显示样式:     当前期刊: Chemico-Biological Interactions    加入关注       排序: 导出
  • COX-2 inhibition by celecoxib in epithelial ovarian cancer attenuates E-cadherin suppression through reduced Snail nuclear translocation
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-20
    Yan-Ping Wang, Qu-Yuan Wang, Chang-Hui Li, Xue-Wei Li

    Elevated cyclooxygenase-2 (COX-2) closely associates with tumor progression and distant metastasis in various human cancers. However, the role of COX-2 in epithelial ovarian cancer (EOC), and its mechanistic details, remain poorly understood. In the present study, we tested hypothesis that COX-2 induces loss of expression of E-cadherin, with resulting promotion of cancer cells' invasiveness in ovarian cancer. First, we observed an inverse relationship between COX-2 and E-cadherin expression as COX-2 was enhanced but E-cadherin was decreased in surgically-resected specimens of EOC. Depletion of COX-2, by celecoxib treatment, resulted in attenuated nuclear translocation of Snail, and, in turn, significantly increased E-cadherin in EOC cell line SKOV3, which was established to be due to the reduced binding of Snail onto E-cadherin promoter. Such COX-2 inhibition resulted in reduced invasion of EOC cells, similar to what was achieved through Snail silencing in SKOV as well as ES-2 EOC cells. These results suggest that COX-2-Snail signaling plays a critical role in regulation of E-cadherin and might provide insights into mechanisms for paracrine inflammation-mediated aggressiveness in EOC.

  • Mitochondrial damage and apoptosis: Key features in BDE-153-induced hepatotoxicity
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-20
    Lilian Cristina Pereira, Luiz Felipe Cabral Miranda, Mariana Furio Franco-Bernardes, Maria Julia Tasso, Filipe Valente Duarte, Ana Teresa Inácio Varela, Anabela Pinto Rolo, Carlos Manuel Marques Palmeira, Daniel Junqueira Dorta

    Brominated flame retardants are used in consumer goods to increase product resistance to fire and/or high temperatures. Polybrominated diphenyl ethers (PBDEs) are the most commonly employed class of brominated flame retardants because they are inexpensive and can effectively prevent flame from spreading. PBDEs are persistent, can bioaccumulate, are transported over long distances, and display toxicity. However, their toxic mechanisms of action have not been well established. Because mitochondria are recognized as the main energy-producing cell organelle and play a vital role in cellular function maintenance, here we apply mitochondria as an experimental model to evaluate the toxic effects of the PBDE congener BDE-153 (Hexa-BDE) at concentrations ranging from 0.1 to 25 μM. We also assess BDE-153 cytotoxicity to HepG2 cells in order to elucidate its mechanisms of toxicity. Exposure to BDE-153 affects isolated mitochondria: this congener can interact with the mitochondrial membrane, to dissipate the membrane potential and to induce significant ATP depletion. Furthermore, BDE-153 can diminish MTT reduction and cell proliferation and can interfere in cell cycle, as evaluated in cell cultures. These cytotoxic effects are related to mitochondrial dysfunction due to mitochondrial membrane potential dissipation and reactive oxygen species accumulation. These effects result in apoptotic cell death, as demonstrated by phosphatidylserine maintenance on the cell membrane external surface, nuclear condensation and fragmentation, and presence of pro-apoptotic factors such as cytochrome c and Apoptosis-inducing Factor (AIF) plus caspase 3 activation in the cytosol. Together, our results show PBDEs can induce cytotoxicity, reinforcing the idea that these compounds pose a risk to the exposed population.

  • 更新日期:2018-06-22
  • Molecular mechanism of composite nanoparticles TiO2/WO3/GO-induced activity changes of catalase and superoxide dismutase
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-21
    Xiaoyan Hao, Li Zhang, Xin Zheng, Wansong Zong, Chunguang Liu
  • The inhibition, reactivation and mechanism of VX-, sarin-, fluoro-VX and fluoro-sarin surrogates following their interaction with HuAChE and HuBuChE
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-18
    Chih-Kai Chao, Narayanaganesh Balasubramanian, John M. Gerdes, Charles M. Thompson
  • Hydroquinone exposure worsens the symptomatology of rheumatoid arthritis
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-15
    Cintia Scucuglia Heluany, Leonard de Vinci Kanda Kupa, Mariana Nascimento Viana, Cristina Maria Fernandes, Sandra Helena Poliselli Farsky

    The genesis of rheumatoid arthritis (RA) is complex and dependent on genetic background and exposure to environmental xenobiotic. Indeed, smoking is associated to developing and worsening pre-existing RA. Nevertheless, the mechanisms and cigarette compounds involved in the harmful processes have not been elucidated. Here, we investigated if the exposure to hydroquinone (HQ), an abundant pro-oxidative compound of cigarette and benzene metabolite, could worsen the ongoing RA. Hence, collagen-induced arthritis (CIA) was induced in male Wistar rats by s.c. injection of 400 μg (200 μL) of bovine collagen type II emulsified in complete Freund's adjuvant on day 1, and a booster injection was performed on day 7. Exposures to nebulized HQ (25 ppm), saline solution or HQ vehicle solution (5% ethanol in saline) were carried out for 1 h, once a day, on days 21–27 after CIA induction. On day 27, animals were euthanized and samples were collected for further analyses. Exposure to HQ caused loss of weight, intensified paw edema, enhanced levels of tumor necrosis factor-α (TNF-α) and anti-citrullinated protein antibody (ACPA) in the serum; augmented synoviocyte proliferation and influx of aril hydrocarbon receptor (AhR) positive cells into the synovial membrane, altered collagen fibre rearrangement in the synovia, and synoviocytes isolated from HQ exposed rats secreted higher levels of pro-inflammatory cytokines, TNF-α and interleukin-1β. Associated, we point out HQ as an environmental pollutant that aggravates RA, suggesting its participation on worsening RA in smoking patients.

  • Antineoplastic activity of mitomycin C formulated in nanoemulsions-based essential oils on HeLa cervical cancer cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-14
    Mayson H. Alkhatib, Waad A. Al-Otaibi, Abdulwahab Noor Wali
  • Monotropein attenuates ovariectomy and LPS-induced bone loss in mice and decreases inflammatory impairment on osteoblast through blocking activation of NF-κB pathway
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-14
    Yu-Qiong He, Hua Yang, Yi Shen, Jian-Hua Zhang, Zhi-Guo Zhang, Lin-Lin Liu, Hong-Tao Song, Bin Lin, Hsien-Yeh Hsu, Lu-Ping Qin, Ting Han, Hai-Liang Xin, Qiao-Yan Zhang
  • Biodistribution and toxicity assessment of intratumorally injected arginine–glycine–aspartic acid peptide conjugated to CdSe/ZnS quantum dots in mice bearing pancreatic neoplasm
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-14
    Ming-Ming Li, Jia Cao, Jia-Chun Yang, Yu-Jie Shen, Xiao-Lei Cai, Yuan-Wen Chen, Chun-Ying Qu, Yi Zhang, Feng Shen, Min Zhou, Lei-Ming Xu

    Quantum dots (QDs) conjugated with arginine–glycine–aspartic acid (RGD) peptides (which are integrin antagonists) are novel nanomaterials with the unique optical property of high molar extinction coefficient, and they have potential utility as photosensitizers in photodynamic therapy (PDT). Our group previously demonstrated significant benefits of using PDT with QD-RGD on pancreatic tumor cells. This study aimed to evaluate the biodistribution and toxicity of QD-RGD in mice prior to in vivo application. Mice with pancreatic neoplasms were intratumorally injected with varying doses of QD-RGD, and the biodistribution 0–24 h post injection was compared to that in control mice (intravenously injected with unconjugated QD). Various tissue samples were collected for toxicity analyses, which included inductively coupled plasma mass spectrometry (ICP-MS) to assess Cd2+ concentrations and hematoxylin-eosin staining for histopathological examination. Fluorescent imaging revealed relatively sufficient radiant efficiency in mice under specific conditions. The ICP-MS and HE data showed no significant signs of necrosis due to Cd2+ release by QDs. The mice survived well and had no apparent weakness or weight loss during the 4 weeks post injection. These findings provide novel insights into the biodistribution of QD-RGD and encourage profound in vivo studies regardless of safety concerns. These findings alleviate safety concerns and provide novel insights into the biodistribution of QD-RGD, offering a solid foundation for comprehensive in vivo studies.

  • Teroxirone motivates apoptotic death in tumorspheres of human lung cancer cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-13
    Yu-Ling Ni, Chang-Heng Hsieh, Jing-Ping Wang, Kang Fang

    Therapy by targeting cancer stem cells (CSCs) is an eligible method to eradicate malignant human tumors. A synthetic triepoxide derivative, teroxirone, was reported effective against growth of human lung cancer cells by injuring cellular mitochondria functions. And yet it remains unclear if the residual but malicious CSCs can be effectively dissipated as a result of treatment. The current study further affirmed that teroxirone inhibited propagation of CSCs as enriched from NSCLC cells by inducing p53 that lead to ultimate apoptosis. More evidence supported that the reduced stemness of the spheroids was associated with apoptotic death. The results consolidate the notion that teroxirone is a viable and effective therapeutic agent for eradicating human lung cancer.

