Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2016

Open Access 01-12-2016 | Research article

Phenolics from Garcinia mangostana alleviate exaggerated vasoconstriction in metabolic syndrome through direct vasodilatation and nitric oxide generation

Authors: Hossam M. Abdallah, Hany M. El-Bassossy, Gamal A. Mohamed, Ali M. El-halawany, Khalid Z. Alshali, Zainy M. Banjar

Published in: BMC Complementary Medicine and Therapies | Issue 1/2016

Login to get access

Abstract

Background

Exaggerated vasoconstriction plays a very important role in the hypertension, a major component of metabolic syndrome (MetS). In the current work, the potential protective effect of methanol extract of fruit hulls of Garcinia mangostana L. on the exaggerated vasoconstriction in MetS has been investigated. In addition, the bioactive fraction and compounds as well as the possible mechanism of action have been illustrated.

Methods

The effect of methanol extract of G. mangostana (GMT) fruit hulls on the vascular reactivity of aorta isolated from animals with MetS was investigated through bioassay-guided fractionation procedures. GMT was partitioned with chloroform (I) and the remaining mother liquor was fractionated on a Diaion HP-20 with H2O, 50 and 100 % methanol to give fractions II, III, and IV, respectively. The effect of total extract (GMT), bioactive fraction and the bioactive compounds on the vasoconstriction were examined in aortae isolated from animals with MetS by incubation for 30 min before exposing aortae to cumulative concentrations of phenylephrine (PE). The direct relaxant effect was also examined by adding cumulative concentrations of the bioactive fraction and its bioactive compounds to PE precontracted vessels. In addition, aortic nitric oxide (NO) and reactive oxygen species (ROS) production was investigated.

Results

Bioassay-guided fractionation of GMT revealed isolation of garcimangosone D (1), aromadendrin-8-C-β-D-glucopyranoside (2), 2,4,3′-trihydroxy benzophenone-6-O-β-D-glucopyranoside (3), maclurin-6-O-β-D-glucopyranoside (rhodanthenone) (4), epicatechin (5), and 2,3′,4,5′,6-pentahydroxy benzophenone (6). Only compounds 2, 4, and 5 significantly alleviated the exaggerated vasoconstriction of MetS aortae and in the same time showed significant vasodilation of PE pre-contracted aortae. To further illustrate the mechanism of action, the observed vasodilation was completely blocked by the nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester hydrochloride and inhibited by guanylate cyclase inhibitor, methylene blue. However, vasodilation was not affected by the potassium channel blocker, tetraethylammonium or the cyclooxygenase inhibitor, indomethacin. In addition, compounds 2, 4, and 5 stimulated NO generation from isolated aortae to levels comparable with acetylcholine. Furthermore, 4 and 5 inhibited reactive oxygen species generation in MetS aortae.

