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Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 January 2016) | Viewed by 91139

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Special Issue Editor

Prof. Dr. Paul B. Tchounwou

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RCMI Center for Urban Health Disparities Research and Innovation, Richard Dixon Research Center, Morgan State University, 1700 E. Cold Spring Lane, Baltimore, MD 21251, USA
Interests: environmental health and diseases; gene-environment interactions; environmental toxicology, mutagenesis and carcinogenesis; environmental epidemiology and disease control; health risk assessment and management; ecological risk assessment and management; environmental chemistry and computational toxicology; environmental genomics and proteomics; environmental medicine; and natural resources damage assessment and management
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Dear Colleagues,

Acute and/or chronic exposure to many environmental compounds and chemotherapeutic drugs has been associated with significant adverse effects in humans and experimental animals. A comprehensive analysis of published data indicates that such exposure induces toxicity to many organs and tissues, including the cardiovascular, hepatic, excretory, developmental, nervous, respiratory, dermatological, digestive, hematologic, muscular, and/or reproductive systems; these effects depend on the type and species of chemical, exposure dose, frequency and route, age, gender, nutritional status, and genetic make-up. For many of these chemicals, both epidemiological studies and experimental investigations have demonstrated strong correlations between exposure and the increase in cancer incidence. Although scientific advances have significantly contributed to our understanding of specific, chemically-induced disease end-points, the detailed molecular and cellular mechanisms of toxicity and carcinogenesis are not fully elucidated. Understanding the basic and underlying mechanisms of xenobiotic-induced toxicity and carcinogenesis at the cellular and molecular levels is essential for identifying new targets and developing new therapeutic strategies for disease prevention and control. This Special Issue will focus on the publication of novel research on the mechanisms of chemical toxicity and carcinogenesis. Both original manuscripts and critical reviews examining the cellular, molecular, genetic, immunologic, necrotic, apoptotic, and/or signal transduction mechanisms involved in the toxico-pathological or pharmacological effects of xenobiotic compounds on various organ systems and tissues, are welcome.

Prof. Dr. Paul B. Tchounwou
Guest Editor

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Keywords

Molecular toxicology, carcinogenesis, therapeutics
Biomarkers of chemical exposure, susceptibility and effect
Oxidative stress biomarkers, transcription factors
Apoptosis and/or necrosis mechanisms
Cancer induction and cancer treatment
Cellular signaling and gene expression
Cellular metabolism and chemical biotransformation

Published Papers (14 papers)

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Research

7870 KiB

Open AccessArticle

Toxicity of Pekinenin C from Euphorbia Pekinensis Radix on Rat Small Intestinal Crypt Epithelial Cell and Its Apoptotic Mechanism

by Yudan Cao, Fangfang Cheng, Weifeng Yao, Beihua Bao, Kaicheng Zhang, Li Zhang and Anwei Ding

Int. J. Mol. Sci. 2016, 17(6), 850; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17060850 - 02 Jun 2016

