Effect of Vernonia Cinerea Extract on Heart and Coronary Artery Fibrosis of Chronic Nicotine-Treated Rat
Abstract
This study was designed to investigate the effects of Vernonia cinerea (VC) on heart fibrosis and coronary artery and inflammation in chronic nicotine treated rats. Male Wistar rat were divided into control (C), nicotine group (N) received daily dose of nicotine i.p. (1 mg/kg), and nicotine with VC orally is a dose of 100 mg/kg/day (NV) for 3 and 6 months respectively. The histopathological changes of heart tissue and coronary wall by H&E staining wasexamined whereas the heart fibrosis was evaluated by Masson’s trichrome staining. LM observation demonstrated that there was histopathology of coronary wall revealed thickness in N group (p<0.05). The histopathological study showed increasing of intercellular collagen bundles accumulation, representing of pro-fibrosis in heart tissue. Regarding inflammation, the nicotine treated rats at 3 and 6 months presented increasing of inflammatory leukocytesneighboring the vascular wall. Moreover, hypertrophy of cardiomyocytes with irregular sizes in diameters were critically demonstrated. The intercellular space was obviously larger when compared with the control group. In addition, the accumulation and deposition of collagen bundles and plasma cells allocating within intercellular space were conspicuously observed. Interestingly, an extract from VC revealed for protection effect in NV rats for 3 and 6 months by reducing the pro-collagen fibers accumulation, decreasing of the intercellular space, and diminishing tissue inflammation. In conclusion, the supplementation with VC provided benefit to prevent the heart fibrosis and coronary wall thickness from nicotine toxicity created in the receiving chronic nicotine replacement therapy (NRT). Keywords: Vernonia cinerea Less., nicotine, heart tissue, fibrosis, coronary arteryReferences
Anderson, J. (2018). An Introduction to Routine and Special Staining. Policies,
https://www.leicabiosystems.com/pathologyleaders/anintroduction-to-routine-
and-special-staining/.
Appadath Beeran, A., Maliyakkal, N., Rao, C.M., & Udupa, N. (2014). The enriched fraction of
Vernonia cinerea L. induces apoptosis and inhibits multi-drug resistance transporters in human
epithelial cancer cells. J Ethnopharmacol, 158 Pt A:33-42. doi: 10.1016/j.jep.2014.10.010.
Epub 2014 Oct 22.
Balakumar, P., & Kaur, J. (2009). Is nicotine a key player or spectator in the induction and
progression of cardiovascular disorders. Pharmacological Research, 60(5), 361-368.
Benowitz, NL. (2010). Nicotine addiction. N Engl J Med, 362(24), 2295–2303.
Benowitz, NL., & Burbank, AD. (2016). Cardiovascular toxicity of nicotine: Implications for
electronic cigarette use. Trends Cardiovasc Med, 26(6), 515–523.
Benowitz, NL., Pomerleau, OF., Pomerleau, CS., & Jacob, P. (2003). Nicotine metabolite ratio as
a predictor of cigarette consumption. Nicotine Tob Res, 5(5),621-4.
Benowitz, NL., & Jacob, P. (1994). Metabolism of nicotine to cotinine studied by a dual stable
isotope method. Clin Pharmacol Ther, 56(5),483-93.
Chaikoolvatana, A., Thanawirun, T., Chaikoolvatana, C., Puchcharanapaponthorn, P.,
Suwanakoot, P., & Saisingha N. (2018). Use of Vernonia cinerea jelly candies for smoking
cessation. Environment Asia, 11(2), 172-191, DOI: 10.14456/ea.2018.32
Cucina, A., Sapienza, P., Borrelli, V., Corvino, V., Foresi, G., Randone, B., Cavallaro, A., &
Santoro-D'Angelo, L. (2000). Nicotine reorganizes cytoskeleton of vascular endothelial cell
through platelet-derived growth factor BB. J Surg Res, 92(2),233-8.
