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Systematic Review

A Comprehensive Review of the Ethnobotanical Uses, Pharmacological, and Toxicological Profiles of Piper capense L.f. (Piperaceae)

by
Gabriel Tchuente Kamsu
* and
Eugene Jamot Ndebia
Department of Human Biology, Faculty of Medicine and Health Sciences, Walter Sisulu University, 5117 Nelson Mandela Drive, Mthatha 5100, South Africa
*
Author to whom correspondence should be addressed.
Drugs Drug Candidates 2024, 3(3), 598-614; https://doi.org/10.3390/ddc3030034
Submission received: 2 July 2024 / Revised: 21 August 2024 / Accepted: 5 September 2024 / Published: 9 September 2024
(This article belongs to the Section Drug Candidates from Natural Sources)
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Abstract

Commonly known as wild pepper, Piper capense (P. capense) is a culinary herb mainly used as a secret in preparation of “Nkui” and “Nah poh” in Bayangam, West Cameroon. However, it also has many interesting pharmacological properties, which is why the people of sub-Saharan Africa so highly prize it for the treatment of multiple human pathologies. This study aimed to highlight the traditional uses, phytochemical composition, biological activities, and toxicological profile of the P. capense plant, to draw the attention of pharmaceutical companies to its enormous potential for the development of future phyto- or pharmaceutical products. Documentary research was meticulously carried out in the Web of Sciences, Scopus, Pubmed/Medline, and Google Scholar databases according to PRISMA 2020 guidelines. The results show that extracts and compounds isolated from Piper capense have interesting anticancer, antibacterial, antimalarial, hypoglycemic, anti-epileptic, and antidepressant activities. Methanolic extracts and essential oils from P. capense exhibit no harmful effects when directly applied to normal human hepatocytes, umbilical cord cells, intestinal cells, and keratinocyte cell lines. Additionally, methanolic extracts administered acutely or subchronically at low doses (≤250 mg/kg body weight) in Wistar rats also demonstrate no adverse effects. In conclusion, given its interesting activities, P. capense is a viable option for developing new antimalarial, anticancer, antibacterial, hypoglycemic, anti-epileptic, and antidepressant drugs. However, many avenues still need to be explored before translation into drugs.

1. Introduction

Throughout its evolution, humans have been confronted with various diseases and have tried to combat them using different approaches to survive [1]. Medicinal plants have played, and continue to play, a key role in the treatment and prevention of various diseases, with the prevalence of their use ranging from 50% in developed countries to 95% in developing countries [2,3]. Despite the development of various major therapies, their traditional uses for medicinal benefits are constantly increasing and are favored by local populations [4]. This enthusiasm for herbal medicine is justified first by growing concerns about the toxicity of the main therapies [5]. Secondly, the phenomenon of multi-drug resistance has led people to classify certain diseases as incurable in conventional medicine [6]. Recently, the use of medicinal plants has come to be seen as an alternative and complementary therapy used in association with other treatments [7,8].
An important source of secondary metabolites [9,10], the plant Piper capense Lin. f. (Piperaceae), or ‘wild pepper’, is commonly used in subtropical and tropical regions of Africa. The undersides of the leaves, upper shoots, and petioles have denser pubescence, setting it apart from other Piper species. The flower spikes are always extremely short, measuring less than 2 cm [11]. P. capense has a high culinary, economic, and medicinal value. This plant is widely distributed in southern, central, eastern, western, and southern Africa, as well as its therapeutic virtues are also intuitively known by great primates who consume its fruits [12].
To date, numerous individual studies have been published on P. capense. However, to our knowledge, no review has focused on this plant’s pharmacological potential and phytochemical composition. Historically, the natural products and related drugs that make up about 35% of the annual global medicine market are mostly derived from plants (25%) microorganisms (13%), and animals (3%), respectively [13]. This percentage is lower in the context of newly registered drugs. According to data from the US Food and Drug Administration (USFDA), new drug approvals in recent years (1562 drugs) show a variety of sources including 141 herb-al mixtures drugs (9.1%), 320 were derived from natural products drugs (21%), 64 pure natural drugs (4%), and 61 synthetic drugs (4%) [14]. However, the proportion derived from natural products and plants particularly, although small, is not negligible, and could be increased given the large diversity of plants worldwide. It is therefore important to review the bibliography on this plant’s various uses and activities to see how it can be used to solve public health problems. In this review, we have given an overview of the compounds isolated from P. capense, their biological activities, and their toxicological profile.

2. Results

2.1. Study Characteristics

A total of 41 studies were included in this study after a thorough database search of the 807 articles initially obtained (see Figure 1). However, the additional references cited provide background. The different studies, although spread over four (4) continents (Europe, America, Asia, and Africa), obtained their plant material from Africa. The plant material (Piper capense) used in these studies came from 7 African countries: Cameroon (15), South Africa (11), Kenya (4), Ethiopia (5), Comoros (3), the Democratic Republic of Congo (2), and São Tomé and Príncipe (1) (see Table 1). The main biological activities explored so far are antibacterial, antifungal, antimalarial, anticancer, antioxidant, anti-epileptic, antidepressant, and antimetabolic disorders.

2.2. Ethnobotanical Use of Piper capense

P. capense has many traditional medicinal uses (see Figure 2), some of which vary from country to country. In South Africa, its roots and fruits are used to treat convulsions and epilepsy [49], mental disorders [20,22], and neurological disorders such as Alzheimer’s [29]. P. capense leaves and roots are used in decoction as sleep aids [52]. The roots are used to treat tuberculosis, coughs, bronchitis, leprosy, and infertility [24]. In conventional medicine, the plant is also utilized to treat fungal infections [38], viral diseases, paralysis, kidney, and heart disease, and as a sexual stimulant [48]. In the Comoros, decoctions of P. capense are used by local people to treat diarrhea, abdominal pain, coughs, and malaria [16,23]. In Kenya, people use P. capense decoctions to treat diabetes [42], malaria, and depression [21]. In the Democratic Republic of the Congo, P. capense fruits are primarily used medicinally as a decoction to treat arterial hypertension [35]. In Ethiopia, the aerial parts of Piper capense are used to treat malaria and indigestion and are also employed as a spice [39]. In Cameroon, P. capense fruits are used as a flavor enhancer and spice in the preparation of ‘Nkui’, ‘Nah poh’, and many other traditional dishes [25]. It is also highly prized in the treatment of pathological infections such as tuberculosis [27], cancer [8,10,27], trypanosomiasis, Helminths [10], urinary tract infections, fever, stomach pain [31], antifungal infections [33], and typhoid fever. It is also used to treat flatulence/colic, sores, abundant leucorrhea, and sore throats and tongues [46].

