Therapeutic Potential of Ugonins: Bioactive Flavonoids from Helminthostachys zeylanica with Multifaceted Biological Activities

Abstract

Ugonins are distinctive chemotaxonomic bioactive metabolites identified in Helminthostachys zeylanica. This uncommon fern species generates a diverse array of flavonoids, including ugonins, which facilitate various biological processes such as anti-inflammatory, neuroprotective, melanogenesis-inhibiting, antioxidant, anti-osteoporotic, and immunomodulatory functions. Our objective in this comprehensive literature review is to deliver a clear and visually engaging analysis of the therapeutic potential inherent in each of the compounds found in H. zeylanica. This review covers the isolation of ugonins A – Y and other metabolites from this plant. These compounds demonstrate a diverse range of biological properties, which are thoroughly discussed in this review. The binding scores of all ugonins A – Y against PTP1B were also presented, indicating their potential activities for future consideration. Ultimately, a thorough understanding of the diverse therapeutic properties inherent in this unique fern can be achieved through a meticulous examination of the existing literature.

Keywords

Helminthostachys zeylanica - ophioglossaceae ugonins - anti-inflammatory - antioxidant - antidiabetic

Introduction

Helminthostachys zeylanica (L.) Hook., Ophioglossaceae, is a terrestrial herbaceous fern found in different regions of the world, including India, Nepal, Sri Lanka, Bangladesh, Assam, China (south-central and southeast), Taiwan, Hainan, Myanmar, Thailand, Vietnam, Laos, Cambodia, Malaya, Borneo, Sulawesi, Sumatera, the Philippines, the Nicobar Islands, the Lesser Sunda Islands, Maluku, the Marianas, the Caroline Islands, the Santa Cruz Islands, the Solomon Islands, New Guinea, New Caledonia, the east and west Himalayas, Western Australia, Northern Territory, Vanuatu, and the Bismarck Archipelago [1]. It is commonly referred to by various names, including daodi-ugon, kamraj, and tunjuk-langit. Like other family members, this species possesses sporangia clusters on its stems that resemble spike-like, fertile fronds. This flowering fern is a terrestrial plant with a vigorous and progressive rhizome growth. It generates several branches that are often widely spaced and often attain a height of 15 to 40 cm [2], [3]. Linnaeus initially documented this species under the binomial name Osmunda zeylanica in his publication Species Plantarum in 1753 [4]. With unique metabolites called ugonins, this medicinal plant has a wide range of biological activity. This edible herb is widely used in traditional medicine and is renowned for its ability to alleviate pain, combat infections, accelerate wound healing, aid in the healing of fractured bones, treat inflammatory conditions, reduce fever, and alleviate symptoms of phlogistic syndromes and jaundice, as well as whooping cough [5]. Because of its traditional use, biological research has concentrated on its anti-inflammatory and antioxidative properties. The various isolates derived from this medicinal plant exhibit a diverse array of biological actions, such as inducing human neutrophils and monocytes through the activation of the NLPR3 inflammasome via Ca²⁺ mobilization and mitochondrial ROS [6]; also, in LPS-induced mice, it blocks the NF-κB and MAPK pathways [7], and by using in vivo hepatotoxicity, the crude extracts of H. zeylanica are also used to assess the anti-inflammatory properties [8]. These unique flavonoids isolated from H. zeylanica also displayed antioxidant activities [9], [10], anti-inflammatory activities [11], [12], [13], [14], melanogenesis inhibitory activities [15], [16], neuroprotection [17], antiosteoporosis [13], [18], [19], potential anti-tumor activity via targeting breast cancer stem cells [20], and immunomodulatory effects [21].

A notable bioactive phytochemical, ugonins, has been derived from the geranyl group, occasionally leading to the formation of a cyclohexyl motif, as they have not been isolated from any other plant species yet and appear to be exclusive to H. zeylanica in terms of chemotaxonomy [22]. Ugonins feature a basic flavonoid structure characterized by either an open-chain or cyclohexyl configuration, usually arising from the addition of geranyl or prenyl groups, which can be positioned on either the B- and/or C-rings. Furthermore, certain compounds possessing sugar moieties were also isolated from H. zeylanica. Compounds exhibiting a comparable substitution pattern, yet possessing a stilbene backbone, are designated as ugonstilbenes. This medicinal plant is rich in many other metabolites like as quercetin 4′-O-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranoside and quercetin-3-O-β-D-glucopyranosyl-4′-O-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranoside [23]. As a whole, the principal metabolites isolated from this plant thus far consist of ugonins.

