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1.
Am J Physiol Heart Circ Physiol ; 322(4): H549-H567, 2022 04 01.
Article in English | MEDLINE | ID: mdl-35089811

ABSTRACT

We recently reported a mouse model of chronic electronic cigarette (e-cig) exposure-induced cardiovascular pathology, where long-term exposure to e-cig vape (ECV) induces cardiac abnormalities, impairment of endothelial function, and systemic hypertension. Here, we delineate the underlying mechanisms of ECV-induced vascular endothelial dysfunction (VED), a central trigger of cardiovascular disease. C57/BL6 male mice were exposed to ECV generated from e-cig liquid containing 0, 6, or 24 mg/mL nicotine for 16 and 60 wk. Time-dependent elevation in blood pressure and systemic vascular resistance were observed, along with an impairment of acetylcholine-induced aortic relaxation in ECV-exposed mice, compared with air-exposed control. Decreased intravascular nitric oxide (NO) levels and increased superoxide generation with elevated 3-nitrotyrosine levels in the aorta of ECV-exposed mice were observed, indicating that ECV-induced superoxide reacts with NO to generate cytotoxic peroxynitrite. Exposure increased NADPH oxidase expression, supporting its role in ECV-induced superoxide generation. Downregulation of endothelial nitric oxide synthase (eNOS) expression and Akt-dependent eNOS phosphorylation occurred in the aorta of ECV-exposed mice, indicating that exposure inhibited de novo NO synthesis. Following ECV exposure, the critical NOS cofactor tetrahydrobiopterin was decreased, with a concomitant loss of its salvage enzyme, dihydrofolate reductase. NADPH oxidase and NOS inhibitors abrogated ECV-induced superoxide generation in the aorta of ECV-exposed mice. Together, our data demonstrate that ECV exposure activates NADPH oxidase and uncouples eNOS, causing a vicious cycle of superoxide generation and vascular oxidant stress that triggers VED and hypertension with predisposition to other cardiovascular disease.NEW & NOTEWORTHY Underlying mechanisms of e-cig-induced vascular endothelial dysfunction are delineated. e-cig exposure activates and increases expression of NADPH oxidase and disrupts activation and coupling of eNOS, leading to a vicious cycle of superoxide generation and peroxynitrite formation, with tetrahydrobiopterin depletion, causing loss of NO that triggers vascular endothelial dysfunction. This process is progressive, increasing with the duration of e-cig exposure, and is more severe in the presence of nicotine, but observed even with nicotine-free vaping.


Subject(s)
Cardiovascular Diseases , Electronic Nicotine Delivery Systems , Hypertension , Animals , Endothelium, Vascular/metabolism , Female , Male , Mice , NADPH Oxidases/metabolism , Nicotine , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/metabolism , Peroxynitrous Acid/metabolism , Superoxides/metabolism
2.
Nitric Oxide ; 119: 9-18, 2022 02 01.
Article in English | MEDLINE | ID: mdl-34875385

ABSTRACT

Cytoglobin (Cygb) has been identified as the major nitric oxide (NO) metabolizing protein in vascular smooth muscle cells (VSMCs) and is crucial for the regulation of vascular tone. In the presence of its requisite cytochrome B5a (B5)/B5 reductase-isoform-3 (B5R) reducing system, Cygb controls NO metabolism through the oxygen-dependent process of NO dioxygenation. Tobacco cigarette smoking (TCS) induces vascular dysfunction; however, the role of Cygb in the pathophysiology of TCS-induced cardiovascular disease has not been previously investigated. While TCS impairs NO biosynthesis, its effect on NO metabolism remains unclear. Therefore, we performed studies in aortic VSMCs with tobacco smoke extract (TSE) exposure to investigate the effects of cigarette smoke constituents on the rates of NO decay, with focus on the alterations that occur in the process of Cygb-mediated NO metabolism. TSE greatly enhanced the rates of NO metabolism by VSMCs. An initial increase in superoxide-mediated NO degradation was seen at 4 h of exposure. This was followed by much larger progressive increases at 24 and 48 h, accompanied by parallel increases in the expression of Cygb and B5/B5R. siRNA-mediated Cygb knockdown greatly decreased these TSE-induced elevations in NO decay rates. Therefore, upregulation of the levels of Cygb and its reducing system accounted for the large increase in NO metabolism rate seen after 24 h of TSE exposure. Thus, increased Cygb-mediated NO degradation would contribute to TCS-induced vascular dysfunction and partial inhibition of Cygb expression or its NO dioxygenase function could be a promising therapeutic target to prevent secondary cardiovascular disease.


