at high levels in basal conditions in melanoma cells, was not essential for cell death process that involved mitochondrial damage, reactive oxygen species production and possible glycolysis inhibition. In conclusion, nutritional shortage in combination with chemotherapeutic drugs as cisplatin can be a valuable new therapeutic strategy to overcome melanoma resistance.

  • Is it safe to use Acorus calamus as a source of promising bioactive compounds in prevention and treatment of cardiovascular diseases?
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-19
    Beata Olas, Magdalena Bryś

    Acorus calamus has a rich history in natural medicine, and offers many health benefits. The plant has anti-inflammatory, antimicrobial, diuretic, antiurolithiatic and other properties. Moreover, various parts, especially the rhizome and roots, are sources of a range of bioactive phenolic compounds with beneficial effects on the cardiovascular system. This review article summarizes the current knowledge of the chemical composition of different parts of A. calamus and their roles in the prevention and treatment of cardiovascular diseases. However, as no human studies have been performed, the review only includes in vitro and animal studies. The paper also briefly reviews the toxicity of A. calamus and its products for human health, especially regarding the cardiovascular system.

  • 更新日期:2017-12-19
  • 1-Hydroxy-3-[(E)-4-(piperazine-diium)but-2-enyloxy]-9,10-anthraquinone ditrifluoroactate induced autophagic cell death in human PC3 cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-19
    A-Mei Huang, Kai-Wei Lin, Wei-Hong Lin, Li-Hung Wu, Hao-Chun Chang, Chujun Ni, Danny Ling Wang, Hsue-Yin Hsu, Chun-Li Su, Chiaho Shih

    The autophagy of human prostate cancer cells (PC3 cells) induced by a new anthraquinone derivative, 1-Hydroxy-3-[(E)-4-(piperazine-diium)but-2-enyloxy]-9,10-anthraquinone ditrifluoroactate (PA) was investigated, and the relationship between autophagy and reactive oxygen species (ROS) generation was studied. The results indicated that PA induced PC3 cell death in a time- and dose-dependent manner, could inhibit PC3 cell growth by G1 phase cell cycle arrest and corresponding decrease in the G2/M cell population and induced S-phase arrest accompanied by a significant decrease G2/M and G1 phase numbers after PC3 cells treated with PA for 48 h, and increased the accumulation of autophagolysosomes and microtubule-associated protein LC3-ll, a marker of autophagy. However, these phenomenon were not observed in the group pretreated with the autophagy inhibitor 3-MA or Bafilomycin A1 (BAF), suggesting that PA induced PC3 cell autophagy. In addition, we found that PA triggered ROS generation in cells, while the levels of ROS decreased in the N-acetylcysteine (NAC) co-treatment, indicating that PA-mediated autophagy was partly blocked by NAC. In summary, the autophagic cell death of human PC3 cells mediated by PA-triggered ROS generation.

  • Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-16
    Abdul-Rehman Phull, Bakht Nasir, Ihsan ul Haq, Song Ja Kim

    There are numerous extra- and intra-cellular processes involved in the production of reactive oxygen species (ROS). Augmented ROS generation can cause the damage of biomolecules such as proteins, nucleic acid and lipids. ROS act as an intracellular signaling component and is associated with various inflammatory responses, chronic arthropathies, including rheumatoid arthritis (RA). It is well documented that ROS can activate different signaling pathways having a vital importance in the patho-physiology of rheumatoid arthritis. Hence, understanding of the molecular pathways and their interaction might be advantageous in the development of novel therapeutic approaches for rheumatoid arthritis.

  • Cellular accumulation and lipid binding of perfluorinated alkylated substances (PFASs) – A comparison with lysosomotropic drugs
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-14
    Diana Sanchez Garcia, Marcus Sjödin, Magnus Hellstrandh, Ulf Norinder, Violetta Nikiforova, Johan Lindberg, Emma Wincent, Åke Bergman, Ian Cotgreave, Vesna Munic Kos

    Many chemicals accumulate in organisms through a variety of different mechanisms. Cationic amphiphilic drugs (CADs) accumulate in lysosomes and bind to membranes causing phospholipidosis, whereas many lipophilic chemicals target adipose tissue. Perfluoroalkyl substances (PFASs) are widely used as surfactants, but many of them are highly bioaccumulating and persistent in the environment, making them notorious environmental toxicants. Understanding the mechanisms of their bioaccumulation is, therefore, important for their regulation and substitution with new, less harmful chemicals. We compared the highly bioaccumulative perfluorooctanesulfonic acid PFOS to its three less bioaccumulative alternatives perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA) and perfluorobutane sulfonic acid (PFBS), in their ability to accumulate and remain in lung epithelial cells (NCI-H292) and adipocytes (3T3-L1K) in vitro. As a reference point we tested a set of cationic amphiphilic drugs (CADs), known to highly accumulate in cells and strongly bind to phospholipids, together with their respective non-CAD controls. Finally, all compounds were examined for their ability to bind to neutral lipids and phospholipids in cell-free systems. Cellular accumulation and retention of the test compounds were highly correlated between the lung epithelial cells and adipocytes. Interestingly, although an anion itself, intensities of PFOS accumulation and retention in cells were comparable to those of CAD compounds, but PFOS failed to induce phospholipidosis or alter lysosomal volume. Compared to other lipophilicity measures, phospholipophilicity shows the highest correlation (Rˆ2 = 0.75) to cellular accumulation data in both cell types and best distinguishes between high and low accumulating compounds. This indicates that binding to phospholipids may be the most important component in driving high cellular accumulation in lung epithelial cells, as well as in adipocytes, and for both CADs and bioaccumulating PFASs. Obtained continuous PLS models based on compound's affinity for phospholipids and neutral lipids can be used as good prediction models of cellular accumulation and retention of PFASs and CADs.

