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Toninello P, Montanari A, Bassetto F, Vindigni V, Paoli A. Nutritional Support for Bariatric Surgery Patients: The Skin beyond the Fat. Nutrients 2021; 13:1565. [PMID: 34066564 PMCID: PMC8148584 DOI: 10.3390/nu13051565] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 12/20/2022] Open
Abstract
Body contouring surgery after the massive weight loss due to bariatric surgery deals with different kinds of complications. The aim of this review is to analyze the role that some nutrients may play in tissue healing after surgery, thus helping plastic surgeons to improve the aesthetic and health outcomes in massive weight loss patients under a multidisciplinary approach. As a matter of fact, preoperative nutritional deficiencies have been shown for vitamins and minerals in a large percentage of post-bariatric patients. Preoperative deficiencies mainly concern iron, zinc, selenium, and vitamins (both fat-soluble and water-soluble), but also total protein. During the postoperative period, these problems may increase because of the patients' very low intake of vitamins and minerals after bariatric surgery (below 50% of the recommended dietary allowance) and the patients' low compliance with the suggested multivitamin supplementation (approximately 60%). In the postoperative period, more attention should be given to nutritional aspects in regard to the length of absorptive area and the percentage of weight loss.
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Affiliation(s)
- Paolo Toninello
- Plastic and Reconstructive Surgery Unit, Department of Neurosciences, University of Padua, 35122 Padua, Italy; (P.T.); (A.M.); (F.B.); (V.V.)
| | - Alvise Montanari
- Plastic and Reconstructive Surgery Unit, Department of Neurosciences, University of Padua, 35122 Padua, Italy; (P.T.); (A.M.); (F.B.); (V.V.)
| | - Franco Bassetto
- Plastic and Reconstructive Surgery Unit, Department of Neurosciences, University of Padua, 35122 Padua, Italy; (P.T.); (A.M.); (F.B.); (V.V.)
| | - Vincenzo Vindigni
- Plastic and Reconstructive Surgery Unit, Department of Neurosciences, University of Padua, 35122 Padua, Italy; (P.T.); (A.M.); (F.B.); (V.V.)
| | - Antonio Paoli
- Department of Biomedical Sciences, University of Padova, 35122 Padua, Italy
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Inaba H, Yoshigai E, Okuyama T, Murakoshi M, Sugiyama K, Nishino H, Nishizawa M. Antipyretic analgesic drugs have different mechanisms for regulation of the expression of inducible nitric oxide synthase in hepatocytes and macrophages. Nitric Oxide 2014; 44:61-70. [PMID: 25499030 DOI: 10.1016/j.niox.2014.12.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 11/14/2014] [Accepted: 12/02/2014] [Indexed: 12/25/2022]
Abstract
Antipyretic analgesic drugs (including non-steroidal anti-inflammatory drugs) inhibit cyclooxygenase-2 and inducible nitric oxide synthase (iNOS), resulting in decreases of the proinflammatory mediators prostaglandin E2 and nitric oxide (NO), respectively. Both mediators are regulated by nuclear factor-kappa B (NF-κB), a key transcription factor in inflammation. Few reports have compared the efficacy and potency of anti-inflammatory drugs as NO inhibitors. In our study, we examined the effects of four popular antipyretic analgesic drugs on NO production induced in hepatocytes and macrophages. Mouse RAW264.7 macrophages treated with bacterial lipopolysaccharide showed the highest efficacy with regard to NO production; aspirin, loxoprofen, ibuprofen, and acetaminophen dose-dependently suppressed NO induction. Ibuprofen showed the highest potency in suppressing the induced production of NO. In rat hepatocytes, all the drugs inhibited interleukin 1β-induced NO production and ibuprofen and loxoprofen inhibited NO induction effectively. Unexpectedly, the potency of NO suppression of each drug in hepatocytes did not always correlate with that observed in RAW264.7 cells. Microarray analyses of mRNA expression in hepatocytes revealed that the effects of the four antipyretic analgesic drugs modulated the NF-κB signaling pathway in a similar manner to the regulation of the expression of genes associated with inflammation, including the iNOS gene. However, the affected signal-transducing molecules in the NF-κB pathway were different for each drug. Therefore, antipyretic analgesic drugs may decrease NO production by modulating the NF-κB pathway in different ways, which could confer different efficacies and potencies with regard to their anti-inflammatory effects.
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Affiliation(s)
- Hiroyuki Inaba
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan; Research and Development Headquarters, Lion Corporation, Odawara, Kanagawa, Japan
| | - Emi Yoshigai
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Tetsuya Okuyama
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan; Graduate School of Science and Engineering, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Michiaki Murakoshi
- Research and Development Headquarters, Lion Corporation, Odawara, Kanagawa, Japan; Department of Biochemistry, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keikichi Sugiyama
- Research and Development Headquarters, Lion Corporation, Odawara, Kanagawa, Japan; Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Hoyoku Nishino
- Department of Biochemistry, Kyoto Prefectural University of Medicine, Kyoto, Japan; Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Mikio Nishizawa
- Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.
