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Genes and Environment : the Official... Aug 2023Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP...
Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP enzymes (Drug Metab Pharmacokinet 2019, 2020, 2021, and 2022) was tested for three phenomena. (1) Possible causal relationships between CYP-mediated metabolisms of β-naphthoflavone and 3-methylcholanthrene and the high inducibility of CYP enzymes were examined. Selective involvement of non-constitutive CYP1A1, but not constitutive CYP1A2, was suggested on the oxidative metabolisms of efficient inducers, β-naphthoflavone and 3-methylcholanthrene. These results supported the view of the causal link of their high inducibility with their inefficient metabolisms due to the lack of CYP1A1 in livers at early periods after the administration of both inducers. (2) Clear differences exist between human and rodent CYP1A1 enzymes on their catalyses with heterocyclic amines, dioxins and polyaromatic hydrocarbons (PAHs). Reciprocal comparison of simulation results with experimental data suggested the rodent specific site and distinct sitting-preferences of ligands on Template for human and rodent CYP1A1 enzymes. (3) Enhancement of metabolic activation and co-mutagenicity have been known as phenomena associated with Salmonella mutagenesis assay. Both the phenomena were examined on CYP-Templates in ways of simultaneous bi-molecule bindings of distinct ligands as trigger and pro-metabolized molecules. α-Naphthoflavone and norharman served consistently as trigger-molecules to support the oxidations of PAHs and arylamines sitting simultaneously as pro-metabolized molecules on Templates of CYP1A1, CYP1A2 and CYP3A4. These CYP-Template simulation systems with deciphering capabilities are promising tools to understand the mechanism basis of metabolic activations and to support confident judgements in safety assessments.
PubMed: 37544994
DOI: 10.1186/s41021-023-00275-4 -
Journal of Cellular Physiology May 2017Endothelial nitric oxide synthase (eNOS) modulates vascular blood pressure and is predominantly expressed in endothelial cells and activated through the protein kinase B...
Endothelial nitric oxide synthase (eNOS) modulates vascular blood pressure and is predominantly expressed in endothelial cells and activated through the protein kinase B (Akt/PKB)-dependent pathway. We previously reported that 3-methylcholanthrene (3MC) activates the aryl hydrocarbon receptor (AhR) and reduces PI3K/Akt phosphorylation. This study investigated the mechanism underlying the downregulatory effects of 3-MC on nitric oxide (NO) production occurring through the AhR/RhoA/Akt-mediated mechanism. The mechanism underlying the effects of 3-MC on eNOS activity and blood pressure was examined in vitro and in vivo through genetic and pharmacological approaches. Results indicated that 3-MC modified heat shock protein 90 (HSP90), caveolin-1, dynein, and eNOS mRNA and protein expression through the AhR/RhoA-dependent mechanism in mouse cerebral vascular endothelial cells (MCVECs) and that 3-MC reduced eNOS phosphorylation through the AhR/RhoA-mediated inactivation of Akt1. The upregulation of dynein expression was associated with decreased eNOS dimer formation (eNOS dimer; an activated form of the enzyme). Coimmunoprecipitation assay results indicated that 3-MC significantly reduced the interaction between eNOS and its regulatory proteins, including Akt1 and HSP90, but increased the interaction between eNOS and caveolin-1. Immunofluorescence and Western blot analysis revealed that 3-MC reduced the amount of membrane-bound activated eNOS, and a modified Griess assay revealed that 3-MC concomitantly reduced NO production. However, simvastatin reduced 3-MC-mediated murine hypertension. Our study results indicate that AhR, RhoA, and eNOS have major roles in blood pressure regulation. Statin intervention might provide a potential therapeutic approach for reducing hypertension caused by 3-MC. J. Cell. Physiol. 232: 1020-1029, 2017. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Cerebrum; Down-Regulation; Endothelial Cells; Hypertension; Methylcholanthrene; Mice; Models, Biological; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroprusside; Protein Binding; Proto-Oncogene Proteins c-akt; Receptors, Aryl Hydrocarbon; Signal Transduction; Simvastatin; Time Factors; rhoA GTP-Binding Protein
PubMed: 27442426
DOI: 10.1002/jcp.25497 -
Molecules (Basel, Switzerland) Oct 2018Isopsoralen (IPRN), one of the main effective ingredients in Linn, has a variety of biological effects, including antiosteoporotic effects. In vivo studies show that...