  • Nature to the natural rescue: Silencing microbial chats
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-14
    Diby Paul, Judy Gopal, Manish Kumar, Muthu Manikandan
  • Evaluation of pro-inflammatory events induced by Bothrops alternatus snake venom
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-14
    Silvina Echeverría, Elbio Leiguez, Carlos Guijas, Neide Galvão do Nascimento, Ofelia Acosta, Catarina Teixeira, Laura C. Leiva, Juan Pablo Rodríguez
  • Traditional herbal medicine-derived sulforaphene promotes mitophagic cell death in lymphoma cells through CRM1-mediated p62/SQSTM1 accumulation and AMPK activation
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-13
    Haina Wang, Fuqiang Wang, Sijin Wu, Zhiheng Liu, Tingting Li, Lei Mao, Jie Zhang, Cheng Li, Caigang Liu, Yongliang Yang

    Sulforaphene (LFS-01) is the major chemical constituent of Raphanus sativus, a medicinal herb used for over a thousand years in traditional Chinese medicine. Here we identified that LFS-01 can selectively eradicate lymphoma cells while sparing normal lymphocytes by triggering concomitant mitophagy and apoptosis. We demonstrated that LFS-01 can retain Nrf2 in the nucleus by covalently modulating CRM1 and consequently upregulate p62/SQSTM1, an essential structural component of the autophagosomes during mitophagic process. We found that LFS-01 treatment also stimulated AMPK and thereby inhibited the mTOR pathway. On the contrary, we revealed that AMPK inhibition can severely impair the LFS-01-mediated mitophagy. Transcriptomic studies confirmed that 15 autophagy-associated genes such as p62/SQSTM1, VCP and BCL2 were differentially expressed after LFS-01 treatment. Furthermore, protein interactome network analysis revealed that the events of apoptosis and the assembly of autophagy vacuole were significant upon LFS-01 exposure. Lastly, we found that LFS-01 exhibited strong efficacy in xenograft mouse model yet with the lack of apparent toxicity to animals. We concluded that LFS-01 triggered mitophagic cell death via CRM1-mediated p62 overexpression and AMPK activation. Our findings provide new insights into the mechanism of action for LFS-01 and highlight its potential applications in treating major human diseases.

  • Effects of a novel microtubule depolymerizer on pro-inflammatory signaling in RAW264.7macrophages
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-13
    Samuel P. Gilmore, Anna L.K. Gonye, Elizabeth C. Li, Santiago Espinosa de los Reyes, John T. Gupton, Omar A. Quintero, Krista Fischer-Stenger

    The Nuclear Factor-kappa B (NF-κB) pathway is vital for immune system regulation and pro-inflammatory signaling. Many inflammatory disorders and diseases, including cancer, are linked to dysregulation of NF-κB signaling. When macrophages recognize the presence of a pathogen, the signaling pathway is activated, resulting in the nuclear translocation of the transcription factor, NF-κB, to turn on pro-inflammatory genes. Here, we demonstrate the effects of a novel microtubule depolymerizer, NT-07-16, a polysubstituted pyrrole compound, on this process. Treatment with NT-07-16 decreased the production of pro-inflammatory cytokines in RAW264.7 mouse macrophages. It appears that the reduction in pro-inflammatory mediators produced by the macrophages after exposure to NT-07-16 may be due to activities upstream of the translocation of NF-κB into the nucleus. NF-κB translocation occurs after its inhibitory protein, IκB-α is phosphorylated which signals for its degradation releasing NF-κB so it is free to move into the nucleus. Previous studies from other laboratories indicate that these processes are associated with the microtubule network. Our results show that exposure to the microtubule-depolymerizer, NT-07-16 reduces the phosphorylation of IκB-α and also decreases the association of NF-κB with tubulin which may affect the ability of NF-κB to translocate into the nucleus. Therefore, the anti-inflammatory activity of NT-07-16 may be explained, at least in part, by alterations in these steps in the NF-κB signaling pathway leading to less NF-κB entering the nucleus and reducing the production of pro-inflammatory mediators by the activated macrophages.

