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• W2742560858 abstract "This study aimed to evaluate the histopathological changes in the aorta and kidneys of mice age of menopause by the ethanol extract of ylang-ylang (Cananga odorata) flowers. Thirty female age of menopause mice was divided into three groups (n = 10 each group), consisting of a group of mice the age of menopause without any treatment, mice age of menopause treated with different dosages of ylang-ylang flower extract (0.1 mg/day and 0.2 mg/day). Histopathological analysis was performed with hematoxylin-eosin staining. The number of endothelial cells and the thickness of the intima in the group treated with high dose of the extract were significantly higher than the lowest dose of the extract or the control group (p < 0.05). The diameter of the Bowman's capsule and the renal glomerulus was significantly higher in the group treated with ylang-ylang flower extract compared with the control group (p < 0.05). Concluded that at the doses administered, ylang flower extract triggers the repair of endothelial cells, but increase the thickness of the intima and hyperplasia of the kidney in mice age of menopause. Thus, ylang flower extract and renal vascular remodeling triggered by the age of menopause. This study aimed to evaluate the histopathological changes in the aorta and kidneys of mice age of menopause by the ethanol extract of ylang-ylang (Cananga odorata) flowers. Thirty female age of menopause mice was divided into three groups (n = 10 each group), consisting of a group of mice the age of menopause without any treatment, mice age of menopause treated with different dosages of ylang-ylang flower extract (0.1 mg/day and 0.2 mg/day). Histopathological analysis was performed with hematoxylin-eosin staining. The number of endothelial cells and the thickness of the intima in the group treated with high dose of the extract were significantly higher than the lowest dose of the extract or the control group (p < 0.05). The diameter of the Bowman's capsule and the renal glomerulus was significantly higher in the group treated with ylang-ylang flower extract compared with the control group (p < 0.05). Concluded that at the doses administered, ylang flower extract triggers the repair of endothelial cells, but increase the thickness of the intima and hyperplasia of the kidney in mice age of menopause. Thus, ylang flower extract and renal vascular remodeling triggered by the age of menopause. Menopause is defined as a natural occurrence in the form of permanent cessation of menstruation and ovulation due to failure in the functions of the ovary [[1]Dolleman M. Verschuren W.M. Eijkemans M.J. Broekmans F.J. van der Schouw Y.T. Added value of anti-Mullerian hormone in prediction of menopause: results from a large prospective cohort study.Hum Reprod. 2015; 30: 1974-1981Crossref PubMed Scopus (30) Google Scholar]. Menopause-related hormonal changes, especially estradiol decrease, can trigger the development of cardiovascular disease. Considering the function of estradiol, which is an antioxidant, in women who have lost this function due to menopausal transition, lipid peroxidation and reactive oxygen compound increase are found [2Ahmad S. Scott J.E. Estradiol enhances cell-associated paraoxonase 1 (PON1) activity in vitro without altering PON1 expression.Biochem Biophys Res Comm. 2010; 397: 441-446Crossref PubMed Scopus (26) Google Scholar, 3Wakatsuki A. Ikenoue N. Sagara Y. Effects of estrogen on susceptibility to oxidation of low-density and high-density lipoprotein in postmenopausal women.Maturitas. 1998; 28: 229-234Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. On the other hand, menopausal transition will be accompanied by changes in body weight, fat distribution and lipid/protein profiles will put women at high risk of chronic inflammation [4Lovejoy J.C. Champagne C.M. de Jonge L. Xie H. Smith S.R. Increased visceral fat and decreased energy expenditure during the menopausal transition.Int J Obes (Lond). 2008; 32: 949-958Crossref PubMed Scopus (604) Google Scholar, 5El Khoudary S.R. Shields K.J. Janssen I. Hanley C. Budoff M.J. Barinas-Mitchell E. et al.Cardiovascular fat, menopause and sex hormones in women: the SWAN cardiovascular fat ancillary study.J Clin Endocrinol Metab. 2015; 100: 3304-3312Crossref PubMed Scopus (61) Google Scholar, 6Matthews K.A. Crawford S.L. Chae C.U. Everson-Rose S.A. Sowers M.F. Sternfeld B. et al.Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition?.J Am Coll Cardiol. 2009; 54: 2366-2373Crossref PubMed Scopus (422) Google Scholar]. In research on experimental animals, it has been proven that bilateral ovariectomy correlates with increased cardiovascular risks and premature death, the younger the age of ovariectomy the higher the risk that will occur [[7]Lobo R.A. Surgical menopause and cardiovascular risks.Menopause. 