{"paper_id":"585e5201-1c26-42b4-97fe-4a93e573fdb5","body_text":"DOI: 10.55522/jmpas.V12I1.4232                                                                                                                                                                        ISSN NO. 2320 –7418            \n    \n \nJournal of medical pharmaceutical and allied sciences , Volume 12 – Issue 1, 4232, January – February 2023, Pages – 5582 -  5587                                 5582 \n \n \n \nReview article \nPhaleria macrocarpa for Endometriosis Treatment: A Review \n \nMaharani Maharani*1,2, Lia Lajuna1, Cut Yuniwati1, Nora Veri3, Sutrisno Sutrisno4,5 \n \n \n \n1 Department of Midwifery, Polytechnic of Health-Ministry of Health, Aceh, Indonesia  \n2 Doctoral Program of Medical Sciences, Faculty of Medicine, University of Brawijaya, Malang, East Java, Indonesia  \n3 Department of Midwifery, Polytechnic of Health-Ministry of Health, Aceh, Langsa, Indonesia  \n4 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Faculty of Medicine,  \nUniversity of Brawijaya/ Saiful Anwar General Hospital, Malang, East  Java, Indonesia \n5 Department of Midwifery, Magister of Midwifery, Faculty of Medicine, University of Brawijaya, Malang, East Java, Indonesia  \n \nABSTRACT \nAround 5—10% women in their productive age could suffer from endometriosis, a condition where viable endometrial tissue is present \noutside the uterine cavity. This disease could progress into ovarian cancer and infertility with long-lasting chronic pain. Thus, innovation for safe \nand efficacious management of this disease is urgent. Exploring the abilities of medicinal plants for endometriosis therapy is quite promising. Of \nwhich, Phaleria macrocarpa has been suggested as a strong candidate for the therapy. This review begins with explanations of endometriosis; its \naetiology and pathobiology. Thereafter, we present the medicinal properties of P. macrocarpa for being anti-inflammatory, anti-angiogenesis, and \nanti-proliferation. Results from pre-clinical studies and an ongoing trial of P. macrocarpa as a therapy for endometriosis were also discussed in \nthis review. Future study will explore the activity of this plant extracts against hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth \nfactor (VEGF), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (BAX). \nKeywords: Anti-angiogenesis, anti-inflammation, anti-proliferation, endometrium, Phaleria macrocarpa \nReceived - 30-08-2022, Accepted- 21-01-2023 \nCorrespondence: Maharani Maharani  maharani@poltekkesaceh.ac.id, Orcid Id: 0000-0002-5021-1274 \nDepartment of Midwifery, Polytechnic of Health-Ministry of Health, Aceh, Indonesia.\n \nINTRODUCTION \nPlant with medicinal properties have been used as \nintegrative medicine for multiple diseases, even it can provide \nsignificant aid tomodern medicine. For example, during the ongoing \nSARS-CoV-2 pandemic, natural products are intensely studied for \ntheir antiviral abilities [1]. This incl udes the orally bioavailable \nmolnupiravir, which was inspired by uridine, a small compound \nfound in human plasma [1, 2]. Extracts from the plants of Annonaceae \nspp. could work synergistically with commercially available \nantibiotics against multiple drugs resistant bacteria [3]. Type 2 \ndiabetes mellitus and multiple cancers could also be treated  \n \nwith medicinal plants through various molecular targets [4-7]. Among \nthe medicinal plants, Phaleriamacrocarpahas been recognized for \nits potent pharmacological properties, including but not limited to \nthe treatments of asthma, dysentery, rheumatoid arthritis, and \ncutaneous diseases [8]. Research from the last few years revealed that \nfractions of P. macrocarpa extracts could be useful in the \nmanagement of a proliferative endometrium [9]. Even in 201 3, a  \nphase 2/3  clinical trial has started to evaluate the efficacy of \nbioactive P. macrocarpa  fraction