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Macrophages inhibit insulin signalling in adipocytes: role of inducible nitric oxide synthase and nitric oxide. Can J Diabetes 2014; 39:36-43. [PMID: 25179174 DOI: 10.1016/j.jcjd.2014.02.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 02/07/2014] [Accepted: 02/20/2014] [Indexed: 01/19/2023]
Abstract
OBJECTIVES The interaction of immune cells with adipocytes within the adipose tissues in obese persons with diabetes mellitus may play a role in insulin resistance. We examined in vitro whether nitric oxide (NO) and inducible nitric oxide synthase (iNOS) play a role in impaired insulin signalling in adipocytes exposed to activated macrophages. METHODS We used a co-culture system in which Raw264.7 macrophages were plated over differentiated, low passage 3T3-L1 cells (dif3T3) at a cell density ratio of 1:2. Inflammation was induced by a challenge with bacterial lipopolysaccharide. RESULTS Significantly (p<0.001) enhanced iNOS expression and NO synthesis was observed in activated co-cultures. In the co-cultures as compared with Raw264.7 cells alone, iNOS protein was induced up to 11-fold above background, and NO release was significantly (p<0.001) increased up to 2.8-fold. Co-culturing dif3T3 and Raw264.7 cells as compared to dif3T3 alone reduced insulin-induced Akt phosphorylation by 50% and AS160 phosphorylation by 42%. This was correlated with reduced glucose consumption when dif3T3 was exposed to 1,3-morpholinosydnonimine. Adiponectin, GLUT4 and AS160 mRNA were reduced by 4-fold, 5-fold and 2-fold, respectively, in co-cultures as compared to dif3T3 alone. On the contrary, GLUT1 mRNA levels were increased by 2-fold in co-cultures as compared to dif3T3. NG-monomethyl-L-arginine abolished NO production with modest reversal of Akt/AS160 phosphorylation. CONCLUSIONS This study demonstrated a potential association between iNOS/NO-mediated inflammation and insulin resistance.
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Jiang CP, He X, Yang XL, Zhang SL, Li H, Song ZJ, Zhang CF, Yang ZL, Li P, Wang CZ, Yuan CS. Anti-rheumatoid arthritic activity of flavonoids from Daphne genkwa. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2014; 21:830-837. [PMID: 24561028 DOI: 10.1016/j.phymed.2014.01.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 10/31/2013] [Accepted: 01/26/2014] [Indexed: 06/03/2023]
Abstract
The aim of the study was to investigate the anti-rheumatoid arthritic activity of four flavonoids from Daphne genkwa (FFD) in vivo and in vitro. Flavonoids of D. genkwa were extracted by refluxing with ethanol and purified by polyamide resin. An in vivo carrageenan-induced paw edema model, tampon-granuloma model and Freund's complete adjuvant (FCA)-induced arthritis mouse model were used to evaluate the anti-rheumatoid arthritic activities of FFD. Moreover, nitric oxide (NO) release and neutral red uptake (NRU) in lipopolysaccharide (LPS)-induced murine macrophage RAW264.7 cells were used to evaluate the anti-inflammatory effect in vitro. In addition, antioxidant effect of FFD was determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. A high dose of FFD significantly reduced the degree of acute inflammatory paw edema in mice as a response to carrageenan administration (p<0.01). FFD displayed a dose-dependent inhibition of granuloma formation in mice (p<0.05). FFD also inhibited chronic inflammation in adjuvant-induced arthritis rats when administered orally at the dose of 50mg/kg/day (p<0.001). In addition, FFD suppressed the production of NO and exhibited immunoregulatory function in LPS-activated RAW264.7 cells in a dose-related manner. Simultaneously, FFD revealed conspicuous antioxidant activity with IC50 values of 18.20μg/ml. FFD possesses significant anti-inflammatory and antioxidant activity, which could be a potential therapeutic agent for chronic inflammatory disorders such as rheumatoid arthritis.
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Affiliation(s)
- Cui-Ping Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Xin He
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210000, China
| | - Xiao-Lin Yang
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China
| | - Su-Li Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Hui Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Zi-Jing Song
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Chun-Feng Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Tang Center of Herbal Medicine Research, and Department of Anesthesia and Critical care, University of Chicago, Chicago, IL 60637, USA.
| | - Zhong-Lin Yang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Chong-Zhi Wang
- Tang Center of Herbal Medicine Research, and Department of Anesthesia and Critical care, University of Chicago, Chicago, IL 60637, USA
| | - Chun-Su Yuan
- Tang Center of Herbal Medicine Research, and Department of Anesthesia and Critical care, University of Chicago, Chicago, IL 60637, USA
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Mortensen A, Lykkesfeldt J. Does vitamin C enhance nitric oxide bioavailability in a tetrahydrobiopterin-dependent manner? In vitro, in vivo and clinical studies. Nitric Oxide 2014; 36:51-7. [PMID: 24333161 DOI: 10.1016/j.niox.2013.12.001] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 10/09/2013] [Accepted: 12/03/2013] [Indexed: 12/31/2022]
Abstract
Ascorbate (Asc) has been shown to increase nitric oxide (NO) bioavailability and thereby improve endothelial function in patients showing signs of endothelial dysfunction. Tetrahydrobiopterin (BH₄) is a co-factor of endothelial nitric oxide synthase (eNOS) which may easily become oxidized to the inactive form dihydrobiopterin (BH₂). Asc may increase NO bioavailability by a number of mechanisms involving BH₄ and eNOS. Asc increases BH₄ bioavailability by either reducing oxidized BH₄ or preventing BH₄ from becoming oxidized in the first place. Asc could also increase NO bioavailability in a BH₄-independent manner by increasing eNOS activity by changing its phosphorylation and S-nitrosylation status or by upregulating eNOS expression. In this review, we discuss the putative mechanisms by which Asc may increase NO bioavailability through its interactions with BH₄ and eNOS.