2.3. Phytochemical Composition of P. capense

Numerous structurally different compounds have been isolated from P. capense via phytochemical studies thus far (Figure 3). Three neolignans: licarin A and B, and 7-(1,3-benzodioXol-5-yl)-7,8-dihydro-8-methyl-5-(2-propenyl)-furo [3,2-e]-1,3-benzodioXole; one benzophenanthridine alkaloid: nitidine isocyanate; two flavonoids, including a flavone, 5-hydroXy-7,4′-dimethoXy- flavone; one chalcone: cardamomin; a glycoside: β-sitosterol 3-O-β-D-glucopyranoside; three steroids, including two sterols: stigmasterol and β-sitosterol, as well as 2 triterpenes: lupeol and oleanolic acid [10]. Two amides: 4,5-dihydropiperine and piperine, were isolated from the ethonolic (1:10 w/v) extract of P. capense roots [49]. The methylene chloride extract of the aerial part of P. capense was used to isolate 1-[1-oxo-3(3,4-methylenedioxy-5-methoxyphenyl)-2Z-propenyl]piperidine and 3-(3-phenylpropanoyl)-7-oxa-3-aza-bicyclo[4.1.0]heptan-2-one, two amide alkaloids commonly known as Kaousine and Z-antiepilepsirine, respectively [16]. Compounds such as tetramethylbicyclo[8.1.0]undeca-2,6-diene, 5-hydroxy-7,4′-dimethoxyflavone, σ-copaene, safrole, β-myrcene, σ-cubebene, β-caryophyllene, germacrene D, α-muurolene, 1,5,9-cyclododecatriene, β-bisabolene, isoshyobunone, 1,5-hexadiene, 1,5-hydroxylene, aromandendrene, 3-tetradecen-5-yne, and 3-tetradecen-5-yne(17bicyclo[4.4.0]dec-1-ene, bicyclo[4.4.0]dec-1-ene, σ-cadinol were isolated from essential oils of P. capense fruits harvested in Ethiopia [39].
GC/MS analysis of the hydrodistilled essential oil of Piper capense from Kenya yielded compounds such as Monoterpene hydrocarbons (trans-Sabinene hydrate, Myrcene, Limonene, Terpinolene, α-Thujene, β-Pinene, Sabinene, Camphene, α-Phellandrene, para-Cymene, β-Phellandrene, (E)-β-Ocimene, α-Pinene, γ-Terpinene, (Z)-β-Ocimene); Oxygenated monoterpenes (cis-para-Menth-2-en-1-ol, 2-Nonanone, Terpinen-4-ol, Linalool, trans-para-Menth-2-en-1-ol, Camphor, Cryptone, Bornyl acetate, trans-Piperitol, Anethole, Piperitone, Safrole); Arylpropanoids (Asaricin, Myristicin, Elemicin, Apiole); Sesquiterpene hyrocarbons (γ-Elemene, β-Cubebene, (E)-Caryophyllene, (Z)-β-Farnesne, α-Cubebene, allo-Aromadendrene, β-Bourbonene, α-Copaene, α-Humulene, Germacrene B, γ-muurolene, β-Bisabolene, β-Selinene, δ-Cadinene, Bicyclogermacrene, Germacrene D, α-Muurolene); Oxygenated sesquiterpenes (5-epi-7-epi-α-Eudesmol, Spathulenol, Shyobunol, Caryophyllene oxide) [28]. However, GC-MS analysis of the essential oil of fruit from Cameroon detected the presence of cis-Sabinene hydrate, δ-3-Carene, Borneol, Myrtenal, Terpinen-4-ol, Camphor, α-Terpinene, 1,8-Cineole, Pinocarvone, α-Terpineol, Myrtenol, trans-Pinocarveol, Isobornyl acetate, β-Elemene, (E)-Caryophyllene, 6,9-Guaiadiene, α-Humulene, trans-Muurola-4(14),5-diene, α-Muurolene, β-Copaene, n-Pentadecane, trans-Calamenene, Germacrene B, (E)-β-Farnesene, Spathulenol, (E)-Nerolidol, δ-Cadinene, Caryophyllene oxide, 1,10-di-epi-Cubenol, trans-Cadina-1,4-diene, Salvial-4(14)-en-1-one, Humulene epoxide II, Caryophylla-4(12),8(13)-dien-5-ol, Cubenol, α-Muurolol, Eudesma-4(15),7-dien-1-β-ol which are not present in the Kenyan variety [9]. Phytochemistry using the GC-MS method of the essential oils of the fruits of P. capense yielded 21 compounds in Ethiopia, 52 compounds in Kenya, and 62 compounds in Cameroon, showing that the phytochemical composition of this plant varies from one country to another and is justified by the variation in its medicinal uses from one country to another.

