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Open Access Original Research
Tropical Medicinal Plant Extracts from Indonesia as Antifungal Agents against Candida Albicans
Almando Geraldi1,2,3,*, Andika Pramudya Wardana4, Nanik Siti Aminah1,4, Alfinda Novi Kristanti1,4, Aliffa Yusti Sadila2, Nabilla Hapsari Wijaya2, Mellya Rimadha Andra Wijaya2, Noviana Indah Dwi Diningrum2, Versa Rachmania Hajar2, Yosephine Sri Wulan Manuhara1,2,*
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1 Biotechnology of Tropical Medicinal Plants Research Group, Universitas Airlangga, 60115 Surabaya, Indonesia
2 Department of Biology, Faculty of Science and Technology, Universitas Airlangga, 60115 Surabaya, Indonesia
3 University CoE-Research Center for Bio-Molecule Engineering, Universitas Airlangga, 60115 Surabaya, Indonesia
4 Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, 60115 Surabaya, Indonesia
*Correspondence: almando.geraldi@fst.unair.ac.id (Almando Geraldi); yosephine-s-w-m@fst.unair.ac.id (Yosephine Sri Wulan Manuhara)
Academic Editor: Marcello Iriti
Front. Biosci. (Landmark Ed) 2022, 27(9), 274; https://doi.org/10.31083/j.fbl2709274
Submitted: 4 August 2022 | Revised: 13 September 2022 | Accepted: 21 September 2022 | Published: 29 September 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
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Abstract

Background: Candida albicans is responsible for a wide range of medical ailments, from harmless cutaneous to life-threatening bloodstream infections. Growing cases of antifungal-drug resistance strains of C. albicans become a rationale to explore and develop novel anti-candida agents. In this paper, we assessed the anti-candida activity of the methanolic extracts of various tropical medicinal plants from Myrtaceae, Poaceae, and Zingiberaceae, commonly used in Indonesia to treat fungal infections. Methods: Candida albicans strain ATCC 10231 was used as a subject to assess the anti-Candida activities of plant methanolic extracts through disc diffusion assay. Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) were observed. Results: All plant extracts in this study showed antifungal activities against C. albicans. Among them, Cymbopogon citratus, Curcuma xanthorrhiza, Curcuma aeruginosa, and Zingiber officinale var. rubrum showed the lowest MIC and MFC value of 3.8 mg/mL. Conclusions: The growth inhibition of C. albicans on disc diffusion assay was demonstrated by Z. officinale var. rubrum and C. longa, which were comparable to antifungal nystatin. Further investigation of the chemical constituents of the extracts and the cytotoxicity test is needed to further develop plant-derived anti-candida agents.

Keywords
health care
tropical medicinal plants
Candida albicans
methanolic extract
minimum inhibitory concentration
minimum fungicidal concentration
1. Introduction

Candidiasis refers to infections caused by fungi of the genus Candida [1, 2]. These infections may be cutaneous, mucosal (oral, oesophageal, and vulvovaginal candidiasis), or invasive (bloodstream and deep-seated candidiasis) [3, 4, 5]. The clinical spectrum of candidiasis varies from mild mucocutaneous infections to life-threatening candidemia (bloodstream infections), brain abscess, and endocarditis (infection of heart’s inner lining) [6, 7]. Candidiasis is recognized as one of the most common infections, with the global burden for superficial cutaneous and mucosal candidiasis being over 1,000,000,000 and 130,000,000 annual cases, respectively [8, 9]. Furthermore, the estimated annual invasive candidiasis are 750,000 cases with a mortality rate of 40%–55%, especially in patients with risk factors such as immunodeficiency, advanced age, exposure to broad-spectrum antibiotics, cancer chemotherapy, organ transplantation, and prolonged stay in an intensive care setting [8, 10, 11].

Candida albicans, an opportunistic pathogen which is also a part of the normal human microflora, is the most common causing agent of candidiasis [12, 13]. C. albicans is responsible for >90% and >40% of mucosal and invasive candidiasis cases in various countries, respectively [14, 15, 16]. Current therapies for C. albicans infection mainly involve administering antifungal drugs such as polyenes, azoles, echinocandins, and 5-Flucytosine (5FC) [17, 18]. Unfortunately, as in the case of antibiotics for bacterial infection, there are rising cases of antifungal-resistant C. albicans due to extensive use of antifungal drugs in clinical settings [19, 20]. Thus, finding alternative anti-candidal agents is of urgent importance.