2007; 14: 562-566Crossref PubMed Scopus (110) Google Scholar]. This underlying mechanism is caused by hypoestrogenism that contributes to increased atherosclerosis [8Clarkson T.B. Estrogen effects on arteries vary with stage of reproductive life and extent of subclinical atherosclerosis progression.Menopause. 2007; 14: 373-384Crossref PubMed Scopus (15) Google Scholar, 9Merz C.N.B. Johnson B.D. Sharaf B.L. Bittner V. Berga S.L. Braunstein G.D. et al.Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study.J Am Coll Cardiol. 2003; 41: 413-419Crossref PubMed Scopus (237) Google Scholar], and this risk can be prevented by administering estrogen replacement [[10]Dubey R.K. Imthurn B. Barton M. Jackson E.K. Vascular consequences of menopause and hormone therapy: importance of timing of treatment and type of estrogen.Cardiovasc Res. 2005; 66: 295-306Crossref PubMed Scopus (194) Google Scholar]. Estrogen deficiency increases cardiovascular risks, as a result of atherogenic modification of lipid profile in plasma, renin-angiotensin system activation, and excessive production of reactive oxygen compound that will bind nitric oxide. In addition, the decrease in estrogen receptor associated with menopause will correlate with the low expression and activation of nitric oxide synthase [11Maynar M. Mahedero G. Maynar I. Maynar J.I. Tuya I.R. Caballero M.J. Menopause-induced changes in lipid fractions and total fatty acids in plasma.Endocr Res. 2001; 27: 357-365Crossref PubMed Scopus (18) Google Scholar, 12Yung L.M. Wong W.T. Tian X.Y. Leung F.P. Yung L.H. Chen Z.Y. et al.Inhibition of renin-angiotensin system reverses endothelial dysfunction and oxidative stress in estrogen deficient rats.PLoS One. 2011; 6e17437Crossref PubMed Scopus (63) Google Scholar, 13Gavin K.M. Seals D.R. Silver A.E. Moreau K.L. Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women.J Clin Endocrinol Metab. 2009; 94: 3513-3520Crossref PubMed Scopus (123) Google Scholar, 14Loyer X. Damy T. Chvojkova Z. Robidel E. Marotte F. Oliviero P. et al.17beta-estradiol regulates constitutive nitric oxide synthase expression differentially in the myocardium in response to pressure overload.Endocrinology. 2007; 148: 4579-4584Crossref PubMed Scopus (22) Google Scholar]. Even the decline in estrogen level during post-menopause can accelerate the development of cardiorenal syndrome [[15]Pei J. Harakalova M. den Ruijter H. Pasterkamp G. Duncker D.J. Verhaar M.C. et al.Cardiorenal disease connection during post-menopause: the protective role of estrogen in uremic toxins induced microvascular dysfunction.Int J Cardiol. 2017; 238: 22-30Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Therefore, menopause condition is a non-physiological condition that triggers various changes in the systems, organs and homeostasis of the body. To overcome the homeostasis change, many women use complementary and alternative medical treatments [[16]Melby M.K. Lampl M. Menopause, a biocultural perspective.Annu Rev Anthropol. 2011; 40: 53-70Crossref Scopus (24) Google Scholar], among others, natural products [[17]Tonob D. Maleby M.K. Broadening our perspectives on complementary and alternative medicine for menopause: a narrative review.Maturitas. 2017; 99: 79-85Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. Ylang-ylang plant (Cananga odorata) is a plant native to Southeast Asia [[18]Saedi N. Crawford G.H. Botanical briefs: ylang-ylang oil—extracts from the tree Cananga odorata.Cutis. 2006; 77: 149-150PubMed Google Scholar]. The pharmacological action of the root, wood and stem parts of this plant is that they can be used as remedies for abdominal pain, constipation, wound healing, post-partum recovery, diarrhea, malaria and back pain [[19]Chassagne F. Hul S. Deharo E. Bourdy G. Natural remedies used by Bunong people in Mondulkiri province (Northeast Cambodia) with special reference to the treatment of 11 most common ailments.J Ethnopharmacol. 2016; 191: 41-70Crossref PubMed Scopus (33) Google Scholar]. Ylang-ylang flower can be used as a freshener in essential oil [[20]Van Wyk B.E. A review of commercially important African medicinal plants.J Ethnopharmacol. 2015; 176: 118-134Crossref PubMed Scopus (86) Google Scholar] and as euphoria stimulant and antidepressant in sexual activities [[21]Holt S. Part 2: stimulants and dietary supplements.Altern Complement Ther. 1999; 5: 279-285Crossref Scopus (2) Google Scholar]. To date, the utilization of ylang-ylang flower to maintain the vascular and kidney in menopause has never been performed. Therefore, this study is intended to evaluate histopathology changes in the aorta and kidney in menopausal mice that is given an ethanol extract of ylang-ylang flower. The subject of this study was female mice from a BALB/c strain aged 15 months, with average body weight of 25–40 g, white colored fur, healthy condition, active movement and normal behavior, no sign of anatomical defects. 