Subject(s)
Cytoglobin/metabolism , Myocytes, Smooth Muscle/metabolism , Nitric Oxide/metabolism , Tobacco Smoke Pollution/adverse effects , Animals , Aorta/cytology , Cell Survival/drug effects , Cytochrome-B(5) Reductase/metabolism , Cytochromes b5/metabolism , Cytoglobin/genetics , Gene Knockdown Techniques , Mice , Muscle, Smooth, Vascular/cytology , Superoxides/metabolism , Up-Regulation/drug effects
3.
Proc Natl Acad Sci U S A ; 118(52)2021 12 28.
Article in English | MEDLINE | ID: mdl-34930834

ABSTRACT

Cytoglobin (Cygb) was discovered as a novel type of globin that is expressed in mammals; however, its functions remain uncertain. While Cygb protects against oxidant stress, the basis for this is unclear, and the effect of Cygb on superoxide metabolism is unknown. From dose-dependent studies of the effect of Cygb on superoxide catabolism, we identify that Cygb has potent superoxide dismutase (SOD) function. Initial assays using cytochrome c showed that Cygb exhibits a high rate of superoxide dismutation on the order of 108 M-1 ⋅ s-1 Spin-trapping studies also demonstrated that the rate of Cygb-mediated superoxide dismutation (1.6 × 108 M-1 ⋅ s-1) was only ∼10-fold less than Cu,Zn-SOD. Stopped-flow experiments confirmed that Cygb rapidly dismutates superoxide with rates within an order of magnitude of Cu,Zn-SOD or Mn-SOD. The SOD function of Cygb was inhibited by cyanide and CO that coordinate to Fe3+-Cygb and Fe2+-Cygb, respectively, suggesting that dismutation involves iron redox cycling, and this was confirmed by spectrophotometric titrations. In control smooth-muscle cells and cells with siRNA-mediated Cygb knockdown subjected to extracellular superoxide stress from xanthine/xanthine oxidase or intracellular superoxide stress triggered by the uncoupler, menadione, Cygb had a prominent role in superoxide metabolism and protected against superoxide-mediated death. Similar experiments in vessels showed higher levels of superoxide in Cygb-/- mice than wild type. Thus, Cygb has potent SOD function and can rapidly dismutate superoxide in cells, conferring protection against oxidant injury. In view of its ubiquitous cellular expression at micromolar concentrations in smooth-muscle and other cells, Cygb can play an important role in cellular superoxide metabolism.


Subject(s)
Cytoglobin , Superoxide Dismutase , Animals , Cell Line , Cytoglobin/chemistry , Cytoglobin/genetics , Cytoglobin/metabolism , Electron Spin Resonance Spectroscopy , Male , Mice , Mice, Knockout , Reactive Oxygen Species/metabolism , Superoxide Dismutase/chemistry , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism
4.
J Biol Chem ; 296: 100196, 2021.
Article in English | MEDLINE | ID: mdl-33334890