One alternative of anti-candidal compounds is provided by plants. Some plant species produce secondary metabolites with anti-candidal activities, such as terpenes, terpenoids, and aromatic compounds [21]. A study reported that terpenes could inhibit cell growth, initiate apoptosis, and induce cell cycle arrest of yeast-like fungi, including C. albicans [22]. Terpenoids, a modified class of terpenes, can disrupt cell membrane integrity of C. albicans [23]. Meanwhile, eugenol, an aromatic compound, can kill C. albicans cell by disrupting its membrane morphology and function, causing oxidative stresses [24].

As a tropical country, Indonesia has a variety of medicinal plants which are traditionally used for treating C. albicans infection [25]. Plants from the Zingiberaceae family, such as Alpinia galanga, Curcuma longa, and Curcuma xanthorrhiza, were used for treating candidiasis [26, 27, 28]. Those plants produce anti-candidal secondary metabolites such as terpenoids (i.e., xanthorrhizol and curcumenol) and aromatic compounds (i.e., flavonoids and curcumin) [29, 30]. Another example is the fruit of clove Syzygium aromaticum L. (Myrtaceae), a native Indonesian plant whose main bioactive compound is anti-candidal eugenol [31].

Bioactive compounds from medicinal plants must be extracted first to be utilized as anti-candidal. The solvent is critical in the extraction process [32]. Methanol is an effective solvent for extracting anti-candidal compounds such as terpenoids, flavonoids, and polyphenol [33, 34]. Besides that, the maceration method can prevent the damage of samples’ bioactive components, especially the thermolabile ones [35]. This study aims to investigate the anti-candida (i.e., C. albicans strain ATCC 10231) activities of methanolic extracts of 11 medicinal plants from Indonesia. The result of this study is essential for developing anti-candidal food supplements and drugs.

2. Materials and Methods
2.1 Methanolic Extract Preparation

This study used 11 plant species from three families, i.e., Myrtaceae, Poaceae, and Zingiberaceae (Table 1, Ref. [31, 36, 37, 38, 39, 40, 41, 42, 43, 44]). Plant materials were collected from Lawu Mountain, Jogorogo Village, Ngawi, East Java, Indonesia, at 7°3’31” S latitude and 112°32’0” E longitude (357 meters above sea level). Methanolic extract preparation was conducted based on a method developed by Wardana et al. [45]. One (1) kg of each plant powder was macerated with 3 L methanol for 24 hours at room temperature. The maceration process was repeated three times, after which the filtrate was passed through a Buchner funnel to obtain methanol extract. Each plant extract was then concentrated on a rotary vacuum evaporator to obtain a thick methanol extract. The thick methanol extract was then diluted in Dimethyl sulfoxide (DMSO) to obtain extract concentration of 500, 250, 125, 100, 50, and 25 mg/mL for anti-candida assay.

