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Research Progression of the Genus Merremia: A Comprehensive Review on the Nutritional Value, Ethnomedicinal Uses, Phytochemistry, Pharmacology, and Toxicity

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The genus Merremia Dennst. ex Endl. (Convolvulaceae) is a rich source of structurally diverse phytochemicals with therapeutic relevance. This review presents the first comprehensive, up-to-date information and research progression on the nutritional value, ethnomedicinal uses, phyto-chemistry, pharmacological activities, and toxicity of the genus Merremia. Using the key search term "Merremia", relevant documents and information were retrieved from electronic databases. Relevant documents were uploaded in RStudio with installed bibliometric software packages and used for data retrieval, tabulation, and network visualization. Bibliometric analysis revealed that ca. 55% of the studies related to Merremia were published in the last decade, which can be grouped into four thematic areas: (i) drug formulation, (ii) taxonomy, (iii) chemical analysis, and (iv) treatment of diseases. Ethnomedicinal uses, phytochemistry, and biological activities studies showed that species in the genus are promising medicinal plants with various pharmaceutical potentials. However, clinical studies to validate the efficacy of the reported bioactivities and the mechanisms underlying the various activities are lacking and should constitute a future research focus. Additionally, reports on the nutritional and antinutritional constituents of Merremia species revealed that the species meet high nutritional quality criteria for animals and are therefore suitable for inclusion in livestock diets. The few available investigations on toxicity indicated that most Merremia species are safe for human and animal use but not with prolonged chronic administration.
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Review
Research Progression of the Genus Merremia: A Comprehensive
Review on the Nutritional Value, Ethnomedicinal Uses,
Phytochemistry, Pharmacology, and Toxicity
Tomi Lois Olatunji 1, * , Ademola Emmanuel Adetunji 2, Chijioke Olisah 3, Oladayo Amed Idris 1,
Oluwaseyi Damilare Saliu 4and Frances Siebert 1


Citation: Olatunji, T.L.; Adetunji,
A.E.; Olisah, C.; Idris, O.A.; Saliu,
O.D.; Siebert, F. Research Progression
of the Genus Merremia:
A Comprehensive Review on the
Nutritional Value, Ethnomedicinal
Uses, Phytochemistry, Pharmacology,
and Toxicity. Plants 2021,10, 2070.
https://doi.org/10.3390/plants10102070
Academic Editors:
Mariangela Marrelli and Luigi Milella
Received: 16 August 2021
Accepted: 24 September 2021
Published: 30 September 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Unit for Environmental Sciences and Management (UESM), Faculty of Natural and Agricultural
Sciences, North-West University, Potchefstroom 2520, South Africa; dayoamed@yahoo.com (O.A.I.);
frances.siebert@nwu.ac.za (F.S.)
2School of Life Sciences, University of KwaZulu-Natal, Durban 4001, South Africa;
adetunjiademola@hotmail.com
3Department of Botany, Institute for Coastal and Marine Research, Nelson Mandela University,
Port Elizabeth 6031, South Africa; olisah.chijioke@gmail.com
4Department of Chemical Sciences, University of Johannesburg, Johannesburg 2028, South Africa;
oluwaseyi229@gmail.com
*Correspondence: lois.olatunji@gmail.com
Abstract:
The genus Merremia Dennst. ex Endl. (Convolvulaceae) is a rich source of structurally
diverse phytochemicals with therapeutic relevance. This review presents the first comprehensive,
up-to-date information and research progression on the nutritional value, ethnomedicinal uses,
phytochemistry, pharmacological activities, and toxicity of the genus Merremia. Using the key search
term “Merremia”, relevant documents and information were retrieved from electronic databases.
Relevant documents were uploaded in RStudio with installed bibliometric software packages and
used for data retrieval, tabulation, and network visualization. Bibliometric analysis revealed that ca.
55% of the studies related to Merremia were published in the last decade, which can be grouped into
four thematic areas: (i) drug formulation, (ii) taxonomy, (iii) chemical analysis, and (iv) treatment of
diseases. Ethnomedicinal uses, phytochemistry, and biological activities studies showed that species
in the genus are promising medicinal plants with various pharmaceutical potentials. However, clinical
studies to validate the efficacy of the reported bioactivities and the mechanisms underlying the
various activities are lacking and should constitute a future research focus. Additionally, reports on
the nutritional and antinutritional constituents of Merremia species revealed that the species meet
high nutritional quality criteria for animals and are therefore suitable for inclusion in livestock diets.
The few available investigations on toxicity indicated that most Merremia species are safe for human
and animal use but not with prolonged chronic administration.
Keywords: bibliometric; Convolvulaceae; fodder; Merremia; merremins; resin glycosides
1. Introduction
Natural medicines, whether from standardized plant extracts or pure compounds
from plants, are valuable sources of new drugs in the pharmaceutical industries because
of their diverse biologically active phytochemicals [
1
,
2
]. Over the years, medicinal plants
have been used in many human populations all over the world [
3
] in the treatment of
different ailments and diseases. This is largely due to their health benefits, effectiveness [
4
],
affordability, and little or no side effects when compared to synthetic drugs that are
expensive and may have adverse effects [5].
A large proportion of species used in traditional medicine globally are forbs (syn.
herbs), which are one of the most species-rich plant life forms, especially in open ecosystems
worldwide [
6
,
7
]. Several indigenous rangeland forb species are consumed as vegetables,
Plants 2021,10, 2070. https://doi.org/10.3390/plants10102070 https://www.mdpi.com/journal/plants
Plants 2021,10, 2070 2 of 49
thus forming a part of local people’s diet. They are economically useful crops that had
bolstered food security historically when the main crops failed, and thus should be in-
creased in production to solve the global food crises [
8
]. Forbs are important nutritive
dietary components of several browsers as components of mixed pastures and have been
reported to contain higher levels of phosphorus and crude protein, and lower fiber levels
than shrubs or grasses [
6
]. Additionally, many of the forb species are used in traditional
medicine to treat different ailments, and the broad range of bioactive phytochemicals
present in some forb species can be potentially employed for the treatment and prevention
of several diseases in modern medicine. Of these forbs, species in the genus Merremia have
been the focus of several pharmacological and phytochemical studies.
Merremia Dennst. ex Endl. is a large genus of over 100 species of flowering plants in
the Convolvulaceae (morning glory) family [
9
]. Members of the family Convolvulaceae are
usually recognized by their colorful funnel-shaped flowers [
10
,
11
]. Resin glycosides [
12
,
13
],
calystegines [14], and tropane alkaloids [15] are considered the chemotaxonomic markers
of the Convolvulaceae family.
The genus Merremia, commonly referred to as wood roses, is distributed in tropical
and sub-tropical regions all over the world [
16
]. Several species in the genus are of reputed
medicinal value and are used in traditional medicine across continents. For example,
in Sri Lanka, the whole plant of M. emarginata is prepared as a decoction and used in
the traditional treatment of diabetes [
17
]. In India, leaves of M. hederacea have been re-
ported to be used in treating chapped hands and feet [
18
]. In the Philippines, the leaves of
M. peltata are used for treating skin sores, inflammation, and stomach pain [
19
]. The leaves
and rhizomes of M. vitifolia are used in the traditional treatment of eye inflammation, dysen-
tery, urinary diseases, and jaundice in Bangladesh [
20
]. It is also evident from the literature
that the genus Merremia is a rich source of biologically active phytochemicals [
21
23
] since
extracts from the different species have shown pharmacological activities in several
in vitro
and
in vivo
studies. Thus, species in the genus Merremia would be promising alternative
sources of new pharmaceutical leads in treating several diseases and ailments. Despite the
widespread ethnopharmacological importance and different scientific investigations of phy-
tochemistry and pharmacological activities, there is no comprehensive review analyzing,
documenting, and revealing the pharmacological importance of this genus.
Bibliometric analysis has been recognized as a useful statistical method that can
qualitatively and quantitatively evaluate the trend in research efforts in a given area of in-
terest [
24
,
25
]. Bibliometrics can thus be employed to assess both national and international
research focus and is particularly useful in providing insights for future research [26].
This review presents the first comprehensive, up-to-date information and research
progression on the nutritional value, ethnomedicinal uses, phytochemistry, and pharma-
cological activities of the species in the genus Merremia. Hence, this review is aimed to (i)
identify the international research focus of the genus, (ii) provide insight into the emerging
pharmacological potentials of Merremia species, (iii) highlight biological activities of ex-
tracts and isolated phytochemicals, (iv) highlight its potentials as livestock forage and (v)
provide the scientific basis for further research on the nutritional value, pharmacological
potentials and their mainstream application.
2. Materials and Methods
For the global bibliometric analysis of the genus Merremia, document retrieval and
statistical analysis were conducted based on the method described in [
27
,
28
]. In summary,
document information related to Merremia (between 1990–2020) was retrieved from 10
databases indexed in the Web of Science (WoS) (“SCI EXPANDED, SSCI, A&HCI, CPCI-S,
CPCI-SSH, BKCI-S, BKCI-SSH, ESCI, CCR EXPANDED, and IC”). The term “Merremia
was inputted as a search term in the topic module on the WoS database hosted in Clar-
ivate Analytics as well as in the Scopus topical search engine. Only document types
including “Article”, “Review,” “Editorial Material”, and “Book Chapter” were searched.
Other document types such as “Meeting Abstract”, “Proceeding Paper”, and “Notes”
Plants 2021,10, 2070 3 of 49
were excluded. A total of 194 documents satisfied the search criteria in the WoS database.
The total search yielded a total of 261 publications from the Scopus database. It should be
noted that the documents excluded from both databases were because they were either
pre-publication data that may have been published as an article or post-article data taken
from the primary articles [
26
,
27
]. The identified number of articles from both databases
were downloaded in Bibtex and uploaded in RStudio for further statistical processing.
RStudio Inc. (Version 1.1.463—
©
2021–2018, Boston, MA, USA) with installed biblio-
metric software packages was used for data retrieval, tabulation, and network visualization.
Duplicate records from the hybrid databases were merged using R codes, and these were
taken as a single article. A total number of 357 publications were used for bibliometric anal-
ysis. Commands for analyzing bibliometric indicators were retrieved from https://cran.r-
project.org/web/packages/bibliometrix/vignettes/bibliometrix-vignette.html, accessed
on 15 February 2021.
Keyword network map was visualized using VOS viewer (Nees Jan van Eck and Ludo
Waltman; Leiden; The Netherlands, version 1.6.15—© 2021–2020).
Information on the nutritional value, ethnomedicinal uses, phytochemistry, biological
activities, and toxicity studies were retrieved from relevant articles, books, webpages and
other online materials searched using different databases. The search period was from
inception to July 2021 in the different databases. The Boolean string used was “Merremia”,
searching the “title”, “abstract”, “authors keyword”, and “keyword plus” of the documents.
The search was limited to materials available in English. The relevant materials retrieved
were used to present a comprehensive and up-to-date review write-up on the subject matter.
All species names and synonyms were confirmed from the “World Flora Online (WFO)”.
All chemical structures were drawn with Chem Draw.
3. Results
3.1. Bibliometric Overview of the Genus—Merremia
A total of 357 documents with an average citation per article of 10.39 was retrieved
from the merged databases (WoS and Scopus) (Table 1). Of all the documents present,
341 were research articles and 12 review articles. Other document types included book
chapters and editorial materials, which revealed two documents in each. Documents were
obtained from 188 journals and included 1005 author keywords and 2727 keywords plus.
There was a slightly steady increase in documents produced between 1990 and 2020 with a
major fluctuation in the first (1990–2000) and last (2011–2020) decades of the survey period.
Peak numbers were recorded in 2009 with 33 articles, followed by 2020 and 2010 with 26
and 25 articles, respectively. Approximately 55% of the articles published on studies related
to Merremia were published in the last decade (2011–2020). A high number of articles in
these years may be due to the availability of funds, the advent of research ideas, and the
emergence of sophisticated analytical tools for chemical analysis.
Table 1. Summarized bibliographic data.
Bibliographic Information Numerical Outputs
Publications 357
Sources (Journals, Books, etc.) 188
Keywords Plus (ID) 2727
Author’s Keywords (DE) 1005
Period 1990–2020
Average citations per document 10.39
Authors 948
Author Appearances 1537
Authors of multi-authored documents 937
Single-authored documents 18
Average documents per author 0.377
Average authors per document 2.66
Average co-authors per document 4.31
Average collaboration index 2.76
Plants 2021,10, 2070 4 of 49
3.2. Most Productive Countries
To avoid multiple representations of authors, authors from the same country in an
article were computed as one. We prioritized this bibliometric tool to recognize the most
prolific countries on Merremia related research. As shown in Table 2, authors’ countries
were ranked based on the number of articles and citations accumulated over the survey
period. Brazil had the highest number of articles (n= 116), with 32.5% of the total number of
articles. This was followed by India (n= 51, 14.3%), Japan (n= 27, 7.6%), USA (n= 26, 7.3%),
and China (n= 18, 5.0%). Based on continental production, Asia and America were more
prolific, having seven countries each in the top 20 authors’ countries on studies related
to the genus Merremia. Most of the Merremia species are found in the Asian continent,
which may be responsible for their high number of articles (https://www.cabi.org/isc/
datasheet/33477, accessed on 23 March 2021). As for the Americas, the United States
Department of Agriculture (USDA) plants database reported that seven species of Merremia
occur in North America. Four of these species remain unique to the North American
region, while three have been neutralized in other parts of the world. These species
include M. quinquefolia,M. cissoids, and M. umbellata that are native to Florida, while
M. dissecta (Alamo vine) occurs in Texas, Pennsylvania, and states in the south-eastern
region (https://www.wildflower.org/expert/show.php?id=7618, accessed on 28 March
2021). A country that hosts a substantial number of studied species is expected to attract
more scientific research compared to other countries [
29
], which explains why the USA is
ranked fourth in the total number of article outputs on Merremia. The species M. aegyptia
is a native of South Africa only, which may explain why South Africa is the only African
country listed under the top 20 most productive countries with respect to Merremia research.
Table 2.
Top 20 authors’ countries on studies related to the genus—Merremia from 1990–2020. SCP—single country
publications. MCP—multiple country publications. MCP/P—multiple country publications per publication.
