Herbal medicine AnoSpray suppresses proinflammatory cytokines COX‑2 and RANTES in the management of hemorrhoids, acute anal fissures and perineal wounds

Porwal,Ashwin; Kundu,Gopal C.; Bhagwat,Gajanan; Butti,Ramesh

doi:10.3892/etm.2021.11009

Herbal medicine AnoSpray suppresses proinflammatory cytokines COX‑2 and RANTES in the management of hemorrhoids, acute anal fissures and perineal wounds

Authors:
- Ashwin Porwal
- Gopal C. Kundu
- Gajanan Bhagwat
- Ramesh Butti
View Affiliations

Affiliations: Healing Hands Clinic, Pune, Maharashtra 411001, India, Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, Pune, Maharashtra 411007, India, R&D Center, Healing Hands & Herbs Pvt. Ltd., Pune, Maharashtra 411002, India
Published online on: November 25, 2021 https://doi.org/10.3892/etm.2021.11009
Article Number: 86
Copyright: © Porwal et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hemorrhoids, anal fistula and fissure are common anorectal complications. Anorectal diseases are associated with severe pain, inflammation, swelling, itching and bleeding. These diseases may be managed with different medical treatments or surgical procedures, depending on their severity. Surgical procedures, however, are highly invasive and are associated with higher costs and the possibility of recurrence. In addition, surgical removal of fistula‑in‑ano leads to the formation of perineal wounds. Therefore, developing therapeutic interventions that are effective in alleviating inflammation and pain are desirable for the effective management of anorectal diseases. Herbal compounds have previously been indicated to suppress inflammation and pain in different pathological conditions. The aim of the present study was to examine the effects elicited by a polyherbal formulation, AnoSpray^®, on the migration of inflammatory cells and on the expression of inflammatory cytokines in anorectal diseases. The effect of AnoSpray on cell viability and migration was studied using MTT and wound‑migration assays, respectively. Furthermore, the effects of AnoSpray on the expression of the inflammatory cytokines regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and VEGF, as well as on cyclooxygenase‑2 (COX)‑2, were investigated using western blot analysis. The expression of RANTES and COX‑2 in human hemorrhoid specimens was also analyzed to corroborate the in vitro findings. The results obtained revealed that AnoSpray did not exhibit any cytotoxic effects; however, it did lead to a significant suppression in the migration of RAW 264.7 and BJ cells. Furthermore, the results suggested that AnoSpray suppressed the expression of the inflammatory cytokines RANTES and VEGF, and also the expression of COX‑2. In addition, RANTES and COX‑2 were significantly downregulated in the clinical specimens of AnoSpray‑treated hemorrhoids compared with the controls. Taken together, the results of the present study suggested that AnoSpray may be a potential therapeutic agent in the treatment of bleeding hemorrhoids, anal fissures and perineal wounds.

