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Search on : Benzoquinones [Words]
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[PMID]: 29486369
[Au] Autor:Zhao Y; Lu Y; Li R; He J; Zhang H; Wang X; Ge Z; Li R
[Ad] Address:State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
[Ti] Title:Discovery and optimization of 2-thio-5-amino substituted benzoquinones as potent anticancer agents.
[So] Source:Eur J Med Chem;149:1-9, 2018 Feb 21.
[Is] ISSN:1768-3254
[Cp] Country of publication:France
[La] Language:eng
[Ab] Abstract:Based on our discovered novel lead compound 1 through phenotypic drug discovery (PDD) approaches, systematic structural optimization was performed. A series of 2-allylthio-5-amino substituted benzoquinones were synthesized and evaluated for their in-vitro anticancer activities against human prostate cancer cell line PC3. The compound 7a was found inhibit the growth of PC3 with an IC of 0.22 µM, which is over 20-fold improvement compared to lead compound 1. It is noteworthy that compound 7a also showed potent anti-proliferation activity toward a panel of cancer cells with relatively less cytotoxicity to nonmalignant cell, as well as good water solubility.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180227
[Lr] Last revision date:180227
[St] Status:Publisher

  2 / 7742 MEDLINE  
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[PMID]: 29304125
[Au] Autor:Barisone GA; O'Donnell RT; Ma Y; Abuhay MW; Lundeberg K; Gowda S; Tuscano JM
[Ad] Address:Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis, Sacramento, California, United States of America.
[Ti] Title:A purified, fermented, extract of Triticum aestivum has lymphomacidal activity mediated via natural killer cell activation.
[So] Source:PLoS One;13(1):e0190860, 2018.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Non-Hodgkin lymphoma (NHL) affects over 400,000 people in the United States; its incidence increases with age. Treatment options are numerous and expanding, yet efficacy is often limited by toxicity, particularly in the elderly. Nearly 70% patients eventually die of the disease. Many patients explore less toxic alternative therapeutics proposed to boost anti-tumor immunity, despite a paucity of rigorous scientific data. Here we evaluate the lymphomacidal and immunomodulatory activities of a protein fraction isolated from fermented wheat germ. Fermented wheat germ extract was produced by fermenting wheat germ with Saccharomyces cerevisiae. A protein fraction was tested for lymphomacidal activity in vitro using NHL cell lines and in vivo using mouse xenografts. Mechanisms of action were explored in vitro by evaluating apoptosis and cell cycle and in vivo by immunophenotyping and measurement of NK cell activity. Potent lymphomacidal activity was observed in a panel of NHL cell lines and mice bearing NHL xenografts. This activity was not dependent on wheat germ agglutinin or benzoquinones. Fermented wheat germ proteins induced apoptosis in NHL cells, and augmented immune effector mechanisms, as measured by NK cell killing activity, degranulation and production of IFNγ. Fermented wheat germ extract can be easily produced and is efficacious in a human lymphoma xenograft model. The protein fraction is quantifiable and more potent, shows direct pro-apoptotic properties, and enhances immune-mediated tumor eradication. The results presented herein support the novel concept that proteins in fermented wheat germ have direct pro-apoptotic activity on lymphoma cells and augment host immune effector mechanisms.
[Mh] MeSH terms primary: Antineoplastic Agents/pharmacology
Killer Cells, Natural/immunology
Lymphocyte Activation/drug effects
Lymphoma, Non-Hodgkin/pathology
Plant Extracts/pharmacology
Triticum/metabolism
[Mh] MeSH terms secundary: Animals
Apoptosis/drug effects
Cell Line, Tumor
Female
Fermentation
Humans
Lymphoma, Non-Hodgkin/immunology
Mice
Mice, Nude
Plant Proteins/pharmacology
Xenograft Model Antitumor Assays
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Antineoplastic Agents); 0 (Plant Extracts); 0 (Plant Proteins)
[Em] Entry month:1802
[Cu] Class update date: 180223
[Lr] Last revision date:180223
[Js] Journal subset:IM
[Da] Date of entry for processing:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190860

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[PMID]: 29288942
[Au] Autor:Martín-Acosta P; Haider S; Amesty Á; Aichele D; Jose J; Estévez-Braun A
[Ad] Address:Instituto Universitario de Bio-Orgánica Antonio González (CIBICAN), Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez Nº 2, 38206, La Laguna, Tenerife, Spain.