Most Productive Countries Total Number of Citations per Country
Rank Countries Articles % of
Total Freq SCP MCP MCP/P
Ratio Rank Country Article
Citations
Citation
Average
1 Brazil 116 32.5 0.34 112 4 0.03 1 India 769 15.1
2 India 51 14.3 0.15 49 2 0.04 2 Brazil 697 6.0
3 Japan 27 7.6 0.08 26 1 0.04 3 Japan 536 19.9
4 USA 26 7.3 0.08 19 7 0.27 4
Germany
399 30.7
5 China 18 5.0 0.05 16 2 0.11 5 USA 295 11.4
6
Germany
13 3.6 0.04 10 3 0.23 6 Mexico 173 17.3
7
Indonesia
13 3.6 0.04 13 0 0.00 7
Malaysia
117 29.3
8 Mexico 10 2.8 0.03 8 2 0.20 8 China 102 5.7
9
Belgium
6 1.7 0.02 3 3 0.50 9
Panama
89 22.3
10
Venezuela
6 1.7 0.02 5 1 0.17 10 Spain 77 25.7
11
Australia
5 1.4 0.01 4 1 0.20 11
Colombia
67 22.3
12 South
Africa 5 1.4 0.01 5 0 0.00 12 South
Africa 53 10.6
13
Malaysia
4 1.1 0.01 4 0 0.00 13 Canada 41 20.5
14
Panama
4 1.1 0.01 2 2 0.50 14
Australia
40 8.0
15
Argentina
3 0.8 0.01 2 1 0.33 15
Argentina
36 12.0
16
Colombia
3 0.8 0.01 1 2 0.67 16
Belgium
31 5.2
17 Spain 3 0.8 0.01 1 2 0.67 17
Indonesia
28 2.2
18
Thailand
3 0.8 0.01 3 0 0.00 18
Venezuela
26 4.3
19
United
King-
dom
3 0.8 0.01 1 2 0.67 19 Togo 22 22.0
20
Bangladesh
2 0.6 0.01 2 0 0.00 20
Thailand
17 5.7
Plants 2021,10, 2070 5 of 49
3.3. Keyword Analysis
Keywords reflect the core content of an article, and its analysis in this study aims to
recognize the evolving research topic. Figure 1shows the keyword network generated in
the VOS viewer. The keyword network map generated shows the major thematic areas
in the literature. Colored clusters represent thematic domains, while words enclosed in
large dotted nodes represent the most frequently used terms. Lines between terms show
the frequency of occurrence in articles. The map reveals that studies related to Merremia
species can be grouped into four thematic areas—Drug formulation, taxonomy, chemical
analysis, and treatment of diseases.
Figure 1.
Top keyword co-occurrence networks based on research articles on Merremia. Colored clusters represent different
research fields, while terms enclosed in colored squares represent the most frequently used keywords.
3.4. Genus Merremia
3.4.1. Taxonomy, Botanical Description, and Distribution
The genus Merremia has been reported to be a polyphyletic genus with strong evidence
from different molecular analyses [
11
,
30
,
31
]. The taxonomic classification of the genus is
provided in Table 3Approximately 182 species, including infraspecific names, have been
reported to belong to the genus Merremia, although only 71 correspond to an accepted
name, of which 38 are synonyms and 73 listed as unresolved on the Plant List database [
32
].
Table 3. Taxonomic classification of the genus Merremia.
Domain Eukaryota
Kingdom Plantae
Phylum Spermatophyta
Subphylum Angiospermae
Class Dicotyledonae
Order Solanales
Family Convolvulaceae
Genus Merremia
Merremia species are mostly shrubs or herbs (i.e., herbaceous forbs) with a gener-
ally twining or prostrate, but rarely erect growth form. The leaves are entire, lobed,
or compound with 3–7 leaflets. Flowers are axillary and solitary or in few- to many-
Plants 2021,10, 2070 6 of 49
flowered cymes. Bracts are small, ovate or elliptic, and linear. Sepals five, usually subequal,
elliptical ovate or ovate-oblong. Corollas are campanulate or funnel-shaped, lobed or
entire, yellow or white, sometimes with a dark brown or purple center. Stamens five,
filaments filiform, subequal or equal, and are usually widened and glabrous at the base.
The anthers are usually twisted with full dehiscence. Pollen grains are smooth and can be
3, 5–6, 9–12-colpate, or 12-rugate. Ovary 2–4-celled, usually with 4 ovules; style filiform;
stigmas 2, which are globose or biglobose. Fruits are capsules, usually four-valved that
dehisce longitudinally. The seeds are usually 4–6 in number, pubescent, or glabrous.
Conventionally, species in the genus are recognized by white or yellow flowers with
two globos stigmas, anthers that are twisted when flowers are fully opened and func-
tional, and non-spiny pollen grains that could be zonocolpate, tricolpate, pantoporate,
pantocolpate, non-spinulose, and valvate fruit dehiscence [10,33] (Figure 2).
Figure 2. Cont.
Plants 2021,10, 2070 7 of 49
Figure 2.
Images of some Merremia species. (
a
)Merremia palmata Image:
©
Riana Fourie, (CC-BY-
NC) [
34
]. (
b
)Merremia pterygocaulos Image:
©
Thierrycordenos, (CC-BY-NC) [
35
]. (
c
)Merremia
platylphylla Image:
©
Alexis López Hernández [
36
]. (
d
)Merremia peltata Image:
©
Matthew Cock [
37
].
(
e
)Merremia emarginata Image:
©
Convolvulaceae unlimited [
38
]. (
f
)Merremia gemella Image:
©
Wan-hsuan [39].
Merremia species are distributed in tropical and subtropical regions around the world.
Merremia is native to Africa, Asia, Australia, North America, and South America. Its full
distribution listing is shown in Figure 3and Supplementary Table S1.
Figure 3. Global distribution of Merremia species (Image © OpenStreetMap contributors, GBIF, © OpenMapTiles) [40].
Plants 2021,10, 2070 8 of 49
3.4.2. Nutritional Value of Merremia Species
Some Merremia species are a good source of food and are particularly useful as im-
portant fodders for livestock feed. The whole plant of M. emarginata is famous for salad
in Central Myanmar, Korea [
41
]. In Argentina, the roots of M. dissecta var. edentata are
used for food by some indigenous people [
42
]. The leaves of M. tridentata are cooked as
vegetables in Guinea-Bissau, West Africa [
43
]. The nutritional analysis of the whole plant
of M. emarginata revealed important nutritional constituents, which included carbohydrate
(63.10%) fat (1.05%), fiber (15.55%), protein (3.28%), ash (7.29%), and moisture (9.73%) [
41
].
Nunes et al. [
44
] carried out an ethnobotanical survey of plants used as animal forage
in two rural communities in north-eastern Brazil and determined their nutritional and
anti-nutritional constituents. Merremia aegyptia was listed among the forage plants with
a local preference for feeding ruminants given its promotive effect in terms of weight
gain and milk production. The analysis of the nutritional composition revealed that M.
aegyptia has good potential for use in ruminant diets in terms of crude protein contents
(20.33
±
6.26%) and mineral matter (14.06%). The anti-nutritional analysis further sug-
gested that M. aegyptia contained condensed tannin and lignin at low concentrations,
making it more suitable for inclusion in ruminant diets.
In another study, M. tridentata (synonym: Xenostegia tridentata) was included in a
feeding trial to investigate its use as a supplementary feed to a common foraged grass,
Panicum maximum in West African dwarf sheep during the rainy season because of its high
acceptability by the animals [
45
]. In addition, the crude nutrient and tannin contents of
M. tridentata were analyzed. There was a significant increase in the total food intake in
sheep whose ration was supplemented with M. tridentata compared with those fed with P.
maximum only. The crude nutrient analysis revealed higher protein content (15.3% DM) in
M. tridentata when compared with P. maximum (8.6% DM). The tannin content (0.7% DM)
of M. tridentata did not reduce its palatability and feeding value [45].
Galat-Luong et al. [
46
] studied the diet preferences of the Western giant eland group
from the native Sudanian habitat to a wildlife reserve in a Sahelian area. Merremia pen-
taphylla (35.41% feeding bouts) was the second most preferred food item in the list of
herbaceous species consumed by the animal.
In order to develop a suitable feeding strategy for improving grazing sheep production
in India, Rajendran and Balakrishnan [
47
] evaluated the herbage composition, biomass,
preference index, and mineral contents in mountain land, fallow land, and waste/roadside
land during the Southwest monsoon season. Merremia tridentata and M. emarginata were
listed among the herbage species in the mountain land, fallow land, and waste/roadside
land. Merremia tridentata had the highest preference index (2.57
±
2.42) by the sheep
in the waste/roadside land. The maximum preference index recorded in M. tridentata
suggests that the species is more edible than other herbage species consumed by the sheep.
In addition, the mineral contents analysis revealed that M. tridentata and M. emarginata,
together with other herbage species contained several minerals such as Ca, Fe, Cu, Zn, Mn,
and Co above the critical level, but the phosphorous level was below the critical level.
Collectively from these data, it is evident that Merremia species are valuable dietary
constituents for humans and particularly for livestock feed. With the ever-increasing human
population, changes in consumption patterns caused by raise in income and urbanization,
as well as the economic growth of many Asian countries, it is likely that the demand
for livestock products will double in the next two decades [
48
,
49
]. A major challenge
in livestock production in many developing countries is the shortage and fluctuating
quantity and quality of feed supply all year round. In addition, livestock is majorly fed
on roughages that are of low quality such as sugar cane by-products, cereal straws, all of
which contain a high amount of ligno-cellulose materials and are deficient in nutrients
(protein, minerals, vitamins, and energy) [
49
]. These challenges call for supplementation
of livestock feed that can improve the low-quality roughages, and contribute to increased
profitability and productivity of livestock. Many forb species, including those of the genus
Merremia, provide high-quality nutrient resources, particularly when there is inadequate
Plants 2021,10, 2070 9 of 49
forage in the perennial grass-based pasture system [
6
]. The utilization of Merremia species
in supplementing livestock feed is therefore encouraged.
3.4.3. Ethnomedicinal Uses of Merremia Species
Various species in the genus Merremia have been reported in different parts of the
world for the treatment of different diseases. The species M. tridentata (20%) and M.
emarginata (16%) are the most commonly reported, and India has the highest number of
research articles reporting the ethnomedicinal uses of Merremia species. This may be due to
India’s long history of well-developed traditional medical systems (Ayurveda) [50].
In India, a decoction made from leaves of M. emarginata has been employed in the
treatment of fever, neuralgia, urinary infection, rheumatism, liver and kidney diseases [
51
],
inflammation, cough, and headache [
21
]. The roots of M. tridentata prepared by maceration
are beneficial in the treatment of diabetes [
52
] rheumatism, hemiplegia, piles, swellings,
and urinary infections [
53
]. In addition, the whole plant and aerial parts of M. tridentata,
prepared by maceration have been recorded to be useful in the treatment of leprosy, piles,
swellings, rheumatism, stiffness of the joints, hemiplegia, urinary infections [
54
], and
toothache [55].
In Indonesia, the leaf and whole plant of M. mammosa, prepared by infusion and mac-
eration, respectively, have been reported to be beneficial in the treatment and management
of diabetes [
56
] and diabetic ulcers [
57
]. The leaves of M. peltata prepared by maceration
have been employed in the treatment of different forms of cancer, diarrhea, abdominal
pain, cough, sore eyes, wounds, and inflammation [58].
The whole plant of M. peltata prepared by maceration has been used as an anti-
inflammatory, analgesic, anticancer, anti-viral, anti-malarial, anti-bacterial, and anti-fungal
in the Philippines [19].
In Malaysia, the leaves [
22
] and aerial parts [
59
] of M. borneensis prepared by macera-
tion have been employed in the treatment and relief of breast cancer.
In China, a decoction prepared from the whole plant of M.yunnanensis has been used
to treat typhoid and stroke [
60
]. An infusion from the leaf and fruit of M.yunnanensis is
taken to treat stroke, hemiplegia, typhoid fever, and headache [61].
In Columbia, the leaves of M. umbellata prepared by maceration are used as an antibac-
terial, antifungal, and anti-inflammatory agent [62].
The leaves of M. vitifolia prepared by maceration are used in the treatment of fever,
headache, eye inflammation, rheumatism, dysentery, jaundice, and urinary diseases in
Bangladesh [
20
]. The ethnomedicinal uses of the different species in the genus Merremia
are summarized in Table 4.
Table 4. Ethnomedicinal uses of Merremia species.
Species Ethnomedicinal
Uses Part Used Type of
Extraction Country Location of
Collection Reference
M. borneensis Relieve breast
cancer Leaf Maceration Malaysia Unspecified [22]
Hair treatment Leaf Maceration Brunei
Darussalam Madang [63]
Relieve breast
cancer Aerial parts Maceration Malaysia
University of
Malaysia,
Sabah area
[59]
M. emarginata
Rheumatism,
neuralgia,
cough, and
headache
Leaf Maceration India Dharmapuri,
Tamil Nadu [21]
Plants 2021,10, 2070 10 of 49
Table 4. Cont.
Species Ethnomedicinal
Uses Part Used Type of
Extraction Country Location of
Collection Reference
Antimicrobial
effect, anti-
inflammatory
activity
Leaf Maceration India Dharmapuri,
Tamil Nadu [64]
Fever,
neuralgia,
urinary
infection,
rheumatism,
inflammation,
liver and
kidney diseases
Leaf Maceration and
decoction India
Varakkalpattu
village,
Cuddalore
District, Tamil
Nadu
[51]
M. mammosa Breast cancer Whole plant Maceration Indonesia Surabaya [65]
Diabetic
therapy Leaf Infusion Indonesia
Meru Betiri
National Park,
Jember
[56]
Diabetic ulcers Whole plant Maceration Indonesia Klaten, Central
Java Province [57]
M. peltata
Anti-
inflammatory,
analgesic,
anti-cancer,
anti-viral,
anti-malarial,
anti-bacterial,
and anti-fungal
Whole plant Maceration Philippines Rogongon,
Iligan City [19]
Anti-cancer,
diarrhea,
abdominal pain,
cough, sore
eyes, wound
and
inflammation
Leaf Maceration and
Fractionation Indonesia Padang City,
West Sumatra [58]
M. tridentata
Rheumatism,
hemiplegia,
piles, swellings,
and urinary
disorders
Root Maceration India
Udupi, Manipal
[53]
Toothache Whole plant Maceration India
Xavier’s
College
campus,
Palayamkottai,
Tirunelveli
District, Tamil
Nadu
[55]
Plants 2021,10, 2070 11 of 49
Table 4. Cont.