In this review, we aim to shed light on the diverse array of metabolites and extracts obtained from H. zeylanica, each of which plays a major role in a multitude of biological activities. These compounds or extracts demonstrate exceptional effectiveness in treating a wide range of conditions. Using a thorough investigation of these complex biological characteristics, our goal is to provide a sophisticated and visually pleasing comprehension of the medicinal possibilities contained in the components of H. zeylanica.

Literature Search Strategy

The methodology involves a comprehensive retrieval of relevant literature from the PubMed and Web of Science databases, encompassing all available manuscripts relating to ugonins and H. zeylanica. The search terms included combinations of “Helminthostachys zeylanica”, “ugonins”, “pharmacological activities”, “anti-inflammatory”, “antioxidant”, and “traditional uses”. The search covered articles published up to 2024. The chemical structures were drawn using ChemDraw 22.2.0.

Ugonins and Other Metabolites from Helminthostachys zeylanica

Ugonins from A – Y have been isolated from H. zeylanica so far, along with other metabolites. The structures of all ugonins are presented in [Fig. 1] and [Fig. 2]. Most of these metabolites have been isolated successively in 2003, 2009, and 2017 [10], [11], [13]. Ugonins A – D were isolated for the first time by Murakami et al. [24], [25]. Along with many compounds, sugar moieties at different positions, either attached to the B-ring or attached to the C-ring at position 3, have also been isolated ([Fig. 3]) [11], [13], [15]. Chen et al. [9] isolated and characterized the cyclized geranyl stilbenes from the rhizomes of H. zeylanica. Acetogenin, 6-hydroxy-8-pentadecyloxocane-2,7-dione with a unique structure, has also been isolated from the target plant ([Fig. 4]) [12]. Finally, a simple structure, “3-hydroxyacetophenone”, is reported from the dried rhizome of H. zeylanica [9], as shown in [Fig. 4].

Fig. 1 Structure of ugonins A – M.

Fig. 2 Structure of ugonins N – Y.

Fig. 3 Structure of compounds isolated from H. zeylanica.

Fig. 4 Structure of compounds isolated from H. zeylanica.

Biological Properties of Isolates and Extract of H. zeylanica

Antidiabetic activity

During the process of identifying bioactive metabolites, the rhizome of H. zeylanica was subjected to bioassay-guided isolation, resulting in the successful separation of major metabolites that demonstrated substantial inhibitory effects on two diabetic enzymes: α-glucosidase, which is linked to glucose absorption, and protein tyrosine phosphatase 1B (PTP1B), associated with diabetes and obesity. The IC₅₀ values for ugonins J, L, M, S, and U and a derivative of eriodyctiol demonstrated notable inhibitory activity against PTP1B, with values ranging from 0.6 to 7.3 µM, and against α-glucosidase, ranging from 3.9 to 32.9 µM. Moreover, in these in vitro studies, ugonin J outperformed its mother skeleton, luteolin, by a factor of 26 when it came to PTP1B and a factor of 15 when it came to α-glucosidase. The cyclohexyl motif, which is connected to the core luteolin structure, is primarily responsible for these compoundsʼ potency [22], [26], [27]. Ridhasya et al. also verified the effectiveness of ugonins J and K in inhibiting α-glucosidase in an in vitro study. The antidiabetic activity of ugonin J was seen at a concentration of IC₅₀ 273.13 ppm, whereas ugonin K exhibited antidiabetic activity at a concentration of IC₅₀ 138.21 ppm [28]. A study was undertaken to induce steatosis in human HuS-E/2 cells through the application of free fatty acids, alongside generating non-alcoholic fatty liver disease (NAFLD) in murine models via a high-fat dietary regimen. The research aimed to investigate the protective properties of H. zeylanica extract. The results showed that treating the HuS-E/2 cells with H. zeylanica extract significantly reduced lipid deposition and facilitated AMPK and ACC activation. It was also confirmed by HPLC that the major components of the H. zeylanica extract were ugonins J and K. Following a 12-week high-fat diet (HFD) supplemented with H. zeylanica extract, the HFD mice exhibited protection against hyperglycemia and hyperlipidemia. In the HFD mice, H. zeylanica extract inhibited adipocyte hypertrophy, adipose tissue growth, and body weight gain in this in vivo analysis [29]. Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition globally, affecting around 24% of the population. It is considered the liver manifestation of metabolic syndrome and is the leading cause of chronic liver disease. Metabolic syndrome, which affects approximately 25 – 30% of the worldwide population, increases the likelihood of developing type 2 diabetes mellitus (T2DM) and cardiovascular illnesses. One of the in vivo studies has found that ugonin J effectively decreases hepatic inflammation, adipocyte hypertrophy, glucose insensitivity, insulin resistance, body weight gain, and dyslipidemia in obese mice produced by a high-fat diet. Importantly, this beneficial effect is achieved without causing any injury to the kidneys or pancreas [30]. These findings primarily suggested that H. zeylanica, mainly the ugonin compounds, have the potential to treat diabetes.

