Key findings:

Our investigation into 23 commercially available herbal capsules revealed 33 medicinal plants from 26 families, with Garcinia mangostana and Curcuma longa being notable contributors. The network analysis identified 333 interactions and 137 plant diseases, emphasizing antioxidants and the need for clinical testing to ensure safety and efficacy in healthcare.

What is known and what is new?

The study provides a comprehensive analysis of 23 commercial herbal capsules, highlighting their medicinal plant content and therapeutic claims through network analysis. It reveals the predominant use of leaves and the recurrent inclusion of Garcinia mangostana, emphasizing alpha-mangostin and γ-mangostin. The study underscores the importance of scrutinizing bioactive compounds and advocating for rigorous clinical testing in herbal formulations.

What is the implication, and what should change now?

The study's implications are significant for the herbal medicine industry and healthcare practices. It underscores the need for stricter regulation and quality control in herbal capsule production to ensure the safety and efficacy of these products. Manufacturers should prioritize testing and transparency regarding the bioactive compounds in their capsules. Healthcare providers should be aware of these findings to make informed decisions about herbal medicine use with their patients.

In the evolving landscape of healthcare, herbal medicines are experiencing a resurgence, capturing attention for their intrinsic ties to tradition and the potential for natural healing. At the core of this revival is the prevalence of composite herbal formulations—sophisticated blends of diverse plant constituents deeply ingrained in historical practices across generations. The intricate composition of these formulations necessitates a meticulous scientific examination, aiming not only to identify the specific plant constituents but also to decipher the intricate interplay among their bioactive compounds.

Transitioning beyond a superficial analysis, our research delves into the intricate dynamics inherent in these herbal blends. Leveraging network analysis as a sophisticated computational tool, coupled with an exhaustive literature review, the study seeks a nuanced understanding of the inherent complexities in these botanical combinations. As the global acceptance of herbal remedies continues to escalate, the need to substantiate traditional practices with empirical evidence gains heightened significance. While historical wisdom provides foundational insights into the efficacy of these remedies, contemporary focus shifts towards unraveling the nuanced biochemical dialogues within these herbal mixtures.

Network analysis assumes a pivotal role in navigating the intricacies of herbal formulations. It goes beyond the mere identification of constituent plants, enabling a nuanced comprehension of the intricate biochemical interactions among their compounds. The primary objective extends beyond decoding individual impacts; it endeavors to discern how these compounds collectively interact to address human health needs. This comprehensive approach not only enhances the understanding of herbal medicines but also underscores the urgency of integrating traditional wisdom with the analysis of big data. It emphasizes the need for evidence-based practices, positioning herbal medicines as credible components within the modern healthcare paradigm. The study contributes not only to the scientific understanding of herbal formulations but also serves as a bridge between traditional knowledge and contemporary validation using big data sets, fostering a holistic approach to the integration of herbal remedies into evidence.

2.1 Collection of Samples

Herbal capsules sold in malls, and drugstores were surveyed, their botanical components documented including formulations and therapeutic claims was meticulously compiled. Additionally, a web search was conducted to supplement the primary data with secondary information obtained from studies published in journals, reports, books, and theses related to ethnobotanical uses. The collated secondary data encompassed essential details such as family name, genus name, scientific name, local and common names, country of origin, utilized plant part, and reported ethnobotanical uses. Microsoft Excel was employed as the tool for organizing and compiling the collected data.

2.2 Network Analysis 

             Utilizing a dual license comprising the CDDL and GNU General Public Version 3 (2008-2023), the network analysis for this study was executed through Gephi software (version 0.10.1). This program, recognized for its efficacy in analyzing and visualizing networks, constructs narratives by discerning patterns from the data.1 In the context of this investigation, the boundaries of the Network signify the relationships between diseases, with each node representing a specific disease. Given the asymmetric nature of relationships between medicinal plants (i.e., a particular medicinal plant providing relief for a specific disease without necessarily curing the disease itself), a directed graph was employed. The layout of the resulting diagram was adjusted using the Force Atlas 2 algorithm.