Table 1.Data of plant species used in this study.
Family/species Local name Common name Part used Reported bioactive compounds References
Myrtaceae
Syzygium aromaticum Cengkeh Clove Fruit Eugenol, β-Caryophyllene, vanillin, crategolic acid/maslinic acid, kaempferol, rhamnetin, eugenitin, eugenin, ellagic acid, gallic acid, biflorin, myricetin, campesterol, stigmasterol. oleanolic acid, bicornin, quercetin, carvacrol [31]
Poaceae
Cymbopogon citratus Serai/Sereh Lemon grass Bulb Geraniol, geranial, geranyl acetate, myrcene, neral [36]
Zingiberaceae
Boesenbergia rotunda Temu kunci Fingerroot Rhizome Kaempferol, quercetin, hesperidin, caffeic acid, naringin, chlorogenic acid, p-coumaric acid, luteolin, diosmin [37]
Curcuma aeruginosa Temu hitam - Rhizome Camphor, germacrone, borneol, 1,8-cineole, curzerene, germacrene a, germacrene b, camphene, limonene [38]
Curcuma longa Kunyit Turmeric Rhizome Digalloyl-hexoside, caffeic acid hexoside, curdione, coumaric acid, caffeic acid, sinapic acid, qurecetin-3-d-galactoside, casuarinin, bisdemethoxycurcumin, curcuminol, demethoxycurcumin, isorhamnetin, valoneic acid bilactone, curcumin, curcumin-O-glucuronide [39]
Curcuma heyneana Temu giring - Rhizome Curcumanolide A, oxycurcumenol, curcumenone, labda-8(17),12-diene-15,16-dial, isocurcumenol, curcumenol, germacrone [40]
Curcuma xanthorrhiza Temulawak Javanese turmeric Rhizome Xanthorrhizol, α-terpinolene, p-cymen-7-ol, camphene, curcumin, α-pinene, camphor, p-cymene, germacrone, 1,8-cineole [38]
Curcuma zedoaria Kunyit putih White turmeric Rhizome Curcumin, ethyl paramethoxycinnamate, β-turmerone, β-eudesmol, zingiberene, dihydrocurcumin, furanodiene, α-phellandrene, 1,8 cineole, β-elemene, germacrone [41]
Zingiber montanum Bangle - Rhizome cis-3-(3’,4’-dimethoxyphenyl)-4-[(E)-3”’,4”’-dimethoxystyryl]cyclohex1-ene, (E)-4-(3’,4’-dimethoxyphenyl) but-3-en-1-ol, 3,4-dimethoxybenzoic acid, 8-(13,14-dimethoxyphenyl)-2-methoxynaphto-1,4-quinone, and β-sitosterol [42]
Zingiber officinale var. rubrum Jahe merah Red ginger Rhizome 6-gingerol, 8- gingerol, 6-shogaol, 8-shogaol, quercetin, catechin, rutin, gallic acid, epicatechin, kaempferol, cinnamic acid, tannic acid, syringic acid, ferulic acid, geraniol, 1.8- cineole, linalool, farnesol [43]
Zingiber officinale Rosc Jahe putih White ginger Rhizome Eudesmol, γ-terpinene, α-curcumene, zingiberene, alloaromadendrene, α-pinene, δ-cadinene, elemol, farnesal, (E)-β-farnesene, neril acetate, β-myrcene [44]
2.2 Anti-Candida Activities of the Plant Methanolic Extracts

The anti-candida activity of the 11 plants’ methanolic extract was tested using a modified version of document M27-A3 published by the Clinical and Laboratory Standards Institute (CLSI) [46, 47, 48]. All assays were done in duplicate.

2.2.1 Inoculum Preparation of C. albicans

C. albicans ATCC 10231 used in this study was obtained from the Microbiology Laboratory, Department of Biology, Universitas Airlangga, Indonesia. One colony of C. albicans ATCC 10231 was inoculated in a Potato Dextrose Broth (PDB) and grown overnight at 37 °C (150 rpm). 60 μL of overnight culture was transferred into 3 mL PDB and grown at 37 °C (150 rpm) until their Optical Density (OD) at 600 nm was equal to 0.5 McFarland standard.

2.2.2 Disc Diffusion Assay

C. albicans culture from the previous step (100 μL) was spread onto Potato Dextrose Agar (PDA) using a sterile cotton swab. The PDA plates were then incubated at 37 °C for 48 hours with filter discs (6 mm) saturated with different dilutions of the methanolic extracts (25, 50, 100, 125, 250, 500 mg/mL). The solvents DMSO and nystatin (100 unit/disc) were used to dilute extract and acted as the negative and positive controls, respectively. The diameter of the clear area around the disc (i.e., inhibition zone) was measured using a vernier caliper, recorded, and considered an indication of antifungal activity of the plant methanolic extracts.

2.2.3 Determination of Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) of the Plant Methanolic Extracts

Different concentrations of the methanolic extracts (1.85–250 mg/mL) were added to PDB media inoculated with 105 CFU/mL C. albicans in a 96-well microplate. The OD at 600 nm was measured using a microplate reader before and after incubation at 37 °C for 48 hours. The minimum inhibitory concentration (MIC) or the lowest concentration of the plant methanolic extract that prevents C. albicans’ growth is observed when there is no increase in OD600 value after 48 hours of incubation. Meanwhile, the minimum fungicidal concentration (MFC) was determined by spreading 100 μL of C. albicans culture treated by plant methanolic extract at MIC concentration and two concentrations above it onto PDA plates. MFC is the lowest concentration that inhibits any C. albicans growth in the PDA plates.