Gepner, AD., Piper, ME., Johnson, HM., Fiore, MC., Baker, TB., & Stein, JH. (2011). Effects of
Smoking and Smoking Cessation on Lipids and Lipoproteins: Outcomes from a Randomized
Clinical Trial. Am Heart J, 161(1), 145–151, doi: 10.1016/j.ahj.2010.09.023
Herum, K.M., Lunde, I.G., McCulloch, A.D., & Christensen, G. (2017). The Soft- and Hard-
Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in
Fibrosis of the Heart. J. Clin. Med, 6(5), 53; https://doi.org/10.3390/jcm6050053
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. (2012). Personal
Habits and Indoor Combustions. Volume 100E. A Review of Human Carcinogens.
IARC Monogr Eval Carcinog Risks Hum, 100(Pt E), 1-538.
Jie, WU. (2009). Understanding of nicotinic acetylcholine receptors. Acta Pharmacol Sin, 30(6),
653–655.
Jong, S.D., van Veen, T. A. B., de Bakker, J. M. T. & van Rijen, H. V. M. (2012). Monitoring
cardiac fibrosis: a technical challenge. Neth Heart J, 20, 44–48. Doi: 10.1007/s12471-011-0226-x.
Ketsuwan, N., Leelarungrayub, J., Kothan, S., & Singhatong, S. (2017). Antioxidant compounds
and activities of the stem, flower, and leaf extracts of the anti-smoking Thai medicinal plant:
Vernonia cinerea Less. Drug Des Devel Ther, 11, 383–391, Doi: 10.2147/DDDT.S126882.
Kumpunya, S., & Praputbut, S. (2014). Antioxidant Activities of Vernonia cinerea L. Extract in
Endotoxin and Cytokine Stimulated Macrophages. ThaiJournal of pharmacology, 36 (2), 29-43.
Lan, X., Lederman, R., Eng, JM., Shoshtari, SSM., Saleem, MA., Malhotra, A.. (2016).
Nicotine induces podocyte apoptosis through increasing oxidative stress. PLoS One, 11(12),
e0167071, Doi: 10.1371/journal.pone.0167071.
Lau, PP., Li, L., Merched, AJ., Zhang, AL., Ko, KW.S., & Chan, L. (2006). Nicotine induces
proinflammatory responses in macrophages and the aorta leading to acceleration of atherosclerosis
in low-density lipoprotein receptor (-/-) mice. Arterioscler Thromb Vasc Biol, 26(1), 143-9.
Li, J.M., Cui, T.X., Shiuchi, T., Liu, H.W., Min, L.J., Okumura, M, Jinno, T., Wu, L., Iwai, M., &
Horiuchi, M. (2004). Nicotine enhances angiotensin II-induced mitogenic response in vascular
smooth muscle cells and fibroblasts. Arterioscler Thromb Vasc Biol, 24(1),80-84.
Lim, R., & Sobey, CG. (2011). Maternal nicotine exposure and fetal programming of vascular
oxidative stress in adult offspring. Br J Pharmacol, 164(5), 1397–1399.
Lucas, JA., Zhang, Y., Li, P., Gong, K., Miller, AP., Hassan, E., Hage, F., Xing, D., Wells, B.,
Oparil, S., Chen, YF. (2010). Inhibition of transforming growth factor-beta signaling induces left
ventricular dilation and dysfunction in the pressure-overloaded heart. Am J Physiol Heart Circ Physiol,
298, H424–H432.
National List of Essential Medicines (NLEM). (2013). Rebrieved February 5, 2019,
From http://www.thaihof.org/sites/default/files/herbal_book_56_0.pdf (2013).
Nisell, M., Nomikos, GG., & Svensson, TH. (1994). Systemic nicotine-induced dopamine release
in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area.
Synapse, 16(1), 36-44.
Pittilo, RM. (2000). Cigarette smoking, endothelial injury and cardiovascular disease. Int J Exp Pathol, 81(4),
219–230.doi: 10.1046/j.1365-2613.2000.00162.x
Pratheeshkumar, P. & Kuttan, G. (2010). Protective role of Vernonia cinereal L. against gamma
radiation induced immunosupression and oxidative stress in mice. Human and Experimental
Toxicology, 30(8), 1022–1038.