Cited by 19 | Viewed by 6050

Abstract

Pekinenin C is a casbane diterpenoid separated from the root of the traditional Chinese medicine, Euphorbia pekinensis Rupr., which is used as drug for the treatment of edema, ascites, and hydrothorax. Whereas pekinenin C exhibits severe cytotoxicity, the exact toxicity mechanism is unclear. In this study, the effects of pekinenin C on cell inhibition, cell cycle, and cell apoptosis were examined to explain its toxic mechanism. The proliferation of IEC-6 cells was accessed via MTT colorimetric assay after incubated with different concentrations of pekinenin C. Pekinenin C-treated IEC-6 cells labeled with RNase/PI and Annexin V/PI were analyzed by flow cytometric analyses for evaluation of cell cycle distribution and cell apoptosis, respectively. The apoptosis mechanism of pekinenin C on IEC-6 was investigated through assaying the activities of caspase-3, 8, 9 by enzyme-linked immunosorbent assay (ELISA), protein expression of Bax, Bcl-2, apoptosis-inducing factor (AIF), Apaf-1, Fas-associated death domain (FADD) and type 1-associated death domain (TRADD) by Western-blot, mRNA expression of Fas receptor (FasR), Fas ligand (FasL), tumor necrosis factor receptor (TNFR1) and NF-κB by RT-PCR. The results showed that pekinenin C has exhibited obvious IEC-6 cells toxicity and the IC₅₀ value was 2.1 μg·mL⁻¹. Typical apoptosis characteristics were observed under a transmission electron microscopy, and it was found that pekinenin C could cause G0/G1 phase arrest in IEC-6 cells in a dose-dependent manner and induce apoptosis of IEC-6 cells. Additionally, pekinenin C could increase the expressions of Bax, AIF, Apaf-1, FasR, FasL, TNFR1 and NF-κB, suppress the expression of Bcl-2, FADD and TRADD, then activate caspase-3, 8, 9 cascades, and at last result in apoptosis. These results demonstrated that pekinenin C effectively promoted cell apoptosis, and induced IEC-6 cells apoptosis through both the mitochondrial and death receptor pathways. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Rapid Diminution in the Level and Activity of DNA-Dependent Protein Kinase in Cancer Cells by a Reactive Nitro-Benzoxadiazole Compound

by Viviane A. O. Silva, Florian Lafont, Houda Benhelli-Mokrani, Magali Le Breton, Philippe Hulin, Thomas Chabot, François Paris, Vehary Sakanyan and Fabrice Fleury

Int. J. Mol. Sci. 2016, 17(5), 703; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17050703 - 11 May 2016

Cited by 13 | Viewed by 5325

Abstract

The expression and activity of DNA-dependent protein kinase (DNA-PK) is related to DNA repair status in the response of cells to exogenous and endogenous factors. Recent studies indicate that Epidermal Growth Factor Receptor (EGFR) is involved in modulating DNA-PK. It has been shown that a compound 4-nitro-7-[(1-oxidopyridin-2-yl)sulfanyl]-2,1,3-benzoxadiazole (NSC), bearing a nitro-benzoxadiazole (NBD) scaffold, enhances tyrosine phosphorylation of EGFR and triggers downstream signaling pathways. Here, we studied the behavior of DNA-PK and other DNA repair proteins in prostate cancer cells exposed to compound NSC. We showed that both the expression and activity of DNA-PKcs (catalytic subunit of DNA-PK) rapidly decreased upon exposure of cells to the compound. The decline in DNA-PKcs was associated with enhanced protein ubiquitination, indicating the activation of cellular proteasome. However, pretreatment of cells with thioglycerol abolished the action of compound NSC and restored the level of DNA-PKcs. Moreover, the decreased level of DNA-PKcs was associated with the production of intracellular hydrogen peroxide by stable dimeric forms of Cu/Zn SOD1 induced by NSC. Our findings indicate that reactive oxygen species and electrophilic intermediates, generated and accumulated during the redox transformation of NBD compounds, are primarily responsible for the rapid modulation of DNA-PKcs functions in cancer cells. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Autophagic Cell Death and Apoptosis Jointly Mediate Cisatracurium Besylate-Induced Cell Injury

by Haixia Zhuang, Weili Tian, Wen Li, Xingli Zhang, Jingjing Wang, Yue Yang, Xin Liu, Zhengyuan Xia, Du Feng and Liangqing Zhang

Int. J. Mol. Sci. 2016, 17(4), 515; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17040515 - 06 Apr 2016