ABSTRACT

In smooth muscle, cytoglobin (Cygb) functions as a potent nitric oxide (NO) dioxygenase and regulates NO metabolism and vascular tone. Major questions remain regarding which cellular reducing systems regulate Cygb-mediated NO metabolism. To better define the Cygb-mediated NO dioxygenation process in vascular smooth muscle cells (SMCs), and the requisite reducing systems that regulate cellular NO decay, we assessed the intracellular concentrations of Cygb and its putative reducing systems and examined their roles in the process of NO decay. Cygb and the reducing systems, cytochrome b5 (B5)/cytochrome b5 reductase (B5R) and cytochrome P450 reductase (CPR) were measured in aortic SMCs. Intracellular Cygb concentration was estimated as 3.5 µM, while B5R, B5, and CPR were 0.88, 0.38, and 0.15 µM, respectively. NO decay in SMCs was measured following bolus addition of NO to air-equilibrated cells. siRNA-mediated knockdown experiments indicated that âˆ¼78% of NO metabolism in SMCs is Cygb-dependent. Of this, ∼87% was B5R- and B5-dependent. CPR knockdown resulted in a small decrease in the NO dioxygenation rate (VNO), while depletion of ascorbate had no effect. Kinetic analysis of VNO for the B5/B5R/Cygb system with variation of B5 or B5R concentrations from their SMC levels showed that VNO exhibits apparent Michaelis-Menten behavior for B5 and B5R. In contrast, linear variation was seen with change in Cygb concentration. Overall, B5/B5R was demonstrated to be the major reducing system supporting Cygb-mediated NO metabolism in SMCs with changes in cellular B5/B5R levels modulating the process of NO decay.


Subject(s)
Cytochromes b5/metabolism , Cytoglobin/metabolism , Muscle, Smooth, Vascular/metabolism , Nitric Oxide/metabolism , Oxygenases/metabolism , Animals , Biochemical Phenomena , Cells, Cultured , Humans , Kinetics , Mice
5.
Basic Clin Pharmacol Toxicol ; 127(4): 265-277, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32306544

ABSTRACT

Gastric ulcer is a widespread inflammatory disease with high socio-economic burden. C-phycocyanin is one of the active constituents of Spirulina microalgae, and although it is well known for its antioxidant and anti-inflammatory properties, its protective effects against gastric ulcer have not yet been identified. High-mobility group box 1 (HMGB1) is a nuclear protein that, once secreted extracellularly, initiates several inflammatory reactions, and it is involved in the pathogenesis of gastric ulcer. The aim of the present study was to investigate the anti-inflammatory and anti-ulcerogenic effects of C-phycocyanin against ethanol-induced gastric ulcer targeting HMGB1/NLRP3/NF-κB pathway. Ulcer induction showed increase in HMGB1 expression through activation of nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome and nuclear factor kappa p65 (NF-κB p65). Moreover, oxidative stress and inflammatory markers were elevated in the ulcer-treated group compared to the normal control group. However, pre-treatment with C-phycocyanin significantly reduced HMGB1 expression via suppression of NLRP3/NF-κB, oxidative markers, IL-1ß, tumour necrosis factor-α (TNF-α) and ulcer index value. These results were consistent with histopathological and immunohistochemistry examination. Thus, C-phycocyanin is a potential therapeutic strategy with anti-inflammatory and anti-ulcerogenic effects against ethanol-induced gastric ulcer.


Subject(s)
Anti-Inflammatory Agents/pharmacology , HMGB1 Protein/metabolism , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phycocyanin/pharmacology , Stomach Ulcer/prevention & control , Animals , Ethanol/adverse effects , Gastric Mucosa/injuries , Gastric Mucosa/pathology , Inflammation/drug therapy , Interleukin-1beta/metabolism , Male , Oxidative Stress/drug effects , Peroxidase/metabolism , Protective Agents/pharmacology , Rats , Rats, Wistar , Receptor for Advanced Glycation End Products/metabolism , Stomach Ulcer/chemically induced , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolism
6.
Physiol Behav ; 208: 112571, 2019 09 01.
Article in English | MEDLINE | ID: mdl-31175888

