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Yeo SG, Oh YJ, Lee JM, Yeo JH, Kim SS, Park DC. Production and Role of Nitric Oxide in Endometrial Cancer. Antioxidants (Basel) 2025; 14:369. [PMID: 40227440 PMCID: PMC11939365 DOI: 10.3390/antiox14030369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 04/15/2025] Open
Abstract
Endometrial cancer ranks as the fourth most common cancer among women in the United States. While early-stage treatment is generally effective with a cure rate of approximately 90%, the five-year survival rate dramatically decreases to 10-15% for advanced-stage diagnoses. Consequently, ongoing research seeks to improve treatment outcomes for endometrial cancer. Nitric oxide (NO) is implicated in various biological processes, including cancer progression, and is believed to play a significant role in human endometrial cancer. However, its specific function remains controversial. This study aims to elucidate the effects of NO in endometrial cancer through a comprehensive literature review. A thorough review of the literature was conducted using Cochrane Libraries, EMBASE, Google Scholar, PubMed, and SCOPUS databases to assess the induction and role of NO in the development of endometrial cancer. Out of 33 initially reviewed articles, 7 studies were included in the final review after excluding those unrelated to endometrial cancer or NO. Of these, six studies (85.7%) reported increased NO levels in endometrial cancer, whereas one study (14.3%) noted decreased NO levels or a defensive mechanism role. NO production was linked to tumor-promoting effects such as invasiveness, metastasis, angiogenesis, interaction with omental adipose stromal cells (O-ASCs), adipogenesis, and mitochondrial suppression. Conversely, NO also exhibited tumor-suppressive effects, including cell-cycle arrest, apoptosis induction, promotion of cancer stem-like cells, and upregulation of tumor suppressor genes like CDKN1A and RASSF1A. NO production is associated with the pathogenesis, development, and prognosis of endometrial cancer, with effects varying based on NO level fluctuations. Differences in NO production and function were observed according to the type of nitric oxide synthase (NOS) involved, control conditions, subtype, grade, and invasiveness of the cancer, as well as the experimental methodologies employed. NO demonstrated dual action in endometrial cancer: low concentrations promoted tumor growth by protecting cells and inhibiting apoptosis, while high concentrations exerted cytotoxic effects, suppressing tumor growth. However, no studies have precisely defined the concentration thresholds or mechanisms by which NO contributes to either tumorigenesis or tumor suppression in endometrial cancer. To effectively harness the therapeutic potential of NO in treating endometrial cancer, a deeper understanding of these dual-effect mechanisms is necessary.
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Affiliation(s)
- Seung Geun Yeo
- Department of Medicine, College of Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea; (S.G.Y.); (Y.J.O.); (J.M.L.)
- Department of Precision Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Convergence Medicine, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Yeon Ju Oh
- Department of Medicine, College of Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea; (S.G.Y.); (Y.J.O.); (J.M.L.)
| | - Jae Min Lee
- Department of Medicine, College of Medicine, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea; (S.G.Y.); (Y.J.O.); (J.M.L.)
| | - Joon Hyung Yeo
- Public Health Center, Danyang-gun 27010, Chungcheongbuk-do, Republic of Korea;
| | - Sung Soo Kim
- Department of Biochemistry and Molecular Biology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Dong Choon Park
- Department of Obstetrics and Gynecology, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 02447, Republic of Korea
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Solanki K, Rajpoot S, Bezsonov EE, Orekhov AN, Saluja R, Wary A, Axen C, Wary K, Baig MS. The expanding roles of neuronal nitric oxide synthase (NOS1). PeerJ 2022; 10:e13651. [PMID: 35821897 PMCID: PMC9271274 DOI: 10.7717/peerj.13651] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/07/2022] [Indexed: 01/17/2023] Open
Abstract
The nitric oxide synthases (NOS; EC 1.14.13.39) use L-arginine as a substrate to produce nitric oxide (NO) as a by-product in the tissue microenvironment. NOS1 represents the predominant NO-producing enzyme highly enriched in the brain and known to mediate multiple functions, ranging from learning and memory development to maintaining synaptic plasticity and neuronal development, Alzheimer's disease (AD), psychiatric disorders and behavioral deficits. However, accumulating evidence indicate both canonical and non-canonical roles of NOS1-derived NO in several other tissues and chronic diseases. A better understanding of NOS1-derived NO signaling, and identification and characterization of NO-metabolites in non-neuronal tissues could become useful in diagnosis and prognosis of diseases associated with NOS1 expression. Continued investigation on the roles of NOS1, therefore, will synthesize new knowledge and aid in the discovery of small molecules which could be used to titrate the activities of NOS1-derived NO signaling and NO-metabolites. Here, we address the significance of NOS1 and its byproduct NO in modifying pathophysiological events, which could be beneficial in understanding both the disease mechanisms and therapeutics.