2.4. Pharmacological Properties of Piper capense

2.4.1. Antibacterial Activity of P. capense

Piper capense extracts have a large spectrum of activity as detailed in Table 2. Against bacteria of the Staphylococcus genus, in particular Staphylococcus aureus ATCC12600 and Staphylococcus epidermidis, the methanolic extract of Piper bark has significant activity (MIC of 0.52 mg/mL) [15]. The work of Green et al. [24] reported significant activities (MIC = 100 µg/mL) with the acetone extract of the roots against strain ATCC25177 and resistant clinical isolates of Mycobacterium tuberculosis obtained in South Africa. In Cameroon, Tekwu et al. [26] reported moderate activity (MIC of 512 µg/mL) with methanolic extracts on test strains (M. tuberculosis ATCC27294 and ATCC25177). Fankam et al. [32] reported moderate activity (MIC = 256 µg/mL) against E. coli strain ATCC10536 and isolates of E. aerogenes EA294, K. pneumoniae KP63, and P. stuatuii NEA16 with methanolic extracts of P. capense fruits. Root extracts of P. capense are highly active (9 mm < inhibition diameter < 11 mm) against Streptococcus pyogenes, S. aureus, and Corynebacterium xerosis at a concentration of 100 µg/mL [50]. The essential oil of P. capense fruits and its main constituents ((E)-caryophyllene, β pinene, and α pinene) have interesting activities (6 cm ≤ inhibition diameter ≤ 10 cm) against multi-resistant E. coli ATCC 25922, E. faecalis ATCC 29212, P. aeruginosa ATCC 27853, and S. aureus ATCC 25923 [9].

2.4.2. Antifungal Activities of P. capense

The antifungal activities of P. capense extend over a wide range of fungi as detailed in Table 3. The methanolic extract of its bark has significant activity against strain ATCC10231 and resistant clinical isolates of Candida albicans (MIC = 0.56 mg/mL) [18]. The methylene chloride-methanol extract (1:3 v/v) has significant activity against Cryptococcus neoformans and Cryptococcus lusitaniae (MIC = 1.56 mg/mL) and moderate activity against C. albicans, C. guiliermondii, C. parapsilosis, and C. krusei, (MIC of 3.12 mg/mL) [33]. The acetone extract of the roots showed significant activity against Candida neoformans (MIC = 0.12 mg/mL), and C. albicans and C. krusei (MIC = 1.88 mg/mL). However, the hexane extract of its roots had moderate activity against C. Kruseii, and C. albicans (MIC = 3.75 mg/mL) [33]. The essential oil of P. capense fruits and its main constituents ((E)-caryophyllene, β pinene, and α pinene) have interesting activities (8 cm ≤ inhibition diameter ≤ 11 cm against multi-resistant Candida albicans ATCC24433) [9]. Similarly, a 1:2000 dilution of P. capense essential oil of the fruits has interesting activity against Gloeophyllum trabeum ATCC11539, Coniophora puteana ATCC9351, and Coriolus versicolor ATCC12679 [47].

2.4.3. Antimalarial Activities of P. capense

The methanolic extract of P. capense has significant anti-Plasmodium falciparum activity (IC50 < 10 µg/mL) [21]. Similarly, the methylene chloride extract showed significant anti-plasmodial activity (IC50 = 7 µg/mL) against P. falciparum species resistant to chloroquine, pyrimethamine, and proguanil from Vietnam [23]. The essential oil of Piper capense also has interesting anti-larval activities on Anopheles gambiae, with LC90 and LC50 values of 85.0 and 34.9 ppm, respectively [40]. The anti-larval activity of this essential oil of P. capense was superior to that of the commercial larvicide Pylarvex®. The ethyl acetate fraction of Piper capense also showed adulticidal activity (Anopheles arabiensis) with LC90 and LC50 values of 30.59 and 10.72 ppm, respectively [43,44]. P. capense essential fruit oils also have insecticidal activity with an LD50 = 16.1 µL/g [37]. Two amide alkaloids: Z-antiepilepsirine and Kaousine isolated from P. capense have significant activity (IC50 = 7 and 20 µg/mL, respectively) against Plasmodium falciparum type W2 resistant to proguanil, pyrimethamine and chloroquine from Vietnam [16]. Summaries of antimalaria activities are given in Table 4.

2.4.4. Anticancer Activities of P. capense

The methanolic extract of P. capense has been reported to have cytotoxic activity in vitro on multiple cancer cell lines as detailed in Table 5. This extract has selective cytotoxicity against cell line of murine melanoma B16-F10 (IC50 = 47.38 µg/mL) [8]; cell line of leukemia CCRF-CEM (6.95 ≤ IC50 ≤ 7.03 µg/mL), CEM/ADR5000 (IC50 = 6.56 µg/mL), HL60AR (IC50: 11.22 µg/mL), and HL60 (IC50 = 8.16 µg/mL); cell line of glioblastoma U87MG.ΔEGFR (IC50 = 7.44 µg/mL) and U87MG (IC50 = 13.48 µg/mL); cell line of colon carcinoma HCT116 p53−/− (IC50: 4.62 µg/mL) and HCT116 p53+/+ (IC50: 4.64 µg/mL); cell line of mammary adenocarcinoma MDA-MB231/BCRP (IC50 = 19.45 µg/mL), and MDAMB231 (IC50 = 4.17 µg/mL) [25,27]. This extract induced apoptosis of CCRF-CEM cells by increasing the production of ROS and the loss of MMPs, which are the mechanisms by which methanolic extract induces apoptosis of cancer cells [27]. P. capense essential oil has activity against human colon carcinoma HCT116, breast adenocarcinoma MDA-MB 231, and malignant melanoma A375, with, respectively, IC50 values of 26.3, 22.7, and 76.0 μg/mL [9]. The main constituents of P. capense essential oil, (E)-Caryophyllene and β-Pinene, have low IC50 according to the classification scale of Kuete and Efferth [54]. Licarin A, one of the compounds isolated from P. capense methanolic extract, also has excellent activity on cancerous lines, with cytotoxic activity ranging from 4.31 μM to 21.77 μM against CCRF-CEM (leukemia cells) and HCT116p53−/− (knockout clone of colon cancer cells), respectively [10]. This compound acts by inducing apoptosis in cancer cells via the activation of caspases 3/7, 8, and 9, alteration of MMPs, and increased production of ROS [10]. The work of Wamba et al. [8] reported that in vivo, methanolic extract of P. capense alone (at 100 mg/kg) and in association with dacarbazine (80 mg/kg + extract at 100 mg/kg) prevented the progression and clonogenicity of B16-F10 melanoma cells in C57BL/6J mice.