PTP1B functions as a non-receptor phosphatase that exerts negative regulation on critical signaling pathways, notably those associated with insulin and leptin, in addition to pathways implicated in inflammation and cancer progression. Inhibition of PTP1B has emerged as a potential therapeutic strategy for T2DM, obesity, and specific cancers. Currently, there is no study available that clearly indicates that PTP1B inhibition can target the pathways related to ugonin inhibition and these diseases. PTP1B inhibition shows potential; however, the current study has notable limitations. The current study is based on in vitro models. There is a necessity for mechanistic validation in animal models or clinical studies. Additionally, it is essential to identify binding sites and conduct structure–activity relationship studies for all ugonins. Most importantly, exploring off-target effects and specificity is crucial. The same applies to α-glucosidase inhibition, which is a crucial enzyme in T2DM and requires further study in terms of in vivo models and clinical studies. Furthermore, additional studies focusing on diabetes using H. zeylanica extracts are primarily in vitro, such as those involving HuS-E/2 cells. It is essential to assess individual ugonins rather than the extracts, and further animal-based and clinical experiments are required. A study conducted in vivo demonstrated that ugonin J effectively reduces hepatic inflammation, adipocyte hypertrophy, glucose insensitivity, insulin resistance, body weight gain, and dyslipidemia in obese mice. Further clinical evaluations and comparative studies with other ugonins are warranted.

Melanogenesis inhibitory activity

The pigment known as melanin, which is found in the skin, is thought to be essential in protecting the skin from ultraviolet (UV) radiation and preventing skin cancer. However, excessive amounts of melanin accumulation on the skinʼs surface result in the formation of mottled skin, which is unsightly and may have consequences for the general health of the skin. L-tyrosine is biologically converted to melanin by melanocyte cells. Tyrosinase, an enzyme that contains copper and catalyzes two important processes in the complex process of melanin formation, is the primary enzyme that regulates this process [31], [32], [33]. Researchers used B16 melanoma cells to study the melanogenic effects of ugonins both intra- and extracellularly. The results showed that, in comparison to the control, ugonin J gradually reduced the amount of extracellular melanin to 75%, 16%, and 14% at concentrations of 12.5, 25, and 50 µM, respectively. Interestingly, ugonin K outperformed ugonin J in terms of inhibitory efficacy, showing considerably more marked inhibition with reductions in extracellular melanin at the comparable doses of 19%, 8%, and 9% [16]. The melanogenesis inhibitory activity of ugonin K is significantly influenced by the catechol moiety present in the B-ring of the flavone structure. To examine the structural activity relationship in vitro between ugonins J and K, as both compounds contain the catechol moiety, the methoxy difference at the C-7 position between the two is evident. Furthermore, the researcher demonstrated that the activity was improved by the low polarity substituents at the C-7 position, which were subsequently synthesized into more potent compounds exhibiting enhanced melanogenesis inhibitory activity [34].

The MAPK signaling cascade, particularly the ERK (extracellular signal-regulated kinase) pathway, is essential in the regulation of melanogenesis through its impact on microphthalmia-associated transcription factor (MITF) stability. The continuous activation of ERK leads to the phosphorylation and subsequent proteasomal degradation of MITF, which in turn inhibits the transcription of melanogenic enzymes, including tyrosinase [35], [36]. Currently, the ugonins, especially J and K, have been studied in in vitro B16 melanoma cell models, which do not fully reflect human melanocyte physiology. The specific targets of ugonins present in the MAPK cascade have not yet been studied. The mechanism through which ugonins influence ERK remains unclear–precisely, whether they act upstream of ERK or affect ERK phosphorylation through indirect pathways. The second study, which describes the catechol moiety and the differences at the C-7 position in ugonins, primarily consists of in vitro research and focuses largely on specific ugonins, thereby limiting the comprehensive analysis of ugonins in this context. Based on these, further Western blot or inhibitor-based studies are necessary to confirm the specificity in pathways (e.g., using ERK inhibitors). Also, in vivo studies or 3D skin models are necessary to confirm the efficacy and safety for dermatology applications.