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Affiliation(s)
- Kundan Solanki
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India
| | - Sajjan Rajpoot
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India
| | - Evgeny E. Bezsonov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, Moscow, Russia
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
- Department of Biology and General Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Alexander N. Orekhov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, Moscow, Russia
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Rohit Saluja
- Department of Biochemistry, All India Institute of Medical Sciences, Bibinagar, Hyderabad, India
| | - Anita Wary
- Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Cassondra Axen
- Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Kishore Wary
- Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Mirza S. Baig
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India
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NOS1 expression promotes proliferation and invasion and enhances chemoresistance in ovarian cancer. Oncol Lett 2020; 19:2989-2995. [PMID: 32218855 DOI: 10.3892/ol.2020.11355] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 07/03/2018] [Indexed: 01/16/2023] Open
Abstract
Nitric oxide (NO), an important chemical messenger, serves a dual role in tumor progression. Nitric oxide synthase isoform 1 (NOS1) was observed to be increasingly expressed in various types of cancer, and its expression has been associated with tumor progression. However, the level of NOS1 expression and the associated functions of NOS1 in human ovarian cancer remain undefined. Using gene expression profiles of ovarian cancer from the Gene Expression Omnibus (GEO) database, the present study revealed that NOS1 was increasingly expressed in ovarian cancer tissues. The present study investigated the level of NOS1 expression and its effects on in vitro cell function, including proliferation, migration and invasion as well as chemoresistance to cispatin (DDP) treatment in OVCAR3 cells. Reverse transcription-quantitative polymerase chain reaction demonstrated that the level of NOS1 mRNA expression varied in different ovarian cancer lines. However, immunoblotting indicated that the level of NOS1 protein expression was constitutively high in ovarian cancer cell lines. Treatment with NOS inhibitor NG-nitro-L-arginine methyl ester or transfection with NOS1 short hairpin RNA significantly inhibited cell proliferation, migration and invasion compared with the control, whereas the sensitivity of OVCAR3 cells to DDP treatment was increased. The results of the present study indicated that NOS1 promoted the function of ovarian cancer cells, including proliferation, invasion and chemoresistance, providing a potential target for ovarian cancer therapeutic.
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S-nitrosylation and its role in breast cancer angiogenesis and metastasis. Nitric Oxide 2019; 87:52-59. [PMID: 30862477 DOI: 10.1016/j.niox.2019.03.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 01/23/2019] [Accepted: 03/06/2019] [Indexed: 12/24/2022]
Abstract
S-nitrosylation, the modification by nitric oxide of free sulfhydryl groups in cysteines, has become an important regulatory mechanism in carcinogenesis and metastasis. S-nitrosylation of targets in tumor cells contributes to metastasis regulating epithelial to mesenchymal transition, migration and invasion. In the tumor environment, the role of S-nitrosylation in endothelium has not been addressed; however, the evidence points out that S-nitrosylation of endothelial proteins may regulate angiogenesis, adhesion of tumor cells to the endothelium, intra and extravasation of tumor cells and contribute to metastasis.