15 months of age were determined as mice menopausal age. The study consisted of three groups (10 mice per group), that included a group of menopausal mice that did not receive any treatment (control), a group of menopausal mice that was given ylang-ylang flower (C. odorata) extract with the dose of 0.1 mg/day, and a group of menopausal mice that was provided with ylang-ylang flower (C. odorata) extract with the dose of 0.2 mg/day. The ylang-ylang flower extract was administered orally using a feeding tube and administered daily for a period of 14 days with doses according to group's treatment. The ylang-ylang flowers (C. odorata) in this study were obtained from the market in the City of Langsa, East Aceh, Indonesia. The doses of ylang-ylang flower extract were 0.1 mg/mice/day and 0.2 mg/mice/day. Extraction process was performed with maceration method. Maceration method is the extraction process that uses solvent with occasional shaking or stirring at room temperature. Observations performed were in the number of endothelial cells, thickness of tunica intima, diameter of the glomerulus and the diameter of Bowman's capsule, with the utilization of hematoxylin eosin (HE) staining. The description of number of endothelial cells, thickness of tunica intima, the glomerulus and Bowman's capsule were observed descriptively using Olympus BX51 microscope with 400× magnification. For this study, the ethical clearance was granted by the Health Research Ethics Committee of the Health Polytechnic of the Ministry of Health, Langsa, Aceh, Indonesia. Data were presented as mean ± SD and differences between treatment groups were analyzed with ANOVA test. The analysis was performed using SPSS 23.0 statistical package program for Windows. The probability value (p < 0.05) was declared to differ significantly. The numbers of endothelial cells in the various treatment groups are presented in Fig. 1. The number of endothelial cells in the group that was given the second dose was significantly higher compared to that of the group that was given the first dose of extract or that of the control group (p < 0.05). Figure 2 shows the thickness of the tunica intima in various treatment groups. Increased thickness of tunica intima occurred in groups that were provided with the second dose of ylang-ylang flower extracts compared to that of the control group (p < 0.05). Thickness of the tunica intima in the group that was given the second dose of the extract was significantly higher compared to that of the group that was given the first dose of extract (p < 0.05). The histology description of the various study groups can be seen in Fig. 3. In control mice there were epithelial cells that constituted the Bowman's capsule and glomerulus cells that appeared smaller, irregular-structured glomerulus and shrinking Bowman's capsule could be seen as well as an indistinct cell nucleus (karyolysis) with unclear cell border. On the application of the first dose of ylang-ylang flower extract, the size of Bowman's capsule and the kidney glomerulus appeared to have enlarged. On the application of the second dose of ylang-ylang flower extract, the diameter of Bowman's capsule and glomerulus appeared to be larger, there was also kidney improvement which was shown in glomerulus structure. Bowman's capsule was composed of flat epithelial cells that could be seen clearly whose structure was still intact. A glomerular capillary wall that consisted of epithelial cells, glomerulus basal membrane and endothelial cells appeared to be intact. The average diameter of Bowman's capsule and kidney glomerulus are presented in Fig. 4. The average diameter of Bowman's capsule of the group that was given ylang-ylang flower extract was significantly larger compared to that of the control group. This finding was also acquired for the average of the kidney glomerulus, which was the significantly increased diameter of kidney glomerulus in the group that was provided with a significantly higher dose of ylang-ylang flower extract compared to that of control group (p < 0.05), as shown in Fig. 5.Fig. 5Glomerulus diameter of various research groups. Note: data are presented in mean ± standard deviation; ap < 0.05 compared to control group; μm: micrometer.View Large Image Figure ViewerDownload Hi-res image Download (PPT) To date, there has not been any study that evaluates the toxic effect of ylang-ylang (C. odorata) extract administered through oral treatment [[22]Burdock G.A. Carabin I.G. Safety assessment of ylang–ylang (Cananga spp.) as a food ingredient.Food Chem Toxicol. 