Conclusion

The phenolic compounds 2, 4, and 5 ameliorated the exaggerated vasoconstriction in MetS aortae through vasodilatation-NO generation mechanism.
Appendix
Available only for authorised users
Literature
2.
go back to reference Nisoli E, Clementi E, Carruba MO, Moncada S. Defective mitochondrial biogenesis: a hallmark of the high cardiovascular risk in the metabolic syndrome? Circul Res. 2007;100(6):795–806.CrossRef Nisoli E, Clementi E, Carruba MO, Moncada S. Defective mitochondrial biogenesis: a hallmark of the high cardiovascular risk in the metabolic syndrome? Circul Res. 2007;100(6):795–806.CrossRef
3.
go back to reference Avogaro A, Albiero M, Menegazzo L, de Kreutzenberg S, Fadini GP. Endothelial dysfunction in diabetes the role of reparatory mechanisms. Diab Care. 2011;34(Supplement 2):S285–90.CrossRef Avogaro A, Albiero M, Menegazzo L, de Kreutzenberg S, Fadini GP. Endothelial dysfunction in diabetes the role of reparatory mechanisms. Diab Care. 2011;34(Supplement 2):S285–90.CrossRef
4.
go back to reference Patel Timir B, Patel L, Patel Tejas B, Makwana Sunil H, Patel Tushar R, Adeshara S. Effects of atorvastatin as antioxidants in diabetic associated cardiovascular complications. Vascular. 2010;11(12):13–4. Patel Timir B, Patel L, Patel Tejas B, Makwana Sunil H, Patel Tushar R, Adeshara S. Effects of atorvastatin as antioxidants in diabetic associated cardiovascular complications. Vascular. 2010;11(12):13–4.
5.
go back to reference Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996;97(11):2601–10.CrossRefPubMedPubMedCentral Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest. 1996;97(11):2601–10.CrossRefPubMedPubMedCentral
6.
go back to reference De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes. Brit J Pharmacol. 2000;130(5):963–74.CrossRef De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes. Brit J Pharmacol. 2000;130(5):963–74.CrossRef
7.
go back to reference Roman-Ramos R, Flores-Saenz J, Alarcon-Aguilar F. Anti-hyperglycemic effect of some edible plants. J Ethnopharmacol. 1995;48(1):25–32.CrossRefPubMed Roman-Ramos R, Flores-Saenz J, Alarcon-Aguilar F. Anti-hyperglycemic effect of some edible plants. J Ethnopharmacol. 1995;48(1):25–32.CrossRefPubMed
8.
go back to reference El Bassossy HM, Hassan NA, Mahmoud MF, Fahmy A. Baicalein protects against hypertension associated with diabetes: effect on vascular reactivity and stiffness. Phytomedicine. 2014;21(12):1742–5.CrossRefPubMed El Bassossy HM, Hassan NA, Mahmoud MF, Fahmy A. Baicalein protects against hypertension associated with diabetes: effect on vascular reactivity and stiffness. Phytomedicine. 2014;21(12):1742–5.CrossRefPubMed
9.
go back to reference El-Bassossy HM, Abo-Warda SM, Fahmy A. Chrysin and luteolin attenuate diabetes-induced impairment in endothelial-dependent relaxation: Effect on lipid profile, AGEs and NO generation. Phytother Res. 2013;27(11):1678–84.CrossRefPubMed El-Bassossy HM, Abo-Warda SM, Fahmy A. Chrysin and luteolin attenuate diabetes-induced impairment in endothelial-dependent relaxation: Effect on lipid profile, AGEs and NO generation. Phytother Res. 2013;27(11):1678–84.CrossRefPubMed
10.
go back to reference Devalaraja S, Jain S, Yadav H. Exotic fruits as therapeutic complements for diabetes, obesity and metabolic syndrome. Food Res Inter. 2011;44(7):1856–65.CrossRef Devalaraja S, Jain S, Yadav H. Exotic fruits as therapeutic complements for diabetes, obesity and metabolic syndrome. Food Res Inter. 2011;44(7):1856–65.CrossRef
11.