  • Synthesis of newly functionalized 1,4-naphthoquinone derivatives and their effects on wound healing in alloxan-induced diabetic mice
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-11
    Silvia Helena Cardoso, Cleidijane Rodrigues de Oliveira, Ari Souza Guimarães, Jadiely Nascimento, Julianderson de Oliveira dos Santos Carmo, Jamylle Nunes de Souza Ferro, Ana Carolina de Carvalho Correia, Emiliano Barreto

    Naphthoquinone derivatives have various pharmacological properties. Here, we describe the synthesis of new 1,4-naphthoquinone derivatives inspired by lawsone and β-lapachone and their effects on both migration of fibroblasts in vitro and dermal wound healing in diabetic mice. NMR and FTIR spectroscopy aided characterization of chemical composition and demonstrated the molecular variations after the synthesis of four different derivatives, namely 2-bromo-1,4-naphthoquinone (termed derivative S3), 2-N-phenylamino-1,4-naphthoquinone (derivative S5), 2-N-isonicotinoyl-hydrazide-1,4-naphthoquinone (derivative S6), and 1-N-isonicotinoyl-hydrazone-[2-hydroxy-3-(3-methyl-2-butenyl)]-1,4-naphthoquinone (derivative S7). Our results indicate that derivatives S3, S5, S6 and S7 were non-toxic to the 3T3 fibroblast cell line. In scratch assays, derivatives S3 and S6, but not S5 or S7, stimulated the migration of fibroblasts. Compared with untreated diabetic mice, S3, S6 and S7 treatments accelerated wound closure. However, derivative S3 was optimal for the stimulation of epithelization, thereby increasing the number of keratinocyte layers and blood vessels, and reducing diffuse cellular infiltration, compared to derivatives S6 and S7. Our results suggest that novel 1,4-naphthoquinone derivatives promote fibroblast migration and accelerate wound closure under diabetic conditions.

  • Cannabidiol did not induce teratogenicity or neurotoxicity in exposed zebrafish embryos
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-11
    Tamires Amabile Valim Brigante, Flavia R. Abe, Antônio Waldo Zuardi, Jaime Eduardo Cecílio Hallak, José Alexandre S. Crippa, Danielle P. de Oliveira

    Cannabidiol (CBD) is a non-psychotomimetic compound of the Cannabis sativa that has been used for the treatment of severe epilepsy as well as other diseases of nervous system. However, toxicity studies of CBD have great relevance to guarantee the patients safety. In this context, morphological analyses of zebrafish can contribute to evaluate the teratogenic potential, as well as evaluation of acetylcholinesterase activity and motor activity of zebrafish are valuable tools to verify the neurotoxicity potential. In the present work, we use this methodology to test the toxicity of CBD to zebrafish embryos. No malformation was observed in morphological analysis of embryos exposed to all tested concentrations of CBD. Although, twenty per cent of embryos exposed to maximal dose of CBD (300 μg/L) hatched after 96hpf, while embryos in control solution had already hatched in this period. Embryos exposed to CBD did not show differences in acetylcholinesterase activity, but embryos exposed to CBD 20–300 μg/L were 1.4 up to 1.7-fold more active when compared to the control. Despite that, at 48 hpf, motor activity returned to control values. Our results suggest that the effects observed after CBD exposure are intimately related to CB1 receptor that is present in zebrafish since early stages of development. The present work showed early light effects induced by CBD exposure in concentrations that did not alter biochemical activity.

  • microRNA-199a/b-5p enhance imatinib efficacy via repressing WNT2 signaling-mediated protective autophagy in imatinib-resistant chronic myeloid leukemia cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-08
    Peng-Hsu Chen, Ann-Jeng Liu, Kuo-Hao Ho, Ya-Ting Chiu, Zhe-Harn Anne Lin, Yi-Ting Lee, Chwen-Ming Shih, Ku-Chung Chen
  • From epidemiology to treatment: Aspirin's prevention of brain and breast-cancer and cardioprotection May associate with its metabolite gentisic acid
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-07
    Meric A. Altinoz, Ilhan Elmaci, Salih Cengiz, Ebru Emekli-Alturfan, Aysel Ozpinar

    Background Epidemiological studies indicate that aspirin consumption reduces the risk of tumors, which is especially relevant for colonic adenoma and carcinoma. Similar observations were made for glial brain tumors and breast cancers, yet the results are inconsistent. Gentisic acid (GA) is a minor catabolite of aspirin; yet humans carrying CYP2C9-variants incapable to catabolize aspirin to GA do not benefit from aspirin in prevention against colonic adenoma. GA blocks binding of Fibroblastic Growth Factor to its receptor and its sulphonate metabolite dobesilic acid blocks growth of C6 glioblastoma in vivo. GA is also an endogenously produced siderophore in mammalians for the transport of iron, a trace element which stimulates tumor growth and enhances anthracycline cardiotoxicity. Materials and Methods In this study, we assessed whether GA exerts direct antitumor activity on C6 glioma cells in vitro (cytotoxicity, colony growth, 3H-thymidine labeling analysis of DNA synthesis); and whether it can modify growth of Ehrlich breast ascites carcinoma (EAC) and solid tumors (EST) in vivo. GA and antitumoral trace element selenium block 12-lipoxygenase activity and aspirin's paradoxical inflammatory effects are seen in selenium-deficient humans; thus, we also investigated antitumor interactions between GA and sodium selenite. Lastly, we evaluated whether GA could protect against doxorubicin cardiotoxicity due to its function to chelate iron. Results Clinically achievable doses of GA blocked growth, colony formation and DNA synthesis of C6 glioma in vitro with high significance. GA enhanced the survival of EAC-bearing mice at a dosage of 0.4 mg/mice/day, in which 33% of the treated animals survived more than 3-weeks, when all untreated mice succumbed to their tumors. Selenium decreased EST volumes initially, yet increased tumor volumes at later stages in surviving mice. GA alone reduced solid tumor growth and did not modify selenite antineoplasticity initially, but blocked the late tumor-stimulating effects of selenite. Lastly, doxorubicin-induced cardiac myofibrillary and endothelial damage and hyalinization necrosis were attenuated with GA treatment. Conclusions GA highly merits to be studied in further animal models as an anticancer and chemoprotective drug.

  • NMDA and GABA receptor presence in rat heart mitochondria
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-06
    Semen V. Nesterov, Yulia A. Skorobogatova, Alisa A. Panteleeva, Lyubov L. Pavlik, Irina B. Mikheeva, Lev S. Yaguzhinsky, Yaroslav R. Nartsissov

    The purpose of this study is to demonstrate the presence of three more receptors in mitochondria. Two N-methyl-d-aspartate receptor (NMDAR) subunits (NR1 and NR2B) are found by protein immunoblot and immunogold labeling in mitochondria fraction isolated from rat heart. These data allow supposing NMDAR presence and functioning in the inner mitochondrial membrane. There are no signs of receptor presence obtained in heart tissue lysate, that indicates the receptor localization exactly in mitochondria. The possible receptor functions discussed are its participation in calcium transport and in excitation-metabolism coupling. Besides, preliminary evidence is obtained of GABAA and GABAB receptors presence in heart mitochondria. One can surmise their role in metabolism regulation and their possible co-operation with NMDAR just as in the nervous system.

  • Alisol A 24-acetate ameliorates nonalcoholic steatohepatitis by inhibiting oxidative stress and stimulating autophagy through the AMPK/mTOR pathway
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-06
    Chenqu Wu, Menghui Jing, Lijuan Yang, Lei Jin, Yicun Ding, Juan Lu, Qin Cao, Yuanye Jiang

    Alisol A 24-acetate (AA), a natural triterpenoid isolated from the traditional Chinese medicine Rhizoma Alismatis, has various therapeutic effects. We investigated the anti-nonalcoholic steatohepatitis (NASH) effect of AA and its underlying mechanisms in vitro and in vivo. C57BL/6 mice were fed a methionine and choline-deficient (MCD) diet for 4 weeks to induce NASH. The mice were simultaneously treated with a daily dose of AA (15, 30, and 60 mg kg−1, ig) for 4 weeks. On the last day, the animals were sacrificed and plasma and liver tissue were collected. Serum and liver tissue biochemical analyses and histological observation were performed. The human hepatic stellate cell line LX-2 was used to build NASH models by culturing with conditioned medium from WRL-68 liver cells after exposure to MCD medium in vitro. Liver oxidative stress and inflammatory indices and autophagy markers were examined. The results showed that AA suppressed reactive oxygen species (ROS) and inflammation in a NASH mouse model and inhibited the expression of inflammatory cytokines and ROS in LX-2 cells in MCD medium. Furthermore, we found AA stimulated autophagy in mice liver and LX-2, which could be the underlying mechanism of AA in NASH. To further investigate the role of autophagy in LX-2 cells, we found that AA regulated autophagy via the AMPK/mTOR/ULK1 pathway and dorsomorphin, a selective AMPK inhibitor, led to the suppression of AA-induced autophagy. Taken together, our results indicate that AA could be a possible therapy for NASH by inhibiting oxidative stress and stimulating autophagy.

  • Removal of azo dye using Fenton and Fenton-like processes: Evaluation of process factors by Box–Behnken design and ecotoxicity tests
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-06
    Neemias Cintra Fernandes, Lara Barroso Brito, Gessyca Gonçalves Costa, Stephânia Fleury Taveira, Marcílio Sérgio Soares Cunha–Filho, Gisele Augusto Rodrigues Oliveira, Ricardo Neves Marreto

    The conventional treatment of textile effluents is usually inefficient in removing azo dyes and can even generate more toxic products than the original dyes. The aim of the present study was to optimize the process factors in the degradation of Disperse Red 343 by Fenton and Fenton-like processes, as well as to investigate the ecotoxicity of the samples treated under optimized conditions. A Box–Behnken design integrated with the desirability function was used to optimize dye degradation, the amount of residual H2O2 [H2O2residual], and the ecotoxicity of the treated samples (lettuce seed, Artemia salina, and zebrafish in their early-life stages). Dye degradation was affected only by catalyst concentration [Fe] in both the Fenton and Fenton-like processes. In the Fenton reaction, [H2O2residual] was significantly affected by initial [H2O2] and its interaction with [Fe]; however, in the Fenton-like reaction, it was affected by initial [H2O2] only. A. salina mortality was affected by different process factors in both processes, which suggests the formation of different toxic products in each process. The desirability function was applied to determine the best process parameters and predict the responses, which were confirmed experimentally. Optimal conditions facilitated the complete degradation of the dye without [H2O2residual] or toxicity for samples treated with the Fenton-like process, whereas the Fenton process induced significant mortality for A. salina. Results indicate that the Fenton-like process is superior to the Fenton reaction to degrade Disperse Red 343.

