Next Article in Journal
Linker Length Drives Heterogeneity of Multivalent Complexes of Hub Protein LC8 and Transcription Factor ASCIZ
Previous Article in Journal
Immunoexpression Pattern of Autophagy Markers in Developing and Postnatal Kidneys of Dab1−/−(yotari) Mice
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Chemistry and Pharmacology of Bergenin or Its Derivatives: A Promising Molecule

by
Zeca M. Salimo
1,
Michael N. Yakubu
1,
Emanuelle L. da Silva
1,
Anne C. G. de Almeida
2,
Yury O. Chaves
3,
Emmanoel V. Costa
4,
Felipe M. A. da Silva
5,
Josean F. Tavares
6,
Wuelton M. Monteiro
1,2,
Gisely C. de Melo
1,2,* and
Hector H. F. Koolen
1,6,7,*
1
Programa de Pós-graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus 69040-000, Brazil
2
Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus 69040-000, Brazil
3
Instituto Leônidas e Maria Deane, Fundação Oswaldo Cruz, Manaus 69057-070, Brazil
4
Departamento de Química, Universidade Federal do Amazonas, Manaus 69067-005, Brazil
5
Centro de Apoio Multidisciplinar, Universidade Federal do Amazonas, Manaus 69067-005, Brazil
6
Programa de Pós-graduação em Produtos Naturais e Sintéticos Bioativos, Universidade Federal da Paraíba, João Pessoa 58051-900, Brazil
7
Grupo de Pesquisa em Metabolômica e Espectrometria de Massas, Universidade do Estado do Amazonas, Manaus 69065-001, Brazil
*
Authors to whom correspondence should be addressed.
Biomolecules 2023, 13(3), 403; https://doi.org/10.3390/biom13030403
Submission received: 31 December 2022 / Revised: 14 February 2023 / Accepted: 15 February 2023 / Published: 21 February 2023

Abstract

:
Bergenin is a glycosidic derivative of trihydroxybenzoic acid that was discovered in 1880 by Garreau and Machelart from the rhizomes of the medicinal plant Bergenia crassifolia (currently: Saxifraga crassifolia—Saxifragaceae), though was later isolated from several other plant sources. Since its first report, it has aroused interest because it has several pharmacological activities, mainly antioxidant and anti-inflammatory. In addition to this, bergenin has shown potential antimalarial, antileishmanial, trypanocidal, antiviral, antibacterial, antifungal, antinociceptive, antiarthritic, antiulcerogenic, antidiabetic/antiobesity, antiarrhythmic, anticancer, hepatoprotective, neuroprotective and cardioprotective activities. Thus, this review aimed to describe the sources of isolation of bergenin and its in vitro and in vivo biological and pharmacological activities. Bergenin is distributed in many plant species (at least 112 species belonging to 34 families). Both its derivatives (natural and semisynthetic) and extracts with phytochemical proof of its highest concentration are well studied, and none of the studies showed cytotoxicity for healthy cells.