[Ti] Title:A new family of densely functionalized fused-benzoquinones as potent human protein kinase CK2 inhibitors.
[So] Source:Eur J Med Chem;144:410-423, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] Country of publication:France
[La] Language:eng
[Ab] Abstract:A new series of 2-amino-4-phenyl-6-hydroxy-7-alkyl-pyranobenzoquinones was synthesized as ATP-competitive CK2 inhibitors. They were readily synthesized through a three-component Knoevenagel condensation-Michael addition-heterocyclization reaction from aldehydes, malononitrile, and 3-alkyl-2,5-dihydroxybenzoquinones. Some of the synthesized compounds presented interesting inhibitory activity with IC values in the submicromolar range. A structure-activity relationship study was carried out and the mode of binding was analysed by docking studies and supported by ATP competition assays.
[Mh] MeSH terms primary: Benzoquinones/pharmacology
Casein Kinase II/antagonists & inhibitors
Protein Kinase Inhibitors/pharmacology
[Mh] MeSH terms secundary: Benzoquinones/chemical synthesis
Benzoquinones/chemistry
Casein Kinase II/metabolism
Cell Survival/drug effects
Dose-Response Relationship, Drug
Humans
MCF-7 Cells
Molecular Structure
Protein Kinase Inhibitors/chemical synthesis
Protein Kinase Inhibitors/chemistry
Structure-Activity Relationship
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Benzoquinones); 0 (Protein Kinase Inhibitors); EC 2.7.11.1 (Casein Kinase II)
[Em] Entry month:1802
[Cu] Class update date: 180223
[Lr] Last revision date:180223
[Js] Journal subset:IM
[Da] Date of entry for processing:171231
[St] Status:MEDLINE

  4 / 7742 MEDLINE  
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[PMID]: 29254287
[Au] Autor:Jiang L; Li H; Zhao N
[Ad] Address:Department of Anesthesiology, No. 215 Hospital of Shaanxi Nuclear Industry, Xianyang, Shaanxi, China.
[Ti] Title:Thymoquinone protects against cobalt chloride-induced neurotoxicity via Nrf2/GCL-regulated glutathione homeostasis.
[So] Source:J Biol Regul Homeost Agents;31(4):843-853, 2017 Oct-Dec.
[Is] ISSN:0393-974X
[Cp] Country of publication:Italy
[La] Language:eng
[Ab] Abstract:The prevalence of neurodegenerative diseases worldwide has increased dramatically in the last decades. Hypoxia and oxidative stress play a central role in the pathogenesis of neurodegenerative diseases. Thymoquinone (TQ) is a monoterpenoid hydrocarbon compound that possesses potent antioxidant activity. In the current study, we investigated the neuroprotective effects of TQ against CoCl2, a widely used hypoxia-inducing agent. We found that TQ inhibited CoCl2-indcued cytotoxicity in vitro, as reflected by an increase of cell viability and decrease of apoptosis in CoCl2-treated PC12 cells. TQ exhibited a potent protective effect against CoCl2-induced neurotoxicity in vivo, as evidenced by decreased time spent to find the platform site in the Probe trials, reduced escape latencies, decreased traveling distance and reduction of apoptotic cell death in brains in CoCl2-treated rats. CoCl2-resulted decrease of glutathione (GSH) and increase of malondialdehyde (MDA) levels were significantly inhibited by TQ. Inhibition of GSH synthesis by buthionine sulphoximine (BSO) significantly attenuated TQ-induced neuroprotective effects against CoCl2 in rats and in PC12 cells. TQ could upregulate nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/glutamate-cysteine ligase catalytic subunit (GCLc) and Nrf2/glutamate-cysteine ligase modifier subunit (GCLm) pathway which contributed to antioxidant and neuroprotective effects of TQ. In summary, we found that TQ exhibited protective effects against neurotoxicity via upregulation of Nrf2/GCL signaling. Upregulation of Nrf2/GCL signaling promoted the synthesis of GSH and contributed to attenuation of oxidative stress, neuronal cell apoptosis and neurotoxicity. These data have appointed a new path toward the understanding of the neuroprotective activities of TQ.