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Affiliation(s)
- Alan Mortensen
- Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Jens Lykkesfeldt
- Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
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Garcia-Diaz DF, Campion J, Quintero P, Milagro FI, Moreno-Aliaga MJ, Martinez JA. Vitamin C modulates the interaction between adipocytes and macrophages. Mol Nutr Food Res 2011; 55 Suppl 2:S257-63. [PMID: 21796779 DOI: 10.1002/mnfr.201100296] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Revised: 05/02/2011] [Accepted: 05/15/2011] [Indexed: 02/05/2023]
Abstract
SCOPE Increased adiposity is related with monocyte infiltration into the adipose tissue that accentuates inflammation. Antioxidant treatments emerge as approaches to counteract this phenomenon. METHODS AND RESULTS Cocultures of differentiated 3T3-L1 adipocytes and RAW264.7 macrophages were incubated for 24-72 h with/without 100 nM insulin and/or 200 μM vitamin C (VC). Nitric oxide (NO) secretion (24 h) was measured. Also, expression (24 h) and secretion (72 h) of MCP-1, leptin and apelin were analyzed. NO secretion was significantly inhibited by insulin and VC only in cocultures. MCP-1 expression/secretion was enhanced in cocultures. Insulin incubation reduced MCP-1 expression in both cultures and VC only in controls. Both treatments inhibited MCP-1 secretion in cocultures. Apelin gene expression was induced in cocultures. Insulin induced apelin mRNA expression, but VC inhibited its expression in cocultures under insulin treatment. Apelin secretion was notably induced by insulin and inhibited by VC in cocultures. Leptin expression was decreased in coculture, while presented no effects by VC. CONCLUSION VC importantly modulates the established pro-inflammatory state in the interaction between adipocytes and macrophages.
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Affiliation(s)
- Diego F Garcia-Diaz
- Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, Pamplona, Spain
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Potential Impacts of Nutritional Deficiency of Postbariatric Patients on Body Contouring Surgery. Plast Reconstr Surg 2008; 122:1901-1914. [DOI: 10.1097/prs.0b013e31818d20d6] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Aguirre R, May JM. Inflammation in the vascular bed: importance of vitamin C. Pharmacol Ther 2008; 119:96-103. [PMID: 18582947 PMCID: PMC2538426 DOI: 10.1016/j.pharmthera.2008.05.002] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2008] [Accepted: 05/09/2008] [Indexed: 02/07/2023]
Abstract
Despite decreases in atherosclerotic coronary vascular disease over the last several decades, atherosclerosis remains a major cause of mortality in developed nations. One possible contributor to this residual risk is oxidant stress, which is generated by the inflammatory response of atherosclerosis. Although there is a wealth of in vitro, cellular, and animal data supporting a protective role for antioxidant vitamins and nutrients in the atherosclerotic process, the best clinical trials have been negative. This may be due to the fact that antioxidant therapies are applied "too little and too late." This review considers the role of vitamin C, or ascorbic acid in preventing the earliest inflammatory changes in atherosclerosis. It focuses on the three major vascular cell types involved in atherosclerosis: endothelial cells, vascular smooth muscle cells, and macrophages. Ascorbate chemistry, recycling, and function are described for these cell types, with emphasis on whether and how the vitamin might affect the inflammatory process. For endothelial cells, ascorbate helps to prevent endothelial dysfunction, stimulates type IV collagen synthesis, and enhances cell proliferation. For vascular smooth muscle cells, ascorbate inhibits dedifferentiation, recruitment, and proliferation in areas of vascular damage. For macrophages, ascorbate decreases oxidant stress related to their activation, decreases uptake and degradation of oxidized LDL in some studies, and enhances several aspects of their function. Although further studies of ascorbate function in these cell types and in novel animal models are needed, available evidence generally supports a salutary role for this vitamin in ameliorating the earliest stages of atherosclerosis.
