Begell House Inc.
Journal of Environmental Pathology, Toxicology and Oncology
JEP(T)
0731-8898
38
1
2019
Mangiferin Attenuated Diethynitrosamine-Induced Hepatocellular Carcinoma in Sprague-Dawley Rats via Alteration of Oxidative Stress and Apoptotic Pathway
1-12
10.1615/JEnvironPatholToxicolOncol.2018027392
Guang
Yang
The First Hospital of Jilin University Cancer Center, Changchun City, Jilin Province, China
Xiao
Shang
The First Hospital of Jilin University Cancer Center, Changchun City, Jilin Province, China
Guozhen
Cui
The First Hospital of Jilin University Cancer Center, Changchun City, Jilin Province, China
Lingling
Zhao
The First Hospital of Jilin University Cancer Center, Changchun City, Jilin Province, China
Hengjun
Zhao
The First Hospital of Jilin University Cancer Center, Changchun City, Jilin Province, China
Nanya
Wang
The First Hospital of Jilin University Cancer Center, Changchun City, Jilin Province, China
liver cancer
DEN
mangiferin
oxidative stress
tumor markers
apoptosis
Liver cancer is the fifth commonly occurring cancer worldwide with the annual death rate of 9.1%. Hepatocellular carcinoma is the most frequent kind of primary liver cancer and occurs mostly in patients with chronic liver disease and cirrhosis. Because the cancer is generally detected only in the later stages, it is often treated with therapies such as radiation, ablation, and chemotherapy, which produces serious side effects and has a low recovery rate. Therefore, researchers are now focused on herbal-based drugs with increased efficacy and with no side effects to treat cancer. One such drug is mangiferin, a xanthanoid possessing augmented antioxidant, anti-inflammatory, and antidiabetic properties. The present study investigated the anticarcinogenic property of mangiferin against DEN-induced hepatocellular carcinoma. Hepatocellular carcinoma was induced in healthy Sprague-Dawley rats by treating them with 0.01% diethylnitrosamine (DEN) in the drinking water for 12 weeks, followed by 50 mg of mangiferin for a period of 8 weeks. Biochemical, oxidative
stress markers, antioxidant status, and tumor marker level in the DEN- and DEN + mangiferin-treated rats liver were assessed to detect the efficacy of mangiferin in inhibiting cancer induction. The anticarcinogenic property of mangiferin was confirmed by evaluating the apoptotic protein expression and histological analysis of liver tissue from DEN- and DEN + mangiferin-treated rats. Our results show that mangiferin possesess anticarcinogenic properties against DEN-induced hepatocellular carcinoma. We predict that further investigation will reveal mangiferin as a potent drug to treat liver cancer.
Autophagy is Required to Regulate Mitochondria Renewal, Cell Attachment, and All-trans–Retinoic Acid–Induced Differentiation in NB4 Acute Promyelocytic Leukemia Cells
13-20
10.1615/JEnvironPatholToxicolOncol.2018027885
Ibrahim
Tekedereli
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Ugur
Akar
Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
S. Neslihan
Alpay
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Gabriel
Lopez-Berestein
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Bulent
Ozpolat
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX
acute promyelocytic leukemia
NB4
ATRA
differentiation
TG2
LC3
ATG5
All-trans–retinoic acid (ATRA) is a potent inducer of cellular differentiation, growth arrest, and apoptosis as well as a front-line therapy for acute promyelocytic leukemia (APL). The present study provides evidence that induction of autophagy is required for ATRA to induce differentiation of APL (NB4) cells into granulocytes. ATRA treatment causes ~12-fold increase in the number of acidic vesicular organelles and induces marked up-regulation of LC3-II, autophagy-related 5 (ATG5), and Beclin-1. Transmission electron microscopy (TEM) revealed a decrease in mitochondria and ATRA-induced differentiation. To determine the role of autophagy in the differentiation of APL, we knocked down ATG5 in NB4 cells to find that ATRA-induced differentiation is significantly inhibited during ATG5 knock down in cells, indicating the role of autophagy
in differentiation of APL. Further experiments revealed restriction of autophagy during ATRA-induced differentiation and inhibition of tissue transglutaminase 2 (TG2) and phospho–focal adhesion kinase (p-FAK), which are known to have roles in differentiation and cell attachment. We examined expression of Beclin-1 and B-cell lymphoma–2 (Bcl-2) and levels of mechanistic target of rapamycin (mTOR) after ATRA treatment. ATRA inhibits Bcl-2, up-regulates Beclin-1 expression, and reduces induction of mTOR activation/phosphorylation in NB4 cells. Our results reveal that autophagy has roles in regulation of differentiation, mitochondria elimination, and cell attachment during ATRA-induced APL differentiation.