ABSTRACT

Several reports have highlighted the role of vinpocetine in Alzheimer's disease (AD). However, the role of vinpocetine in AD under social isolation conditions has not yet been elucidated. Henceforth, this study aimed to investigate the potential neuroprotective effect of vinpocetine in aluminum-induced AD model associated with social isolation. Social isolation increased the escape latency in Morris water maze (MWM) test, elevated the immobility score and decreased swimming score in forced swimming test (FST) in aluminum treated rats. However, vinpocetine enhanced acquisition in MWM test and exerted anti-depressive effect in FST. The histopathological examination showed marked deterioration in the cerebral cortex and hippocampus of AD isolated rats, while vinpocetine revealed overt improvement. In addition, the levels of amyloid-ß protein (Aß), phosphorylated-tau (Ser396), malondialdehyde (MDA), interleukin 1-beta (IL-1ß), tumor necrosis alpha (TNFα), p- Glycogen synthase kinase-3ß (p-GSK3ß) (Tyr216), and ß-secretase (BACE1) gene expression were increased in socially isolated aluminum treated rats, yet, vinpocetine treatment reversed these deteriorating effects. Hence, this study provides profound insights into the role of vinpocetine in AD particularly in the conditions of social isolation. The effects of vinpocetine might be attributed not only to its antioxidant and anti-inflammatory properties, but also to its suppressing effect on GSK3ß activity and its downstream BACE1.


Subject(s)
Aluminum/adverse effects , Cognitive Dysfunction/drug therapy , Neuroprotective Agents/therapeutic use , Social Isolation/psychology , Vinca Alkaloids/therapeutic use , Amyloid Precursor Protein Secretases/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Brain/drug effects , Brain/metabolism , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/etiology , Cognitive Dysfunction/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Male , Maze Learning/drug effects , Rats , Rats, Wistar , Signal Transduction/drug effects
7.
Chem Biol Interact ; 309: 108689, 2019 Aug 25.
Article in English | MEDLINE | ID: mdl-31173751

ABSTRACT

Diabetes mellitus is an independent risk factor for renal impairment in patients exposed to contrast media. It doubles the risk and decreases survival rate of contrast induced nephropathy (CIN). Sulforaphane has antioxidant properties via Nrf2 activation. The interaction of diabetes and/or sulforaphane with contrast media on Nrf2 regulation is not yet understood. Herein, diabetes was induced by a single intra-peritoneal injection of streptozotocin. Animals were then divided into five groups; control non-diabetic group; diabetic group; diabetic/sulforaphane group; diabetic/CIN group; diabetic/CIN/sulforaphane group. Animals were assessed 24 h after CIN induction. Sulforaphane improved the impaired nephrotoxicity parameters, histopathological features, and oxidative stress markers induced by contrast media (meglumine diatrizoate) in diabetic rats. Immunofluorescence detection revealed increased Nrf2 expression in kidney sections after sulforaphane pretreatment. Moreover, gene expression of Nrf2 and HO-1 were up-regulated, while IL-6 and caspase3 were down-regulated in kidney tissues of animals pretreated with sulforaphane. In NRK-52E cells, sulforaphane pretreatment significantly ameliorated the cytotoxicity of meglumine diatrizoate. However, silencing Nrf2 using small interfering RNA (siRNA) abolished the cytoprotective effects of sulforaphane. Collectively, the results of this study suggest that Nrf2/HO-1 pathway has a protective role against CIN and support the clinical implication of Nrf2 activators, such as sulforaphane, in CIN particularly in diabetic patients.


Subject(s)
Apoptosis/drug effects , Contrast Media/toxicity , DNA Damage/drug effects , Diabetes Mellitus, Experimental/pathology , Diatrizoate Meglumine/toxicity , Isothiocyanates/chemistry , NF-E2-Related Factor 2/metabolism , Animals , Antioxidants/chemistry , Cell Line , Contrast Media/chemistry , Diabetes Mellitus, Experimental/chemically induced , Diatrizoate Meglumine/chemistry , Gene Expression Regulation/drug effects , Heme Oxygenase-1/metabolism , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , Nephritis/chemically induced , Nephritis/metabolism , Nephritis/pathology , RNA Interference , RNA, Small Interfering , Rats , Rats, Wistar , Signal Transduction/drug effects , Sulfoxides
8.
Biomed Pharmacother ; 109: 2136-2144, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30551471