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Affiliation(s)
- Rene Aguirre
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6303, USA
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9
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Li BF, Liu YF, Cheng Y, Zhang KZ, Li TM, Zhao N. Protective effect of inducible nitric oxide synthase inhibitor on pancreas transplantation in rats. World J Gastroenterol 2008; 13:6066-71. [PMID: 18023101 PMCID: PMC4250892 DOI: 10.3748/wjg.v13.45.6066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of inducible nitric oxide synthase inhibitor, aminoguanidine, on pancreas transplantation in rats. METHODS A model of pancreas transplantation was established in rats. Streptozotocin-induced diabetic male Wistar rats were randomly assigned to sham-operation control group (n = 6), transplant control group (n = 6), and aminoguanidine (AG) treatment group (n = 18). In the AG group, aminoguanidine was added to intravascular infusion as the onset of reperfusion at the dose of 60 mg/kg, 80 mg/kg, 100 mg/kg body weight, respectively. Serum nitric oxide (NO) level, blood sugar and amylase activity were detected. Nitric oxide synthase (NOS) test kit was used to detect the pancreas cNOS and inducible NOS (iNOS) activity. Pancreas sections stained with HE and immunohistochemistry were evaluated under a light microscope. RESULTS As compared with the transplant control group, the serum NO level and amylase activity decreased obviously and the evidence for pancreas injury was much less in the AG group. The AG (80 mg/kg body weight) group showed the most significant difference in NO and amylase (NO: 66.0 +/- 16.6 vs 192.3 +/- 60.0, P < 0.01 and amylase: 1426 +/- 177 vs 4477 +/- 630, P < 0.01). The expression and activity of tissue iNOS, and blood sugar in the AG (80 mg/kg body weight) group were much lower than those in the transplant control group (iNOS: 2.01 +/- 0.23 vs 26.59 +/- 5.78, P < 0.01 and blood sugar: 14.2 +/- 0.9 vs 16.8 +/- 1.1, P < 0.01). CONCLUSION Selective iNOS inhibitor, aminoguanidine as a free radical, has a protective effect on pancreas transplantation in rats by inhibiting NO and reducing its toxicity.
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Affiliation(s)
- Bai-Feng Li
- Department of Surgery and Organ Transplant Unit, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China
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May JM, Li L, Qu ZC, Huang J. Ascorbate uptake and antioxidant function in peritoneal macrophages. Arch Biochem Biophys 2005; 440:165-72. [PMID: 16054587 DOI: 10.1016/j.abb.2005.06.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2005] [Revised: 06/14/2005] [Accepted: 06/21/2005] [Indexed: 11/24/2022]
Abstract
Since activated macrophages generate potentially deleterious reactive oxygen species, we studied whether ascorbic acid might function as an antioxidant in these cells. Thioglycollate-elicited murine peritoneal macrophages contained about 3 mM ascorbate that was halved by culture in ascorbate-free medium. However, the cells took up added ascorbate to concentrations of 6-8 mM by a high-affinity sodium-dependent transport mechanism. This likely reflected the activity of the SVCT2 ascorbate transporter, since its message and protein were present in the cells. Activation of the cells by phagocytosis of latex particles depleted intracellular ascorbate, although not below the basal levels present in the cells in culture. Glutathione (GSH) was unaffected by phagocytosis, suggesting that ascorbate was more sensitive to the oxidant stress of phagocytosis than GSH. Phagocytosis induced a modest increase in reactive oxygen species as well as a progressive loss of alpha-tocopherol, both of which were prevented in cells loaded with ascorbate. These results suggest that activated macrophages can use ascorbate to lessen self-generated oxidant stress and spare alpha-tocopherol, which may protect these long-lived cells from necrosis or apoptosis.
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Affiliation(s)
- James M May
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6303, USA.
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Walsh KA, Megyesi JF, Wilson JX, Crukley J, Laubach VE, Hammond RR. Antioxidant protection from HIV-1 gp120-induced neuroglial toxicity. J Neuroinflammation 2004; 1:8. [PMID: 15285794 PMCID: PMC483061 DOI: 10.1186/1742-2094-1-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2004] [Accepted: 05/27/2004] [Indexed: 11/17/2022] Open
Abstract
Background The pathogenesis of HIV-1 glycoprotein 120 (gp120) associated neuroglial toxicity remains unresolved, but oxidative injury has been widely implicated as a contributing factor. In previous studies, exposure of primary human central nervous system tissue cultures to gp120 led to a simplification of neuronal dendritic elements as well as astrocytic hypertrophy and hyperplasia; neuropathological features of HIV-1-associated dementia. Gp120 and proinflammatory cytokines upregulate inducible nitric oxide synthase (iNOS), an important source of nitric oxide (NO) and nitrosative stress. Because ascorbate scavenges reactive nitrogen and oxygen species, we studied the effect of ascorbate supplementation on iNOS expression as well as the neuronal and glial structural changes associated with gp120 exposure. Methods Human CNS cultures were derived from 16–18 week gestation post-mortem fetal brain. Cultures were incubated with 400 μM ascorbate-2-O-phosphate (Asc-p) or vehicle for 18 hours then exposed to 1 nM gp120 for 24 hours. The expression of iNOS and neuronal (MAP2) and astrocytic (GFAP) structural proteins was examined by immunohistochemistry and immunofluorescence using confocal scanning laser microscopy (CSLM). Results Following gp120 exposure iNOS was markedly upregulated from undetectable levels at baseline. Double label CSLM studies revealed astrocytes to be the prime source of iNOS with rare neurons expressing iNOS. This upregulation was attenuated by the preincubation with Asc-p, which raised the intracellular concentration of ascorbate. Astrocytic hypertrophy and neuronal injury caused by gp120 were also prevented by preincubation with ascorbate. Conclusions Ascorbate supplementation prevents the deleterious upregulation of iNOS and associated neuronal and astrocytic protein expression and structural changes caused by gp120 in human brain cell cultures.
