Skip to main content
SpringerLink
Log in
Book cover

Pulmonary Vasculature Redox Signaling in Health and Disease pp 161–178Cite as

Natural Antioxidants as Potential Therapy, and a Promising Role for Melatonin Against Pulmonary Hypertension

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 967))

Abstract

Plasma and serum samples, and lung/heart tissue of pulmonary hypertension (PH) patients and animal models of PH display elevated oxidative stress. Moreover, the severity of PH and levels of oxidative stress increase concurrently, which suggests that oxidative stress could be utilized as a biomarker for PH progression. Accumulating evidence has well established that oxidative stress is also key role player in the development of PH. Preclinical studies have demonstrated that natural antioxidants improved PH condition, and, therefore, antioxidant therapy has been proposed as a potential therapeutic strategy against PH. These natural antioxidants include medicinal plant extracts and compounds such as resveratrol and melatonin. Recent studies suggest that melatonin provides health benefit against PH, by enhancing antioxidant capacity, increasing vasodilation, counteracting lung and cardiac fibrosis, and stunting right ventricular (RV) hypertrophy/failure. This chapter comprehensively reviews and discusses a variety of natural antioxidants and their efficacy in modulating experimental PH. This chapter also demonstrates that antioxidant therapy remains a therapeutic strategy for PH, and particularly identifies melatonin as a safe, cost-effective, and promising antioxidant therapy.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

MCT:

Monocrotaline

MPAP:

Mean pulmonary arterial pressure

PA:

Pulmonary artery

PAAT:

Pulmonary artery acceleration time

PAP:

Pulmonary arterial pressure

PASMCs:

Pulmonary arterial smooth muscle cells

PH:

Pulmonary hypertension

PVR:

Pulmonary vascular resistance

RV:

Right ventricle/right ventricular

References

  1. Sanchez, O., Marcos, E., Perros, F., Fadel, E., Tu, L., Humbert, M., Dartevelle, P., Simonneau, G., Adnot, S., & Eddahibi, S. (2007). Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 176(10), 1041–1047. doi:10.1164/rccm.200610-1559OC.

    Article  CAS  PubMed  Google Scholar 

  2. Guignabert, C., Tu, L., Le Hiress, M., Ricard, N., Sattler, C., Seferian, A., Huertas, A., Humbert, M., & Montani, D. (2013). Pathogenesis of pulmonary arterial hypertension: Lessons from cancer. European Respiratory Review, 22(130), 543–551. doi:10.1183/09059180.00007513.

    Article  PubMed  Google Scholar 

  3. Balabanian, K., Foussat, A., Dorfmuller, P., Durand-Gasselin, I., Capel, F., Bouchet-Delbos, L., Portier, A., Marfaing-Koka, A., Krzysiek, R., Rimaniol, A. C., Simonneau, G., Emilie, D., & Humbert, M. (2002). CX(3)C chemokine fractalkine in pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 165(10), 1419–1425. doi:10.1164/rccm.2106007.

    Article  PubMed  Google Scholar 

  4. Todorovich-Hunter, L., Dodo, H., Ye, C., McCready, L., Keeley, F. W., & Rabinovitch, M. (1992). Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. The American Review of Respiratory Disease, 146(1), 213–223. doi:10.1164/ajrccm/146.1.213.

    Article  CAS  PubMed  Google Scholar 

  5. Rabinovitch, M. (2012). Molecular pathogenesis of pulmonary arterial hypertension. The Journal of Clinical Investigation, 122(12), 4306–4313. doi:10.1172/JCI60658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Huertas, A., Perros, F., Tu, L., Cohen-Kaminsky, S., Montani, D., Dorfmuller, P., Guignabert, C., & Humbert, M. (2014). Immune dysregulation and endothelial dysfunction in pulmonary arterial hypertension: A complex interplay. Circulation, 129(12), 1332–1340. doi:10.1161/CIRCULATIONAHA.113.004555.

    Article  PubMed  Google Scholar 

  7. Rabinovitch, M. (1998). Elastase and the pathobiology of unexplained pulmonary hypertension. Chest, 114(3 Suppl), 213S–224S.

    Article  CAS  PubMed  Google Scholar 

  8. Rabinovitch, M. (1999). Pulmonary hypertension: Pathophysiology as a basis for clinical decision making. The Journal of Heart and Lung Transplantation, 18(11), 1041–1053.

    Article  CAS  PubMed  Google Scholar 

  9. Rabinovitch, M. (2007). Pathobiology of pulmonary hypertension. Annual Review of Pathology, 2, 369–399. doi:10.1146/annurev.pathol.2.010506.092033.

    Article  CAS  PubMed  Google Scholar 

  10. Christman, B. W., McPherson, C. D., Newman, J. H., King, G. A., Bernard, G. R., Groves, B. M., & Loyd, J. E. (1992). An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. The New England Journal of Medicine, 327(2), 70–75. doi:10.1056/NEJM199207093270202.

    Article  CAS  PubMed  Google Scholar 

  11. Xia, X. D., Xu, Z. J., Hu, X. G., Wu, C. Y., Dai, Y. R., & Yang, L. (2012). Impaired iNOS-sGC-cGMP signalling contributes to chronic hypoxic and hypercapnic pulmonary hypertension in rat. Cell Biochemistry and Function, 30(4), 279–285. doi:10.1002/cbf.2796.

    Article  CAS  PubMed  Google Scholar 

  12. Cogan, J. D., Vnencak-Jones, C. L., Phillips, J. A., III,Lane, K. B., Wheeler, L. A., Robbins, I. M., Garrison, G., Hedges, L. K., & Loyd, J. E. (2005). Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genetics in Medicine, 7(3), 169–174. doi: 10.109701.GIM.0000156525.09595.E9.

    Article  CAS  PubMed  Google Scholar 

  13. Morrell, N. W. (2006). Pulmonary hypertension due to BMPR2 mutation: A new paradigm for tissue remodeling? Proceedings of the American Thoracic Society, 3(8), 680–686. doi:10.1513/pats.200605-118SF.

    Article  CAS  PubMed  Google Scholar 

  14. Ghasemzadeh, N., Patel, R. S., Eapen, D. J., Veledar, E., Al Kassem, H., Manocha, P., Khayata, M., Zafari, A. M., Sperling, L., Jones, D. P., & Quyyumi, A. A. (2014). Oxidative stress is associated with increased pulmonary artery systolic pressure in humans. Hypertension, 63(6), 1270–1275. doi:10.1161/HYPERTENSIONAHA.113.02360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang, S., Yang, T., Xu, X., Wang, M., Zhong, L., Yang, Y., Zhai, Z., Xiao, F., & Wang, C. (2015). Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: A case control study. BMC Pulmonary Medicine, 15(1), 50. doi:10.1186/s12890-015-0045-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Teixeira-Mendonca, C., & Henriques-Coelho, T. (2013). Pathophysiology of pulmonary hypertension in newborns: Therapeutic indications. Revista Portuguesa de Cardiologia, 32(12), 1005–1012. doi:10.1016/j.repc.2013.06.010.

    Article  PubMed  Google Scholar 

  17. Voelkel, N. F., Gomez-Arroyo, J., Abbate, A., Bogaard, H. J., & Nicolls, M. R. (2012). Pathobiology of pulmonary arterial hypertension and right ventricular failure. The European Respiratory Journal, 40(6), 1555–1565. doi:10.1183/09031936.00046612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Demarco, V. G., Whaley-Connell, A. T., Sowers, J. R., Habibi, J., & Dellsperger, K. C. (2010). Contribution of oxidative stress to pulmonary arterial hypertension. World Journal of Cardiology, 2(10), 316–324. doi:10.4330/wjc.v2.i10.316.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Crosswhite, P., & Sun, Z. (2010). Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. Journal of Hypertension, 28(2), 201–212. doi:10.1097/HJH.0b013e328332bcdb.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ahmed, L. A., Obaid, A. A., Zaki, H. F., & Agha, A. M. (2014). Role of oxidative stress, inflammation, nitric oxide and transforming growth factor-beta in the protective effect of diosgenin in monocrotaline-induced pulmonary hypertension in rats. European Journal of Pharmacology, 740, 379–387. doi:10.1016/j.ejphar.2014.07.026.