View Figures

View References

1	Foxx-Orenstein AE, Umar SB and Crowell MD: Common anorectal disorders. Gastroenterol Hepatol (NY). 10:294–301. 2014.PubMed/NCBI
2	Hollingshead JR and Phillips RK: Haemorrhoids: Modern diagnosis and treatment. Postgrad Med J. 92:4–8. 2016.PubMed/NCBI View Article : Google Scholar
3	Mott T, Latimer K and Edwards C: Hemorrhoids: Diagnosis and treatment options. Am Fam Physician. 97:172–179. 2018.PubMed/NCBI
4	Guindic LC: Treatment of uncomplicated hemorrhoids with a Hemor-Rite^® cryotherapy device: A randomized, prospective, comparative study. J Pain Res. 7:57–63. 2014.PubMed/NCBI View Article : Google Scholar
5	Lorenzo-Rivero S: Hemorrhoids: Diagnosis and current management. Am Surg. 75:635–642. 2009.PubMed/NCBI
6	Sun Z and Migaly J: Review of hemorrhoid disease: Presentation and management. Clin Colon Rectal Surg. 29:22–29. 2016.PubMed/NCBI View Article : Google Scholar
7	Chong PS and Bartolo DC: Hemorrhoids and fissure in ano. Gastroenterol Clin North Am. 37:627–644, ix. 2008.PubMed/NCBI View Article : Google Scholar
8	Jacobs D: Clinical practice. Hemorrhoids. N Engl J Med. 371:944–951. 2014.PubMed/NCBI View Article : Google Scholar
9	Riss S, Weiser FA, Schwameis K, Riss T, Mittlböck M, Steiner G and Stift A: The prevalence of hemorrhoids in adults. Int J Colorectal Dis. 27:215–220. 2012.PubMed/NCBI View Article : Google Scholar
10	Lohsiriwat V: Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 18:2009–2017. 2012.PubMed/NCBI View Article : Google Scholar
11	Morgado PJ, Suárez JA, Gómez LG and Morgado PJ Jr: Histoclinical basis for a new classification of hemorrhoidal disease. Dis Colon Rectum. 31:474–480. 1988.PubMed/NCBI View Article : Google Scholar
12	Han W, Wang ZJ, Zhao B, Yang XQ, Wang D, Wang JP, Tang XY, Zhao F and Hung YT: Pathologic change of elastic fibers with difference of microvessel density and expression of angiogenesis-related proteins in internal hemorrhoid tissues. Zhonghua Wei Chang Wai Ke Za Zhi. 8:56–59. 2005.PubMed/NCBI(In Chinese).
13	Yoon SO, Park SJ, Yun CH and Chung AS: Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biochem Mol Biol. 36:128–137. 2003.PubMed/NCBI View Article : Google Scholar
14	Zagriadskiĭ EA, Bogomazov AM and Golovko EB: Conservative treatment of hemorrhoids: Results of an observational multicenter study. Adv Ther. 35:1979–1992. 2018.PubMed/NCBI View Article : Google Scholar
15	Cerato MM, Cerato NL, Passos P, Treigue A and Damin DC: Surgical treatment of hemorrhoids: A critical appraisal of the current options. Arq Bras Cir Dig. 27:66–70. 2014.PubMed/NCBI View Article : Google Scholar
16	Santos GD, Coutinho CP, Meyer MM, Sampaio DV and Cruz GM: Surgical complications in 2,840 cases of hemorrhoidectomy by Milligan-Morgan, Ferguson and combined techniques. J Coloproctol (Rio J). 32:271–290. 2012.
17	Higuero T: Update on the management of anal fissure. J Visc Surg. 152 (Suppl 2):S37–S43. 2015.PubMed/NCBI View Article : Google Scholar
18	Villalba H, Villalba S and Abbas MA: Anal fissure: A common cause of anal pain. Perm J. 11:62–65. 2007.PubMed/NCBI View Article : Google Scholar
19	Notaras MJ: Anal fissure and stenosis. Surg Clin North Am. 68:1427–1440. 1988.PubMed/NCBI View Article : Google Scholar
20	Tranqui P, Trottier DC, Victor C and Freeman JB: Nonsurgical treatment of chronic anal fissure: Nitroglycerin and dilatation versus nifedipine and botulinum toxin. Can J Surg. 49:41–45. 2006.PubMed/NCBI
21	Nottingham JM and Rentea RM: Anal Fistulotomy (Seton Placement). In: StatPearls. StatPearls Publishing, Treasure Island, FL, 2020.
22	Gardner IH, Siddharthan RV and Tsikitis VL: Benign anorectal disease: Hemorrhoids, fissures, and fistulas. Ann Gastroenterol. 33:9–18. 2020.PubMed/NCBI View Article : Google Scholar
23	Sharma RK and Parashar A: The management of perineal wounds. Indian J Plast Surg. 4:352–363. 2012.PubMed/NCBI View Article : Google Scholar
24	Whiteford MH: Perianal abscess/fistula disease. Clin Colon Rectal Surg. 20:102–109. 2007.PubMed/NCBI View Article : Google Scholar
25	Bullard KM, Trudel JL, Baxter NN and Rothenberger DA: Primary perineal wound closure after preoperative radiotherapy and abdominoperineal resection has a high incidence of wound failure. Dis Colon Rectum. 48:438–443. 2005.PubMed/NCBI View Article : Google Scholar