Isopsoralen (IPRN), one of the main effective ingredients in Linn, has a variety of biological effects, including antiosteoporotic effects. In vivo studies show that IPRN can increase bone strength and trabecular bone microstructure in a sex hormone deficiency-induced osteoporosis model. However, the mechanism underlying this osteogenic potential has not been investigated in detail. In the present study, we investigated the molecular mechanism of IPRN-induced osteogenesis in MC3T3-E1 cells. Isopsoralen promoted osteoblast differentiation and mineralization, increased calcium nodule levels and alkaline phosphatase (ALP) activity and upregulated osteoblast markers, including ALP, runt-related transcription factor 2 (RUNX2), and collagen type I alpha 1 chain (COL1A1). Furthermore, IPRN limited the nucleocytoplasmic shuttling of aryl hydrocarbon receptor (AhR) by directly binding to AhR. The AhR target gene cytochrome P450 family 1 subfamily A member 1 (CYP1A1) was also inhibited in vitro and in vivo. This effect was inhibited by the AhR agonists indole-3-carbinol (I3C) and 3-methylcholanthrene (3MC). Moreover, IPRN also increased estrogen receptor alpha (ERα) expression in an AhR-dependent manner. Taken together, these results suggest that IPRN acts as an AhR antagonist and promotes osteoblast differentiation via the AhR/ERα axis.
Topics: Animals; Calcification, Physiologic; Cell Differentiation; Cell Line; Estrogen Receptor alpha; Furocoumarins; Gene Expression Regulation; Mice; Molecular Structure; Osteoblasts; Osteogenesis; Protein Binding; Protein Transport; Receptors, Aryl Hydrocarbon
PubMed: 30314280
DOI: 10.3390/molecules23102600 -
Chemico-biological Interactions Oct 2018Glutathione S-transferases (GSTs), the versatile phase II biotransformation enzymes, metabolize and detoxify a wide variety of toxic chemical compounds like carcinogens,... (Review)
Review
Glutathione S-transferases (GSTs), the versatile phase II biotransformation enzymes, metabolize and detoxify a wide variety of toxic chemical compounds like carcinogens, chemotherapeutic drugs, environmental pollutants and oxidative stress products. GSTs are currently of great interest in drug discovery, nanotechnology and biotechnology because of their involvement in many major cellular processes. GSTs, which are either homo or hetero dimeric proteins mediate catalytic binding between glutathione (GSH) and an array of either endogenous or exogenous toxic compounds to form a highly soluble detoxified complex which is then eliminated. Polycyclic aromatic hydrocarbons (PAHs) which are composed of two or more benzene rings bonded as linear, cluster or angular arrangements are used as intermediaries in pharmaceuticals, agricultural products, photographic products, thermosetting plastics, lubricating materials and other chemical products. Foods those cooked at high temperatures by grilling, roasting, frying and smoking are the main sources for the persistent bio-accumulation of PAHs in food chain. The carcinogenic, mutagenic and immunosuppressive effects of PAHs are well established. A well-known polycyclic aromatic hydrocarbon, methylcholanthrene is a potential carcinogenic, neurotoxic, mutagenic and tumour causing agent that is used as an experimental carcinogen in biological research. Methylcholanthrene converts into reactive metabolites when it enters living cells and those reactive metabolites oxidize DNA, RNA, proteins and lipids and form DNA and protein adducts as well. GSTs play major role in the detoxification of reactive metabolites of methylcholanthrene by mediating catalytic binding with GSH to form a highly soluble detoxified complex which is then eliminated. This review summarizes the role of GSTs in the detoxification of a polycyclic aromatic hydrocarbon, methylcholanthrene.