Predicting the Efficacy of 5-Fluorouracil–Based Adjuvant Chemotherapy in Gastric Cancer by Microsatellite Instability: A Meta-Analysis
21-28
10.1615/JEnvironPatholToxicolOncol.2018026876
Fuxing
Zhao
Department of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
Xinyue
Yuan
Department of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
Dengfeng
Ren
Department of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
Guoshuang
Shen
Department of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
Ziyi
Wang
Department of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
Fangchao
Zheng
Department of Medical Oncology, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai
University, Xining, 810000, China; Department of Medical Oncology, Shouguang Hospital of Traditional Chinese Medicine, Weifang,
261000, China
Raees
Ahmad
Department of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
Zhijun
Ma
Department of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
Jiuda
Zhao
Department of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, China
gastric cancer
microsatellite instability
fluorouracil
Microsatellite instability (MSI) implies the deletion of mismatch repair genes caused by DNA methylation or gene mutation. MSI is a good predictor for efficacy of 5-fluorouracil (FU)–based chemotherapy in the treatment of colorectal cancer. Some gastric cancer studies have reported that MSI has no apparent impact on prognosis after patients receive 5-FU–based adjuvant chemotherapy. However, other studies suggest that high-frequency MSI (MSI-H) status reduced survival in patients receiving 5-FU–based adjuvant chemotherapy. Thus, the correlation between MSI status and efficacy of 5-FU–based adjuvant chemotherapy for gastric cancer remains controversial. We performed a PubMed, Embase,
and Cochrane search to retrieve studies that explore the correlation between MSI status and 5-FU–based adjuvant chemotherapy efficacy in gastric cancer. After extracting 65 potentially eligible studies, four were ultimately included in this meta-analysis using Stata software (ver. 12.0). For each study, we estimated the hazard ratio (HR) value for overall survival (OS), and HR was extracted per the survival curve in the studies. Heterogeneity was estimated using the random-effects model. Overall, 1174 patients after operation were included: 84 patients were classed as MSI-H and 1090 as microsatellite stable (MSS)/low-frequency MSI (MSI-L). For the four studies, the overall estimate of HR for OS between MSI-H and MSS/MSI-L groups was 1.90 (95% confidence interval: 0.91–3.93; p = 0.08). We found no correlation to exist between MSI status and efficacy of 5-FU–based adjuvant chemotherapy for gastric cancer. Although MSI can effectively predict efficacy of 5-FU–based chemotherapy in patients with colorectal cancer, the correlation between MSI status and efficacy of 5-FU–based adjuvant chemotherapy for gastric cancer remains controversial. This meta-analysis suggests that MSI status is unrelated to efficacy of 5-FU–based adjuvant chemotherapy in gastric cancer, and more prospective clinical studies are needed to further investigate predictive value of MSI status in patients with gastric cancer who, after operation, receive 5-FU–based adjuvant chemotherapy.