2008; 46: 433-445Crossref PubMed Scopus (35) Google Scholar]. In this study, the numbers of endothelial cells in the highest dose treated with ylang-ylang flower extract are significantly higher compared to that of the control group (p < 0.05). This indicates that ylang-ylang flower extract at this dose application triggers endothelial cells improvement in vascular of menopause mice. We expect that ylang-ylang flower extract is capable of stimulating the endothelial progenitor cells to differentiate into endothelial cells. Increased apoptosis of endothelial cells may trigger atherosclerosis [[23]Stoneman V.E. Bennett M.R. Role of apoptosis in atherosclerosis and its therapeutic implications.Clin Sci (Lond). 2004; 107: 343-354Crossref PubMed Scopus (193) Google Scholar]. The researcher expects ylang-ylang flower extract mechanism triggers endothelial cells improvement in the vascular through antioxidant mechanism, as has been proven in previous study [[24]Kusuma I.W. Murdiyanto M. Arung E.T. Syafrizal S. Kim Y. Antimicrobial and antioxidant properties of medicinal plants used by the Bentian tribe from Indonesia.Food Sci Hum Wellness. 2014; 3: 191-196Crossref Scopus (52) Google Scholar]. Our study extends previous study that cinnamaldehyde is one active compound of ylang-ylang can not inhibit endothelial proliferation [[25]Lu J. Zhang K. Nam S. Anderson R.A. Jove R. Wen W. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling.Carcinogenesis. 2010; 31: 481-488Crossref PubMed Scopus (119) Google Scholar]. This study contradicts previous findings that the active ingredient of the ylang-ylang can inhibit molecules for tissue remodeling [[26]Han X. Beaumont C. Stevens N. Chemical composition analysis and in vitro biological activities of ten essential oils in human skin cells.Biochim Open. 2017; 5: 1-7Crossref Scopus (35) Google Scholar]. Carotid wall thickness and plaque existence reflect preclinical atherosclerosis in other location (such as coronary artery), and serve as predictor of future cardiovascular episode [27Crouse J.R. Craven T.E. Hagaman A.P. Bond M.G. Association of coronary disease with segment-specific intimal-medial thickening of the extracranial carotid artery.Circulation. 1995; 92: 1141-1147Crossref PubMed Scopus (329) Google Scholar, 28Bots M.L. Hoes A.W. Koudstaal P.J. Hofman A. Grobbee D.E. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study.Circulation. 1997; 96: 1432-1437Crossref PubMed Scopus (2099) Google Scholar]. The progression rate of carotid artery intima media thickness in menopausal women <6 years lower compared to menopausal women >10 years [[29]Hodis H.N. Mack W.J. Shoupe D. Azen S.P. Stanczyk F.Z. Hwang-Levine J. et al.Testing the menopausal hormone therapy timing hypothesis: the early versus late intervention trial with estradiol.Circulation. 2014; 130Google Scholar]. In this study, ylang-ylang flower extract triggers a thickness increase of tunica intima in both doses compared to that of the control group (p < 0.05), the effect is significantly higher in the group that is given the second dose of extract compared to that of the group that is given the first dose of extract (p < 0.05). This indicates that ylang-ylang flower extract triggers the growth of cells that compose vascular tunica intima. This finding is inconsistent with previous findings that ylang can inhibit molecules for tissue remodeling [[26]Han X. Beaumont C. Stevens N. Chemical composition analysis and in vitro biological activities of ten essential oils in human skin cells.Biochim Open. 2017; 5: 1-7Crossref Scopus (35) Google Scholar]. In this study, the average diameter of Bowman's capsule and kidney glomerulus of the groups that are treated with ylang-ylang flower extract are significantly higher compared to that of the control group (p < 0.05). This indicates the application of ylang-ylang flower extract causes a change in kidney histology structure that leads to kidney glomerulus cell hyperplasia. One of the mechanisms is through macrophage activation. Macrophage is an important inflammatory cell and plays a role in adaptive and innate immune response. The macrophage infiltration in the glomerulus is responsible for kidney tissue damage [[30]Wang Y. Lu H. Huang Z. Lin H. Lei Z. Chen X. et al.Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.Biochem Biophys Res Comm. 2014; 450: 788-793Crossref PubMed Scopus (11) Google Scholar]. It is concluded that at the administered dose, ylang-ylang flower extract triggers endothelial cells improvement, but increases tunica intima thickness and kidney hyperplasia in menopausal mice. Therefore, ylang-ylang flower extract triggers vascular and kidney remodeling at menopause age. All authors declare there is no conflict of interest with regard to this study or the publication of this article." @default.
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• W2742560858 title "The effect of ethanol extract of ylang-ylang flower ( Cananga odorata ) on vascular and kidney histology in menopausal mice" @default.
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