ABSTRACT

Metformin is one of the most commonly prescribed antidiabetic drugs. A recent clinical study has highlighted the protective role of metformin against cardiac complications in type I diabetes. Curcumin is a natural compound with well-known antioxidant and anti-inflammatory properties. The present study was designed to investigate the possible role of curcumin in potentiating metformin`s putative effects. Rats received single injection of 52.5 mg/kg streptozocin and the diabetic rats were treated with metformin (200 mg/kg/day), curcumin (100 mg/kg/day) and their combination for 6 weeks. Diabetic rats showed degenerated myocardium as well as significant increase in Creatine Kinase-MB (CK-MB), troponin I and TGF-ß1 levels. In addition, cardiac levels of lipid peroxidation, IL-6, and NF-κB were significantly elevated. Although treatment with metformin restored most of the measured parameters, it showed insignificant improvement in histopathological architecture accompanied by absence of antioxidant effect. Interestingly, concomitant administration of curcumin along with metformin revealed more protection than metformin alone. Inhibition of JAK/STAT pathway and activation of Nrf2/HO-1 pathway seems to be among the mechanisms mediating the effects of curcumin and metformin. The findings of this study highlight the benefits of metformin/curcumin combination in preventing diabetic cardiomyopathy.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Cardiotonic Agents/administration & dosage , Curcumin/administration & dosage , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 1/drug therapy , Metformin/administration & dosage , Animals , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/metabolism , Drug Synergism , Heart/drug effects , Heme Oxygenase-1/metabolism , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Male , Membrane Proteins/metabolism , Myocardium/metabolism , NF-E2-Related Factor 2/metabolism , Rats , Rats, Wistar , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/metabolism , Treatment Outcome
9.
J Egypt Natl Canc Inst ; 30(1): 39-44, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29429892

ABSTRACT

INTRODUCTION: Osteosarcoma (OS) is a primary bone malignancy, characterized by spindle cells producing osteoid. The objective of this study is to describe the magnetic resonance imaging (MRI) features of different OS subtypes, record their attenuation diffusion coefficient (ADC) values and to point to the relation of their pathologic base and their corresponding ADC value. PATIENTS AND METHODS: We performed a retrospective observational lesion-based analysis for 31 pathologically proven osteosarcoma subtypes: osteoblastic (n = 9), fibroblastic (n = 8), chondroblastic (n = 6), para-osteal (n = 3), periosteal (n = 1), telangiectatic (n = 2), small cell (n = 1) and extra-skeletal (n = 1). On conventional images we recorded: bone of origin, epicenter, intra-articular extension, and invasion of articulating bones, skip lesions, distant metastases, pathological fractures, ossified matrix, hemorrhage and necrosis. We measured the mean ADC value for each lesion. RESULTS: Among the included OS lesions, 51.6% originated at the femur, 29% showed intra-articular extension, 16% invaded neighboring bone, 9% were associated with pathological fracture and 25.8% were associated with distant metastases. On MRI, all lesions showed ossified matrix, 35.5% showed hemorrhage and 58% showed necrosis. The mean ADC values for OS lesions ranged from 0.74 × 10-3 mm2/s (recorded for conventional osteoblastic OS) to 1.50 × 10-3 mm2/s (recorded for telangiectatic OS) with an average value of 1.16 ±â€¯0.18 × 10-3 mm2/s. Conventional chondroblastic OS recorded higher values compared to the other two conventional subtypes. CONCLUSION: Osteosarcoma has different pathologic subtypes which correspondingly vary in their imaging criteria and their ADC values.