Astringent,
calefacient,
laxative,
anodyne,
hemiplegia,
hemorrhoids,
uropathy,
mouth wash,
piles,
inflammation,
fever, and
leprosy
Aerial parts Maceration India
Tamil Nadu
Medicinal Plant
Farms and
Herbal
Medicine,
Chennai
[66]
Piles, swellings,
rheumatism,
stiffness of the
joints,
hemiplegia, and
urinary
infections
Whole plant Maceration India Coimbatore,
Tamil Nadu [54]
Treatment of
diabetes Root Maceration India Coimbatore,
Tamil Nadu [52]
M. umbellata
Antibacterial,
antifungal, and
anti-
inflammatory
Leaf Maceration Colombia Pueblo Nuevo,
Bolívar, [60]
M. yunnanensis
Typhoid and
stroke
treatment
Whole plant Decoction China
Heqing
Country, Dali
Prefecture,
Yunnan
province
[60]
Stroke
hemiplegia,
typhoid fever,
and headache
Fruit/Leaf Infusion China
Heqing County
of Yunnan
Province
[61]
M. vitifolia
Fever,
headache, eye
inflammation,
rheumatism,
dysentery,
jaundice, and
urinary
diseases
Leaf Maceration Bangladesh Chittagong [20]
Generally, from the reported ethnomedicinal uses of the plant, the herbal formulations
of the species are prepared by decoction, maceration, and infusion (Table 4). Furthermore,
the leaves of the different species are the most widely utilized (50%) part in ethnomedicine,
followed by the whole plant (25.0%), aerial parts (12.50%), roots (8.33%), and fruits (4.16%).
3.4.4. Phytochemistry of Species in the Genus Merremia
A wide array of phytochemicals has been identified and isolated from different extracts
and fractions of Merremia species. Phytochemical investigations have been conducted on
the whole plant, the aerial parts, and other individual plant parts including roots and leaves.
Most of the reported phytochemicals were found in the roots (Table 5. However, there
are overlapping compounds obtained from different parts of the plant and across species
from the genus. Extraction methods are mainly maceration and infusion. The major
Plants 2021,10, 2070 12 of 49
class of the phytoconstituents widely isolated and identified from this genus is resin
glycosides. Other classes of phytoconstituents from this genus are flavonoids, tropane
alkaloids, phenolic compounds, isoflavones, coumarins, and sesquiterpenoid. Many of the
compounds isolated in the genus Merremia are therapeutically relevant, with some used as
pharmaceutical ingredients in a few commercial drugs.
Devadasu et al. [
67
] carried out phytochemical screening of M. emarginata leaves.
The results revealed the presence of alkaloids, steroids, glycosides, flavonoids, and phenols.
In the same study, a prenylflavonoid, 8-prenylnaringenin (1) was isolated from the leaves
of M. emarginata using silica thin layer chromatography. In addition to the good antioxidant
activity displayed by 8-prenylnaringenin (
1
) in the study, this compound is a known
phytoestrogen and also has anticarcinogen potential [68].
Phytochemical investigations conducted on the root of M. yunnanensis for the first
time led to the isolation and structure elucidation of two new eudesmane derivatives viz:
1
α
,6
β
,9
β
-trihydroxy-eudesm-3-ene-1-O-
β
-D-glucopyranoside (
29
) and 1
α
,6
β
,9
β
-trihydroxy-
eudesm-3-ene-1-(6-cinnamoyl)-O-
β
-D-glucopyranoside (
30
) [
60
]. In another recent study,
phytochemical investigations were conducted on M. yunnanensis (root and leaves) [
61
].
This study led to the isolation of a new compound, namely 1
α
,4
β
,8
β
,9
β
-eudesmane-tetrol-
1-O-
β
-D-glucopyranoside (
31
), together with the isolation of other known compounds viz:
tyrosol (
35
), hydroxypinoresinol (
58
), scopoletin (
42
), hydroxycoumarin (
43
), quercetin-
7-O-glucoside (
3
), and 2-C-methylerythritol (
6
). The researchers further reported that
compounds (
6
), (
43
), and (
58
) were reported for the first time in the genus Merremia,
and compounds (
31
) and (
35
) were isolated and reported for the first time in the family
Convolvulaceae. The results imply that the compounds isolated in M.yunnanensis can be
considered important chemotaxonomic markers for M.yunnanensis. Some of the isolated
compounds in M. yunnanensis are therapeutically relevant. For example, tyrosol (
35
) is well
known as a strong antioxidant [
69
]. Antioxidants have health benefits, quenching reactive
oxidants [70,71] and slowing down cell damage/death and inflammation. Quercetin-7-O-
glucoside (
3
) has been reported to suppress pancreatic cancer by inhibiting the epidermal
growth factor receptor (EGFR) signaling in the cell [
72
]. Rutin has been reported to inhibit
SARS-CoV-2 main protease proteins and could be a potential cure for SARS-CoV-2 [73].
In another study, five new pentasaccharide resin glycosides, named merremins A
E
(
7
10
), (
13
), two new pentasaccharide resin glycoside methyl esters, named merremins
F (
16
) and G (
17
), and four known resin glycosides, murucoidin IV (
12
), murucoidin V
(
14
), stoloniferin IV (
11
), and murucoidin XVII (
15
) were isolated for the first time from the
aerial parts of M. hederacea. All these compounds showed multi-drug resistance reversal
activities when evaluated further [74].
A chemotaxonomy study of the genus Merremia (using 18 species) based on the distri-
bution of tropane alkaloids revealed a total of 74 tropanes and 13 pyrrolidines based on
GC-MS analysis [
15
]. This study further led to the isolation and structure elucidation of
four new aromatic 3
α
-acyloxytropanes named merresectines A–D (
45
,
47
49
), (from the
roots of M. dissecta and M. guerichii), one new 3
α
,6
β
-di-(4-methoxybenzoyloxy) tropane
(named merredissine (
53
)) from M. dissecta, and datumetine (
46
) (from M. dissecta and M.
guerichii). The results from this study led to the grouping of Merremia species into three
chemo-taxonomical categories: (1) taxa free of tropanes, (2) taxa with simple tropanes, and
(3) taxa with merresectines in addition to simple tropanes. This grouping contributes to
the solution of infrageneric taxonomic problems in the genus. According to the study of
Rahman et al. [
73
], caffeic acid derivatives (CAFDs) isolated in M. umbellata [
64
,
75
] were
reported to inhibit SARS-CoV-2 [
76
]. Esculetin (
44
) and luteolin (
5
) isolated in M. umbel-
lata [
75
] were reported to decrease angiotensin-converting enzyme 2 (ACE-2) expression,
and could therefore reduce SARS-CoV-2 infection [
77
]. However, rosmarinic acid (
37
)
isolated in M. umbellata [
64
,
75
] was reported to increase the expression of ACE-2, which
could aggravate SARS-CoV-2 infection [
77
]. Shimming et al. [
14
] reported the presence
of calystegine B
2
(
55
) in the leaves and flowers of M. dissecta. This compound has been
reported to have antidiabetic properties as it was a potent inhibitor of R-galactosidases
Plants 2021,10, 2070 13 of 49
and
α
-glucosidases [
78
]. Using ultra-performance liquid chromatography-tandem mass
spectrometry (UPLC-MS/MS) and reverse phase-high performance liquid chromatography
(RP-HPLC), Angappan et al. [
79
] identified chlorogenic acid (
41
) in the aqueous leaf extract
of M. emarginata, which was attributed to the diuretic activity of the extract. In another
study, Santos et al. [
80
] isolated ursolic acid (
59
) and cis-tiliroside (
2
) from M. tomentosa leaf
extract, and these compounds were thought to be responsible for the insecticidal activity
of the extract. The medicinal characteristic of the species of Merremia and other medicinal
plants depends on the structure, quantity, and quality of the phytochemical constituents.
The phytochemicals detected and isolated in the genus Merremia, alongside their structures
are summarized in Table 5, and Figure 4.
Table 5. Phytochemicals isolated from the genus Merremia.
Species Isolated
Compounds
Molecular
Formula
Class of
Isolated
Compound
Part Extraction
Type
Bioactivity
of the Tested
Isolated
Compound
Reference
M. emarginata
8-
prenylnaringenin
(1)
C20H20 O5Flavonoid Leaf Maceration
Antioxidant
and antimy-
cobacterial
activities
[67]
Chlorogenic acid
(41)C16H18 O9Phenolic
compound Leaf Maceration Diuretic
activity [79]
M. hederacea Merremin A (7) C58H98O26 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Merremin B (8) C61H104O26 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Merremin C (9) C59H98O26 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Merremin D (10) C63H108O26 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Murucoidin IV (
12
)
C57H98 O29 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Stoloniferin IV (
11
)
C61H106 O25 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Merremin E (13) C51H88O24 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Murucoidin V (14) C56H96 O25 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Plants 2021,10, 2070 14 of 49
Table 5. Cont.
Species Isolated
Compounds
Molecular
Formula
Class of
Isolated
Compound
Part Extraction
Type
Bioactivity
of the Tested
Isolated
Compound
Reference
Murucoidin XVII
(15)C65H101 O26 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Merremin F (16) C52H92O25 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
Merremin G (17) C52H92O25 Resin
glycoside Aerial Infusion
Multidrug
resistance
reversal
activity
[74]
M. tomentosa Ursolic acid (59) C30H48 O3Triterpenoid Leaf Maceration Insecticidal
activity [80]
cis-Tiliroside (2) C30H26O13 Flavonoid Leaf Maceration Insecticidal
activity [80]
M.
yunnanensis
1α,6β,9β-
trihydroxy-
eudesm-3-ene-1-O-
β-D-
glucopyranoside
(29)
C21H36 O8
Sesquiterpenoid
Root Decoction N/A [60]
1α,6β,9β-
trihydroxy-
eudesm-3-ene-1-(6-
cinnamoyl)-O-β-D-
glucopyranoside
(30)
C30H42 O9
Sesquiterpenoid
Root Decoction N/A [60]
Eeudesmane-
1α,4β,8β,9β
-tetrol-1-O-β-D
-glucopyranoside
(31)
C21H38 O9
Sesquiterpenoid
Root Infusion N/A [61]
Tyrosol (35) C8H10O2Phenolic
compound Root Infusion N/A [61]
Hydroxypinoresinol
(58)C20H22 O7Lignan Leaf Infusion N/A [61]
Scopoletin (42) C10H8O4Coumarin Leaf Infusion N/A [61]
Hydroxycoumarin
(43)C9H6O3Coumarin Leaf Infusion N/A [61]
Quercetin-7-O-
glucoside
(3)
C21H20 O12 Flavonoid Root Infusion N/A [61]
2-C-
methylerythritol
(6)
C5H12O4Polyol Leaf infusion N/A [61]
Plants 2021,10, 2070 15 of 49
Table 5. Cont.
Species Isolated
Compounds
Molecular
Formula
Class of
Isolated
Compound
Part Extraction
Type
Bioactivity
of the Tested
Isolated
Compound
Reference
M. umbellata
SA 2-O-β-D
-(30,60-dicaffeoyl)-
glucopyranoside
(36)
C31H28 O14 Phenolic
Compound Whole plant Maceration
Allelopathic
effect on
Arabidopsis
seed
germination
[75]
Rosmarinic acid
(37)C18H16 O8Phenolic
Compound Whole plant Maceration
Allelopathic
effect on
Arabidopsis
seed
germination
[64,75]
Paprazine (38) C17H17 NO3Phenolic
Compound Whole plant Maceration
Allelopathic
effect on
Arabidopsis
seed
germination
[75]
N-p-cis-
coumaroyltyramine
(39)
C17H17 NO Phenolic
Compound Whole plant Maceration
Allelopathic
effect on
Arabidopsis
seed
germination
[75]
Caffeic acid (40) C9H8O4Phenolic
Compound Whole plant Maceration
Allelopathic
effect on
Arabidopsis
seed
germination
[64,75]
Esculetin (44) C9H6O4Coumarin Whole plant Maceration
Allelopathic
effect on
Arabidopsis
seed
germination
[75]
Quercetin (4) C15H10O7Flavonoid Whole plant Maceration
Allelopathic
effect on
Arabidopsis
seed
germination
[64,75]
Luteolin (5) C15H10 O6Flavonoid Whole plant Maceration
Allelopathic
effect on
Arabidopsis
seed
germination
[75]
M.
kentrocaulos
Merrekentrones
A and B (32)C15H14 O3
Sesquiterpenoid
Root Maceration N/A [81]
Merrekentrones C
(33)C15H16 O4
Sesquiterpenoid
Root Maceration N/A [81]
Merrekentrones D
(34)C15H18 O3
Sesquiterpenoid
Root Maceration N/A [81]
M. mammosa
Mammoside A (
22
)
and B (23)C48H82 O20 Resin
glycosides Root Maceration N/A [82]
Plants 2021,10, 2070 16 of 49
Table 5. Cont.
Species Isolated
Compounds
Molecular
Formula
Class of
Isolated
Compound
Part Extraction
Type
Bioactivity
of the Tested
Isolated
Compound
Reference
Mammoside H1
(20)C54H92 O25 Resin
glycosides Root Maceration N/A [82]
Mammoside H2
(21)C54H92 O25 Resin
glycosides Root Maceration N/A [82]
M.
quinquefolia
Merresectine
A (45)C15H19 NO3Tropane
alkaloid Root Maceration N/A [15]
M. cissoides
and M.
quinquefolia
Merresectine
B/kurameric acid
(47)
C31H45 NO8Tropane
alkaloid Root Maceration N/A [15]
M. cissoides
and M.
quinquefolia
Merresectine C
(48)C25H35 NO3Tropane
alkaloid Root Maceration N/A [15]
M. cissoides
and M.
quinquefolia
Merredissine (53) C24H27NO6Tropane
alkaloid Root Maceration N/A [15]
M. dissecta Datumetine (46) C16H21 NO3Tropane
alkaloid Root Maceration NA [15]
M. guerichii Merresectine D
(49)C27H39 NO9Tropane
alkaloid Root Maceration N/A [15]
Merresectine
β-D–glucoside (50)C27H39 NO9Tropane
alkaloid Root Maceration N/A [15]
M. quinata Consabatine (54) C20H31 NO4Tropane
alkaloid Root Maceration N/A [15]
M. cissoides
and M.
quinquefolia
Merresectine E (
51
)
and Merresectine E
β-D-glucoside (52)
C20H27 NO3Tropane
alkaloid Root Maceration N/A [15]
M. tuberosa Octadecanonyl
caffeate (56)C27H44O4
Caffeate ester
Root Maceration NA [83]
6-
Methylheptadecanoyl
caffeate (57)
C27H42 O5
Caffeate ester
Root Maceration NA [83]
M. dissecta Octadecanonyl
caffeate (56)C27H44O4
Caffeate ester
Root Maceration NA [83]
6-
Methylheptadecanoyl
Caffeate (57)
C27H42 O5
Caffeate ester
Root Maceration NA [83]
Calystegine B
2
(
55
)
C7H13NO4Tropane
alkaloid Leaf, Flower N/A Antidiabetic
activity [14,78]
M. mammosa Merremoside
A (22)C50H86 O20 Resin
glycosides Tuber Maceration NA [84]
Merremoside B
(23)C48H82 O20 Resin
glycosides Tuber Maceration NA [84]
Plants 2021,10, 2070 17 of 49
Table 5. Cont.