Promputta, C., Anupunpisit, V., Panyarachun, B., Sawatpanich, T., Watthanachaiyingcharoen,
R., Paeratakul, O. (2012). Effect of Vernonia cinerea in improvement of respiratory tissue in chronic nicotine treatment. J Med Assoc Thai. 95 Suppl (12), S47-55. (in Thai)
Puttarak, P., Pornpanyanukul, P., Meetam, T., Bunditanukul, K., & Chaiyakunapruk, N. (2018).
Efficacy and safety of Vernonia cinerea (L.) Less. for smoking cessation: A systematic review
and meta-analysis of randomized controlled trials. Complement Therapies in Medicine, 37, 37-42.
Doi: 10.1016/j.ctim.2018.01.009.
Saraphanchotiwitthayaa, A., & Sripalakitb, P. (2015). Anti-inflammatory activity of a Vernonia
cinerea methanolic extract in vitro. ScienceAsia 41 (2015): 392–399. doi: 10.2306/scienceasia1513-
1874.2015.41.392
Schilström, B., Svensson, HM., Svensson, TH., Nomikos, GG. (1998). Nicotine and food induced
dopamine release in the nucleus accumbens of the rat: putative role of alpha7 nicotinic receptors
in the ventral tegmental area. Neuroscience, 85(4), 1005-9.
Sekhon, HS., Proskocil, BJ., Clark, JA., & Spindel, ER. (2004). Prenatal nicotine exposure
increases connective tissue expression in foetal monkey pulmonary. Eur Respir J, 23(6), 906-15,
Doi: 10.1016/j.yjmcc.2013.11.015
Sziráki, I., Sershen, H., Hashim, A., & Lajtha, A. (2002). Receptors in the ventral tegmental area
mediating nicotine-induced dopamine release in the nucleus accumbens. Neurochemical, 27(3),
253–261.
Wongwiwatthananukit, S., Benjanakaskul, P., Songsak T., Suwanamajo, S., & Veracha, V. (2009).
Efficacy of vernonia cinerea for smoking cessation. Journal Health Res, 23(1), 31-36.
Yoshiyama, S., Chen, Z., Okagaki, T., Kohama, K., Nasu-Kawaharada, R., Izumi, T., Ohshima, N., Nagai, T., &
Nakamura, A. (2014). Nicotine exposure alters human vascular smooth muscle cell phenotype from a
contractile to a synthetic type. Atherosclerosis, 7(2),464-70. doi: 10.1016/j.atherosclerosis.2014.10.019.
Zevin, S. (2001). Cardiovascular effects of Carbon monoxide and cigarette smoking.
Journal of the American College of Cardiology, 38(6),1633-8.DOI:10.1016/S0735-1097(01)01616-3 ·
Zhou, X., Sheng, Y., Yang, R., & Kong, X. (2010). Nicotine promotes cardiomyocyte apoptosis via oxidative stress
and altered apoptosis-related gene expression cardiology. Cardiology,115, 243–250.
https://www.leicabiosystems.com/pathologyleaders/anintroduction-to-routine-
and-special-staining/.
Appadath Beeran, A., Maliyakkal, N., Rao, C.M., & Udupa, N. (2014). The enriched fraction of
Vernonia cinerea L. induces apoptosis and inhibits multi-drug resistance transporters in human
epithelial cancer cells. J Ethnopharmacol, 158 Pt A:33-42. doi: 10.1016/j.jep.2014.10.010.
Epub 2014 Oct 22.
Balakumar, P., & Kaur, J. (2009). Is nicotine a key player or spectator in the induction and
progression of cardiovascular disorders. Pharmacological Research, 60(5), 361-368.
Benowitz, NL. (2010). Nicotine addiction. N Engl J Med, 362(24), 2295–2303.
Benowitz, NL., & Burbank, AD. (2016). Cardiovascular toxicity of nicotine: Implications for
electronic cigarette use. Trends Cardiovasc Med, 26(6), 515–523.
Benowitz, NL., Pomerleau, OF., Pomerleau, CS., & Jacob, P. (2003). Nicotine metabolite ratio as
a predictor of cigarette consumption. Nicotine Tob Res, 5(5),621-4.
