Phaleria macrocarpa for Endometriosis Treatment: A Review

Around 5—10% women in their productive age could suffer from endometriosis, a condition where viable endometrial tissue is present outside the uterine cavity. This disease could progress into ovarian cancer and infertility with long-lasting chronic pain. Thus, innovation for safe and efficacious management of this disease is urgent. Exploring the abilities of medicinal plants for endometriosis therapy is quite promising. Of which, Phaleria macrocarpa has been suggested as a strong candidate for the therapy. This review begins with explanations of endometriosis; its aetiology and pathobiology. Thereafter, we present the medicinal properties of P. macrocarpa for being anti-inflammatory, anti-angiogenesis, and anti-proliferation. Results from pre-clinical studies and an ongoing trial of P. macrocarpa as a therapy for endometriosis were also discussed in this review. Future study will explore the activity of this plant extracts against hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (BAX).

Anti-angiogenesis, anti-inflammation, anti-proliferation, endometrium, Phaleria macrocarpa Received - 30-08-2022, Accepted- 21-01-2023 Correspondence: Maharani Maharani  [email protected], Orcid Id: 0000-0002-5021-1274 Department of Midwifery, Polytechnic of Health-Ministry of Health, Aceh, Indonesia.

Plant with medicinal properties have been used as integrative medicine for multiple diseases, even it can provide significant aid tomodern medicine. For example, during the ongoing SARS-CoV-2 pandemic, natural products are intensely studied for their antiviral abilities [1]. This incl udes the orally bioavailable molnupiravir, which was inspired by uridine, a small compound found in human plasma [1, 2]. Extracts from the plants of Annonaceae spp. could work synergistically with commercially available antibiotics against multiple drugs resistant bacteria [3]. Type 2 diabetes mellitus and multiple cancers could also be treated with medicinal plants through various molecular targets [4-7]. Among the medicinal plants, Phaleriamacrocarpahas been recognized for its potent pharmacological properties, including but not limited to the treatments of asthma, dysentery, rheumatoid arthritis, and cutaneous diseases [8]. Research from the last few years revealed that fractions of P. macrocarpa extracts could be useful in the management of a proliferative endometrium [9]. Even in 201 3, a phase 2/3 clinical trial has started to evaluate the efficacy of bioactive P. macrocarpa fraction against endometriosis (NCT01942122) [10]. Figure 1: Graphical Abstract DOI: 10.55522/jmpas.V12I1.4232 ISSN NO. 2320 –7418 Journal of medical pharmaceutical and allied sciences , Volume 12 – Issue 1, 4232, January – February 2023, Pages – 5582 - 5587 5583 In 2010, the incidence of endometriosis was recorded at 5 —10% among reproductive women, while its prevalence could increase to 20—50% in women with infertilityand chronic pelvic pain. The cases were predominated by individuals aged between 25 and 30 years old [11]. Clinical features of endometriosis include dyspareunia, dysuria, chronic abdominal pain, pelvic pain, pain during defecation, and menstrual pain [12]. The pain occurs due to the excessive blood outflow into the pelvic cavity stimulating peritoneum and uterine contractions following the increased levels of locally secreted prostaglandins in endometrial tissue [12]. Women with endometriosis could have the disease progression into ovarian cancer and infertility with long lasting chronic pain [13]. In this light, this review article provides the insights on the aetiology and pathobiology of endometriosis along with the potential of P. macrocarpa to act as a therapy for endometriosis. Aetiology and pathobiology of endometriosis Endometriosis is a gynaecological disorder that is benign but has the potential for malignancy [14]. A report stated that the presence of this disease is characterized by the presence of viable endometrial tissue outside the uterine cavity [15]. Endometriosis is considered a cancer precursor and a risk factor for ovarian cancer. There is a similar pattern in terms of local invasion, spread and responsiveness