  • Antiproliferative effect of p-Coumaric acid targets UPR activation by downregulating Grp78 in colon cancer
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-05
    Sharada H. Sharma, Vinothkumar Rajamanickam, Sangeetha Nagarajan
  • Nanoceria acts as antioxidant in tumoral and transformed cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-06-04
    Laura Rubio, Ricard Marcos, Alba Hernández

    Antioxidant/prooxidant properties of cerium oxide nanoparticles (nanoceria) have been reported. It has been proposed that this protective/adverse role would depend of the cell status. In tumoral cells, nanoceria would act as prooxidant, while in normal cells it would act as antioxidant. In this context our work aims to study the nanoceria antioxidant/prooxidant capacity in different tumoral cell lines, studying how cell origin (non-tumoral vs tumoral), or extracellular environment could affect its protective/adverse effect. We have determined the ability of nanoceria to reduce the levels of reactive-oxygen-species (ROS) generated by the antitumoral agent cisplatin in five human tumoral cells. Results indicate that combined treatment reduces the levels of induced ROS in practically all cases. Prooxidant effects were never observed. The growth of A549 cell line in a forced acidic environment showed that the antioxidant properties of nanoceria were not influenced. A normal mouse embryonic fibroblast cell line (MEF) and its arsenic-transformed isogenic counterpart (AsT-MEF) were also evaluated. As in the other cases, nanoceria elicited an antioxidant effect in both MEF and AsT-MEF. In addition, nanoceria pretreatment also reduced the levels of apoptosis and cell death induced by cisplatin. From our results, we can conclude that the tumoral state of the cells is not a general argument to explain a potential non-protective role of nanoceria.

  • 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.

  • 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.

  • 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.

  • 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
    Ariraman Subastri, Viswanathan Arun, Preeti Sharma, Ezhuthupurakkal Preedia babu, Arumugam Suyavaran, Subramaniyam Nithyananthan, Ghedeir M. Alshammari, Balakrishnan Aristatile, Venkataraman Dharuman, Chinnasamy Thirunavukkarasu

    Therapeutic applications of arsenic trioxide (ATO) are limited due to their severe adverse effects. However, nanoparticles of ATO might possess inimitable biologic effects based on their structure and size which differ from their parent molecules. Based on this conception, AsNPs were synthesized from ATO and comparatively analysed for their interaction mechanism with DNA using spectroscopic & electrochemical techniques. Finally, anti-proliferative activity was assessed against different breast cancer cells (MDA-MB-231 & MCF-7) and normal non-cancerous cells (HEK-293). The DNA interaction study revealed that AsNPs and ATO exhibit binding constant values in the order of 106 which indicates strong binding interaction. Binding of AsNPs did not disturb the structural integrity of DNA, on the other hand an opposing effect was observed with ATO through biophysical techniques. Further, in vitro study, confirms cytotoxicity of ATO and AsNPs against different cells, however at particular concentration ATO exhibits more cytotoxicity than that of AsNPs. Furthermore, cytotoxicity was confirmed through acridine orange and comet assay. In conclusion, AsNPs are safer than ATO with comparable efficacy and might be a suitable candidate for the development of novel therapeutic agent against breast cancer and other solid tumours.

  • Improvement of antihyperglycemic activity of nano-thymoquinone in rat model of type-2 diabetes
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-05
    Ruma Rani, Shakti Dahiya, Dinesh Dhingra, Neeraj Dilbaghi, Ki-Hyun Kim, Sandeep Kumar

    Thymoquinone is a bioactive constituent of Nigella sativa seeds. It has been reported to possess antihyperglycemic effect in rats. However, the effect of nanoformulation (NF) of thymoquinone has not been reported in literature. So, the present study was designed with the aim to investigate the effect of nanoformulation of thymoquinone in streptozotocin-nicotinamide induced type-2 diabetic rats and compare its effect with pure bioactive compound as well as metformin, a standard antidiabetic drug. It is the first study reporting the use of thymoquinone NF against diabetes.Polymeric nanocapsules (NCs) of thymoquinone and metformin were prepared by nanoprecipitation method using gum rosin, a biocompatible polymer. Box-Behnken statistical analysis tool was used for the optimization of polymer and other excipients. The NCs were then characterized with respect to particle size, stability, morphology, and in vitro drug dissolution profiles. Furthermore, thymoquinone (20, 40 & 80 mg/kg), metformin (150 mg/kg) and their nanoformulations (20, 40 & 80 mg/kg for thymoquinone and 80 mg/kg for metformin) per se were administered for 21 successive days to type-2 diabetic rats. Body weight and blood glucose levels were measured every week for 3 weeks. Serum lipid profile and glycosylated hemoglobin were estimated on 22nd day.The nanocapsules were stable, spherical in shape and size was less than 100 nm. Thymoquinone-and metformin-loaded NCs showed sustained release profile as compared to their pure forms. Oral administration of thymoquinone, metformin and their nanoformulations significantly decreased blood glucose level and glycated haemoglobin; and improved the lipid profile of diabetic rats as compared to diabetic control rats. Thymoquinone-loaded NCs (containing 10, 20 and 40 mg of thymoquinone) produced dose-dependent antihyperglycemic effect and this effect was comparable to thymoquinone and metformin. In conclusion, thymoquinone nanocapsules (actually containing half of the doses of thymoquinone) produced better antihyperglycemic effect in type-2 diabetic rats as compared to thymoquinone alone.

  • In-ovo exposed carbon black nanoparticles altered mRNA gene transcripts of antioxidants, proinflammatory and apoptotic pathways in the brain of chicken embryo
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-02-26
    Dalia H. Samak, Yasser S. El-Sayed, Hazem M. Shaheen, Ali H. El-Far, Atsuto Onoda, Mohamed M. Abdel-Daim, Masakazu Umezawa

    With ubiquitous applications of nanotechnology, there are increasing probabilities of exposure to manufactured nanoparticles (NPs), which might be posing emerging health concerns on the next generation. Recent data suggest that generation of reactive oxygen species may play an integral role in the carbon black nanoparticles (CBNPs)-induced oxidative injury; however, the exact molecular mechanism has not been clarified. Hence, the role of oxidative stress, inflammation and apoptosis pathways in the CBNPs-induced neuronal toxicity following in-ovo exposure of chicken embryo was elucidated. Specific pathogen-free fertilized Sasso eggs were inoculated with 4.8, 9.5 and 14 μg CBNPs/egg at the 3rd day of incubation alongside vehicle controls. In a concentration-dependent manner, CBNPs inoculation induced oxidative stress, which was ascertained by enhancement of lipid peroxides and diminishing total antioxidant capacity and glutathione levels, and catalase activity in brain tissues. mRNA transcript levels of antioxidant genes showed up-regulation of heme oxygenase-1 and superoxide dismutase-1, with marked down-regulation of glutathione S-transferase-α. Additionally, the pro-inflammatory genes; nuclear factor-κB1 was up-regulated, while interferon-γ was down-regulated. There is also a clear down-regulation in apoptotic markers caspase-8, caspase-3, cytochrome c and B-cell CLL/lymphoma 2 at the different concentrations, while caspase-2 is up-regulated only at higher concentration. Collectively, these results show that CBNPs exposure-mediated overproduction of the free radicals, particularly at higher concentration contributes to inflammation and subsequent cellular apoptosis at the gene expression level, thus unveiling possible molecular relationship between CBNPs and genes linked to the oxidant, inflammatory and apoptotic responses.

  • Adsorption of human serum albumin on functionalized single-walled carbon nanotubes reduced cytotoxicity
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-03-27
    Naihao Lu, Yinhua Sui, Yun Ding, Rong Tian, Li Li, Fufeng Liu

    With the potential uses of carbon nanotubes (CNTs) in biomedical and biotechnological applications, and the growing concerns about nanotoxicity of these engineered nanoparticles, the importance of protein–nanoparticle interaction has not been well stressed. In this study, we used both experimental and theoretical approaches to investigate the interactions of different functionalized single-walled CNTs (SWCNTs) with human serum albumin (HSA). It was found that the HSA adsorption capacities of CNTs followed the order carboxylated SWCNTs > hydroxylated SWCNTs > amined SWCNTs. The fluorescence intensity of HSA was quenched by all of the three SWCNTs in static mode, which was authenticated by Stern-Volmer calculations. Our molecular dynamics simulations revealed that both atom-atom contact numbers and binding energies between functionalized SWCNTs and HSA played critical roles in determining their adsorption capacity, in agreement with the experimental findings. Additional cytotoxicity assays revealed that coating of carboxylated CNTs with HSA more significantly reduced their cytotoxicity than the other two CNTs, in agreement with their protein adsorption capacities in vitro. These findings will be helpful to clarify the mechanism of interactions of functionalized SWCNTs with human serum proteins, and provide more insight into the understanding of how to design the safe nanoparticles by preconsideration of their interactions with proteins.

  • Metformin alleviated endotoxemia-induced acute lung injury via restoring AMPK-dependent suppression of mTOR
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-31
    Kejia Wu, Rui Tian, Jing Huang, Yongqiang Yang, Jie Dai, Rong Jiang, Li Zhang

    Inflammation requires intensive metabolic support and modulation of the metabolic pathways might become a novel strategy to limit inflammatory injury. Recent studies have revealed the anti-inflammatory effects of the anti-diabetic reagent metformin, but the underlying mechanisms remain unclear. In the present study, the potential effects of metformin on endotoxemia-induced acute lung injury (ALI) and their relationship with the representative metabolic regulator, including AMPK, sirtuin 1 and mTOR, were investigated. The results indicated that treatment with metformin suppressed LPS-induced upregulation of IL-6 and TNF-α, alleviated pulmonary histological abnormalities, improved the survival rate of LPS-challenged mice. Treatment with metformin reversed LPS-induced decline of AMPK phosphorylation. Co-administration of the AMPK inhibitor compound C abolished the stimulatory effects of metformin on AMPK phosphorylation, the suppressive effects of metformin on IL-6 induction and pulmonary lesions. In addition, co-administration of the mTOR activator 3BDO but not the sirtuin 1 inhibitor EX-527 abolished the effects of metformin on IL-6 induction and pulmonary lesions. Finally, treatment with metformin suppressed LPS-induced p70S6K1 phosphorylation, which was abolished by the AMPK inhibitor. These data suggest that metformin might provide anti-inflammatory benefits in endotoxemia-induced inflammatory lung injury via restoring AMPK-dependent suppression of mTOR.