[Mh] MeSH terms primary: Antioxidants/pharmacology
Benzoquinones/pharmacology
Cobalt/pharmacology
Hypoxia/prevention & control
Neuroprotective Agents/pharmacology
[Mh] MeSH terms secundary: Animals
Apoptosis/drug effects
Buthionine Sulfoximine/antagonists & inhibitors
Buthionine Sulfoximine/pharmacology
Cell Hypoxia/drug effects
Cell Survival/drug effects
Exploratory Behavior/drug effects
Gene Expression Regulation/drug effects
Glutamate-Cysteine Ligase/genetics
Glutamate-Cysteine Ligase/metabolism
Glutathione/agonists
Glutathione/metabolism
Humans
Hypoxia/chemically induced
Hypoxia/genetics
Hypoxia/pathology
Male
Malondialdehyde/antagonists & inhibitors
Malondialdehyde/metabolism
NF-E2-Related Factor 2/genetics
NF-E2-Related Factor 2/metabolism
PC12 Cells
Rats
Rats, Wistar
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Antioxidants); 0 (Benzoquinones); 0 (NF-E2-Related Factor 2); 0 (Neuroprotective Agents); 0 (Nfe2l2 protein, rat); 3G0H8C9362 (Cobalt); 490-91-5 (thymoquinone); 4Y8F71G49Q (Malondialdehyde); 5072-26-4 (Buthionine Sulfoximine); EC 6.3.2.2 (GCLM protein, rat); EC 6.3.2.2 (Glutamate-Cysteine Ligase); EC 6.3.2.2. (GCLC protein, rat); EVS87XF13W (cobaltous chloride); GAN16C9B8O (Glutathione)
[Em] Entry month:1802
[Cu] Class update date: 180222
[Lr] Last revision date:180222
[Js] Journal subset:IM
[Da] Date of entry for processing:171220
[St] Status:MEDLINE

  5 / 7742 MEDLINE  
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[PMID]: 29406097
[Au] Autor:Xu T; Yin J; Chen S; Zhang D; Wang H
[Ad] Address:State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Centre for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: xutianstudent@126.com.
[Ti] Title:Elevated 8-oxo-7,8-dihydro-2'-deoxyguanosine in genome of T24 bladder cancer cells induced by halobenzoquinones.
[So] Source:J Environ Sci (China);63:133-139, 2018 Jan.
[Is] ISSN:1001-0742
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Halobenzoquinones (HBQs) are an emerging class of halogenated disinfection byproducts (DBPs) in drinking water, which raised public concerns due to potential carcinogenic effects to human bladder. Our previous work demonstrated that HBQs and hydrogen peroxide (H O ) together generated oxidative DNA damage via a metal-independent and intercalation-enhanced oxidation mechanism in vitro. This study further investigated the efficiency of various HBQs to induce oxidative DNA damage in T24 bladder cancer cells. Compared with T24 cells without treatment (3.1 lesions per 10 dG), the level of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) significantly increased by 1.4, 3.2, 8.8, and 9.2 times after treatment with tetrabromo-1,4-benzoquinone (TBBQ), terachloro-1,4-benzoquinone (TCBQ), 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ) and 2,5-dichloro-1,4-benzoquinone (2,5-DCBQ) for 24hr, respectively. Interestingly, we found that the oxidative potency of HBQs in T24 cells (2,5-DCBQ≈2,6-DCBQ>TCBQ>TBBQ) is inconsistent with that of in vitro dsDNA oxidation (TCBQ>TBBQ>2,5-DCBQ>2,6-DCBQ), suggesting HBQs induce oxidative lesions in cellular genomic DNA probably involved with a complex mechanism.
[Mh] MeSH terms primary: Benzoquinones/toxicity
Deoxyguanosine/analogs & derivatives
Hazardous Substances/toxicity
[Mh] MeSH terms secundary: Cell Line, Tumor
Deoxyguanosine/metabolism
Humans
Hydrogen Peroxide
Urinary Bladder Neoplasms
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Benzoquinones); 0 (Hazardous Substances); 88847-89-6 (8-oxo-7-hydrodeoxyguanosine); BBX060AN9V (Hydrogen Peroxide); G9481N71RO (Deoxyguanosine)
[Em] Entry month:1802
[Cu] Class update date: 180216
[Lr] Last revision date:180216
[Js] Journal subset:IM
[Da] Date of entry for processing:180207
[St] Status:MEDLINE

  6 / 7742 MEDLINE  
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[PMID]: 29406093
[Au] Autor:Ge F; Xiao Y; Yang Y; Wang W; Moe B; Li XF
[Ad] Address:College of Environment and Resources, Xiangtan University, Xiangtan, Hunan 411105, China. Electronic address: gefei@xtu.edu.cn.