  • Molecular mechanism for miR-350 in regulating of titanium dioxide nanoparticles in macrophage RAW264.7 cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-13
    Jing Sui, Yanyun Fu, Yanqiu Zhang, Shumei Ma, Lihong Yin, Yuepu Pu, Geyu Liang

    This study investigated the role of microRNA(miRNA) in regulating the cytotoxicity of TiO2 nanoparticles (nano-TiO2) to RAW264.7 cells. RAW264.7 cells were treated with 0 and 100 μg/ml nano-TiO2 for 24 h (for miRNA analysis). The differentially expressed miRNAs were detected using Illumina HiSeq™ 2000 sequencing. Through the bio-informatics analysis, miR-350 was found to play an important role in multiple signaling pathways, including MAPK signaling pathway, NF-kappa B signaling pathway and Apoptosis. To characterize the miR-350 function, miR-350 mimic was transfected into RAW264.7 cells for 24 h. MTT and Flow Cytometry were performed to detect cell proliferation, apoptosis and cell cycle (repetition), respectively. QRT-PCR, Western Blot methods and Luciferase assays were applied to detect expression of putative target gene PIK3R3. The results showed that miRNA profiles were differentially dysregulated. The apoptosis rate of miR-350 mimic group was significantly higher than negative control group (p < .05). Cell proliferation and cell cycle had no significant differences between treatment and negative control group. Compared with negative control, the level of protein of PIK3R3 was significantly decreased (p < .05), and the expression of 3′UTR constructs of PIK3R3 was significantly decreased (p < .05) in miR-350 mimic group. The expression of miRNAs was changed after exposed to nano-TiO2, and biological function and target gene results showed miR-350 may promote RAW264.7 cell apoptosis through the negative regulation of PIK3R3 gene. Our results could provide a basis for further understanding of toxicity and possible mechanisms of nano-TiO2 exposure.

  • In vitro apoptotic mechanism of a novel synthetic Quinazolinyl derivative: Induces caspase-dependent intrinsic pathway on THP-1, leukemia cell line
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-08
    V. Sridhar, S.K. Arepalli, L.R. Velatooru, J. Venkateswara Rao, P. Kavin Kennedy, B. Narsaiah

    Several quinazoline derivatives have been found to possess a broad spectrum of biological activities. Previously our research group has synthesized and studied the anti-proliferative effects of N-Decyl-N-(2-Methyl-4-Quinazolinyl) Amine (DMQA). The current study evaluated the cytotoxic and apoptotic properties of DMQA in THP-1 cells. The cytotoxic potential of DMQA was assessed using MTT assay on a panel of cancer cell lines which include HeLa, Mia PaCa-2, A 375, B16-F10, A 549,A 431, U937, THP-1, HL-60 and peripheral blood mononuclear cells (PBMC's). Preliminary data revealed that the highest cytotoxic activity was against THP-1 leukemia cell line (IC50=0.66 μg/ml). The apoptotic properties of DMQA on THP-1 cells were characterized by change in nuclear morphology, DNA fragmentation, reduction of pro-caspases-3, 9, Bax/Bcl-2 levels, cleavage of poly (ADP-ribose) polymerase and cytosolic release of cytochrome c. Further investigation revealed a sub-G1 peak, phosphatidyl serine exposure and loss of mitochondrial membrane potential (MMP) in THP-1 cells. The role of caspases was crucial and was demonstrated by the inhibitors Z-VAD-FMK and Z-DEVD-FMK. Moreover DMQA was markedly less effective in inhibiting the growth of normal cells (PBMC's, IC50 =62.17 μg/ml). Based on the results we suggest that DMQA induced apoptosis via intrinsic pathway and could be a promising anticancer agent.

  • 9-Hydroxycanthin-6-one isolated from stem bark of Ailanthus altissima induces ovarian cancer cell apoptosis and inhibits the activation of tumor-associated macrophages
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-07
    Miran Jeong, Hye Mi Kim, Ji-Hye Ahn, Kyung-Tae Lee, Dae Sik Jang, Jung-Hye Choi