Daidzein Ameliorates Dextran Sulfate Sodium-Induced Experimental Colitis in Mice by Regulating NF-κB Signaling
29-39
10.1615/JEnvironPatholToxicolOncol.2018027531
Jiangli
Shen
Department of Anorectal, Xianyang Central Hospital, Xianyang, Shaanxi, China
Na
Li
Department of Anorectal, Xianyang Central Hospital, Xianyang, Shaanxi, China
Xi
Zhang
Department of Anorectal, Xi'an Hospital of TCM, Xi'an, Shaanxi, China
Ulcerative colitis
daidzein
p65-NF-kB
TNF-a
IL-6
Ulcerative colitis (UC) and Crohn’s disease (CD) are collectively referred to as inflammatory bowel diseases
(IBDs). The increased pathogenesis of UC leads to a series of complications. We aimed to analyze the anticolitic effect of daidzein (DA) in a dextran sulfate sodium (DSS)-induced colitis mouse model and in activated macrophage RAW264.7 cells. Thirty BALB/c male mice were randomly divided into three groups: control, DSS-treated, and DSS DA (10 mg/kg body weight for seven days). DA supplementation was found to improve the disease activity index, colon length, and spleen weight. Microscopic analysis revealed that DSS-induced mice showed more inflammatory cell infiltration
and erosion in the villi. Supplementation of DA reduced these signs significantly. Furthermore, oral administration of DA decreased the level of myeloperoxidase (MPO) and inhibited the expression of p65-NF-κB, p-IκB-α, and p-IKK as well as several inflammatory factors, including TNF-α, IL-1β, and IL-6, in the colonic tissues. DA also inhibited the production of nitric oxide and prostaglandin E2 in LPS-stimulated RAW 264.7 macrophages. Taken together, these results suggest that DA could inhibit DSS-induced ulcerative colitis and decrease inflammatory factor expression. Thus, DA might be applicable in the treatment of UC.
Asthma-Alleviating Potential of 6-Gingerol: Effect on Cytokines, Related mRNA and c-Myc, and NFAT1 Expression in Ovalbumin-Sensitized Asthma in Rats
41-50
10.1615/JEnvironPatholToxicolOncol.2018027172
Zaoni
Li
Medical Clinic of Shangluo Central Hospital, Shangluo, Shaanxi Province, China-726000
Zhongxi
Liu
Department of Respiratory
Medicine in Daqing Oilfield General Hospital, Daqing, Heilongjiang Province, China-163000
V. V. Sathibabu
Uddandrao
Department of Biochemistry,
Centre for Biological Sciences, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, Namakkal Dt, Tamilnadu-637215
Ponmurugan
Ponnusamy
Department of Botany, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
Santhanaraj
Balakrishnan
College of Applied Medical Sciences, Majmaah University, Al Majmaah, The Kingdom of Saudi Arabia- 15341; Department of Bio-Medical Engineering, Velalar College of Engineering and Technology, Thindal, Erode-638012, Tamilnadu, India
P.
Brahmanaidu
ICMR-National Animal Resource Facility for Biomedical Research (NARFBR), Hyderabad,
Telangana, India-500007
S.
Vadivukkarasi
Department of Biochemistry,
Centre for Biological Sciences, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, Namakkal Dt, Tamilnadu-637215
Saravanan
Ganapathy
Department of Biochemistry, Centre for Biological Sciences, K.S. Rangasamy College of Arts and Science (Autonomous), Tiruchengode, Namakkal Dt, Tamilnadu-637215
6-gingerol
asthma
natural products
lung disorders
In this study, we aimed at assessing the therapeutical potential of 6-gingerol ([5S]-5-hydroxy-1-[4-hydroxy-
3-methoxyphenyl]-3-decanone) against ovalbumin-sensitized asthma in rats. The rats were treated intraperitoneally
with 6-gingerol (75 mg/kg body weight) for 30 days and a theophylline (200 mg/kg body weight)-treated group as a control. Changes in the levels of T-cell-linked cytokines (interleukin-4 [IL-4], IL-5, IL-13, and interferon-gamma [IFN-?]), total immunoglobulin E (IgE), gene expressions of bitter taste-sensing type 2-receptor 10 (T2R10), inositol 1,4,5-triphosphate receptor 1 (IP3R1), Orai1 and protein expressions of nuclear factor of activated T cells 1 (NFAT1), c-Myc and histopathological changes were observed in rats. 6-Gingerol exerts its beneficial impacts like theophylline in lessening IL-4, IL-5, and IL-13, and IgE and increasing the level of IFN-?. Significant down-regulation of T2R10 gene expression and up-regulation of IP3R1 and Orai1 gene expression were observed in experimental rats and these alterations were normalized after treatment with 6-gingerol or theophylline. The histopathological study revealed that the accumulation of glycoprotein and thickness of alveolar epithelium in asthmatic rats and supplementation with 6-gingerol or theophylline in asthmatic rats restored these changes to normal. In conclusion, 6-gingerol has a protective effect on lungs in ovalbumin-sensitized asthma in rats.