26	Musters GD, Sloothaak DA, Roodbeen S, van Geloven AA, Bemelman WA and Tanis PJ: Perineal wound healing after abdominoperineal resection for rectal cancer: A two-centre experience in the era of intensified oncological treatment. Int J Colorectal Dis. 29:1151–1157. 2014.PubMed/NCBI View Article : Google Scholar
27	Althumairi AA, Canner JK, Gearhart SL, Safar B, Sacks J and Efron JE: Predictors of perineal wound complications and prolonged time to perineal wound healing after abdominoperineal resection. World J Surg. 40:1755–1762. 2016.PubMed/NCBI View Article : Google Scholar
28	Christian CK, Kwaan MR, Betensky RA, Breen EM, Zinner MJ and Bleday R: Risk factors for perineal wound complications following abdominoperineal resection. Dis Colon Rectum. 48:43–48. 2005.PubMed/NCBI View Article : Google Scholar
29	Artioukh DY, Smith RA and Gokul K: Risk factors for impaired healing of the perineal wound after abdominoperineal resection of rectum for carcinoma. Colorectal Dis. 9:362–367. 2007.PubMed/NCBI View Article : Google Scholar
30	Chang CC, Lan YT, Jiang JK, Chang SC, Yang SH, Lin CC, Lin HH, Wang HS, Chen WS, Lin TC and Lin JK: Risk factors for delayed perineal wound healing and its impact on prolonged hospital stay after abdominoperineal resection. World J Surg Oncol. 17(226)2019.PubMed/NCBI View Article : Google Scholar
31	Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, et al: Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol Adv. 33:1582–1614. 2015.PubMed/NCBI View Article : Google Scholar
32	Ibrahim N', Wong SK, Mohamed IN, Mohamed N, Chin KY, Ima-Nirwana S and Shuid AN: Wound healing properties of selected natural products. Int J Environ Res Public Health. 15(2360)2018.PubMed/NCBI View Article : Google Scholar
33	Santana FP, Pinheiro NM, Mernak MI, Righetti RF, Martins MA, Lago JH, Lopes FD, Tibério IF and Prado CM: Evidences of herbal medicine-derived natural products effects in inflammatory lung diseases. Mediators Inflamm. 2016(2348968)2016.PubMed/NCBI View Article : Google Scholar
34	Llorián-Salvador M and González-Rodríguez S: Painful understanding of VEGF. Front Pharmacol. 9(1267)2018.PubMed/NCBI View Article : Google Scholar
35	Sobolewski C, Cerella C, Dicato M, Ghibelli L and Diederich M: The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol. 2010(215158)2010.PubMed/NCBI View Article : Google Scholar
36	Cragg GM and Newman DJ: Natural products: A continuing source of novel drug leads. Biochim Biophys Acta. 1830:3670–3695. 2013.PubMed/NCBI View Article : Google Scholar
37	Porwal A, Gandhi P and Kulkarni D: An open label, randomized, comparative, parallel group, single center study to evaluate safety and efficacy of Ano spray in a comparison with betadine solution application in acute perineum wounds. Ayushdhara. 4:1409–1412. 2017.
38	Kumar D, Haldar S, Gorain M, Kumar S, Mulani FA, Yadav AS, Miele L, Thulasiram HV and Kundu GC: Epoxyazadiradione suppresses breast tumor growth through mitochondrial depolarization and caspase-dependent apoptosis by targeting PI3K/Akt pathway. BMC Cancer. 18(52)2018.PubMed/NCBI View Article : Google Scholar
39	Chakraborty G, Jain S and Kundu GC: Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms. Cancer Res. 68:152–161. 2008.PubMed/NCBI View Article : Google Scholar
40	Kumar D, Kumar S, Gorain M, Tomar D, Patil HS, Radharani NN, Kumar TV, Patil TV, Thulasiram HV and Kundu GC: Notch1-MAPK signaling axis regulates CD133⁺ cancer stem cell-mediated melanoma growth and angiogenesis. J Invest Dermatol. 136:2462–2474. 2016.PubMed/NCBI View Article : Google Scholar
41	Landén NX, Li D and Ståhle M: Transition from inflammation to proliferation: A critical step during wound healing. Cell Mol Life Sci. 73:3861–3885. 2016.PubMed/NCBI View Article : Google Scholar
42	Guo S and Dipietro LA: Factors affecting wound healing. J Dent Res. 89:219–229. 2010.PubMed/NCBI View Article : Google Scholar
43	Chen S and Yu Q: A new theory on the cause of anal fissure-impaction theory. J Coloproctol (Rio J). 40:321–325. 2020.
44	Segre D, Dal Corso HM, Landra M and Giuffrida MC: Management of the unhealed perineal wound. In: Inflammatory bowel disease and familial adenomatous polyposis. Springer, Milano, pp463-472, 2006.
45	Bertone AL: Principles of wound healing. Vet Clin North Am Equine Pract. 5:449–463. 1989.PubMed/NCBI View Article : Google Scholar
46	Derakhshan AR: Natural treatments for fissure in ano used by traditional persian scholars, Razi (Rhazes) and Ibn Sina (Avicenna). J Evid Based Complementary Altern Med. 22:324–333. 2017.PubMed/NCBI View Article : Google Scholar