    The stem bark of Ailanthus altissima is used in traditional medicine in Asia to treat a variety of diseases, including cancer. The aim of this study was to identify compounds with tumoricidal activity from A. altissima stem bark and to investigate their mechanisms of action. Among the 13 compounds isolated from the ethyl acetate fraction of A. altissima stem bark, the β-carboline alkaloid 9-hydroxycanthin-6-one had potent cytotoxicity in all three ovarian cancer cell types examined. 9-Hydroxycanthin-6-one induced apoptosis through the activation of caspases-3, -8, and -9.9-Hydroxycanthin-6-one increased the intracellular levels of reactive oxygen species (ROS), and pre-treatment with the antioxidant N-acetyl-l-cysteine (NAC) attenuated the pro-apoptotic activity of 9-hydroxycanthin-6-one. Additionally, 9-hydroxycanthin-6-one was found to decrease the expressions of MCP-1 and RANTES, major determinants of macrophage recruitment at tumor sites, in ovarian cancer cells. Treatment with 9-hydroxycanthin-6-one inhibited the levels of M2 phenotype markers and some cancer-promoting factors, such as MMP-2, MMP-9, and VEGF, in macrophages educated in ovarian cancer conditioned medium. Taken together, these data suggest that 9-hydroxycanthin-6-one isolated from A. altissima stem bark induces apoptosis in human ovarian cancer cells through the caspase- and ROS-dependent pathways and inhibits the activation of tumor-associated macrophages.

  • Noval nitroaromatic compound activates autophagy and apoptosis pathways in HL60 cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-06
    Gabriele Mendes M.C. Perdigão, Marcela Silva Lopes, Lucas Bonfim Marques, Pedro Henrique Dias Moura Prazeres, Kamila de Sousa Gomes, Renata Barbosa de Oliveira, Mauro Cunha Xavier Pinto, Elaine Maria de Souza-Fagundes
  • In vitro co-culture models to evaluate acute cytotoxicity of individual and combined mycotoxin exposures on Caco-2, THP-1 and HepaRG human cell lines
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-06
    Marie-Caroline Smith, Alexiane Gheux, Monika Coton, Stéphanie Madec, Nolwenn Hymery, Emmanuel Coton

    Deoxynivalenol (DON) and zearalenone (ZEA) are mycotoxins primarily produced by Fusarium species and commonly co-occur in European grains. Some in vitro studies reported synergistic combined effects on cell viability reduction for these two natural food contaminants. However, most of these studies were carried out on conventional cell culture systems involving only one cell type and thus, did not accurately reflect in vivo conditions, including cell-cell communication. In this context, we developed easy bi- and tri-culture systems using the Caco-2 (intestinal epithelial cells), THP-1 (monocytes) and HepaRG (hepatocytes) human cell lines. Individual and combined cytotoxicity effects of DON and ZEA were then assessed using co-cultures during 48 h. In bi-culture systems, results showed that only the highest tested dose of ZEA (IC30) induced a significant reduction in THP-1 viability with both Caco-2 and HepaRG cells cultured in transwells above. On the contrary, only the highest tested dose of DON (IC30) significantly affected HepaRG cell viability located under the Caco-2 cell monolayer. In addition, the DON + ZEA combination seemed to induce higher cytotoxicity than each toxin alone. Mycotoxin quantification in the abluminal compartment by QTOF LC-MS suggested uptake of both mycotoxins by the different cell lines, and depending on the co-culturing cell type, thus indicating possible cell-cell interactions. Finally, in the tri-culture system, no cytotoxic effects were observed, regardless of the treatment. These findings highlighted the importance of the proposed models to better decipher toxicological impacts of mycotoxins on more complex cellular systems.

  • Hesperidin attenuates iron-induced oxidative damage and dopamine depletion in Drosophila melanogaster model of Parkinson's disease
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-02
    Márcia Rósula Poetini, Stífani Machado Araujo, Mariane Trindade de Paula, Vandreza Cardoso Bortolotto, Luana Barreto Meichtry, Francielli Polet de Almeida, Cristiano Ricardo Jesse, Simone Noremberg Kunz, Marina Prigol

    This study has evaluated the action of flavonoid hesperidin on the neurotoxic effects caused by the intake of iron (Fe) in Drosophila melanogaster. Male adult flies, aged 1–3 days, have been divided into four groups of 50 each: (1) control, (2) Hsd 10 μM, (3) Fe 20 mM 4) Hsd 10 μM + Fe 20 mM. During the exposure protocol, the flies have been exposed to a diet containing Hsd and/or Fe for 48 h. The survival and behavioral analyses have been carried out in vivo, and ex vivo. The analyses involved acetylcholinesterase (AChE) activity and Fe levels in the flies' heads and bodies and determination of dopaminergic levels, cellular and mitochondrial viability, activities of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reactive species levels (RS), thiobarbituric acid reactive substances (TBARS) and contents of total thiols and non-proteic thiols (NPSH) in the flies' heads. A significant negative correlation between Fe levels in the head of the flies and the survival, dopamine levels and antioxidant enzymes in the head of the flies has been found. Additionally, significant positive correlation between Fe levels in the head of the flies with negative geotaxis RS and AChE activity in the head of the flies has been found. It demonstrates that the flies which had higher levels of Fe in their heads have demonstrated more susceptibility to neurotoxicity. An important result from our study is that Hsd treatment promotes a decrease in Fe concentration in the head, restores dopamine levels and cholinergic activity of the flies and improves motor function caused by Fe. Hsd also ameliorates Fe induced mortality, oxidative stress and mitochondrial dysfunction. Our results have demonstrated the neuroprotective effect of Hsd and it suggests that flavonoid acts in different ways to protect against the Parkinson disease caused by Fe exposure such as the direct scavenging of RS and activation of antioxidant enzymes.