Species Isolated
Compounds
Molecular
Formula
Class of
Isolated
Compound
Part Extraction
Type
Bioactivity
of the Tested
Isolated
Compound
Reference
Merremoside C
(24)C49H84 O20 Resin
glycosides Tuber Maceration NA [84]
Merremoside D
(25)C48H82 O20 Resin
glycosides Tuber Maceration NA [84]
Merremoside E
(26)C48H82 O20 Resin
glycosides Tuber Maceration NA [84]
Merremoside F
(27)C55H94 O25 Resin
glycosides Tuber Maceration NA [85]
Merremoside G
(28)C54H92 O25 Resin
glycosides Tuber Maceration NA [85]
N/A: Not available.
Figure 4. Cont.
Plants 2021,10, 2070 18 of 49
Figure 4. Cont.
Plants 2021,10, 2070 19 of 49
Figure 4. Cont.
Plants 2021,10, 2070 20 of 49
Figure 4. Cont.
Plants 2021,10, 2070 21 of 49
Figure 4. Cont.
Plants 2021,10, 2070 22 of 49
Figure 4. Structures of isolated phytochemicals in the genus Merremia.
3.4.5. Biological and Pharmacological Activities
Due to the different ethnomedicinal usage and phytochemicals present in the genus
Merremia, several biological and pharmacological have been assessed in 11 species (viz.
M. aegyptia, M. borneensis,M. dissecta, M. emarginata,M. hederacea,M. mammosa,M. peltata,
M. tridentata,M. tomentosa,M. umbellata, and M. vitifolia). Antimicrobial and antioxidant
activities are the most studied, with M. emarginata being the most researched species.
The various scientific studies documenting the relevant biological activity of Merremia
species are presented below and summarized in Table 6. The activities are presented in
terms of the plant extract types, experimental methodologies, extract concentrations/doses,
and possible mechanisms of action where the information was available.
Cancer Cell Cytotoxicity
In recent years, research on medicinal plants as potential chemotherapeutic agents has
increased globally because of their actions that prevent cancer initiation and proliferation
with limited toxicity, as well as their anti-multidrug reversal ability [
86
,
87
]. There are very
few scientific studies on Merremia species as anticancer agents, but their traditional use
in treating breast cancer may have prompted investigations on their potential anticancer
and antiproliferative properties as discussed below. The antiproliferative activities of three
solvent extracts (50
µ
g mL
1
ethyl acetate, hexane, and methanol) from whole plants of M.
emarginata were investigated on human cancer cell lines using the 3-(4,5-Dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay [
3
]. The results demonstrated
antiproliferative effects of the extracts against the cell lines of which the ethyl acetate extract
Plants 2021,10, 2070 23 of 49
was the most effective, inhibiting the proliferation of cell lines A549, KB, MIA-PaCa-2, and
DU-145 with IC
50
values of 28.5
µ
g mL
1
, 37.2
µ
g mL
1
, 51
µ
g mL
1
, and 69.4
µ
g mL
1
,
respectively at 50
µ
g mL
1
. In another study, the antiproliferative potential of the leaf
extracts (methanol, ethyl acetate, and hexane) of M. emarginata and different parts of nine
other medicinal plants on human cancer cell lines and monkey normal kidney epithelial
cells (VERO) was investigated [
88
]. The leaf extracts were tested at different concentrations
(range: 3.13–200
µ
g mL
1
) and time intervals (24, 48, and 72 h). The antiproliferative study
was done using the MTT assay, while flow cytometry was used to determine apoptosis.
The results revealed that M. emarginata hexane extract exhibited cytotoxic effects in all
the cell lines in a concentration- and time-dependent manner, ranking fifth out of the
10 plants used in the trial. The hexane extract (25
µ
g mL
1
) particularly inhibited A549
and COLO 320 DM cell line proliferation (with IC
50
values of 15.5
µ
g mL
1
and 18.4
µ
g
mL
1
, respectively) and had minimal toxicity (IC
50
value of 65.2
µ
g mL
1
) for VERO
cells at 72 h. The authors speculated that the inhibition of cell line proliferation by M.
emarginata extract might be due to its antiproliferative potential to demonstrate cancer
cell-specific death. Wang et al. [
74
] tested the cytotoxicity and multidrug resistance reversal
activity of different types of isolated pentasaccharide resin glycoside compounds (25
µ
M of
merremins A
G (
7
10
,
13
,
16
,
17
) and murucoidin IV (
12
), murucoidin V (
14
), stoloniferin
IV (
11
), and murucoidin XVII (
15
)) from M. hederacea aerial parts in KB/VCR cell lines
using a sulforhodamine B assay. Vinblastine served as a reference. Merremins A (
7
), E (
13
),
G (
17
), and murucoidin V (
14
) were non-cytotoxic at 25 Mm but enhanced the cytotoxicity
of vinblastine 2.3
142.5-fold at 25 Mm, and demonstrated anti-multidrug reversal activity.
Taken together, the results suggest that the investigated extracts and compounds from
Merremia species have the potential to be developed into chemotherapeutic agents as
they showed significant cytotoxic effects and inhibited the proliferation of cancer cells.
However, more
in vivo
studies and clinical trials are required. Other Merremia species
must be investigated for their anticancer activities, particularly those species (M. borneensis,
M. peltata and M. mammosa) that have been reported to be used in treating cancer in
traditional medicine.
Anti-Diabetic Activity
Diabetes is a chronic disease marked by high blood sugar resulting from a decrease
in insulin production by pancreatic beta cells, or when the body cannot effectively use
the insulin it produces [
89
,
90
]. In 2019, diabetes was the direct cause of 1.5 million deaths
globally, and it has been projected that diabetes will be the seventh leading cause of
death by 2030 [
89
]. Additionally, diabetes has been associated with increased mortal-
ity and severity of COVID-19 disease [
91
,
92
]. Several alpha-glucosidase inhibitor drugs
(such as Miglitor Acarbose, and Voglibose) are used in the treatment of diabetes [
90
].
Several
in vivo
and
in vitro
studies have reported that members of the genus Merremia
demonstrated inhibitor activity of alpha-amylase and alpha-glucosidase enzymes.
In vitro
studies reported that the ethanolic and ethyl acetate leaf and stem extracts of M. peltata
(IC50 value 47.44–72.85
µ
g/mL) [
90
], the ethanolic leaf extract of M. hederacea (91.44%
inhibition) [
18
], and the hexane fraction of M. mammosa (66.19
±
0.41% inhibition) [
56
]
demonstrated good alpha-amylase inhibition. In all these studies, extracts from Merremia
species had higher
α
-glucosidase inhibition compared to the reference anti-diabetic drug
(acarbose).
In vivo
studies using streptozotocin-induced diabetic male Wistar rats reported
that the aqueous extract of M. tridentata roots [
52
], methanolic extract of M. emarginata
whole plant [
93
], and ethanolic leaf extract of M. hederacea [
18
] demonstrated potent an-
tidiabetic activities in streptozotocin-induced diabetic rats that were comparable to the
reference drug (glibenclamide) used. Overall, the anti-diabetic effects exhibited by extracts
of the Merremia species studied were attributed to their phytochemical constituents par-
ticularly flavonoids and phenolic compounds. Although the results of the
in vitro
and
in vivo
studies corroborate the ethnomedicinal claims of Merremia species as antidiabetic
plants, it is recommended that longer duration studies on the chronic model are carried
Plants 2021,10, 2070 24 of 49
out to explicate the mechanism of action in order to develop these species as potential
antidiabetic drugs.
Antimicrobial Activities
Several studies have shown that Merremia species have antibacterial and antifungal
effects, and thus have the potential to be developed as antimicrobial agents. Different
parts of Merremia species extracts show inhibitory actions on several bacteria and fungi to
different degrees. The antibacterial activity of the methanolic leaf extracts of Convolvu-
laceae family members, including M.tridentata was assessed against two Gram-positive
bacteria (Bacillus subtilis and Staphylococcus aureus) and two Gram-negative bacteria (Es-
cherichia coli and Vibrio parahaemolyticus) [
94
]. The extracts had more antibacterial activity
on Gram-positive bacteria (MIC range: 0.25–0.5 mg mL
1
; zone formation range: 10 mm-14
mm) than Gram-negative bacteria (MIC range: 0.5–1 mg mL
1
; zone formation range:
9 mm-11 mm). Pavithra et al. [
66
] also reported that the methanol stem extracts of M.
tridentata showed strong antibacterial activity only on Gram-positive bacteria (S. aureus
and B. subtilis) with inhibition zones of 12.0 mm and 11.3 mm, respectively. These extracts
were evaluated for antibacterial activity using the broth dilution and disk diffusion assays.
The extracts demonstrated antibacterial effects comparable to the standard drugs (ampi-
cillin and gentamicin). The bactericidal effect was attributed to the extract’s phytochemical
constituents like alkaloids, triterpenoids, tannins, glycosides, and steroids. In another
study, the aqueous, petroleum ether and methanol extracts (concentration range of 10
µ
g
mL
1
, 25
µ
g mL
1
, and 50
µ
g mL
1
, 100
µ
g mL
1
) of M. emarginata leaves showed antibac-
terial activities against B. cereus,E. coli,P. aeruginosa, and S. aureus [
95
]. The leaf extracts
exhibited higher antibacterial activity (with a zone of inhibition range of 0.7–13.7 mm)
on all the bacteria compared with penicillin (16.0–17.0 mm). The observed antibacterial
activity of M. emarginata leaf extracts was ascribed to the presence of chemical compounds
such as flavonoids, glycosides, terpenoids, starch, and amino acids in the aqueous ex-
tract; flavonoids, tannins, carbohydrates, and amino acids in the methanol extract, and
flavonoids, tannins, glycosides, carbohydrates, and amino acids in the petroleum ether
extract. Diwan and Gadhikar [
96
] reported that all four extract solvents (aqueous, acetone,
chloroform, and petroleum ether) of M. emarginata leaves were effective against bacteria
(A. viscoscus,B. subtilis,E. coli,L. rhamnosus,S. aureus,S. epidermidis, and S. mutans) known
to cause oral diseases in human. Acetone extract had maximum inhibitory (24%) action
against S.epidermidis and was the most effective. The extracts’ antibacterial properties were
imputed to their aromatic phytochemical contents (e.g., phenolics).
Using Luria-Bertani agar disk diffusion assay, Rameshkumar et al. [
21
] investigated
the antibacterial activity of M. emarginata aqueous leaf extract, thioglycolic acid-capped
cadmium telluride quantum dots (TGA-capped-CdTe QDs, hereafter), and their mixture
(T-M complex, hereafter) (1
×
10
6
M and 100
µ
g, respectively) against a Gram-negative
bacterium, E. coli. The T-M complex served as an antimicrobial agent. The results showed
that the plant extract alone and T-M complex showed 10 mm and 16 mm zones of inhibition,
respectively. Compared with M. emarginata extract, the antibacterial activity of the T-M
complex was thought to be due to electrostatic interactions. The observed antimicrobial
activity of the T-M complex was ascribed to the capability of TGA-capped-CdTe QDs and
M. emarginata extract phytochemical constituents (e.g., alkaloids, flavonoids, phenolics,
saponins, steroids, and terpenoids) to induce oxidative stress on the bacteria (E.coli) surface
biomolecules thereby damaging its membrane. Merremia umbellata methanol leaf extract
(1000
µ
g mL
1
) showed antibacterial activities with percentage inhibition of 32%, 55%,
and 67% on Klebsiella pneumoniae (13883), S. aureus (25923), and Pseudomonas aeruginosa
(27853), respectively [
62
]. The observed antibacterial effect was ascribed to phytochemicals
such as leucoanthocyanidins, terpenes, and/or steroids and tannins present in the extract.
The ethanol leaf extract of M. peltata showed a 5.7-mm average zone of inhibition against
B. subtilis and S. aureus (at 10
µ
g mL
1
and 20
µ
g mL
1
, respectively), relative to the 2 mm
by streptomycin. M. peltata ethanol leaf extract had 4.7-mm and 2.7-mm average zones of
Plants 2021,10, 2070 25 of 49
inhibition against P. aeruginosa and E. coli (at 15
µ
g mL
1
and 5
µ
g mL
1
, respectively),
relative to the 1 mm by chloramphenicol [19].
Luciardi et al. [
4
] reported that M. dissecta methanol leaf extracts showed a high an-
tibacterial effect against P. aeruginosa and biofilm inhibition effects against P. aeruginosa
and S. aureus, compared with azithromycin which served as the control. The observed
antibacterial activity was ascribed to lipophilic compounds present in the extract, suggest-
ing that the extract was toxic to cell membranes by causing loss of chemiosmotic control.
It was suggested that volatile plant metabolites, like spathulenol, present in the extracts
may be responsible for decreasing the biosynthesis of N-acyl homoserine lactone by 72%,
attenuating the expression of virulence factors such as elastase activity (27%) and biofilm
production (55%) in P. aeruginosa.
Studies on antifungal activities have only been done on M.tridentata and M. borneensis.
In both studies, although the antifungal activities were tested on mould and yeast fungal
strains, both species only showed antifungal activity on yeast. The methanol leaf extract of
M.tridentata (at 0.01 mg mL
1
, 0.05 mg mL
1
, 0.1 mg mL
1
, 0.25, 0.5 mg mL
1
and 1 mg
mL
1
) showed antifungal activity on yeast (MIC range: 0.25–0.5 mg mL
1
; zone formation
range: 10–15 mm) [
94
]. Zulhamizan et al. [
63
] reported that methanol leaf extract of
M. borneensis showed antifungal activity against S. cerevisiae with increasing concentration
(60–400 mg mL
1
) and the inhibition zones ranged between 5.5–15.5 mm. The observed
antifungal activity was attributed to the presence of palmitic acid in the methanol leaf
extract only.
The above studies suggest that Merremia species possess antimicrobial (antibacterial
and antifungal) properties. However, the studies are
in vitro
studies and may not show the
same effects in
in vivo
investigations. For more reliable and valid results, the antimicrobial
activities of Merremia species extracts should be investigated in
in vivo
models infected
with clinically isolated strains and specific microorganisms to demonstrate efficacy and
elucidate their mechanism of action.
Anti-Influenza Activity
Influenza is a highly transmissible and widespread respiratory disease that is caused
by influenza viruses and occurs throughout the year in tropical areas [
97
]. Accord-
ing to WHO, global influenza epidemics result in 3–5 million severe illness cases and
290,000-650,000 mortalities yearly [
98
]. Several anti-influenza viral drugs including
Zanamivir are used for treating influenza viral infection. However, the emergence of
resistance of viruses to these drugs, as well as adverse side effects, has been reported [
97
].