2.4.5. Antioxidant Activities of P. capense

The antioxidant power of P. capense has been demonstrated in several studies. The methanolic extract has the ability to reduce 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) (IC50 = 40.2 μg/mL) [19,29], 2,2-Diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 44.3 μg/mL) [29,30], and RNS (Reactive Ritrogen Species) (IC50 = 635.4 μg/mL) [30], Ferric Reducing Antioxidant Power (FRAP), and Phosphomolybdenum antioxidant power (PAP) (127.97 et 164.54 mg ascorbic acid equivalent/g of extract, respectively) [19]. Ethanolic extract, essential oil, and the compound 5-hydroxy-7,4′dimethoxyflavone have IC50 ≤ 25 μg/mL [39]. The essential oil of P. capense protects the cosmetic cream from oxidation during the accelerated aging process [45]. Therefore, the creams’ protective effect can also be applied to the skin to prevent premature aging. These antioxidant activities are justified by the high phenolic compound content of P. capense, which is renowned for its antioxidant activities. This plant contains approximately 480 mg gallic acid/g of extract of total phenol, 250 mg quercetin/g of extract of flavonoids [29,30], and 88.34 mg tannic acid/g of extract of tannins [19].

2.4.6. Activities of P. capense on Nervous System Pathologies

P. capense is active against a wide range of nervous system pathologies. Flumazenil’s (Ro 15-1788) binding is competitively inhibited by the ethanolic extract, which explains why it has been used traditionally to treat epilepsy. The extract binds to GABAA-benzodiazepine receptors with an effective 84.1% binding rate [22]. Similarly, piperine (IC50 = 1.2 mM) and 4,5-dihydropiperine (IC50 = 1.0 mM) isolated from the ethanolic extract have significant affinities for the benzodiazepine site of the GABAA [55]. Ethyl acetate and ethanolic extracts of the roots have good acetylcholinesterase inhibitory activities with IC50 ≤ 40.7 μg/mL [29]. Likewise, P. capense aqueous extract could have antidepressant activity, being able to remove over 60% and 79% of the [3H]citalopram bound to the transport protein at 1 and 5 mg/mL, respectively [20].

2.4.7. Activity of P. capense against Metabolic Disorders

Oral administration of a 25 mg/kg body weight dose of Piper capense aqueous extract normalizes induced hyperglycemia after 4 h in Mice, indicating the plant’s anti-diabetic activity [42].

2.5. Toxicological Profile of P. capense

The toxicological profile of P. capense has been documented in several studies to date. The methanolic extract was found to be less harmful against AML12 normal hepatocytes (IC50 > 40 μg/mL) [10,27] and HUVEC human umbilical cord cells (IC50 > 80 μg/mL) [25,27]. The essential oil of P. capense has weak cytotoxic effects against intestinal cell lines (Caco-2) (IC50 = 950 μg/mL) and human keratinocyte cell lines (HaCaT) (IC50 = 540 μg/mL) [45]. The acute toxicological study of the methanolic extract revealed no deaths or behavioral disorders in Wistar rats, with an LD50 > 5000 mg/kg [31]. Repeated administration of the methanolic extract of this plant for 28 days revealed no toxicity effects on the liver, kidney, hematological system, or physical health at doses of 250 mg/kg in Wistar males and females, but toxicity could be possible at dose >1000 mg/kg body weight/day [31].