  • Xanthine-derived KMUP-1 reverses glucotoxicity-activated Kv channels through the cAMP/PKA signaling pathway in rat pancreatic β cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-11-26
    Chien-Hsing Lee, Chih-Sheng Chu, Han-Jie Tsai, Liang-Yin Ke, Hsiang-Chun Lee, Jwu-Lai Yeh, Chu-Huang Chen, Bin-Nan Wu

    Hyperglycemia-associated glucotoxicity induces β-cell dysfunction and a reduction in insulin secretion. Voltage-dependent K+ (Kv) channels in pancreatic β-cells play a key role in glucose-dependent insulin secretion. KMUP-1, a xanthine derivative, has been demonstrated to modulate Kv channel activity in smooth muscles; however, the role of KMUP-1 in glucotoxicity-activated Kv channels in pancreatic β-cells remains unclear. In this study we examined the mechanisms by which KMUP-1 could inhibit high glucose (25 mM) activated Kv currents (IKv) in pancreatic β-cells. Pancreatic β-cells were isolated from Wistar rats and IKv was monitored by perforated patch-clamp recording. The peak IKv in high glucose-treated β-cells was ∼1.4-fold greater than for normal glucose (5.6 mM). KMUP-1 (1, 10, 30 μM) prevented high glucose-stimulated IKv in a concentration-dependent manner. Reduction of high glucose-activated IKv was also found for protein kinase A (PKA) activator 8-Br-cAMP (100 μM). Additionally, KMUP-1 (30 μM) current inhibition was reversed by the PKA inhibitor H-89 (1 μM). Otherwise, pretreatment with the PKC activator or inhibitor had no effect on IKv in high glucose exposure. In conclusion, glucotoxicity-diminished insulin secretion was due to IKv activation. KMUP-1 attenuated high glucose-stimulated IKv via the PKA but not the PKC signaling pathway. This finding provides evidence that KMUP-1 might be a promising agent for treating hyperglycemia-induced insulin resistance.

  • Zinc oxide nanoparticles inhibit dimethylnitrosamine induced liver injury in rat
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-10-10
    Varsha Rani, Yeshvandra Verma, Kavita Rana, Suresh Vir Singh Rana

    Dimethylnitrosamine (DMN) is a potent hepatotoxic, carcinogenic and mutagenic compound. It induces massive liver cell necrosis and death in experimental animals. Several drugs have been tested in the past for their protective behavior against DMN toxicity. However, it is for the first time that therapeutic intervention of ZnONPs (zinc oxide nanoparticles) has been studied against its toxicity. Present results show that a post treatment of ZnONPs (50 mg/kg) to DMN (2 μl/100 g body weight) treated rats reduces lipid peroxidation, oxidative stress and fibrosis in the liver. It diminishes serum ALT (alanine transaminases), AST (aspartate transaminases) and LDH (lactate dehydrogenase) showing improvement in liver function. Reduced values of proinflammatory cytokines viz. TNF-α and IL-12 also support its protective effects. Histopathological observations also indicate improvement in liver cell morphology. It is postulated that ZnONPs offer protection through selective toxicity to proliferating tissue including adenomatous islands formed in the liver. Zinc metallothionein (Zn-MT) induced by ZnONPs may also contribute in the amelioration of DMN induced toxic effects. Diminution of oxidative stress by ZnONPs remains to be the key mechanism involved in its protective effects. However, toxicity of ZnONPs in the liver needs to be monitored simultaneously.

  • Safety of novel liposomal drugs for cancer treatment: Advances and prospects
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-09-15
    Keyu He, Meng Tang

    Liposome is a kind of prospective abiotic drug delivery system for cancer treatment. Novel liposomes modified with PEG, cationic lipids and highly selective molecules achieve better stability, half-life and selectivity as well as less severe side effects. However, novel liposomes are still not nontoxic. PEG on the surface of liposomes interfere the combination of cancer cells and drugs. Cationic liposomes can induce oxidative damage and cytotoxicity to normal tissues. To further improve the safety of liposomal drugs, liposomal drugs must be highly selective to cancer tissues and cancer cells, at the same time, induce minimum damage to normal cells. It is necessary to gather several advantages of novel liposomes. The ideal targeted drug delivery system is like a multistage rocket. Firstly, the liposomal drugs should be sensitive to the specific environment of cancer tissues and accumulate in there. Secondly, the liposomes could selectively combine with cancer cells by surface modification. Lastly, in cancer cells, drugs release from the carriers rapidly. What's more, form the records of clinical researches, the side effects induced by liposomal drugs, such as acute infusion reaction and hand-foot syndrome(HFS), are also unignorable. More attention should be paid to these safety problems in new liposomal drugs research and development.