  • Venlafaxine mitigates cisplatin-induced nephrotoxicity via down-regulating apoptotic pathway in rats
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-29
    Dalia H. El-Kashef, Maha H. Sharawy

    The antidepressant venlafaxine, a norepinephrine and serotonin reuptake inhibitor, is recently identified for its anti-inflammatory role against many experimental models. In this study, the effect of venlafaxine against cisplatin-induced nephrotoxicity and bladder rings hypersensitivity towards acetylcholine were explored. Single injection of cisplatin (7 mg/kg, ip) in Sprague-Dawley rats instigated nephrotoxicity evidenced by hindering renal function (changes in kidney/body weight ratio, serum creatinine, BUN, albumin and urinary total protein levels which were supported by histopathology). In addition, cisplatin caused a profound oxidative stress, inflammation and apoptosis. Treatment with venlafaxine (50 mg/kg, po) managed to alleviate the nephrotoxicity indices and rehabilitate the antioxidant parameters (MDA, GSH, SOD and CAT) in addition to retaining NOx levels to the normal levels. Moreover, venlafaxine caused a decline in LDH and NF-κB levels supporting its anti-inflammatory effect. Additionally, the antiapoptotic effect was demonstrated by increasing Bcl-2, suppressing p53 and Bax renal levels, decreasing caspase-3 expression and by flow cytometry (annexin V and PI) that showed an increase in viable cells and a decrease in early apoptotic and necrotic cells. Furthermore, venlafaxine ameliorated bladder rings hyperreactivity to acetylcholine and improved histopathologic findings. In brief, venlafaxine ameliorated nephrotoxicity and bladder rings hyperreactivity caused by cisplatin through acting as an antioxidant, anti-inflammatory and antiapoptotic agent.

  • Ganoderic Acid A improves high fat diet-induced obesity, lipid accumulation and insulin sensitivity through regulating SREBP pathway
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-29
    Jing Zhu, Jie Jin, Jiexia Ding, Siying Li, Panpan Cen, Keyi Wang, Hai Wang, Junbo Xia

    Obesity and its major co-morbidity, type 2 diabetes, have been an alarming epidemic prevalence without an effective treatment available. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. Therefore, inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Here, we identify a small molecule, Ganoderic Acid A (GAA), inhibits the SREBP expression and decreases the cellular levels of cholesterol and fatty acid in vitro. GAA also ameliorates body weight gain and fat accumulation in liver or adipose tissues, and improves serum lipid levels and insulin sensitivity in high fat diet (HFD)-induced obese mice. Consistently, GAA regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Taken together, GAA could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance.

  • Impact of prepubertal exposure to dietary protocatechuic acid on the hypothalamus-pituitary-testicular axis in rats
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-26
    Isaac A. Adedara, Olubunmi Omole, Edozie S. Okpara, Opeyemi B. Fasina, Modupe F. Ayeni, Olamide M. Ajayi, Esther O. Busari, Ebenezer O. Farombi

    Protocatechuic acid (PCA; 3, 4-dihydroxybenzoic acid) is a phenolic compound widely found in many edible fruits, vegetables, grape wine and plant-derived beverages. The present study investigated the impact of PCA on the hypothalamus-pituitary-testicular axis of rats orally treated with PCA during the period of prepubertal development to adulthood. Protocatechuic acid was administered to prepubertal male rats at doses of 0, 5, 10, 50 and 100 mg/kg body for 45 consecutive days. The results revealed no treatment-related changes in the body weight gain and organo-somatic indices of the hypothalamus, testes, epididymis, prostate gland and seminal vesicle in rats administered with PCA when compared with control. However, prepubertal exposure to PCA significantly enhanced antioxidant enzyme activities and glutathione level whereas it markedly decreased biomarkers of inflammation and oxidative stress in the hypothalamus, testes and epididymis of the treated rats. Protocatechuic acid significantly increased circulatory concentrations of luteinizing hormone and follicle-stimulating hormone with concomitant increase in serum and intra-testicular testosterone levels. Moreover, PCA-treated rats exhibited significant increase in marker enzymes of testicular function namely acid phosphatase, alkaline phosphatase, lactate dehydrogenase and glucose-6-phosphate dehydrogenase without statistically significant increase in spermatogenesis and sperm functional characteristics including sperm count, motility and viability. Light microscopic examination of the hypothalamus, testes and epididymis of rats treated with PCA showed histo-architectures similar to control. In conclusion, prepubertal exposure to PCA is safe and positively impacted reproductive function at sexual maturity in male rats. The observed beneficial effects of PCA is related to its anti-inflammatory and redox regulatory mechanisms.

  • 更新日期:2018-05-27
  • 更新日期:2018-05-25
  • Electro-behavioral phenotype and cell injury following exposure to paraoxon-ethyl in mice: Effect of the genetic background
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-22
    Benjamin Baccus, Stéphane Auvin, Frédéric Dorandeu

    Organophosphorus compounds (OP) are irreversible inhibitors of both central and peripheral cholinesterases (ChE). They still represent a major health issue in some countries as well as a terrorist and military threat. In order to design appropriate medical counter-measures, a better understanding of the pathophysiology of the poisoning is needed. Little to nothing is known regarding the impact of the genetic background on OP-induced seizures and seizure-related cell injury. Using two different mouse strains, Swiss and C57BL/6J, exposed to a convulsing dose of the OP pesticide paraoxon-ethyl (POX), our study focused on seizure susceptibility, especially the occurrence of SE and related mortality. We also evaluated the initial neuropathological response and SE-induced cell injury.Following the administration of 2.4 mg/kg POX, more Swiss mice experienced SE than C57BL/6J (55.6% versus 17.2%) but the duration of their SE, based on EEG recordings, was shorter (64.3 ± 19.5 min versus 180.8 ± 36.8 min). No significant difference was observed between strains regarding mortality (33% versus 14%). In both strains limited cell injury was observed in the medial temporal cortex, the dentate gyrus and the CA3 field without inter-strain differences (Fluorojade C-positive cells/mm2). Conversely, only C57BL/6J mice showed cell injury in the CA1 field. There was no obvious correlation between the number of Fluorojade C-positive cells and the duration of the EEG discharges.Our work suggests some differences between Swiss and C57BL/6J mice and lay ground to further studies on the impact of strains in the development of central nervous system toxicity of OP.

  • Vosaroxin induces mitochondrial dysfunction and apoptosis in cervical cancer HeLa cells: Involvement of AMPK/Sirt3/HIF-1 pathway
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-22
    Xian-Li Zhao, Chun-Zhi Yu

    Vosaroxin is a quinolone-derivative anticancer agent with inhibitory activity on type II DNA topoisomerases (TOP2). The aim of the present study was to investigate its cytotoxic effect and potential molecular mechanisms in human cervical cancer HeLa cells. Vosaroxin decreased cell viability and increased lactate dehydrogenase (LDH) release in a dose- and time-dependent manner in HeLa cells, but not in normal cervical epithelial cells. Vosaroxin also induced apoptosis and increased caspase-3 activity in HeLa cells. These effects were accompanied by increased mitochondrial reactive oxygen species (ROS) generation, lipid peroxidation, mitochondrial swelling and reduced ATP production. Western blot analysis showed that vosaroxin significantly reduced hypoxia-inducible factor 1α (HIF-1α) protein levels. However, it had no effect on HIF-1α protein degradation and HIF-1α mRNA levels. The results showed that vosaroxin inhibited the synthesis of HIF-1α protein and interfered with the dimerization of HIF-1α and aryl hydrocarbon receptor nuclear translocator (ARNT). In addition, vosaroxin stimulated mitochondrial enzyme activities and superoxide dismutase 2 (SOD2) deacetylation via activating (Sir2 like protein 3) Sirt3. More importantly, vosaroxin-induced inhibition on HIF-1α and its cytotoxic effects, as measured by cell viability, LDH release and apoptosis, were partially prevented by Sirt3 knockdown or the AMP-activated protein kinase (AMPK) inhibitor compound C. Overall, vosaroxin is demonstrated to be a chemotherapeutic agent targeting the Sirt3/HIF-1 pathway and could be beneficial for inducing cytotoxicity in human cervical cancer cells.

  • DNA binding efficacy with functionalized folic acid-PAMAM nanoparticles
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-22
    P. Chanphai, H.A. Tajmir-Riahi
  • Simultaneous determination of intestinal permeability and potential drug interactions of complex mixtures using Caco-2 cells and high-resolution mass spectrometry: Studies with Rauwolfia serpentina extract
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-19
    Thomas J. Flynn, Sanah N. Vohra

    Caco-2 cells are a commonly used model for estimating the intestinal bioavailability of single chemical entity pharmaceuticals. Caco-2 cells, when induced with calcitriol, also express other biological functions such as phase I (CYP) and phase II (glucuronosyltransferases) drug metabolizing enzymes which are relevant to drug-supplement interactions. Intestinal bioavailability is an important factor in the overall safety assessment of products consumed orally. Foods, including herbal dietary supplements, are complex substances with multiple chemical components. Because of potential interactions between components of complex mixtures, more reliable safety assessments can be obtained by studying the commercial products “as consumed” rather than by testing individual chemical components one at a time. The present study evaluated the apparent intestinal permeability (Papp) of a model herbal extract, Rauwolfia serpentina, using both whole plant extracts and the individual purified Rauwolfia alkaloids. All test compounds, endpoint substrates, and their metabolites were quantified using liquid chromatography and high-resolution mass spectrometry. The Papp values for individual Rauwolfia alkaloids were comparable whether measured individually or as components of the complete extract. Both Rauwolfia extract and all individual Rauwolfia alkaloids except yohimbine inhibited CYP3A4 activity (midazolam 1′-hydroxylation). Both Rauwolfia extract and all individual Rauwolfia alkaloids except corynanthine and reserpic acid significantly increased glucuronosyltransferase activity (glucuronidation of 4-methylumbelliferone). The positive control, ketoconazole, significantly inhibited both CYP3A4 and glucuronosyltransferase activities. These findings suggest that the Caco-2 assay is capable of simultaneously identifying both bioavailability and potentially hazardous intestinal drug-supplement interactions in complex mixtures.