    Article  CAS  PubMed  Google Scholar 

  21. Majzunova, M., Dovinova, I., Barancik, M., & Chan, J. Y. (2013). Redox signaling in pathophysiology of hypertension. Journal of Biomedical Science, 20, 69. doi:10.1186/1423-0127-20-69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bowers, R., Cool, C., Murphy, R. C., Tuder, R. M., Hopken, M. W., Flores, S. C., & Voelkel, N. F. (2004). Oxidative stress in severe pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine, 169(6), 764–769. doi:10.1164/rccm.200301-147OC.

    Article  PubMed  Google Scholar 

  23. Farber, H. W., & Loscalzo, J. (2004). Pulmonary arterial hypertension. The New England Journal of Medicine, 351(16), 1655–1665. doi:10.1056/NEJMra035488.

    Article  CAS  PubMed  Google Scholar 

  24. Farley, K. S., Wang, L., & Mehta, S. (2009). Septic pulmonary microvascular endothelial cell injury: Role of alveolar macrophage NADPH oxidase. American Journal of Physiology. Lung Cellular and Molecular Physiology, 296(3), L480–L488. doi:10.1152/ajplung.90201.2008.

    Article  CAS  PubMed  Google Scholar 

  25. Jurasz, P., Courtman, D., Babaie, S., & Stewart, D. J. (2010). Role of apoptosis in pulmonary hypertension: From experimental models to clinical trials. Pharmacology & Therapeutics, 126(1), 1–8. doi:10.1016/j.pharmthera.2009.12.006.

    Article  CAS  Google Scholar 

  26. Jonigk, D., Golpon, H., Bockmeyer, C. L., Maegel, L., Hoeper, M. M., Gottlieb, J., Nickel, N., Hussein, K., Maus, U., Lehmann, U., Janciauskiene, S., Welte, T., Haverich, A., Rische, J., Kreipe, H., & Laenger, F. (2011). Plexiform lesions in pulmonary arterial hypertension composition, architecture, and microenvironment. The American Journal of Pathology, 179(1), 167–179. doi:10.1016/j.ajpath.2011.03.040.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Abe, K., Toba, M., Alzoubi, A., Ito, M., Fagan, K. A., Cool, C. D., Voelkel, N. F., McMurtry, I. F., & Oka, M. (2010). Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation, 121(25), 2747–2754. doi:10.1161/CIRCULATIONAHA.109.927681.

    Article  PubMed  Google Scholar 

  28. Voelkel, N. F., Gomez-Arroyo, J., Abbate, A., & Bogaard, H. J. (2013). Mechanisms of right heart failure—A work in progress and a plea for failure prevention. Pulmonary Circulation, 3(1), 137–143. doi:10.4103/2045-8932.109957.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Vonk-Noordegraaf, A., Haddad, F., Chin, K. M., Forfia, P. R., Kawut, S. M., Lumens, J., Naeije, R., Newman, J., Oudiz, R. J., Provencher, S., Torbicki, A., Voelkel, N. F., & Hassoun, P. M. (2013). Right heart adaptation to pulmonary arterial hypertension: Physiology and pathobiology. Journal of the American College of Cardiology, 62(25 Suppl), D22–D33. doi:10.1016/j.jacc.2013.10.027.

    Article  PubMed  Google Scholar 

  30. Ruocco, G., & Palazzuoli, A. (2015). Early detection of pulmonary arterial hypertension: Do not forget the right ventricle. Nature Reviews. Cardiology, 12(3), 134. doi:10.1038/nrcardio.2014.191-c1.

    Article  PubMed  Google Scholar 

  31. Ryan, J. J., & Archer, S. L. (2015). Emerging concepts in the molecular basis of pulmonary arterial hypertension: Part I: Metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension. Circulation, 131(19), 1691–1702. doi:10.1161/CIRCULATIONAHA.114.006979.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ryan, J. J., & Archer, S. L. (2014). The right ventricle in pulmonary arterial hypertension: Disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. Circulation Research, 115(1), 176–188. doi:10.1161/CIRCRESAHA.113.301129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Harrison, A., Hatton, N., & Ryan, J. J. (2015). The right ventricle under pressure: Evaluating the adaptive and maladaptive changes in the right ventricle in pulmonary arterial hypertension using echocardiography (2013 Grover conference series). Pulmonary Circulation, 5(1), 29–47. doi:10.1086/679699.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Voelkel, N. F., Bogaard, H. J., Al Husseini, A., Farkas, L., Gomez-Arroyo, J., & Natarajan, R. (2013). Antioxidants for the treatment of patients with severe angioproliferative pulmonary hypertension? Antioxidants & Redox Signaling, 18(14), 1810–1817. doi:10.1089/ars.2012.4828.

    Article  CAS  Google Scholar 

  35. Wong, C. M., Bansal, G., Pavlickova, L., Marcocci, L., & Suzuki, Y. J. (2013). Reactive oxygen species and antioxidants in pulmonary hypertension. Antioxidants & Redox Signaling, 18(14), 1789–1796. doi:10.1089/ars.2012.4568.

    Article  CAS  Google Scholar 

  36. Ardalan, M. R., & Rafieian-Kopaei, M. (2014). Antioxidant supplementation in hypertension. Journal of Renal Injury Prevention, 3(2), 39–40. doi:10.12861/jrip.2014.13.

    PubMed  Google Scholar 

  37. Chaumais, M. C., Ranchoux, B., Montani, D., Dorfmuller, P., Tu, L., Lecerf, F., Raymond, N., Guignabert, C., Price, L., Simonneau, G., Cohen-Kaminsky, S., Humbert, M., & Perros, F. (2014). N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats. Respiratory Research, 15, 65. doi:10.1186/1465-9921-15-65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Chen, K. H., Chen, Y. J., Yang, C. H., Liu, K. W., Chang, J. L., Pan, S. F., Lin, T. B., & Chen, M. J. (2012). Attenuation of the extract from Moringa oleifera on monocrotaline-induced pulmonary hypertension in rats. The Chinese Journal of Physiology, 55(1), 22–30. doi:10.4077/CJP.2012.AMM104.

    Article  CAS  PubMed  Google Scholar 

  39. Rakotomalala, G., Agard, C., Tonnerre, P., Tesse, A., Derbre, S., Michalet, S., Hamzaoui, J., Rio, M., Cario-Toumaniantz, C., Richomme, P., Charreau, B., Loirand, G., & Pacaud, P. (2013). Extract from Mimosa pigra attenuates chronic experimental pulmonary hypertension. Journal of Ethnopharmacology, 148(1), 106–116. doi:10.1016/j.jep.2013.03.075.

    Article  CAS  PubMed  Google Scholar 

  40. Ahmadipour, B., Hassanpour, H., Asadi, E., Khajali, F., Rafiei, F., & Khajali, F. (2015). Kelussia odoratissima Mozzaf—A promising medicinal herb to prevent pulmonary hypertension in broiler chickens reared at high altitude. Journal of Ethnopharmacology, 159, 49–54. doi:10.1016/j.jep.2014.10.043.

    Article  PubMed  Google Scholar 

  41. Roleira, F. M., Tavares-da-Silva, E. J., Varela, C. L., Costa, S. C., Silva, T., Garrido, J., & Borges, F. (2015).Plant derived and dietary phenolic antioxidants: Anticancer properties. Food Chemistry, 183, 235–258. doi:10.1016/j.foodchem.2015.03.039.

    Article  CAS  PubMed  Google Scholar 

  42. Kosanovic, D., Tian, X., Pak, O., Lai, Y. J., Hsieh, Y. L., Seimetz, M., Weissmann, N., Schermuly, R. T., & Dahal, B. K. (2013). Rhodiola: An ordinary plant or a promising future therapy for pulmonary hypertension? A brief review. Pulmonary Circulation, 3(3), 499–506. doi:10.1086/674303.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Azad, G. K., & Tomar, R. S. (2014). Ebselen, a promising antioxidant drug: Mechanisms of action and targets of biological pathways. Molecular Biology Reports, 41(8), 4865–4879. doi:10.1007/s11033-014-3417-x.