  • Metal nanoparticles in dermatology and cosmetology: Interactions with human skin cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-06-19
    Karolina Niska, Ewelina Zielinska, Marek Witold Radomski, Iwona Inkielewicz-Stepniak

    Nanotechnology is a rapidly developing branch of science, which studies control of phenomena and materials sized below 100 nm. Nanotechnology is applicable in many areas of life and medicine including skin care and personal hygiene. The nanoparticles (NPs) of metals and metal oxides are increasingly used in dermatology and cosmetology, especially in prevention and treatment of bacterial and fungal infections, in protection against the harmful effects of the sun and in preparations reducing the visibility of scars by accelerating the repair processes of skin cells. NPs may also be used for skin care and dermatological treatments to improve the quality of life of patients. Nanodermatology and nanocosmetology offer effective, safe, fast-acting product formulations, thus minimizing the side effects of the products used so far. The unique properties of NPs: high surface area relative to the size as well as the ability to penetrate biological membranes and barriers greatly reduces systemic dose thus potential side effects and toxicity. Recent studies show very promising clinical potential of NPs to serve as controlled release and delivery systems for drugs/active substances. In addition, NPs can be used in diagnostic imaging of skin diseases. However, NPs may also carry a risk of cytotoxicity and side effects. The present review focuses on the use of metal and metal oxide NPs in dermatology and cosmetology and their interactions with skin cells.

  • Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-07
    Nazlıhan Aztopal, Merve Erkisa, Elif Erturk, Engin Ulukaya, Asuman Hatice Tokullugil, Ferda Ari

    Cancer stem–like cells (CSCs) are a cell subpopulation that can reinitiate tumors, resist chemotherapy, give rise to metastases and lead to disease relapse because of an acquired resistance to apoptosis. Especially, epigenetic alterations play a crucial role in the regulation of stemness and also have been implicated in the development of drug resistance. Hence, in the present study, we examined the cytotoxic and apoptotic activity of valproic acid (VPA) as an inhibitor of histone deacetylases (HDACs) against breast CSCs (BCSCs). Increased expression of stemness markers were determined by western blotting in mammospheres (MCF-7s, a cancer stem cell-enriched population) propagated from parental MCF-7 cells. Anti-growth activity of VPA was determined via ATP viability assay. The sphere formation assay (SFA) was performed to assess the inhibitory effect of VPA on the self-renewal capacity of MCF-7s cells. Acetylation of histon H3 was detected with ELISA assay. Cell death mode was performed by Hoechst dye 33342 and propidium iodide-based flouresent stainings (for pyknosis and membrane integrity), by M30 and M65 ELISA assays (for apoptosis and primary or secondary necrosis) as well as cytofluorimetric analysis (caspase 3/7 activity and annexin-V-FITC staining for early and late stage apoptosis). VPA exhibited anti-growth effect against both MCF-7 and MCF-7s cells in a dose (0.6–20 mM) and time (24, 48, 72 h) dependent manner. As expected, MCF-7s cells were found more resistant to VPA than MCF-7 cells. It was observed that VPA prevented mammosphere formation at relatively lower doses (2.5 and 5 mM) while the acetylation of histon H3 was increased. At the same doses, VPA increased the M30 levels, annexin-V-FITC positivity and caspase 3/7 activation, implying the induction of apoptosis. The secondary necrosis (late stage of apoptosis) was also evidenced by nuclear pyknosis with propidium iodide staining positivity. Taken together, inhibition of HDACs is cytotoxic to BCSCs by apoptosis. Our results suggested that targeting the epigenetic regulation of histones may be a novel approach and hold significant promise for successful treatment of breast cancer.

  • Regulation and role of nuclear factor-E2-related factor2 (Nrf2) in multidrug resistance of hepatocellular carcinoma
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-06
    Bing Tian, Zhen-Ning Lu, Xiu-Li Guo

    Hepatocellular carcinoma (HCC) chemoresistance, which is regarded as a kind of stress management reaction to chemotherapy drugs, severely hinders the therapy outcomes of HCC treatment. Stress management is generally achieved by activating certain signal pathways and chemical factors, among which, nuclear factor-E2-related factor2 (Nrf2) is a key factor in HCC chemoresistance formation. Nrf2 is a nuclear factor that coordinates the induction and expression of a battery of genes encoding cytoprotective proteins when participating in the Nrf2antioxidant response element (Nrf2/ARE) pathway, which is one of the most important intracellular antioxidant stress pathways. This review summarizes the recent understanding of the involvement of Nrf2 in the chemoresistance of liver cancer, its target proteins, expression regulation and potential Nrf2 inhibitors that sensitize chemotherapy drugs in HCC.

