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Biological & Pharmaceutical Bulletin May 2018Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte... (Comparative Study)
Comparative Study
Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Enzyme activities in differentiated HepaRG cells were comparable to those in human hepatocytes and much higher than those in HepG2 cells, except for SULT activity. Second, we examined the cytotoxicity of hepatotoxic compounds, acetaminophen (APAP), aflatoxin B1 (AFB1), cyclophosphamide (CPA), tamoxifen (TAM), and troglitazone (TGZ) in HepaRG cells and human hepatocytes. AFB1- and CPA-induced cytotoxicities against HepaRG cells were comparable to those against human hepatocytes. Furthermore, the cytotoxicities of these compounds were inhibited by 1-aminobenzotriazole (ABT), a broad CYP inhibitor, in both cells and were likely mediated by metabolic activation by CYP. Finally, toxicogenomics analysis of HepG2 and HepaRG cells after exposure to AFB1 and CPA revealed that numerous p53-related genes were upregulated- and the expression of these genes was greater in HepaRG than in HepG2 cells. These results suggest that gene expression profiles of HepaRG cells were affected more considerably by the toxic mechanisms of AFB1 and CPA than the profiles of HepG2 cells were. Therefore, our investigation shows that HepaRG cells could be useful human hepatic cellular models for toxicity studies.
Topics: Cell Line; Cells, Cultured; Cytochrome P-450 Enzyme System; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Gene Expression Profiling; Glucuronosyltransferase; Hep G2 Cells; Hepatocytes; Humans; Pharmaceutical Preparations; Sulfotransferases; Toxicity Tests; Tumor Suppressor Protein p53
PubMed: 29445054
DOI: 10.1248/bpb.b17-00913 -
Memorias Do Instituto Oswaldo Cruz Nov 2017Cutaneous leishmaniasis (CL) is a chronic disease caused by species of the protozoan Leishmania and characterised by the presence of ulcerated skin lesions. Both... (Review)
Review
Cutaneous leishmaniasis (CL) is a chronic disease caused by species of the protozoan Leishmania and characterised by the presence of ulcerated skin lesions. Both parasite and host factors affect the clinical presentation of the disease. The development of skin ulcers in CL is associated with an inflammatory response mediated by cells that control parasite growth but also contribute to pathogenesis. CD8+ T cells contribute to deleterious inflammatory responses in patients with CL through cytotoxic mechanisms. In addition, natural killer cells also limit Leishmania infections by production of interferon-γ and cytotoxicity. In this review, we focus on studies of cytotoxicity in CL and its contribution to the pathogenesis of this disease.
Topics: Animals; CD8-Positive T-Lymphocytes; Cytotoxicity, Immunologic; Disease Models, Animal; Humans; Killer Cells, Natural; Leishmaniasis, Cutaneous; T-Lymphocytes, Cytotoxic
PubMed: 29091132
DOI: 10.1590/0074-02760170109 -
Toxicological Research Oct 2022Endocrine-disrupting chemicals (EDCs) are a structurally diverse class of synthetic and natural compounds. EDCs can cause non-communicable diseases such as obesity, type...
Endocrine-disrupting chemicals (EDCs) are a structurally diverse class of synthetic and natural compounds. EDCs can cause non-communicable diseases such as obesity, type 2 diabetes, thyroid disorders, neurodevelopmental disease, hormone-dependent cancers, and reproductive disorders. The embryoid body test (EBT) is a developmental toxicity test method that determines the size of embryoid bodies (EBs) and the viability of mouse embryonic stem cells (mESCs) and fibroblasts (3T3 cells). The present study used the EBT to perform cytotoxicity evaluations of 10 EDCs and assessed the mechanistic relationship between endoplasmic reticulum (ER) stress and cytotoxicity. According to the statistical analysis and prediction model results, methylparaben, butylparaben, propylparaben, ethylparaben, triclosan, octylphenol, methoxychlor, bisphenol A, and diethylstilbestrol were classified as cytotoxic, but trichloroacetic acid was non-toxic. Classification accuracy was 90%. The mechanistic study showed that the cytotoxicities of butylparaben, propylparaben, octylphenol, and triclosan were induced by ER stress. The mRNA expressions of BiP, CHOP, and ATF4 were significantly higher following treatments with four EDCs compared to those after the control treatment. Compared to the control treatment, the mRNA levels of XBP1u and XBP1s increased significantly after butylparaben and propylparaben treatments, but did not increase with octylphenol and triclosan treatments. These results indicate that the EBT can be applied as an alternative toxicity test when evaluating the cytotoxicity of EDCs.