The methodology outlined in the referenced literature served as the basis for computing network modularity and network centrality metrics (degrees, closeness, betweenness, Eigenvector) using Gephi software. Subsequent to the analysis, patterns, and data narratives derived from the network analysis results were thoroughly evaluated.

3.1 Herbal Medicinal Capsule and its Therapeutic Claims 

Examination of the different capsules show numerous companies routinely employ various formulations (Table 1) available in the market for treating ailments (see Figure 1). A thorough documentation was made regarding the medicinal plant composition in twenty-three (23) herbal capsules. Table 2 enumerates the families and species from each of the following orders were found as major components of the commercialized capsules: Poaceae (comprising three species), Asteraceae (comprising two species), Lamiaceae (comprising two species), and Ericaceae (comprising two species). The Poaceae family hosts the highest number of documented taxa, particularly prevalent due to its extensive use in traditional medicine (Hordeum vulgare, Cymbopogon citratus, and Agropyron desertorum) [2-3].

Mangostana is the botanical species most frequently incorporated into capsule formulations, such as Xanthone Plus, Green Life, Vitasteen, Melter, AX5, and Mx3.4 These capsules claim diverse therapeutic benefits, ranging from antimicrobial and antiparasitic properties to wound healing and anticancer effects [5-10].

Malunggay (Moringa oleifera Lam), turmeric Turmeric (Curcuma longa L.), Lagundi Lagundi (Vitex negundo L.), and Sambong (Blumea balsamifera), traditionally known for their bioactive properties, are recurrently integrated into botanical capsule formulations since these herbs were reported to exhibit antioxidant properties and are applied in traditional medicine across diverse regions. Malunggay (Moringa oleifera Lam) is employed for treating high fever, anemia, and diabetes [3,11]. Turmeric (Curcuma longa L.) addresses dysentery, infections, and skin conditions [12]. Lagundi (Vitex negundo L.) is utilized for cough, rheumatism, and various other purposes [13]. Each of these herbs offers a unique set of medicinal benefits.

The formulation of polyherbal capsules, a combination of various herbal plants, is thought to be strategically designed for treating chronic diseases, including cancer. Noteworthy herbs like red Ganoderma (Ganoderma lucidum), cinnamon (Cinnamomum verum), oldendandia (Oldenlandia diffusa), papaya (Carica papaya), guyabano (Annona muricata), and Pau d'arco (Tabebuia impetiginosa) were important botanical components being argued to contribute to anticancer effects [14-17]. Ganoderma lucidum for example was known to exhibit antitumor properties, while cinnamon induces apoptosis in cancer cells. Ursolic acid in Oldenlandia and isothiocyanate in papaya have demonstrated effectiveness against various cancer types. Guyabano and Pau d'arco have been traditionally recognized for their anticancer potential [18-20].

Table 1. List of Formulated Herbal Capsule and Therapeutic Use

3.2 Plants Part Used

The predominant plant part used in the production of the various herbal medicine capsules is the leaves. Various plant components also were found to be included, including fruits, fruit hulls, cloves, aerial plant parts, roots, legumes or seeds, and rhizomes. Scientific reports highlight that chemical substances, such as inulin, essential oils, alkaloids, tannins, coumarins, and flavonoids, are primarily synthesized and stored in the leaves of plants through photosynthesis [21] this could be the basis for the formulations. Notably, inulin emerged as the key active components in the majority of herbal formulations. It can be argued that the emphasis on leaves serves a dual purpose. Firstly, it aligns with conservation efforts, as utilizing foliage allows for plant preservation without the need to uproot the entire plant or its roots, thereby supporting sustainable practices. Secondly, leaves are chosen for their accessibility and abundance, ensuring a continuous and renewable source for herbal preparations. Moreover, the consumption of various leaves enhances the efficacy of extract formulation [22]. This strategic use of plant parts not only underscores the importance of leaves but also promotes sustainable practices in herbal medicine production.

Table 2:  List of families and Species of plants in the Formulated Herbal Capsule and the plant parts used

3.3 Statistical Description

3.3.1 Network of Commercialized Herbal Capsules and their therapeutic claims (Fig. 1)

It can be surmised in the network analysis that Serpentina capsules exhibit notable interactions with a variety of other capsules, suggesting potential commonality in bioactive compounds and ingredients among them. The extensive connections, as indicated by the Network's average degree of 1.196 and Serpentina's average of 31 interactions per capsule, imply a broad spectrum of therapeutic claims shared with other herbal capsules.