against endometriosis \n(NCT01942122) [10]. \nFigure 1: Graphical Abstract\n \n \n\n\nDOI: 10.55522/jmpas.V12I1.4232                                                                                                                                                                        ISSN NO. 2320 –7418            \n    \n \nJournal of medical pharmaceutical and allied sciences , Volume 12 – Issue 1, 4232, January – February 2023, Pages – 5582 -  5587                                 5583 \nIn 2010, the incidence of endometriosis was recorded at 5 —10% \namong reproductive women, while its prevalence could increase to \n20—50% in women with infertilityand chronic pelvic pain.  The \ncases were predominated by individuals aged between 25 and 30 \nyears old [11]. Clinical features of endometriosis include dyspareunia, \ndysuria, chronic abdominal pain, pelvic pain, pain during defecation, \nand menstrual pain [12]. The pain occurs due to the excessive blood \noutflow into the pelvic cavity stimulating peritoneum and uterine \ncontractions following the increased levels of locally secreted \nprostaglandins in endometrial tissue [12]. Women with endometriosis \ncould have the disease progression into ovarian cancer and infertility \nwith long lasting chronic pain  [13]. In this light, this review article \nprovides the insights on the aetiology and pathobiology of \nendometriosis along with the potential of P. macrocarpa to act as a \ntherapy for endometriosis. \nAetiology and pathobiology of endometriosis \nEndometriosis is a gynaecological disorder that is benign \nbut has the potential for malignancy [14]. A report stated that the \npresence of this disease is characterized by the presence  of viable \nendometrial tissue outside the uterine cavity [15]. Endometriosis is \nconsidered a cancer precursor and a risk factor for ovarian cancer. \nThere is a similar pattern in terms of  local invasion, spread and \nresponsiveness to estrogen in inducing growth signals in \nendometriosis and ovarian cancer [16]. The cause of endometriosis is \nnot known with certainty and is very complex and varies from on e \ncase to another. \nRetrograde theory \nRetrograde theory was first reported by by John Sampson \nin 1927, where he describes the endometrial cells shedding along \nwith menstrual blood returned to the peritoneal cavity and stimulate \nperitoneal metaplasia to inva de, implant and proliferate . \nFurthermore, it stimulates angiogenesis, where in endometriosis \nlesions are often found to have increased vascularity [15]. \nImmunology theory \nIn patients with endometriosis, there is an immune system \ndisorder characterized by reduced T cells and natural killer cell \nresponses [17]. The immune system of patients with endometriosis \nshows an increase in the humoral immune response and macrophage \nactivity [10]. The peritoneum reacts to menstrual blood fragments in \nthe form of cessation of adhesion of viable endometrial cells to the \nperitoneum, which then transforms into endometrial lesions. \nEndometriotic lesions secrete haptoglobulin which causes \nmacrophages instead of  acting as a cleanser to remove ectopic \nendometrial cells, but inhibiting their cleaning function [14]. \nGenetic theory \nEndometriosis has been observed to be closely associated  \nwith hereditary medical history.The  risk 7 —10 times higher in \nwomen with hereditary or family history of endometriosis in \ncomparison to those without. Some families may carry a gene that \nallows abnormal cells to survive and grow in an ectopic pelvic \ncavity. However, little progress has been  made in identifying the \ngenetic variants that play a role in endometriosis [14]. \nHormonal theory \nThe concept of endometriosis as an estrogen dependent \ndisorder is supported by molecular evidence. In endometrium, \nincreased and decreased levels were found on aromatase and 17β-\nhydroxysteroid dehydrogenase (17β–HSD) type 2, respectively [12]. \nThe formation of estradiol in endometrial tissue occurs in 2 ways, \nnamely the aromatase pathway by converting ovarian \nandrostenedione to estrone (E1), and through 17β-HDS type 1, E1 is \nconverted to significantly estrogenic E2.  