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Affiliation(s)
- Kimberley A Walsh
- Department of Pathology, London Health Sciences Centre, University of Western Ontario, London, ON, Canada
| | - Joseph F Megyesi
- Department of Pathology, London Health Sciences Centre, University of Western Ontario, London, ON, Canada
- Department Clinical Neurological Sciences, London Health Sciences Centre, University of Western Ontario, London, ON, Canada
| | - John X Wilson
- Department Physiology, University of Western Ontario, London, ON, Canada
| | - Jeff Crukley
- Department of Pathology, London Health Sciences Centre, University of Western Ontario, London, ON, Canada
| | - Victor E Laubach
- Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA
| | - Robert R Hammond
- Department of Pathology, London Health Sciences Centre, University of Western Ontario, London, ON, Canada
- Department Clinical Neurological Sciences, London Health Sciences Centre, University of Western Ontario, London, ON, Canada
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Nakai K, Urushihara M, Kubota Y, Kosaka H. Ascorbate enhances iNOS activity by increasing tetrahydrobiopterin in RAW 264.7 cells. Free Radic Biol Med 2003; 35:929-37. [PMID: 14556857 DOI: 10.1016/s0891-5849(03)00463-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Studies on the effect of ascorbic acid on inducible nitric oxide synthase (iNOS) activity are few and diverse, likely to be dependent on the species of cells. We investigated a role of ascorbic acid in iNOS induction and nitric oxide (NO) generation in mouse macrophage cell line RAW 264.7. Although interferon- (IFN-) gamma alone produced NO end products, ascorbic acid enhanced NO production only when cells were synergistically stimulated with IFN-gamma plus Escherichia coli lipopolysaccharide (LPS). Ascorbate neither enhanced nor decreased the expression of iNOS protein in RAW 264.7 cells, in contrast to the reports that ascorbic acid augments iNOS induction in a mouse macrophage-like cell line J774.1 and that ascorbate suppresses iNOS induction in rat skeletal muscle endothelial cells. Intracellular levels of tetrahydrobiopterin (BH4), a cofactor for iNOS, were increased by ascorbate in RAW 264.7 cells. However, ascorbate did not increase GTP cyclohydrolase I mRNA, the main enzyme at the critical steps in the BH4 synthetic pathway, expression levels and activity. Sepiapterin, which supplies BH4 via salvage pathway, more efficiently enhanced NO production if ascorbate was added. These data suggest that enhanced activation of iNOS by ascorbic acid is mediated by increasing the stability of BH4 in RAW 264.7 cells.
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Affiliation(s)
- Kozo Nakai
- Department of Dermatology, Kagawa Medical University, Kagawa, Japan
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Schindler TH, Nitzsche EU, Munzel T, Olschewski M, Brink I, Jeserich M, Mix M, Buser PT, Pfisterer M, Solzbach U, Just H. Coronary vasoregulation in patients with various risk factors in response to cold pressor testing: contrasting myocardial blood flow responses to short- and long-term vitamin C administration. J Am Coll Cardiol 2003; 42:814-22. [PMID: 12957426 DOI: 10.1016/s0735-1097(03)00851-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES We sought to determine whether abnormal myocardial blood flow (MBF) responses to the cold pressor test (CPT) in patients with various risk factors may involve different mechanisms that could lead to varying responses of short- and long-term administration of antioxidants. BACKGROUND There is a growing body of evidence that increased vascular production of reactive oxygen species markedly reduces the bioavailability of endothelium-derived nitric oxide, leading to impaired vasodilator function. It is unknown whether increased oxidative stress is the prevalent mechanism underlying endothelial dysfunction in patients with different coronary risk factors. METHODS Fifty patients with normal coronary angiograms were studied. The MBF responses to CPT was determined by means of positron emission tomography before and after intravenous infusion of 3 g vitamin C or saline (placebo), as well as after 3 months and 2 years of 2 g vitamin C or placebo supplementation daily. RESULTS In hypertensive patients, the change in MBF (DeltaMBF) was not modified significantly by short-term vitamin C administration challenges (0.20 +/- 0.20 ml/g/min; p = NS) but was significantly increased after three months and two years of treatment with vitamin C versus baseline (0.58 +/- 0.27 and 0.63 +/- 0.17 vs. 0.14 +/- 0.18 ml/g/min; both p < or = 0.001). In smokers, DeltaMBF in response to CPT was significantly increased after short-term vitamin C infusion and long-term vitamin C treatment (0.52 +/- 0.10, 0.54 +/- 0.13, 0.50 +/- 0.07 vs. -0.08 +/- 0.10 ml/g/min; all p < or = 0.001). In hypercholesterolemic patients, no improvement in DeltaMBF during CPT was observed after short- and long-term vitamin C treatment (0.05 +/- 0.14, 0.08 +/- 0.18, 0.02 +/- 0.19 vs. 0.08 +/- 0.16 ml/g/min; p = NS). The CPT-induced DeltaMBF in hypertensive patients and smokers after follow-up was significant as compared with placebo and control subjects (p < or = 0.001). CONCLUSIONS The present study revealed marked heterogeneous responses in MBF changes to short- and long-term vitamin C treatment in patients with various risk factors, which highlights the quite complex nature underlying abnormal coronary vasomotion.
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Affiliation(s)
- Thomas H Schindler
- Division of Cardiology and Nuclear Medicine, Medical Clinic III, University Hospital of the Albert Ludwig University, Freiburg, Germany.