Conversely, capsules such as Lagundi and Sambong present a contrasting picture. Their limited connections, illustrated by the degree distribution where three capsules achieve a grade surpassing 11, suggest a more specialized and narrow medical usage. Unlike Serpentina, which engages in numerous connections, these capsules seem to have specific applications and interactions, indicating a focused therapeutic profile.

In essence, the network analysis highlights that while Serpentina capsules demonstrate versatility with potential commonalities in bioactive compounds across various herbal capsules, others like Lagundi and Sambong exhibit a more specialized and targeted medical usage. The results underscore the intricate interplay of herbal capsules, providing insights into both their versatility and specialization within the broader Network.

Figure 1: A Network of commercialized herbal capsules and their therapeutic claims

3.3.2. Commercialized Individualized Capsulized Medicinal Plants 

     The application of Gephi to analyze the ethnopharmacological properties of commercially available capsulated medicinal plants unveiled 334 edges and 137 nodes. These figures denote a comprehensive network of 334 interactions depicting medicinal properties among the nodes, comprising 137 distinct medicinal plants and associated diseases. The insights derived from this analysis are visually represented in Figure 2. 

   Figure 2: Network Analysis of Commercialized Capsulized Medicinal Plants Based on Data Mining.

     For in-degree distribution, Antioxidants stand out as pivotal players in addressing a spectrum of health concerns, given their prevalence in a diverse array of interconnected plants as shown in the network. These herbs where some are used as spices notably, G. max, M. oleifera Lam, Rosa L., C. longa, G. biloba, M. charantia, P. ovata, T. aestivum L., G. mangostana, V. vinifera, H. vulgare, A. sativum L., A. muricata, C. papaya, A. paniculata, G. lucidum, A. platensis, C. verum, and M. spicata comprise this botanical repertoire. Herbs and spices are known rich sources of antioxidants, contributing to the prevention and inhibition of oxidative stress's detrimental effects. Laden with phenolic compounds, flavonoids, and polyphenols, these plants serve as effective scavengers of free radicals. The significance of antioxidants extends to drug formulations employed in preventing and treating various conditions, including cancer, diabetes, Alzheimer's disease, stroke, and atherosclerosis [23].

The network also spotlights Xanthone Plus Gold capsule, a synergistic blend of A. platensis, M. charantia, M. oleifera Lam., and G. mangostana. This capsule emerges as a potent antioxidant and immunity booster, contributing to cancer prevention, heart health enhancement, blood sugar control support, cholesterol reduction, body cleansing, hypertension mitigation, body detoxification, digestive health improvement, and cognitive decline prevention. Notably, the network analysis concurs, identifying these four plants as possessing antioxidant properties, reinforcing the brand’s standing as a robust antioxidant formulation.

For out-degree distribution, C. longa emerges as a botanical powerhouse, establishing the most extensive associations among all plants within the Network. With an impressive total of twenty-five (25) ties to medicinal applications, it stands out as the most prominently linked plant with a myriad of health benefits. The capsule's manufacturer claims that C. longa offers a diverse range of health advantages, including the prevention of prostate cancer, melanoma, childhood leukemia, liver detoxification, anti-inflammatory properties, hindrance and deceleration of Alzheimer's disease progression, prevention of multiple sclerosis, assistance in fat metabolism, treatment for depression, inhibition of tumor growth, alleviation of psoriasis, and relief from arthritis and rheumatoid arthritis.

Scientific studies have supported these assertions, revealing that curcumin, the active compound extracted from Curcuma longa, exhibits potential therapeutic effects against Alzheimer's disease, psoriasis, and can [10,24]. The multifaceted benefits of Curcuma longa are attributed to its anti-inflammatory and antioxidant agents, as evidenced by various studies [25-28].

According to the findings of the network analysis, C. longa exhibits associations with cancer, melancholy, and rheumatism while showcasing potent antioxidant and antimicrobial properties. Notably, these associations align with the diseases mentioned in the capsule, reinforcing the remarkable therapeutic properties of C. longa in the treatment of rheumatism, cancer, and depression (Fig 2).