  • Indole-3-Carbinol (I3C) enhances the sensitivity of murine breast adenocarcinoma cells to doxorubicin (DOX) through inhibition of NF-κβ, blocking angiogenesis and regulation of mitochondrial apoptotic pathway
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-15
    Subhadip Hajra, Arup Ranjan Patra, Abhishek Basu, Prosenjit Saha, Sudin Bhattacharya

    Various epidemiological and preclinical studies have already established the cancer chemopreventive potential of naturally occurring glucosinolate breakdown product Indole-3-Carbinol (I3C) as well as its abilities to induce selective cell death towards malignant cell. Therefore, the objective of the present study is to improve the therapeutic efficacy and prevention of doxorubicin (DOX)-induced toxicity, by the concurrent use of Indole-3-Carbinol (I3C). In this study, I3C was administered (20 mg/kg b.w., p.o.) to breast adenocarcinoma (Ehrlich ascites carcinoma) induced solid tumor bearing mice alone as well as in combination with DOX (5 mg/kg b.w., i.p.) in concomitant and pretreatment schedule. The results showed that concurrent administration of I3C and DOX significantly (P < 0.05) improved therapeutic efficacy as evidenced by reduction of tumor size and enhancement of host survivability. Oral administration of I3C significantly (P < 0.05) inhibited the expression of NF-κβ in both tumor cells and cardiac tissue as well as maximizes the therapeutic outcome in terms of tumor cell killing and toxicity. In addition, I3C sensitized tumor cells to DOX-therapy by down-regulating the expression of anti-apoptotic protein Bcl-2 and by up-regulating molecules like Bax, cytochrome c, caspases, which led to PARP cleavage and apoptosis. Significant inhibition of angiogenesis along with reduction in the serum levels of VEGF-A and MMP-9 further contribute to the sensitization accomplished by I3C. Moreover, we also found that I3C provided additional host survival advantages by attenuated DOX-induced toxicities through modulation of Nrf2/ARE pathway and promoted expression of cytoprotective proteins HO-1, NQO1 and GSTπ in cardiac tissue. In addition, I3C significantly attenuated DOX-induced inflammation by down-regulation of NF-kβ, iNOS, COX-2 and IL-6 in cardiac tissue. Thus, the present study clearly suggested therapeutic benefit of I3C in combination with DOX by augmenting anticancer efficacy and diminishing toxicity to the host.

  • D-pinitol attenuates cisplatin-induced nephrotoxicity in rats: Impact on pro-inflammatory cytokines
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-09
    Nita vasaikar, Umesh Mahajan, Kalpesh R. Patil, Kapil Suchal, Chandragouda R. Patil, Shreesh Ojha, Sameer N. Goyal

    Cisplatin has been widely used as a first-line agent against various forms of solid cancers. However, nephrotoxicity is the major limiting factor for its clinical use. Several clinical and pre-clinical studies have suggested different strategies for the reduction of cisplatin-induced nephrotoxicity. The present study was conducted to investigate the efficacy of D-Pinitol, against cisplatin-induced nephrotoxicity in Swiss albino mice. A single intraperitoneal injection of cisplatin (20 mg/kg) was used to induce nephrotoxicity in mice. Administration of cisplatin in mice is linked with elevated oxidative stress, imbalanced biochemical parameters, apoptosis and stimulation of mitogen-activated protein kinase (MAPK) pathway. D-Pinitol is a member of the flavonoid family and a chief constituent of Sutherlandia fruitesecnce. It was administered with saline water (10, 20, 40 mg/kg, p.o.) for seven consecutive days after a single dose of cisplatin. At the end of experiment, animals were sacrificed and biochemical parameters in serum and urine were recorded. Kidneys were isolated for the estimation of tumor necrosis factor-alpha, interleukin-1β, interlukin-6 levels and histopathological evaluations. It was noted that D-Pinitol significantly ameliorated biochemical levels of serum and urinary creatinine and blood urea nitrogen. Tissue homogenate levels of TNF-α, IL-6, IL-1β and the renal expression of tissue nitrites were also significantly decreased in D-Pinitol treated mice. These results were supplemented by histopathological findings. This study highlights the potential role of D-Pinitol against cisplatin-induced toxicity, exhibited through favorable alterations in biochemical and histological changes as well as reduction in oxidative stress and cytokine levels.

  • Mesalazine, an osteopontin inhibitor: The potential prophylactic and remedial roles in induced liver fibrosis in rats
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-05-05
    A. Ramadan, Nehal Afifi, Nemat Z. Yassin, Rehab F. Abdel-Rahman, Sahar S. Abd El-Rahman, Hany M. Fayed

    Liver fibrosis is a major health issue leading to high morbidity and mortality. The potential anti-fibrotic activity and the effect of mesalazine on osteopontin (OPN), an extra cellular matrix (ECM) component were evaluated in TAA-induced liver fibrosis in rats. For this purpose, forty-two adult male Wistar rats were divided into six groups. All animals, except the normal control, were intraperitoneally injected with TAA (200 mg/kg) twice per week for 6 weeks. In the hepato-protective study, animals were administered mesalazine (50 and 100 mg/kg, orally) for 4 weeks before induction of liver fibrosis then concomitantly with TAA injection. In the hepato-therapeutic study, animals were administered mesalazine for 6 weeks after TAA discontinuation with the same doses. In both studies, mesalazine administration improved liver biomarkers through decreasing serum levels of AST, ALT and total bilirubin when compared to fibrotic group with significant increase in total protein and albumin levels. Mesalazine significantly decreased hepatic MDA level and counteracted the depletion of hepatic GSH content and SOD activity. Additionally, it limits the elevation of OPN and TGF-β1 concentrations and suppressed TNF-α as well as α-SMA levels in hepatic tissue homogenate. Histopathologically, mesalazine as a treatment showed a good restoration of the hepatic parenchymal cells with an obvious decreased intensity and retraction of fibrous proliferation, while as a prophylaxis it didn't achieve enough protection against the harmful effect of TAA, although it decreased the intensity of portal to portal fibrosis and pseudolobulation. Furthermore, mesalazine could suppress the expression of both α-SMA and caspase-3 in immunohistochemical sections. In conclusion, mesalazine could have a potential new indication as anti-fibrotic agent through limiting the oxidative damage and altering TNF-ɑ pathway as an anti-inflammatory drug with down-regulating TGF-β1, OPN, α-SMA and caspase-3 signaling pathways.

  • Inhibitory effect of α-terpinyl acetate on cytochrome P450 2B6 enzymatic activity
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-30
    Yejin Lee, Hyoung-Goo Park, Vitchan Kim, Myung-A. Cho, Harim Kim, Thien-Hoang Ho, Kyoung Sang Cho, Im-Soon Lee, Donghak Kim

    Human cytochrome P450 2B6 is an important hepatic enzyme for the metabolism of xenobiotics and clinical drugs. Recently, more attention has been paid to P450 2B6 because of the increasing number of drugs it metabolizes. It has been known to interact with terpenes, the major constituents of the essential oils used for various medicinal purposes. In this study, the effect of monoterpenes on P450 2B6 catalytic activity was investigated. Recombinant P450 2B6 was expressed in Escherichia coli and purified using Ni-affinity chromatography. The purified P450 2B6 enzyme displayed bupropion hydroxylation activity in gas-mass spectrometry (GC-MS) analysis with a kcat of 0.5 min−1 and a Km of 47 μM. Many terpenes displayed the type I binding spectra to purified P450 2B6 enzyme and α-terpinyl acetate showed strong binding affinity with a Kd value of 5.4 μM. In GC-MS analysis, P450 2B6 converted α-terpinyl acetate to a putative oxidative product. The bupropion hydroxylation activity of P450 2B6 was inhibited by α-terpinyl acetate and its IC50 value was 10.4 μM α-Terpinyl acetate was determined to be a competitive inhibitor of P450 2B6 with a Ki value of 7.6 μM. The molecular docking model of the binding site of the P450 2B6 complex with α-terpinyl acetate was constructed. It showed the tight binding of α-terpinyl acetate in the active site of P450 2B6, which suggests that it could be a competitive substrate for P450 2B6.

  • Potential of siRNA-albumin complex against cancer
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-27
    Na Liu, Yan-Hua Qi, Chuan-Tao Cheng, Wen Bin Yang, Anshoo Malhotra, Qi Zhou

    RNA interference is a highly specific as well as efficient technology for gene therapy application in molecular oncology. The present study was planned to develop an efficient and stable tumor selective delivery mechanism for siRNA gene therapy for the purpose of both diagnosis as well as therapy. We have used 20 Male wistar rats for the formation of colon cancer model and utilized albumin as carrier molecule for the delivery of siRNA against vascular endothelial growth factor receptor 2 (VEGF R2). The study results confirmed efficient delivery of siRNA at tumor site as confirmed by tagging of siRNA-albumin complex with 99mTC. Moreover, the expression of VEGF also showed decline after efficient delivery of siRNA at tumor site. The study concluded that albumin is an efficient molecule for the efficient delivery of siRNA at tumor sites.

  • Effect of the alkyl group in the piperazine N-substitution on the therapeutic action of rifamycins: A drug-membrane interaction study
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-27
    Emílio V. Lage, Joana Magalhães, Marina Pinheiro, Salette Reis

    In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism. In this study, surface pressure-area isotherms, as well as spectroscopic and microscopic techniques of characterization of phospholipid monolayers at the air/water interface were used to gain insight into drug-membrane interactions. Differences in the affinity for lipid membranes for both drugs, given by the vibration frequency of characteristic chemical groups in the lipid, as well as by reflectivity and mean molecular area of the monolayer, seems to be due to the N-alkyl substituent and can contribute to provided a molecular explanation as why they pose different choices in the chemotherapy against the deadliest infectious disease, tuberculosis.