Mitogen-Activated Protein Kinase (MAPK): New Insights in Breast Cancer
51-59
10.1615/JEnvironPatholToxicolOncol.2018028386
Huanyu
Lu
Shandong University, Cheeloo College of Medicine, Jinan, Shandong Province, 250012, China
Yue
Guo
Shandong University, Cheeloo College of Medicine, Jinan, Shandong Province, 250012, China
Gaurav
Gupta
School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura 302017, Jaipur, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
Xingsong
Tian
Shandong University, Cheeloo College of Medicine, Jinan, Shandong Province, 250012, China
MAPK
breast cancer
mortality
PI3K-AKT signaling
The eukaryotic cell cycle via mitogen-activated protein kinase (MAPK) has been considered as an effective signaling
cascade pathway for anticancer therapy. In addition to the MAPK signaling pathway, the Rat Sarcoma Virus (Ras)/Rapidly Accelerated Fibrosarcoma (Raf)/MAPK–ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway is a signaling cascade that has a crucial role to play in cell survival and development of cancer, especially breast cancer. Novel drugs and clinical trials need to be investigated, taking into consideration the already studied genetic defects related to genesis of tumors in certain populations. The present review provides novel insights into current anticancer treatments involving the MAPK pathway.
Common Variants rs3815188 and rs1043994 on Notch3 Gene Confer Susceptibility to Lung Cancer: A Hospital-Based Case–Control Study
61-68
10.1615/JEnvironPatholToxicolOncol.2018028403
Emine
Yagci
Eskisehir Osmangazi University, Medical Faculty, Department of Medical Biology, Eskisehir, Turkey
Irfan
Degirmenci
Kutahya Health Sciences University, Medical Faculty, Department of Medical Biology, Kutahya, Turkey
Cansu
Ozbayer
Kutahya Health Sciences University, Faculty of Health Sciences, Kutahya, Turkey
Guntulu
Ak
Eskisehir Osmangazi University, Faculty of Medicine, Department of Pulmonary Diseases, Lung and Pleural Cancers Research and Clinical Center, Eskisehir, Turkey
Faruk
Saydam
Recep Tayyip Erdogan University, Medical Faculty, Department of Medical Biology and Genetics, Rize, Turkey
Muzaffer
Metintaş
Eskisehir Osmangazi University Medical Faculty, Department of Chest Diseases, Lung and Pleural Cancers Research and Clinical Center, Eskisehir, Turkey
Notch3 gene
lung cancer
polymorphism
rs3815188
rs1043994
The Notch signaling pathway is a mechanism that plays a role in the determination of cell fate during cell development. Signals between neighbor cells are amplified through the Notch receptors. Notch activity is related to general growth stages such as organogenesis and morphogenesis and has effects on cell differentiation, cell proliferation, and apoptosis. Lung cancer associated with degradation of proteins which regulate cellular activities such as cell growth, differentiation, proliferation and apoptosis or the loss of function of proteins due to mutations in the genes which that express these proteins. We aimed to determine the frequency of the Notch3 rs3815188 (C381T) and rs1043994 (G684A) polymorphisms and to investigate whether this gene is associated with genetic predisposition of development of lung cancer. In this study, DNA samples were extracted from the venous blood sample of 200 subjects (100 lung cancer patients and 100 controls). Notch3 rs3815188 (C381T) and rs1043994 (G684A) polymorphisms were determined using the restriction fragment length polymorphism method. A statistically significant difference was found between the patient and control groups for Notch3 gene rs3815188 and rs1043994 polymorphisms when evaluated in terms of genotype (p = 0.002 and p < 0.001, respectively) and allele frequencies (p < 0.05). In conclusion, the rs3815188 variant and rs1043994 variant of the Notch3 gene is associated with lung cancer risk in patients of Turkish origin.