    Article  CAS  PubMed  Google Scholar 

  44. Kamezaki, F., Tasaki, H., Yamashita, K., Tsutsui, M., Koide, S., Nakata, S., Tanimoto, A., Okazaki, M., Sasaguri, Y., Adachi, T., & Otsuji, Y. (2008). Gene transfer of extracellular superoxide dismutase ameliorates pulmonary hypertension in rats. American Journal of Respiratory and Critical Care Medicine, 177(2), 219–226. doi:10.1164/rccm.200702-264OC.

    Article  CAS  PubMed  Google Scholar 

  45. McLendon, J. M., Joshi, S. R., Sparks, J., Matar, M., Fewell, J. G., Abe, K., Oka, M., McMurtry, I. F., & Gerthoffer, W. T. (2015). Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension. Journal of Controlled Release, 210, 67–75. doi:10.1016/j.jconrel.2015.05.261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Niu, J., Wang, K., & Kolattukudy, P. E. (2011). Cerium oxide nanoparticles inhibit oxidative stress and nuclear factor-kappaB activation in H9c2 cardiomyocytes exposed to cigarette smoke extract. The Journal of Pharmacology and Experimental Therapeutics, 338(1), 53–61. doi:10.1124/jpet.111.179978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Spivak, M. Y., Bubnov, R. V., Yemets, I. M., Lazarenko, L. M., Tymoshok, N. O., & Ulberg, Z. R. (2013). Development and testing of gold nanoparticles for drug delivery and treatment of heart failure: A theranostic potential for PPP cardiology. The EPMA Journal, 4(1), 20. doi:10.1186/1878-5085-4-20.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lee, D., Bae, S., Hong, D., Lim, H., Yoon, J. H., Hwang, O., Park, S., Ke, Q., Khang, G., & Kang, P. M. (2013). H2O2-responsive molecularly engineered polymer nanoparticles as ischemia/reperfusion-targeted nanotherapeutic agents. Scientific Reports, 3, 2233. doi:10.1038/srep02233.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Shukia, R., Sharma, S. B., Puri, D., Prabhu, K. M., & Murthy, P. S. (2000). Medicinal plants for treatment of diabetes mellitus. Indian Journal of Clinical Biochemistry, 15(Suppl 1), 169–177. doi:10.1007/BF02867556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Eddouks, M., Maghrani, M., Lemhadri, A., Ouahidi, M. L., & Jouad, H. (2002). Ethnopharmacological survey of medicinal plants used for the treatment of diabetes mellitus, hypertension and cardiac diseases in the south-east region of Morocco (Tafilalet). Journal of Ethnopharmacology, 82(2–3), 97–103.

    Article  CAS  PubMed  Google Scholar 

  51. Eddouks, M., Chattopadhyay, D., De Feo, V., & Cho, W. C. (2014). Medicinal plants in the prevention and treatment of chronic diseases 2013. Evidence-based Complementary and Alternative Medicine, 2014, 180981. doi:10.1155/2014/180981.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Vasanthi, H. R., ShriShriMal, N., & Das, D. K. (2012). Phytochemicals from plants to combat cardiovascular disease. Current Medicinal Chemistry, 19(14), 2242–2251.

    Article  CAS  PubMed  Google Scholar 

  53. Huisamen, B., George, C., Dietrich, D., & Genade, S. (2013). Cardioprotective and anti-hypertensive effects of Prosopis glandulosa in rat models of pre-diabetes. Cardiovascular Journal of Africa, 24(2), 10–16. doi:10.5830/CVJA-2012-069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. George, C., Lochner, A., & Huisamen, B. (2011). The efficacy of Prosopis glandulosa as antidiabetic treatment in rat models of diabetes and insulin resistance. Journal of Ethnopharmacology, 137(1), 298–304. doi:10.1016/j.jep.2011.05.023.

    Article  CAS  PubMed  Google Scholar 

  55. George, C., Smith, C., Isaacs, A. W., & Huisamen, B. (2015). Chronic Prosopis glandulosa treatment blunts neutrophil infiltration and enhances muscle repair after contusion injury. Nutrients, 7(2), 815–830. doi:10.3390/nu7020815.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Musabayane, C. T. (2012). The effects of medicinal plants on renal function and blood pressure in diabetes mellitus. Cardiovascular Journal of Africa, 23(8), 462–468. doi:10.5830/CVJA-2012-025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Madlala, H. P., Van Heerden, F. R., Mubagwa, K., & Musabayane, C. T. (2015). Changes in renal function and oxidative status associated with the hypotensive effects of oleanolic acid and related synthetic derivatives in experimental animals. PloS One, 10(6), e0128192. doi:10.1371/journal.pone.0128192.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Zaidi, S. F., Muhammad, J. S., Shahryar, S., Usmanghani, K., Gilani, A. H., Jafri, W., & Sugiyama, T. (2012). Anti-inflammatory and cytoprotective effects of selected Pakistani medicinal plants in helicobacter pylori-infected gastric epithelial cells. Journal of Ethnopharmacology, 141(1), 403–410. doi:10.1016/j.jep.2012.03.001.

    Article  PubMed  Google Scholar 

  59. Duval, F., Moreno-Cuevas, J. E., Gonzalez-Garza, M. T., Rodriguez-Montalvo, C., & Cruz-Vega, D. E. (2014). Liver fibrosis and protection mechanisms action of medicinal plants targeting apoptosis of hepatocytes and hepatic stellate cells. Advances in Pharmacological Sciences, 2014, 373295. doi:10.1155/2014/373295.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Ghoneim, A. I. (2009). Effects of curcumin on ethanol-induced hepatocyte necrosis and apoptosis: Implication of lipid peroxidation and cytochrome c. Naunyn-Schmiedeberg's Archives of Pharmacology, 379(1), 47–60. doi:10.1007/s00210-008-0335-2.

    Article  CAS  PubMed  Google Scholar 

  61. Strange, G., Gabbay, E., Kermeen, F., Williams, T., Carrington, M., Stewart, S., & Keogh, A. (2013). Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: The delay study. Pulmonary Circulation, 3(1), 89–94. doi:10.4103/2045-8932.109919.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Lau, E. M., Tamura, Y., McGoon, M. D., & Sitbon, O. (2015). The 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: A practical chronicle of progress. The European Respiratory Journal, 46(4), 879–882. doi:10.1183/13993003.01177-2015.

    Article  PubMed  Google Scholar 

  63. Galie, N., Humbert, M., Vachiery, J. L., Gibbs, S., Lang, I., Torbicki, A., Simonneau, G., Peacock, A., Vonk Noordegraaf, A., Beghetti, M., Ghofrani, A., Gomez Sanchez, M. A., Hansmann, G., Klepetko, W., Lancellotti, P., Matucci, M., McDonagh, T., Pierard, L. A., Trindade, P. T., Zompatori, M., & Hoeper, M. (2015). 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). The European Respiratory Journal, 46(4), 903–975. doi:10.1183/13993003.01032-2015.

    Article  CAS  PubMed  Google Scholar 

  64. Haeck, M. L., & Vliegen, H. W. (2015). Diagnosis and treatment of pulmonary hypertension. Heart, 101(4), 311–319. doi:10.1136/heartjnl-2011-301386.

    Article  PubMed  Google Scholar 

  65. Grosvenor, P. W., Supriono, A., & Gray, D. O. (1995). Medicinal plants from Riau province, Sumatra, Indonesia. Part 2: Antibacterial and antifungal activity. Journal of Ethnopharmacology, 45(2), 97–111.

    Article  CAS  PubMed  Google Scholar 

  66. Grosvenor, P. W., Gothard, P. K., McWilliam, N. C., Supriono, A., & Gray, D. O. (1995). Medicinal plants from Riau province, Sumatra, Indonesia. Part 1: Uses. Journal of Ethnopharmacology, 45(2), 75–95.

    Article  CAS  PubMed  Google Scholar 

  67. Rosado-Vallado, M., Brito-Loeza, W., Mena-Rejon, G. J., Quintero-Marmol, E., & Flores-Guido, J. S. (2000). Antimicrobial activity of Fabaceae species used in Yucatan traditional medicine. Fitoterapia, 71(5), 570–573.

    Article  CAS  PubMed  Google Scholar 

  68. Rabbani, M., Sajjadi, S. E., & Sadeghi, M. (2011). Chemical composition of the essential oil from kelussia odoratissima Mozaff. and the evaluation of its sedative and anxiolytic effects in mice. Clinics (Sao Paulo), 66(5), 843–848.