1. Introduction

The rapid development of the chemistry of natural products has led to the isolation of a variety of secondary metabolites. In particular, bergenin, also known as ardisic acid B, bergenit, bergenitol, cuscutin, peltophorin, and vakerin [1,2]. Its name is derived from where it was isolated, i.e., from the ornamental and medicinal plant Bergenia crassifolia L. (currently: Saxifraga crassifolia L.—Saxifragaceae), and it was obtained from the rhizomes of this plant [1,2]. Although originally obtained from a small plant distributed in the temperate regions of North-Central Asia, mainly in Russia, the bergenin molecule has been found in several plant species distributed worldwide. To date, bergenin has been obtained from different species of different families (Table 1).
Plants biosynthesize bergenin and other natural compounds as an adaptive mechanism in response to abiotic and biotic stresses, in addition to attracting animals and protecting against ultraviolet radiation [3]. In recent years, bergenin has received increasing attention due to its presence in food and medicinal plants, including the Amazonian plant “uchi” (Endopleura uchi). Its fruit is used as a food item and as a medicine and is consumed raw or as a juice, in ice cream or popsicles, and the oil produced from its seeds can be used in foods and for the treatment of sinusitis in children and constipation in adults. Its seeds are used in making handicrafts, smoking meats, and as amulets [4]. Studies with uchi fruit pulp have indicated a rich nutritional composition (fatty acids, fiber, steroids, mineral salts, and vitamins C and E) [4,5]. In addition, studies suggest that bergenin has multifunctional properties, including antimalarial [6], antidiabetic [7], antioxidant [8], antiviral [9], and anti-inflammatory [10] activities, among others. The aim of this review is to describe the sources for the isolation of bergenin or its derivatives and its in vitro and in vivo biological and pharmacological activities.
Table 1. Plant species with bioavailability of bergenin.
Table 1. Plant species with bioavailability of bergenin.
FamilyScientific Name of the PlantPart of Plant UsedVernacular Plant NameNative Location of the PlantReference
AcanthaceaeGendarussa vulgaris Nees.Aerial partsJusticia gendarussaIndia, Malaysia[11]
AsclepiadaceaeStreptocaulon griffithii Hook. F.Root-China[12]
AraceaeArisaema franchetianum Engl.Tuber-Central Africa[13]
BombaceaeBombax malabaricum L.FlowersRed silk cotton treeIndia[14]
BignoniaceaeWinter bignonia (Ker Gawl.) Miers.Rhizome-India[15]
CaryophyllaceaeBrachystemma calycinum D.Don.Aerial parts-Nepal[16]
ConnaraceaeConnarus monocarpusRoot-Peninsula of India[17]
ConvolvulaceaeRivea hypocrateriformis (Desr.) ChoisyStem-South Asia[18]
ClusiaceaeGarcinia malaccensis Hook. F.Stem bark-China[11]
CompositaePulicaria wightiana C.B.ClarkeAerial partsSonaphuliIndia[19]
CapprifoliaceaeBrachystemma calycinum D.Don.Aerial parts-Nepal[16]
CrassulaceaeCrassula ovata cv. Obligua.BarkJade plantSouth Africa and Mozambique[8,20]
Rhodiola kirilowii RegLeafRose bushHimalayas[21]
DilleniaceaeDoliocarpus dentatus (Aubl.)LeavesThirsty vineMexico and tropical America[22]
DipterocarpaceaeDipterocarpus grandflorus BlancoStemKeruing BilinbingAsia[2,23]
Dryobalonops aroniatica C.F. Gaertn.Stem bark and heartwoodBorneo camphorSumatra, Borneo, Peninsular Malaysia[2,24]
Hopea utilis (Bedd.) BoleLeafBlack konguIndia[2,25]
Hopea sangal Korth.LeafMersiputSingapore[2,26]
Shorea leprosula PROSEA.HeartwoodRed merantiIndonesia[27]
Shorea robusta Roth.Leaf and rootSalIndia[28]
Vatica pauciflora (Korth.) Blume.Stem bark-Malaysia, Sumatera, Thailand and Vietnam[29,30]
Vatica albiramis Van.Stem-Indonesia[31]
Vatica bantamensis (Hassk.) Benth. & Hook.F.Leaf-Indonesia[32]
Vatica diospyroides S.Stem-Malaysia[33]
Vatica mangachpoiLeafResakMalaysia[34]
Vateria indica C.F. Gaertn.Leaf, seed, and stem bark-Asia[35]
EbenaceaeDiospyros sanza-minika PROTAWoodLiberia ebonyAfrica[36]
Mussaenda erythrophylla Schumach. & ThonnAerial partsPink mousseendaAsia[37]
EricaceaeArctostaphylos uva-ursi L.Leafy shootBearberryWestern America[38]
EuphorbiaceaeFluggea virosa (willd.) voigtAerial partsChinese waterberrySaudi Arabia[39]
Fluggea leucopyrus WilldLeaf-Asia[40]
Fluggea microcarpa BlumeLeaf-Southern Africa[41]
Fluggea luvangetinaRoot-Paleotropics[41]
Fluggea religiosa L.Bark-Paleotropics[42]
Fluggea virens L.Bark-Paleotropics[42]
Fluggea glomerata L.Bark-Paleotropics[42]
Fluggea benghalensis L.Bark-Paleotropics[42]