Cited by 6 | Viewed by 7049

Abstract

Cisatracurium besylate is an ideal non-depolarizing muscle relaxant which is widely used in clinical application. However, some studies have suggested that cisatracurium besylate can affect cell proliferation. Moreover, its specific mechanism of action remains unclear. Here, we found that the number of GFP-LC3 (green fluoresent protein-light chain 3) positive autophagosomes and the rate of mitochondria fracture both increased significantly in drug-treated GFP-LC3 and MitoDsRed stable HeLa cells. Moreover, cisatracurium promoted the co-localization of LC3 and mitochondria and induced formation of autolysosomes. Levels of mitochondrial proteins decreased, which were reversed by the lysosome inhibitor Bafinomycin A1. Similar results with evidence of dose-dependent effects were found in both HeLa and Human Umbilical Vein Endothelial Cells (HUVECs). Cisatracurium lowered HUVEC viability to 0.16 (OD490) at 100 µM and to 0.05 (OD490) after 48 h in vitro; it increased the cell death rate to 56% at 100 µM and to 60% after 24 h in a concentration- and time-dependent manner (p < 0.01). Cell proliferation decreased significantly by four fold in Atg5 WT (wildtype) MEF (mouse embryonic fibroblast) (p < 0.01) but was unaffected in Atg5 KO (Knockout) MEF, even upon treatment with a high dose of cisatracurium. Cisatracurium induced significant increase in cell death of wild-type MEFs even in the presence of the apoptosis inhibitor zVAD. Thus, we conclude that activation of both the autophagic cell death and cell apoptosis pathways contributes to cisatracurium-mediated cell injury. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Arsenite Regulates Prolongation of Glycan Residues of Membrane Glycoprotein: A Pivotal Study via Wax Physisorption Kinetics and FTIR Imaging

by Chih-Hung Lee, Chia-Yen Hsu, Pei-Yu Huang, Ching-Iue Chen, Yao-Chang Lee and Hsin-Su Yu

Int. J. Mol. Sci. 2016, 17(3), 427; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030427 - 22 Mar 2016

Cited by 6 | Viewed by 5912

Abstract

Arsenic exposure results in several human cancers, including those of the skin, lung, and bladder. As skin cancers are the most common form, epidermal keratinocytes (KC) are the main target of arsenic exposure. The mechanisms by which arsenic induces carcinogenesis remains unclear, but aberrant cell proliferation and dysregulated energy homeostasis play a significant role. Protein glycosylation is involved in many key physiological processes, including cell proliferation and differentiation. To evaluate whether arsenite exposure affected protein glycosylation, the alteration of chain length of glycan residues in arsenite treated skin cells was estimated. Herein we demonstrated that the protein glycosylation was adenosine triphosphate (ATP)-dependent and regulated by arsenite exposure by using Fourier transform infrared (FTIR) reflectance spectroscopy, synchrotron-radiation-based FTIR (SR-FTIR) microspectroscopy, and wax physisorption kinetics coupled with focal-plane-array-based FTIR (WPK-FPA-FTIR) imaging. We were able to estimate the relative length of surface protein-linked glycan residues on arsenite-treated skin cells, including primary KC and two skin cancer cell lines, HSC-1 and HaCaT cells. Differential physisorption of wax adsorbents adhered to long-chain (elongated type) and short-chain (regular type) glycan residues of glycoprotein of skin cell samples treated with various concentration of arsenite was measured. The physisorption ratio of beeswax remain/n-pentacosane remain for KC cells was increased during arsenite exposure. Interestingly, this increase was reversed after oligomycin (an ATP synthase inhibitor) pretreatment, suggesting the chain length of protein-linked glycan residues is likely ATP-dependent. This is the first study to demonstrate the elongation and termination of surface protein-linked glycan residues using WPK-FPA-FTIR imaging in eukaryotes. Herein the result may provide a scientific basis to target surface protein-linked glycan residues in the process of arsenic carcinogenesis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Effects of Two Sublethal Concentrations of Mercury Chloride on the Morphology and Metallothionein Activity in the Liver of Zebrafish (Danio rerio)

by Rachele Macirella, Antonello Guardia, Daniela Pellegrino, Ilaria Bernabò, Valentina Tronci, Lars O. E. Ebbesson, Settimio Sesti, Sandro Tripepi and Elvira Brunelli

Int. J. Mol. Sci. 2016, 17(3), 361; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030361 - 11 Mar 2016