Natural products with good tolerability and greater efficacy than existing anti-influenza
drugs are of interest in the treatment of influenza virus infection. Only one report is
available on the anti-influenza activity of Merremia species. Using hemagglutinin assay,
the anti-influenza A (subtype H1N1) activity of ethyl acetate fraction of methanol extract
of M. mammosa tuber was evaluated on embryonic chicken eggs injected with the H1N1
virus [
99
]. The virus subtype H1N1 (with no treatment extract) and Zanamivir (10
µ
g mL
1
)
served as negative and positive controls, respectively. The result showed that the ethyl
acetate fraction of the M. mammosa tuber extract (1000
µ
g mL
1
) had an anti-influenza effect
similar to Zanamivir, reducing hemagglutinin virus titer by 94% and 100%, respectively.
The activity was attributed to the flavonoid and terpenoids contents of the ethyl acetate
fraction. The result indicates that M. mammosa tuber extract may be a potential alternative
medicine for the treatment of the influenza virus. However, this is an
in vitro
study,
in vivo
studies are required to evaluate whether M. mammosa tuber extract will result in antiviral
activity
in vivo
and to elucidate the mechanism of action. Furthermore, other species in
the genus should be investigated for their anti-influenza activities.
Anti-Inflammatory Activity
Inflammation is a defense mechanism of the body’s immune system against unwanted
foreign substances, tissue injury, or pathogens that attack tissue cells. However, unreg-
Plants 2021,10, 2070 26 of 49
ulated inflammation often results in chronic inflammation, consequently leading to the
development of various chronic cardiovascular and pulmonary diseases [
100
]. Several
pro-inflammatory mediators such as inducible cyclooxygenase enzyme (COX-2) and tu-
mor necrosis factor-alpha (TNF—
α
) are usually observed in numerous inflammatory
diseases, including inflammatory vascular diseases and rheumatoid arthritis [
101
]. Medici-
nal plants that can selectively and effectively inhibit the expression or activation of these
pro-inflammatory mediators are of significant clinical importance. The anti-inflammatory
activity of orally administered whole plant M. tridentata extracts (water, ethanol, benzene,
petroleum ether, and chloroform) on male albino rats using the carrageenan-induced rat
paw inflammation method was assessed [
55
]. Normal saline and indomethacin were used
as the control and standard drug, respectively. The extracts inhibited paw volume at a
range of 15.6–38.3%; the ethanol extract was the most effective with 38.3% and 42.8% inflam-
mation inhibition at 100 mg kg
1
and 200 mg kg
1
doses, respectively, relative to that the
standard drug (48.5%) after 3 h. The ethyl acetate extract of M.emarginata at a concentration
of 50
µ
g mL
1
effectively inhibited TNF-
α
production (IC
50
of 5.9
µ
g mL
1
) in lipopolysac-
charide (LPS)-induced human acute monocytic leukemia cells (THP-1) [
3
]. In another
study, the anti-inflammatory activity of different extracts (250 mg kg
1
of petroleum ether
and 300 mg kg
1
of ethyl acetate, solvent ether, butanol, and butanone) fractionated from
M. tridentata ethanol roots extract was tested by the authors of [
53
] in albino mice using
the carrageenan-induced rat paw edema method. Orally administered Tween 80 solution
and aspirin served as the control and standard drug, respectively. The results showed
that solvent ether, ethyl acetate, butanol, and butanone fractions were more effective (87%,
84%, 72%, and 68% at 300 mg kg
1
, respectively) at inhibiting rat paw edema, relative
to the standard (59.7%) and control (no inhibition). The anti-inflammatory activity was
attributed to the antimicrobial property of flavonoids present in the extracts. Using the com-
plete Freund’s adjuvant-induced arthritis model, Kamalutheen et al. [
55
] reported that the
methanolic extract of M.tridentata whole plant demonstrated 49.0% and 51.7% anti-arthritic
activity at 100 mg kg
1
and 200 mg kg
1
on male albino rats. The anti-arthritic activity of
the extract was comparable to the standard drug (indomethacin) (55.5%). In another
in vitro
anti-arthritic study using the protein denaturation inhibition method, at 250
µ
g mL
1
, the
ethanol extract of M. emarginata whole plant and its methanol and ethyl acetate fractions
exhibited high protein denaturation inhibition percentages of 95.4%, 87.7%, and 72.6%,
respectively, which was comparable with the standard (diclofenac sodium) (98.4%) [
102
].
However, using this same protein denaturation inhibition technique in a recent study,
the aqueous portion of fractionated methanol extract (APFME) of M. vitifolia leaves only
showed anti-arthritic activity of 64% at a higher concentration of 500 µg mL1[20].
Collectively, these findings demonstrate that the investigated Merremia species extracts
possess remarkable
in vitro
and
in vivo
anti-inflammatory activities, which support the
traditional use of some of these species in the treatment of various inflammatory diseases.
Anti-Nociceptive Activity
Pain is an unpleasant sensory and emotional experience linked with or resembling
that related to actual or potential tissue damage [
103
]. To relieve pain, non-steroidal anti-
inflammatory drugs such as salicylates and acetic acid derivatives, and opioids are used.
However, the prolonged use of these medications leads to decreased gastrointestinal system
function [
104
]. Antinociceptive drugs developed from plant extracts with little or no side
effects are of interest in modern medicine. Using formalin-induced paw licking (at early
and late stages) and acetic acid-induced writhing tests, the
in vivo
antinociceptive activity
of M. vitifolia APFME (200 mg kg
1
and 400 mg kg
1
BW, PO) was assessed in Swiss
Albino mice [
20
]. Diclofenac sodium (10 mL kg
1
BW, administered intraperitoneally (IP))
served as the standard drug. In the formalin-induced paw licking test, the findings of the
study demonstrated that the APFME at 200 mg kg
1
and 400 mg kg
1
BW PO showed
dose-dependent higher anti-nociceptive activity (44% and 26%, 30%, and 20% in both
early and late test stages, respectively) relative to the control (20% and 15%, respectively)
Plants 2021,10, 2070 27 of 49
at the same concentrations. Similarly, reduced (44% and 30%, respectively) abdominal
contortions with increasing doses of APFME relative to the control (21%) were observed in
the acetic acid-induced writhing test. Future studies should investigate more species in
the genus for their antinociceptive activity and attempt to identify pure compounds and
elucidate the mechanism of action responsible for the activity.
Thrombolytic Activity
Several thrombolytic drugs including streptokinase, are used to treat acute coronary
disorders resulting from thrombosis [
20
]. However, there are reports of hypertension
and severe hemorrhagic transformation resulting from the use of thrombolytic drugs [
20
].
Alternative medicines from medicinal plants with thrombolytic activity are increasingly
being researched for their safety profile to overcome the side effects resulting from modern
thrombolytic drugs. Only one report, however, is available on the thrombolytic activity of
Merremia species. The aqueous portion of fractionated methanol extract of M. vitifolia leaves
(500
µ
g mL
1
) was reported to demonstrate significant thrombolytic activity (42.5% clot
lysis) in blood samples from male and female adult human volunteers as compared with the
negative control (normal saline; 4.80%) [
20
]. However, the positive control (streptokinase)
demonstrated much higher thrombolytic activity (72.2%) than M. vitifolia. This study was
assessed in blood samples from male and female (1:1) adult human volunteers with no
anticoagulant and oral contraceptive treatments history. The inhibition of clot formation
in the subjects was attributed to various phytochemicals (alkaloids, flavonoids, tannins,
and triterpenoids) in M. vitifolia. Studies to identify the major compound responsible for
this activity, as well as its mechanism of action, should be conducted. Although M. vitifolia
leaf extract gave low thrombolytic activity as compared with the positive control in this
study, other species in the genus may give higher thrombolytic activity if evaluated. Future
studies should evaluate these species for thrombolytic activity.
Anti-Urolithiatic Activity
Urolithiasis (commonly referred to as kidney stones) is the formation of solid parti-
cles anywhere in the urinary tract and it is the most prevalent type of all urinary stone
diseases [
105
,
106
]. Usually, the solid particles are very small and can dissolve and leave
the body without any problem. However, the blockage of the flow of urine by even a
small stone results in excruciating pain, which requires immediate medical attention [
106
].
Several pharmaceutical drugs and medical technologies such as percutaneous nephrolitho-
tomy and extracorporeal shock wave lithotripsy are available to treat and prevent urolithi-
asis. However, these medications and techniques are expensive and there are risks of side
effects and reoccurrence of urolithiasis even with medication [
106
]. Several medicinal
plants, including Merremia species, have the potency to inhibit stone formation as well as
break formed stones.
A dissolution model study was carried out by Neeraja Kamakshi et al. [
107
] on the
anti-urolithiatic activity of methanol extracts of the M.emarginata plant. Artificial stones
(calcium phosphate and calcium oxalate) were produced by homogenous precipitation,
while eggs’ semi-permeable membrane served as dissolution bags; Cystone
®
served as
a positive control. M.emarginata showed anti-urolithiatic activity in a dose-dependent
manner (with calcium phosphate and calcium oxalate mineralization inhibition of 81%
and 84%, respectively, relative to 91% by the standard drug at 400
µ
g mL
1
). The ob-
served bioactivity was attributed to the presence of phytochemicals such as alkaloids and
flavonoids in the plant extract. The result implies that the methanolic extract of the M.
emarginata plant has great potential to be developed as a pharmaceutical agent for the
treatment of urolithiasis. However,
in vivo
and clinical studies are required to clarify
the mechanism of action and identify the exact compound responsible for this activity.
Other species in the genus should be investigated for their anti- urolithiatic activities.
Plants 2021,10, 2070 28 of 49
Nephroprotective Activity
Nephrotoxicity usually results from the frequent use of therapeutic and chemothera-
peutic drugs like aminoglycoside antibiotics (gentamicin) and cisplatin, chronic diseases,
and exposure to heavy metals. These causes often result in End-Stage Renal Disease (ESRD)
and death. The few therapeutic drugs currently available to treat nephrotoxicity only
delay and do not stop the progression of nephrotoxicity [
108
]. There is increasing research
focus on medicinal plants with nephroprotective activities that can be used as safer and
better alternatives in treating nephrotoxicity. The nephroprotective activity of ethanol
extract of M. emarginata leaves (150, 200, and 250 mg kg
1
BW, PO) in adult albino Wistar
rats was investigated by Rameshkumar et al. [
64
] using a histopathology examination.
Nephrotoxicity was induced with gentamicin (20 mg kg
1
BW, IP); normal drinking water
(10 mg kg
1
BW) served as control. The results revealed that the extracts caused regenera-
tion of glomerular, tubular, and proximal tubular epithelial cells of damaged kidneys in
M. emarginata extract-treated rats (especially at 250 mg kg
1
). The leaf extract’s nephropro-
tective activity was ascribed to its antioxidant (polyphenolics) contents. The result supports
the traditional use of M.emarginata leaves in treating kidney disorders. Further studies
should be carried out to determine the exact polyphenolics and their mechanism against
nephrotoxicity. Other Merremia species (M. tridentata and M. vitifolia) that are used in
traditional medicines to treat various kidney and urinary disorders should be investigated
for their nephroprotective activities.
Diuretic/Blood Pressure-Lowering Activity
Diuretics are medications that elevate the amount of water and salt expelled from
the body as urine and are widely used in the treatment of kidney and liver diseases,
edema, hypertension, and congenital heart failure [
79
]. Commercial diuretic drugs have
been reported to be associated with many side effects (such as dehydration, hypokalemia,
fever, bleeding, and cough). Diuretic drugs of medicinal plant origins without harm-
ful effects can be considered a better alternative to commercial drugs. The angiotensin-
converting-enzyme inhibitory (ACEI), diuretic, and hypotensive effects of the aqueous
methanol crude extract of M. emarginata aerial parts administered intravenously were
tested in Sprague-Dawley rats by the authors of [
109
]. Dimethyl sulphoxide and capto-
pril served as the control and standard drugs, respectively, for the ACEI test. For the
diuretic test, normal saline and frusemide (10 mL Kg
1
, IP) served as control and stan-
dard drug, respectively. M. emarginata extract showed serum ACEI activity (IC
50
value of
422
µ
g mL
1
; 2.0 mg mL
1
extract had the highest (81%) ACEI effect compared with capto-
pril (89%)). Additionally, the extract increased the volume of urine and excretion of urinary
Na
+
at 30 mg Kg
1
and 50 mg Kg
1
doses. The extract’s ACEI activity was ascribed to
the presence of phytochemicals (like tannins, flavonoids, and alkaloids) via enzyme metal
co-factor sequestration, protein precipitation, or other mechanisms. Similarly, the diuretic
activity was ascribed to the phytochemical (such as alkaloids and phenolics) contents of
M. emarginata extract. The extract exhibited a dose-dependent drop in the average arterial
blood pressure range of 21.5–61.7% at a concentration range of 0.1–3.0 mg Kg
1
. The au-
thors alluded to vasodilation with heightened cardiac output to have led to a remarkable
decrease in diastolic blood pressure. Additionally, it was reported that the plant extract
caused heart rate decline, which was attributed to reflex mechanism involvement. Other
mechanisms, such as indirect and/or direct effect on heart, inhibition, and/or relaxation
of vascular smooth muscle contraction, leading to decreased total peripheral resistance or
combination of mechanisms, were suggested.
In an
in vivo
study, the diuretic activity of the aqueous extract of M. emarginata leaves
(200, 400, and 600 mg/kg b.w.) was investigated in adult female Wistar albino rats [
79
].
Normal drinking water (10 mL/kg b.w) and a commercial diuretic drug (furosemide
20mg/kg b.w) served as controls. The diuretic activity of the extract was confirmed by
analyzing the disparity in the total volume of urine and diuretic markers, compared to
the controls. Merremia emarginata leaf extract demonstrated a significantly higher diuretic
Plants 2021,10, 2070 29 of 49
effect in treated rats compared to the control group rats. This diuretic activity was without
side effects such as proteinuria or glycosuria. Furthermore, a polyphenolic compound
(chlorogenic acid) (
6
) was identified through ultra-performance liquid chromatography-
tandem mass spectrometry (UPLC-MS/MS) and reverse phase-high performance liquid
chromatography (RP-HPLC) to be responsible for the diuretic activity. These results suggest
that M. emarginata may potentially act as a good diuretic agent without causing harmful
side effects.
Wound Healing Property
Wounds result from physical injuries, that lead to a break or opening of the skin [
110
].