    Article  Google Scholar 

  69. Lu, Q., Qiu, T. Q., & Yang, H. (2006). Ligustilide inhibits vascular smooth muscle cells proliferation. European Journal of Pharmacology, 542(1–3), 136–140. doi:10.1016/j.ejphar.2006.04.023.

    Article  CAS  PubMed  Google Scholar 

  70. Kuang, X., Du, J. R., Liu, Y. X., Zhang, G. Y., & Peng, H. Y. (2008). Postischemic administration of Z-Ligustilide ameliorates cognitive dysfunction and brain damage induced by permanent forebrain ischemia in rats. Pharmacology, Biochemistry, and Behavior, 88(3), 213–221. doi:10.1016/j.pbb.2007.08.006.

    Article  CAS  PubMed  Google Scholar 

  71. Shevtsov, V. A., Zholus, B. I., Shervarly, V. I., Vol'skij, V. B., Korovin, Y. P., Khristich, M. P., Roslyakova, N. A., & Wikman, G. (2003). A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine, 10(2–3), 95–105. doi:10.1078/094471103321659780.

    Article  CAS  PubMed  Google Scholar 

  72. Yan, X., Wang, Y., Guo, S., & Shang, X. (2004). [Seasonal variations in biomass and salidroside content in roots of Rhodiola sachalinensis as affected by gauze and red film shading]. Ying Yong Sheng Tai Xue Bao, 15(3), 382–386.

    Google Scholar 

  73. Seo, W. G., Pae, H. O., Oh, G. S., Kim, N. Y., Kwon, T. O., Shin, M. K., Chai, K. Y., & Chung, H. T. (2001). The aqueous extract of Rhodiola sachalinensis root enhances the expression of inducible nitric oxide synthase gene in RAW264.7 macrophages. Journal of Ethnopharmacology, 76(1), 119–123.

    Article  CAS  PubMed  Google Scholar 

  74. Lee, M. W., Lee, Y. A., Park, H. M., Toh, S. H., Lee, E. J., Jang, H. D., & Kim, Y. H. (2000). Antioxidative phenolic compounds from the roots of Rhodiola sachalinensis A. Bor. Archives of Pharmacal Research, 23(5), 455–458.

    Article  CAS  PubMed  Google Scholar 

  75. Choe, K. I., Kwon, J. H., Park, K. H., Oh, M. H., Kim, M. H., Kim, H. H., Cho, S. H., Chung, E. K., Ha, S. Y., & Lee, M. W. (2012). The antioxidant and anti-inflammatory effects of phenolic compounds isolated from the root of Rhodiola sachalinensis A. BOR. Molecules, 17(10), 11484–11494. doi:10.3390/molecules171011484.

    Article  CAS  PubMed  Google Scholar 

  76. Bai, M. K., Guo, Y., Bian, B. D., Dong, H., Wang, T., Luo, F., Wen, F. Q., & Cui, C. Y. (2011). [Integripetal rhodiola herb attenuates high altitude-induced pulmonary arterial remodeling and expression of vascular endothelial growth factor in rats]. Sheng Li Xue Bao, 63(2), 143–148.

    Google Scholar 

  77. Balentine, D. A., Albano, M. C., & Nair, M. G. (1999). Role of medicinal plants, herbs, and spices in protecting human health. Nutrition Reviews, 57(9 Pt 2), S41–S45.

    CAS  PubMed  Google Scholar 

  78. Sen, T., & Samanta, S. K. (2015). Medicinal plants, human health and biodiversity: A broad review. Advances in Biochemical Engineering/Biotechnology, 147, 59–110. doi:10.1007/10_2014_273.

    Article  CAS  PubMed  Google Scholar 

  79. Briskin, D. P. (2000). Medicinal plants and phytomedicines. Linking plant biochemistry and physiology to human health. Plant Physiology, 124(2), 507–514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kitula, R. A. (2007). Use of medicinal plants for human health in Udzungwa Mountains Forests: A case study of New Dabaga Ulongambi Forest Reserve, Tanzania. Journal of Ethnobiology and Ethnomedicine, 3, 7. doi:10.1186/1746-4269-3-7.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Zank, S., Peroni, N., de Araujo, E. L., & Hanazaki, N. (2015). Local health practices and the knowledge of medicinal plants in a Brazilian semi-arid region: Environmental benefits to human health. Journal of Ethnobiology and Ethnomedicine, 11, 11. doi:10.1186/1746-4269-11-11.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Csiszar, A., Labinskyy, N., Olson, S., Pinto, J. T., Gupte, S., Wu, J. M., Hu, F., Ballabh, P., Podlutsky, A., Losonczy, G., de Cabo, R., Mathew, R., Wolin, M. S., & Ungvari, Z. (2009). Resveratrol prevents monocrotaline-induced pulmonary hypertension in rats. Hypertension, 54(3), 668–675. doi:10.1161/HYPERTENSIONAHA.109.133397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Raj, P., Louis, X. L., Thandapilly, S. J., Movahed, A., Zieroth, S., & Netticadan, T. (2014). Potential of resveratrol in the treatment of heart failure. Life Sciences, 95(2), 63–71. doi:10.1016/j.lfs.2013.12.011.

    Article  CAS  PubMed  Google Scholar 

  84. Sahebkar, A. (2013). Effects of resveratrol supplementation on plasma lipids: A systematic review and meta-analysis of randomized controlled trials. Nutrition Reviews, 71(12), 822–835. doi:10.1111/nure.12081.

    Article  PubMed  Google Scholar 

  85. Yang, D. L., Zhang, H. G., Xu, Y. L., Gao, Y. H., Yang, X. J., Hao, X. Q., & Li, X. H. (2010). Resveratrol inhibits right ventricular hypertrophy induced by monocrotaline in rats. Clinical and Experimental Pharmacology & Physiology, 37(2), 150–155. doi:10.1111/j.1440-1681.2009.05231.x.

    Article  CAS  Google Scholar 

  86. Paffett, M. L., Lucas, S. N., & Campen, M. J. (2012). Resveratrol reverses monocrotaline-induced pulmonary vascular and cardiac dysfunction: A potential role for atrogin-1 in smooth muscle. Vascular Pharmacology, 56(1–2), 64–73. doi:10.1016/j.vph.2011.11.002.

    Article  CAS  PubMed  Google Scholar 

  87. Tome-Carneiro, J., Gonzalvez, M., Larrosa, M., Yanez-Gascon, M. J., Garcia-Almagro, F. J., Ruiz-Ros, J. A., Tomas-Barberan, F. A., Garcia-Conesa, M. T., & Espin, J. C. (2013). Resveratrol in primary and secondary prevention of cardiovascular disease: A dietary and clinical perspective. Annals of the New York Academy of Sciences, 1290, 37–51. doi:10.1111/nyas.12150.

    Article  CAS  PubMed  Google Scholar 

  88. Liu, Y., Ma, W., Zhang, P., He, S., & Huang, D. (2015). Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials. Clinical Nutrition, 34(1), 27–34. doi:10.1016/j.clnu.2014.03.009.

    Article  PubMed  CAS  Google Scholar 

  89. Samuni, Y., Goldstein, S., Dean, O. M., & Berk, M. (2013). The chemistry and biological activities of N-acetylcysteine. Biochimica et Biophysica Acta, 1830(8), 4117–4129. doi:10.1016/j.bbagen.2013.04.016.

    Article  CAS  PubMed  Google Scholar 

  90. Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez, F. J., de Andrade, J. A., Anstrom, K. J., King, T. E., Jr., & Raghu, G. (2014). Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. The New England Journal of Medicine, 370(22), 2093–2101. doi:10.1056/NEJMoa1401739.

    Article  CAS  Google Scholar 

  91. Demedts, M., Behr, J., Buhl, R., Costabel, U., Dekhuijzen, R., Jansen, H. M., MacNee, W., Thomeer, M., Wallaert, B., Laurent, F., Nicholson, A. G., Verbeken, E. K., Verschakelen, J., Flower, C. D., Capron, F., Petruzzelli, S., De Vuyst, P., van den Bosch, J. M., Rodriguez-Becerra, E., Corvasce, G., Lankhorst, I., Sardina, M., Montanari, M., & IFIGENIA Study Group. (2005). High-dose acetylcysteine in idiopathic pulmonary fibrosis. The New England Journal of Medicine, 353(21), 2229–2242. doi:10.1056/NEJMoa042976.