3. Discussion, Critical Assessment, and Future Work

This work compiles recent data on pharmacological and toxicological investigations, phytochemical composition, and traditional uses of Piper capense. It also identifies gaps in existing research and proposes future study directions. The study revealed 31 traditional uses of Piper capense, most of which have been scientifically confirmed by in vitro and/or in vivo studies, and many of these uses are similar to those reported for Piper guineense [56,57]. This similarity may be due to their shared genus and similar habitats, although variations in secondary metabolite composition based on climate and soil type [58] could explain these similarities. Piper capense is a rich source of secondary metabolites, including approximately 92 compounds from alkaloids, phenolic compounds, and terpenes [9,10,16,28,39,49], many of which are common to other Piper species [59,60]. This study also confirms that all research on Piper capense has utilized plant material sourced from Africa, a fact previously noted by [12].
The methanolic extract of Piper capense demonstrates significant activity against various cancers, fungi, and bacteria, including tuberculosis and multidrug-resistant malaria, without being toxic to healthy cells [31]. Compounds such as Z-antiepilepsirine, Kaousine, Licarin A, and piperine also show significant activity against multidrug-resistant malaria, cancer, and nervous system pathologies, respectively, while remaining non-toxic to normal cells [10,27,45]. Studies indicate that plant extracts or fractions may exhibit greater activity against certain cancer cell lines than the purified compounds due to synergistic effects [61]. However, only two studies [8,33] have reported in vivo activities of extracts, and no in vivo studies have been conducted on compounds. In contrast to in vitro tests, where cells are directly exposed to biocidal substances, in vivo conditions involve additional factors such as camouflage in hollow tissues, drug resistance, and bioavailability challenges [62,63,64]. Thus, further in vivo studies are essential to verify if observed in vitro activities are preserved or enhanced in living organisms.
The biological activities reported for Piper capense have also been observed in Piper nigrum and Piper longum. The methanolic extract and essential oil of Piper capense exhibit antibacterial activity comparable to that of Piper nigrum against S. aureus (MIC = 520 µg/mL) and E. coli (MIC = 520 µg/mL) on the same strains [65]. Similarly, P. longum and Piper capense have demonstrated comparable antibacterial activity, with an MIC of 100 µg/mL against M. tuberculosis [66]. Regarding antifungal activities, the essential oils of P. longum and Piper betle have shown MIC values ranging from 400 to 500 µg/mL against C. albicans, which are similar to those observed with P. capense (MIC = 560 µg/mL) [67,68]. In terms of antimalarial activity, the methanolic extract of P. capense displays superior activity against P. falciparum (IC50 < 10 µg/mL) compared to P. longum (IC50 = 12 µg/mL) and Piper nigrum (IC50 = 15 µg/mL). For anticancer activity, P. capense, P. nigrum, and P. longum exhibit similar effects with IC50 values ranging from 20 to 30 µg/mL against breast and prostate cancer cells [67,69]. Furthermore, all three species (P. capense, P. nigrum, and P. longum) share neuroprotective effects, evidenced by their inhibition of acetylcholinesterase [70,71], and exhibit hypoglycemic effects, with similar outcomes in glucose regulation studies [72].
Additionally, Piper capense shares pharmacological properties with other Piper species, including anti-inflammatory, antioxidant, and antimicrobial activities, attributed to its alkaloids (Piperine, Piperidine, and Piperlongumine) and flavonoids (Quercetin and Rutin) [73]. Like Piper guineense, Piper nigrum, and Piper longum, Piper capense is traditionally used for digestive health and general wellness, although differences in compound concentrations lead to unique therapeutic profiles [74].
Key limitations include the lack of extensive pharmacological studies on Piper capense compounds, variations in extract activity due to harvesting conditions, and the predominance of in vitro studies. While significant in vivo activity has been observed in animal models, clinical studies are still lacking. It is important to conduct more in vivo research and repeat studies with purified compounds to ensure result reproducibility. Additionally, many antifungal studies rely on visual observation, which may compromise the result reliability. Future research should focus on the pharmacokinetics of Piper capense extracts and compounds, and clinical studies to maximize the plant’s potential. Despite frequent use in treating arterial hypertension in the DRC [35], this evidence remains unconfirmed. Another limitation of our study is that, although IC50 values are presented, we were unable to establish the statistical significance of these results. Future studies should explore the biological activity of purified compounds, metabolic profiling, and metabolomics to discover new therapeutic agents and enhance understanding of the plant’s pharmacological properties. Exporting Piper capense for cultivation on other continents may also reveal new compounds or enhance its biological activities. It is crucial to emphasize the need for in vivo studies and clinical trials to validate the efficacy and safety of Piper capense as a therapeutic agent. These studies are essential to establish the plant’s therapeutic potential and ensure that it can be used safely in clinical practice. Further investigation into the pharmacokinetics and pharmacodynamics of the active compounds in Piper capense is also recommended. Such research would provide valuable insights into the absorption, distribution, metabolism, and excretion of these compounds, as well as their mechanisms of action, thereby supporting the development of effective and safe therapeutic applications.

4. Materials and Methods

4.1. Data Sources, Search Strategy, and Eligibility Criteria

Scientific literature published before May 2024 was collected in Web of Sciences, Scopus, PubMed/Medline, and Google Scholar databases and methodically evaluated in this work according to the PRISMA 2020 guidelines (see Supplementary Materials Table S1) [75,76]. The search terms included “Piper capense”; OR “Piper spp.” AND “Traditional uses” AND “Phytochemistry” AND “Biological activity” OR “Pharmacological activity” AND “Toxicity” OR “Toxicology profile” OR “Cytotoxicity”. Studies were included if they evaluated, in primary or secondary objectives, the ethnobotanical or ethnopharmacological potential, the phytochemical composition, as well as the biological and toxicological properties of Piper capense. Only studies that were original and had been published were included. Studies focusing on other species of the genus Piper were excluded from this work. Review articles, conference abstracts, and editorials were also excluded. No restrictions as to the language of the research or date were applied to this study.

4.2. Selection Process and Data Collection

The search results were first exported to Endnote, where duplicates were removed, and then transferred to the Rayyan 1.4.4. software to better organize the selection and review process [77]. The authors (EJN and GTK) independently screened the titles and abstracts. Then, a second independent selection was carried out by examining the full text of the articles retained at the end of the first review. Any disagreement was resolved via discussion. Outcomes such as traditional use, phytochemical composition, biological activities, and toxicology of piper extracts and active metabolites were extracted from the various studies. For biological activities, study results (MIC, IC50, therapeutic doses, etc.) were extracted, while for toxicological properties, concentrations or doses without adverse effects were independently extracted from the studies by the authors.

4.3. Synthesis Methods

The data synthesis and analysis were conducted systematically, starting with a broad overview of the studies before systematically categorizing them to obtain more detailed insights. A comprehensive summary table was created to effectively encapsulate the characteristics of the included studies. Given that this was a systematic review, a narrative synthesis was employed, following the guidelines established by [78]. The studies were evaluated based on criteria including relevance, reliability, validity, and applicability to assess their quality. To appraise the quality of the evidence, the authors utilized the GRADE system [79].

5. Conclusions

In this review, we showed that Piper capense is a viable option for pharmaceutical companies looking to produce novel medications. Its most promising fields of action are multi-resistant cancers, multi-resistant microbes and parasites (Plasmodium falciparum), diabetes, and nervous system pathologies (epilepsy, depression, etc.). We advise researchers and pharmaceutical companies to further investigate this plant due to its lower in vitro and in vivo toxicity. Potential uses for this plant include nutraceuticals, phytomedicines that can be used in conjunction with conventional medicines for synergistic effects, and novel medicines based on their secondary metabolites.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ddc3030034/s1, Table S1: PRISMA 2020 Checklist.

Author Contributions

All authors have participated in conceptualization, methodology, software, validation, formal analysis, investigation, resources, and data curation. Writing—original draft preparation, G.T.K.; writing—review and editing, E.J.N.; visualization, E.J.N.; supervision, E.J.N.; project administration, G.T.K.; funding acquisition, E.J.N. All authors have read and agreed to the published version of the manuscript.