Proper wound healing is important to restore the disrupted functional status of the skin, as
well as the interrupted anatomical continuity [
110
]. Several medicinal plants are used in
traditional medicine to treat wounds because of their wound-healing properties [
110
,
111
].
Such medicinal plants promote wound healing by the activities of their bioactive sub-
stances (e.g., flavonoids, phenolic acids, tannins, etc.). The bioactive compounds in
medicinal plants exhibit exceptional fast healing by reducing lipid peroxidation, thereby
improving vascularity and preventing or slowing the onset of necrosis, and initiating
skin cell differentiation [
110
,
111
]. The wound-healing activity of different ethanol ex-
tract fractions (solvent ether, petroleum ether, ethyl acetate, butanol, and butanone) of
M. tridentata roots was tested in albino mice by Bidkar et al. [
53
] using the tensile strength of
wound models (re-sutured incision and grass pith granuloma) on the 10th day after wound-
ing. Orally administered Tween 80 solution served as the control. The results showed
that all extract fractions (250 mg kg
1
or 300 mg kg
1
) exhibited considerably higher
tensile strength (215.4 g, 213 g, 243.7 g, 236.1 g, and 232.9 g, respectively) than the control
(144.3 g) in the re-sutured incision model. Similarly, all extract fractions exhibited consider-
ably higher tensile strength (221.7 g, 210 g, 264.1 g, 332.8 g, and 335.7 g, respectively) than
the control (155.4 g) in the granuloma model. The wound-healing effect was attributed to
the astringent property of flavonoid (present in the extracts), which allowed for wound
contraction and enhanced epithelialization rate.
Sakinah et al. [
112
] fractionated M. mammosa ethanol extract and used 25 mg of
ethyl acetate, n-hexane, and water fractions to evaluate the wound-healing properties of
M. mammosa plant in diabetic male Wistar rats. Diabetes was induced in rats by administer-
ing streptozotocin (40 mg kg
1
BW, IP), while the wound was excised using the Morton
method; aqua dest and gentamicin served as negative and positive controls, respectively.
The ethyl acetate, n-hexane and water fractions of M. mammosa extract showed the smallest
wound diameter (72%, 62%, and 54%, respectively) compared with the negative control
(114 mm) on day 11. Additionally, M. mammosa extract fractions showed wound reduction
(89%, 90%, and 93% in ethyl acetate, n-hexane, and water fractions, respectively) similar to
the positive control (92%) and higher than the negative control (82%) on day 11. It was sug-
gested that the anti-inflammatory effect of the flavonoid glycoside content of M. mammosa
extract fractions might be responsible for the wound-healing property.
In another study, Marchianti et al. [
57
] investigated the wound-healing potency of
1.5% M. mammosa plant gel formulations (incorporation of hydroxypropylmethylcellulose
(HPMC), Carbopol, or sodium carboxymethylcellulose (Na CMC) into 10% water fraction
of the plant’s ethanol extract) in diabetic Wistar rats by percentage wound size reduction,
vascular endothelial growth factor expression, hydroxyproline levels, and histopathology
assessments. Diabetes was induced by streptozotocin (40 mg kg
1
BW, IP), while the
wound was excised using the Morton method. The rats were divided into five treatment
groups, viz. distilled water (negative control), neomycin sulfate and placenta extract gel
(positive control), and 10% water fraction of M. mammosa extract in the gelling agents (3.
HPMC, 4. Carbopol, and 5. Na CMC). All three M. mammosa gel formulations showed
improved healing than the negative control and similar healing effect relative to the
positive control in terms of optimum level vascular endothelial growth factor expression,
hydroxyproline levels, and collagen density. The improved wound-healing effect of the
Plants 2021,10, 2070 30 of 49
three gel formulations was ascribed to the activities of flavonoid, as well as resin glycosides
present in M. mammosa water fraction, restoring the delayed diabetic wound-healing
process. The different investigations on the wound healing properties of Merremia species
show that the extracts and fractions have potent wound healing abilities which support the
traditional use of these species in treating wounds and inflammation.
Antioxidant Activity
Usually, the body keeps up a balance between the production of free radicals and
their elimination. However, overproduction of reactive oxygen species leads to a dispro-
portion between pro and antioxidants, resulting in oxidative stress [
113
]. Oxidative stress
disrupts and damages DNA, cell structures, proteins, and lipids in the body and conse-
quently results in neurodegenerative diseases, cancer, and diabetes, among others [
113
,
114
].
Antioxidants are useful chemical compounds that can reduce free radicals, decrease the
rate of production, and even quench free radicals in the body [
115
]. Plants, including
Merremia species, are rich sources of antioxidants. The antioxidant activities of the crude
extracts (ethyl acetate, hexane, methanol, and 25% aqueous methanol) of M. emarginata
whole plant were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide
radical scavenging activity methods [
116
]. Vitamin C served as the antioxidant standard.
Of the different extracts tested, the greatest potential scavenging activity was found to be
the methanol crude extract (IC
50
8.6
µ
g mL
1
). However, the scavenging activity of the
reference drug (IC
50
3.3
µ
g mL
1
) was higher than all extracts tested. The authors inferred
that the phytochemical constituents of M. emarginata were responsible for the observed
bioactivity. In another study, the antioxidant activity of 50–200
µ
g mL
1
solvent extracts
(acetone, chloroform, methanol, and hot water) of M. tridentata roots and aerial parts
were evaluated using DPPH, 2,2
0
-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS),
ferric reducing antioxidant power (FRAP), phosphomolybdenum reduction, ferrous ion
(Fe
2+
) chelation,
β
-carotene/linoleic acid peroxidation inhibition, and antihemolytic ac-
tivity assays [
54
]. Acetone root extract exhibited a higher antioxidant activity (IC
50
26.6
µ
g mL
1
) than that of
α
-tocopherol standard in the DPPH assay. Compared to other
extracts, M. tridentata acetone root extract exhibited the highest total antioxidant activity
(26,270.8
µ
mol g
1
) in the ABTS assay, highest ferric reducing antioxidant activity (2656.7
mmol Fe (II) mg
1
) in the FRAP assay, and the strongest phosphomolybdenum reduction
(56.7 g ascorbic acid/100 g) in the phosphomolybdenum reduction assay. The reducing
power activity of the extracts was linked to high levels of phenolics. Also, the results
showed a concentration-dependent OH
scavenging activity (range: 29.6–59.3% and 34.8–
52.9% by the root and aerial parts extracts at 200
µ
g mL
1
). In the Fe
2+
chelation assay,
the hot water extract of M. tridentata aerial parts exhibited the highest activity (8.0 mg
EDTA g
1
extracts). All the plant extracts inhibited
β
-carotene bleaching (range: 20.7–36.1%
by the root extract and 13.3–32.9% by the aerial parts extract at 200
µ
g mL
1
); acetone
extracts (aerial parts and roots) and methanol root extract exhibited activities (32.9%, 36.1%,
and 31.8%, respectively) comparable with BHA standard (36.6%). The distinct activity of
M. tridentata acetone extract was suggested to be due to its high polyphenolics content.
All the extracts showed higher peroxidation inhibition activity (aerial parts: 13.3–32.9%,
roots: 20.7–36.1% at 200
µ
g mL
1
) compared with
α
-tocopherol standard. The results of the
antihemolytic activity assay showed that the acetone extract of M. tridentata roots was the
most effective with 82.7% red blood cell hemolysis inhibition. The methanol and acetone
extracts of the aerial parts showed comparable (70.5% and 74.0%, respectively) hemolysis
inhibiting activity. The results of this study clearly show that the various solvent extracts of
M. tridentata roots and aerial parts (particularly the acetone root extract) possess significant
free radical scavenging and antioxidant activities. In another similar study, the antioxidant
potency of different concentrations of aqueous extract of M. emarginata leaves was carried
out in an
in vitro
study using reducing power, DPPH, ABTS, superoxide anion scavenging,
and lipid peroxidation inhibition assays [
21
]. The authors also evaluated the leaf extract’s
antioxidant activity based on fluorescence quenching using TGA-capped-CdTe QDs as
Plants 2021,10, 2070 31 of 49
fluorescent probes. The results showed that the reducing power of M. emarginata leaf
extract increased proportionally to concentration. The extract showed optical density (0.79)
comparable to butylated hydroxytoluene standard (1.32) at 1000
µ
g mL
1
. The leaf extract’s
reducing power was attributed to reductones’ presence, stabilizing and terminating radical
chain reactions. The DPPH assay results showed that the leaf extract had antioxidant
potency (IC
50
value of 86.5
µ
g mL
1
) relative to butylated hydroxytoluene standards (IC
50
value of 23.4
µ
g mL
1
), and the effect was ascribed to its antioxidant (e.g., flavonoids and
polyphenolics) contents. In the ABTS assay, the extract (100
µ
g mL
1
) showed ca. 71%
inhibition (with IC
50
value of 30.1
µ
g mL
1
) relative to butylated hydroxytoluene standards
(IC
50
value of 27.2
µ
g mL
1
). The leaf extract showed superoxide anion scavenging activity
(IC
50
value of 40.3
µ
g mL
1
). The results of the TGA-capped-CdTe QD assay showed fluo-
rescence emission quenching by M. emarginata extract. The quenching of fluorescence emis-
sion was attributed to the prevention of the electron-hole recombination process, causing a
decrease in the fluorescence intensity due to the trapping of TGA-capped-CdTe QD holes by
M. emarginata leaf extract.
Purushoth et al. [
102
] also subjected M. emarginata whole plant ethanol extract and
its fractions (chloroform, ethyl acetate, hexane and methanol) to an
in vitro
antioxidant
potency test using
α
,
α
-diphenyl-
β
-picrylhydrazyl (DPPH) scavenging, hydrogen peroxide
scavenging, ABTS scavenging, and hydroxyl radical in the para-nitroso dimethylaniline
assays. The DPPH assay results showed that the extracts had moderate to high antioxidant
potency. However, the ethanol extract and methanol fraction had the highest antioxidant
potency (IC
50
values of 26.5
µ
g mL
1
and 27.5
µ
g mL
1
, respectively). All extracts showed
high antioxidant activity in the ABTS assay with IC
50
values range of 15–38
µ
g mL
1
relative to ascorbic acid and rutin standards (IC
50
values of 18.5
µ
g mL
1
and 12.7
µ
g
mL
1
, respectively). The antioxidant potency of the essential oil and different extracts
(aqueous ethanol, butanol, chloroform, ethyl acetate, and hexane) of M. borneensis leaves
and stems measured by reducing power (phosphomolybdenum method),
β
-carotene-
linoleate model system, and DPPH radical scavenging assays revealed that all M. borneensis
extracts showed antioxidant potency. However, the aqueous ethanol extracts showed
the highest antioxidant potency in all the assays (with 31% antioxidant capacity in the
phosphomolybdenum method, 84% inhibition of
β
-carotene bleaching, and 80% DPPH
radical scavenging activity at 100
µ
g mL
1
). It was suggested that antioxidant responses
might be due to the quantity and/or variety of phenolics present in the leaf extracts
of M. borneensis [
22
]. In another study by Joshi et al. [
117
],the antioxidant potential of
methanol extract of different parts (callus, leaf, seed and stem) of M. dissecta and M. aegyptia
was evaluated using DPPH free radical scavenging assay; ascorbic acid was used as a
standard. The study revealed an increasing free radical scavenging activity with increasing
plant extracts concentration in both Merremia species. The leaf, seed, and stem extracts of
M. dissecta had 75%, 90%, and 93% free radical scavenging effects with IC
50
values of 82,
80 and 61
µ
g mL
1
, respectively, while the seed extract of M. aegyptia had a free radical
scavenging effect of 90% comparable to ascorbic acid with 92% at 500
µ
g mL
1
. The authors
attributed the observed antioxidant activity to the possible presence of other bioactive
compounds like ascorbic acid, tocopherol, and pigments in the plants since the flavonoid
contents did not correlate with observed antioxidant activity. To assess the pharmacological
properties of a Thai traditional herbal formula (Sahatsatara), Thamsermsang et al. [
118
]
used 2,2-dipheny-1-picrylhydrazyl (DPPH) assay to test the free radical scavenging activity
of the ethanol extracts (3.75
µ
g mL
1
, 15
µ
g mL
1
, 30
µ
g mL
1
, 60
µ
g mL
1
, 120
µ
g mL
1
)
of its 21 ingredients, including M. vitifolia stem. Gallic acid, L-ascorbic acid and piperine
were used as references. M. vitifolia showed a dose-dependent free radical scavenging
ability, ranking fourth (with the IC
30
value of 25
µ
g mL
1
) relative to other components.
The free radical scavenging activity of Sahatsatara was thus attributed to gallic acid and
other unidentified bioactive compounds present in the formula’s components.
In a recent study, the antioxidant potency of 2 mg GAE mL
1
of hexane, ethyl acetate
and methanol extracts of M. mammosa plant was tested using DPPH, hydroxyl radical and
Plants 2021,10, 2070 32 of 49
superoxide anion scavenging methods [
56
]. In the DPPH assay, M. mammosa methanol
extract showed higher antioxidant activity relative to the positive control with IC
50
values of
0.7 GAE ml
1
and 0.9 GAE ml
1
, respectively. In the hydroxyl radical scavenging assays, M.
mammosa methanol extract exhibited higher antioxidant activity relative to positive control
with 92% and 89% inhibition values, respectively. The superoxide anion assay showed
that M. mammosa methanol extract had higher antioxidant activity relative to hexane and
ethyl acetate extracts (with inhibition values of 25%, 20%, and 19%, respectively). In a more
recent study, the antioxidant activity of different extracts (N-Heksan, ethyl acetate, and
methanol) of M. peltata leaf and stem was determined by DPPH radical scavenging and
FRAP methods [
90
]. Ascorbic acid served as the standard antioxidant. Of all the sample
extracts, the methanolic stem extract showed the best antioxidant activity (IC
50
values
47.37
µ
g/mL) in the DPPH radical scavenging assay as well as the highest total antioxidant
power (with value 207.08
µ
mol/g) in the FRAP assay. However, these activities were still
lower than that of ascorbic acid with an IC
50
value of 10.49
µ
g/mL in the DPPH assay and
a total antioxidant power value of 340.04 µmol/g in the FRAP assay.
Collectively, the results from the different antioxidant potency evaluations of Merremia
species indicate that the extracts are effective as natural antioxidants. None of the extracts
tested demonstrated weak or inactive antiradical potential, rather the antioxidant activities
displayed could be classified as either very strong, strong, and moderate. Antioxidant
activity is classified into four groups based on IC
50
values; very strong (<50
µ
g/mL),
strong (50–100
µ
g/mL), moderate (101–250
µ
g/mL), weak (251–500
µ
g/mL) and inactive
(
>
500
µ
g/mL) [
119
]. Hence, Merremia species extracts can be utilized for use as dietary
supplements or as functional ingredients in nutraceutical and pharmaceutical products.