Benowitz, NL., & Jacob, P. (1994). Metabolism of nicotine to cotinine studied by a dual stable
isotope method. Clin Pharmacol Ther, 56(5),483-93.
Chaikoolvatana, A., Thanawirun, T., Chaikoolvatana, C., Puchcharanapaponthorn, P.,
Suwanakoot, P., & Saisingha N. (2018). Use of Vernonia cinerea jelly candies for smoking
cessation. Environment Asia, 11(2), 172-191, DOI: 10.14456/ea.2018.32
Cucina, A., Sapienza, P., Borrelli, V., Corvino, V., Foresi, G., Randone, B., Cavallaro, A., &
Santoro-D'Angelo, L. (2000). Nicotine reorganizes cytoskeleton of vascular endothelial cell
through platelet-derived growth factor BB. J Surg Res, 92(2),233-8.
Gepner, AD., Piper, ME., Johnson, HM., Fiore, MC., Baker, TB., & Stein, JH. (2011). Effects of
Smoking and Smoking Cessation on Lipids and Lipoproteins: Outcomes from a Randomized
Clinical Trial. Am Heart J, 161(1), 145–151, doi: 10.1016/j.ahj.2010.09.023
Herum, K.M., Lunde, I.G., McCulloch, A.D., & Christensen, G. (2017). The Soft- and Hard-
Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in
Fibrosis of the Heart. J. Clin. Med, 6(5), 53; https://doi.org/10.3390/jcm6050053
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. (2012). Personal
Habits and Indoor Combustions. Volume 100E. A Review of Human Carcinogens.
IARC Monogr Eval Carcinog Risks Hum, 100(Pt E), 1-538.
Jie, WU. (2009). Understanding of nicotinic acetylcholine receptors. Acta Pharmacol Sin, 30(6),
653–655.
Jong, S.D., van Veen, T. A. B., de Bakker, J. M. T. & van Rijen, H. V. M. (2012). Monitoring
cardiac fibrosis: a technical challenge. Neth Heart J, 20, 44–48. Doi: 10.1007/s12471-011-0226-x.
Ketsuwan, N., Leelarungrayub, J., Kothan, S., & Singhatong, S. (2017). Antioxidant compounds
and activities of the stem, flower, and leaf extracts of the anti-smoking Thai medicinal plant:
Vernonia cinerea Less. Drug Des Devel Ther, 11, 383–391, Doi: 10.2147/DDDT.S126882.
Kumpunya, S., & Praputbut, S. (2014). Antioxidant Activities of Vernonia cinerea L. Extract in
Endotoxin and Cytokine Stimulated Macrophages. ThaiJournal of pharmacology, 36 (2), 29-43.
Lan, X., Lederman, R., Eng, JM., Shoshtari, SSM., Saleem, MA., Malhotra, A.. (2016).
Nicotine induces podocyte apoptosis through increasing oxidative stress. PLoS One, 11(12),
e0167071, Doi: 10.1371/journal.pone.0167071.
Lau, PP., Li, L., Merched, AJ., Zhang, AL., Ko, KW.S., & Chan, L. (2006). Nicotine induces
proinflammatory responses in macrophages and the aorta leading to acceleration of atherosclerosis
in low-density lipoprotein receptor (-/-) mice. Arterioscler Thromb Vasc Biol, 26(1), 143-9.
Li, J.M., Cui, T.X., Shiuchi, T., Liu, H.W., Min, L.J., Okumura, M, Jinno, T., Wu, L., Iwai, M., &
Horiuchi, M. (2004). Nicotine enhances angiotensin II-induced mitogenic response in vascular
smooth muscle cells and fibroblasts. Arterioscler Thromb Vasc Biol, 24(1),80-84.
Lim, R., & Sobey, CG. (2011). Maternal nicotine exposure and fetal programming of vascular
oxidative stress in adult offspring. Br J Pharmacol, 164(5), 1397–1399.