Subject(s)
Bone Neoplasms/diagnostic imaging , Bone Neoplasms/pathology , Osteosarcoma/diagnostic imaging , Osteosarcoma/pathology , Adolescent , Adult , Child , Diffusion Magnetic Resonance Imaging , Female , Humans , Image Interpretation, Computer-Assisted , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Staging , Retrospective Studies , Young Adult
10.
J Pharm Investig ; 48(6): 673-683, 2018.
Article in English | MEDLINE | ID: mdl-30595939

ABSTRACT

The objective of the present study was to develop rectal mucoadhesive hydrogels loaded with Tolmetin Sodium, a non-steroidal anti-inflammatory drug, for prolonged duration of action and increased bioavailability. Fourteen formulae were prepared with different types and concentrations of polymers as hydroxypropylmethyl cellulose, hydroxylethyl cellulose, carboxymethyl cellulose and sodium alginate. Each formulation contain Tolmetin Sodium equivalent to 5% w/w active drug. The effect of the employed gel bases on pH, gel strength, mucoadhesion, viscosity and the in vitro release profile of drug was examined. In addition, hydrogel formulations were subjected to rheological and stability studies. The physicochemical characterization revealed that all hydrogels had a suitable pH (6.64-7.75) and gel strength (15.5-65.29 s) for rectal application. The in-vitro drug release from the formulations showed a controlled drug release pattern, reaching 72-92.6% after 8 h. The kinetic analysis of the release data revealed that the drug release from all tested hydrogel bases obeyed the diffusion mechanism. The degradation of Tolmetin Sodium from its rectal hydrogel formulations was found to be a zero-order reaction. All formulations except sodium alginate hydrogel were quite stable. Considering the in-vitro release, rheological properties and shelf life, (CMC; 2%w/w) hydrogel formula was the best among the studied formulations. Therefore, further histopathological and bioavailability studies were carried out to detect different pharmacokinetic parameters of the established formulations compared with commercially available capsules. Formula containing 2% CMC showed relative bioavailability 357.93%. Finally, good correlation was observed between in-vitro and in-vivo profile.

11.
Chem Biol Interact ; 270: 33-40, 2017 May 25.
Article in English | MEDLINE | ID: mdl-28412091

ABSTRACT

Contrast-induced nephropathy (CIN) is an important cause of acute kidney injury characterized by significant mortality and morbidity. To date, there is no successful protective regimen for CIN especially in poor kidney function patients. Lansoprazole has been shown to exert antioxidant action through induction of nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. The aim of the present study is to investigate the potential of lansoprazole to activate Nrf2 pathway in the kidney and consequently to protect against oxidative stress induced by iodinated contrast media. Lansoprazole, at a dose of 100 mg/kg, showed a significant induction of Nrf2 mRNA after 3 h. Administration of contrast media induced significant increase in serum creatinine and blood urea nitrogen, histological deterioration, and reduction in total antioxidant capacity. Moreover, it instigated the defensive Nrf2 gene expression and immunoreactivity. In addition, there were overexpression of HO-1, caspase 3, p53 and IL6 genes and downregulation of Bcl2 gene. Pre-treatment with lansoprazole (100 mg/kg) ameliorated the nephrotoxicity parameters and oxidative stress, improved histological lesions, and hijacked apoptotic and inflammatory markers that were provoked by contrast media. In conclusion, lansoprazole attenuates experimental CIN which might be due to activation of Nrf2 antioxidant defence pathway. These findings highlight the potential benefit of incorporating lansoprazole in the protective regimen against CIN especially for susceptible patients.