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Trinh B, Ko SY, Haria D, Barengo N, Naora H. The homeoprotein DLX4 controls inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer. Mol Cancer 2015; 14:97. [PMID: 25924901 PMCID: PMC4427985 DOI: 10.1186/s12943-015-0368-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 04/17/2015] [Indexed: 12/24/2022] Open
Abstract
Background Homeobox genes encode transcription factors that control patterning of virtually all organ systems including the vasculature. Tumor angiogenesis is stimulated by several homeobox genes that are overexpressed in tumor cells, but the mechanisms of these genes are poorly understood. In this study, we investigated the mechanisms by which DLX4, a homeobox gene that is associated with increased tumor microvessel density, stimulates ovarian tumor angiogenesis. Methods Expression of DLX4 and nitric oxide synthases was analyzed in publicly available transcriptional profiles of ovarian cancer clinical specimens. Levels of inducible nitric oxide synthase (iNOS) were evaluated by quantitative RT-PCR, flow cytometry and nitric oxide assays using ovarian cancer cell lines in which DLX4 was overexpressed or knocked down. Signal Transducer and Activator of Transcription 1 (STAT1) expression and activity were evaluated by luciferase reporter assays, immunofluorescence staining, Western blot and immunoprecipitation. Endothelial cell growth and tumor angiogenesis were evaluated in in vitro assays and xenograft models. Results We identified that DLX4 induces expression of iNOS, an enzyme that stimulates angiogenesis by generating nitric oxide. Analysis of datasets of two independent patient cohorts revealed that high DLX4 expression in ovarian cancer is strongly associated with elevated expression of iNOS but not of other nitric oxide synthases. Studies using STAT1-expressing and STAT1-deficient cells revealed that DLX4 interacts with STAT1 and induces iNOS expression in part by stimulating STAT1 activity. Expression of DLX4 in ovarian cancer cells stimulated endothelial cell growth in vitro and increased microvessel density in xenograft models, and these stimulatory effects of DLX4 were abrogated when its induction of iNOS was inhibited. Conclusion These findings indicate that DLX4 promotes ovarian tumor angiogenesis in part by stimulating iNOS expression. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0368-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Bon Trinh
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Song Yi Ko
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Dhwani Haria
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Nicolas Barengo
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Honami Naora
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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Wang YZ, Cao YQ, Wu JN, Chen M, Cha XY. Expression of nitric oxide synthase in human gastric carcinoma and its relation to p53, PCNA. World J Gastroenterol 2005; 11:46-50. [PMID: 15609395 PMCID: PMC4205382 DOI: 10.3748/wjg.v11.i1.46] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of NOS in gastric carcinoma, and to explore the relationship between the expression of nitric oxide synthases (NOS) and p53, PCNA, pathological features and clinical staging of gastric cancer.
METHODS: The activity of NOS protein was investigated in 85 samples of human gastric carcinoma and 25 samples of normal gastric mucosal tissue by biochemical assay. We then examined the expression of NOS, p53, PCNA in 85 samples of human gastric cancer was examined by immunohistochemistry, and NOS mRNA expression in 85 gastric cancer tissue specimens by in situ hybridization.
RESULTS: Biochemical assay showed that the activity of NOS was significantly higher in gastric carcinoma than in normal gastric mucosal tissues (t = 0.4161, P<0.01). Immunohistochemistry revealed that endothelial nitric oxide synthase (eNOS) expressed in all samples of normal gastric mucosa, but only 6 cases of 85 gastric cancer specimens showed weak positive immunohistochemical reactions to eNOS (20%). Inducible nitric oxide synthase (iNOS) was expressed strongly in human gastric carcinoma (81.2%). In situ hybridization analysis showed that iNOS mRNA expression was significantly stronger than eNOS mRNA expression in gastric cancer tissue (χ2 = 10.23, P<0.01). The expression of iNOS in gastric cancer was associated with differentiation, clinical stages or lymph node metastases (r = 0.3426, P<0.05). However, iNOS expression did not correlate with histological classifications and morphological types. The expression of iNOS was significantly correlated with p53 or PCNA expression (r = 0.3612, P<0.05). The expression of neuronal nitric oxide synthase (nNOS) was not examined by immunohistochemistry and in situ hybridization in gastric cancer specimens and normal gastric mucosa.
CONCLUSION: In human gastric cancer, there is an enhanced expression of iNOS, but not of eNOS. NOS promotes the proliferation of tumor cells and plays an important role in gastric cancer spread. Inactivation of antioncogene p53 and overexpression of iNOS might play a synergetic role in the process of carcinogenesis of human gastric carcinoma.
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Affiliation(s)
- Yong-Zhong Wang
- Department of Pathology, the Affiliated Hospital of Jiangsu University, Zhenjiang 212001, Jiangsu Province, China.
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Chen T, Stoner GD. Inducible nitric oxide synthase expression inN-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. Mol Carcinog 2004; 40:232-40. [PMID: 15264214 DOI: 10.1002/mc.20035] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Nitric oxide (NO), an important regulatory molecule for immune response and cytotoxicity, is endogenously generated from L-arginine by NO synthase (NOS). One mechanism for NO-induced cytotoxicity is through its interaction with superoxide to produce peroxynitrite, which causes DNA damage. Three distinct isoforms of NOS have been isolated and represent the products of three different genes. The inducible form, inducible nitric oxide synthase (iNOS), is a mediator of inflammation and a regulator of epithelial cell growth. Upregulation of iNOS has been linked to epithelial tumorigenesis in various human and animal tissues. In the current investigation, normal esophagus and N-nitrosomethylbenzylamine (NMBA)-induced preneoplastic and papillomatous lesions of the rat esophagus were characterized for expression of iNOS. F344 rats were injected subcutaneously with NMBA (0.5 mg/kg body weight) three times per week for 5 wk. At 3, 6, 9, 12, 15, 18, 21, 24, 30, and 36 wk following initiation of NMBA treatment, esophagi were collected from 12 untreated and 12 NMBA treated animals. Results of reverse transcription (RT)-polymerase chain reaction (PCR) and immunohistochemistry demonstrated a correlation between the upregulation of iNOS and neoplastic progression in the rat esophagus. The expression of iNOS mRNA in preneoplastic tissues and papillomas was significantly elevated when compared to normal tissues. Immunohistochemical analysis showed more extensive cytoplasmic staining of iNOS protein in preneoplastic tissues and papillomas than in normal tissues. Our data suggest, therefore, that the production of iNOS by the epithelium of the esophagus is associated with the development of NMBA-induced esophageal tumorigenesis in rats.