Glochidion obovatum Siebold & Zucc.Leaf-Japan[43]
Glochidion obliquum Siebold & Zucc.Leaf-Japan[44]
Excoecaria agallocha L.LeafButa-ButaSingapore[45]
Mallotus japonicus Müll. Arg.Bark and cortexAkamegashiwaEast Asia[46]
Mallotus repandus (Rottler) Müll. Arg.StemLiana creeperTropical and Subtropical Asia[47]
Mallotus anisopodus Gagnep.Aerial parts-Vietnam[48]
Mallotus philippinensis (Lam.) Mull.Arg.Leaf and stem barkKamala treeAsia and Australia[49]
Mallotus roxburghianus (Lam.) Müll.Arg.Leaf-India[50]
Mollotus oppositifoliusLeaf--[51]
Macaranga peltata (Roxb.) Müll.ArgBarkChandadaIndia[2,52]
Phyllanthus columnaris Müll.Arg.Root bark-Andaman Islands[53]
Phyllanthus flexuosus Müll.Arg.Stem bark-China[54]
Phyllanthus wightianus Müll.Arg.Whole plant-India[54]
Securinega virosa (Roxb.)LeafItachen-gadoNigeria[55]
Securinega melanthesoides (F. Muell.) Airy ShawLeaf-Madagascar and Mascarene Islands[56,57]
FabaceaePeltophorum africanum Sond.RootWeeping wattleAfrica[6]
Peltophorum inerme (Roxb.) Náves.FlowerYellow cassiaSoutheast Asia[58,59]
Peltophorum pterocarpumFlowerYellow-flamboyantTropical Southeastem Asia[60,61]
Peltophorum ferruginium (DC.) BackerBarkYellow PoincianaSoutheast Asia[2]
Ciser microphyllumAerial parts-Himalayas[62]
Teramnus labialis (L.f.) Spreng.Aerial partsBlue wissTropical Africa[63]
GentianaceaeTripterospermum chinense (Migo) Harry Sm.Aerial parts-China[2]
HamamelidaceaeCorylopsis coreana UyekiLeaf-Eastern Asia[64]
Corylopsis spicataBarkWinter Hazel Japan[65]
Corylopsis willmottiaeWhole plantChinese winter HazelChina[2]
AsteraceaeTridax procumbens L.AerialBullweedTropical Americas[66]
HumiriaceaeEndopleura uchi (Huber.) Cuatrec.BarkUchiBrazilian Amazon[67]
Humiria balsamifera (Aubl.) A.St.—Hil.Aerial partsUmiri de cheiroBrazilian Amazon[39,68]
Sacoglottis gabonensis Urb.BarkBitterbark treeTropical Africa and South America[69,70]
LythraceaeWoodfordia fruticosa (L.) KurzStemFire-flame bushAsia[71]
Lagerstroemia speciosa L.Flowers--[14]
LeguminosaeCaesalpinia decapetala (Roth)Root-China[2]
Caesalpinia mimosoides Lam.Root-China[2]
Caesalpinia pluviosa DStem Bark--[2]
Caesalpinia digyna Rottl.Root-Eastern Himalayas, Assam, and West Bengal[72]
Cenostigma macrophyllum Tul.Stem barkCaneleiroBrazil[73]
Cenostigma gardnerianum Tul.Stem barkCinnamonBrazil[73]
Pentaclethra macrophylla Benth.RootAfrican bean West and Central Africa[74,75]
MalvaceaeBrachystenuna calycinum D. Don-GBIFRoot-China[2]
Thespesia popunea L.Bark--[42]
MoraceaeFicus racemosa L.BarkRed river figAustralia and tropical Asia[76]
MyrsinaceaeArdisia crenata Sims.RootCoral bush; Blueberry.East Asia[77]
Ardisia colorata Blume.FruitMarlberryChina[78]
Ardisia japonica Blume.Aerial partsPassion fruitEast China, Japan, and Korea[79]
Ardisia elliptica Andr.RootDuck’s-eyesWest coast of India[2]
Ardisia punctata (Reinw.)RootCommon LabisiaSoutheast Asia[2]
Ardisia pusilla A. DC.RootMarlberryAsia[80]
Ardisia escalloniodes S. and D.SeedMarlberryAsia[77]
Ardisia compressa (Kunth.)SeedMarlberryAsia[77]
Ardisia mamillata (Hance.)SeedMarlberryAsia[77]
Ardisia gigantifolia Stapf.RootMarlberryAsia[81]
OleaceaeOlea dioca Roxb.FlowersMarlberryAsia[14]
PinaceaePinus roxburghii Charg.LeafMarlberryAsia[82]
RanunculaceaeCimicifuga foetida L.Rhizome-Europa and Siberia[2]
Pulsatilla koreana Mill.Root-Korea[2]
RubiaceaeWendlandia thyrsoidea (Roth) Steud.Flowers-India[2]
SaxifragaceaeAstilbe chinensis (Maxim.) Engl.Rhizome-Japan[83,84]
Astilbe rivularis Buch. Ham.RhizomeRiver AstilbeEast Asian[85]
Astilbe myriantha Diels.RhizomeRabbit earEast Asian[2,86]
Astilbe thunbergii Miq.Rhizome-Japan[86]
Bergenia scopulosaRhizome-China[2,87]
Bergenia ligulata Wall.Leaf-Central Asia[87]
Bergenia purpurascens (Hook.f. e Thomson) Engl.Rhizome-Asia[82]
Bergenia stracheyi (Hook. f. e Thomson) Engl.Whole plant-Central Asia[88]
Bergenia cordifolia (Haw.) Sternb.RhizomeSiberian teaCentral Asia
Boykinia lycoctonifolia (Maxim) Engl.Rhizome-North America and Asia[83,84]
Peltiphyllum peltatum L.RhizomeIndian-appleMato Grosso (Brasil)[2]
Peltoboykinia watanabei L.Rhizome-Japan[2]
Rodgersia sambucifoliaRootElderberryChina[2]
Rodgersia pinnataRhizomeBronze PeacockChina[2]
Rodgersia aesculifolia Bet.Rhizome-Northern China[1]
Saxifraga crassifolia L.LeafSiberian teaCentral Asia[1]
Saxifraga melanocentra FRANCH.Leaf-China[88]
Saxifraga stolonifera Curtis.Leaf-China[89]
SapindaceaeAllophylus edulis var. edulisLeafPigeon fruitLatin America[90]
VitaceaeCissus javana DC.RootRex begonia vineThailand[91]