  • Gold nanoparticles induce serum amyloid A 1–Toll-like receptor 2 mediated NF-kB signaling in lung cells in vitro
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-26
    Cheng Teng Ng, Wai Cheong George Yip, Ee Sin Chen, Wan Yan Rebecca Poh, Boon Huat Bay, Lin Yue Lanry Yung

    Gold nanoparticles (AuNPs) have emerging applications in biomedicine and the industry. Exposure to AuNPs has previously been shown to alter the transcriptional activity of nuclear factor kappa B (NF-kB), which is known to mediate physiological and pathological processes. This study seeks to provide mechanistic insights into AuNP-induced NF-kB activation in Small Airway Epithelial Cells (SAECs) in vitro. Increased NF-kB transcriptional activity (quantified by the luciferase reporter assay) was observed in AuNP-treated SAECs. Transcriptomic analysis revealed differential expression of 42 genes, which regulate functional processes that include cellular response to stimulus, chemicals, stress and immune response. Notably, the gene expression of serum amyloid A1 (SAA1), an acute phase protein and Toll-like receptor 2 (TLR2) were found to be up-regulated. As TLR2 is known to be a functional receptor of SAA1, a co-immunoprecipitation assay was performed. SAA1 was observed to be co-immunoprecipitated with the TLR2 protein and this protein-protein interaction was further supported by in silico computer based protein modeling. The present study suggests that AuNPs may potentially induce SAA1-TLR2-mediated NF-kB transcription factor activation in lung epithelial cells, highlighting that nano-bio interactionscould result in biological effects that may affect cells.

  • NGAL attenuates renal ischemia/reperfusion injury through autophagy activation and apoptosis inhibition in rats
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-25
    Ya-li Zhang, Shu-kai Qiao, Rong-ying Wang, Xiao-nan Guo

    Ischemia/reperfusion (I/R) injury is a main cause of acute kidney injury (AKI), and currently lacks effective therapies. This study is to investigate the level of Neutrophil gelatinase-associated lipocalin (NGAL) and autophagy status during renal I/R injury, so as to determine whether the exogenous NGAL protein could exert a protective effect for I/R injury and explore the potential mechanisms. Forty male Wistar rats were randomly divided into the following four groups: Sham, I/R, pre-treated with NGAL before I/R (I/R + pre-N), treated with NGAL after I/R (I/R + post-N). All rats were subjected to clamping the left renal pedicle for 45 min after right nephrectomy, followed by 24 h of reperfusion. Serum creatinine (SCr) and blood urea nitrogen (BUN) were used for renal function, tubular cell apoptosis and autophagy were measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, histological examination and electron microscope, respectively. The tubular cell proliferation was assessed by the protein expression of proliferating cell nuclear antigen (PCNA). Western blotting was used to quantitate the levels of LC3, Beclin-1, Bcl-2 and Bax in kidney tissues. Exogenous NGAL protein intervention significantly improved renal function, reduced tubular cell apoptosis, increased tubular cell proliferation and promoted autophagy activation after renal I/R injury. Further, the efficacy in pre-N was significantly better than post-N. The mechanisms were involved in the regulation of several autophagy and apoptosis-related genes. Our study demonstrated that exogenous NGAL protein play a protective role during I/R injury, which may offer a novel may for prevention and treatment of renal I/R injury.

  • Free fatty acid receptor 1 as a novel therapeutic target for type 2 diabetes mellitus-current status
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-25
    Chinedum Eleazu, Ayogu Charles, Kate Eleazu, Ngozi Achi

    The incidence of type 2 diabetes mellitus (T2DM) has been on the increase in recent times. Although several oral treatments for T2DM are available, some of them have been found to elicit undesirable side effects. This therefore underscores the need for new treatment options with lesser side effects than the existing ones for people with T2DM. Free fatty acid receptor 1 (FFAR1), also known as GPR40, belongs to a class of G-protein coupled receptors that are encoded by FFAR1 genes in humans. It is expressed in the pancreatic β-cells and it is activated by medium- and long-chain saturated and unsaturated fatty acids. Thus it responds to endogenous medium and long chain unsaturated fatty acids, resulting in enhancement of insulin secretion during increased glucose levels. The glucose dependency of insulin secretion has made this receptor a very good target for developing therapies that could be efficacious with fewer side effects than the existing therapies for the treatment of T2DM. Given that tremendous efforts have been made in recent times in developing novel FFAR1 agonists with antidiabetic potentials, this article provides a current status of knowledge on the efforts made so far in developing novel FFAR1 agonists that would be of relevance in the management of T2DM.

  • Oxyresveratrol ameliorates nonalcoholic fatty liver disease by regulating hepatic lipogenesis and fatty acid oxidation through liver kinase B1 and AMP-activated protein kinase
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-24
    Ju-Hee Lee, Su Youn Baek, Eun Jeong Jang, Sae Kwang Ku, Kyu Min Kim, Sung Hwan Ki, Chang-Eop Kim, Kwang Il Park, Sang Chan Kim, Young Woo Kim

    Oxyresveratrol (OXY) is a naturally occurring polyhydroxylated stilbene that is abundant in mulberry wood (Morus alba L.), which has frequently been supplied as a herbal medicine. It has been shown that OXY has regulatory effects on inflammation and oxidative stress, and may have potential in preventing or curing nonalcoholic fatty liver disease (NAFLD). This study examined the effects of OXY on in vitro model of NAFLD in hepatocyte by the liver X receptor α (LXRα)-mediated induction of lipogenic genes and in vivo model in mice along with its molecular mechanism. OXY inhibited the LXRα agonists-mediated sterol regulatory element binding protein-1c (SREBP-1c) induction and expression of the lipogenic genes and upregulated the mRNA of fatty acid β-oxidation-related genes in hepatocytes, which is more potent than genistein and daidzein. OXY also induced AMP-activated protein kinase (AMPK) activation in a time-dependent manner. Moreover, AMPK activation by the OXY treatment helped inhibit SREBP-1c using compound C as an AMPK antagonist. Oral administration of OXY decreased the Oil Red O stained-positive areas significantly, indicating lipid droplets and hepatic steatosis regions, as well as the serum parameters, such as fasting glucose, total cholesterol, and low density lipoprotein-cholesterol in high fat diet fed-mice, as similar with orally treatment of atorvastatin. Overall, this result suggests that OXY has the potency to inhibit hepatic lipogenesis through the AMPK/SREBP-1c pathway and can be used in the development of pharmaceuticals to prevent a fatty liver.

  • Cytochrome P450 mediated metabolic activation of chrysophanol
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-24
    Ying Sun, Xin Xin, Kehan Zhang, Tiantian Cui, Ying Peng, Jiang Zheng

    Chrysophanol, a major anthraquinone component occurring in many traditional Chinese herbs, is accepted as important active component with various pharmacological actions such as antibacterial and anticancer activity. Previous studies demonstrated that exposure to chrysophanol induced cytotoxicity, but the mechanisms of the toxic effects remain unknown. In the present metabolism study, three oxidative metabolites (M1-M3, aloe-emodine, 7-hydroxychrysophanol, and 2-hydroxychrysophanol) and five GSH conjugates (M4-M8) were detected in rat and human liver microsomal incubations of chrysophanol supplemented with GSH, and the formation of the metabolites was NADPH dependent except M4 and M5. M4 and M5 were directly derived from parent compound chrysophanol, M6 arose from M2, and M7 and M8 resulted from the oxidation of M4 and M5. Metabolites M5 and M6 were also observed in bile of rats after exposure to chrysophanol, M1-M3 and one NAC conjugate (M9) were detected in urine of rats administrated chrysophanol, and urinary metabolite M9 originated from the degradation of biliary GSH conjugation M6. Recombinant P450 enzyme incubation and microsome inhibition studies demonstrated that P450 1A2 was the primary enzyme responsible for the metabolic activation of chrysophanol and that P450 2B6 and P450 3A4 also participated in the generation of the oxidative metabolites. These findings helped us to understand the mechanisms of chrysophanol-induced cytotoxicity.

  • Flavan enantiomers from Daphne giraldii selectively induce apoptotic cell death in p53-null hepatocarcinoma cells in vitro
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-24
    Guo-Dong Yao, Qian Sun, Xiao-Yu Song, Xiao-Xiao Huang, Shao-Jiang Song

    Hepatocellular carcinoma (HCC) is a primary malignant tumor with very poor prognosis. To search for more effective compounds for HCC treatment, two new pairs of flavan enantiomers, daphnegiranol C1/C2 (1a/1b) and daphnegiranol D1/D2 (2a/2b), were isolated from the stem bark and roots of Daphne giraldii by using chiral chromatography. MTT assay was applied to evaluate their cytotoxicity against three hepatocarcinoma cell lines (Hep3B, MHCC97H, HepG2) as well as a normal liver cell line L02. The results showed that these compounds preferred to inhibit the growth of Hep3B cells (p53 null). Among them, 2a/2b (the IC50 value was 4.87 and 3.35 μM, respectively) exhibited a stronger cytotoxic effect than sorafenib (IC50 = 6.59 μM) in Hep3B cells. A further study demonstrated that 2a/2b could induce apoptotic cell death with an increase in reactive oxygen species (ROS) in Hep3B cells. In addition, the IC50 values of 2a/2b in HepG2 and MHCC97H cells (both harbored p53 gene) were more than 10-folds greater when compared with Hep3B cells, indicating that 2a/2b selectively exhibited cytotoxicity in p53-null hepatocarcinoma cells. Moreover, inhibition of p53 increased the inhibitory effect in p53-wild hepatocarcinoma cells, as well as apoptotic cells and ROS generation. Taken together, flavan enantiomers 2a/2b selectively induced apoptosis in Hep3B cells because of p53 deficiency.