[Ti] Title:Formation of water disinfection byproduct 2,6-dichloro-1,4-benzoquinone from chlorination of green algae.
[So] Source:J Environ Sci (China);63:1-8, 2018 Jan.
[Is] ISSN:1001-0742
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:We report that green algae in lakes and rivers can serve as precursors of halobenzoquinone (HBQ) disinfection byproducts (DBPs) produced during chlorination. Chlorination of a common green alga, Chlorella vulgaris, produced 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), the most prevalent HBQ DBP in disinfected water. Under varying pH conditions (pH6.0-9.0), 2,6-DCBQ formation ranged from 0.3 to 2.1µg/mg C with maximum formation at pH8.0. To evaluate the contribution of organic components of C. vulgaris to 2,6-DCBQ formation, we separated the organics into two fractions, the protein-rich fraction of intracellular organic matter (IOM) and the polysaccharide-laden fraction of extracellular organic matter (EOM). Chlorination of IOM and EOM produced 1.4µg/mg C and 0.7µg/mg C of 2,6-DCBQ, respectively. The IOM generated a two-fold higher 2,6-DCBQ formation potential than the EOM fraction, suggesting that proteins are potent 2,6-DCBQ precursors. This was confirmed by the chlorination of proteins extracted from C. vulgaris: the amount of 2,6-DCBQ produced is linearly correlated with the concentration of total algal protein (R =0.98). These results support that proteins are the primary precursors of 2,6-DCBQ in algae, and control of green algal bloom outbreaks in source waters is important for management of HBQ DBPs.
[Mh] MeSH terms primary: Benzoquinones/metabolism
Chlorella vulgaris/physiology
Disinfectants/metabolism
Water Pollutants, Chemical/metabolism
[Mh] MeSH terms secundary: Benzoquinones/analysis
Chlorophyta
Disinfectants/analysis
Disinfection
Halogenation
Water Pollutants, Chemical/analysis
Water Purification/methods
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Benzoquinones); 0 (Disinfectants); 0 (Water Pollutants, Chemical)
[Em] Entry month:1802
[Cu] Class update date: 180216
[Lr] Last revision date:180216
[Js] Journal subset:IM
[Da] Date of entry for processing:180207
[St] Status:MEDLINE

  7 / 7742 MEDLINE  
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[PMID]: 29273526
[Au] Autor:Stueber T; Meyer S; Jangra A; Hage A; Eberhardt M; Leffler A
[Ad] Address:Department of Anaesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
[Ti] Title:Activation of the capsaicin-receptor TRPV1 by the acetaminophen metabolite N-arachidonoylaminophenol results in cytotoxicity.
[So] Source:Life Sci;194:67-74, 2018 Feb 01.
[Is] ISSN:1879-0631
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:AIMS: The anandamide reuptake inhibitor N-arachidonoylaminophenol (AM404) and the reactive substance N-acetyl-p-benzoquinone imine (NAPQI) are both metabolites of acetaminophen and may contribute to acetaminophen-induced analgesia by acting at TRPV1 expressed in the peripheral or central nervous system. While NAPQI slowly sensitizes and activates TRPV1 by interacting with distinct intracellular cysteine residues, detailed properties of AM404 as an agonist of TRPV1 have not yet been reported on. We explored the effects of AM404 on recombinant human TRPV1 and in rodent dorsal root ganglion (DRG) neurons. MATERIALS AND METHODS: HEK 293 cells expressing different isoforms of recombinant TRPV1 and rodent DRG neurons were employed for patch clamp and calcium imaging experiments. Cytotoxicity was assessed by propidium iodide and Annexin V staining on TRPV1-HEK 293 cells and with trypan blue staining on DRG neurons. KEY FINDINGS: AM404 activates hTRPV1 at concentrations >1µM and in a concentration-dependent manner. AM404 also potentiates TRPV1-mediated currents evoked by heat and anandamide. Moreover, AM404-evoked currents are potentiated by NAPQI. While the partly capsaicin-insensitive rabbit (o) TRPV1 fails to respond to AM404, AM404-sensitivity is restored by insertion of the capsaicin binding-domain of rat TRPV1 into oTRPV1. In DRG neurons, AM404-evoked calcium influx as well as cell death is mediated by TRPV1. SIGNIFICANCE: AM404 gates TRPV1 by interacting with the vanilloid-binding site, and TRPV1 is the main receptor for AM404 in DRG neurons. While direct activation of TRPV1 requires high concentrations of AM404, it is possible that synergistic effects of AM404 with further TRPV1-agonists may occur at clinically relevant concentrations.