to estrogen in inducing growth signals in endometriosis and ovarian cancer [16]. The cause of endometriosis is not known with certainty and is very complex and varies from on e case to another. Retrograde theory Retrograde theory was first reported by by John Sampson in 1927, where he describes the endometrial cells shedding along with menstrual blood returned to the peritoneal cavity and stimulate peritoneal metaplasia to inva de, implant and proliferate . Furthermore, it stimulates angiogenesis, where in endometriosis lesions are often found to have increased vascularity [15]. Immunology theory In patients with endometriosis, there is an immune system disorder characterized by reduced T cells and natural killer cell responses [17]. The immune system of patients with endometriosis shows an increase in the humoral immune response and macrophage activity [10]. The peritoneum reacts to menstrual blood fragments in the form of cessation of adhesion of viable endometrial cells to the peritoneum, which then transforms into endometrial lesions. Endometriotic lesions secrete haptoglobulin which causes macrophages instead of acting as a cleanser to remove ectopic endometrial cells, but inhibiting their cleaning function [14]. Genetic theory Endometriosis has been observed to be closely associated with hereditary medical history.The risk 7 —10 times higher in women with hereditary or family history of endometriosis in comparison to those without. Some families may carry a gene that allows abnormal cells to survive and grow in an ectopic pelvic cavity. However, little progress has been made in identifying the genetic variants that play a role in endometriosis [14]. Hormonal theory The concept of endometriosis as an estrogen dependent disorder is supported by molecular evidence. In endometrium, increased and decreased levels were found on aromatase and 17β- hydroxysteroid dehydrogenase (17β–HSD) type 2, respectively [12]. The formation of estradiol in endometrial tissue occurs in 2 ways, namely the aromatase pathway by converting ovarian androstenedione to estrone (E1), and through 17β-HDS type 1, E1 is converted to significantly estrogenic E2. The next is sulfatase pathway, where sulfatase converts estrogen sulfate into E1, which will then be activated by 17β-HDS type 1 into E2[14]. E2 stimulates the production of PGE2 which stimulates further aromatase activity. An increase in the enzyme 20α-hydroxysteroid dehydrogenase will inactivate progesterone by converting it to a less active form, which has a low affinity for the progesterone receptor. Changes in progesterone cause local E2 effects to be more dominant in endometriosis. Hormonal changes can affect the ability of endometrial cells, mesothelium tissue to proliferate, and/or evade the immune system-mediated cleansing system [18]. Coelomic metaplasia theory Based on a report, the coelomic epithelium is found to be the origin of endometrial and peritoneal cells, allowing the transformation of one cell type into another that is affected by inflammation from the flow of refluxed menstrual blood [19]. Certain cells are pluripotent which when stimulated could change their shape into different cell types. This may explain the finding of endometriosis in women without menstrual cycles and in men. Phaleria macrocarpa for endometriosis treatment Phytochemical profile of Phaleria macrocarpa Alkaloids, flavonoids, terpenoids, and saponins are usually found in P. macrocarpa. In detail, some of the phytocompounds identified in P. macrocarpa have been presented in Table 1. Phytocompounds themselves have been evaluated for their efficacies against endometriosis [20]. Phalerin and mahkoside A are identical in P. macrocarpa, in which these compounds have been reported in the methanol extract [21], aqueous extract [22], and more others [23]. A phytosterol, kaempferol, was also found in P. macrocarpa [24]. These phytocompounds could act as anti-inflammation [25], analgesic, anti- proliferation [26], and anti-angiogenesis [27]. Anti-inflammatory properties of Phaleria macrocarpa Inflammation reaction occurs during the endometriosis could be reduced by the extracts of P. macrocarpa. Several studies have shown anti-inflammatory