An Exploration of the Active Ingredients of <i>Cortex phellodendri</i> in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology

Xianchang Yu; Xiongdong Zhong

doi:doi:10.11648/j.js.20200806.17

| Peer-Reviewed

An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology

Xianchang Yu, Xiongdong Zhong

Published in Journal of Surgery (Volume 8, Issue 6)

Received: 20 November 2020 Accepted: 30 November 2020 Published: 4 December 2020

Views: Downloads:

Download PDF

Share This Article

Twitter
Linked In
Facebook

Abstract

Background: Huangbo, also known as Cortex phellodendri in Latin, is an important drug which has the pharmacological action of clearing heat, drying dampness, purging fire and detoxifying. In recent years, it has been reported that Huangbo also has the activity of treating hemorrhoids. Objective: The aim of this study was to explore the Active Ingredients of Cortex phellodendri in the Treatment of hemorrhoids and Its Mechanism. Study Design: We analyzed Active components and target genes of Cortex phellodendri in the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform. We then searched the GeneCards database for target genes related to hemorrhoids and the intersection of these genes with the active components of Cortex phellodendri. Target genes related to hemorrhoids were taken as common potential target genes of Cortex phellodendri, which could act on hemorrhoids. Using the R programming language, we drew a Venn map of these common potential target genes. The “component–target gene–disease” network of Cortex phellodendri in the treatment of hemorrhoids was established using Cytoscape software version 3.7.1; the protein–protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. With the help of R and Perl languages, we performed gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential target genes of Cortex phellodendri in the treatment of hemorrhoids. Results: We extracted a total of 10 active components from Cortex phellodendri, including quercetin and rutaecarpine and so on, as well as 29 potential target genes for hemorrhoids. According to the Degree ranking in Cytoscape3.7.1 software, the top 10 potential target genes were interleukin-6 (IL-6), CCL2, CXCL8, MMP9, vascular endothelial growth factor A (VEGFA), Myc, IL-10, ICAM1, MMP2, and MMP3. Pathway enrichment mainly involved signaling pathways such as advanced glycation end products and receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, hypoxia-inducible factor 1 (HIF-1), IL-17, and Relaxin. Conclusion: Based on network pharmacology, Cortex phellodendri is expected to be mined as a candidate Traditional Chinese Medicine (TCM) for the treatment of hemorrhoids. Its mechanism for treating this disease operates via multiple components and pathways. This study provides the basic theory and the basis for further research.

Published in	Journal of Surgery (Volume 8, Issue 6)
DOI	10.11648/j.js.20200806.17
Page(s)	209-216
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2020. Published by Science Publishing Group

Keywords

Cortex phellodendri, Hemorrhoids, Network Pharmacology, Target Gene, GO Function Enrichment Analysis, KEGG Pathway Enrichment Analysis