Subject(s)
Heme Oxygenase-1/metabolism , Kidney/drug effects , Lansoprazole/pharmacology , Lansoprazole/therapeutic use , NF-E2-Related Factor 2/drug effects , Nephritis/drug therapy , Signal Transduction/drug effects , Administration, Oral , Animals , Contrast Media/toxicity , Fluorescent Antibody Technique , Kidney/pathology , Male , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Nephritis/chemically induced , Rats , Rats, Wistar , Real-Time Polymerase Chain Reaction , Up-Regulation/drug effects
12.
Pharmacol Rep ; 69(2): 268-275, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28129600

ABSTRACT

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease with significant morbidity. Cardamonin is a natural chalcone derivative with considerable anti-inflammatory activity. Herein, the potential protective effect of cardamonin against UC was tested in a rat model. METHODS: Rats were given 10 or 30mg/kg/day of cardamonin orally for 14days before induction of UC. On the 14th day of treatment, UC was induced by intrarectal instillation of 2ml 3% acetic acid. Twenty four h after acetic acid instillation, rats were sacrificed and colons were analyzed by macroscopic and histopathological examination. Colon lipid peroxidation was examined by biochemical evaluation of malondialdehyde (MDA). Myeloperoxidase (MPO), iNOS, NF-κB, TNFα levels were measured by ELISA. Moreover, caspase-3 and COX-2 were assessed by immunohistochemical analysis. RESULTS: Cardamonin at 10 and 30mg/kg decreased the disease activity index and macroscopic damage index scores, and significantly reduced histopathological deterioration. Additionally, cardamonin reduced levels of MPO, iNOS, NF-κB, TNFα and MDA (p<0.05). Immunohistochemistry revealed down-regulation of COX-2 and caspase-3 in groups treated with cardamonin. CONCLUSION: Cardamonin has a protective effect against acetic acid-induced colitis. This effect may be due to reducing inflammation, oxidative stress and apoptosis.


Subject(s)
Acetic Acid/pharmacology , Chalcones/pharmacology , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Protective Agents/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Caspase 3/metabolism , Colitis, Ulcerative/metabolism , Colon/drug effects , Colon/metabolism , Cyclooxygenase 2/metabolism , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Lipid Peroxidation/drug effects , Male , Malondialdehyde/metabolism , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , Peroxidase/metabolism , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/metabolism
13.
Sci Rep ; 6: 36855, 2016 11 14.
Article in English | MEDLINE | ID: mdl-27841296

ABSTRACT

Doxorubicin (DOX) has limited efficacy in colorectal cancer due to multi-drug resistance. Resveratrol (RES) and didox (DID) are polyhydroxyphenols with potential chemosensitizing effects. Herein, we assessed the chemomodulatory effects of RES and DID to DOX in colorectal cancer cells. Equitoxic combination of DOX with RES and DID in HCT 116 reduced the IC50 of DOX from 0.96 ± 0.02 µM to 0.52 ± 0.05 µM and 0.4 ± 0.06 µM, respectively. Similarly, combination of DOX with RES and DID in HT-29 decreased the IC50's of DOX from 0.88 ± 0.03 µM to 0.47 ± 0.02 µM and 0.29 ± 0.04 µM, respectively. The expressions of p53 and Bax genes were markedly elevated in HCT 116 cells after exposure to DOX/DID. In HT-29 cells, the expression of Bcl-XL gene was significantly decreased after exposure to DOX/DID. In addition, combination of DOX with RES significantly increased the expression of Bax gene in HCT 116 cells. RES treatment induced significant S-phase arrest in DOX-treated HCT 116 cells, while DID induced G2/M- and S-phase arrest in HCT 116 and HT-29, respectively. Both RES and DID significantly enhanced the intracellular entrapment of DOX due to blocking the efflux activity of p-glycoprotein pump. In conclusion, RES and DID sensitize colorectal cancer cells to DOX via facilitating apoptosis and enhancing intracellular entrapment of DOX.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/metabolism , Doxorubicin/pharmacology , Hydroxamic Acids/pharmacology , Stilbenes/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis , Cell Survival/drug effects , Colorectal Neoplasms/drug therapy , Drug Synergism , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , HT29 Cells , Humans , Resveratrol
14.
Pediatr Blood Cancer ; 63(9): 1539-45, 2016 09.
Article in English | MEDLINE | ID: mdl-27163515