Cited by 36 | Viewed by 7447

Abstract

Mercury (Hg) is a highly hazardous pollutant widely used in industrial, pharmaceutical and agricultural fields. Mercury is found in the environment in several forms, elemental, inorganic (iHg) and organic, all of which are toxic. Considering that the liver is the organ primarily involved in the regulation of metabolic pathways, homeostasis and detoxification we investigated the morphological and ultrastructural effects in Danio rerio liver after 96 h exposure to two low HgCl₂ concentrations (7.7 and 38.5 μg/L). We showed that a short-term exposure to very low concentrations of iHg severely affects liver morphology and ultrastructure. The main effects recorded in this work were: cytoplasm vacuolization, decrease in both lipid droplets and glycogen granules, increase in number of mitochondria, increase of rough endoplasmic reticulum and pyknotic nuclei. Pathological alterations observed were dose dependent. Trough immunohistochemistry, in situ hybridization and real-time PCR analysis, the induction of metallothionein (MT) under stressor conditions was also evaluated. Some of observed alterations could be considered as a general response of tissue to heavy metals, whereas others (such as increased number of mitochondria and increase of RER) may be considered as an adaptive response to mercury. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Gleditsia sinensis Thorn Attenuates the Collagen-Based Migration of PC3 Prostate Cancer Cells through the Suppression of α2β1 Integrin Expression

by Sujin Ryu, Ki Moon Park and Seung Ho Lee

Int. J. Mol. Sci. 2016, 17(3), 328; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17030328 - 02 Mar 2016

Cited by 21 | Viewed by 6690

Abstract

Gleditsia sinensis thorns (GST) have been used as a traditional medicine for carbuncles and skin diseases. The purpose of this study was to decide whether non-toxicological levels of water extract of GST (WEGST) are effective in inhibiting the progress of prostate cancer formation and to identify the target molecule involved in the WEGST-mediated inhibitory process of prostate cancer cell migration and in vivo tumor formation. Through the Boyden chamber migration assay, we found that non-toxic levels of WEGST could not attenuate the PC3 migration to the bottom area coated with serum but significantly inhibited PC3 cell migration to the collagen-coated bottom area. We also found that non-toxic levels of WEGST significantly attenuated collagen against adhesion. Interestingly, ectopic administration of WEGST could not affect the expression of α2β1 integrin, which is known as a receptor of collagen. However, when the PC3 cells adhered to a collagen-coated plate, the expression of α2 integrin but not that of β1 integrin was significantly inhibited by the administration of non-toxic levels of WEGST, leading to the inhibition of focal adhesion kinase (FAK) phosphorylation. Furthermore, oral administration of WEGST (25 mg/kg/day) significantly inhibited the size of a PC3 cell-xenografted tumor. Taken together, these results suggest a novel molecular mechanism for WEGST to inhibit prostate cancer progression at particular stages, such as collagen-mediated adhesion and migration, and it might provide further development for the therapeutic use of WEGST in the treatment of prostate cancer progression. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Therapeutic Effect of Losartan, an Angiotensin II Type 1 Receptor Antagonist, on CCl₄-Induced Skeletal Muscle Injury

by Ok-Kyung Hwang, Jin-Kyu Park, Eun-Joo Lee, Eun-Mi Lee, Ah-Young Kim and Kyu-Shik Jeong

Int. J. Mol. Sci. 2016, 17(2), 227; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020227 - 08 Feb 2016