47	Dey YN, Wanjari MM, Kumar D, Lomash V and Jadhav AD: Curative effect of Amorphophallus paeoniifolius tuber on experimental hemorrhoids in rats. J Ethnopharmacol. 192:183–191. 2016.PubMed/NCBI View Article : Google Scholar
48	Azeemuddin M, Viswanatha GL, Rafiq M, Thippeswamy AH, Baig MR, Kavya KJ, Patki PS and Shyam R: An improved experimental model of hemorrhoids in rats: Evaluation of antihemorrhoidal activity of an herbal formulation. ISRN Pharmacol. 2014(530931)2014.PubMed/NCBI View Article : Google Scholar
49	Wojdasiewicz P, Poniatowski ŁA and Szukiewicz D: The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm. 2014(561459)2014.PubMed/NCBI View Article : Google Scholar
50	Sprague AH and Khalil RA: Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol. 78:539–552. 2009.PubMed/NCBI View Article : Google Scholar
51	Fitzgerald SM, Lee SA, Hall HK, Chi DS and Krishnaswamy G: Human lung fibroblasts express interleukin-6 in response to signaling after mast cell contact. Am J Respir Cell Mol Biol. 30:585–593. 2004.PubMed/NCBI View Article : Google Scholar
52	Arango Duque G and Descoteaux A: Macrophage cytokines: Involvement in immunity and infectious diseases. Front Immunol. 5(491)2014.PubMed/NCBI View Article : Google Scholar
53	Lohsiriwat V: Treatment of hemorrhoids: A coloproctologist's view. World J Gastroenterol. 21:9245–9252. 2015.PubMed/NCBI View Article : Google Scholar
54	Mounsey AL, Halladay J and Sadiq TS: Hemorrhoids. Am Fam Physician. 84:204–210. 2011.PubMed/NCBI
55	Bhardwaj R and Parker MC: Modern perspectives in the treatment of chronic anal fissures. Ann R Coll Surg Engl. 89:472–478. 2007.PubMed/NCBI View Article : Google Scholar
56	Dias DA, Urban S and Roessner U: A historical overview of natural products in drug discovery. Metabolites. 2:303–336. 2012.PubMed/NCBI View Article : Google Scholar
57	Thakur R, Jain N, Pathak R and Sandhu SS: Practices in wound healing studies of plants. Evid Based Complement Alternat Med. 2011(438056)2011.PubMed/NCBI View Article : Google Scholar
58	Chandel RS and Rastogi RP: Triterpenoid saponins and sapogenins: 1973-1978. Phytochemistry. 19:1889–1908. 1980.
59	Harbone JB: Phytochemical methods: A guide to modern techniques of plants analysis. Fakenham Press Limited: New York, NY, USA, 1973.
60	Tsala DE, Amadou D and Habtemariam S: Natural wound healing and bioactive natural products. Phytopharmacology. 4:532–560. 2013.
61	Ricciotti E and FitzGerald GA: Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 31:986–1000. 2011.PubMed/NCBI View Article : Google Scholar
62	Merecz-Sadowska A, Sitarek P, Śliwiński T and Zajdel R: Anti-inflammatory activity of extracts and pure compounds derived from plants via modulation of signaling pathways, especially PI3K/AKT in macrophages. Int J Mol Sci. 21(9605)2020.PubMed/NCBI View Article : Google Scholar
63	Potdar D, Hirwani RR and Dhulap S: Phyto-chemical and pharmacological applications of Berberis aristata. Fitoterapia. 83:817–830. 2012.PubMed/NCBI View Article : Google Scholar
64	Acharya N, Acharya S, Shah U, Shah R and Hingorani L: A comprehensive analysis on Symplocos racemosa Roxb.: Traditional uses, botany, phytochemistry and pharmacological activities. J Ethnopharmacol. 181:236–251. 2016.PubMed/NCBI View Article : Google Scholar
65	Shenoy RR, Sudheendra AT, Nayak PG, Paul P, Kutty NG and Rao CM: Normal and delayed wound healing is improved by sesamol, an active constituent of Sesamum indicum (L.) in albino rats. J Ethnopharmacol. 133:608–612. 2011.PubMed/NCBI View Article : Google Scholar
66	Rameshwar V, Kishor D, Tushar G, Siddharth G and Sudarshan G: A pharmacognostic and pharmacological overview on Bombax ceiba. Sch Acad J Pharm. 3:100–107. 2014.
67	Ananthakrishnan R and Rameshkumar KB: Phytochemicals and bioactivities of Garcinia indica (thouars) choisy-a review. Divers Garcinia Species West Ghats: Phytochem Perspect. 142:151–161. 2016.
68	Sen PK and Garg S: Wound repair and regenerating effect of ethyl acetate soluble fraction of ethanolic extract of Cinnamomum camphora leaves in wistar albino rats. J Drug Deliv Ther. 9:1173–1176. 2019.
69	Modarresi M, Farahpour MR and Baradaran B: Topical application of Mentha piperita essential oil accelerates wound healing in infected mice model. Inflammopharmacology. 27:531–537. 2019.PubMed/NCBI View Article : Google Scholar