References

[1]	Muguruma N, Takayama T. Endoscopic sclerotherapy with aluminum potassium sulfate and tannic acid: An effective and less invasive strategy for internal hemorrhoids [J]. Clin Endosc, 2019, 52 (6): 521-522.
[2]	Mishra S, Sahoo A K, Elamurugan T P, et al. Polidocanol versus phenol in oil injection sclerotherapy in treatment of internal hemorrhoids: A randomized controlled trial [J]. Turk J Gastroenterol, 2020, 31 (5): 378-383.
[3]	Lee K Y, Lee J I, Park Y Y, et al. Hemorrhoids are associated with urinary incontinence [J]. J Womens Health (Larchmt), 2020, 29 (11): 1464-1468.
[4]	Lambert L, Jahoda J, Grusova G, et al. Ct colonography has low sensitivity but high specificity in the detection of internal hemorrhoids [J]. Diagn Interv Radiol, 2020, 26 (2): 82-86.
[5]	Shen K, Wang C, Gao Z D, et al. [procedure for prolapse and hemorrhoids versus stapled transanal rectal resection in the treatment of grade iv hemorrhoids] [J]. Zhonghua Wei Chang Wai Ke Za Zhi, 2019, 22 (12): 1165-1169.
[6]	Ji L, Li L, Weng L, et al. Tissue selecting technique mega-window stapler combined with anal canal epithelial preservation operation for the treatment of severe prolapsed hemorrhoids: A study protocol for a randomized controlled trial [J]. Medicine (Baltimore), 2020, 99 (45): e23122.
[7]	Xiongdong Zhong. An Exploration of the Active Ingredients of Salvia miltiorrhiza in the Treatment of Gastric Cancer and Its Mechanism Based on Network Pharmacology. Journal of Cancer Treatment and Research. Vol. 8, No. 2, 2020, pp. 34-44.
[8]	Shi S Y, Zhou Q, He Z Q, et al. Traditional chinese medicine (liang-xue-di-huang decoction) for hemorrhoid hemorrhage: Study protocol clinical trial (spirit compliant) [J]. Medicine (Baltimore), 2020, 99 (16): e19720.
[9]	Gan T, Liu Y D, Wang Y, et al. Traditional chinese medicine herbs for stopping bleeding from haemorrhoids [J]. Cochrane Database Syst Rev, 2010, (10): CD006791.
[10]	Boost M, Yau P, Yap M, et al. Determination of cytotoxicity of traditional chinese medicine herbs, rhizoma coptidis, radix scutellariae, and cortex phellodendri, by three methods [J]. Cont Lens Anterior Eye. 2016, 39 (2): 128-132.
[11]	Zhang Z, Zhang Y, Zhang Z, et al. Comparative analysis of DNA barcoding and hplc fingerprint to trace species of phellodendri cortex, an important traditional chinese medicine from multiple sources [J]. Biol Pharm Bull. 2016, 39 (8): 1325-1330.
[12]	Li CY, Lu HJ, Lin CH, et al. A rapid and simple determination of protoberberine alkaloids in cortex phellodendri by 1h nmr and its application for quality control of commercial traditional chinese medicine prescriptions [J]. J Pharm Biomed Anal. 2006, 40 (1): 173-178.
[13]	Zhang DH, Zhang X, Peng B, et al. Network pharmacology suggests biochemical rationale for treating covid-19 symptoms with a traditional chinese medicine [J]. Commun Biol. 2020, 3 (1): 466.
[14]	Ren CP. Combined traditional chinese and western medicine sclerosing therapy in internal hemorrhoids [J]. Chin Med J (Engl). 1977, 3 (2): 137-142.
[15]	Zhou HY, Wang D, Cui Z. Ferulates, amurenlactone a and amurenamide a from traditional chinese medicine cortex phellodendri amurensis [J]. J Asian Nat Prod Res. 2008, 10 (5-6): 409-413.
[16]	Kim SG, Sung JY, Kim JR, et al. Quercetin-induced apoptosis ameliorates vascular smooth muscle cell senescence through amp-activated protein kinase signaling pathway [J]. Korean J Physiol Pharmacol. 2020, 24 (1): 69-79.
[17]	Surbala L, Singh CB, Devi RV, et al. Rutaecarpine exhibits anti-diabetic potential in high fat diet-multiple low dose streptozotocin induced type 2 diabetic mice and in vitro by modulating hepatic glucose homeostasis [J]. J Pharmacol Sci. 2020, 143 (4): 307-314.
[18]	Chen L, Zhu L, Chen J, et al. Crystal structure-guided design of berberine-based novel chitinase inhibitors [J]. J Enzyme Inhib Med Chem. 2020, 35 (1): 1937-1943.
[19]	Townsend EA, Emala CW, Sr. Quercetin acutely relaxes airway smooth muscle and potentiates beta-agonist-induced relaxation via dual phosphodiesterase inhibition of plcbeta and pde 4 [J]. Am J Physiol Lung Cell Mol Physiol. 2013, 305 (5): L396-403.
[20]	Triantos C, Kalafateli M, Aggeletopoulou I, et al. Vitamin d-related immunomodulation in patients with liver cirrhosis [J]. Eur J Gastroenterol Hepatol. 2020, 32 (7): 867-876.
[21]	Milajerdi A, Mousavi SM, Sadeghi A, et al. The effect of probiotics on inflammatory biomarkers: A meta-analysis of randomized clinical trials [J]. Eur J Nutr. 2020, 59 (2): 633-649.
[22]	Ohchi Y, Goto K, Yasuda N, et al. High efficiency removal of cytokines and hmgb-1 by continuous hemofiltration with a dual layered polyethersulfone membrane: An ex vivo study [J]. Ther Apher Dial. 2019, 23 (2): 173-179.
[23]	Atilgan R, Pala S, Yavuzkir S, et al. What is the impact of short- and long-term supplementation of either cabergoline or clarithromycin on resolving rat ovarian hyperstimulation syndrome (ohss) model [J]. J Obstet Gynaecol. 2019, 39 (5): 687-694.
[24]	Semeniuk LM, Likhachov VK, Yuzvenko TY, et al. Risk markers of reproductive loss in women with hyperandrogenism [J]. Wiad Lek. 2018, 71 (8): 1550-1553.
[25]	Catano Canizales YG, Uresti Rivera EE, Garcia Jacobo RE, et al. Increased levels of aim2 and circulating mitochondrial DNA in type 2 diabetes [J]. Iran J Immunol. 2018, 15 (2): 142-155.
[26]	Velayoudom-Cephise FL, Cano-Sanchez M, Bercion S, et al. Receptor for advanced glycation end products modulates oxidative stress and mitochondrial function in the soleus muscle of mice fed a high-fat diet [J]. Appl Physiol Nutr Metab. 2020, 45 (10): 1107-1117.
[27]	Prasad K. Age-rage stress in the pathophysiology of pulmonary hypertension and its treatment [J]. Int J Angiol. 2019, 28 (2): 71-79.
[28]	Isoyama N, Machowska A, Qureshi AR, et al. Elevated circulating s100a 12 associates with vascular disease and worse clinical outcome in peritoneal dialysis patients [J]. Perit Dial Int. 2016, 36 (3): 269-276.
[29]	Kim JK, Park S, Lee MJ, et al. Plasma levels of soluble receptor for advanced glycation end products (srage) and proinflammatory ligand for rage (en-rage) are associated with carotid atherosclerosis in patients with peritoneal dialysis [J]. Atherosclerosis. 2012, 220 (1): 208-214.