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Linke A, Recchia F, Zhang X, Hintze TH. Acute and chronic endothelial dysfunction: implications for the development of heart failure. Heart Fail Rev 2003; 8:87-97. [PMID: 12652162 DOI: 10.1023/a:1022151106019] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Heart failure has been characterized by a reduction in cardiac contractile function resulting in reduced cardiac output. The clinical symptoms including mild tachycardia, reduced arterial pressure, increased venous or filling pressure and exercise intolerance have conceptually, to a large degree, been attributed to cardiac myocyte dysfunction. More recently, a vascular component has been recognized to contribute to heart failure. Among the most studied vascular mechanisms that might contribute to the development of heart failure has been the reduced production of nitric oxide or the reduced bioactivity of NO associated with both basic models of heart failure and disease in patients. The still evolving concept that heart failure is a cytokine activated state has, in addition, focused attention on the possibility that the cytokine driven isoform of NO synthase (NOS), iNOS, may produce sufficient quantities of NO to actually suppress cardiac myocyte function contributing to the reduced inotropic state in the failing heart. Thus, our view of the role of NO in the development of heart failure has evolved from simply a reduction in production of NO in blood vessels, to altered substrate availability (i.e. L-arginine), to increased scavenging of NO by superoxide anion, to increased production of NO from iNOS. As these concepts develop, our approach to the therapeutics of heart failure has also progressed with the recognition of the need to develop treatments directed towards addressing one or more of these etiologies. This review will focus on these aspects of the involvement of NO in the development of heart failure and some of the treatments that have developed from our understanding of the basic biology of NO to address these pathohysiologic states.
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Affiliation(s)
- Axel Linke
- Department of Physiology, New York Medical College, Valhalla, NY 10595, USA
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15
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Nahrevanian H, Dascombe MJ. Expression of inducible nitric oxide synthase (iNOS) mRNA in target organs of lethal and non-lethal strains of murine malaria. Parasite Immunol 2002; 24:471-8. [PMID: 12654089 DOI: 10.1046/j.1365-3024.2002.00490.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Nitric oxide (NO) is a putative mediator of the immunological and/or pathological responses to malaria, consequently it is a potential target for novel drug therapy. Numerous cell types increase expression of inducible nitric oxide synthase (iNOS) under inflammatory conditions, the most relevant stimuli being cytokines and endotoxins. In this study the expression of iNOS mRNA in several target organs (brain, liver, spleen) of malaria have been investigated in MF1 mice during lethal Plasmodium (P.) berghei and non-lethal P. c. chabaudi infection. In P. berghei malaria, iNOS mRNA decreased in liver and was unchanged in spleen during the period of rising parasitaemia, but increased in both organs late in the infection, when parasitaemia was high and death imminent. In mice infected with P. c. chabaudi, spleen iNOS mRNA increased progressively throughout the early, peak and recovery periods of parasitaemia, but decreased in liver. Brain iNOS mRNA decreased in samples collected throughout the time courses of both infections. Hence it is evident that changes in iNOS mRNA in murine malaria depend upon the tissue, day of infection, degree of parasitaemia and strain of Plasmodium. These data indicate induction of iNOS mRNA in the spleen has a role in combating these strains of Plasmodium in MF1 mice. Failure to clear lethal P. berghei parasitaemia was associated with increased iNOS mRNA expression in the liver, which may contribute to the pathology of this malaria.
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16
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Abstract
Pregnancy sickness, a suite of "symptoms" that frequently co-occur during pregnancy, may be an adaptation providing behavioral prophylaxis against infection. Maternal immunosupression, necessary for tolerance of the fetus, results in gestational vulnerability to pathogens. Throughout the period of maximal vulnerability, dietary behavior is significantly altered via changes in nausea susceptibility and olfaction and the development of marked aversions and cravings. Of food types, meat is both the most likely to carry pathogens and the principal target of gestational aversions and pregnancy taboos. Because meat was prominent in ancestral human diets but hygienic procedures that effectively eliminate the risk of meat-borne infection are recent, such pathogens likely constituted a source of selective pressure on pregnant females throughout human history. Both the relatively low protein and energy demands of the first trimester and the existense of nonmeat alternatives would have allowed for the evolution of time-limited gestational meat-avoidance mechanisms.Complementing these mechanisms, gestational cravings target substances that may influence immune functioning and affect the availability of iron in the gastro-intestinal tract, thereby limiting the proliferation of iron-dependent pathogens. Clinical and ethnographic findings are examined in light of these proposals, and directions for future research are outlined.
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17
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Abstract
Heart failure is characterized by neurohumoral alterations, such as activation of the sympathetic nervous system, stimulation of the renin-angiotensin system, increased activity of the endothelin system, increased production of norepinephrine, and increased circulating levels of cytokines. Oxidative stress is associated with the formation of reactive oxygen species (ROS). The myocardium has enzymes that stimulate ROS generation and enzymes with antioxidant effects. Several studies have suggested that ROS are increased in the failing heart. ROS may contribute to the pathophysiology of heart failure by initiating myocyte apoptosis and exerting direct negatively inotropic effects through the reduction of cytosolic intracellular free calcium. However, mechanisms such as endothelial dysfunction and inflammation have also been involved in the progression of heart failure. Antioxidants (eg, vitamin C) seem to improve endothelial functionality and reduce the inflammatory response in patients with heart failure. Therefore, in this review, we analyzed the involvement of ROS in the cellular and molecular mechanisms associated with endothelial dysfunction in heart failure.