    Article  CAS  PubMed  Google Scholar 

  92. Inci, I., Zhai, W., Arni, S., Hillinger, S., Vogt, P., & Weder, W. (2007). N-acetylcysteine attenuates lung ischemia-reperfusion injury after lung transplantation. The Annals of Thoracic Surgery, 84(1), 240–246.; Discussion 6. doi:10.1016/j.athoracsur.2007.03.082.

    Article  PubMed  Google Scholar 

  93. Mahmoud, K. M., & Ammar, A. S. (2011). Effect of N-acetylcysteine on cardiac injury and oxidative stress after abdominal aortic aneurysm repair: A randomized controlled trial. Acta Anaesthesiologica Scandinavica, 55(8), 1015–1021. doi:10.1111/j.1399-6576.2011.02492.x.

    Article  CAS  PubMed  Google Scholar 

  94. Amrouche-Mekkioui, I., & Djerdjouri, B. (2012). N-acetylcysteine improves redox status, mitochondrial dysfunction, mucin-depleted crypts and epithelial hyperplasia in dextran sulfate sodium-induced oxidative colitis in mice. European Journal of Pharmacology, 691(1–3), 209–217. doi:10.1016/j.ejphar.2012.06.014.

    Article  CAS  PubMed  Google Scholar 

  95. Ohnishi, T., Bandow, K., Kakimoto, K., Kusuyama, J., & Matsuguchi, T. (2014). Long-time treatment by low-dose N-acetyl-L-cysteine enhances proinflammatory cytokine expressions in LPS-stimulated macrophages. PloS One, 9(2), e87229. doi:10.1371/journal.pone.0087229.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Wang, H. W., Yang, W., Lu, J. Y., Li, F., Sun, J. Z., Zhang, W., Guo, N. N., Gao, L., & Kang, J. R. (2013). N-acetylcysteine administration is associated with reduced activation of NF-kB and preserves lung dendritic cells function in a zymosan-induced generalized inflammation model. Journal of Clinical Immunology, 33(3), 649–660. doi:10.1007/s10875-012-9852-3.

    Article  CAS  PubMed  Google Scholar 

  97. Lee, J. H., Jo, Y. H., Kim, K., Lee, J. H., Rim, K. P., Kwon, W. Y., Suh, G. J., & Rhee, J. E. (2013). Effect of N-acetylcysteine (NAC) on acute lung injury and acute kidney injury in hemorrhagic shock. Resuscitation, 84(1), 121–127. doi:10.1016/j.resuscitation.2012.05.017.

    Article  CAS  PubMed  Google Scholar 

  98. Cortijo, J., Cerda-Nicolas, M., Serrano, A., Bioque, G., Estrela, J. M., Santangelo, F., Esteras, A., Llombart-Bosch, A., & Morcillo, E. J. (2001). Attenuation by oral N-acetylcysteine of bleomycin-induced lung injury in rats. The European Respiratory Journal, 17(6), 1228–1235.

    Article  CAS  PubMed  Google Scholar 

  99. Haleagrahara, N., Julian, V., & Chakravarthi, S. (2011). N-acetylcysteine offers cardioprotection by decreasing cardiac lipid hydroperoxides and 8-isoprostane level in isoproterenol-induced cardiotoxicity in rats. Cardiovascular Toxicology, 11(4), 373–381. doi:10.1007/s12012-011-9132-0.

    Article  CAS  PubMed  Google Scholar 

  100. Mokra, D., Drgova, A., Petras, M., Mokry, J., Antosova, M., & Calkovska, A. (2015). N-acetylcysteine alleviates the meconium-induced acute lung injury. Advances in Experimental Medicine and Biology, 832, 59–67. doi:10.1007/5584_2014_7.

    Article  CAS  PubMed  Google Scholar 

  101. Ghanizadeh, A., & Moghimi-Sarani, E. (2013). A randomized double blind placebo controlled clinical trial of N-acetylcysteine added to risperidone for treating autistic disorders. BMC Psychiatry, 13, 196. doi:10.1186/1471-244X-13-196.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Deepmala, Slattery, J., Kumar, N., Delhey, L., Berk, M., Dean, O., Spielholz, C., & Frye, R. (2015). Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neuroscience & Biobehavioral Reviews, 55, 294–321. doi:10.1016/j.neubiorev.2015.04.015.

  103. Zheng, J. P., Wen, F. Q., Bai, C. X., Wan, H. Y., Kang, J., Chen, P., Yao, W. Z., Ma, L. J., Li, X., Raiteri, L., Sardina, M., Gao, Y., Wang, B. S., Zhong, N. S., & PANTHEON study group. (2014). Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): A randomised, double-blind placebo-controlled trial. The Lancet Respiratory Medicine, 2(3), 187–194. doi:10.1016/S2213-2600(13)70286-8.

    Article  CAS  PubMed  Google Scholar 

  104. Covvey, J. R., & Mancl, E. E. (2014). Recent evidence for pharmacological treatment of idiopathic pulmonary fibrosis. The Annals of Pharmacotherapy, 48(12), 1611–1619. doi:10.1177/1060028014551015.

    Article  PubMed  CAS  Google Scholar 

  105. Spagnolo, P., Wells, A. U., & Collard, H. R. (2015). Pharmacological treatment of idiopathic pulmonary fibrosis: An update. Drug Discovery Today, 20(5), 514–524. doi:10.1016/j.drudis.2015.01.001.

    Article  CAS  PubMed  Google Scholar 

  106. Reiter, R. J., Manchester, L. C., Fuentes-Broto, L., & Tan, D. X. (2010). Cardiac hypertrophy and remodelling: Pathophysiological consequences and protective effects of melatonin. Journal of Hypertension, 28(Suppl 1), S7–12. doi:10.1097/01.hjh.0000388488.51083.2b.

    Article  CAS  PubMed  Google Scholar 

  107. Reiter, R. J., Tan, D. X., & Fuentes-Broto, L. (2010). Melatonin: A multitasking molecule. Progress in Brain Research, 181, 127–151. doi:10.1016/S0079-6123(08)81008-4. S0079-6123(08)81008-4 [pii].

    Article  CAS  PubMed  Google Scholar 

  108. Reiter, R. J., Tan, D. X., Paredes, S. D., & Fuentes-Broto, L. (2010). Beneficial effects of melatonin in cardiovascular disease. Annals of Medicine, 42(4), 276–285. doi:10.3109/07853890903485748.

    Article  CAS  PubMed  Google Scholar 

  109. Boutin, J. A., Audinot, V., Ferry, G., & Delagrange, P. (2005). Molecular tools to study melatonin pathways and actions. Trends in Pharmacological Sciences, 26(8), 412–419. doi:10.1016/j.tips.2005.06.006.

    Article  CAS  PubMed  Google Scholar 

  110. Konturek, S. J., Konturek, P. C., Brzozowski, T., & Bubenik, G. A. (2007). Role of melatonin in upper gastrointestinal tract. Journal of Physiology and Pharmacology, 58(Suppl 6), 23–52.

    PubMed  Google Scholar 

  111. Yorgancioglu, A., Cruz, A. A., Bousquet, J., Khaltaev, N., Mendis, S., Chuchalin, A., Bateman, E. D., Camargos, P., Chavannes, N. H., Bai, C., Deleanu, D., Kolek, V., Kuna, P., Laurendi, G., Masjedi, M. R., Mele, S., Mihaltan, F., Pinto, J. R., Samolinski, B., Scalera, G., Sooronbaev, T., Tageldin, M. A., Tuyetlan le, T., Yusuf, O., Akdis, C., Baigenzhin, A., Cagnani, C. B., Fletcher, M., Gemicioglu, B., Muhammed, Y., Sagra, H., To, T., & Wagner, A. H. (2014). The Global Alliance against Respiratory Diseases (GARD) country report. Primary Care Respiratory Journal, 23(1), 98–101. doi:10.4104/pcrj.2014.00014.