Cite This Article

Plain Text BibTeX RIS

APA Style

Xianchang Yu, Xiongdong Zhong. (2020). An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology. Journal of Surgery, 8(6), 209-216. https://doi.org/10.11648/j.js.20200806.17

Copy | Download

ACS Style

Xianchang Yu; Xiongdong Zhong. An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology. J. Surg. 2020, 8(6), 209-216. doi: 10.11648/j.js.20200806.17

Copy | Download

AMA Style

Xianchang Yu, Xiongdong Zhong. An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology. J Surg. 2020;8(6):209-216. doi: 10.11648/j.js.20200806.17

Copy | Download

@article{10.11648/j.js.20200806.17,
  author = {Xianchang Yu and Xiongdong Zhong},
  title = {An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology},
  journal = {Journal of Surgery},
  volume = {8},
  number = {6},
  pages = {209-216},
  doi = {10.11648/j.js.20200806.17},
  url = {https://doi.org/10.11648/j.js.20200806.17},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.js.20200806.17},
  abstract = {Background: Huangbo, also known as Cortex phellodendri in Latin, is an important drug which has the pharmacological action of clearing heat, drying dampness, purging fire and detoxifying. In recent years, it has been reported that Huangbo also has the activity of treating hemorrhoids. Objective: The aim of this study was to explore the Active Ingredients of Cortex phellodendri in the Treatment of hemorrhoids and Its Mechanism. Study Design: We analyzed Active components and target genes of Cortex phellodendri in the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform. We then searched the GeneCards database for target genes related to hemorrhoids and the intersection of these genes with the active components of Cortex phellodendri. Target genes related to hemorrhoids were taken as common potential target genes of Cortex phellodendri, which could act on hemorrhoids. Using the R programming language, we drew a Venn map of these common potential target genes. The “component–target gene–disease” network of Cortex phellodendri in the treatment of hemorrhoids was established using Cytoscape software version 3.7.1; the protein–protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. With the help of R and Perl languages, we performed gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential target genes of Cortex phellodendri in the treatment of hemorrhoids. Results: We extracted a total of 10 active components from Cortex phellodendri, including quercetin and rutaecarpine and so on, as well as 29 potential target genes for hemorrhoids. According to the Degree ranking in Cytoscape3.7.1 software, the top 10 potential target genes were interleukin-6 (IL-6), CCL2, CXCL8, MMP9, vascular endothelial growth factor A (VEGFA), Myc, IL-10, ICAM1, MMP2, and MMP3. Pathway enrichment mainly involved signaling pathways such as advanced glycation end products and receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, hypoxia-inducible factor 1 (HIF-1), IL-17, and Relaxin. Conclusion: Based on network pharmacology, Cortex phellodendri is expected to be mined as a candidate Traditional Chinese Medicine (TCM) for the treatment of hemorrhoids. Its mechanism for treating this disease operates via multiple components and pathways. This study provides the basic theory and the basis for further research.},
 year = {2020}
}