  • Combined effects of cadmium and tetrabromobisphenol a (TBBPA) on development, antioxidant enzymes activity and thyroid hormones in female rats
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-24
    Yunjiang Yu, Ruixue Ma, Lin Yu, Ze Cai, Hongyan Li, You Zuo, Zhengdong Wang, Hui Li

    Tetrabromobisphenol A (TBBPA) is one of the world's most widely used brominated flame retardants (BFRs) and considered as persistent halogenated contaminant. E-wastes contain a range of toxic chemicals, including BFRs and heavy metals, exerting adverse impacts to human health and environment. Nevertheless, comprehensive evaluation on combined toxicity of these co-existing pollutants is limited. This study conducted a subchronic effects of cadmium and TBBPA on the development and antioxidative defense system as well as thyroid functions in female rats through single and combined exposure at environmentally relevant doses for a 20-day consecutive administration. Body indexes, histopathology, redox status, and thyroid hormones levels were assessed. Slower body weight gains and reduced ovary weight (20.8% and 32.4% for combined and single-Cd exposures, respectively) were observed with significant variation from controls in high dose treatments. Co-exposure resulted in a slight enhancement in TSH levels compared to control (by 7.6% for high dose) without significance. TBBPA-Cd interactions are involved in the changes of kidney weight as well as the induction of SOD activities and MDA levels. The disturbances in the redox status may be a result of an independent effect of Cd and/or TBBPA and also of their interaction. The results implied under these treatment, kidney was more sensitive with significant increased organ coefficient and alteration for antioxidative indices (increasing by 46% for SOD activity). This study represents the toxic effects of Cd and TBBPA co-exposure through oral administration in pubertal rats, which may provide useful information for health risk assessment for young exposed individuals.

  • Inhibitory Effects of Danshen components on CYP2C8 and CYP2J2
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-22
    Mei-juan Xu, Li-feng Jiang, Ting Wu, Ji-hong Chu, Yi-dan Wei, Ji-ye Aa, Guang-ji Wang, Hai-ping Hao, Wen-zheng Ju, Ping Li

    The use of Chinese herbal medicines and natural products has become increasingly popular in both China and Western societies as an alternative medicine for the treatment of diseases or as a health supplement. Danshen, the dried root of Salvia miltiorrhiza (Fam.Labiatae), which is rich in phenolic acids and tanshinones, is a widely used herbal medicine for the treatment of cardio-cerebrovascular diseases. The goal of this study was to examine the inhibitory effects of fifteen components derived from Danshen on CYP2C8 and CYP2J2, which are expressed both in human liver and cardiovascular systems. Recombinant CYP2C8 and CYP2J2 were used, and the mechanism, kinetics, and type of inhibition were determined. Taxol 6-hydroxylation and astemizole O-desmethyastemizole were determined as probe activities for CYP2C8 and CYP2J2, respectively. Metabolites formations were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results demonstrated that salvianolic acid A was a competitive inhibitor of CYP2C8 (Ki = 2.5 μM) and mixed-type inhibitor of CYP2J2 (Ki = 7.44 μM). Salvianolic acid C had moderate noncompetitive and mixed-type inhibitions on CYP2C8 (Ki = 4.82 μM) and CYP2J2 (Ki = 5.75 μM), respectively. Tanshinone IIA was a moderate competitive inhibitor of CYP2C8 (Ki = 1.18 μM). Dihydrotanshinone I had moderate noncompetitive inhibition on CYP2J2 (Ki = 6.59 μM), but mechanism-based inhibition on CYP2C8 (KI = 0.43 μM, kinact = 0.097 min−1). Tanshinone I was a moderate competitive inhibitor of CYP2C8 (Ki = 4.20 μM). These findings suggested that Danshen preparations appear not likely to pose a significant risk of drug interactions mediated by CYP2C8 after oral administration; but their inhibitory effects on intestinal CYP2J2 mediated drug metabolism should not be neglected when they are given orally in combination with other drugs. Additionally, this study provided novel insights into the underling pharmacological mechanisms of Danshen components from the perspective of CYP2C8 and CYP2J2 inhibition.

  • 6-formylindolo(3,2-b)carbazole induced aryl hydrocarbon receptor activation prevents intestinal barrier dysfunction through regulation of claudin-2 expression
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-20
    Yuanhang Ma, Qimeng Wang, Kun Yu, Xin Fan, Weidong Xiao, Yujiao Cai, Pengyuan Xu, Min Yu, Hua Yang

    6-formylindolo (3,2-b) carbazole (FICZ), a high-affinity aryl hydrocarbon receptor (AhR) ligand, plays a protective role in inflammatory bowel disease (IBD) through activation of AhR. Interleukin-6 (IL-6) induced intestinal epithelial barrier dysfunction is involved in the pathological process of IBD. In this study, we investigated the protective effects of FICZ on IL-6 induced intestinal epithelial barrier injury. Our data show that AhR activation by FICZ ameliorated colonic inflammation, decreased IL-6 and claudin-2 expression, and maintained intestinal barrier function in a mouse model of dextran sulphate sodium (DSS)-induced colitis. In Caco-2 and T84 intestinal epithelial cells, FICZ also prevented the increase of intestinal epithelial permeability and claudin-2 expression induced by IL-6. Depletion of AhR expression by small interfering (si)RNA reversed FICZ induced decrease of claudin-2. Furthermore, IL-6 induced upregulation of claudin-2 was required for increased caudal-related homeobox (CDX-2) and hepatocyte-nuclear factor (HNF)-1α. However, FICZ repressed the increase of CDX-2 and HNF-1α expression induced by IL-6. These results reveal the protective effects of FICZ on IL-6 induced disruption of intestinal epithelial barrier function through suppressing the expression of claudin-2. In addition, CDX-2 and HNF-1α are involved in the regulation of claudin-2 after IL-6 and FICZ treatment. Therefore, AhR-related compounds may be a potential pharmaceutical agent as a potential treatment of IBD.

  • CHM-1, a novel microtubule-destabilizing agent exhibits antitumor activity via inducing the expression of SIRT2 in human breast cancer cells
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-18
    Chin-Wei Liu, Ying-Chao Lin, Chao-Ming Hung, Bing-Lan Liu, Sheng-Chu Kuo, Chi-Tang Ho, Tzong-Der Way, Chih-Hsin Hung

    Breast cancer is a major public health problem throughout the world. In this report, we investigated whether CHM-1, a novel synthetic antimitotic agent could be developed into a potent antitumor agent for treating human breast cancer. CHM-1 induced growth inhibition in MDA-MB-231, MDA-MB-453 and MCF-7 cells in a concentration-dependent manner. Importantly, CHM-1 is less toxic to normal breast (HBL-100) cells. CHM-1 interacted with tubulin, markedly inhibited tubulin polymerization, and disrupted microtubule organization. Proteins from control and CHM-1-treated animal tumor specimens were analyzed by two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Our results indicated that CHM-1 increased the expression of SIRT2 protein, an NAD-dependent tubulin deacetylase. A prodrug strategy was also investigated to address the problem of low aqueous solubility and low bioavailability of the antitumor agent CHM-1. The water-soluble prodrug of CHM-1 (CHM-1-P) was synthesized. After oral and intravenous administration, CHM-1-P induced a dose-dependent inhibition of tumor growth. The aforementioned excellent anti-tumor activity profiles of CHM-1 and its prodrug CHM-1-P, suggests that CHM-1-P deserves to further develop as a clinical trial candidate for treating human breast carcinoma.

  • Antitumor activity of a molecularly imprinted nanopreparation of 5-flurouracil against Ehrlich's carcinoma solid tumors grown in mice: Comparison to free 5-flurouracil
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-17
    Ahmed R. Gardouh, Bassant M. Barakat, Mona K.E. Qushawy, Amany Y. El-kazzaz, Manal M. Sami, Sawsan A. Zaitone

    Recently, nanotechnology has received great attention in war against cancer. The present study investigated the antitumor efficacy of molecularly imprinted nanopreparation of 5-fluorouracil (nano-5-FU) against Ehrlich ascites carcinoma (EAC) solid tumors grown in mice. Tumor cells were transplanted into female albino mice. Mice were allocated into 5 groups; Group 1: control EAC bearing mice. Groups 2&3: EAC-bearing mice treated orally with 5-FU (5 and 10 mg/kg) twice weekly. Groups 4&5: EAC bearing mice treated with nano-5-FU (5 and 10 mg/kg) twice weekly. Treatment with nano-5-FU showed higher antitumor effect compared to free 5-FU as indicated by enhanced apoptosis and reduction in tumor weight. Additionally, lower number of mitotic figures and greater area for necrosis were observed in the tumor specimens alongside with a decline in the number of intratumoral proliferating nuclei in comparison to free 5-FU. Furthermore, the results showed a significant down-regulation in tumoral expression of caspase-3 and vascular endothelial growth factor. Together, these results further support the potential of using nanotechnology to enhance anticancer efficacy of 5-FU.

  • miR-223-RhoB signaling pathway regulates the proliferation and apoptosis of colon adenocarcinoma
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-13
    Li-Juan Wei, Jun-An Li, Dong-Mei Bai, Ying Song

    MicroRNAs (miRNAs) can function as tumor suppressor or oncogenic genes. The putative targets of miR-223 include tumor suppressor gene, RhoB. Here we sought to investigate the role of miR-223-RhoB signaling pathway in proliferation of colon cancer. We used Western blot, immunofluorescence staining, or RT-PCR to detect expression levels of miR-223 and RhoB in colon adenocarcinoma and adjacent non-cancerous tissue samples, or in human colon adenocarcinoma cell lines. MTT assay was used to determine proliferation and apoptosis in cell lines. We further used Western blot to determine levels of cell cycle regulators CDK1 and Cyclin B1 with anti-miR-223 or apoptosis with overexpression of RhoB. The expression level of miR-223 was significantly upregulated in clinical samples and cell lines of colon adenocarcinoma, in contrast to down-regulation of RhoB. In addition, we showed that inhibition of miR-223 led to upregulation of RhoB and in turn suppression of proliferation of colon adenocarcinoma. Moreover, inhibition of miR-223 or overexpression of RhoB induced cell arrest or apoptosis in colon adenocarcinoma. These results suggest that miR-223-RhoB signaling pathway plays an important role in modulation of proliferation, cell arrest, and apoptosis in colon cancer.