2. Materials and Methods

Data Collection

The bibliographic research methodology was adopted and conducted using the databases available for institutional access, i.e., Google Scholar, Medline, Pubmed andSciFinder. Regarding the latter, the research was carried out both using keywords and by searching for similarities with the chemical structure of the molecule bergenin. The following terms were used as descriptors of the bibliographic research: “bergenin”, “plant extracts”, “in vitro assays”, “in vivo assays”, “natural sources”, “chemical aspects”, “derivatives”, “antimalarial activity”, “antileishmanial activity”, “trypanocidal activity”, “antiviral activity”, “antibacterial activity”, “antifungal activity”, “anti-inflammatory activity”, “antinociceptive activity”, “antiarthritic activity”, “antiulcerogenic activity”, “antidiabetic/antiobesity”, “antiarrhythmic activity”, “anticancer activity”, “antioxidant activity”, “hepatoprotective activity”, “neuroprotective activity”, “cardioprotective activity”, and using the Boolean operators “AND” and “OR”. A total of 6550 papers, 6 master’s dissertations, and 2 doctoral theses were found, of which 210 papers, 2 master’s dissertations, and 2 doctoral theses published in the period from 1880 to 2022 were selected. The inclusion criteria were articles written in Portuguese, Spanish, or English, and their abstracts were available. Doctoral theses and master’s dissertations were also included. Papers, dissertations, and theses that studied biological and pharmacological activities of bergenin, natural derivatives of bergenin, semisynthetic derivatives of bergenin, and plant extracts with phytochemical confirmation that bergenin is one of the constituents were selected. The exclusion criteria were studies that did not refer to at least one of the research themes and papers that had been retracted.