Cited by 15 | Viewed by 6457

Abstract

TGF-β1 is known to inhibit muscle regeneration after muscle injury. However, it is unknown if high systemic levels of TGF-β can affect the muscle regeneration process. In the present study, we demonstrated the effect of a CCl₄ intra-peritoneal injection and losartan (an angiotensin II type 1 receptor antagonist) on skeletal muscle (gastrocnemius muscle) injury and regeneration. Male C57BL/6 mice were grouped randomly as follows: control (n = 7), CCl₄-treatment group (n = 7), and CCl₄ + losartan treatment group (n = 7). After CCl₄ treatment for a 16-week period, the animals were sacrificed and analyzed. The expression of dystrophin significantly decreased in the muscle tissues of the control group, as compared with that of the CCl₄ + losartan group (p < 0.01). p(phospho)-Smad2/3 expression significantly increased in the muscles of the control group compared to that in the CCl₄ + losartan group (p < 0.01). The expressions of Pax7, MyoD, and myogenin increased in skeletal muscles of the CCl₄ + losartan group compared to the corresponding levels in the control group (p < 0.01). We hypothesize that systemically elevated TGF-β1 as a result of CCl₄-induced liver injury causes skeletal muscle injury, while losartan promotes muscle repair from injury via blockade of TGF-β1 signaling. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Liensinine- and Neferine-Induced Cardiotoxicity in Primary Neonatal Rat Cardiomyocytes and Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

by Yangyang Yu, Shennan Sun, Shifeng Wang, Qiao Zhang, Ming Li, Feng Lan, Shiyou Li and Chunsheng Liu

Int. J. Mol. Sci. 2016, 17(2), 186; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020186 - 29 Jan 2016

Cited by 33 | Viewed by 6056

Abstract

Due to drug-induced potential congestive heart failure and irreversible dilated cardiomyopathies, preclinical evaluation of cardiac dysfunction is important to assess the safety of traditional or novel treatments. The embryos of Nelumbo nucifera Gaertner seeds are a homology of traditional Chinese medicine and food. In this study, we applied the real time cellular analysis (RTCA) Cardio system, which can real-time monitor the contractility of cardiomyocytes (CMs), to evaluate drug safety in rat neonatal CMs and human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). This study showed detailed biomechanical CM contractility in vitro, and provided insights into the cardiac dysfunctions associated with liensinine and neferine treatment. These effects exhibited dose and time-dependent recovery. Neferine showed stronger blocking effect in rat neonatal CMs than liensinine. In addition, the effects of liensinine and neferine were further evaluated on hiPS-CMs. Our study also indicated that both liensinine and neferine can cause disruption of calcium homeostasis. For the first time, we demonstrated the potential cardiac side effects of liensinine or neferine. While the same inhibition was observed on hiPS-CMs, more importantly, this study introduced an efficient and effective approach to evaluate the cardiotoxicity of the existing and novel drug candidates. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Subchronic Exposure to Arsenic Represses the TH/TRβ1-CaMK IV Signaling Pathway in Mouse Cerebellum

by Huai Guan, Shuangyue Li, Yanjie Guo, Xiaofeng Liu, Yi Yang, Jinqiu Guo, Sheng Li, Cong Zhang, Lixin Shang and Fengyuan Piao

Int. J. Mol. Sci. 2016, 17(2), 157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17020157 - 26 Jan 2016

Cited by 12 | Viewed by 5267

Abstract

We previously reported that arsenic (As) impaired learning and memory by down-regulating calmodulin-dependent protein kinase IV (CaMK IV) in mouse cerebellum. It has been documented that the thyroid hormone receptor (TR)/retinoid X receptor (RXR) heterodimer and thyroid hormone (TH) may be involved in the regulation of CaMK IV. To investigate whether As affects the TR/RXR heterodimer and TH, we determined As concentration in serum and cerebellum, 3,5,3’-triiodothyronine (T3) and thyroxin (T4) levels in serum, and expression of CaMK IV, TR and RXR in cerebellum of mice exposed to As. Cognition function was examined by the step-down passive avoidance task and Morris water maze (MWM) tests. Morphology of the cerebellum was observed by Hematoxylin-Eosin staining under light microscope. Our results showed that the concentrations of As in the serum and cerebellum of mice both increased with increasing As-exposure level. A significant positive correlation was found between the two processes. Adeficit in learning and memory was found in the exposed mice. Abnormal morphologic changes of Purkinje cells were observed in cerebellum of the exposed mice. Moreover, the cerebellar expressions of CaMK IV protein and the TRβ gene, and TRβ1 protein were significantly lower in As-exposed mice than those in controls. Subchronic exposure to As appears to increase its level in serum and cerebella of mice, impairing learning and memory and down-regulating expression of TRβ1 as well as down-stream CaMK IV. It is also suggested that the increased As may be responsible for down-regulation of TRβ1 and CaMK IV in cerebellum and that the down-regulated TRβ1 may be involved in As-induced impairment of learning and memory via inhibiting CaMK IV and its down-stream pathway. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer

by Deodutta Roy, Marisa Morgan, Changwon Yoo, Alok Deoraj, Sandhya Roy, Vijay Kumar Yadav, Mohannad Garoub, Hamza Assaggaf and Mayur Doke

Int. J. Mol. Sci. 2015, 16(10), 25285-25322; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms161025285 - 23 Oct 2015

Cited by 48 | Viewed by 8707

Abstract

We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Lead Poisoning Disturbs Oligodendrocytes Differentiation Involved in Decreased Expression of NCX3 Inducing Intracellular Calcium Overload

by Teng Ma, Xiyan Wu, Qiyan Cai, Yun Wang, Lan Xiao, Yanping Tian and Hongli Li

Int. J. Mol. Sci. 2015, 16(8), 19096-19110; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160819096 - 13 Aug 2015

Cited by 19 | Viewed by 5345

Abstract

Lead (Pb) poisoning has always been a serious health concern, as it permanently damages the central nervous system. Chronic Pb accumulation in the human body disturbs oligodendrocytes (OLs) differentiation, resulting in dysmyelination, but the molecular mechanism remains unknown. In this study, Pb at 1 μM inhibits OLs precursor cells (OPCs) differentiation via decreasing the expression of Olig 2, CNPase proteins in vitro. Moreover, Pb treatment inhibits the sodium/calcium exchanger 3 (NCX3) mRNA expression, one of the major means of calcium (Ca²⁺) extrusion at the plasma membrane during OPCs differentiation. Also addition of KB-R7943, NCX3 inhibitor, to simulate Pb toxicity, resulted in decreased myelin basic protein (MBP) expression and cell branching. Ca²⁺ response trace with Pb and KB-R7943 treatment did not drop down in the same recovery time as the control, which elevated intracellular Ca²⁺ concentration reducing MBP expression. In contrast, over-expression of NCX3 in Pb exposed OPCs displayed significant increase MBP fluorescence signal in positive regions and CNPase expression, which recovered OPCs differentiation to counterbalance Pb toxicity. In conclusion, Pb exposure disturbs OLs differentiation via affecting the function of NCX3 by inducing intracellular calcium overload. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Novel Radiolytic Rotenone Derivative, Rotenoisin B with Potent Anti-Carcinogenic Activity in Hepatic Cancer Cells

by Srilatha Badaboina, Hyoung-Woo Bai, Yun Hee Na, Chul-Hong Park, Tae Hoon Kim, Tae-Hoon Lee and Byung Yeoup Chung

Int. J. Mol. Sci. 2015, 16(8), 16806-16815; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160816806 - 24 Jul 2015

Cited by 18 | Viewed by 5723

Abstract

Rotenone, isolated from roots of derris plant, has been shown to possess various biological activities, which lead to attempting to develop a potent drug against several diseases. However, recent studies have demonstrated that rotenone has the potential to induce several adverse effects such as a neurodegenerative disease. Radiolytic transformation of the rotenone with gamma-irradiation created a new product, named rotenoisin B. The present work was designed to investigate the anticancer activity of rotenoisin B with low toxicity and its molecular mechanism in hepatic cancer cells compared to a parent compound, rotenone. Our results showed rotenoisin B inhibited hepatic cancer cells’ proliferation in a dose dependent manner and increased in apoptotic cells. Interestingly, rotenoisin B showed low toxic effects on normal cells compared to rotenone. Mitochondrial transmembrane potential has been decreased, which leads to cytochrome c release. Down regulation of anti-apoptotic Bcl-2 levels as well as the up regulation of proapoptotic Bax levels were observed. The cleaved PARP (poly ADP-ribose polymerase) level increased as well. Moreover, phosphorylation of extracellular signal regulated kinase (ERK) and p38 slightly up regulated and intracellular reactive oxygen species (ROS) increased as well as cell cycle arrest predominantly at the G₂/M phase observed. These results suggest that rotenoisin B might be a potent anticancer candidate similar to rotenone in hepatic cancer cells with low toxicity to normal cells even at high concentrations compared to rotenone. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Baicalin Protects Mice from Aristolochic Acid I-Induced Kidney Injury by Induction of CYP1A through the Aromatic Hydrocarbon Receptor