Insecticidal Activity
The development of plant-based insect repellents that are effective, non-toxic, and
have a short half-life will benefit both farmers and the environment by preventing the
spread of vector-borne diseases [
120
,
121
]. The exploitation of bioactive constituents in
plants with insecticidal activity are being considered as alternatives to chemical insecti-
cides and pesticides as a result of their lower persistence in the environment, as well as
low toxicity effects on non-target organisms [
120
,
121
]. Some Merremia species have been
investigated for their insecticidal activities. Oliveira et al. [
122
] screened 94 extracts from 10
plants, including the extracts (250
µ
g mL
1
of acetone and its fractions (hexane, chloroform,
ethyl acetate, and methanol)) of M. aegyptia leaves, for larvicidal activity against Aedes
aegypti commonly found in the Northeast region of Brazil. Dimethyl sulfoxide (DMSO)
and Temephos (a synthetic insecticide) served as the negative control and positive con-
trols, respectively. It was reported that nine extracts, including acetone extract and the
hexane fraction of M. aegyptia leaves exhibited over 100% activity (with LD
50
values of
120.7
µ
g mL
1
and 144.3
µ
g mL
1
, respectively) against the mosquitoes fourth instar larvae.
The larvicidal activity was suggested to be due to the presence of bioactive compounds.
Table 6. Summary of the biological activities of Merremia species.
Species Biological
Activity Plant Part Extract Concentration or
Dose Model Result Reference
M. aegyptia Antioxidant
activity Seeds Methanol 500 µg mL1
In vitro: DPPH
assay; ascorbic
acid was used as
a standard
Extract had 90%
(IC50 values of
84) free radical
scavenging effect
[117]
Insecticidal
activity Leaves Acetone and its
hexane fraction 250 µg mL1
In vivo:
larvicidal
activity against
Aedes aegypti
fourth instar
larvae;
Temephos
served as a
standard
Extracts
exhibited over
100% activity
(with LD50
values of 120.7
µg mL1and
144.3 µg mL1,
respectively)
[122]
Plants 2021,10, 2070 33 of 49
Table 6. Cont.
Species Biological
Activity Plant Part Extract Concentration
or Dose Model Result Reference
M. borneensis Antifungal Leaves Methanol 60–400 mg
mL1
In vitro: antifungal
activity against a mold
strain (A. brasiliensis)
and two yeast strains
(Candida albicans and S.
cerevisiae) using agar
well diffusion method
Extract showed
concentration-
dependent activity
(inhibition zones range:
5.5–15.5 mm)
[63]
Antioxidant
activity Leaves, stems Aqueous
ethanol 100 µg mL1
In vitro:
phosphomolybdenum
method,
β-carotene-linoleate
model system and
DPPH assays; ascorbic
acid and BHA served as
references
Phosphomolybdenum
method: 31%
antioxidant capacity,
β-carotene bleaching:
84% inhibition, DPPH:
80% radical scavenging
[22]
M. dissecta Antibacterial Leaves,
flowers
Diethyl ether,
methanol 100 µg mL1
In vitro: antibacterial
activity against S.
aureus,P. aeruginosa by
biofilm inhibition;
quorum sensing
inhibitor (azithromycin)
served as a control
Extracts decreased the
biosynthesis of N-acyl
homoserine lactone by
72%, attenuated the
expression of elastase
activity (27%) and
biofilm production
(55%) in P. aeruginosa
[4]
Antioxidant
activity
Leaves, seeds,
stems Methanol 500 µg mL1
In vitro: DPPH assay;
ascorbic acid was used
as a standard
Leaves, seeds and stems
extracts exhibited 75%,
90%, and 93%, free
radical scavenging with
IC50 of 82, 80, and 61 µg
mL1, respectively
[117]
M.emarginata Cancer cell
cytotoxicity Whole plant Ethyl acetate 50 µg mL1
In vitro: human cancer
cell lines (prostate
carcinoma (DU-145);
Lung carcinoma (A549),
mouth carcinoma (KB)
and pancreas carcinoma
(MIA-PaCa-2)) using
the 3-(4,5-
Dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium
bromide (MTT)
reduction assay
Ethyl acetate extract
was the most effective,
inhibiting the
proliferation of cell lines
A549, KB, MIA-PaCa-2,
and DU-145 with the
IC50 values of 28.5 µg
mL1, 37.2 µg mL1, 51
µg mL1, and 69.4 µg
mL1, respectively
[3]
Cancer cell
cytotoxicity Leaves Hexane 25 µg mL1
In vitro: human cancer
cell lines (lung (A549),
breast (MCF-7),
stomach (AGS), colon
(COLO 320 DM)) and
monkey normal kidney
epithelial cells (VERO)
Extract inhibited A549
and COLO 320 DM cell
line proliferation (with
IC50 values of 15.5 µg
mL1and 18.4 µg
mL1, respectively) and
had minimal toxicity
(IC50 value of 65.2 µg
mL1) for VERO
[88]
Plants 2021,10, 2070 34 of 49
Table 6. Cont.
Species Biological
Activity Plant Part Extract Concentration
or Dose Model Result Reference
Anti-diabetic Whole plant Methanol 100, 200, and
400 mg kg1
In vivo:
streptozotocin-induced
(intraperitoneally)
diabetic male Wistar
rats; assessment of
blood glucose levels,
plasma insulin and
body weight,
glycosylated
hemoglobin, total
hemoglobin, serum
creatinine, serum urea,
hexokinase, fructose-1,
6-bisphosphatase and
glucose-6-phosphatase,
total protein and
pancreatic tissue
histology
All extract doses
lowered blood glucose
levels to values
comparable to standard
drug (glibenclamide)
and restored plasma
insulin, body weight,
glycosylated
hemoglobin, total
hemoglobin, serum
creatinine, serum urea,
hexokinase, fructose-1,
6-bisphosphatase, and
glucose-6-phosphatase,
and total protein to
levels near normal
control (sodium
chloride). In the
histological assessment,
the extracts (100 and 200
mg kg1, respectively)
showed mild and
moderate expansion of
the diabetic rats’
pancreatic islets, while
the 400 mg kg1extract
showed prominent
hyperplastic islet
similar to that of the
glibenclamide-treated
group
[93]
Antibacterial Leaves
Aqueous,
petroleum
ether, and
methanol
10 µg mL1,
25 µg mL1,
50 µg mL1,
100 µg mL1
In vitro: antibacterial
activity against B. cereus,
E. coli,P. aeruginosa, and
S. aureus by disk
diffusion assay;
penicillin standard drug
All solvent extracts
were effective against
all the bacteria (zone of
inhibition range:
0.7–13.7 mm) compared
with penicillin
(16.0–17.0 mm)
[95]
Antibacterial Leaves
Aqueous,
acetone,
chloroform,
petroleum
ether
200 mg mL1
In vitro: antibacterial
activity against seven
bacteria by paper disk
diffusion; Ciprofloxacin
as a reference drug
All solvent extracts
were effective against
five bacteria,
particularly L.
rhamnosus (20% zone of
inhibition each); the
most effective (acetone
extract) had maximum
inhibitory (24%) against
S.epidermidis
[96]
Antibacterial Leaves
Aqueous,
thioglycolic
acid-capped
cadmium
telluride
quantum dots,
their mixture
(T-M complex)
1×106M,
100 µg
In vitro: antibacterial
activity against E. coli
using the Luria-Bertani
agar disk diffusion
assay
Extract alone and T-M
complex showed
10-mm and 16-mm
zones of inhibition,
respectively
[21]
Anti-
inflammatory Whole plant Ethyl acetate 50 µg mL1
In vitro: inhibition of
pro-inflammatory
cytokine, tumor
necrosis factor alpha
(TNF-α); recombinant
human TNF-αserved
as standard
Extract inhibited TNF-α
production with the
IC50 of 5.9 µg mL1.
[3]
Anti-arthritic Whole plant
Ethanol
extract and its
methanol and
ethyl acetate
fractions
250 µg mL1
In vitro: anti-arthritic
activity by protein
denaturation inhibition
method; diclofenac
sodium served as a
reference
Extracts had protein
denaturation inhibition
of 95.4%, 87.7%, and
72.6%, respectively,
relative to the standard
(98.4%)
[102]
Antioxidant
activity Whole plant Methanol 300 µg mL1
In vitro: DPPH and
superoxide radical
scavenging assays;
Vitamin C served as a
standard drug
IC50 8.6 µg mL1
relative to vitamin C
(IC50 3.3 µg mL1)
[116]
Plants 2021,10, 2070 35 of 49
Table 6. Cont.
Species Biological
Activity Plant Part Extract Concentration
or Dose Model Result Reference
Antioxidant
activity Leaves Aqueous
100 µg mL1
or 1000 µg
mL1
In vitro: reducing
power, DPPH, ABTS,
superoxide anion
scavenging, and lipid
peroxidation inhibition
assays, fluorescence
quenching using
TGA-capped-CdTe QDs
as fluorescent probes;
butylated
hydroxytoluene served
as standards
Reducing power assay:
optical density (0.79)
comparable to
butylated
hydroxytoluene
standard (1.32); DPPH
assay: IC50 of 86.5 µg
mL1; ABTS assay: 71%
inhibition with IC50 of
30.1 µg mL1;
superoxide anion
scavenging activity:
IC50 of 40.3 µg mL1;
TGA-capped-CdTe QD
assay showed
fluorescence emission
quenching
[21]
Antioxidant
activity Whole plant
Ethanol
extract and its
methanol
fraction
In vitro: DPPH,
hydrogen peroxide
scavenging, ABTS
scavenging, and
hydroxy radical in the
para-nitroso
dimethylaniline assays;
ascorbic acid, rutin, and
BHA served as
standards
DPPH assay: ethanol
extract and its methanol
fraction had IC50 of 26.5
µg mL1and 27.5 µg
mL1, respectively),
ABTS assay: all extracts
showed IC50 range of
15–38 µg mL1
[102]
Anti-
urolithiatic
activity
Whole plant Methanol 400 µg mL1
In vitro: anti-urolithiatic
activity using a
dissolution model;
Cystone®served as a
positive control
Extract had calcium
phosphate and calcium
oxalate mineralization
inhibition of 81% and
84%, respectively,
relative to the standard
drug (91%)
[107]
Blood
pressure-
lowering
property
Aerial parts Aqueous
methanol
30 mg Kg1,
50 mg Kg1;
0.1–3.0 mg
Kg1
In vivo: angiotensin-
converting-enzyme
inhibitory (ACEI),
diuretic and
hypotensive effects in
Sprague-Dawley rats;
captopril and frusemide
served as standard
drugs, respectively
Extract exhibited 81%
ACEI activity, increased
the volume of urine and
excretion of urinary
Na+, drop in average
arterial blood pressure
range of 21.5–61.7%
[109]
Insecticidal
activity Leaves Leaf silver
nanoparticles 20 µg mL1
In vivo: larvicidal
activity against late
third instar larvae of A.
stephensi,A. aegypti and
C. quinquefasciatus;
distilled water and
silver nitrate served as a
control
Larvicidal activity on A.
stephensi,A. aegypti and
C. quinquefasciatus
larvae with LC50 values
of 8.4 µg mL1, 9.2 µg
mL1, and 10.0 µg
mL1, respectively
[123]
Nephroprotective
activity Leaves Ethanol 250 mg kg1
In vivo:
nephroprotective
activity against
gentamicin-induced
(intraperitoneally)
nephrotoxicity in adult
albino Wistar rats using
a histopathology
examination
Extract caused
regeneration of
glomerular, tubular, and
proximal tubular
epithelial cells of
damaged kidney
[64]
M. hederacea
Multidrug
resistance
reversal
activity
Aerial parts
Isolated
compounds
(merremins
AG and
murucoidin IV,
murucoidin V,
stoloniferin IV,
and
murucoidin
XVII)
25 µM
In vivo: multidrug
resistance reversal
activity in KB/VCR cell
lines using a
sulforhodamine B assay;
vinblastine served as a
reference
Noncytotoxic inhibition
ratios less than 50%
(0.91%, 0.08%. 0.23%.
7.73%, respectively at 25
µM) for compounds A,
E, F, and murucoidin V
with IC50 values of
0.253, 0.036, 0.230, 0.004,
and 0.570
[74]
Plants 2021,10, 2070 36 of 49
Table 6. Cont.
Species Biological
Activity Plant Part Extract Concentration
or Dose Model Result Reference
M. mammosa Anti-diabetic Whole plant
Hexane, ethyl
acetate,
methanol
25 µg GAE
mL1, 100 µL
In vitro: α-amylase and
α-glucosidase
inhibition
Extracts exhibited
α-amylase inhibition
(48%, 43%, and 12%,
respectively) and
α-glucosidase
inhibition (66%, 52%,
and 13%, respectively)
[56]
Anti-influenza Tuber
Ethyl acetate
fraction of
methanol
extract
1000 µg mL1
In vivo: anti-influenza
A (subtype H1N1)
activity using
hemagglutinin assay;
Zanamivir served as
positive control
Extract had a strong
anti-influenza effect
similar to Zanamivir,
reducing hemagglutinin
virus titer by 94% and
100%, respectively, at
1000 µg mL1
[99]
Antioxidant
activity Whole plant Methanol 2 mg GAE
mL1
In vitro: DPPH,
hydroxyl radical, and
superoxide anion
scavenging; methanol
and vitamin C served as
negative and positive
controls, respectively
Methanol extract
showed IC50 value of
0.7 GAE ml1relative to
the positive control (0.9
GAE ml1) in the DPPH
assay, 92% inhibition in
the hydroxyl radical
scavenging assays, 25%
inhibition in the
superoxide anion assay
[56]
Wound-
healing
property
Whole plant
Ethyl acetate,
n-hexane, and
water fractions
of ethanol
25 mg kg1
In vivo: wound-healing
effect in
streptozotocin-induced
(intraperitoneally)
diabetic male Winstar
rats; wound was
excised using the
Morton method;
aquadest and
gentamicin served as
negative and positive
controls, respectively
Extracts showed wound
diameter (72%, 62%,
and 54%, respectively)
compared with the
negative control (114
mm), and percentage
wound reduction (89%,
90%, and 93%,
respectively) similar to
the positive control
(92%)
[112]
Wound-
healing
property
Whole plant
Gel
formulations
(hydrox-
ypropyl-
methylcellu-
lose (HPMC),
Carbopol or
sodium car-
boxymethyl-
cellulose (Na
CMC) in 10%
water fraction)
of ethanol
extract
1.5% gelling
agent
In vivo: vascular
endothelial growth
factor, hydroxyproline
levels, and collagen
density assessments in
streptozotocin-induced
(intraperitoneally)
diabetic Winstar rats;
wound was excised
using the Morton
method; distilled water
(negative control),
neomycin sulfate, and
placenta extract gel
(positive control)
Extracts had similar
healing effect relative to
the positive control in
terms of optimum level
vascular endothelial
growth factor
expression,
hydroxyproline levels,
and collagen density
[57]
M. peltata Anti-diabetic Leaves and
stem
Hexane, ethyl
acetate, and
methanol
20-100 µg
mL1,
In vitro: alpha
glucosidase enzyme
inhibition
Stem methanolic extract
had the best activity
with IC50 value 47.44
µg/mL, almost two
times better than
acarbose as a positive
control (IC50 = 98.38
µg/mL). Leaves
methanolic extract,
leaves ethyl acetate
extract, and stem ethyl
acetate extract also give
better activity of alpha
glucosidase inhibitors
than acarbose with IC50
value 67.24 µg/mL,
69.38 µg/mL, and 72.85
µg/mL, respectively.