3. Natural Sources of Bergenin

The bergenin molecule has been isolated/identified in at least 112 plant species distributed in 34 plant families: Euphorbiaceae (23 species belonging to 6 genera), Saxifragaceae (18 species belonging to 7 genera), Dipterocarpaceae (12 species belonging to 6 genera), Leguminosae (7 species belonging to 5 genera) Humiriaceae (3 species belonging to 3 genera), Fabaceae (6 species belonging to 3 genera), Myrsinaceae (10 species belonging to 1 genus), Hamamelidaceae (3 species belonging to 1 genus), Crassulaceae (2 species belonging to 2 genera), Lythraceae (2 species belonging to 2 genera) Connaraceae (1 species), Convolvulaceae (1 species), Malvaceae (2 species belonging to 2 genera), Ranunculaceae (2 species belonging to 2 genera), Ebenaceae (2 species belonging to 2 genera), Clusiaceae (1 species), Acanthaceae (1 species), Ericaceae (1 species), Araceae (1 species), Caryophyllaceae (1 species), Compositae (1 species), Asclepiadaceae (1 species), Asteraceae (1 species), Capprifoliaceae (1 species), Gentianaceae (1 species), Bombaceae (1 species), Dilleniaceae (1 species), Oleaceae (1 species), Pinaceae (1 species), Rubiaceae (1 species), Sapindaceae (1 species), Vitaceae (1 species) and Moraceae (1 species) (Table 1). In terms of geographical distribution, most of the species with bioavailability of bergenin are located on the Asian continent, with emphasis on China. The concentration of bergenin in tissues or organs in the plant will depend on each species. However, four most frequently stand out: rhizomes, roots, leaves, and trunk bark (Table 1).

4. Chemical Aspects of Bergenin

Bergenin (IUPAC name: 4-methoxy-2-[(1S,2R,3S,4S,5R)-3,4,5,6-tetrahydro-3,4,5-trihydroxy-6-(hydroxymethyl)-2H-pyran-2-yl]-α-resorcylic acid) (Figure 1) is a C-glycosylated derivative of 4-O-methyl gallic acid [92,93]. It is a hydrolyzable phenolic glycoside that is obtained as a colorless crystal, has low solubility in water, degrades easily in basic solution (for example, Dimethyl sulfoxide in the concentration of 0.01–5%), and its stability depends mainly on storage conditions (best storage condition at −80 °C) [94]. It was discovered in 1880 by Garreau and Machelart [92]. The first proposals on the structure of bergenin were provided by Tschitschibabin et al. (1929). First, a chemical structure with only two rings and one aliphatic chain was proposed. Later, in 1950, the structure was revised by Shimokoriyama and proposed with three rings of six members [92,93] (Figure 1).
The biosynthesis of bergenin is directly related to the biosynthesis of gallic acid, which originates in the combination of erythrose-4-phosphate with phosphoenolpyruvate, which leads to the formation of 3-dehydroquinic acid. Dehydration of the latter leads to the formation of 3-dehydroshikimic acid, which in turn is converted to gallic acid through oxidation and enolization reactions. Other alternative routes would be the degradation of the side chain of hydroxycinnamic acids or through the condensation of an acetyl-CoA group with three malonyl-CoA units. Regarding the C-glycosylation step, previous experiments have shown contrasting results since the use of isotopically labeled [7-14C] benzoic acid and hydroxycinnamic acids indicated that C-glycosylation would occur in C6-C3 compounds, to the detriment of the C6-C1 derivative such as benzoic acid [95]. On the other hand, the use of the molecule labeled D-[U-14C] glucose in the presence of labeled gallic acid indicated that the C-glycosylation step occurs preferentially in the C6-C1 derivative [96]. Subsequently, the condensation of the glycosidic portion with the carboxylic acid of the gallic acid portion occurs, which leads to the formation of the lactone portion observed in the bergenin structure. Finally, more recent studies have suggested that the C-glycosylation step occurs prior to the O-methylation of the phenolic hydroxyl of the gallic acid-derived portion by O-methyltransferases [97].
Several bergenin derivatives have been isolated from plants, but not all showed marked biological activities. The main substances derived from bergenin with this type of potential are demethylated analogs, or those which are esterified with phenolic acids (e.g., gallic acid). Among the natural derivatives of bergenin, the following stand out: riverbergenin A isolated from the trunk of R. hypocrateriformis [18], norbergenin from the leaves of A. japonica [79], 11-O-galloylbergenin from the rhizome of A. gigantifolia [81] 11-O-veratroylbergenin from the rhizome of A. gigantifolia [81], 4-O-galloylnorbergenin isolated from the stem bark of M. japonicus [98], 8-O-methylnorbegenin from all parts of S. stolonifera [99], 11-O-acetylbergenin from the aerial parts of F. virosa [100], 11-O-vanilloylbergenin from the roots of A. crenata [101], 11-O-p-hydroxybenzolynorbergenin, 4-O-(3′-O-methylgalloyl)norbergenin and 4-O-syringoylnorbergenin from the bark of the stem of D. sanza-minika [36,102]. In addition to these, some semisynthetic derivatives have been designed in order to increase their pharmacological potential, for which several modifications have been proposed. Figure 2 lists all the natural and semisynthetic derivatives of bergenin cited in this review.