PubMed: 36277366
DOI: 10.1007/s43188-022-00132-6 -
Toxicology Research Mar 2016Mycotoxins are secondary metabolites produced by many microfungi. Hitherto, over 300 mycotoxins with diverse structures have been identified. They contaminate most... (Review)
Review
Mycotoxins are secondary metabolites produced by many microfungi. Hitherto, over 300 mycotoxins with diverse structures have been identified. They contaminate most cereals and feedstuffs, which threaten human and animal health by exerting acute, sub-acute and chronic toxicological effects, with some considered as carcinogens. Many mycotoxins at low concentrations are able to induce the expression of cytochrome P450 and other enzymes implicated in the biotransformation and metabolization of mycotoxins and . Mycotoxins and their metabolites elicit different cellular disorders and adverse effects such as oxidative stress, inhibition of translation, DNA damage and apoptosis in host cells, thus causing various kinds of cytotoxicities. In this review, we summarize the biotransformation of mycotoxins in animal cells by CYP450 isoforms and other enzymes, their altered expression under mycotoxin exposure, and recent progress in mycotoxin cytotoxicity in different cell lines. Furthermore, we try to generalize the molecular mechanisms of mycotoxin effects in human and animal cells.
PubMed: 30090353
DOI: 10.1039/c5tx00293a -
Chemical & Pharmaceutical Bulletin 2022Two series of 2-substituted benzimidazole conjugated 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activities against the...
Two series of 2-substituted benzimidazole conjugated 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activities against the three human cancer cell lines (cervical cancer (HeLa), breast cancer (MCF-7) and lung cancer (A549)). As the results 14 compounds demonstrated consistent to stronger cytotoxicities compared to the control 5-fluorouracil (5-FU) towards the tested cell lines including 4c (HeLa); 4b, 4e, 4h, 7i-j, 7m-n, 7s (MCF-7); 7b (MCF-7, A549); 7h (HeLa, MCF-7); and 4d, 4i, 7c (HeLa, MCF-7, A549), with the IC ranging from 2.7 to 38 µM. Notably, compound 4b illustrated almost 5-fold activity against the MCF-7 while 4d, 4i were 9- and 8-fold (HeLa), 4.5- and 13-fold (MCF-7), 4.7- and 4-fold (A549) increase in activity compared to 5-FU, respectively, and were found as lead compounds. These findings suggest that compounds 4b, 4d and 4i merit further characterization and can serve as promising scaffolds in the discovery of new potent anticancer agents.
Topics: Antineoplastic Agents; Benzimidazoles; Drug Screening Assays, Antitumor; Fluorouracil; Humans; Oxadiazoles; Structure-Activity Relationship
PubMed: 35650042
DOI: 10.1248/cpb.c22-00162 -
ACS Medicinal Chemistry Letters Mar 2022MHI-I () and QuatCy-I () were compared in terms of properties important for early-stage photodynamic therapy preclinical candidates. Thus, experiments were performed to...
MHI-I () and QuatCy-I () were compared in terms of properties important for early-stage photodynamic therapy preclinical candidates. Thus, experiments were performed to monitor dark cytotoxicities, light/dark cytotoxicity ratios, selectivity of localization in tumors over other organs, and clearance from the plasma.
PubMed: 35300076
DOI: 10.1021/acsmedchemlett.1c00640 -
Journal of Oncology Pharmacy Practice :... Mar 2023This evidence-based practice guideline was developed to update and address new issues in the handling of hazardous drugs including being compliant with NAPRA (National...
This evidence-based practice guideline was developed to update and address new issues in the handling of hazardous drugs including being compliant with NAPRA (National Association of Pharmacy Regulatory Authorities) and USP 800 (United States Pharmacopeia) standards, the use of personal protective equipment and treatment in diverse settings including in the home setting. This guideline was developed from an adaptation and endorsement of existing guidelines and from three systematic reviews. Prior to publication, this guideline underwent a series of peer, patient, methodological and external reviews to gather feedback. All comments were addressed and the guideline was amended when required. This guideline applies to and is intended for all health care workers who may come into contact with hazardous drugs at any point in the medication circuit. The recommendations represent a reasonable and practical set of procedures that the intended users of this guideline should implement to minimize the opportunity for accidental exposure. These recommendations are not limited to just the point of care, but cover the entire chain of handling of cytotoxics from the time they enter the institution until they leave in the patient or as waste. Decreasing the likelihood of accidental exposure to cytotoxic agents within the medication circuit is the main objective of this evidenced-based guideline. The recommendations differ slightly from previous guidelines due to new evidence.