    Article  PubMed  Google Scholar 

  112. Reiter, R. J., Tan, D. X., Mayo, J. C., Sainz, R. M., Leon, J., & Czarnocki, Z. (2003). Melatonin as an antioxidant: Biochemical mechanisms and pathophysiological implications in humans. Acta Biochimica Polonica, 50(4), 1129–1146. doi:0350041129.

    CAS  PubMed  Google Scholar 

  113. Pieri, C., Marra, M., Moroni, F., Recchioni, R., & Marcheselli, F. (1994). Melatonin: A peroxyl radical scavenger more effective than vitamin E. Life Sciences, 55(15), PL271–PL276.

    Article  CAS  PubMed  Google Scholar 

  114. Marchiafava, P. L., & Longoni, B. (1999). Melatonin as an antioxidant in retinal photoreceptors. Journal of Pineal Research, 26(3), 184–189.

    Article  CAS  PubMed  Google Scholar 

  115. Rezzani, R., Rodella, L. F., Fraschini, F., Gasco, M. R., Demartini, G., Musicanti, C., & Reiter, R. J. (2009). Melatonin delivery in solid lipid nanoparticles: Prevention of cyclosporine A induced cardiac damage. Journal of Pineal Research, 46(3), 255–261. doi:10.1111/j.1600-079X.2008.00651.x.

    Article  CAS  PubMed  Google Scholar 

  116. Scheer, F. A., Van Montfrans, G. A., van Someren, E. J., Mairuhu, G., & Buijs, R. M. (2004). Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension, 43(2), 192–197. doi:10.1161/01.HYP.0000113293.15186.3b.

    Article  CAS  PubMed  Google Scholar 

  117. Grossman, E., Laudon, M., Yalcin, R., Zengil, H., Peleg, E., Sharabi, Y., Kamari, Y., Shen-Orr, Z., & Zisapel, N. (2006). Melatonin reduces night blood pressure in patients with nocturnal hypertension. The American Journal of Medicine, 119(10), 898–902. doi:10.1016/j.amjmed.2006.02.002.

    Article  CAS  PubMed  Google Scholar 

  118. Reiter, R. J., Tan, D. X., & Galano, A. (2014). Melatonin: Exceeding expectations. Physiology (Bethesda, MD.), 29(5), 325–333. doi:10.1152/physiol.00011.2014.

    CAS  Google Scholar 

  119. Piechota, A., Lipinska, S., Szemraj, J., & Goraca, A. (2010). Long-term melatonin administration enhances the antioxidant potential of human plasma maintained after discontinuation of the treatment. General Physiology and Biophysics, 29(2), 144–150.

    Article  CAS  PubMed  Google Scholar 

  120. Cagnacci, A., Cannoletta, M., Renzi, A., Baldassari, F., Arangino, S., & Volpe, A. (2005). Prolonged melatonin administration decreases nocturnal blood pressure in women. American Journal of Hypertension, 18(12 Pt 1), 1614–1618. doi:10.1016/j.amjhyper.2005.05.008.

    Article  CAS  PubMed  Google Scholar 

  121. Mansoor, G. A. (2002). Ambulatory blood pressure monitoring in clinical trials in adults and children. American Journal of Hypertension, 15(2 Pt 2), 38S–42S.

    Article  PubMed  Google Scholar 

  122. de Matos Cavalcante, A. G., de Bruin, P. F., de Bruin, V. M., Nunes, D. M., Pereira, E. D., Cavalcante, M. M., & Andrade, G. M. (2012). Melatonin reduces lung oxidative stress in patients with chronic obstructive pulmonary disease: A randomized, double-blind, placebo-controlled study. Journal of Pineal Research, 53(3), 238–244. doi:10.1111/j.1600-079X.2012.00992.x.

    Article  PubMed  CAS  Google Scholar 

  123. Das, R., Balonan, L., Ballard, H. J., & Ho, S. (2008). Chronic hypoxia inhibits the antihypertensive effect of melatonin on pulmonary artery. International Journal of Cardiology, 126(3), 340–345. doi:10.1016/j.ijcard.2007.04.030.

    Article  PubMed  Google Scholar 

  124. Jin, H., Wang, Y., Zhou, L., Liu, L., Zhang, P., Deng, W., & Yuan, Y. (2014). Melatonin attenuates hypoxic pulmonary hypertension by inhibiting the inflammation and the proliferation of pulmonary arterial smooth muscle cells. Journal of Pineal Research, 57(4), 442–450. doi:10.1111/jpi.12184.

    Article  CAS  PubMed  Google Scholar 

  125. Calbet, J. A. (2003). Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans. The Journal of Physiology, 551(Pt 1), 379–386. doi:10.1113/jphysiol.2003.045112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Mirrakhimov, A. E., & Strohl, K. P. (2016). High-altitude pulmonary hypertension: An update on disease pathogenesis and management. Open Cardiovascular Medicine Journal, 10, 19–27. doi:10.2174/1874192401610010019.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Giussani, D. A., & Davidge, S. T. (2013). Developmental programming of cardiovascular disease by prenatal hypoxia. Journal of Developmental Origins of Health and Disease, 4(5), 328–337. doi:10.1017/S204017441300010X.

    Article  CAS  PubMed  Google Scholar 

  128. Niermeyer, S., Andrade Mollinedo, P., & Huicho, L. (2009). Child health and living at high altitude. Archives of Disease in Childhood, 94(10), 806–811. doi:10.1136/adc.2008.141838.

    Article  CAS  PubMed  Google Scholar 

  129. Torres, F., Gonzalez-Candia, A., Montt, C., Ebensperger, G., Chubretovic, M., Seron-Ferre, M., Reyes, R. V., Llanos, A. J., & Herrera, E. A. (2015). Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep. Journal of Pineal Research. doi:10.1111/jpi.12222.

  130. Thakor, A. S., Allison, B. J., Niu, Y., Botting, K. J., Seron-Ferre, M., Herrera, E. A., & Giussani, D. A. (2015). Melatonin modulates the fetal cardiovascular defense response to acute hypoxia. Journal of Pineal Research. doi:10.1111/jpi.12242.

  131. Maarman, G., Blackhurst, D., Thienemann, F., Blauwet, L., Butrous, G., Davies, N., Sliwa, K., & Lecour, S. (2015). Melatonin as a preventive and curative therapy against pulmonary hypertension. Journal of Pineal Research, 59(3), 343–353. doi:10.1111/jpi.12263.

    Article  CAS  PubMed  Google Scholar 

  132. Tan, D. X., Poeggeler, B., Reiter, R. J., Chen, L. D., Chen, S., Manchester, L. C., & Barlow-Walden, L. R. (1993). The pineal hormone melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in vivo. Cancer Letters, 70(1–2), 65–71.

    Article  CAS  PubMed  Google Scholar 

  133. Stasica, P., Paneth, P., & Rosiak, J. M. (2000). Hydroxyl radical reaction with melatonin molecule: A computational study. Journal of Pineal Research, 29(2), 125–127.

    Article  CAS  PubMed  Google Scholar 

  134. Tan, D. X., Manchester, L. C., Reiter, R. J., Plummer, B. F., Limson, J., Weintraub, S. T., & Qi, W. (2000). Melatonin directly scavenges hydrogen peroxide: A potentially new metabolic pathway of melatonin biotransformation. Free Radical Biology & Medicine, 29(11), 1177–1185.

    Article  CAS  Google Scholar 

  135. Tengattini, S., Reiter, R. J., Tan, D. X., Terron, M. P., Rodella, L. F., & Rezzani, R. (2008). Cardiovascular diseases: Protective effects of melatonin. Journal of Pineal Research, 44(1), 16–25. doi:10.1111/j.1600-079X.2007.00518.x.

    CAS  PubMed  Google Scholar 

  136. Tan, D. X., Zanghi, B. M., Manchester, L. C., & Reiter, R. J. (2014). Melatonin identified in meats and other food stuffs: Potentially nutritional impact. Journal of Pineal Research, 57(2), 213–218. doi:10.1111/jpi.12152.

    Article  CAS  PubMed  Google Scholar 

  137. Santibanez, J. F., Quintanilla, M., & Bernabeu, C. (2011). TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. Clinical Science (London, England), 121(6), 233–251. doi:10.1042/CS20110086.