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Affiliation(s)
- A López Farré
- Cardiovascular Research and Hypertension Laboratory, Fundación Jiménez Díaz, Madrid, Spain.
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18
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Edwards YS. Stretch stimulation: its effects on alveolar type II cell function in the lung. Comp Biochem Physiol A Mol Integr Physiol 2001; 129:245-60. [PMID: 11369549 DOI: 10.1016/s1095-6433(01)00321-x] [Citation(s) in RCA: 84] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mechanical stimuli regulate cell function in much the same way as chemical signals do. This has been studied in various cell types, particularly those with defined mechanical roles. The alveolar type II cell (ATII) cell, which is part of the alveolar epithelium of the lung, is responsible for the synthesis and secretion of pulmonary surfactant. It is now widely believed that stretch of ATII cells, which occurs during breathing, is the predominant physiological trigger for surfactant release. To study this, investigators have used an increasingly sophisticated array of in vitro and in vivo models. Using various stretch devices and models of lung ventilation and expansion, it has been shown that stretch regulates multiple activities in ATII cells. In addition to surfactant secretion, stretch triggers the differentiation of ATII to alveolar type I cells, as well as ATII cell apoptosis. In doing so, stretch modulates the proportion of these cells in the lung epithelium during both development and maturation of the lung and following lung injury. From such studies, it appears that mechanical distortion plays an integral part in maintaining the overall structure and function of the lung.
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Affiliation(s)
- Y S Edwards
- Department of Environmental Biology, University of Adelaide, South Australia, 5005, Adelaide, Australia.
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Ellis GR, Anderson RA, Chirkov YY, Morris-Thurgood J, Jackson SK, Lewis MJ, Horowitz JD, Frenneaux MP. Acute effects of vitamin C on platelet responsiveness to nitric oxide donors and endothelial function in patients with chronic heart failure. J Cardiovasc Pharmacol 2001; 37:564-70. [PMID: 11336107 DOI: 10.1097/00005344-200105000-00008] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Chronic heart failure (CHF) is characterized by a prothrombotic state, which may relate to increased platelet aggregability, endothelial dysfunction, and increased oxidative stress. We investigated the effect of vitamin C in CHF on ex vivo platelet aggregation and platelet responsiveness to the anti-aggregatory effects of the nitric oxide (NO) donors glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). We also examined parameters of oxidative stress and endothelial function in patients. In this double-blind, randomized, crossover study vitamin C (2 g) or placebo was given intravenously to 10 patients with CHF. We measured adenosine 5-diphosphate (ADP)-induced platelet aggregation, flow-mediated dilatation (FMD) in the brachial artery using ultrasonic wall-tracking, and plasma levels of lipid-derived free radicals using electron paramagnetic resonance spectroscopy. Vitamin C did not affect ex vivo platelet aggregability but enhanced the inhibition of platelet aggregation by SNP (62.7+/-10.2 to 82.7+/-4.8%, p = 0.03) and tended to increase responses to GTN (40.5+/-9.0 to 53.4+/-7.3, p = 0.06). The effect of vitamin C on platelet responsiveness to the antiaggregatory effects of SNP was inversely related to basal response to SNP (r = -0.9, p < 0.01); a similar trend was observed with GTN (r = -0.6, p = 0.1). Vitamin C also increased FMD (1.9+/-0.6 to 5.8+/-1.5%, p = 0.02) and reduced plasma lipid-derived free radicals by 49+/-19% (p < 0.05). In patients with CHF acute intravenous administration of vitamin C enhances platelet responsiveness to the anti-aggregatory effects of NO donors and improves endothelial function, suggesting a potential role for vitamin C as a therapeutic agent in CHF.
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Affiliation(s)
- G R Ellis
- Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Cardiff, UK.
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20
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Moini H, Rimbach G, Packer L. Molecular aspects of procyanidin biological activity: disease preventative and therapeutic potentials. DRUG METABOLISM AND DRUG INTERACTIONS 2001; 17:237-59. [PMID: 11201298 DOI: 10.1515/dmdi.2000.17.1-4.237] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
There is a growing interest in the utilization of procyanidins for their dietary and pharmacological properties. A wide spectrum of beneficial activity for human health has been advocated for procyanidins due, in part, to their strong antioxidant activity. More recently the ability of procyanidins to affect gene expression and cell response in vitro has been reported, providing a novel mechanistic perspective on the biological activity of these phytochemicals. This article reviews recent cellular and molecular aspects of the biological activity of procyandins and discusses their disease preventative and therapeutic potentials.