Funding

We thank the National Research Foundation (NRF) and the Medical Research Council (MRC) for supporting this work (Grants number: SRUG200512521370).

Acknowledgments

We also acknowledge the assistance of the librarian in helping us create the search strategies that we used to find studies in the databases, as well as Walter Sisulu University for providing free internet.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Flow diagram for the selection of the studies.
Figure 1. Flow diagram for the selection of the studies.
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Figure 2. Summary illustration of the medicinal uses of P. capense. The plant image source is [53].
Figure 2. Summary illustration of the medicinal uses of P. capense. The plant image source is [53].
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Figure 3. Structure of the different molecules extracted from Piper capense [10,16,28,49].
Figure 3. Structure of the different molecules extracted from Piper capense [10,16,28,49].
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Table 1. Characteristics of the included studies.
Table 1. Characteristics of the included studies.
Country of StudyOrigin of P. capenseExtract/CompoundsModel of the StudyType of ScreeningMicroorganisms or Species Used for ToxicologyReferences
South AfricaSouth AfricaMethanolic extract
Aqueous extract		In vitro antibacterial activityMIC methodsS. epidermidis, S. aureus[15]
FranceComoros CH2Cl2 extract/Kaousine/Z-antiepilepsirine/apigenine dimethyletherIn vitro antiplasmodial activityIC50
Cytotoxicity methods		Plasmodium falciparum type W2 resistant to chloroquine, pyrimethamine, proguanil[16]
PortugalSão Tomé and PríncipeEssentials oilsPhytochemical composition GC and GC-MS methods/[17]
South AfricaSouth AfricaMethanolic extract
Aqueous extract		In vitro AntifungalMIC methodsCandida albicans ATCC10231 and 5 clinical isolates[18]
IndiaCameroon Methanolic extractPhytochemistry composition and in vitro AntioxidantABTS, DPPH, PAP, and FRAP methods,
and HPLC analysis		/[19]
South AfricaSouth Africa70% ethanolic extractIn vitro antidepressantAffinity to the serotonin reuptake transport protein methodsSuspension of Albino Wistar rat brains[20]
USAKenyaChloroform extractIn vitro antimalarialD6 clone methods
cytotoxicity methods		D6 clone of Plasmodium falciparum.
Human Oral epidermoid cancer (KB).		[21]
South AfricaSouth Africaethanolic extractIn vitro anti-epilepticAffinity to the GABA-benzodiazepine receptor assaySuspension of Albino Wistar rat brains[22]
FranceComorosDecoction extractIn vitro antimalarial and Antiproliferative activitiesParasitaemia determination, and Cytotoxicity assay on THP1Plasmodium falciparum type W2 resistant to chloroquine, pyrimethamine, proguanil
Human monocytic THP1 cells		[23]
South AfricaSouth AfricaAcetone extractIn vitro antituberculosisREMA assayMycobacterium tuberculosis H37Ra ATCC 25177[24]
GermanyCameroonMethanolic extractIn vitro anticancerCytotoxicity methodsMiaPaCa-2, multidrug resistant CCRF-CEM, and CEM/ADR5000[25]
CameroonCameroonMethanolic extractIn vitro antibacterial activityMIC and MBC methodsMycobacterium tuberculosis H37Ra (ATCC 25177) and H37Rv (ATCC 27294)[26]
GermanyCameroonMethanolic extractIn vitro anticancerCytotoxicity using MTT methodsCCRF-CEM, HL-60, HL60AR, MDA-MB231, MDA-MB231BCRP, HCT116P53+/+, HCT116P53−/−, U87MG, U87MG∆EGFR, Hep-G2, and AML12[27]
GermanyCameroonMethanolic extractIn vitro anticancerCytotoxicity using MTT methodsCCRF-CEM, resistant CEM/ADR5000, MDA-MB231-pcDNA, MDA-MB231-BCRP, HCT116P53+/+, HCT116P53−/−, U87MG, resistant U87MG∆EGFR, Hep-G2, and AML12[10]
KenyaKenyaEssentials oilsPhytochemical composition and in vitro antiplasmodial activityGC-MS methods
Larvicidal assays		Anopheles gambiae[28]
South AfricaSouth AfricaMethanolic extract
Ethyl-acetate extract		In vitro anti-Alzheimer’s and antioxidant activitiesAcetylcholinesterase inhibitors assays/[29]
EthiopiaEthiopiaMethanolic extract
Aqueous extract		In vitro AntioxidantDPPH, RNS, FRAP assays/[30]
CameroonCameroonMethanolic extractIn vivo toxicology profileAcute and subchronic assaysAlbino Wistar rats (Male and female)[31]
CameroonCameroonMethanolic extractIn vitro antibacterial activityMIC, MBC assaysE. coli (8 strains), E. aerogenes (7 strains), E. cloacae (3 strains), K. pneumoniae (5 strains), P. stuartuii (4 strains), P. aeruginosa (2 strains)[32]
CameroonCameroonMethanolic extractIn vitro and in vivo antifungal activityMIC, MFC assays
Animal induction and treatment methods		C. albicans, C. neoformans, C. tropicalis, C. krusei, C. parapsilosis, C. lusitaniae, C. guillermondii, C. glabrata
Animal model: Albino Wistar rats		[33]
CameroonCameroonMethanolic extractIn vitro antibacterial and antifungal activitiesMIC, MBC, MFC assaysC. albicans, S. saprophyticus, S. typhi, S aureus, K. pneumoniae, E. coli[34]