3. Results
3.1 Plant Extraction Yield

Methanol extraction of 1 kg dry powdered plant materials yielded concentrated extract ranging from 72.1 to 183.5 gr (Table 2). The highest yield of plant extract was obtained from C. longa, while C. citratus gave the lowest result.

Table 2.Yield percentage of plant methanolic extract.
Plant species pH % Yield
Syzygium aromaticum 5.7 15.77
Cymbopogon citratus 5.5 7.21
Boesenbergia rotunda 5.9 16.28
Curcuma aeruginosa 6.2 15.03
C. longa 6.1 18.35
C. heyneana 6.1 15.15
C. xantorrhiza 6.2 17.87
C. zedoaria 6.0 13.52
Zingiber montanum 5.8 10.06
Z. officinale var. rubrum 5.9 10.80
Z. officinale Rosc 5.9 9.42
3.2 Anti-Candida Activities of the Plant Methanolic Extracts

Using a disc diffusion assay, 11 plant species commonly used in Indonesian traditional medicine were evaluated for their antifungal activity against C. albicans. The results revealed that all plant extracts could inhibit C. albicans growth (Table 3). Two species, i.e., Z. officinalevar. rubrum and C. longa showed a more extensive inhibition zone than nystatin at concentrations as low as 25 mg/mL (Table 3 and Fig. 1). The concentration of MIC and MBC from 11 plant species ranged from 3.91 to 15.62 mg/mL (Table 4). Methanolic extract of four species (i.e., C. citratus, C. aeruginosa, C. xanthorrhiza, and Z. officinale var. rubrum) had the lowest MIC and MBC value at 3.9 mg/mL (Table 4).

Table 3.The results of disc diffusion assay of plant methanolic extracts against C. albicans.
Plant species Concentration (mg/mL) Inhibition Zone (mm)
Syzygium aromaticum 25 7.25 ± 0.64
50 7.60 ± 0.28
100 8.40 ± 0.07
125 8.18 ± 1.17
250 11.08 ± 0.68
500 11.10 ± 0.78
Cymbopogon citratus 25 7.08 ± 0.59
50 6.95 ± 0.28
100 6.95 ± 0.07
125 6.73 ± 0.04
250 7.03 ± 0.25
500 6.68 ± 0.11
Boesenbergia rotunda 25 7.98 ± 0.53
50 8.54 ± 0.62
100 7.95 ± 0.00
125 10.47 ± 0.05
250 11.73 ± 1.80
500 15.15 ± 0.28
Curcuma aeruginosa 25 6.70 ± 0.28
50 7.30 ± 0.28
100 7.53 ± 0.32
125 7.25 ± 0.07
250 7.58 ± 0.32
500 7.30 ± 0.07
C. longa 25 14.30 ± 1.41
50 14.63 ± 0.32
100 13.95 ± 0.35
125 14.68 ± 0.18
250 17.13 ± 2.79
500 19.60 ± 2.33
C. heyneana 25 6.75 ± 0.07
50 7.63 ± 1.03
100 7.03 ± 0.04
125 6.63 ± 0.18
250 7.53 ± 0.25
500 8.53 ± 2.23
C. xantorrhiza 25 9.53 ± 4.84
50 9.15 ± 3.32
100 8.33 ± 3.01
125 9.15 ± 1.41
250 10.00 ± 0.28
500 12.73 ± 5.06
C. zedoaria 25 6.63 ± 0.46
50 6.38 ± 0.04
100 6.73 ± 0.74
125 7.55 ± 1.41
250 6.80 ± 0.21
500 7.05 ± 0.42
Zingiber montanum 25 6.15 ± 0.07
50 6.34 ± 0.02
100 6.19 ± 0.09
125 6.10 ± 0.00
250 6.13 ± 0.04
500 6.83 ± 0.53
Z. officinale var. rubrum 25 12.48 ± 0.60
50 14.18 ± 2.09
100 13.68 ± 0.39
125 14.20 ± 0.21
250 16.60 ± 0.14
500 16.48 ± 0.11
Z. officinale Rosc 25 6.47 ± 0.40
50 6.73 ± 0.25
100 7.45 ± 0.71
125 7.40 ± 0.64
250 6.83 ± 0.25
500 6.63 ± 0.11
Nystatin 100 unit/disc 12.20 ± 0.11
DMSO - 0 ± 0
Fig. 1.