go back to reference Ryu HW, Cho JK, Curtis-Long MJ, Yuk HJ, Kim YS, Jung S, Kim YS, Lee BW, Park KH. α-Glucosidase inhibition and antihyperglycemic activity of prenylated xanthones from Garcinia mangostana. Phytochemistry. 2011;72(17):2148–54.CrossRefPubMed Ryu HW, Cho JK, Curtis-Long MJ, Yuk HJ, Kim YS, Jung S, Kim YS, Lee BW, Park KH. α-Glucosidase inhibition and antihyperglycemic activity of prenylated xanthones from Garcinia mangostana. Phytochemistry. 2011;72(17):2148–54.CrossRefPubMed
12.
go back to reference Abdallah H, El-Bassossy H, El-Halawany A, Mohamed G, Alshali K, Banjar Z. PP. 14.02: Psiadia punctulata and Garcinia mangostana have potent vasorelaxant activity on isolated rat aorta. J Hypertension. 2015;33:e246.CrossRef Abdallah H, El-Bassossy H, El-Halawany A, Mohamed G, Alshali K, Banjar Z. PP. 14.02: Psiadia punctulata and Garcinia mangostana have potent vasorelaxant activity on isolated rat aorta. J Hypertension. 2015;33:e246.CrossRef
13.
go back to reference Abdallah HM, El-Bassossy H, Mohamed GA, El-Halawany AM, Alshali KZ, Banjar ZM. Phenolics from garcinia mangostana inhibit advanced glycation endproducts formation: effect on amadori products, cross-linked structures and protein thiols. Molecules. 2016;21(2):251.CrossRefPubMed Abdallah HM, El-Bassossy H, Mohamed GA, El-Halawany AM, Alshali KZ, Banjar ZM. Phenolics from garcinia mangostana inhibit advanced glycation endproducts formation: effect on amadori products, cross-linked structures and protein thiols. Molecules. 2016;21(2):251.CrossRefPubMed
14.
go back to reference Obolskiy D, Pischel I, Siriwatanametanon N, Heinrich M. Garcinia mangostana L.: a phytochemical and pharmacological review. Phytother Res. 2009;23(8):1047–65.CrossRefPubMed Obolskiy D, Pischel I, Siriwatanametanon N, Heinrich M. Garcinia mangostana L.: a phytochemical and pharmacological review. Phytother Res. 2009;23(8):1047–65.CrossRefPubMed
15.
go back to reference Mohamed GA, Ibrahim SR, Shaaban MI, Ross SA. Mangostanaxanthones I and II, new xanthones from the pericarp of Garcinia mangostana. Fitoterapia. 2014;98:215–21.CrossRefPubMed Mohamed GA, Ibrahim SR, Shaaban MI, Ross SA. Mangostanaxanthones I and II, new xanthones from the pericarp of Garcinia mangostana. Fitoterapia. 2014;98:215–21.CrossRefPubMed
16.
go back to reference Desoky N, El-Bassossy HM, Fahmy A. Characterization of a rat model of insulin deficiency induced vascular complication. Zagazig Univ Med J. 2014;16(6):569–75. Desoky N, El-Bassossy HM, Fahmy A. Characterization of a rat model of insulin deficiency induced vascular complication. Zagazig Univ Med J. 2014;16(6):569–75.
17.
go back to reference El-Bassossy HM, Elberry AA, Ghareib SA. Geraniol improves the impaired vascular reactivity in diabetes and metabolic syndrome through calcium channel blocking effect. J Diabetes Comp. 2016;30(6):1008–1016. El-Bassossy HM, Elberry AA, Ghareib SA. Geraniol improves the impaired vascular reactivity in diabetes and metabolic syndrome through calcium channel blocking effect. J Diabetes Comp. 2016;30(6):1008–1016.
18.
go back to reference El-Bassossy HM, Dsokey N, Fahmy A. Characterization of vascular complications in experimental model of fructose-induced metabolic syndrome. Toxicol Mech Methods. 2014;24(8):536–43.CrossRefPubMed El-Bassossy HM, Dsokey N, Fahmy A. Characterization of vascular complications in experimental model of fructose-induced metabolic syndrome. Toxicol Mech Methods. 2014;24(8):536–43.CrossRefPubMed
19.