The next is sulfatase \npathway, where sulfatase converts estrogen sulfate into E1, which \nwill then be activated by 17β-HDS type 1 into E2[14]. E2 stimulates \nthe production of PGE2 which stimulates further aromatase activity. \nAn increase in the enzyme 20α-hydroxysteroid dehydrogenase will \ninactivate progesterone by converting it to a less active form, which \nhas a low affinity for the progesterone receptor. Changes in \nprogesterone cause local E2 effects to be more dominant in \nendometriosis. Hormonal changes can affect the ability of \nendometrial cells, mesothelium tissue to proliferate, and/or evade the \nimmune system-mediated cleansing system [18]. \nCoelomic metaplasia theory \nBased on a report, the coelomic epithelium is found to be \nthe origin of endometrial and peritoneal cells, allowing the \ntransformation of one cell type into another that is affected by \ninflammation from the flow of refluxed menstrual blood [19]. Certain \ncells are pluripotent which when stimulated could change their shape \ninto different cell types. This may explain the finding of \nendometriosis in women without menstrual cycles and in men. \nPhaleria macrocarpa for endometriosis treatment \nPhytochemical profile of Phaleria macrocarpa \nAlkaloids, flavonoids, terpenoids, and saponins are usually found in \nP. macrocarpa. In detail, some of the phytocompounds identified in \nP. macrocarpa have been presented in  Table 1. Phytocompounds \nthemselves have been evaluated for their efficacies against \nendometriosis [20]. Phalerin and mahkoside A are identical in P. \nmacrocarpa, in which these compounds have been reported in the \nmethanol extract [21], aqueous extract [22], and more others [23]. A \nphytosterol, kaempferol, was also found in P. macrocarpa [24]. These \nphytocompounds could act as anti-inflammation [25], analgesic, anti-\nproliferation [26], and anti-angiogenesis [27].  \nAnti-inflammatory properties of Phaleria macrocarpa \nInflammation reaction occurs during the endometriosis \ncould be reduced by the extracts of P. macrocarpa. Several studies \nhave shown anti-inflammatory activities of P. macrocarpa extracts \n(Table 2). The anti -inflammatory properties have been observed \nthrough the swelling reductions [24, 31]. \n \n\nDOI: 10.55522/jmpas.V12I1.4232                                                                                                                                                                        ISSN NO. 2320 –7418            \n    \n \nJournal of medical pharmaceutical and allied sciences , Volume 12 – Issue 1, 4232, January – February 2023, Pages – 5582 -  5587                                 5584 \nTable 1: Phytocompounds identified in Phaleria macrocarpa \nYear \n[Ref] \nSample and extraction Phytochemical content \n2022 \n[28] \nFruits were macerated in ethanol 96%  Alkaloids, glycosides, flavonoids, tannins, saponins  \n2022 \n[29] \nPeel extraction with ultrasound assistance Phenolic compounds, tannins, saponins, and alkaloids  \n2021 [9] Hexane and n-butanol partition from the fruit ethanol extract  Eriodictyol, glycitin, 5-O-methylgenistein, (+)-catechin 7-O-beta-D-xyloside, (-)-\n8-prenylnaringenin, (±)-naringenin \n2016[24] Fruits and seeds were macerated using ethanol 70% Kaempferol-3-O-β-D-glucoside, gallic acid, 29-norcucurbitacin, fevicordin A and \nfevicordin A glucosides, and Cucurbitacins . \n2020[21] The leaves were macerated in methanol 80%  Mahkoside A, dodecanoic acid, palmitic acid, des -acetyl flavicordin-A, \nflavicordin-A, flavicordin-D,Flavicordin-A glucoside, ethyl stearate, and lignans \nsucrose. \n2020[23] Methanolic maceration of different parts of the