[Mh] MeSH terms primary: Acetaminophen/pharmacology
Analgesics, Non-Narcotic/pharmacology
Arachidonic Acids/pharmacology
Ganglia, Spinal/drug effects
TRPV Cation Channels/metabolism
[Mh] MeSH terms secundary: Acetaminophen/metabolism
Analgesia
Analgesics, Non-Narcotic/metabolism
Animals
Arachidonic Acids/metabolism
Benzoquinones/metabolism
Capsaicin/pharmacology
Ganglia, Spinal/cytology
HEK293 Cells
Humans
Imines/metabolism
Mice, Inbred C57BL
Neurons/drug effects
Neurons/metabolism
Rabbits
Rats, Sprague-Dawley
Sensory System Agents/pharmacology
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Analgesics, Non-Narcotic); 0 (Arachidonic Acids); 0 (Benzoquinones); 0 (Imines); 0 (Sensory System Agents); 0 (TRPV Cation Channels); 0 (TRPV1 protein, human); 362O9ITL9D (Acetaminophen); G6S9BN13TI (N-acetyl-4-benzoquinoneimine); S07O44R1ZM (Capsaicin); XVJ94H0U21 (N-(4-hydroxyphenyl)arachidonylamide)
[Em] Entry month:1802
[Cu] Class update date: 180213
[Lr] Last revision date:180213
[Js] Journal subset:IM
[Da] Date of entry for processing:171224
[St] Status:MEDLINE

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[PMID]: 28463500
[Au] Autor:Kobylarz MJ; Heieis GA; Loutet SA; Murphy MEP
[Ad] Address:The Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia , Vancouver, British Columbia V6T 1Z3; Canada.
[Ti] Title:Iron Uptake Oxidoreductase (IruO) Uses a Flavin Adenine Dinucleotide Semiquinone Intermediate for Iron-Siderophore Reduction.
[So] Source:ACS Chem Biol;12(7):1778-1786, 2017 Jul 21.
[Is] ISSN:1554-8937
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Many pathogenic bacteria including Staphylococcus aureus use iron-chelating siderophores to acquire iron. Iron uptake oxidoreductase (IruO), a flavin adenine dinucleotide (FAD)-containing nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase from S. aureus, functions as a reductase for IsdG and IsdI, two paralogous heme degrading enzymes. Also, the gene encoding for IruO was shown to be required for growth of S. aureus on hydroxamate siderophores as a sole iron source. Here, we show that IruO binds the hydroxamate-type siderophores desferrioxamine B and ferrichrome A with low micromolar affinity and in the presence of NADPH, Fe(II) was released. Steady-state kinetics of Fe(II) release provides k /K values in the range of 600 to 7000 M s for these siderophores supporting a role for IruO as a siderophore reductase in iron utilization. Crystal structures of IruO were solved in two distinct conformational states mediated by the formation of an intramolecular disulfide bond. A putative siderophore binding site was identified adjacent to the FAD cofactor. This site is partly occluded in the oxidized IruO structure consistent with this form being less active than reduced IruO. This reduction in activity could have a physiological role to limit iron release under oxidative stress conditions. Visible spectroscopy of anaerobically reduced IruO showed that the reaction proceeds by a single electron transfer mechanism through an FAD semiquinone intermediate. From the data, a model for single electron siderophore reduction by IruO using NADPH is described.