Antioxidant and anti-inflammatory activities

Reactive oxygen species (ROS) are free radicals produced during oxidative stress and are linked to various diseases like diabetes, atherosclerosis, cancer, and neurological illnesses. These by-products of oxygen metabolism can be eliminated by endogenous antioxidants like catalase and superoxide dismutase. ROS can damage various cell parts, including proteins, lipids, and DNA. Compounds with antioxidant potential may offer a therapeutic option for treating ROS-induced illnesses due to their ability to scavenge radicals [37], [38], [39]. While looking for strong antioxidants through the DPPH test, Haung et al. [10] demonstrated that eight ugonins (E – L) have stronger antioxidant properties than Trolox. Since ROS are essential signaling molecules, they have a significant impact on how inflammatory diseases develop. To that end, two neougonins, A and B, were identified. A exhibited an IC₅₀ value of 3.32 µM, inhibiting the formation of nitric oxide (NO) in RAW264.7 cells stimulated by lipopolysaccharide (LPS) [40]. In addition, ugonin K had the most potent inhibitory effect on RANKL-induced osteoclast development in RAW264.7 cells, with an IC₅₀ value of 1.8 µM [13], and ugonins L, M, O, Q, S, and T displayed the inhibition of superoxide generation in the range of 0.25 to 5.8 µM [11]. The DPPH assay showed that the cyclized geranyl stilbenes, ugonstilbene A, ugonstilbene B, and ugonstilbene C, which were extracted from H. zeylanica, exhibited moderate antioxidant activity with IC₂₀ values of 11.31, 38.72, and 30.80 µM, respectively, whereas Trolox had an IC₂₀ value of 8.70 µM [9]. Finally, in in vivo analysis, when tested on mice with asthma, the aqueous extract of H. zeylanica reduced oxidative stress and Th2 cytokine production, which improved airway hyperresponsiveness and eosinophil infiltration [41].

ROS plays a significant role by regulating biological processes like immune response, inflammation, and apoptosis. Excessive ROS production leads to oxidative stress, contributing to chronic inflammatory diseases, neurodegeneration, and cancer. The current research on ugonins in this context primarily relies on cell-based assays, such as RAW264.7 macrophages, which serve as a standard yet simplistic model of inflammation. The specific targets of ugonins, such as iNOS, NOX enzymes, and MAPK subunits, have not been thoroughly studied to date. The in vivo studies primarily focused on the extract rather than isolated compounds, complicating the assessment of ugoninsʼ effects on ROS and inflammation. Further studies should focus on pathway-specific assays, like NF-κB or MAPK reporter systems, to validate the molecular mechanisms. Along with this, chemical proteomics, docking studies, and pharmacokinetic and toxicity studies of ugonins are necessary to confirm the suitability for therapeutic applications.

Remaining biological activities

From the literature review, H. zeylanica is demonstrated to be a potent medicinal plant in a wide spectrum of biological activities. For instance, estrogens interact with estrogen receptors, which are members of the superfamily of nuclear transcription factors that are controlled by ligands to trigger their physiological effects on certain tissues. So far, two estrogen receptors, estrogen receptor-α and estrogen receptor-β, have been identified. Both receptors have been found in the progenitors of osteoblasts and osteoclasts. An estrogen receptor-dependent activation of a non-classical signaling route mediated by phosphorylation of c-Src may be the mechanism by which ugonin K increased osteogenesis. Furthermore, a transactivation potential via a classical approach toward estrogen receptor-α may not be excluded [19], [42].

Ankle fractures, which occurred at an incidence rate of 4.22/10 000 person-years in the United States between 2012 and 2016, are among the most common lower-limb fractures that affect younger males and senior women; researchers conducted a double-blind, randomized, controlled clinical experiment in this regard, and the findings showed that oral administration of H. zeylanica taken for 42 days has been shown to lower radiographic healing time and raise the serum amino-terminal propeptide of the type 1 procollagen levels. Thus, patients who need surgery for ankle fractures can be treated with H. zeylanica. But for subsequent research, a bigger sample size is required [43], [44].