Growth inhibition of C. albicans by Z. officinale var rubrum and C. longa. The methanol plant extract concentration used were 25, 50, 100, 125, 250, and 500 mg/mL. DMSO and nystatin (100 Units/disc) were used as the negative and positive control, respectively.

Table 4.The MIC and MFC values of eleven plant species’ methanolic extracts against C. albicans.
Plant species MIC (mg/mL) MFC (mg/mL)
Syzygium aromaticum 7.81 7.81
Cymbopogon citratus 3.91 3.91
Boesenbergia rotunda 15.62 15.62
Curcuma aeruginosa 3.91 3.91
Curcuma longa 7.81 7.81
Curcuma heyneana 7.81 7.81
Curcuma xantorrhiza 3.91 3.91
Curcuma zedoaria 15.62 15.62
Zingiber montanum 7.81 7.81
Zingiber officinale var. rubrum 3.91 3.91
Zingiber officinale Rosc 7.81 7.81
4. Discussion

In many Southeast Asian countries, medicinal plants are commonly used for antifungal activities. Among others, three plant species, i.e., S. aromaticum, C. citratus, C. xanthorrhiza, are widely used for treating candidiasis in Indonesia, Malaysia, and Thailand [26, 49, 50]. Extracting their organic solvent is one of the approaches to improve their anti-candida activities by bringing out related bioactive compounds [51, 52].

Clove fruit (S. aromaticum) methanolic extract contains anti-candidal compounds such as flavonoids, polyphenols, and terpenoids [53, 54]. However, there are limited reports on the antifungal activity of clove fruit methanolic extract. To date, only one study by Vizhi et al. [54] evaluated the antifungal activity of the undiluted methanolic extract against C. albicans via disc diffusion assay. The reported inhibition activity was weaker than the results of the current study, where a much lower concentration of clove fruit methanolic extract was used. Furthermore, to our knowledge, our results are the first to report the MIC and MFC of clove fruit methanolic extract against C. albicans. When compared to extracts from different solvents (methanolic, diethyl ether, ethyl acetate, and n-hexane) of other parts of the plant (e.g., buds), our results are still superior in terms of growth inhibition observed in disc diffusion assay [55].

Methanolic extract of C. citratus bulb contained anti-candidal monoterpenes such as citral and geraniol. Citral can block the cell membrane synthesis and inhibit the cellular respiration of C. albicans [56]. Meanwhile, geraniol disrupts C. albicans membrane integrity and function by inhibiting ergosterol biosynthesis and plasma membrane H+-ATPase [57]. Previous studies reported various effects of C. citratus methanolic extract on C. albicans growth. Aina et al. [58] and Ewansiha et al. [59] showed no inhibition of C. albicans growth, whereas a study by Zulfa et al. [60] showed lower MIC and MFC values than this study.

Two other species, i.e., C. longa and Z. officinale Rosc, are extensively explored for their anti-candidal activities. The main anti-candidal compound of these plants are polyphenol curcumin and gingerol, respectively, which damage C. albicans cell wall and plasma membrane [61, 62]. Previous studies [63, 64] reported a higher MIC and MFC of C. longa methanolic extract than ours. Meanwhile, MIC and MFC of Z. officinale Rosc from our study are higher than previously reported results [65, 66].

Up to our knowledge, there have not been any previous reports on MIC and MFC values of B. rotunda, C. heyneana, C. zedoaria, and Z. montanum methanolic extract. However, previous studies using the ethanolic extract from B. rotunda and C. zedoaria showed lower MIC and MFC values from the ethanolic extract of B. rotunda (MIC: 2.5 mg/mL, MFC: 5 mg/mL) and C. zedoaria (MIC90: 7.8 mg/mL) as compared to our results [67, 68, 69, 70]. On the other hand, a previous study usingan essential oil extracted from hydrodistillation of Z. montanum also showed higher MIC and MFC values than our results [71]. Meanwhile, the only study in anti-candidal activity of C. heyneana [72] reported an inhibition zone in disc diffusion assay comparable to our result.