  • Isolated mangiferin and naringenin exert antidiabetic effect via PPARγ/GLUT4 dual agonistic action with strong metabolic regulation
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-06
    Ashok K. Singh, Vinit Raj, Amit K. Keshari, Amit Rai, Pranesh Kumar, Atul Rawat, Biswanath Maity, Dinesh Kumar, Anand Prakash, Arnab De, Amalesh Samanta, Bolay Bhattacharya, Sudipta Saha

    In this study, we isolated two compounds from the leaves of Salacia oblonga (SA1, mangiferin and SA2, naringenin), and their structures were confirmed by infrared spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. SA1 and SA2 were orally administered to streptozotocin-induced diabetic rats at 50 and 100 mg/kg daily for 15 days. Blood glucose level, serum lipid profile, oxidative stress parameters, histopathology, docking, molecular parameters, and NMR-based metabolic perturbation studies were performed to investigate the pharmacological activities of SA1 and SA2. Results suggested that both compounds reduced blood glucose level, restored body weight, and normalized lipid concentrations in the serum and oxidative stress biomarkers in the liver and pancreas. In addition, the docking study on several diabetes-associated targets revealed that both compounds had a strong binding affinity towards peroxisome proliferator-activated receptor gamma (PPARγ) and glucose transporter type 4 (GLUT4). Further real-time reverse transcription polymerase chain reaction and western blot analyses were performed to confirm the gene and protein expression levels of PPARγ and GLUT4 in the pancreatic tissues. Data obtained from the molecular studies showed that both compounds exhibited antidiabetic effects through dual activation of PPARγ/GLUT4 signaling pathways. Finally, the NMR-based metabolic studies showed that both compounds normalized the diabetogenic metabolites in the serum. Altogether, we concluded that SA1 and SA2 might be potential antidiabetic lead compounds for future drug development.

  • N-(3-oxododecanoyl)-l-homoserine-lactone, a quorum sensing molecule, affects cellular content of nonprotein thiol content in rat lymphocytes: Its relation with intracellular Zn2+
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-06
    Yumiko Nishimura-Danjobara, Keisuke Oyama, Kaori Kanemaru, Keiko Takahashi, Kumio Yokoigawa, Yasuo Oyama

    Cellular actions of N-(3-oxododecanoyl)-l-homoserine-lactone (ODHL), a quorum sensing molecule of bacteria, were studied on rat thymocytes using a flow cytometer with appropriate fluorescent dyes to elucidate the effects of ODHL on host cells. A bell-shaped concentration-response relation was observed in the ODHL-induced changes in cellular glutathione content ([GSH]i). ODHL concentration-dependently increased intracellular Zn2+ levels ([Zn2+]i) and cellular O2− content ([O2−]i). The bell-shaped relation induced by ODHL can be explained as follows: a low concentration of ODHL is expected to induce moderate oxidative stress that intracellularly releases Zn2+ by converting thiols to disulfides. A slight elevation of [Zn2+]i may increase the [GSH]i. On the other hand, it is likely that a high concentration of ODHL causes severe oxidative stress that further causes both the decrease in [GSH]i and the increase in [Zn2+]i. Excessive increase in [Zn2+]i may augment oxidative stress that further decreases the [GSH]i. Other notable actions induced by ODHL included the elevation of [Zn2+]i by Zn2+ influx and the increase in [GSH]i under Zn2+-free conditions. Therefore, it is suggested that ODHL elicits diverse actions on host cells.

  • Biocompatible sulfenamide and sulfonamide derivatives of metformin can exert beneficial effects on plasma haemostasis
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-05
    Magdalena Markowicz-Piasecka, Kristiina M. Huttunen, Elżbieta Mikiciuk-Olasik, Joanna Sikora

    As the pharmacokinetic properties of metformin are unfavourable, several analogues and prodrugs have been synthesised to improve its bioavailability. The aim of this study was to assess the plasma stability of sulfenamide and sulfonamide derivatives of metformin and establish their effects on plasma haemostasis and integrity of red blood cells (RBCs). The overall haemostasis potential was evaluated spectrophotometrically by clot formation and lysis test (CL-test). PT (Prothrombin Time) and APTT (Activated Partial Tromboplastin Time) were used to evaluate the effects if the compounds on the extrinsic and intrinsic coagulation pathway. Haemolysis assay, microscopy and flow cytometry studies were conducted to determine the effect of the compounds on RBCs. Two sulfonamide and one sulfenamide derivatives of metformin were associated with a statistically significant decrease in the overall potential of clot formation and fibrinolysis (↓ CLAUC), suggesting that these compounds may exert beneficial effects regarding plasma haemostasis, which is frequently impaired in diabetic patients. p- and o-Nitrobenzene sulfonamides contributed to the beneficial change in kinetic parameters of clot formation and fibrinolysis. o-Nitrobenzene sulfonamide significantly increased thrombin generation time (↑ TGt) and was also found to prolong both APTT and PT. All compounds did not exert any effects on the integrity of RBCs over the concentration range 0.006–0.6 μmol/mL which constitutes the expected therapeutic concentration. In conclusion, sulfonamide derivatives of metformin present potentially beneficial properties in terms of plasma haemostasis which is frequently impaired in T2DM patients. Therefore, metformin sulfonamides may become a prototype for further design and synthesis of novel metformin analogues and prodrugs with improved pharmacokinetic properties.