In the pathophysiology of various microbial disorders, including the production of biofilms, bacterial neuraminidase is a key player. Ugonins J, L, M, S, and U and a derivative of eriodyctiol were investigated against bacterial neuraminidase and biofilm; as a result, these compounds demonstrated strong activity at the nanomolar level. Specifically, in this in vitro analysis, ugonin J inhibited the formation of Escherichia coli biofilm dose-dependently up to 150 µM without causing bacterial inhibition [45]. The extract of H. zeylanica is utilized in the activity against the foodborne pathogen Bacillus cereus. A broth microdilution assay revealed that the MIC of the extract on B. cereus was around 6.25 mg/ml, while the MBC was determined to be 12.5 mg/ml. The extract exhibited bactericidal activity against B. cereus [46]. Additionally, this plant is utilized in the treatment of ulcers in male Wistar rats. The root ethanol component was utilized as an antiulcer treatment in the management of acute gastric lesions [47].

The first and most important stage in the host defense mechanism is the recognition of harmful bacteria, which sets off a chain of events needed to eradicate the pathogens. To identify infections or other danger signals, the innate immune system makes use of a variety of pattern recognition receptors (PRR), such as Toll-like receptors, nucleotide-binding oligomerization domain-like receptors (NOD-like receptors, NLRs), and RIG-like receptors. Researchers demonstrated how ugonin U causes the release of ROS from the mitochondria and the mobilization of Ca²⁺ to activate the NLRP3 inflammasome. They also showed that ugonin U mediated NLRP3 inflammasome activation and enhances human monocytes bactericidal activity. Ugonin U has the ability to activate the NLRP3 inflammasome, which is an intriguing target for developing anti-infective drugs. It also stimulates human neutrophils and monocytes, both of which are competent phagocytes. These findings suggest that ugonin U treatment could be a new and effective approach for managing infectious diseases [6], [48]. Acetogenin and ugonins from H. zeylanica also exhibited the inhibitory activity on superoxide production and elastase release by neutrophils [12].

Ugonin J treatment effectively inhibited the growth of mammospheres and dramatically decreased the tumorigenicity of MCF-7 cells. The suppressive effect of ugonin J can be counteracted by either adding a p53 inhibitor or overexpressing NANOG, suggesting that p53 activation and NANOG decrease were the likely causes of this suppression [20]. Lin et al. [49] recently synthesized ugonstilbenes A, B, and C from H. zeylanica, which showed cytotoxic action against a variety of cancer cell lines. Additionally, ugonin L has been shown to suppress the NF-κB and MAPK pathways, which suppresses osteoclast apoptosis and reduces osteoclast development [50]. Ugonin M, via TLR4-mediated MAPK and NF-Kb signaling pathways, prevents LPS-induced acute lung injury [14]. Also, by inhibiting DPP-4 expression and stimulating the synthesis of miR-130b-5p, ugonin P reduces the motility of lung cancer cells [51]. Lastly, Tsai et al. [52] investigated the anticancer effects of H. zeylanica ethyl acetate extracts on gastric cancer cells in humans by downregulating the COX-2-cPLA2-PGE2 pathway, which is triggered by TNF-α. According to their findings, H. zeylanica ethyle acetate extract may prove to be a useful new adjuvant treatment for stomach cancer. Most recently, ugonin V was used for the first time in a mouse model to inhibit the spread of chondrosarcoma. This represents the moment human chondrosarcoma cells can be hindered by decreasing the level of MMP7. It will be helpful that ugonin V is a potential bioactive compound for preventing such types of cancer. Ugonins J and P were also used in such a study, but ugonin V displayed a notable activity in this case [53].

A recent pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which resulted in the coronavirus disease 2019 (COVID-19), has had a noteworthy impact on human behavior, psychology, and the economy in addition to endangering worldwide public health. Severe “flu-like” symptoms are the initial sign of a SARS-CoV-2 infection, which can lead to pneumonia, renal failure, acute respiratory distress syndrome, and even death. Ugonin J not only stops SARS-CoV-2 infection but also suppresses SARS-CoV-2 3CLpro activity. Specifically, ugonin J forms hydrogen bonds and/or van der Waals interactions with many key residues that are involved in the core pharmacophore anchoring of SARS-CoV-2 3CLpro. Ugonin J, being a direct-acting antiviral, hinders the activity of a crucial SARS-CoV protease [54], [55]. A summary of the main biological activities of ugonins are displayed in [Table 1].