Lucas, JA., Zhang, Y., Li, P., Gong, K., Miller, AP., Hassan, E., Hage, F., Xing, D., Wells, B.,
Oparil, S., Chen, YF. (2010). Inhibition of transforming growth factor-beta signaling induces left
ventricular dilation and dysfunction in the pressure-overloaded heart. Am J Physiol Heart Circ Physiol,
298, H424–H432.
National List of Essential Medicines (NLEM). (2013). Rebrieved February 5, 2019,
From http://www.thaihof.org/sites/default/files/herbal_book_56_0.pdf (2013).
Nisell, M., Nomikos, GG., & Svensson, TH. (1994). Systemic nicotine-induced dopamine release
in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area.
Synapse, 16(1), 36-44.
Pittilo, RM. (2000). Cigarette smoking, endothelial injury and cardiovascular disease. Int J Exp Pathol, 81(4),
219–230.doi: 10.1046/j.1365-2613.2000.00162.x
Pratheeshkumar, P. & Kuttan, G. (2010). Protective role of Vernonia cinereal L. against gamma
radiation induced immunosupression and oxidative stress in mice. Human and Experimental
Toxicology, 30(8), 1022–1038.
Promputta, C., Anupunpisit, V., Panyarachun, B., Sawatpanich, T., Watthanachaiyingcharoen,
R., Paeratakul, O. (2012). Effect of Vernonia cinerea in improvement of respiratory tissue in chronic nicotine treatment. J Med Assoc Thai. 95 Suppl (12), S47-55. (in Thai)
Puttarak, P., Pornpanyanukul, P., Meetam, T., Bunditanukul, K., & Chaiyakunapruk, N. (2018).
Efficacy and safety of Vernonia cinerea (L.) Less. for smoking cessation: A systematic review
and meta-analysis of randomized controlled trials. Complement Therapies in Medicine, 37, 37-42.
Doi: 10.1016/j.ctim.2018.01.009.
Saraphanchotiwitthayaa, A., & Sripalakitb, P. (2015). Anti-inflammatory activity of a Vernonia
cinerea methanolic extract in vitro. ScienceAsia 41 (2015): 392–399. doi: 10.2306/scienceasia1513-
1874.2015.41.392
Schilström, B., Svensson, HM., Svensson, TH., Nomikos, GG. (1998). Nicotine and food induced
dopamine release in the nucleus accumbens of the rat: putative role of alpha7 nicotinic receptors
in the ventral tegmental area. Neuroscience, 85(4), 1005-9.
Sekhon, HS., Proskocil, BJ., Clark, JA., & Spindel, ER. (2004). Prenatal nicotine exposure
increases connective tissue expression in foetal monkey pulmonary. Eur Respir J, 23(6), 906-15,
Doi: 10.1016/j.yjmcc.2013.11.015
Sziráki, I., Sershen, H., Hashim, A., & Lajtha, A. (2002). Receptors in the ventral tegmental area
mediating nicotine-induced dopamine release in the nucleus accumbens. Neurochemical, 27(3),
253–261.
Wongwiwatthananukit, S., Benjanakaskul, P., Songsak T., Suwanamajo, S., & Veracha, V. (2009).
Efficacy of vernonia cinerea for smoking cessation. Journal Health Res, 23(1), 31-36.
Yoshiyama, S., Chen, Z., Okagaki, T., Kohama, K., Nasu-Kawaharada, R., Izumi, T., Ohshima, N., Nagai, T., &
Nakamura, A. (2014). Nicotine exposure alters human vascular smooth muscle cell phenotype from a
contractile to a synthetic type. Atherosclerosis, 7(2),464-70. doi: 10.1016/j.atherosclerosis.2014.10.019.
Zevin, S. (2001). Cardiovascular effects of Carbon monoxide and cigarette smoking.
Journal of the American College of Cardiology, 38(6),1633-8.DOI:10.1016/S0735-1097(01)01616-3 ·
Zhou, X., Sheng, Y., Yang, R., & Kong, X. (2010). Nicotine promotes cardiomyocyte apoptosis via oxidative stress
and altered apoptosis-related gene expression cardiology. Cardiology,115, 243–250.
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2020-01-09
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