[Mh] MeSH terms primary: Benzoquinones/chemistry
Flavin-Adenine Dinucleotide/chemistry
Iron/metabolism
Oxidoreductases/metabolism
Siderophores/metabolism
[Mh] MeSH terms secundary: Anaerobiosis
Binding Sites
Cloning, Molecular
Crystallography, X-Ray
Kinetics
Models, Molecular
NADP/chemistry
Oxidation-Reduction
Oxidoreductases/chemistry
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Benzoquinones); 0 (Siderophores); 146-14-5 (Flavin-Adenine Dinucleotide); 3225-29-4 (semiquinone radicals); 53-59-8 (NADP); E1UOL152H7 (Iron); EC 1.- (Oxidoreductases)
[Em] Entry month:1802
[Cu] Class update date: 180207
[Lr] Last revision date:180207
[Js] Journal subset:IM
[Da] Date of entry for processing:170503
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00203

  9 / 7742 MEDLINE  
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[PMID]: 28448463
[Au] Autor:Atta MS; Almadaly EA; El-Far AH; Saleh RM; Assar DH; Al Jaouni SK; Mousa SA
[Ad] Address:Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt. mostafa.ataa@vet.kfs.edu.eg.
[Ti] Title:Thymoquinone Defeats Diabetes-Induced Testicular Damage in Rats Targeting Antioxidant, Inflammatory and Aromatase Expression.
[So] Source:Int J Mol Sci;18(5), 2017 Apr 27.
[Is] ISSN:1422-0067
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:Antioxidants have valuable effects on the process of spermatogenesis, particularly with diabetes mellitus (DM). Therefore, the present study investigated the impact and the intracellular mechanisms by which thymoquinone (TQ) works against diabetes-induced testicular deteriorations in rats. Wistar male rats ( = 60) were randomly allocated into four groups; Control, Diabetic (streptozotocin (STZ)-treated rats where diabetes was induced by intraperitoneal injection of STZ, 65 mg/kg), Diabetic + TQ (diabetic rats treated with TQ (50 mg/kg) orally once daily), and TQ (non-diabetic rats treated with TQ) for 12 weeks. Results revealed that TQ significantly improved the sperm parameters with a reduction in nitric oxide (NO) and malondialdehyde (MDA) levels in testicular tissue. Also, it increased testicular reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity. Interestingly, TQ induced downregulation of testicular inducible nitric oxide synthase (iNOS) and nuclear factor kappa-B (NF-κB) and significantly upregulated the aromatase protein expression levels in testicles in comparison with the diabetic rats. In conclusion, TQ treatment exerted a protective effect against reproductive dysfunction induced by diabetes not only through its powerful antioxidant and hypoglycemic effects but also through its downregulation of testicular iNOS and NF-κB along with upregulation of aromatase expression levels in diabetic rats.
[Mh] MeSH terms primary: Antioxidants/metabolism
Aromatase/metabolism
Benzoquinones/pharmacology
Protective Agents/pharmacology
Spermatogenesis/drug effects
Testis/drug effects
[Mh] MeSH terms secundary: Animals
Body Weight/drug effects
Diabetes Mellitus, Experimental/chemically induced
Diabetes Mellitus, Experimental/pathology
Glutathione/metabolism
Male
Malondialdehyde/metabolism
NF-kappa B/metabolism
Nitric Oxide/metabolism
Nitric Oxide Synthase Type II/metabolism
Oxidative Stress/drug effects
Rats
Rats, Wistar
Streptozocin/toxicity
Superoxide Dismutase/metabolism
Testis/metabolism
Testis/pathology
Up-Regulation/drug effects
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Antioxidants); 0 (Benzoquinones); 0 (NF-kappa B); 0 (Protective Agents); 31C4KY9ESH (Nitric Oxide); 490-91-5 (thymoquinone); 4Y8F71G49Q (Malondialdehyde); 5W494URQ81 (Streptozocin); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 1.14.14.1 (Aromatase); EC 1.15.1.1 (Superoxide Dismutase); GAN16C9B8O (Glutathione)
[Em] Entry month:1801
[Cu] Class update date: 180122
[Lr] Last revision date:180122
[Js] Journal subset:IM
[Da] Date of entry for processing:170428
[St] Status:MEDLINE

  10 / 7742 MEDLINE  
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[PMID]: 29179175
[Au] Autor:Tu RH; Li QJ; Huang Z; He Y; Meng JJ; Zheng HL; Zeng ZY; Zhong GQ
[Ad] Address:Department of Geriatric Cardiology, Nanning, China.
[Ti] Title:Novel Functional Role of Heat Shock Protein 90 in Mitochondrial Connexin 43-Mediated Hypoxic Postconditioning.