    Article  CAS  Google Scholar 

  138. Ramos, M. F., Lame, M. W., Segall, H. J., & Wilson, D. W. (2008). Smad signaling in the rat model of monocrotaline pulmonary hypertension. Toxicologic Pathology, 36(2), 311–320. doi:10.1177/0192623307311402.

    Article  CAS  PubMed  Google Scholar 

  139. Zaiman, A. L., Podowski, M., Medicherla, S., Gordy, K., Xu, F., Zhen, L., Shimoda, L. A., Neptune, E., Higgins, L., Murphy, A., Chakravarty, S., Protter, A., Sehgal, P. B., Champion, H. C., & Tuder, R. M. (2008). Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. American Journal of Respiratory and Critical Care Medicine, 177(8), 896–905. doi:10.1164/rccm.200707-1083OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Zakrzewicz, A., Kouri, F. M., Nejman, B., Kwapiszewska, G., Hecker, M., Sandu, R., Dony, E., Seeger, W., Schermuly, R. T., Eickelberg, O., & Morty, R. E. (2007). The transforming growth factor-beta/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension. The European Respiratory Journal, 29(6), 1094–1104. doi:10.1183/09031936.00138206.

    Article  CAS  PubMed  Google Scholar 

  141. Wang, H., Ji, R., Meng, J., Cui, Q., Zou, W., Li, L., Wang, G., Sun, L., Li, Z., Huo, L., Fan, Y., & Penny, D. J. (2014). Functional changes in pulmonary arterial endothelial cells associated with BMPR2 mutations. PloS One, 9(9), e106703. doi:10.1371/journal.pone.0106703.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Bizzarri, M., Cucina, A., Valente, M. G., Tagliaferri, F., Borrelli, V., Stipa, F., & Cavallaro, A. (2003). Melatonin and vitamin D3 increase TGF-beta1 release and induce growth inhibition in breast cancer cell cultures. The Journal of Surgical Research, 110(2), 332–337.

    Article  CAS  PubMed  Google Scholar 

  143. Nakamura, E., Otsuka, F., Terasaka, T., Inagaki, K., Hosoya, T., Tsukamoto-Yamauchi, N., Toma, K., & Makino, H. (2014). Melatonin counteracts BMP-6 regulation of steroidogenesis by rat granulosa cells. The Journal of Steroid Biochemistry and Molecular Biology, 143, 233–239. doi:10.1016/j.jsbmb.2014.04.003.

    Article  CAS  PubMed  Google Scholar 

  144. Tsukamoto, N., Otsuka, F., Ogura-Ochi, K., Inagaki, K., Nakamura, E., Toma, K., Terasaka, T., Iwasaki, Y., & Makino, H. (2013). Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells. Molecular and Cellular Endocrinology, 375(1–2), 1–9. doi:10.1016/j.mce.2013.05.010.

    Article  CAS  PubMed  Google Scholar 

  145. Girouard, H., Chulak, C., Lejossec, M., Lamontagne, D., & de Champlain, J. (2001). Vasorelaxant effects of the chronic treatment with melatonin on mesenteric artery and aorta of spontaneously hypertensive rats. Journal of Hypertension, 19(8), 1369–1377.

    Article  CAS  PubMed  Google Scholar 

  146. Cook, J. S., Sauder, C. L., & Ray, C. A. (2011). Melatonin differentially affects vascular blood flow in humans. American Journal of Physiology. Heart and Circulatory Physiology, 300(2), H670–H674. doi:10.1152/ajpheart.00710.2010.

    Article  CAS  PubMed  Google Scholar 

  147. Paulis, L., Vazan, R., Simko, F., Pechanova, O., Styk, J., Babal, P., & Janega, P. (2007). Morphological alterations and NO-synthase expression in the heart after continuous light exposure of rats. Physiological Research, 56(Suppl 2), S71–S76.

    CAS  PubMed  Google Scholar 

  148. Tschudi, M. R., Mesaros, S., Luscher, T. F., & Malinski, T. (1996). Direct in situ measurement of nitric oxide in mesenteric resistance arteries. Increased decomposition by superoxide in hypertension. Hypertension, 27(1), 32–35.

    Article  CAS  PubMed  Google Scholar 

  149. Schiffrin, E. L. (2008). Oxidative stress, nitric oxide synthase, and superoxide dismutase: A matter of imbalance underlies endothelial dysfunction in the human coronary circulation. Hypertension, 51(1), 31–32. doi:10.1161/HYPERTENSIONAHA.107.103226.

    Article  CAS  PubMed  Google Scholar 

  150. Watal, G., Watal, A., Rai, P. K., Rai, D. K., Sharma, G., & Sharma, B. (2013). Biomedical applications of nano-antioxidant. Methods in Molecular Biology, 1028, 147–151. doi:10.1007/978-1-62703-475-3_9.

    Article  CAS  PubMed  Google Scholar 

  151. Souto, E. B., Severino, P., Basso, R., & Santana, M. H. (2013). Encapsulation of antioxidants in gastrointestinal-resistant nanoparticulate carriers. Methods in Molecular Biology, 1028, 37–46. doi:10.1007/978-1-62703-475-3_3.

    Article  CAS  PubMed  Google Scholar 

  152. Russcher, M., Koch, B. C., Nagtegaal, J. E., van Ittersum, F. J., Pasker-de Jong, P. C., Hagen, E. C., van Dorp, W. T., Gabreels, B., Wildbergh, T. X., van der Westerlaken, M. M., Gaillard, C. A., & Ter Wee, P. M. (2013). Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): A randomized controlled trial. British Journal of Clinical Pharmacology, 76(5), 668–679. doi:10.1111/bcp.12093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Pandi-Perumal, S. R., Verster, J. C., Kayumov, L., Lowe, A. D., Santana, M. G., Pires, M. L., Tufik, S., & Mello, M. T. (2006). Sleep disorders, sleepiness and traffic safety: A public health menace. Brazilian Journal of Medical and Biological Research, 39(7), 863–871.

    Article  CAS  PubMed  Google Scholar 

  154. Tan, D. X., Manchester, L. C., Reiter, R. J., Plummer, B. F., Hardies, L. J., Weintraub, S. T., Vijayalaxmi, Shepherd, A. M. (1998). A novel melatonin metabolite, cyclic 3-hydroxymelatonin: A biomarker of in vivo hydroxyl radical generation. Biochemical and Biophysical Research Communications, 253(3), 614–620.

    Google Scholar 

  155. Hardeland, R. (2005). Antioxidative protection by melatonin: Multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine, 27(2), 119–130.

    Article  CAS  PubMed  Google Scholar 

  156. DeMuro, R. L., Nafziger, A. N., Blask, D. E., Menhinick, A. M., & Bertino, J. S., Jr. (2000). The absolute bioavailability of oral melatonin. Journal of Clinical Pharmacology, 40(7), 781–784.

    Article  CAS  PubMed  Google Scholar 

  157. Waldhauser, F., Waldhauser, M., Lieberman, H. R., Deng, M. H., Lynch, H. J., & Wurtman, R. J. (1984). Bioavailability of oral melatonin in humans. Neuroendocrinology, 39(4), 307–313.

    Article  CAS  PubMed  Google Scholar 

  158. Aldhous, M., Franey, C., Wright, J., & Arendt, J. (1985). Plasma concentrations of melatonin in man following oral absorption of different preparations. British Journal of Clinical Pharmacology, 19(4), 517–521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Bartoli, A., De Gregori, S., Molinaro, M., Broglia, M., Tinelli, C., & Imberti, R. (2012). Bioavailability of a new oral spray melatonin emulsion compared with a standard oral formulation in healthy volunteers. Journal of Bioequivalence & Bioavailability, 4(7), 96–99. doi:10.4172/jbb.1000120.

    CAS  Google Scholar 

  160. Mao, S., Chen, J., Wei, Z., Liu, H., & Bi, D. (2004). Intranasal administration of melatonin starch microspheres. International Journal of Pharmaceutics, 272(1–2), 37–43. doi:10.1016/j.ijpharm.2003.11.028.

    Article  CAS  PubMed  Google Scholar 

  161. Hickie, I. B., & Rogers, N. L. (2011). Novel melatonin-based therapies: Potential advances in the treatment of major depression. Lancet, 378(9791), 621–631. doi:10.1016/S0140-6736(11)60095-0.