  • 4-methylesculetin, a coumarin derivative, ameliorates dextran sulfate sodium-induced intestinal inflammation
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-05
    Aline Witaicenis, Ellen Cristina Souza de Oliveira, Alexandre Tanimoto, Sofia Fernanda Gonçalves Zorzella-Pezavento, Silvio Luiz de Oliveira, Alexandrina Sartori, Luiz Claudio Di Stasi

    4-methylesculetin is one of the coumarin derivatives with great anti-oxidant and anti-inflammatory activities. Recent studies shown that 4-methylesculetin has a promising potentiality to treat inflammatory diseases, especially those related to reactive oxygen species, as inflammatory bowel disease. Based on this, the present study aims to investigate the intestinal anti-inflammatory activity of 4-methylesculetin in dextran sulfate sodium (DSS) model. For this purpose, mice received DSS 5% for 5 days followed by 2 days of filtered tap water. Treated groups received orally 5 or 25 mg/kg of 4-methylesculetin daily since the first day. Macroscopic, microscopic and biochemical parameters were evaluated. 4-methylesculetin (25 mg/kg) improved microscopic parameters, decreased MPO activity, reduced the colonic levels of IL-6 and counteracted GSH depletion when compared with DSS-control group. Our results show the intestinal anti-inflammatory activity of 4-methylesculetin in DSS model, which is related to its antioxidant and anti-inflammatory properties. This way, 4-methylesculetin, is a new potential compound for treatment of both types of IBD.

  • Apigenin sensitizes hepatocellular carcinoma cells to doxorubic through regulating miR-520b/ATG7 axis
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-12-02
    Ai-Mei Gao, Xiao-Yu Zhang, Juan-Ni Hu, Zun-Ping Ke

    Chemo-resistance is a serious obstacle for successful treatment of cancer. Apigenin, a dietary flavonoid, has been reported as an anticancer drug in various malignant cancers. This study aimed to investigate the potential chemo-sensitization effect of apigenin in doxorubicin-resistant hepatocellular carcinoma cell line BEL-7402/ADM. We observed that apigenin significantly enhanced doxorubicin sensitivity, induced miR-520b expression and inhibited ATG7-dependent autophagy in BEL-7402/ADM cells. In addition, we also showed that miR-520b mimics increased doxorubicin sensitivity and inhibited ATG7-dependent autophagy. Meanwhile, we indicated that ATG7 was a potential target of miR-520b. Furthermore, APG inhibited the growth of hepatocellar carcinoma xenografts in nude mice by up-regulating miR-520b and inhibiting ATG7. Our finding provides evidence that apigenin sensitizes BEL-7402/ADM cells to doxorubicin through miR-520b/ATG7 pathway, which furtherly supports apigenin as a potential chemo-sensitizer for hepatocellular carcinoma.

  • Salvianic acid A sodium protects HUVEC cells against tert-butyl hydroperoxide induced oxidative injury via mitochondria-dependent pathway
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2017-11-08
    Dan Jia, Tian Li, Xiaofei Chen, Xuan Ding, Yifeng Chai, Alex F. Chen, Zhenyu Zhu, Chuan Zhang

    Salvianic acid A (Danshensu) is a major water-soluble component in Salvia miltiorrhiza (Danshen), which has been widely used in clinic in China for treatment of cardiovascular diseases (CVDs). This study aimed to investigate the protective effects of salvianic acid A sodium (SAAS) against tert-butyl hydroperoxide (t-BHP) induced human umbilical vein endothelial cell (HUVEC) oxidative injury and the potential molecular mechanisms. In the antioxidant activity-assessing models, SAAS significantly prevented t-BHP induced cell proliferation inhibition and apoptosis. An ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) based-metabolic profiling was developed to investigate the metabolic changes of HUVEC cells in response to t-BHP and SAAS. The results revealed that t-BHP stimuli up-regulated 13 metabolites mainly involved in tryptophan metabolism and phenylalanine metabolism which were strongly correlated with mitochondrial functions and oxidative stress, and 50 μM SAAS pretreatment effectively reversed these metabolic changes. Further biomedical research indicated that SAAS effectively prevented t-BHP induced increased generation of lactate dehydrogenase (LDH), intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and mitochondrial potential (MMP), and the down-regulation of key antioxidant enzymes through mitochondria anti-oxidative pathways via JAK2/STAT3 and PI3K/Akt/GSK-3β signaling. Taken together, we propose that SAAS protects HUVEC cells against t-BHP induced oxidative injury through mitochondrial anti-oxidative defense systems.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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