Among all methanolic extracts from Zingiberaceae plants used in this study, three samples (i.e., C. aeruginosa, C. xantorrhiza, and Zingiber officinale var. rubrum) showed the lowest MIC and MBC. The rhizomes of C. aeruginosa and C. xantorrhiza mainly contain anti-candidal monoterpene compounds camphor and terpinolene, respectively [38]. Camphor can downregulate genes related to biofilm formation, thus reducing the virulence of C. albicans [73]. Terpinolene works by disrupting C. albicans membrane integrity [74]. Another bioactive compound from C. xantorrhiza is xanthorhizzol, a bisabolane-type sesquiterpenoid that can disrupt C. albicans cell membrane [75]. Meanwhile, the main bioactive compounds of Z. officinale var. rubrum with antifungal activity are geraniol, 1.8-cineole, linalool, and farnesol which modify the permeability of C. albicans cell wall and sesquiterpenes ar-curcumene, which disrupts the cell membrane structure [27, 76].

Philip et al. [77] showed no inhibition zone in the disc diffusion assay of C. aeruginosa methanolic extract, even at a high concentration of 500 mg/mL. Another study by Rukayadi et al. [78] showed a higher MIC and MFC values of methanolic extract of C. aeruginosa, which is around 7 times and 13 times than our study, respectively. In the case of C. xantorrhiza, Novianti et al. [79] showed a higher inhibition zone (12.5 mm) than our result using 20 mg/mL methanolic extract. No studies reported MIC and MFC of methanolic C. xantorrhiza. However, two studies [80, 81] reported a higher MIC and MFC of C. xantorrhiza from ethanolic extract than ours. For a similar reason, only one study [82] that used an ethanolic extract of Z. officinale var. rubrum showed a comparable MIC and MFC to our results.

Even though the MIC values from all 11 methanolic plant extracts are sometimes lower than in similar studies, they still showed antifungal activity against Candida albicans. The MIC values of this study can be considered in the moderate to low range of anti-candida activity compared to other similar studies [83, 84, 85, 86]. The differences in anti-candida activity from previous studies might be influenced by several factors, such as the soil and climate where the plant materials were sampled [87, 88, 89]. Further investigation of the chemical constituents of the extracts and the cytotoxicity test against mammalian cells and test animals are needed to further develop plant extracts as the components of anti-candida drugs and health supplements.

5. Conclusions

Our results confirm the antifungal activities of methanolic extracts of 11 tropical medicinal plants from Indonesia against Candida albicans ATCC 10231. Among them, the methanolic extracts of C. citratus, C. xanthorrhiza, C. aeruginosa, and Z. officinale var. rubrum had the lowest MIC and MFC value, whereas in relatively low concentration, Z. officinale var. rubrum and C. longa showed antifungal activity comparable to nystatin. This study provides the first report on MIC and MFC values of S. aromaticum fruit, C. xantorrhiza, and Z. officinale var. rubrum methanolic extract. However, these results need to be interpreted cautiously, as this study only tested one strain of C. albicans. Different C. albicans strains can give different results due to their difference in sensitivity toward anti-candida plant extract. Therefore, further study using other C. albicans strains, including the ones obtained from patients (clinical strain), will be necessary to offer a bigger picture of anti-candida activity of plant extracts on C. albicans.

Author Contributions

AG and YSWM conceptualized the research study. AG and APW designed the research methodology. AG, APW, AYS, MRAW, NHW, VRH and NIDD performed the research and analyzed the data. AG, APW, AYS, MRAW, NHW, VRH and NIDD wrote the manuscript. AG, YSWM and ANK reviewed and contributed to editorial changes in the manuscript. AG, YSWM, NSA and ANK supervised the research. YSWM acquired the funding for the research. All authors read and approved the final manuscript.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This research was funded by Universitas Airlangga via the “Hibah Penelitian Riset Grup”, with research grant No. 343/UN3.14/PT/2020.

Conflict of Interest

The authors declare no conflict of interest.

Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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