Democratic Republic of CongoDemocratic Republic of CongoInfusion extractAntihypertension activityEthnopharmacological assays/[35]
India CameroonMethanolic extractIn vitro and in vivo anticancer activityCytotoxicity using MTT methods; Animal Induction and treatment methodsB16-F10 murine melanoma
Male mice strain C57BL/6J		[8]
CameroonCameroonEssential oilsIn vitro insecticidal and antifungal activitiesFumigation assay
MIC, MFC assays		Acanthoscelides obtectus insects
Fungi (A. flavus, A. niger, F. solani, F. nivale, Penicillium sp., F. oxysporum, F. crookwellense, F. moniliforme)		[36]
CameroonCameroonEssential oilsIn vitro insecticidal activityContact toxicity assaySitophilus zeamais insects[37]
South AfricaSouth AfricaAcetone and hexane extractsIn vitro antifungal activityMIC, MFC assaysC. albicans, C. krusei, C. neoformans[38]
EthiopiaEthiopiaAcetate and n-hexane: EtOAc extracts
Essential oils		phytochemical composition and in vitro antioxidantTLC, GC-MS analysis
DPPH, FRAP assays		/[39]
KenyaKenyaEssential oilsphytochemical composition and in vitro Antifungal activityMIC assaysAspergillus spp. (10 strains), Fusarium spp. (16 strains), Penicillium spp. (14 strains)[40]
South AfricaSouth AfricaEthanolic extractIn vitro antibacterial activityMIC, MBC assaysMethicillin-sensitive Staphylococcus aureus (ATCC 12600)[41]
KenyaKenyaAqueous extractIn vivo anti-diabetic activityProvokes Hyperglycemia methodsAlbino mice[42]
CameroonCameroonEssential oilsIn vitro antioxidant, anticancer and antimicrobial activitiesDPPH, ABTS, TEAC, MIC, Cytotoxicity using MTT methodsMDA-MB 231, A357, HCT116 cells lines
Bacteria (S. aureus, E. faecalis, E. coli, P. aeruginosa, C. albicans)		[9]
EthiopiaEthiopiaMethanolic extractPhytochemical composition and in vitro antiplasmodial activityHPLC methods
Larvicidal and Insecticidal assays		Anopheles arabiensis[43]
EthiopiaEthiopiaMethanolic extractIn vitro antiplasmodial activityLarvicidal and Insecticidal assaysAnopheles arabiensis[44]
CameroonCameroonEssential oilsIn vitro Antioxidant activity in cosmetic cream
In vitro toxicity		GC-MS analysis; BRAI, PI tests; Cytotoxicity using MTT methodsHuman Keratinocytes (HaCaT), intestinal (Caco-2) cell lines[45]
CameroonCameroonAqueous extractAnti-epilepsy activityEthnobotanical/[46]
MoroccoComorosEssential oilsPhytochemical composition and in vitro Antifungal activityGC-MS methods
MIC assays		Gloeophyllum trabeum ATCC 11539
Poria placenta ATCC 9891, Coniophora puteana ATCC 9351, Coriolus versicolor ATCC 12679		[47]
South AfricaSouth AfricaAqueous extractIn vitro Antiparasitic activityAnti-protozoan assaysTrichomonas vaginalis[48]
DernmarkSouth AfricaPiperine/4,5-dihydropiperineIn vitro anti-epilepsy activityAffinity to the GABA-benzodiazepine receptor assaySuspension Rat brain cortex[49]
South AfricaSouth AfricaAqueous extractIn vitro antibacterial activityDisc diffusion methodsB. cereus, S. aureus, B. subtilis, S. pyogenes, E. coli, Shigella spp., S. typhi, P. aeruginosa, P. mirabilis/vulgaris[50]
EthiopiaEthiopiaEthyl acetate extractPhytochemical compositionTLC analytical/[51]
Democratic Republic of CongoDemocratic Republic of CongoMethanolic extractIn vitro Antioxidant activityDPPH assays/[12]
Table 2. Summary of antibacterial efficacy for Piper capense extracts and compounds.
Table 2. Summary of antibacterial efficacy for Piper capense extracts and compounds.
Extracts/CompoundsBacteria StrainsActivities (MIC)Evaluation MethodsReferences
Methanolic extractStaphylococcus aureus ATCC12600, and Staphylococcus epidermidis0.52 mg/mLPlate-hole diffusion and broth microdilution[15]
M. tuberculosis ATCC27294 and ATCC25177512 µg/mLResazurin microplate assay[26]
E. coli ATCC10536 and isolates; E. aerogenes EA294, K. pneumoniae KP63, and P. stuatuii NEA16256 µg/mLPlate-hole diffusion and broth microdilution[32]
Streptococcus pyogenes, S. aureus, and Corynebacterium xerosis11, 10, and 9 mm, respectively, at 100 µg/mLDisc diffusion test[50]
Acetone extractM. tuberculosis ATCC25177 and clinical isolate Mtb2 100 µg/mLResazurin microplate assay [24]
Fruit hydrolateS. saprophyticus, S. aureus, S. epidermidis, E. colis, K. pneumoniae, S. typhi7, 185, 556, 2, 62, and 21 µg/mL, respectivelyPlate-hole diffusion and broth microdilution[34]
Ethanolic extractMethicillin-sensitive S. aureus ATCC 6126003.125 mg/mLPlate-hole diffusion and broth microdilution[41]
Essential oilE. coli ATCC 25922, E. faecalis ATCC 29212, P. aeruginosa ATCC 27853, and S. aureus ATCC 259236, 10, 6, 10 mm respectivelyDisc diffusion test[9]
α pinene, 6 mm on all bacteria
(E)-caryophyllene,8, 10, 6, and 8 mm, respectively
β pinene6 mm on all bacteria
Table 3. Summary of antifungal efficacy for Piper capense extracts and compounds.