go back to reference El-Bassossy HM, El-Fawal R, Fahmy A, Watson ML. Arginase inhibition alleviates hypertension in the metabolic syndrome. Brit J Pharmacol. 2013;169(3):693–703.CrossRef El-Bassossy HM, El-Fawal R, Fahmy A, Watson ML. Arginase inhibition alleviates hypertension in the metabolic syndrome. Brit J Pharmacol. 2013;169(3):693–703.CrossRef
20.
go back to reference Ghareib SA, El-Bassossy HM, Elberry AA, Azhar A, Watson ML, Banjar ZM, Alahdal AM. Protective effect of zingerone on increased vascular contractility in diabetic rat aorta. Eur J Pharmacol. 2016;780:174–9.CrossRefPubMed Ghareib SA, El-Bassossy HM, Elberry AA, Azhar A, Watson ML, Banjar ZM, Alahdal AM. Protective effect of zingerone on increased vascular contractility in diabetic rat aorta. Eur J Pharmacol. 2016;780:174–9.CrossRefPubMed
21.
go back to reference El-Bassossy HM, El-Fawal R, Fahmy A. Arginase inhibition alleviates hypertension associated with diabetes: effect on endothelial dependent relaxation and NO production. Vasc Pharmacol. 2012;57(5–6):194–200.CrossRef El-Bassossy HM, El-Fawal R, Fahmy A. Arginase inhibition alleviates hypertension associated with diabetes: effect on endothelial dependent relaxation and NO production. Vasc Pharmacol. 2012;57(5–6):194–200.CrossRef
22.
go back to reference Hassan N, El-Bassossy HM, Zakaria MNM. Heme oxygenase-1 induction protects against hypertension associated with diabetes: effect on exaggerated vascular contractility. Naunyn-Schmied Arch Pharmacol. 2013;386(3):217–26.CrossRef Hassan N, El-Bassossy HM, Zakaria MNM. Heme oxygenase-1 induction protects against hypertension associated with diabetes: effect on exaggerated vascular contractility. Naunyn-Schmied Arch Pharmacol. 2013;386(3):217–26.CrossRef
23.
go back to reference Ghareib SA, El-Bassossy HM, Elberry AA, Azhar A, Watson ML, Banjar ZM. 6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation. Drug Des Dev Ther. 2015;9:6019. Ghareib SA, El-Bassossy HM, Elberry AA, Azhar A, Watson ML, Banjar ZM. 6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation. Drug Des Dev Ther. 2015;9:6019.
24.
go back to reference El-Bassossy HM, Fahmy A, Badawy D. Cinnamaldehyde protects from the hypertension associated with diabetes. Food Chem Toxicol. 2011;49(11):3007–12.CrossRefPubMed El-Bassossy HM, Fahmy A, Badawy D. Cinnamaldehyde protects from the hypertension associated with diabetes. Food Chem Toxicol. 2011;49(11):3007–12.CrossRefPubMed
25.
go back to reference El-Bassossy HM, Abo-Warda SM, Fahmy A. Rosiglitazone, a peroxisome proliferator-activated receptor g stimulant, abrogates diabetes-evoked hypertension by rectifying abnormalities in vascular reactivity. Clin Exper Pharmacol and Physiol. 2012;39(8):643–9.CrossRef El-Bassossy HM, Abo-Warda SM, Fahmy A. Rosiglitazone, a peroxisome proliferator-activated receptor g stimulant, abrogates diabetes-evoked hypertension by rectifying abnormalities in vascular reactivity. Clin Exper Pharmacol and Physiol. 2012;39(8):643–9.CrossRef
26.
go back to reference Huang Y-L, Chen C-C, Chen Y-J, Huang R-L, Shieh B-J. Three xanthones and a benzophenone from Garcinia mangostana. J Nat Prod. 2001;64(7):903–6.CrossRefPubMed Huang Y-L, Chen C-C, Chen Y-J, Huang R-L, Shieh B-J. Three xanthones and a benzophenone from Garcinia mangostana. J Nat Prod. 2001;64(7):903–6.CrossRefPubMed
27.
go back to reference Sawi SE. A new rare 8-C-glucosylflavonoid and other eight flavonoids from the molluscicidal plant Acacia saligna Wendl. Pharmac Pharmacol Lett. 2001;11(1):30–3. Sawi SE. A new rare 8-C-glucosylflavonoid and other eight flavonoids from the molluscicidal plant Acacia saligna Wendl. Pharmac Pharmacol Lett. 2001;11(1):30–3.