Copy | Download

TY  - JOUR
T1  - An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology
AU  - Xianchang Yu
AU  - Xiongdong Zhong
Y1  - 2020/12/04
PY  - 2020
N1  - https://doi.org/10.11648/j.js.20200806.17
DO  - 10.11648/j.js.20200806.17
T2  - Journal of Surgery
JF  - Journal of Surgery
JO  - Journal of Surgery
SP  - 209
EP  - 216
PB  - Science Publishing Group
SN  - 2330-0930
UR  - https://doi.org/10.11648/j.js.20200806.17
AB  - Background: Huangbo, also known as Cortex phellodendri in Latin, is an important drug which has the pharmacological action of clearing heat, drying dampness, purging fire and detoxifying. In recent years, it has been reported that Huangbo also has the activity of treating hemorrhoids. Objective: The aim of this study was to explore the Active Ingredients of Cortex phellodendri in the Treatment of hemorrhoids and Its Mechanism. Study Design: We analyzed Active components and target genes of Cortex phellodendri in the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform. We then searched the GeneCards database for target genes related to hemorrhoids and the intersection of these genes with the active components of Cortex phellodendri. Target genes related to hemorrhoids were taken as common potential target genes of Cortex phellodendri, which could act on hemorrhoids. Using the R programming language, we drew a Venn map of these common potential target genes. The “component–target gene–disease” network of Cortex phellodendri in the treatment of hemorrhoids was established using Cytoscape software version 3.7.1; the protein–protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. With the help of R and Perl languages, we performed gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential target genes of Cortex phellodendri in the treatment of hemorrhoids. Results: We extracted a total of 10 active components from Cortex phellodendri, including quercetin and rutaecarpine and so on, as well as 29 potential target genes for hemorrhoids. According to the Degree ranking in Cytoscape3.7.1 software, the top 10 potential target genes were interleukin-6 (IL-6), CCL2, CXCL8, MMP9, vascular endothelial growth factor A (VEGFA), Myc, IL-10, ICAM1, MMP2, and MMP3. Pathway enrichment mainly involved signaling pathways such as advanced glycation end products and receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, hypoxia-inducible factor 1 (HIF-1), IL-17, and Relaxin. Conclusion: Based on network pharmacology, Cortex phellodendri is expected to be mined as a candidate Traditional Chinese Medicine (TCM) for the treatment of hemorrhoids. Its mechanism for treating this disease operates via multiple components and pathways. This study provides the basic theory and the basis for further research.
VL  - 8
IS  - 6
ER  -

Copy | Download

Author Information

Xianchang Yu

Department of Cardiothoracic Surgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, P. R. China
Xiongdong Zhong

Department of Cardiothoracic Surgery, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, P. R. China

Download PDF

Sections

Plain Text BibTeX RIS

APA Style

Xianchang Yu, Xiongdong Zhong. (2020). An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology. Journal of Surgery, 8(6), 209-216. https://doi.org/10.11648/j.js.20200806.17

Copy | Download

ACS Style

Xianchang Yu; Xiongdong Zhong. An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology. J. Surg. 2020, 8(6), 209-216. doi: 10.11648/j.js.20200806.17

Copy | Download

AMA Style

Xianchang Yu, Xiongdong Zhong. An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology. J Surg. 2020;8(6):209-216. doi: 10.11648/j.js.20200806.17