  • Herbacetin, a flaxseed flavonoid, ameliorates high percent dietary fat induced insulin resistance and lipid accumulation through the regulation of hepatic lipid metabolizing and lipid-regulating enzymes
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-11
    Chinnadurai Veeramani, Mohammed A. Alsaif, Khalid S. Al-Numair

    Healthy plants and their constituents have been considered as a safe remedy for the treatment of obesity and obesity associated diseases. Herbacetin is a dietary flavonoid that has been explored for many pharmacological activities; but, the anti-hyperglycaemic and anti-hyperlipidemic properties of herbacetin have not yet been explored. The present study was performed to evaluate the ameliorative effect of herbacetin on high-fat diet-induced hyperglycaemia and hyperlipidemia in 57BL/6 J mice. Obesity associated insulin resistance was induced by continuously feeding the mice with high-fat diet for 10 weeks. Afterwards, mice were subjected to intragastric administration of herbacetin (different doses) daily along with high-fat diet for the next 5 weeks. At the end of 106th day, changes in body weight, blood glucose, insulin, HOMA-IR, and lipids profiles and lipid-regulating enzymes were evaluated. Herbacetin significantly reduced the body weight, plasma glucose, plasma insulin, and HOMA-IR activity in obesity associated insulin resistant mice (OIR). In addition, herbacetin administration significantly reduced the plasma and hepatic total cholesterol, triglycerides, and free fatty acids in OIR mice. Moreover, herbacetin significantly improved the altered hepatic lipid metabolizing and lipid-regulating enzymes such as SREBP-1c, and 2, fatty acid synthase (FAS), fatty acid β-oxidation (β-oxidation), malic enzyme, glucose 6-phosphate dehydrogenase (G6PD), and carnitine palmitoyltransferase (CPT) when compared to OIR control mice. Histopathological examination clearly showed that herbacetin decreases lipid droplets in the liver tissue. Thus, observed results strongly indicate that herbacetin provides remarkable protection against the harmful effects of chronic high-fat diet consumption because of its anti-hyperglycaemic and anti-hyperlipidemic properties through the regulation of hepatic lipid metabolizing and lipid-regulating enzymes.

  • Procyanidin from peanut skin induces antiproliferative effect in human prostate carcinoma cells DU145
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-11
    Liang Chen, Fangfang Yan, Wanbing Chen, Li Zhao, Jiuliang Zhang, Qun Lu, Rui Liu

    In this study, the antiproliferative activity of peanut skin procyanidins (PSP) and six fractions (PSP-1∼6) isolated from PSP by several chromatographic steps on the human prostate cancer DU145 cells were evaluated. The results showed that PSP and PSP-1∼6 significantly inhibited the proliferation of DU145 cells. PSP-2 was the most effective fraction, which was identified as procyanidin B3 mainly and procyanidin dimer [(E)C-luteolin or keampferol] secondarily. Moreover, the mechanism of antiproliferative activity of PSP-2 was investigated. It was observed that PSP-2 induced apoptotic cell death and cell cycle arrest at S phase in DU145 cells. PSP-2 caused the increase of intracellular ROS level and the decrease of Bcl-2/Bax ratio, and triggered the activation of p53 and caspases-3 in DU145 cells. Our findings demonstrated that procyanidins from peanut skin have the potential to be developed as an anti-prostate cancer agent.

  • Vitamin D nanoemulsion enhances hapatoprotective effect of conventional vitamin D in rats fed with a high-fat diet
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-11
    Mohamed El-Sherbiny, Mohamed Eldosoky, Mohamed El-Shafey, Gamal Othman, Hany A. Elkattawy, Tamer Bedir, Nehal Mohsen Elsherbiny

    Background Non-alcoholic fatty liver disease (NAFLD) is associated with hyperlipidemia, obesity and type II diabetes. Due to increasing prevalence of these diseases globally, NAFLD is considered as a common form of chronic liver diseases. Vitamin D is a fat soluble vitamin with reported anti-inflammatory, anti-oxidant and immune modulating activity. Hypovitaminosis D often coexists with NAFLD and various studies reported beneficial role of vitamin D in modulating NAFLD. However, variable oral bioavailability, poor water solubility, and chemical degradation hinder the clinical application of vitamin D. Purpose We evaluated the potential protective effect of Vitamin D nanoemulsion (developed by sonication and pH-Shifting of pea protein isolate and canola oil) compared to conventional vitamin D against liver injury in rats fed with high fat diet (HFD). Methods We analyzed liver function enzymes, lipid profile, lipid metabolism, levels and histopathology of inflammation and fibrosis in rat liver tissues. Results HFD fed rats exhibited deterioration of liver function, poor lipid profile, decreased fatty acid oxidation and up-regulation of inflammatory cytokines and extracellular matrix deposition. Vitamin D administration reduced elevated liver enzymes, improved lipid profile, enhanced fatty acid oxidation and attenuated liver inflammation and fibrosis. Interestingly, vitamin D nanoemulsion was superior to conventional vitamin D with remarkable hepatoprotective effect against HFD-induced liver injury. Conclusion This study demonstrated vitamin D nanoemulsion as a more efficient formulation with more prominent hepatoprotective effect against HFD-induced liver injury compared to conventional oral vitamin D.

  • Aldose reductase inhibitor protects mice from alcoholic steatosis by repressing saturated fatty acid biosynthesis
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-06
    Chang Guo, Lizhu chen, Jie Huang, Yuanfang Wang, Changxuan Shi, Jing Gao, Yannv Hong, Tong Chen, Longxin Qiu

    Alcoholic liver injury results in morbidity and mortality worldwide, but there are currently no effective and safe therapeutics. Previously we demonstrated that aldose reductase (AR) inhibitor ameliorated alcoholic hepatic steatosis. To clarify the mechanism whereby AR inhibitor improves alcoholic hepatic steatosis, herein we investigated the effect of AR inhibitor on hepatic metabolism in mice fed a Lieber-DeCarli liquid diet with 5% ethanol. Nontargeted metabolomics showed carbohydrates and lipids were characteristic categories in ethanol diet-fed mice with or without AR inhibitor treatment, whereas AR inhibitor mainly affected carbohydrates and amino acids. Ethanol-induced galactose metabolism and fatty acid biosynthesis are important for the induction of hepatic steatosis, while AR inhibitor impaired galactose metabolism without perturbing fatty acid biosynthesis. In parallel with successful treatment of steatosis, AR inhibitor suppressed ethanol-activated galactose metabolism and saturated fatty acid biosynthesis. Sorbitol in galactose metabolism and stearic acid in saturated fatty acid biosynthesis were potential biomarkers responsible for ethanol or ethanol plus AR inhibitor treatment. In vitro analysis confirmed that exogenous addition of sorbitol augmented ethanol-induced steatosis and stearic acid. These findings not only reveal metabolic patterns associated with disease and treatment, but also shed light on functional biomarkers contribute to AR inhibition therapy.

  • 3-Chloro-4,5-dihydroxybenzaldehyde inhibits adipogenesis in 3T3-L1 adipocytes by regulating expression of adipogenic transcription factors and AMPK activation
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-06
    Min-Cheol Kang, Yuling Ding, Junseong Kim, Eun-A Kim, I.P. Shanura Fernando, Soo-Jin Heo, Seung-Hong Lee

    Obesity is a serious health issue in many industrialized countries. It is a medical condition with excessive levels of fat accumulated in adipocytes. The objective of the present study was to determine the inhibitory effect of 3-chloro-4,5-dihydroxybenzaldehyde (CDB) on adipogenesis in 3T3-L1 adipocyte cells. CDB suppressed the differentiation and decreased lipid accumulation and triglycerides contents in 3T3-L1 adipocytes. Its suppression effect on fat accumulation was mediated via expression of adipogenesis factors (C/EBPα, SREBP-1c, PPARγ, and adiponectin) during adipocyte differentiation in white adipocyte cells. CDB's ability to suppress fat accumulation was increased in a concentration-dependent manner. It inhibited fatty acid synthesis related proteins including FAS, FABP4, leptin, and perilipin. It also increased expression of phosphorylated AMPK in adipocytes cells. These observations suggest that CDB has potential anti-obesity effect with ability to improve metabolic diseases.

  • 3′-Hydroxy-3,4′-dimethoxyflavone-induced cell death in human leukaemia cells is dependent on caspases and reactive oxygen species and attenuated by the inhibition of JNK/SAPK
    Chem. Biol. Interact. (IF 3.143) Pub Date : 2018-04-06
    Francisco Estévez-Sarmiento, Elisa Hernández, Ignacio Brouard, Francisco León, Celina García, José Quintana, Francisco Estévez

    Flavonoids are phenolic substances that appear to exert beneficial effects in several chronic diseases, including cancer. Structure-activity relationships of the cytotoxic activity of a series of flavonols and their 3-methyl ether derivatives established that 3′-hydroxy-3,4′-dimethoxyflavone (flavonoid 11) displayed strong cytotoxicity against human leukaemia cell lines (HL-60, U-937 and MOLT-3), and cells that over-express the anti-apoptotic proteins, Bcl-2 and Bcl-xL, and against P-glycoprotein-overexpressing K-562/ADR cells. This compound induced G2-M cell cycle arrest and it was a potent apoptotic inducer on HL-60, MOLT-3, U-937 and U-937/Bcl-2 cell lines. Cell death was (i) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD-fmk and reduced by a selective caspase-9 inhibitor, (ii) associated with cytochrome c release, the dissipation of the inner mitochondrial membrane potential (ΔΨm) and the activation of the mitogen-activated protein kinase pathway and (iii) partially blocked by the inhibition of c-jun NH2 terminal kinases/stress activated protein kinases (JNK/SAPK) signalling and by the free-radical scavenger N-acetyl-l-cysteine.

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.
化学 • 材料 期刊列表