[90]
Plants 2021,10, 2070 37 of 49
Table 6. Cont.
Species Biological
Activity Plant Part Extract Concentration
or Dose Model Result Reference
Antibacterial Leaves Ethanol 5–20 µg mL1
In vitro: antibacterial
activity against B.
subtilis,S. aureus,P.
aeruginosa,E. coli using
the Kirby-Bauer disk
diffusion method;
streptomycin and
chloramphenicol served
as positive controls
Extract showed 5.7-mm
average zone of
inhibition against B.
subtilis and S. aureus (at
10 µg mL1and 20 µg
mL1, respectively),
4.7-mm and 2.7-mm
average zones of
inhibition against P.
aeruginosa and E. coli (at
15 µg mL1and 5 µg
mL1, respectively)
[19]
Anti-diabetic Leaves and
stem
Hexane, ethyl
acetate, and
methanol
20-100 µg
mL1,
In vitro: DPPH and
FRAP
Stem methanolic extract
had the highest
antioxidant activity
with IC50 value of 47.41
µg/mL in DPPH and
total antioxidant power
of 340.04 µmol/g in
FRAP.
[90]
M. tomentosa Insecticidal
activity Leaves
Methanol and
isolated
compounds
(ursolic acid
and
cis-tiliroside)
8.9 mg mL1
In vivo: oviposition
reduction in L. coffeella;
chlorpyrifos serves as
positive control
Extract and isolated
compounds reduced L.
coffeella oviposition to
6%, 0%, and 11%,
respectively) relative to
the control chlorpyrifos
(0%)
[80]
M. tridentata Anti-diabetic Roots Aqueous 50–150 mg
kg1
In vivo: normoglycemic,
glucose-loaded
hyperglycemic, and
streptozotocin-induced
(intraperitoneally)
diabetic rats; blood
glucose levels, serum
insulin, triglycerides,
total cholesterol,
glycogen (in skeletal
muscle and liver), and
lipid peroxidation in
pancreatic tissue
estimations
All extract doses
lowered blood glucose
levels in
normoglycemic,
glucose-loaded
hyperglycemic and
streptozotocin-induced
diabetic rats (range:
13.4–26.2%, 13.0–20.1%,
and 28.6–49.7%),
respectively) compared
with their control
groups; glibenclamide
(reference drug)
reduced blood glucose
levels by 61.7%; in
streptozotocin-induced
diabetic rats, all extract
doses increased serum
insulin levels
(maximum increase
(14.9 U mL1) was
comparable to
glibenclamide (18.3 U
mL1) at 150 mg kg1;
dose-dependent
reduction (range:
13.9–25.1%) of serum
triglycerides reduction;
100 mg kg1and 150
mg kg1extracts
lowered serum
cholesterol levels (ca. 60
mg dL1) compared
with both normal (66
mg dL1) and diabetic
(139 mg dL1) controls,
increased glycogen
levels compared with
streptozotocin-induced
diabetic control and
reduced lipid
peroxidation levels (0.46
µM g1, 0.47 µM g1)
to near glibenclamide
(0.41 µM g1)
[52]
Plants 2021,10, 2070 38 of 49
Table 6. Cont.
Species Biological
Activity Plant Part Extract Concentration
or Dose Model Result Reference
Antibacterial Leaves Methanol
0.01 mg mL1,
1.00 mg
mL1;0.05 mg
mL1,1 mg
mL1
In vitro: antibacterial
activity against
Gram-positive (Bacillus
subtilis and
Staphylococcus aureus)
and Gram-negative
(Escherichia coli and
Vibrio parahaemolyticus)
bacteria using turbidity
and zone formation
methods
Gram-positive MIC
range: 0.25–0.5 mg
mL1; zone formation
range: 10-14 mm;
Gram-negative MIC
range: 0.5–1 mg mL1;
zone formation range:
9–11 mm
[94]
Antibacterial Stem Methanol 100 mg mL1
In vitro: antibacterial
activity against S. aureus
and B. subtilis,Klebsiella
pneumoniae,E. coli, and
Pseudomonas aeruginosa;
ampicillin and
gentamicin standard
drugs
Extract was effective
against S. aureus and B.
subtilis (inhibition
zones: 12.0 mm and
11.3 mm; MIC: 3.13 mg
mL1and 6.25 mg
mL1, respectively;
minimum bactericidal
concentration: 12.5 mg
mL1and 100 mg mL1,
respectively) relative to
both standard drugs (10
µg mL1
[66]
Antifungal Leaves Methanol 0.01–100 mg
mL1
In vitro: antifungal
activity against
Aspergillus niger,
Saccharomyces cerevisiae
using turbidity and
zone formation
methods
Extracts were more
effective against S.
cerevisiae (MIC range:
0.25–0.5 mg mL1; zone
formation range: 10–15
mm).
[94]
Anti-
inflammatory Whole plant Ethanol 100 mg kg1,
200 mg kg1
In vivo:
anti-inflammatory
activity on male albino
rats using the
carrageenan-induced
rat paw inflammation
method; indomethacin
served as standard drug
Relative to the standard
drug (48.5%), extract
was effective with 38.3%
and 42.8% inflammation
inhibition at 100 mg
kg1and 200 mg kg1
doses, respectively
[55]
Anti-
inflammatory Roots
Solvent ether,
ethyl acetate,
butanol and
butanone
fractions of
ethanol extract
300 mg kg1
In vivo:
anti-inflammatory
activity in albino mice
using the
carrageenan-induced
rat paw edema method;
aspirin served as the
standard drug
Extracts were effective
(87%, 84%, 72%, and
68%, respectively) in
inhibiting rat paw
edema, relative to the
standard (59.7%)
[53]
Anti-arthritic Whole plant Ethanol
100 mg kg1
and 200 mg
kg1
In vivo: anti-arthritic
activity on male albino
rats using the complete
Freund’s
adjuvant-induced
arthritis model;
indomethacin served as
the standard drug
Extract had 49.0% and
51.7% anti-arthritic
activity at 100 mg kg1
and 200 mg kg1,
respectively, which
were comparable to the
standard drug (55.5%)
[55]
Plants 2021,10, 2070 39 of 49
Table 6. Cont.
Species Biological
Activity Plant Part Extract Concentration
or Dose Model Result Reference
Antioxidant
activity
Roots, aerial
parts
Acetone,
chloroform,
methanol, and
hot water
200 µg mL1
In vitro: DPPH and
ABTS, OH, FRAP,
phosphomolybdenum
reduction, Fe2+
chelation,
β-carotene/linoleic
acid peroxidation
inhibition, and
antihemolytic activity
assays
Acetone root extract:
IC50 26.6 µg mL1in
DPPH assay; highest
equivalent trolox, FRAP
and
phosphomolybdenum
reduction values
(26,270.8 µmol g1
extract, 2656.7 mmol Fe
(II) mg1extract and
56.7 g ascorbic acid/100
g extract, respectively);
root and aerial parts
extracts: OH
scavenging activity
range of 29.6–59.3% and
34.8–52.9%; hot water
extract showed activity
of 8.0 mg EDTA g1
extracts in the Fe2+
chelation assay;
inhibition of β-carotene
bleaching (20.7–36.1%
by the root extract and
13.3–32.9% by the aerial
parts extract); acetone
extracts (aerial parts
and roots) and
methanol root extract
exhibited activities
(32.9%, 36.1%, and
31.8%, respectively)
comparable with
BHA standard (36.6%);
higher peroxidation
inhibition activity by all
extracts compared with
α-tocopherol standard;
acetone root extract:
82.7% red blood cell
hemolysis inhibition
[54]
Wound-
healing
property
Roots
Solvent ether,
petroleum
ether, ethyl
acetate,
butanol, and
butanone
fractions of
ethanol
250 mg kg1
or 300 mg
kg1
In vivo: wound-healing
effect in albino mice
using the tensile
strength of wound
models (re-sutured
incision and grass pith
granuloma); Tween 80
solution served as the
control
Extracts exhibited
higher tensile strength
(215.4 g, 213 g, 243.7 g,
236.1 g, and 232.9 g,
respectively) than the
control (144.3 g) in the
re-sutured incision
model; (221.7 g, 210 g,
264.1 g, 332.8 g, and
335.7 g, respectively)
than the control (155.4
g) in the granuloma
model
[53]
M. umbellata Antibacterial Leaves Ethanol 1000 µg mL1
In vitro: antibacterial
activity against
Klebsiella pneumoniae,S.
aureus, and Pseudomonas
aeruginosa using the
broth microdilution
method; gentamicin
was the positive control
Extract had 32%, 55%,
and 67%, respectively,
on the bacterial strains’
growth
[62]
M. vitifolia Anti-arthritic Leaves
Aqueous
fraction from
methanol
extract
500 µg mL1
In vitro: anti-arthritic
activity by protein
denaturation inhibition
method; diclofenac
sodium served as a
reference
Extracts had protein
denaturation inhibition
of 64% relative the
standard drug (87%)
[20]
Plants 2021,10, 2070 40 of 49
Table 6. Cont.
Species Biological
Activity Plant Part Extract Concentration
or Dose Model Result Reference
Anti-
nociceptive
activity
Leaves
Aqueous
fraction from
methanol
extract
200 mg kg1,
400 mg kg1
In vivo:
anti-nociceptive activity
in Swiss Albino mice
using formalin-induced
paw licking (at early
and late stages) and
acetic acid-induced
writhing tests;
diclofenac sodium
(administered
intraperitoneally)
served as a standard
drug
Extract showed
anti-nociceptive activity
(44% and 26%, 30% and
20% in both early and
late test stages,
respectively) relative to
the control (20% and
15%, respectively) in the
formalin-induced paw
licking test; reduced
(44% and 30%,
respectively) abdominal
contortions with
increasing doses of
APFME relative to the
control (21%)
[20]
Antioxidant
activity Stems Ethanol 120 µg mL1
In vitro: DPPH assay;
gallic acid, L-ascorbic
acid, and piperine were
used as references
IC30 of 25 µg mL1[118]
Thrombolytic
activity Leaves
Aqueous
fraction from
methanol
extract
500 µg mL1
In vitro: thrombolytic
activity in blood
samples from male and
female (1:1) adult
human volunteers with
no anticoagulant and
oral contraceptive
treatments history;
streptokinase served as
a positive control
Extract exhibited
thrombolytic activity
(42.5% clot lysis)
relative to the positive
control (72.2%)
[20]
Results are shown for the most effective doses.
In another study, the larvicidal activity of aqueous extract (70
µ
g mL
1
, 140
µ
g mL
1
,
210
µ
g mL
1
, 280
µ
g mL
1
, and 350
µ
g mL
1
) and silver nanoparticles
(4
µ
g mL
1
, 8
µ
g mL
1
, 12
µ
g mL
1
, 16
µ
g mL
1
, and 20
µ
g mL
1
) from M. emarginata
leaves was tested on late third instar larvae of Anopheles stephensi,Aedes aegypti and Culex
quinquefasciatus [
123
]. Distilled water and silver nitrate served as controls. It was reported
that the aqueous leaf extracts and biosynthesized silver nanoparticles had a larvicidal effect
on the mosquitoes in a dose-dependent manner. However, in comparison with the aqueous
leaf extract of M. emarginata, the biosynthesized silver nanoparticles had higher larvicidal
activity against A. stephensi,A. aegypti and C. quinquefasciatus larvae with LC
50
values of 8.4
µ
g mL
1
, 9.2
µ
g mL
1
and 10.0
µ
g mL
1
, respectively at 20
µ
g mL
1
. The M. emarginata
biosynthesized silver nanoparticles were reported to be safer to non-target aquatic biocon-
trol agents (Anisops bouvieri,Diplonychus indicus and Gambusia affinis), with LC
50
range of
416
µ
g mL
1
to 25,154
µ
g mL
1
. It was suggested that the silver nanoparticles enhanced
the leaf extracts’ bioactivity. The authors attributed the larvicidal activity to the silver
nanoparticles and the mosquitoes’ larvae extracellular lipoprotein matrix interaction, in-
creasing cell plasma membrane permeability. They further reported that the interaction(s)
between the silver nanoparticles and phosphorous- or sulfur-containing compounds might
have caused enzymes and organelles denaturation, thereby reducing ATP synthesis, which
leads to the loss of cellular function and death. The low toxicity effect of M. emarginata
silver nanoparticles on non-target organisms was suggested to be partially due to the
bigger body size of organisms compared with mosquito instars.
A study was carried out by Santos et al. [
80
] on the control of coffee plants pest,
Leucoptera coffeella, by oviposition reduction using methanol leaf extracts of 19 plants,
including M. tomentosa (8.9 mg mL
1
). The authors also assessed the effect of three isolated
compounds (cis-tiliroside (
2
), trans-tiliroside, and ursolic acid (
59
)) from M. tomentosa leaves;
Tween 80 and chlorpyrifos served as negative and positive controls. It was reported that
only M. tomentosa methanol extract, ursolic acid (
59
) and cis-tiliroside (
2
) were effective
in reducing L. coffeella oviposition on coffee plant leaves with oviposition reduction of
Plants 2021,10, 2070 41 of 49
6%, 0% and 11%, respectively like the control chlorpyrifos (0%). Two of the isolated
bioactive compounds (ursolic acid (
59
) and cis-tiliroside (
2
)) from M. tomentosa leaf extract
were suggested to be responsible for the oviposition reduction by inhibiting glycogen
phosphorylases (by binding to the pest’s allosteric site) and xanthine dehydrogenases,
respectively. The results suggest a possible use of Merremia species extract in the production