ABSTRACT

BACKGROUND: The aim of the present study is to determine the correlation of hepatitis C virus (HCV) infection and polymorphisms in different genes with toxicity of either methotrexate (MTX) or 6-mercaptopurine (6-MP) administered to children with acute lymphoblastic leukemia (ALL). PROCEDURE: One hundred children with low-risk ALL, who were treated according to the St. Jude Total therapy XV, were recruited. The recruited children were receiving MTX and 6-MP during maintenance phase. Patients were excluded from the study if they had other types of leukemia. Genotyping analyses for the thiopurine methyltransferase (TPMT), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferase (GST) genes were performed using a combination of polymerase chain reaction (PCR) and PCR-RFLP (where RFLP is restriction fragment length polymorphism) protocols. Relevant clinical data on adverse drug reactions were collected objectively (blinded to genotypes) from the patient medical records. RESULTS: There was a significant correlation between the combined presence of HCV and TPMT*3B G460A gene polymorphisms and grades 2-4 hepatotoxicity as aspartate aminotransferase (AST) elevation (P < 0.04). The same observation was seen when comparing either the presence of HCV alone or the presence of the gene polymorphism alone. A significant association between the combined presence of HCV and MTHFR C677T polymorphism and grades 2-4 hepatotoxicity as alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) elevation was observed (P values <0.001, 0.02, and 0.001, respectively). The presence of HCV infection had a significant negative effect on hepatic transaminases. CONCLUSIONS: The present data support a role for combining analysis of genetic variation in drug-metabolizing enzymes and the presence of HCV in the assessment of specific drugs toxicities in multiagent chemotherapeutic treatment regimens.


Subject(s)
Hepacivirus/isolation & purification , Mercaptopurine/adverse effects , Methotrexate/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Child , Child, Preschool , Female , Genotype , Humans , Liver/drug effects , Male , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Methyltransferases/genetics , Polymorphism, Genetic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology
15.
J Clin Oncol ; 33(27): 3018-28, 2015 Sep 20.
Article in English | MEDLINE | ID: mdl-26304902

ABSTRACT

During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges.


Subject(s)
Interdisciplinary Communication , International Cooperation , Medical Oncology , Neoplasms, Germ Cell and Embryonal/therapy , Pediatrics , Adolescent , Age of Onset , Child , Cooperative Behavior , Diffusion of Innovation , Female , History, 20th Century , History, 21st Century , Humans , Male , Medical Oncology/history , Medical Oncology/trends , Neoplasms, Germ Cell and Embryonal/diagnosis , Neoplasms, Germ Cell and Embryonal/history , Neoplasms, Germ Cell and Embryonal/pathology , Pediatrics/history , Pediatrics/trends , Survivors , Time Factors , Treatment Outcome , Young Adult
16.
Pediatr Hematol Oncol ; 29(7): 627-32, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22889151

ABSTRACT

Ursodeoxycholic acid (UDCA) possesses a hepatoprotective effect in drug-induced hepatotoxicity. In a prospective randomized parallel study, 39 children with acute lymphoblastic leukemia (ALL) were randomized to receive UDCA with chemotherapy for 6 months, then discontinued UDCA and were followed up for 3 months, (UDCA group) (N = 19) or receive chemotherapy without UDCA and followed up for 9 months (control group) (N = 20). In this pilot study, UDCA treatment was associated with a trend toward decreased levels of hepatic transaminases when concomitantly administered with chemotherapy and, therefore, safer outcome in children with ALL. Future studies with a larger sample size are needed to confirm the efficacy and safety of UDCA in this setting.


Subject(s)
Antineoplastic Agents/adverse effects , Liver/drug effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protective Agents/therapeutic use , Ursodeoxycholic Acid/therapeutic use , Administration, Oral , Adolescent , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Follow-Up Studies , Humans , Liver/pathology , Prospective Studies , Protective Agents/administration & dosage , Protective Agents/pharmacology , Ursodeoxycholic Acid/administration & dosage , Ursodeoxycholic Acid/pharmacology
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