[So] Source:Cell Physiol Biochem;44(3):982-997, 2017.
[Is] ISSN:1421-9778
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:BACKGROUND/AIMS: Previous studies have shown that heat shock protein 90 (HSP90)-mediated mitochondrial import of connexin 43 (Cx43) is critical in preconditioning cardioprotection. The present study was designed to test whether postconditioning has the same effect as preconditioning in promoting Cx43 translocation to mitochondria and whether mitochondrial HSP90 modulates this effect. METHODS: Cellular models of hypoxic postconditioning (HPC) from rat heart-derived H9c2 cells and neonatal rat cardiomyocytes were employed. The effects of HPC on cardiomyocytes apoptosis were examined by flow cytometry and Hoechst 33342 fluorescent staining. Reactive oxidative species (ROS) production was assessed with the peroxide-sensitive fluorescent probe 2',7'-dichlorofluorescin in diacetate (DCFH-DA). The anti- and pro-apoptotic markers Bcl-2 and Bax, HSP90 and Cx43 protein levels were studied by Western blot analysis in total cell homogenate and sarcolemmal and mitochondrial fractions. The effects on HPC of the HSP90 inhibitor geldanamycin (GA), ROS scavengers superoxide dismutase (SOD) and catalase (CAT), and small interfering RNA (siRNA) targeting Cx43 and HSP90 were also investigated. RESULTS: HPC significantly reduced hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis. These beneficial effects were accompanied by an increase in Bcl-2 levels and a decrease in Bax levels in both sarcolemmal and mitochondrial fractions. HPC with siRNA targeting Cx43 or the ROS scavengers SOD plus CAT significantly prevented ROS generation and HPC cardioprotection, but HPC with either SOD or CAT did not. These data strongly supported the involvement of Cx43 in HPC cardioprotection, likely via modulation of the ROS balance which plays a central role in HPC protection. Furthermore, HPC increased total and mitochondrial levels of HSP90 and the mitochondria-to-sarcolemma ratio of Cx43; blocking the function of HSP90 with the HSP90 inhibitor geldanamycin (GA) or siRNA targeting HSP90 prevented the protection of HPC and the HPC-induced association of Cx43, indicating that mitochondrial HSP90 was important for mitochondrial translocation of Cx43 during HPC. CONCLUSION: Mitochondrial HSP90 played a central role in HPC cardioprotection, and its activity was linked to the mitochondrial targeting of Cx43, the activation of which triggered ROS signaling and the subsequent reduction of redox stress. Consequently, its target gene, Bcl-2, was upregulated, and proapoptotic Bax was inhibited in the sarcolemma and mitochondria, ultimately attenuating H/R-induced cardiomyocyte apoptosis. These data reveal a novel mechanism of HPC protection.
[Mh] MeSH terms primary: Connexin 43/metabolism
HSP90 Heat-Shock Proteins/metabolism
[Mh] MeSH terms secundary: Animals
Apoptosis/drug effects
Benzoquinones/pharmacology
Catalase/pharmacology
Cell Hypoxia
Cell Line
Connexin 43/antagonists & inhibitors
Connexin 43/genetics
HSP90 Heat-Shock Proteins/antagonists & inhibitors
HSP90 Heat-Shock Proteins/genetics
Lactams, Macrocyclic/pharmacology
Microscopy, Fluorescence
Mitochondria/metabolism
Proto-Oncogene Proteins c-bcl-2/metabolism
RNA Interference
RNA, Small Interfering/metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species/chemistry
Reactive Oxygen Species/metabolism
Sarcolemma/metabolism
Superoxide Dismutase/pharmacology
bcl-2-Associated X Protein/metabolism
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Benzoquinones); 0 (Connexin 43); 0 (HSP90 Heat-Shock Proteins); 0 (Lactams, Macrocyclic); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (RNA, Small Interfering); 0 (Reactive Oxygen Species); 0 (bcl-2-Associated X Protein); EC 1.11.1.6 (Catalase); EC 1.15.1.1 (Superoxide Dismutase); Z3K3VJ16KU (geldanamycin)
[Em] Entry month:1801
[Cu] Class update date: 180118
[Lr] Last revision date:180118
[Js] Journal subset:IM
[Da] Date of entry for processing:171128
[St] Status:MEDLINE
[do] DOI:10.1159/000485399


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