28.
go back to reference Kaya D, Yalçın FN, Bedir E, Çalış İ, Steinhauser L, Albert K, Ersöz T. New benzophenone glucosides from the aerial parts of Gentiana verna L. subsp. pontica (Soltok.) Hayek. Phytochem Lett. 2011;4(4):459–61.CrossRef Kaya D, Yalçın FN, Bedir E, Çalış İ, Steinhauser L, Albert K, Ersöz T. New benzophenone glucosides from the aerial parts of Gentiana verna L. subsp. pontica (Soltok.) Hayek. Phytochem Lett. 2011;4(4):459–61.CrossRef
29.
go back to reference Mabry T, Markham K. The systematic identification of flavonoids. New York: Springer; 1970.CrossRef Mabry T, Markham K. The systematic identification of flavonoids. New York: Springer; 1970.CrossRef
30.
go back to reference Jiang HZ, Quan XF, Tian WX, Hu JM, Wang PC, Huang SZ, Cheng ZQ, Liang WJ, Zhou J, Ma XF. Fatty acid synthase inhibitors of phenolic constituents isolated from Garcinia mangostana. Bioorg Med Chem Lett. 2010;20(20):6045–7.CrossRefPubMed Jiang HZ, Quan XF, Tian WX, Hu JM, Wang PC, Huang SZ, Cheng ZQ, Liang WJ, Zhou J, Ma XF. Fatty acid synthase inhibitors of phenolic constituents isolated from Garcinia mangostana. Bioorg Med Chem Lett. 2010;20(20):6045–7.CrossRefPubMed
31.
go back to reference Ansarullah, Bharucha B, Patel V, Ramachandran AV. Oreocnide integrifolia (Gaud.) Miq leaf water extract improves metabolic alterations in high fructose fed insulin resistant and hypertensive rats. Eur J Integ Med. 2010;2(2):79–87.CrossRef Ansarullah, Bharucha B, Patel V, Ramachandran AV. Oreocnide integrifolia (Gaud.) Miq leaf water extract improves metabolic alterations in high fructose fed insulin resistant and hypertensive rats. Eur J Integ Med. 2010;2(2):79–87.CrossRef
32.
go back to reference Mansour SM, Bahgat AK, El-Khatib AS, Khayyal MT. Ginkgo biloba extract (EGb 761) normalizes hypertension in 2 K, 1C hypertensive rats: role of antioxidant mechanisms, ACE inhibiting activity and improvement of endothelial dysfunction. Phytomedicine. 2011;18(8–9):641–7.CrossRefPubMed Mansour SM, Bahgat AK, El-Khatib AS, Khayyal MT. Ginkgo biloba extract (EGb 761) normalizes hypertension in 2 K, 1C hypertensive rats: role of antioxidant mechanisms, ACE inhibiting activity and improvement of endothelial dysfunction. Phytomedicine. 2011;18(8–9):641–7.CrossRefPubMed
33.
go back to reference Badawy D, El-Bassossy HM, Fahmy A, Azhar A. Aldose reductase inhibitors zopolrestat and ferulic acid alleviate hypertension associated with diabetes: effect on vascular reactivity. Canad J Physiol and Pharmacol. 2013;91(2):101–7.CrossRef Badawy D, El-Bassossy HM, Fahmy A, Azhar A. Aldose reductase inhibitors zopolrestat and ferulic acid alleviate hypertension associated with diabetes: effect on vascular reactivity. Canad J Physiol and Pharmacol. 2013;91(2):101–7.CrossRef
34.
go back to reference Iyer SN, Katovich MJ. Vascular reactivity to phenylephrine and angiotensin II in hypertensive rats associated with insulin resistance. Clin Experim Hyperten. 1996;18(2):227–42.CrossRef Iyer SN, Katovich MJ. Vascular reactivity to phenylephrine and angiotensin II in hypertensive rats associated with insulin resistance. Clin Experim Hyperten. 1996;18(2):227–42.CrossRef
35.
go back to reference Galleano M, Bernatova I, Puzserova A, Balis P, Sestakova N, Pechanova O, Fraga CG. (−)‐Epicatechin reduces blood pressure and improves vasorelaxation in spontaneously hypertensive rats by NO‐mediated mechanism. IUBMB Life. 2013;65(8):710–5.CrossRefPubMed Galleano M, Bernatova I, Puzserova A, Balis P, Sestakova N, Pechanova O, Fraga CG. (−)‐Epicatechin reduces blood pressure and improves vasorelaxation in spontaneously hypertensive rats by NO‐mediated mechanism. IUBMB Life. 2013;65(8):710–5.CrossRefPubMed