Topics: Humans; Hazardous Substances; Antineoplastic Agents; Health Personnel; Pharmacy; Personal Protective Equipment; Occupational Exposure
PubMed: 36373754
DOI: 10.1177/10781552221135121 -
Cellular & Molecular Immunology Aug 2005Granule-mediated cytotoxicity is the major mechanism for lymphocytes to kill viruses, intracellular bacteria and tumors. The cytotoxic granules move to the immunological... (Review)
Review
Granule-mediated cytotoxicity is the major mechanism for lymphocytes to kill viruses, intracellular bacteria and tumors. The cytotoxic granules move to the immunological synapse by exocytosis after recognition of a killer cell. The contents of the granules are delivered into target cells with the help of perforin by endocytosis. A group of serine protease granzymes cleave their critical substrates to initiate DNA damage and cell death. The most abundant granzymes are granzyme A and B. They induce cell death through alternate and nonoverlapping pathways. The substrates and functions of the majority of the orphan granzymes have not yet been identified. It is possible that the diversity of granzymes provides fail-safe mechanisms for killing viruses and tumor cells.
Topics: Animals; Antigens, Differentiation, T-Lymphocyte; Apoptosis; Cytotoxicity, Immunologic; Granzymes; Humans; Immunity, Cellular; Perforin; Secretory Vesicles; T-Lymphocytes, Cytotoxic
PubMed: 16274623
DOI: No ID Found -
Molecules (Basel, Switzerland) Mar 2022Cisplatin and other metallodrugs have realised great success in clinical chemotherapeutic applications as anticancer drugs. However, severe toxicity to healthy cells and...
New Triazolyl N^N Bidentate Rh(III), Ir(III), Ru(II) and Os(II) Complexes: Synthesis and Characterization, Probing Possible Relations between Cytotoxicity with Transfer Hydrogenation Efficacy and Interaction with Model Biomolecules.
Cisplatin and other metallodrugs have realised great success in clinical chemotherapeutic applications as anticancer drugs. However, severe toxicity to healthy cells and non-selectivity to cancer cells remains a challenge, warranting the further search for alternative agents. Herein, we report the anticancer potential of a series of complexes of the general formula [MCl(p-cym)(k2-N^N-L)]+ X− and [MCl(Cp*)(k2-N^N-L)]+ X−, where M is the metal centre (Ru(II), Os(II), Rh(III) or Ir(III)), L = 1-benzyl-4-pyridinyl-1-H-1,2,3-triazole for L1 and 1-picolyl-4-pyridinyl-1-H-1,2,3-triazole for L2 and X− = Cl−, BF4−, BPh4−. When evaluated for activity against some cancerous and non-cancerous cell lines (namely, HeLa, HEK293, A549 and MT4 cancer cells and the normal healthy kidney cells (BHK21)), most of the compounds displayed poor cytotoxicities against cancer cells except for complexes C2 ([RuCl(p-cym)(k2-N^N-L1)]+ BPh4−, EC50 = 9−16 µM and SI = 14), C7 ([RuCl(p-cym)(k2-N^N-L2)]+ BPh4−, EC50 = 17−53 µM and SI = 4) and C11 ([IrCl(Cp*)(k2-N^N-L2)]+ BF4−, EC50 < 5 µM and SI > 10). Selected complexes C1 ([RuCl(p-cym)(k2-N^N-L1)]+ BF4−), C5 ([IrCl(Cp*)(k2-N^N-L1)]+ BF4−) and C11 showed significant interactions with model biomolecules such as guanosine-5′-monophosphate (5′-GMP), bovine serum albumin (BSA) and amino acids under physiological conditions, possibly through carbenylation and N-coordination with 5′-GMP, N-coordination with L-Histidine and L-proline. While the compounds showed good activities in reducing pyruvate to lactate, there was no direct correlation between catalytic transfer hydrogenation of pyruvate and the observed cytotoxic activities. As observed in this work, the marked influence of single atom replacement in ligand may provide a pivotal approach to improving the cytotoxicity and fine-tuning the selectivity to cancer cells.
Topics: Antineoplastic Agents; Coordination Complexes; Guanosine Monophosphate; HEK293 Cells; Humans; Hydrogenation; Prostatic Hyperplasia; Pyruvic Acid; Ruthenium; Triazoles
PubMed: 35408457
DOI: 10.3390/molecules27072058 -
OncoTargets and Therapy 2015The development of poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors (PARPi) has progressed greatly over the last few years and has shown... (Review)
Review
The development of poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors (PARPi) has progressed greatly over the last few years and has shown encouraging results in the BRCA1/2 mutation-related cancers. This article attempts to summarize the rationale and theory behind PARPi, the clinical trials already reported, as well as ongoing studies designed to determine the role of PARPi in patients with and without germline mutations of BRCA genes. Future plans for PARPi both as monotherapy and in combination with standard cytotoxics, other biological agents, and as radiosensitizers are also covered. The widening scope of PARPi adds another important targeted agent to the growing list of molecular inhibitors; future and ongoing trials will identify the most effective role for PARPi, including for patients other than BRCA germline mutation carriers.
PubMed: 25750544
DOI: 10.2147/OTT.S30793