Table 1 Summary of main biological activities of ugonins A – Y.

Compound Name	Biological Activity	References
NA= not available
Ugonin A	NA
Ugonin B	NA
Ugonin C	NA
Ugonin D	NA
Ugonin E	NA
Ugonin F	NA
Ugonin G	Antioxidant	[10]
Ugonin H	Antioxidant	[10]
Ugonin I	Antioxidant	[10]
Ugonin J	Anti-inflammatory, antioxidant, inhibit the spreading of breast cancer stem cells, inhibitor of bacterial neuraminidase, α-glucosidase and PTP1B, active against NAFLD, anti-SARS-CoV-2, inhibit cellular migration and neointimal development in clinical restenosis, effective in intra- and extracellular melanogenesis activity	[10], [13], [16], [20], [22], [30], [45], [54], [59]
Ugonin K	Anti-inflammatory, antiosteoporosis, antioxidant, inhibit the spreading of breast cancer stem cells, effective in intra- and extracellular melanogenesis activity, neuroprotective, induces osteoblastic differentiation and maturation, antioxidant	[10], [13], [16], [17], [18], [20], [60]
Ugonin L	Anti-inflammatory, antioxidant, inhibit the spreading of breast cancer stem cells, inhibitor of bacterial neuraminidase, α-glucosidase and PTP1B, inhibits osteoclast formation	[10], [13], [20], [22], [45], [50]
Ugonin M	Suppression of superoxide anion production and elastase secretion by human neutrophils in response to FMLP/CB, anti-inflammatory, inhibitor of bacterial neuraminidase, α-glucosidase and PTP1B, prevents LPS-induced acute lung injury, hepatoprotective	[11], [13], [14], [22], [45], [61]
Ugonin N	Suppression of superoxide anion production and elastase secretion by human neutrophils in response to FMLP/CB, inhibit the spreading of breast cancer stem cells	[11], [20]
Ugonin O	Suppression of superoxide anion production and elastase secretion by human neutrophils in response to FMLP/CB, anti-inflammatory, antiosteoporosis	[11], [13]
Ugonin P	Suppression of superoxide anion production and elastase secretion by human neutrophils in response to FMLP/CB, inhibit the spreading of breast cancer stem cells, anti-lung cancer	[11], [20], [51]
Ugonin Q	Suppression of superoxide anion production and elastase secretion by human neutrophils in response to FMLP/CB, inhibit the spreading of breast cancer stem cells	[11], [20]
Ugonin R	Suppression of superoxide anion production and elastase secretion by human neutrophils in response to FMLP/CB, inhibit the spreading of breast cancer stem cells	[11]
Ugonin S	Suppression of superoxide anion production and elastase secretion by human neutrophils in response to FMLP/CB, anti-inflammatory, antiosteoporosis, inhibit the spreading of breast cancer stem cells, inhibitor of bacterial neuraminidase, α-glucosidase and PTP1B,	[11], [13], [20], [22], [45]
Ugonin T	Suppression of superoxide anion production and elastase secretion by human neutrophils in response to FMLP/CB	[11]
Ugonin U	Inhibitor of bacterial neuraminidase, α-glucosidase and PTP1B, stimulates NLRP3 inflammasome activation, anti-inflammatory	[6], [21], [22], [45]
Ugonin V	Anti-inflammatory, antiosteoporosis, blocks MMP7 synthesis and chondrosarcoma motility	[13], [53]
Ugonin W	Anti-inflammatory, antiosteoporosis	[13]
Ugonin X	Anti-inflammatory	[13]
Ugonin Y	Anti-inflammatory, antiosteoporosis	[13]

While H. zeylanica and its constituent ugonins exhibit promising effects across various biological activities, several limitations remain. The majority of these investigations stem from in vitro studies or are confined to limited in vivo models, which fail to comprehensively examine the pharmacokinetic profiles, toxicity parameters, and dose-response relationships.