36.
go back to reference Aggio A, Grassi D, Onori E, D’Alessandro A, Masedu F, Valenti M, Ferri C. Endothelium/nitric oxide mechanism mediates vasorelaxation and counteracts vasoconstriction induced by low concentration of flavanols. Eur J Nutr. 2013;52(1):263–72.CrossRefPubMed Aggio A, Grassi D, Onori E, D’Alessandro A, Masedu F, Valenti M, Ferri C. Endothelium/nitric oxide mechanism mediates vasorelaxation and counteracts vasoconstriction induced by low concentration of flavanols. Eur J Nutr. 2013;52(1):263–72.CrossRefPubMed
37.
go back to reference Steffen Y, Schewe T, Sies H. (−)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. Biochem Biophys Res Commun. 2007;359(3):828–33.CrossRefPubMed Steffen Y, Schewe T, Sies H. (−)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. Biochem Biophys Res Commun. 2007;359(3):828–33.CrossRefPubMed
38.
go back to reference Badawy D, El-Bassossy HM, Fahmy A, Azhar A. Aldose reductase inhibitors zopolrestat and ferulic acid alleviate hypertension associated with diabetes: effect on vascular reactivity. Canad J Physiol and Pharmacol. 2012;91(2):101–7.CrossRef Badawy D, El-Bassossy HM, Fahmy A, Azhar A. Aldose reductase inhibitors zopolrestat and ferulic acid alleviate hypertension associated with diabetes: effect on vascular reactivity. Canad J Physiol and Pharmacol. 2012;91(2):101–7.CrossRef
40.
go back to reference Delbosc S, Paizanis E, Magous R, Araiz C, Dimo T, Cristol J-P, Cros G, Azay J. Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis. 2005;179(1):43–9.CrossRefPubMed Delbosc S, Paizanis E, Magous R, Araiz C, Dimo T, Cristol J-P, Cros G, Azay J. Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat. Atherosclerosis. 2005;179(1):43–9.CrossRefPubMed
41.
go back to reference Mellor KM, Bell JR, Young MJ, Ritchie RH, Delbridge LM. Myocardial autophagy activation and suppressed survival signaling is associated with insulin resistance in fructose-fed mice. J Molec Cell Cardiol. 2011;50(6):1035–43.CrossRef Mellor KM, Bell JR, Young MJ, Ritchie RH, Delbridge LM. Myocardial autophagy activation and suppressed survival signaling is associated with insulin resistance in fructose-fed mice. J Molec Cell Cardiol. 2011;50(6):1035–43.CrossRef
42.
go back to reference Khoo NK, Rudolph V, Cole MP, Golin-Bisello F, Schopfer FJ, Woodcock SR, Batthyany C, Freeman BA. Activation of vascular endothelial nitric oxide synthase and heme oxygenase-1 expression by electrophilic nitro-fatty acids. Free Rad Biol Med. 2010;48(2):230–9.CrossRefPubMed Khoo NK, Rudolph V, Cole MP, Golin-Bisello F, Schopfer FJ, Woodcock SR, Batthyany C, Freeman BA. Activation of vascular endothelial nitric oxide synthase and heme oxygenase-1 expression by electrophilic nitro-fatty acids. Free Rad Biol Med. 2010;48(2):230–9.CrossRefPubMed
Metadata
Title
Phenolics from Garcinia mangostana alleviate exaggerated vasoconstriction in metabolic syndrome through direct vasodilatation and nitric oxide generation
Authors
Hossam M. Abdallah
Hany M. El-Bassossy
Gamal A. Mohamed
Ali M. El-halawany
Khalid Z. Alshali
Zainy M. Banjar
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2016
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-016-1340-5

Other articles of this Issue 1/2016

BMC Complementary Medicine and Therapies 1/2016 Go to the issue