To have an idea exploring the correlation between specific plants and the documented ailments within the cohort, a network relationship of medicinal Plants and the therapeutic claims of addressing ailments was done.  Results show the distribution of plants and conditions into seven categories presented in Table 3, reflecting the Network of plants and health conditions. Group A, the most prominent, includes 11 plant species like G. vulgare, A. muricata, G. officinali, C. verum, and Z. officinali, known for their antimicrobial properties and potential to inhibit malignancy, combat inflammation, and impede infection spread.^{29,30,31,32,33} Although the analysis does not validate this, previous studies indicate the anticancer potential of A. muricata, C. verum, and G. mangostana, suggesting their suitability for capsule production.

Group B highlights C. papaya, B. balsamifera, and V. negundo. C. papaya, while known for treating fever and various conditions, contradicts the capsule's claim of treating infections. B. balsamifera addresses bleeding, fever, body pain, and more, aligning with the capsule's indications. V. negundo treats eleven diseases, including asthma and cough, which are inconsistent with the capsule's reporting.

Group C emphasizes M. oliefera and M. charantia, recognized for their antioxidant properties. M. charantia is rich in phenolic compounds, and M. oliefera contains antioxidant β-carotene constitue [34-35,10]. The diversity of medicinal plants in herbal capsules, reflected in their therapeutic applications, is evident in the network analysis of commercially available capsulized medicinal plants.

In numerical terms, the distribution into seven categories revealed a minimum of 50 (36.5%) nodes and a maximum of 87 (63.5%) nodes in the top three categories. Group A displayed 11 plant species and 23 maladies, with five predominant plants – G. vulgare, A. muricata, G. officinali, C. verum, and Z. officinali. Group B highlighted three plants – C. papaya, B. balsamifera, and V. negundo. Group C featured two plants – M. oliefera and M. charantia. The numerical breakdown provides a clear snapshot of the distribution and prominence of various plants within the Network.

Table 3: Description of top 3 Communities in the Network

Group	Visualization	Main Medicinal Plants	No. of Edge	Main Diseases
A		Annona muricata Graciana mangostana Zinger officinali Foeniculum vulgare Cinnaomum verum	7 7 7 9 4	Antimicrobial, Anticancer, Anti-inflammatory, Antidepressant
B		Carica papaya Blumea balsamifera Vitis negundo	15 11 11	Skin diseases, Fever and cough
C		Moringa Oliefera L Momordica charantia	8 7	Antioxidant

In the context of contemporary scientific advancements, the study underscores the growing recognition of pharmacologically active components in herbal medicines, revealing potential therapeutic benefits. The investigation points to the scientific validation of certain capsules through laboratory-based studies, affirming specific medicinal assertions associated with commercial herbal products. However, a critical gap exists in the research, particularly concerning the purported effects and potential health risks of numerous plant species encapsulated within these products.

The findings highlight the diverse array of plants used in herbal capsules, either individually or in combination, yet the biochemical interactions among these plants remain largely unknown. Given this, there is a recommendation for further research and clinical trials to comprehensively assess the quality, safety, and efficacy of herbal products, with stability emerging as a paramount consideration. Manufacturers are urged to implement robust protocols to ensure product stability throughout production, storage, transportation, and usage.

Further research should employ exhaustive laboratory analyses to examine the chemical reactions of bioactive compounds derived from individual plants contained within herbal capsules in order to enhance comprehension. The scientific examination is of the utmost importance in determining the pharmacological foundation of these formulations and could potentially facilitate the creation of novel pharmaceuticals.

ACKNOWLEDGEMENTS

The authors thank the Department of Science and Technology under the Accelerated Science and Technology Human Resource Development Program for the research grant and the Center of Integrative Health, the Premier Research Institute of Science and Mathematics (PRISM) for the administrative support and laboratory facilities

Conflict of Interest

The authors declare that they have no conflict of interest.

Funding: No funding sources 

Ethical approval: The study was approved by the Institutional Ethics Committee of Mindanao State University-Iligan Institute of Technology

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