Table 3. Summary of antifungal efficacy for Piper capense extracts and compounds.
Extracts/CompoundsFungal StrainsActivities (MIC)Evaluation MethodsReferences
Methanolic extractC. albicans ATCC10231, and clinical isolates (U1, U7, M42, M43, and M44)0.56 mg/mLPlate-hole diffusion and macro-broth tube dilution[18]
C. albicans, C. neoformans, C. tropicalis, C. krusei, C. parapsilosis, C. lusitaniae, and C. guiliemondi3.12, 1.56, 0.19, 3.12, 3.12, 1.56, 3.12 mg/mL, respectivelyPlate-hole diffusion and broth microdilution with INT as revelator[33]
Acetone extractC. albicans, C. krusei, C. neoformans1.88, 1.88, and 0.12 mg/mL with INT as revelatorPlate-hole diffusion and broth micro-dilution with INT as indicator[38]
Hexane extract3.75, 3.75, and 7.5 with INT as revelator
Aqueous extractC. albicans ATCC10231, and clinical isolates (U1, U7, M42, M43 and M44)4.97, 4.97, 2.48, 4.97, 1.24, and 1.24 mg/mL, respectivelyPlate-hole diffusion and macro-broth tube dilution[18]
Fruit hydrolateTricophyton rubrum, and Candida albicans185, and 556 µg/mL, respectivelyPlate-hole diffusion and broth microdilution[34]
Essential oilA. flavus, A. niger, F. solani, F. nivale, Penicillium sp., F. oxysporum, F. crookwellense, F. moniliforme4.1 mg/mL < MIC < 16.32 mg/mL Plate-hole diffusion and macro-broth tube dilution[36]
Penicillium claviforme, F. graminearum, F. moniliforme, F. sporotrichoides, F. proliferatum, A. niger, A. fumigatus, A. ochraceus, A. wentii, 33.1 mg/mLDisc diffusion test[40]
Gloeophyllum trabeum ATCC 11539
Poria placenta ATCC 9891, Coniophora puteana ATCC 9351, Coriolus versicolor ATCC 12679		1/2000 (v/v)Disc diffusion test[47]
C. albicans8 mmDisc diffusion test[9]
α pinene11 mm
β pinene9 mm
(E)-caryophyllene6 mm
Table 4. Summary of antimalarial efficacy for Piper capense extracts and compounds.
Table 4. Summary of antimalarial efficacy for Piper capense extracts and compounds.
Extracts/CompoundsParasite/Insects TypeActivities (IC50)References
Methanolic extractPlasmodium falciparum<10 µg/mL[21]
Methylene chloride extractP. falciparum species resistant to chloroquine, pyrimethamine, and proguanil7 µg/mL[23]
Essential oilAnopheles gambiae34.9 ppm (LC90 = 85.0 ppm), LD50 = 16.1 µL/g[37,40]
Ethyl acetate fractionAnopheles arabiensis10.72 ppm (LC90 = 30.59)[43,44]
Z-antiepilepsirinePlasmodium falciparum type W2 resistant to proguanil, pyrimethamine, and chloroquine7 µg/mL[16]
Kaousine20 µg/mL
Table 5. Summary of anticancer efficacy for Piper capense extracts and compounds.
Table 5. Summary of anticancer efficacy for Piper capense extracts and compounds.
Extracts/CompoundsCancer Cell LinesActivities (IC50)References
Methanolic extractB16-F1047.38 µg/mL[8]
MiaPaCa-2, multidrug resistant CCRF-CEM, and CEM/ADR50008.96, 7.03, and 6.56 µg/mL[25]
CCRF-CEM, HL-60, HL60AR, MDA-MB231, MDA-MB231BCRP, HCT116P53+/+, HCT116P53−/−, U87MG, U87MG∆EGFR, and Hep-G236.95, 8.16, 11.22, 4.17, 19.45, 4.64, 4.64, 13.48, 7.44, 16.07 µg/mL, respectively[27]
Licarin ACCRF-CEM, resistant CEM/ADR5000, MDA-MB231-pcDNA, MDA-MB231-BCRP, HCT116P53+/+, HCT116P53−/−, U87MG, resistant U87MG∆EGFR, Hep-G2, and AML1210.9, >50, 29.1, 33.5, 11.3, 12.6, 28.4, 9.5, 10.3, and >50 µg/mL, respectively[10]
Licarin B 4.3, 7.3, 17.9, 17.9, 14.5, 21.8, 10.7, 8.4, 10.0, and > 50, µg/mL, respectively
nitidine isocyanate 15.2, 33.2, 21.7, >50, >50, >50, 25.2, >50, >50, >50 µg/mL, respectively
5-hydroXy-7,4′-dimethoXy-flavone9.6, 29.4, >50, >50, 33.0, >50, 4.6, 11.6, >50, >50 µg/mL, respectively
Essential oilMDA-MB231, A375, HCT11626.3, 76.0, 22.7 µg/mL, respectively[9]
β-Pinene78.5, >200, and 59.2 µg/mL, respectively
(E)-caryophyllene45.3, 63.3, and 55.7 µg/mL, respectively
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Kamsu, G.T.; Ndebia, E.J. A Comprehensive Review of the Ethnobotanical Uses, Pharmacological, and Toxicological Profiles of Piper capense L.f. (Piperaceae). Drugs Drug Candidates 2024, 3, 598-614. https://doi.org/10.3390/ddc3030034

AMA Style

Kamsu GT, Ndebia EJ. A Comprehensive Review of the Ethnobotanical Uses, Pharmacological, and Toxicological Profiles of Piper capense L.f. (Piperaceae). Drugs and Drug Candidates. 2024; 3(3):598-614. https://doi.org/10.3390/ddc3030034

Chicago/Turabian Style

Kamsu, Gabriel Tchuente, and Eugene Jamot Ndebia. 2024. "A Comprehensive Review of the Ethnobotanical Uses, Pharmacological, and Toxicological Profiles of Piper capense L.f. (Piperaceae)" Drugs and Drug Candidates 3, no. 3: 598-614. https://doi.org/10.3390/ddc3030034

APA Style

Kamsu, G. T., & Ndebia, E. J. (2024). A Comprehensive Review of the Ethnobotanical Uses, Pharmacological, and Toxicological Profiles of Piper capense L.f. (Piperaceae). Drugs and Drug Candidates, 3(3), 598-614. https://doi.org/10.3390/ddc3030034

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