Topics: Animals; Brain; Glutathione Transferase; Humans; Inactivation, Metabolic; Methylcholanthrene; Polycyclic Aromatic Hydrocarbons
PubMed: 30145136
DOI: 10.1016/j.cbi.2018.08.023 -
Current Research in Toxicology 2022Polycyclic aromatic compounds (PACs) are a broad class of contaminants ubiquitously present in the environment due to natural and anthropogenic activities. With...
Polycyclic aromatic compounds (PACs) are a broad class of contaminants ubiquitously present in the environment due to natural and anthropogenic activities. With increasing industrialization and reliance on petroleum worldwide, PACs are increasingly being detected in different environmental compartments. Previous studies have shown that PACs possess endocrine disruptive properties as these compounds often interfere with hormone signaling and function. In females, the ovary is largely responsible for regulating reproductive and endocrine function and thus, serves as a primary target for PAC-mediated toxicity. Perturbations in the signaling pathways that mediate ovarian folliculogenesis, steroidogenesis and angiogenesis can lead to adverse reproductive outcomes including polycystic ovary syndrome, premature ovarian insufficiency, and infertility. To date, the impact of PACs on ovarian function has focused predominantly on polycyclic aromatic hydrocarbons like benzo(a)pyrene, 3-methylcholanthrene and 7,12-dimethylbenz[a]anthracene. However, investigation into the impact of substituted PACs including halogenated, heterocyclic, and alkylated PACs on mammalian reproduction has been largely overlooked despite the fact that these compounds are found in higher abundance in free-ranging wildlife. This review aims to discuss current literature on the effects of PACs on the ovary in mammals, with a particular focus on folliculogenesis, steroidogenesis and angiogenesis, which are key processes necessary for proper ovarian functions.
PubMed: 35492299
DOI: 10.1016/j.crtox.2022.100070 -
Methods in Cell Biology 2021Lung cancer is one of the deadliest types of cancer and as such requires disease models that are useful for identification of novel pathways for biomarkers as well as to...
Lung cancer is one of the deadliest types of cancer and as such requires disease models that are useful for identification of novel pathways for biomarkers as well as to test therapeutic agents. Adenocarcinoma (ADC), the most prevalent type of lung cancer, is a subtype of non-small cell lung carcinoma (NSCLC) and a disease driven mainly by smoking. However, it is also the most common subtype of lung cancer found in non-smokers with environmental exposures. Chemically driven models of lung cancer, also called primary models of lung cancer, are important because they do not overexpress or delete oncogenes or tumor suppressor genes, respectively, to increase oncogenesis. Instead these models test tumor development without forcing a specific pathway (i.e., Kras). The primary focus of this chapter is to discuss a well-established 2-stage mouse model of lung adenocarcinomas. The initiator (3-methylcholanthrene, MCA) does not elicit many, if any, tumors if not followed by exposure to the tumor promoter (butylated hydroxytoluene, BHT). In sensitive strains, such as A/J, FVB, and BALB, significantly greater numbers of tumors develop following the MCA/BHT protocol compared to MCA alone. BHT does not elicit tumors on its own; it is a non-genotoxic carcinogen and promoter. In these sensitive strains, promotion is also associated with inflammation characterized by infiltrating macrophages, lymphocytes, and neutrophils, and other inflammatory cell types in addition to increases in total protein content reflective of lung hyperpermeability. This 2-stage model is a useful tool to identify unique promotion specific events to then test in future intervention studies.
Topics: Animals; Butylated Hydroxytoluene; Carcinogenesis; Lung; Methylcholanthrene; Mice; Mice, Inbred BALB C
PubMed: 33785163
DOI: 10.1016/bs.mcb.2020.07.003 -
Ophthalmology Sep 2015The purpose of this study was to determine in which species and under what conditions lens tumors occur.
PURPOSE
The purpose of this study was to determine in which species and under what conditions lens tumors occur.