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Affiliation(s)
- Tong Chen
- Division of Environmental Health Sciences, School of Public Health and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA
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Kagoura M, Matsui C, Toyoda M, Morohashi M. Immunohistochemical study of inducible nitric oxide synthase in skin cancers. J Cutan Pathol 2001; 28:476-81. [PMID: 11553314 DOI: 10.1034/j.1600-0560.2001.028009476.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Nitric oxide (NO) is synthesized from the amino acid L-arginine by NO synthase (NOS). Experimental evidence suggests that increased express of inducible NOS (iNOS), which is an NOS isoform and calcium independent, is related to various pathological processes, such as inflammation and cancer. METHODS In this study, we used immunohistochemistry to investigate iNOS expression in a series of basal cell carcinomas (BCC), Bowen's disease, squamous cell carcinomas (SCC), extramammary Paget's disease (EPD) and metastatic tumors of the skin. RESULTS Only 1 of 16 BCC cases was positive for iNOS and the intensity of staining was weak. In most of the 10 cases of Bowen's disease, iNOS was weakly expressed and there was a wide range in the percentage of positive tumor cells. Twelve of the 16 cases of SCC were positive for iNOS and the extent of positivity was greater than in Bowen's disease. Two of the 7 cases of EPD were positive for iNOS, and 12 of the 15 cases of metastatic cancer were positive. Well-differentiated adenocarcinomas were diffusely positive, whereas poorly-differentiated ones showed strong and heterogeneous staining. CONCLUSIONS These results indicated that the expression of iNOS may reflect the proliferation of tumor cells and that a heterogeneous distribution of iNOS may correlate with a wide variety of biological behavior of tumor cells.
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Affiliation(s)
- M Kagoura
- Department of Dermatology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.
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Hussain SP, Raja K, Amstad PA, Sawyer M, Trudel LJ, Wogan GN, Hofseth LJ, Shields PG, Billiar TR, Trautwein C, Hohler T, Galle PR, Phillips DH, Markin R, Marrogi AJ, Harris CC. Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci U S A 2000; 97:12770-5. [PMID: 11050162 PMCID: PMC18839 DOI: 10.1073/pnas.220416097] [Citation(s) in RCA: 171] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:G to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal, an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (AGG to AGT). These results are consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.
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Affiliation(s)
- S P Hussain
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Kröncke KD, Suschek CV, Kolb-Bachofen V. Implications of inducible nitric oxide synthase expression and enzyme activity. Antioxid Redox Signal 2000; 2:585-605. [PMID: 11229370 DOI: 10.1089/15230860050192341] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
We summarize here our current knowledge about inducible nitric oxide synthase (NOS) activity in human diseases and disorders. As basic research discovers more and more effects of low or high concentrations of NO toward molecular and cellular targets, successful therapies involving inhibition of NO synthesis or application of NO to treat human diseases are still lacking. This is in part due to the fact that the impact of NO on cell function or death are complex and often even appear to be contradictory. NO may be cytotoxic but may also protect cells from a toxic insult; it is apoptosis-inducing but also exhibits prominent anti-apoptotic activity. NO is an antioxidant but may also compromise the cellular redox state via oxidation of thiols like glutathione. NO may activate specific signal transduction pathways but is also reported to inhibit exactly these, and NO may activate or inhibit gene transcription. The situation may even be more complicated, because NO, depending on its concentration, may react with oxygen or the superoxide anion radical to yield reactive species with a much broader chemical reaction spectrum than NO itself. Thus, the action of NO during inflammatory reactions has to be considered in the context of timing and duration of its synthesis as well as stages and specific events in inflammation.
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Affiliation(s)
- K D Kröncke
- Research Group Immunobiology in the Biomedical Research Centre, Heinrich-Heine-University, Düsseldorf, Germany.
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