PI3K/Akt Pathway and miR-21 are Involved in N-Ethyl-N-Nitrosourea-Induced F1 Mouse Lung Tumorigenesis: Effect of Inositol Hexaphosphate
69-81
10.1615/JEnvironPatholToxicolOncol.2018026684
Satya
Sahay
Environmental Carcinogenesis Laboratory Council of Scientific and Industrial Research (CSIR)–Indian Institute of Toxicology Research (IITR), Mahatma Gandhi Marg, Lucknow 226001, India
Prakash
Tiwari
Environmental Carcinogenesis Laboratory Council of Scientific and Industrial Research (CSIR)–Indian Institute of Toxicology Research (IITR), Mahatma Gandhi Marg, Lucknow 226001, India
Manuraj
Pandey
Environmental Carcinogenesis Laboratory Council of Scientific and Industrial Research (CSIR)–Indian Institute of Toxicology Research (IITR), Mahatma Gandhi Marg, Lucknow 226001, India
Krishna P.
Gupta
Environmental Carcinogenesis Laboratory Council of Scientific and Industrial Research (CSIR)–Indian Institute of Toxicology Research (IITR), Mahatma Gandhi Marg, Lucknow 226001, India
N-ethyl-N-nitrosourea
transplacental lung tumorigenesis
PI3K/Akt
microRNA
inositol hexaphosphate
The risk of cancer development in offspring due to carcinogen exposure during pregnancy is a serious issue. In this study, we explored the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and microRNA-21 (miR-21) in transplacental lung tumorigenesis and its prevention by dietary compound inositol hexaphosphate (IP6) in F1 mice. Balb/c mice were exposed to the N-ethyl-N-nitrosourea (ENU) intraperitoneally on the 17th day of gestation. After weaning, half of the litters were fed with oral 2% IP6. At the end of 30, 120, or 240 days, we did not observe any effect on fetal viability or weight between ENU-exposed and non-exposed litters and the same was true of IP6. Altered expressions
of the PI3K/Akt pathway were observed in F1 mice. Further, miR-21 expressions were found to be modulated at the respective time as well, along with the activation of matrix metalloproteinase (MMP-9) and vascular endothelial growth factor expression. Akt activation also enhanced the expression of cyclin D1, cyclooxygenase-2 (COX-2), nuclear factor-κB (NF-κBp50), and mammalian target of rapamycin (mTOR). IP6-fed F1 mice showed reduced tumorigenesis along with reduced expression of the PI3K/Akt pathway miR-21 and downstream targets. The PI3K/Akt pathway and miR-21 are involved in transplacental lung tumorigenesis, whereas IP6 seemed to affect lung tumorigenesis by suppressing the expression of the PI3K/Akt pathway in F1 mice.
Reduction of Gamma Radiation–Induced Damage by Hydro-Alcoholic Extract of Nardostachys jatamansi
83-96
10.1615/JEnvironPatholToxicolOncol.2019015395
Aditya
Menon
Origin Diagnostics and Research, Vavakkavu, Karunagappally
Tiju
Chacko
Mar Athanasious College for Advanced Studies, Tiruvalla
Praseetha R.
Nair
Mar Athanasious College for Advanced Studies, Tiruvalla
Teeju
Majeed
Mar Athanasious College for Advanced Studies, Tiruvalla
Cherupally Krishnan Krishnan
Nair
Mar Athanasious College for Advanced Studies, Tiruvalla, Tiruvalla, Kerala, India; St.Gregorios Dental College & Research Centre, Kothamangalam, Kerala, India
Nardostachys jatamansi
radioprotector
bax/bcl2 ratio
antioxidant
The search for a nontoxic radioprotector has not yielded any promising results. Many antioxidant compounds,
though effective under in vitro conditions as radioprotectors, have failed under in vivo settings due to their toxicity. The Indian medical system of Ayurveda uses a variety of plants with antioxidant potential, and these may be harboring molecules with radioprotective properties. In the present work, the radioprotective property of Nardostachys jatamansi was investigated. A hydro-alcoholic extract of this plant provided protection to the cellular DNA and membrane from 4 Gy gamma radiation. Depletion of cellular antioxidant status was also prevented by this extract. Molecular-level analysis in the intestines of mice revealed a lower bax/bcl2 ratio suggestive of a reduction of radiation-induced apoptosis. Expression levels of the DNA repair gene atm were elevated, along with a reduction in the expression of the inflammatory gene cox2. The extract also provided a survival advantage to mice exposed to lethal doses of gamma radiation. These results suggest a possible radioprotective role for Nardostachys jatamansi.