    Article  CAS  PubMed  Google Scholar 

  162. Brioschi, A., Zara, G. P., Calderoni, S., Gasco, M. R., & Mauro, A. (2008). Cholesterylbutyrate solid lipid nanoparticles as a butyric acid prodrug. Molecules, 13(2), 230–254.

    Article  CAS  PubMed  Google Scholar 

  163. Yun, X., Maximov, V. D., Yu, J., Zhu, H., Vertegel, A. A., & Kindy, M. S. (2013). Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury. Journal of Cerebral Blood Flow and Metabolism, 33(4), 583–592. doi:10.1038/jcbfm.2012.209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mura, S., Nicolas, J., & Couvreur, P. (2013). Stimuli-responsive nanocarriers for drug delivery. Nature Materials, 12(11), 991–1003. doi:10.1038/nmat3776.

    Article  CAS  PubMed  Google Scholar 

  165. Onaca, O., Enea, R., Hughes, D. W., & Meier, W. (2009). Stimuli-responsive polymersomes as nanocarriers for drug and gene delivery. Macromolecular Bioscience, 9(2), 129–139. doi:10.1002/mabi.200800248.

    Article  CAS  PubMed  Google Scholar 

  166. Duzgunes, N. (2012). Nanomedicine cancer, diabetes, and cardiovascular, central nervous system, pulmonary and inflammatory diseases. Preface. Methods in Enzymology, 508, xix–xxi. doi:10.1016/B978-0-12-391860-4.00027-6.

    Article  PubMed  Google Scholar 

  167. Matoba, T., & Egashira, K. (2014). Nanoparticle-mediated drug delivery system for cardiovascular disease. International Heart Journal, 55(4), 281–286.

    Article  CAS  PubMed  Google Scholar 

  168. Ferreira, M. P., Balasubramanian, V., Hirvonen, J., Ruskoaho, H., & Santos, H. A. (2015). Advanced nanomedicines for the treatment and diagnosis of myocardial infarction and heart failure. Current Drug Targets, 16(14), 1682–1697.

    Article  CAS  PubMed  Google Scholar 

  169. Spivak, M. Y., Bubnov, R. V., Yemets, I. M., Lazarenko, L. M., Tymoshok, N. O., & Ulberg, Z. R. (2013). Gold nanoparticles—The theranostic challenge for PPPM: Nanocardiology application. The EPMA Journal, 4(1), 18. doi:10.1186/1878-5085-4-18.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Paranjpe, M., & Muller-Goymann, C. C. (2014). Nanoparticle-mediated pulmonary drug delivery: A review. International Journal of Molecular Sciences, 15(4), 5852–5873. doi:10.3390/ijms15045852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Da Silva, A. L., Santos, R. S., Xisto, D. G., Alonso Sdel, V., Morales, M. M., & Rocco, P. R. (2013). Nanoparticle-based therapy for respiratory diseases. Anais da Academia Brasileira de Ciências, 85(1), 137–146.

    Article  PubMed  Google Scholar 

  172. Priano, L., Esposti, D., Esposti, R., Castagna, G., De Medici, C., Fraschini, F., Gasco, M. R., & Mauro, A. (2007). Solid lipid nanoparticles incorporating melatonin as new model for sustained oral and transdermal delivery systems. Journal of Nanoscience and Nanotechnology, 7(10), 3596–3601.

    Article  CAS  PubMed  Google Scholar 

  173. Singh, F., Charles, A. L., Schlagowski, A. I., Bouitbir, J., Bonifacio, A., Piquard, F., Krahenbuhl, S., Geny, B., & Zoll, J. (2015). Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis. Biochimica et Biophysica Acta, 1853(7), 1574–1585. doi:10.1016/j.bbamcr.2015.03.006.

    Article  CAS  PubMed  Google Scholar 

  174. Bouitbir, J., Charles, A. L., Echaniz-Laguna, A., Kindo, M., Daussin, F., Auwerx, J., Piquard, F., Geny, B., & Zoll, J. (2012). Opposite effects of statins on mitochondria of cardiac and skeletal muscles: A ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1. European Heart Journal, 33(11), 1397–1407. doi:10.1093/eurheartj/ehr224.

    Article  CAS  PubMed  Google Scholar 

  175. Sano, M., & Fukuda, K. (2008). Activation of mitochondrial biogenesis by hormesis. Circulation Research, 103(11), 1191–1193. doi:10.1161/CIRCRESAHA.108.189092.

    Article  CAS  PubMed  Google Scholar 

  176. Cornelius, C., Perrotta, R., Graziano, A., Calabrese, E. J., & Calabrese, V. (2013). Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a “chi”. Immunity & Ageing, 10(1), 15. doi:10.1186/1742-4933-10-15.

    Article  CAS  Google Scholar 

  177. Calabrese, V., Cornelius, C., Dinkova-Kostova, A. T., Calabrese, E. J., & Mattson, M. P. (2010). Cellular stress responses, the hormesis paradigm, and vitagenes: Novel targets for therapeutic intervention in neurodegenerative disorders. Antioxidants & Redox Signaling, 13(11), 1763–1811. doi:10.1089/ars.2009.3074.

    Article  CAS  Google Scholar 

  178. Piantadosi, C. A., Carraway, M. S., Babiker, A., & Suliman, H. B. (2008). Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circulation Research, 103(11), 1232–1240. doi:10.1161/01.RES.0000338597.71702.ad.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Deora, A. A., Win, T., Vanhaesebroeck, B., & Lander, H. M. (1998). A redox-triggered ras-effector interaction. Recruitment of phosphatidylinositol 3′-kinase to Ras by redox stress. The Journal of Biological Chemistry, 273(45), 29923–29928.

    Article  CAS  PubMed  Google Scholar 

  180. Reis, G. S., Augusto, V. S., Silveira, A. P., Jordao, A. A., Jr., Baddini-Martinez, J., Poli Neto, O., Rodrigues, A. J., & Evora, P. R. (2013). Oxidative-stress biomarkers in patients with pulmonary hypertension. Pulmonary Circulation, 3(4), 856–861. doi:10.1086/674764.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Kryvenko, V. (2013). [Biomarkers of systemic inflammation, oxidative stress and their interactions in patients with combined flow of chronic obstructive pulmonary disease and arterial hypertension]. Georgian Medical News, (216), 23–28.

    Google Scholar 

  182. Vaidya, B., & Gupta, V. (2015). Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery. Journal of Controlled Release, 211, 118–133. doi:10.1016/j.jconrel.2015.05.287.

    Article  CAS  PubMed  Google Scholar 

  183. Bogaard, H. J., Abe, K., Vonk Noordegraaf, A., & Voelkel, N. F. (2009). The right ventricle under pressure: Cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest, 135(3), 794–804. doi:10.1378/chest.08-0492.

    Article  CAS  PubMed  Google Scholar 

  184. Csiszar, A., Labinskyy, N., Pinto, J. T., Ballabh, P., Zhang, H., Losonczy, G., Pearson, K., de Cabo, R., Pacher, P., Zhang, C., & Ungvari, Z. (2009). Resveratrol induces mitochondrial biogenesis in endothelial cells. American Journal of Physiology. Heart and Circulatory Physiology, 297(1), H13–H20. doi:10.1152/ajpheart.00368.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I would like to thank the National Research Foundation of South Africa, for financial support via the NRF Collaborative Postgraduate Training Award, as well as the University of Cape Town. A further thanks is extended to the Canon Collins Educational Trust, and the Oppenheimer Memorial Trust for financial assistance.

Author information

Authors and Affiliations

  1. Hatter Institute for Cardiovascular Research in Africa (HICRA) and MRC Inter-University, Cape Heart Group, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Gerald J. Maarman Ph.D.

Authors
  1. Gerald J. Maarman Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerald J. Maarman Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New York, USA

    Yong-Xiao Wang

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Maarman, G.J. (2017). Natural Antioxidants as Potential Therapy, and a Promising Role for Melatonin Against Pulmonary Hypertension. In: Wang, YX. (eds) Pulmonary Vasculature Redox Signaling in Health and Disease. Advances in Experimental Medicine and Biology, vol 967. Springer, Cham. https://doi.org/10.1007/978-3-319-63245-2_10

Download citation

Publish with us

Policies and ethics

Search

Navigation