Future perspective and conclusions

Ugonins, unique chemotaxonomic compounds found in H. zeylanica, exhibit diverse biological activities and have been evaluated by scientists worldwide. A recent review article on a similar plant has been published; however, it does not provide an in-depth biological analysis of all compounds [56]. Nevertheless, a more thorough assessment is needed to move these potent compounds from academic research to commercial use in treating human illnesses. We have also tried the docking studies of all ugonins A – Y against a PTP1B enzyme, which has a great role in many disorders like diabetes, cardiometabolic diseases, cancer, and many others [57]. Prior docking investigations of ugonins J and L with PTP1B have revealed encouraging binding affinities, indicating that these compounds might serve as possible inhibitors of PTP1B. The preliminary results established a basis for additional exploration into the PTP1B inhibitory capabilities of other ugonins [21]. We have shown here the molecular docking score to encompass all ugonins, A – Y, with the objective of identifying further candidates displaying robust binding potential and offering a comprehensive view of their potential. The docking studies were conducted in Maestro v12.4, following a previous protocol [58]. The PDB-ID: 2CMC was supplied by the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB). Docking and calculations were conducted utilizing the standard precision (SP) mode of the Glide software. Based on this, the docking score for ugonins A – Y was in the range of − 2.06 to 4.98 kcal/mol ([Table 2]), which further predicated that the compound can be studied further in major disorders. Among all the compounds, ugonins J, K, L, P, Q, R, S, T, and V exhibited binding scores of − 4.20, − 4.03, − 4.26, − 4.43, − 4.98, − 4.28, − 4.03, − 4.68, and − 4.00 kcal/mol, respectively, indicating their potential as future PTP1B inhibitors. The remaining ugonins demonstrated comparable binding scores, thereby strengthening their potential to inhibit PTP1B. The current findings establish a valuable foundation for future experimental validation, given the lack of substantial prior research on PTP1B inhibition by this comprehensive range of ugonins.

Table 2 The docking scores of ugonins A – Y, which target PTP1B, are presented.

Compounds	Docking Score
Ugonin A	− 3.37 643
Ugonin B	− 3.72 796
Ugonin C	− 3.04 875
Ugonin D	− 3.38 888
Ugonin E	− 2.06 587
Ugonin F	− 3.15 499
Ugonin G	− 3.92 537
Ugonin H	− 3.15 525
Ugonin I	− 3.32 849
Ugonin J	− 4.20 895
Ugonin K	− 4.03 228
Ugonin L	− 4.26 316
Ugonin M	− 3.08 252
Ugonin N	− 3.31 918
Ugonin O	− 3.30 784
Ugonin P	− 4.43 605
Ugonin Q	− 4.98 179
Ugonin R	− 4.28 044
Ugonin S	− 4.03 899
Ugonin T	− 4.68 038
Ugonin U	− 3.76 616
Ugonin V	− 4.00 903
Ugonin W	− 3.58 117
Ugonin X	− 2.78 913
Ugonin Y	− 3.17 715

Overall, the main obstacles in natural product chemistry include reproducibility, toxicity, and bioavailability. Regulatory impediments, such as navigating regulatory requirements for commercialization, and production expenses, such as raw ingredient costs, extraction processes, and purification procedures, can pose significant challenges. Largely, addressing these obstacles is crucial for the commercial viability of H. zeylanica and its components in the treatment of human illnesses.

In essence, H. zeylanica is a remarkable source of bioactive marvels, particularly noteworthy for its potential in the areas of anticancer, antidiabetic, and antioxidants. Ugonins J and K, in particular, steal the show and have intriguing prospects as a novel treatment for many disorders, backed by strong early evidence. Beyond these star compounds, other ugonins demonstrate their strength with strong anti-inflammatory and antioxidant properties, suggesting their immense medicinal potential. These ugonins are so precise that they need close examination. In light of this, H. zeylanica appears to be a strong contender for upcoming commercial successes. From an academic interest, the path becomes a dynamic pursuit ready to overcome business obstacles and turn these compoundsʼ potential benefits into real, practical outcomes.

Contributorsʼ Statement

ABS: conceptualization, data curation, original draft preparation, and editing; AB and YJK: formal analysis and investigation; KYL: original draft preparation, supervision, and funding.

Conflict of Interest

The authors declare that there are no conflicts of interest.

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Publikationsverlauf

Eingereicht: 19. März 2025

Angenommen nach Revision: 06. Oktober 2025

Accepted Manuscript online:
06. Oktober 2025

Artikel online veröffentlicht:
04. November 2025