activities of P. macrocarpa extracts (Table 2). The anti -inflammatory properties have been observed through the swelling reductions [24, 31]. DOI: 10.55522/jmpas.V12I1.4232 ISSN NO. 2320 –7418 Journal of medical pharmaceutical and allied sciences , Volume 12 – Issue 1, 4232, January – February 2023, Pages – 5582 - 5587 5584 Table 1: Phytocompounds identified in Phaleria macrocarpa Year [Ref] Sample and extraction Phytochemical content 2022 [28] Fruits were macerated in ethanol 96% Alkaloids, glycosides, flavonoids, tannins, saponins 2022 [29] Peel extraction with ultrasound assistance Phenolic compounds, tannins, saponins, and alkaloids 2021 [9] Hexane and n-butanol partition from the fruit ethanol extract Eriodictyol, glycitin, 5-O-methylgenistein, (+)-catechin 7-O-beta-D-xyloside, (-)- 8-prenylnaringenin, (±)-naringenin 2016[24] Fruits and seeds were macerated using ethanol 70% Kaempferol-3-O-β-D-glucoside, gallic acid, 29-norcucurbitacin, fevicordin A and fevicordin A glucosides, and Cucurbitacins . 2020[21] The leaves were macerated in methanol 80% Mahkoside A, dodecanoic acid, palmitic acid, des -acetyl flavicordin-A, flavicordin-A, flavicordin-D,Flavicordin-A glucoside, ethyl stearate, and lignans sucrose. 2020[23] Methanolic maceration of different parts of the fruits Phalerin, gallic acid, icaricide C, mangiferin, mahkoside A, dodecanoic acid, palmitic acid, desacetylflavicordin -A, flavicordin-A, flavicordin-D, flavicordin-A glucoside, ethyl stearate, lignans, alkaloids and saponins 2019[30] Maceration of the fruit using ethanol 95% Sterols, triterpenes, flavonoids, alkaloids, saponins, glycosides, and tannins. 2020[22] Ultrasonic-assistedextraction of the leaves using methanol Phalerin Pro-inflammatory factors such as interferon -gamma-γ (IFN-γ), inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and tumor necrosis factor -α (TNF -α) could be reduced following the administration of P. macrocarpa extracts [32, 33] . Meanwhile, the increase of endogenous antioxidant such as superoxide dismutase (SOD) and glutathione -s-transferase (GST) were observed in the treatment group. Table 2: Anti-inflammatory properties of Phaleria macrocarpa Year[Ref] Sample and extraction Anti-inflammatory activities 2016[24] Fruits and seeds extract with ethanol 70% Reduce inflammation or swellingeffect 2020[23] Methanolic maceration of different parts of the fruits Inhibit the cascade of inflammation pathway 2018[32] Subcritical water extraction of the fruits Reducing MDA, TNF-α, and TGF-β1 2016 [34] Fruits maceration using ethanol 95% Upregulation of GST and SOD 2011 [33] The fruits were reflux-extracted using methanol Reduction iNOS synthesis via lipopolysaccharide and IFN -γ 2015 [31] Combination of Nigella sativa seed and Phaleria macrocarpa fruits (1:3) was percolated using water. Reduction of paw edema in mice model GST: Glutathione-s-transferase, IFN-γ: Interferon-gamma-γ, iNOS: Inducible nitric oxide synthase, MDA: Malondialdehyde, SOD: Superoxide dismutase, TNF-α: Tumor necrosis factor-α, TGF- β1: Transforming growth fator-β1 Anti-angiogenic and antiproliferativeproperties of Phaleria macrocarpa Extracts from P. macrocarpa have been studied for their abilities against cell proliferation, where the details of the findings have been presented in Table 3. Its leaves have been found to reduce tumor and MCF-7 cells [35, 36]. The leaf extract could also enhance the expression of Caspase-3 which is responsible for cell apoptosis [37]. Fruits samples have been reported to decrease the number of new blood vessel , suppress retinoblastoma tumor, and prevent liver fibrosis [20, 38, 39]. The ethanolic extract from P. macrocarpa ethanolic extract was reported for its ability in inhibiting colorectal cancer concomitant to COX-2 downregulation [40]. Table 3: Anti-angiogenic and antiproliferative properties of Phaleria macrocarpa Year[Ref] Sample and extraction Anti-angiogenic activities 2022[35] Maceration of the leaves using ethanol 70% Reducing tumor volume 2019[40] Stem barks maceration using ethanol Inhibiting colorectal cancer cell line HCT116 via COX -2 downregulation 2014[38] Ethanolic extract ofPhaleria macrocarpa ethanolic extract ofPhaleria macrocarpa