DESIGN
A review of databases of available human and veterinary ocular pathologic material and the previously reported literature.
PARTICIPANTS
Approximately 18 000 patients who had ocular surgical specimens submitted and studied at the University of Wisconsin School of Medicine and Public Health between 1920 and 2014 and 45 000 ocular veterinary cases from the Comparative Ocular Pathology Laboratory of Wisconsin between 1983 and 2014.
METHODS
Material in 2 major archived collections at the University of Wisconsin medical and veterinary schools were studied for occurrence of lens tumors. Tumor was defined as a new growth of tissue characterized by progressive, uncontrolled proliferation of cells. In addition, cases presented at 3 major eye pathologic societies (Verhoeff-Zimmerman Ophthalmic Pathology Society, Eastern Ophthalmic Pathology Society, and The Armed Forces Institute of Pathology Ophthalmic Alumni Society) from 1975 through 2014 were reviewed. Finally, a careful search of the literature was carried out. Approval from the institutional review board to carry out this study was obtained.
MAIN OUTCOME MEASURES
The presence of tumors of the lens.
RESULTS
The database search and literature review failed to find an example of a lens tumor in humans. In contrast, examples of naturally occurring lens tumors were found in cats, dogs, rabbits, and birds. In the veterinary school database, 4.5% of feline intraocular and adnexal neoplasms (234/5153) were designated as feline ocular posttraumatic sarcoma, a tumor previously demonstrated to be of lens epithelial origin. Similar tumors were seen in rabbit eyes, a bird, and in a dog. All 4 species with lens tumors had a history of either ocular trauma or protracted uveitis. The literature search also revealed cases where lens tumors were induced in zebrafish, rainbow trout, hamsters, and mice by carcinogenic agents (methylcholanthrene, thioacetamide), oncogenic viruses (SV40, HPV-16), and genetic manipulation.
CONCLUSIONS
Our results suggest that lens tumors do not occur in humans. In contrast, after lens capsule rupture, a lens tumor can occur in other species. We hypothesize that a genetic mechanism exists that prevents lens tumors in humans.
Topics: Animals; Cats; Cricetinae; Databases, Factual; Dogs; Eye Neoplasms; Female; Human papillomavirus 16; Humans; Lens Diseases; Male; Mice; Mice, Transgenic; Oncorhynchus mykiss; Rabbits; Simian virus 40; Species Specificity; Spheniscidae; Zebrafish
PubMed: 26130328
DOI: 10.1016/j.ophtha.2015.05.028 -
International Journal of Molecular... Mar 20233-methylcholanthrene (3-MC) is a highly toxic environmental pollutant that impairs animal health. 3-MC exposure can cause abnormal spermatogenesis and ovarian...
3-methylcholanthrene (3-MC) is a highly toxic environmental pollutant that impairs animal health. 3-MC exposure can cause abnormal spermatogenesis and ovarian dysfunction. However, the effects of 3-MC exposure on oocyte maturation and embryo development remain unclear. This study revealed the toxic effects of 3-MC exposure on oocyte maturation and embryo development. 3-MC with different concentrations of 0, 25, 50, and 100 μM was applied for in vitro maturation of porcine oocytes. The results showed that 100 μM 3-MC significantly inhibited cumulus expansion and the first polar body extrusion. The rates of cleavage and blastocyst of embryos derived from 3-MC-exposed oocytes were significantly lower than those in the control group. Additionally, the rates of spindle abnormalities and chromosomal misalignments were higher than those in the control group. Furthermore, 3-MC exposure not only decreased the levels of mitochondria, cortical granules (CGs), and acetylated α-Tubulin, but also increased the levels of reactive oxygen species (ROS), DNA damage, and apoptosis. The expression of cumulus expansion and apoptosis-related genes was abnormal in 3-MC-exposed oocytes. In conclusion, 3-MC exposure disrupted the nuclear and cytoplasmic maturation of porcine oocytes through oxidative stress.