fruits Phalerin, gallic acid, icaricide C, mangiferin, mahkoside A, dodecanoic acid, \npalmitic acid, desacetylflavicordin -A, flavicordin-A, flavicordin-D, flavicordin-A \nglucoside, ethyl stearate, lignans, alkaloids and saponins  \n2019[30] Maceration of the fruit using ethanol 95%  Sterols, triterpenes, flavonoids, alkaloids, saponins, glycosides, and tannins. \n2020[22] Ultrasonic-assistedextraction of the leaves using methanol  Phalerin \n \nPro-inflammatory factors such as interferon -gamma-γ \n(IFN-γ), inducible nitric oxide synthase (iNOS), malondialdehyde \n(MDA), and tumor necrosis factor -α (TNF -α) could be reduced \nfollowing the administration of P. macrocarpa extracts [32, 33] . \nMeanwhile, the increase of endogenous antioxidant such as \nsuperoxide dismutase (SOD) and glutathione -s-transferase (GST) \nwere observed in the treatment group. \nTable 2: Anti-inflammatory properties of Phaleria macrocarpa \nYear[Ref] Sample and extraction Anti-inflammatory activities \n2016[24] Fruits and seeds extract with ethanol 70% Reduce inflammation or swellingeffect  \n2020[23] Methanolic maceration of different parts of the fruits  Inhibit the cascade of inflammation pathway  \n2018[32] Subcritical water extraction of the fruits Reducing MDA, TNF-α, and TGF-β1 \n2016 [34] Fruits maceration using ethanol 95%  Upregulation of GST and SOD \n2011 [33] The fruits were reflux-extracted using methanol  Reduction iNOS synthesis via lipopolysaccharide and IFN -γ \n2015 [31] Combination of Nigella sativa seed and Phaleria macrocarpa fruits \n(1:3) was percolated using water.  \nReduction of paw edema in mice model  \nGST: Glutathione-s-transferase, IFN-γ: Interferon-gamma-γ, iNOS: Inducible nitric oxide synthase, MDA: Malondialdehyde, \nSOD: Superoxide dismutase, TNF-α: Tumor necrosis factor-α, TGF- β1: Transforming growth fator-β1 \n \nAnti-angiogenic and antiproliferativeproperties of Phaleria \nmacrocarpa \nExtracts from P. macrocarpa have been studied for their \nabilities against cell proliferation, where the details of the findings \nhave been presented in Table 3. Its leaves have been found to reduce \ntumor and MCF-7 cells [35, 36]. The leaf extract could also enhance \nthe expression of Caspase-3 which is responsible for cell apoptosis \n[37]. Fruits samples have been reported to decrease the number of new \nblood vessel , suppress retinoblastoma tumor, and prevent liver \nfibrosis [20, 38, 39]. The ethanolic extract from P. macrocarpa ethanolic \nextract was reported for its ability in inhibiting colorectal cancer \nconcomitant to COX-2 downregulation [40]. \nTable 3: Anti-angiogenic and antiproliferative properties of Phaleria macrocarpa \nYear[Ref] Sample and extraction Anti-angiogenic activities \n2022[35] Maceration of the leaves using ethanol 70% Reducing tumor volume \n2019[40] Stem barks maceration using ethanol  Inhibiting colorectal cancer cell line HCT116 via COX -2 downregulation \n2014[38] \nEthanolic \nextract  ofPhaleria  macrocarpa \nethanolic \nextract  ofPhaleria  macrocarpa \nethanolic \nextract  ofPhaleria  macrocarpa \nethanolic \nextract  ofPhaleria  macrocarpa \nFruits soxhletation using ethanol 96%  \nDecreasing the number of new blood vessels  \n2021 [37] Leaf powder was macerated with ethanol 70%. Upregulation of Caspase-3 \n2020[39] P. macrocarpa fruit sample of crude ethanol extract Reducing MCM-B2 cell proliferation \n2017[20] Ethyl acetate: water fractionof the fruits (DLBS1425) Attenuating human retinoblastoma tumor cells Y -79 via cyclin E \n2017[36] The leaves were macerated using methano l Inhibitingbreast cancer MCF-7 cell \n2018[32] The fruits were extracted using subcritical water  Preventing liver fibrosis \nCOX-2: Cyclooxygenase-2 \nPreclinical evidence with on-going clinical trial \nPreclinical studies have specifically investigated the \nbioactive natural products from P. macrocarpa for endometriosis \ntreatment (Table 4). An