ethanolic extract ofPhaleria macrocarpa ethanolic extract ofPhaleria macrocarpa Fruits soxhletation using ethanol 96% Decreasing the number of new blood vessels 2021 [37] Leaf powder was macerated with ethanol 70%. Upregulation of Caspase-3 2020[39] P. macrocarpa fruit sample of crude ethanol extract Reducing MCM-B2 cell proliferation 2017[20] Ethyl acetate: water fractionof the fruits (DLBS1425) Attenuating human retinoblastoma tumor cells Y -79 via cyclin E 2017[36] The leaves were macerated using methano l Inhibitingbreast cancer MCF-7 cell 2018[32] The fruits were extracted using subcritical water Preventing liver fibrosis COX-2: Cyclooxygenase-2 Preclinical evidence with on-going clinical trial Preclinical studies have specifically investigated the bioactive natural products from P. macrocarpa for endometriosis treatment (Table 4). An in-vivo studies using Mus muculussuggested thatthe flavonoid isolate from P. macrocarpa could suppress the growth of peritoneal tissue [9]. Moreover, the isolate could improve DOI: 10.55522/jmpas.V12I1.4232 ISSN NO. 2320 –7418 Journal of medical pharmaceutical and allied sciences , Volume 12 – Issue 1, 4232, January – February 2023, Pages – 5582 - 5587 5585 granulomas and increase the apoptotic index [9]. In an in vitro setting, the DLBS1442 was reported to inhibit the angiogenesis and cell migration [41]. Other hormones and pro -inflammatory factors involved during the endometriosis was also attenuated by DLBS1442 [41]. DLBS1442 itself is a bioactive fraction derived from the methanolic extract of P. macrocarpa [42]. An on-going clinical trial (phase II/III) even has been started to evaluate the efficacy of DLBS1442 for endometriosis management (NCT01942122). Based on the interim results, the DLBS could significantly reduce the endometrial cells (Table 4). None of the preclinical research of P. macrocarpa has studied on hypoxia inducible factor -1α (HIF-1α), vascular endothelial growth factor (VEGF),B-cell lymphoma 2 (Bcl- 2), and Bcl-2-associated X protein (BAX) as parameters for endometriosis treatment, regardless their importance in the disease. Hence, future study should explore the activity of P. macrocarpa against the aforementioned molecules. Table 4: Preclinical evidence of the potential of Phaleria macrocarpa in treating endometriosis Study design,Year [Ref] Sample Subject Results In vivo, 2021 [9] Flavonoid isolate Female Mus musculus implanted with myometrial and endometrial tissues under immunodeficient condition Suppressed the growth of peritoneal tissue, i mproved granulomas, and higher apoptotic index. In silico, 2020 [43] DLBS1442 Metabolomic studies were performed on DLBS1442 constituents against progesterone receptor Glyceryl pentacosanoate contained in DLBS1442 otentially acts as progesterone receptor agonist In vitro, 2015 [41] DLBS1442 Human endometrial epithelial cell lineRL95 -2 Inhibition of angiogenesis and cell migration. Upregulation of progesterone receptor and downregulation of estrogen receptor. Inhibition eicosanoid signaling pathway via downregulations of NFκB and iNOS NFκB: Nuclear factor kappa B, iNOS: Inducible nitric oxide synthase

P. macrocarpa is potential for treating endometriosis by targeting multiple molecular targets. The extracts of this plant could act as anti -inflammation, anti-angiogenesis, and anti -proliferation. Composition of its phytocompounds could be ascribed to the extract activities. The bioactive fractions, named DLBS1442, has entered a clinical trial where the updated results show optimism. More research should be carried out to find a particular isolate that is potent against the development of endometrial cells. Our research group warrants the investigation of the activity of P. macrocarpa against HIF-1α, VEGF, Bcl-2, and BAX in-vivo.

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Journal of Applied Pharmaceutical Science 10 , Pages-63-69, DOI:10.7324/JAPS.202 0.10509. How to cite this article Maharani Maharani, Lia Lajuna, Cut Yuniwati, Nora Veri, Sutrisno Sutrisno, 2023. Phaleria macrocarpa for endometriosis treatment a review. Journal of medical pharmaceutical and allied sciences, V 12 - I 1, Pages - 5582 – 5587. DOI: 10.55522/jmpas.V12I1.4232.