by Ke Wang, Chenchen Feng, Chenggang Li, Jun Yao, Xiaofeng Xie, Likun Gong, Yang Luan, Guozhen Xing, Xue Zhu, Xinming Qi and Jin Ren

Int. J. Mol. Sci. 2015, 16(7), 16454-16468; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160716454 - 20 Jul 2015

Cited by 25 | Viewed by 7125

Abstract

Exposure to aristolochic acid I (AAI) can lead to aristolochic acid nephropathy (AAN), Balkan endemic nephropathy (BEN) and urothelial cancer. The induction of hepatic CYP1A, especially CYP1A2, was considered to detoxify AAI so as to reduce its nephrotoxicity. We previously found that baicalin had the strong ability to induce CYP1A2 expression; therefore in this study, we examined the effects of baicalin on AAI toxicity, metabolism and disposition, as well as investigated the underlying mechanisms. Our toxicological studies showed that baicalin reduced the levels of blood urea nitrogen (BUN) and creatinine (CRE) in AAI-treated mice and attenuated renal injury induced by AAI. Pharmacokinetic analysis demonstrated that baicalin markedly decreased AUC of AAI in plasma and the content of AAI in liver and kidney. CYP1A induction assays showed that baicalin exposure significantly increased the hepatic expression of CYP1A1/2, which was completely abolished by inhibitors of the Aromatic hydrocarbon receptor (AhR), 3ʹ,4ʹ-dimethoxyflavone and resveratrol, in vitro and in vivo, respectively. Moreover, the luciferase assays revealed that baicalin significantly increased the luciferase activity of the reporter gene incorporated with the Xenobiotic response elements recognized by AhR. In summary, baicalin significantly reduced the disposition of AAI and ameliorated AAI-induced kidney toxicity through AhR-dependent CYP1A1/2 induction in the liver. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle

Aminomethylphosphonic Acid and Methoxyacetic Acid Induce Apoptosis in Prostate Cancer Cells

by Keshab R. Parajuli, Qiuyang Zhang, Sen Liu and Zongbing You

Int. J. Mol. Sci. 2015, 16(5), 11750-11765; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160511750 - 22 May 2015

Cited by 9 | Viewed by 6561

Abstract

Aminomethylphosphonic acid (AMPA) and its parent compound herbicide glyphosate are analogs to glycine, which have been reported to inhibit proliferation and promote apoptosis of cancer cells, but not normal cells. Methoxyacetic acid (MAA) is the active metabolite of ester phthalates widely used in industry as gelling, viscosity and stabilizer; its exposure is associated with developmental and reproductive toxicities in both rodents and humans. MAA has been reported to suppress prostate cancer cell growth by inducing growth arrest and apoptosis. However, it is unknown whether AMPA and MAA can inhibit cancer cell growth. In this study, we found that AMPA and MAA inhibited cell growth in prostate cancer cell lines (LNCaP, C4-2B, PC-3 and DU-145) through induction of apoptosis and cell cycle arrest at the G1 phase. Importantly, the AMPA-induced apoptosis was potentiated with the addition of MAA, which was due to downregulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2), leading to activation of caspases 7 and 3. These results demonstrate that the combination of AMPA and MAA can promote the apoptosis of prostate cancer cells, suggesting that they can be used as potential therapeutic drugs in the treatment of prostate cancer. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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