in-vivo studies using Mus muculussuggested \nthatthe flavonoid isolate from P. macrocarpa could suppress the \ngrowth of peritoneal tissue [9]. Moreover, the isolate could improve \n\nDOI: 10.55522/jmpas.V12I1.4232                                                                                                                                                                        ISSN NO. 2320 –7418            \n    \n \nJournal of medical pharmaceutical and allied sciences , Volume 12 – Issue 1, 4232, January – February 2023, Pages – 5582 -  5587                                 5585 \ngranulomas and increase the apoptotic index  [9]. In an in vitro \nsetting, the DLBS1442 was reported to inhibit the angiogenesis and \ncell migration [41]. Other hormones and pro -inflammatory factors \ninvolved during the endometriosis was also attenuated by \nDLBS1442 [41]. DLBS1442 itself is a bioactive fraction derived from \nthe methanolic extract of P. macrocarpa [42]. An on-going clinical \ntrial (phase II/III) even has been started to evaluate the efficacy of \nDLBS1442 for endometriosis management (NCT01942122). Based \non the interim results, the DLBS could significantly reduce the \nendometrial cells (Table 4). None of the preclinical research of P. \nmacrocarpa has studied on hypoxia inducible factor -1α (HIF-1α), \nvascular endothelial growth factor (VEGF),B-cell lymphoma 2 (Bcl-\n2), and Bcl-2-associated X protein (BAX) as parameters for \nendometriosis treatment, regardless their importance in the disease. \nHence, future study should explore the activity of P. macrocarpa \nagainst the aforementioned molecules. \nTable 4: Preclinical evidence of the potential of Phaleria macrocarpa in treating endometriosis \nStudy design,Year [Ref] Sample Subject Results \nIn vivo, 2021 [9] Flavonoid \nisolate \nFemale Mus musculus implanted with myometrial \nand endometrial tissues under immunodeficient \ncondition \nSuppressed the growth of peritoneal tissue, i mproved \ngranulomas, and higher apoptotic index. \nIn silico, 2020 [43] DLBS1442 Metabolomic studies were performed on DLBS1442 \nconstituents against progesterone receptor  \nGlyceryl pentacosanoate contained in DLBS1442 \notentially acts as progesterone receptor agonist  \nIn vitro, 2015 [41] DLBS1442 Human endometrial epithelial cell lineRL95 -2 \nInhibition of angiogenesis and cell migration.  \nUpregulation of progesterone receptor and \ndownregulation of estrogen receptor. Inhibition \neicosanoid signaling pathway via downregulations of \nNFκB and iNOS \nNFκB: Nuclear factor kappa B, iNOS: Inducible nitric oxide synthase \nCONCLUSIONS \nP. macrocarpa is potential for treating endometriosis by \ntargeting multiple molecular targets. The extracts of this plant could \nact as anti -inflammation, anti-angiogenesis, and anti -proliferation. \nComposition of its phytocompounds could be ascribed to the extract \nactivities. The bioactive fractions, named DLBS1442, has entered a \nclinical trial where the updated results show optimism. More \nresearch should be carried out to find a particular isolate that is \npotent against the development of endometrial cells. Our research \ngroup warrants the investigation of the activity of P. macrocarpa \nagainst HIF-1α, VEGF, Bcl-2, and BAX in-vivo. \nREFERENCES \n1. Wang ZL, Yang, 2020. Turning the Tide: Natural Products and \nNatural-Product-Inspired Chemicals as Potential Counters to \nSARS-CoV-2 Infection. 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Journal of Applied \nPharmaceutical Science 10 , Pages-63-69, \nDOI:10.7324/JAPS.202 0.10509. \nHow to cite this article \nMaharani Maharani, Lia Lajuna, Cut Yuniwati, Nora Veri, \nSutrisno Sutrisno, 2023. Phaleria macrocarpa for endometriosis \ntreatment a review. Journal of medical pharmaceutical and allied \nsciences, V 12 - I 1, Pages - 5582 – 5587. DOI: \n10.55522/jmpas.V12I1.4232.","source_license":"CC0","license_restricted":false}