Topics: Animals; Swine; Methylcholanthrene; Oogenesis; Oocytes; Oxidative Stress; Reactive Oxygen Species; Embryonic Development; In Vitro Oocyte Maturation Techniques
PubMed: 36982641
DOI: 10.3390/ijms24065567 -
The Journal of Clinical Investigation Sep 2020Cachexia, a devastating wasting syndrome characterized by severe weight loss with specific losses of muscle and adipose tissue, is driven by reduced food intake,...
Cachexia, a devastating wasting syndrome characterized by severe weight loss with specific losses of muscle and adipose tissue, is driven by reduced food intake, increased energy expenditure, excess catabolism, and inflammation. Cachexia is associated with poor prognosis and high mortality and frequently occurs in patients with cancer, chronic kidney disease, infection, and many other illnesses. There is no effective treatment for this condition. Hypothalamic melanocortins have a potent and long-lasting inhibitory effect on feeding and anabolism, and pathophysiological processes increase melanocortin signaling tone, leading to anorexia, metabolic changes, and eventual cachexia. We used 3 rat models of anorexia and cachexia (LPS, methylcholanthrene sarcoma, and 5/6 subtotal nephrectomy) to evaluate efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor. Our data show that peripheral treatment using TCMCB07 with intraperitoneal, subcutaneous, and oral administration increased food intake and body weight and preserved fat mass and lean mass during cachexia and LPS-induced anorexia. Furthermore, administration of TCMCB07 diminished hypothalamic inflammatory gene expression in cancer cachexia. These results suggest that peripheral TCMCB07 treatment effectively inhibits central melanocortin signaling and therefore stimulates appetite and enhances anabolism, indicating that TCMCB07 is a promising drug candidate for treating cachexia.
Topics: Animals; Appetite; Cachexia; Male; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Renal Insufficiency, Chronic; Sarcoma, Experimental
PubMed: 32544087
DOI: 10.1172/JCI138392 -
Frontiers in Pharmacology 2022Acquired cisplatin resistance in cervical cancer therapy is principally caused by reduction in intracellular drug accumulation, which is exerted by hyperactivation of...
Acquired cisplatin resistance in cervical cancer therapy is principally caused by reduction in intracellular drug accumulation, which is exerted by hyperactivation of the oncogenic PI3K/Akt signaling axis and overexpression of cisplatin-exporter MRP2 along with prosurvival effectors NF-κB and IAPs in cervical cancer cells. These activated prosurvival signaling cascades drive drug efflux and evasion of apoptosis for rendering drug-resistant phenotypes. Our study challenges the PI3K/Akt axis in a cisplatin-resistant cervical cancer scenario with phenethylisothiocyanate (PEITC) for chemosensitization of SiHa, a cisplatin-resistant sub-line of SiHa and 3-methylcholanthrene-induced cervical cancer mice models. SiHa exhibited higher MRP2, p-Akt, NF-κB, XIAP, and survivin expressions which cumulatively compromised cisplatin retention capacity and accumulated PEITC better than SiHa. SiHa appeared to favor PEITC uptake as its accumulation rates were found to be positively correlated with MRP2 expressions. PEITC treatment in SiHa for 3 h prior to cisplatin exposure revived intracellular platinum levels, reduced free GSH levels, generated greater ROS, and altered mitochondrial membrane potential compared to SiHa. Western blot and immunofluorescence results indicated that PEITC successfully downregulated MRP2 in addition to suppressing p-Akt, XIAP, survivin, and NF-κB expressions. In mice models, administration of 5 mg/kg body-weight PEITC priming dosage prior to treatment with 3 mg/kg body-weight of cisplatin remediated cervical histology and induced tumor regression in contrast to the group receiving the same dosage of cisplatin only. This suggested PEITC as a potential chemosensitizing agent in light of acquired cisplatin resistance in cervical cancer and established its candidature for Phase I clinical trial.
PubMed: 35548339
DOI: 10.3389/fphar.2022.803114