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Affiliation(s)
- H Moini
- Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, USA
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21
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Edwards YS, Sutherland LM, Murray AW. NO protects alveolar type II cells from stretch-induced apoptosis. A novel role for macrophages in the lung. Am J Physiol Lung Cell Mol Physiol 2000; 279:L1236-42. [PMID: 11076814 DOI: 10.1152/ajplung.2000.279.6.l1236] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We have previously shown that mechanical distortion or stretch of alveolar type II (ATII) cells induces both surfactant release and the induction of apoptosis. We hypothesize that nitric oxide (NO) secreted from alveolar macrophages (AMs) prevents cyclic stretch-induced apoptosis. We show that S-nitroso-N-acetyl-D, L-penicillamine (SNAP), a chemical donor of NO, protects cells against nuclear condensation and DNA fragmentation induced by stretch (30% at 60 cycles/min) as well as by sorbitol. SNAP depleted of NO had no protective effect, and the NO scavenger 2-phenyl-4,4,5, 5-tetramethylimidazoline-1-oxyl 3-oxide blocked the antiapoptotic effect of SNAP. We also show that AMs isolated from rat lung lavage fluid actively synthesize and secrete NO. Using a novel technique in which AMs were cocultured with ATII cells while adhered to floating membrane rafts, we found that NO released from AMs was effective in protecting ATII cells from undergoing apoptosis. We therefore propose that NO secreted by AMs may function as part of a physiological antiapoptotic mechanism that prevents ATII cells from undergoing stretch-induced cell death in the lung.
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Affiliation(s)
- Y S Edwards
- School of Biological Sciences, Faculty of Science and Engineering, Flinders University of South Australia, Adelaide, South Australia 5001, Australia.
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22
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Ellis GR, Anderson RA, Lang D, Blackman DJ, Morris RH, Morris-Thurgood J, McDowell IF, Jackson SK, Lewis MJ, Frenneaux MP. Neutrophil superoxide anion--generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy. J Am Coll Cardiol 2000; 36:1474-82. [PMID: 11079645 DOI: 10.1016/s0735-1097(00)00916-5] [Citation(s) in RCA: 109] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
OBJECTIVES First, we sought to study the effects of short- and long-term vitamin C therapy on oxidative stress and endothelial dysfunction in chronic heart failure (CHF), and second, we sought to investigate the role of neutrophils as a cause of oxidative stress in CHF. BACKGROUND Oxidative stress may contribute to endothelial dysfunction in CHF. Vitamin C ameliorates endothelial dysfunction in CHF, presumably by reducing oxidative stress, but this is unproven. METHODS We studied 55 patients with CHF (ischemic and nonischemic etiologies) and 15 control subjects. Flow-mediated dilation (FMD) in the brachial artery was measured by ultrasound wall-tracking, neutrophil superoxide anion (O2-) generation by lucigenin-enhanced chemiluminescence and oxidative stress by measurement of free radicals (FRs) in venous blood using electron paramagnetic resonance (EPR) spectroscopy and plasma thiobarbituric acid reactive substances (TBARS). Measurements were performed at baseline in all subjects. The effects of short-term (intravenous) and long-term (oral) vitamin C therapy versus placebo were tested in patients with nonischemic CHF. RESULTS At baseline, FRs were higher in patients with CHF than in control subjects (p < 0.01), TBARS were greater (p < 0.005), neutrophil O2- -generating capacity was enhanced (p < 0.005) and FMD was lower (p < 0.0001). Compared with placebo, short-term vitamin C therapy reduced FR levels (p < 0.05), tended to reduce TBARS and increased FMD (p < 0.05), but did not affect neutrophil O2- -generating capacity. Long-term vitamin C therapy reduced FR levels (p < 0.05), reduced TBARS (p < 0.05) and improved FMD (p < 0.05), but also reduced neutrophil O2- -generating capacity (p < 0.05). Endothelial dysfunction was not related to oxidative stress, and improvements in FMD with vitamin C therapy did not relate to reductions in oxidative stress. CONCLUSIONS Oxidative stress is increased in ischemic and nonischemic CHF, and neutrophils may be an important cause. Vitamin C reduces oxidative stress, increases FMD and, when given long term, decreases neutrophil O2- generation, but the lack of a correlation between changes in endothelial function and oxidative stress with vitamin C implies possible additional non-antioxidant benefits of vitamin C.
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Affiliation(s)
- G R Ellis
- Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Cardiff, United Kingdom
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Park YC, Rimbach G, Saliou C, Valacchi G, Packer L. Activity of monomeric, dimeric, and trimeric flavonoids on NO production, TNF-alpha secretion, and NF-kappaB-dependent gene expression in RAW 264.7 macrophages. FEBS Lett 2000; 465:93-7. [PMID: 10631311 DOI: 10.1016/s0014-5793(99)01735-4] [Citation(s) in RCA: 130] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Flavonoids are potent antioxidants and have been associated with lowering the risk of cardiovascular diseases. In this study, the effect of flavonoids (monomers, dimers and a trimer) as well as French maritime pine bark extract, Pycnogenol, on NO production, tumor necrosis factor-alpha (TNF-alpha) secretion and nuclear factor (NF)-kappaB activity was compared. Monomers and dimers repressed NO production, TNF-alpha secretion and NF-kappaB-dependent gene expression induced by interferon gamma, whereas the trimeric procyanidin C2 and Pycnogenol enhanced these parameters. In addition, in unstimulated RAW 264.7 macrophages, both procyanidin C2 and Pycnogenol increased TNF-alpha secretion in a concentration- and time-dependent manner. These results demonstrate that procyanidins act as modulators of the immune response in macrophages.
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Affiliation(s)
- Y C Park
- Department of Molecular and Cell Biology, 251 Life Sciences Addition, University of California, Berkeley, CA 94720-3200, USA
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