Copy | Download

@article{10.11648/j.js.20200806.17,
  author = {Xianchang Yu and Xiongdong Zhong},
  title = {An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology},
  journal = {Journal of Surgery},
  volume = {8},
  number = {6},
  pages = {209-216},
  doi = {10.11648/j.js.20200806.17},
  url = {https://doi.org/10.11648/j.js.20200806.17},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.js.20200806.17},
  abstract = {Background: Huangbo, also known as Cortex phellodendri in Latin, is an important drug which has the pharmacological action of clearing heat, drying dampness, purging fire and detoxifying. In recent years, it has been reported that Huangbo also has the activity of treating hemorrhoids. Objective: The aim of this study was to explore the Active Ingredients of Cortex phellodendri in the Treatment of hemorrhoids and Its Mechanism. Study Design: We analyzed Active components and target genes of Cortex phellodendri in the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform. We then searched the GeneCards database for target genes related to hemorrhoids and the intersection of these genes with the active components of Cortex phellodendri. Target genes related to hemorrhoids were taken as common potential target genes of Cortex phellodendri, which could act on hemorrhoids. Using the R programming language, we drew a Venn map of these common potential target genes. The “component–target gene–disease” network of Cortex phellodendri in the treatment of hemorrhoids was established using Cytoscape software version 3.7.1; the protein–protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. With the help of R and Perl languages, we performed gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential target genes of Cortex phellodendri in the treatment of hemorrhoids. Results: We extracted a total of 10 active components from Cortex phellodendri, including quercetin and rutaecarpine and so on, as well as 29 potential target genes for hemorrhoids. According to the Degree ranking in Cytoscape3.7.1 software, the top 10 potential target genes were interleukin-6 (IL-6), CCL2, CXCL8, MMP9, vascular endothelial growth factor A (VEGFA), Myc, IL-10, ICAM1, MMP2, and MMP3. Pathway enrichment mainly involved signaling pathways such as advanced glycation end products and receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, hypoxia-inducible factor 1 (HIF-1), IL-17, and Relaxin. Conclusion: Based on network pharmacology, Cortex phellodendri is expected to be mined as a candidate Traditional Chinese Medicine (TCM) for the treatment of hemorrhoids. Its mechanism for treating this disease operates via multiple components and pathways. This study provides the basic theory and the basis for further research.},
 year = {2020}
}

Copy | Download

TY  - JOUR
T1  - An Exploration of the Active Ingredients of Cortex phellodendri in the Treatment of Hemorrhoids and Its Mechanism Based on Network Pharmacology
AU  - Xianchang Yu
AU  - Xiongdong Zhong
Y1  - 2020/12/04
PY  - 2020
N1  - https://doi.org/10.11648/j.js.20200806.17
DO  - 10.11648/j.js.20200806.17
T2  - Journal of Surgery
JF  - Journal of Surgery
JO  - Journal of Surgery
SP  - 209
EP  - 216
PB  - Science Publishing Group
SN  - 2330-0930
UR  - https://doi.org/10.11648/j.js.20200806.17
AB  - Background: Huangbo, also known as Cortex phellodendri in Latin, is an important drug which has the pharmacological action of clearing heat, drying dampness, purging fire and detoxifying. In recent years, it has been reported that Huangbo also has the activity of treating hemorrhoids. Objective: The aim of this study was to explore the Active Ingredients of Cortex phellodendri in the Treatment of hemorrhoids and Its Mechanism. Study Design: We analyzed Active components and target genes of Cortex phellodendri in the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform. We then searched the GeneCards database for target genes related to hemorrhoids and the intersection of these genes with the active components of Cortex phellodendri. Target genes related to hemorrhoids were taken as common potential target genes of Cortex phellodendri, which could act on hemorrhoids. Using the R programming language, we drew a Venn map of these common potential target genes. The “component–target gene–disease” network of Cortex phellodendri in the treatment of hemorrhoids was established using Cytoscape software version 3.7.1; the protein–protein interaction (PPI) network was constructed in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. With the help of R and Perl languages, we performed gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of potential target genes of Cortex phellodendri in the treatment of hemorrhoids. Results: We extracted a total of 10 active components from Cortex phellodendri, including quercetin and rutaecarpine and so on, as well as 29 potential target genes for hemorrhoids. According to the Degree ranking in Cytoscape3.7.1 software, the top 10 potential target genes were interleukin-6 (IL-6), CCL2, CXCL8, MMP9, vascular endothelial growth factor A (VEGFA), Myc, IL-10, ICAM1, MMP2, and MMP3. Pathway enrichment mainly involved signaling pathways such as advanced glycation end products and receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications, hypoxia-inducible factor 1 (HIF-1), IL-17, and Relaxin. Conclusion: Based on network pharmacology, Cortex phellodendri is expected to be mined as a candidate Traditional Chinese Medicine (TCM) for the treatment of hemorrhoids. Its mechanism for treating this disease operates via multiple components and pathways. This study provides the basic theory and the basis for further research.
VL  - 8
IS  - 6
ER  -

Copy | Download