5. Biological and Pharmacological Activities of Bergenin

5.1. Antimalarial Activity

Bergenin, or its derivatives and extracts containing bergenin, have been reported to have antimalarial activity in vitro and in vivo studies. To date, about 15 in vitro and 5 in vivo studies on this topic have been published (Table 2).
Singh et al. [39] reported the in vitro antimalarial activity of the crude extract and fractions derived from F. virosa against Plasmodium falciparum using the nucleic acid dye SYBR Green I-based fluorescence assay (MSF). In the study, different concentrations of the extract (0.1 to 100 µg/mL) were incubated with chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum, and subsequently, the plates were examined at 485.20 nm excitation and 530.20 nm emission for fluorescence units (RFUs) per well using a fluorescence reader (FLX800, BIOTEK). The findings indicated that the extracts/fractions significantly inhibited the sensitive (3D7) and resistant (K1) strains of P. falciparum. The crude extract presented an IC50 of 2.35 µg/mL for 3D7 and 4.73 µg/mL for K1, while the fractions presented an IC50 of 1.73 to 8.61 µg/mL for 3D7 and 2.32 to 20 µg/mL for K1 against 5.5 and 2.54 nM of the positive control (chloroquine), respectively [39]. Other studies with the same approach, using extracts with bergenin as one of the constituents, had satisfactory results in vitro: ethanolic and methanolic extract of stems and leaves of H. balsamifera against a culture of BHz 26/28 of P. falciparum resistant to chloroquine, IC50 ranging from 8.37 to 49.65 µg/mL [13]; ethanolic extract of the rhizome of W. bignonia against strains of P. falciparum RKL-9 2, IC50 of 5 µg/mL [15]; ethanolic extract of B. ciliata rhizome against P. falciparum strains RKL-9 and MRC-2, IC50 of 5 µg/mL [15]; methanolic extract of D. Sanza-Minika stem bark against P. falciparum K1, IC50 of 0.6 µg/mL [36].
The IC50 of pure bergenin isolated from different parts of plant species (Table 2) was determined against P. falciparum in vitro, with the following results: 2.41–14.1 µg/mL [37,38,40,50,58,103]. The mechanism of action by which bergenin inhibits the growth of the parasite in vitro is not yet well known, but it is suggested that it is triggered by the inhibition of polymerization of the heme group of the parasite in a similar way to the mechanism of action of artemisinin since both are lactones of the same family [39,104]. In other words, in the first step, bergenin is activated by heme or a free iron (II) ion and produces free radicals and cytotoxic species. In the second step, these species react with the specific protein associated with the parasite’s membrane, thus causing its death [104].
11-O-Galloylbergenin, a bergenin derivative isolated from the root of B. ligulata, was tested against P. falciparum and showed significant activity against a resistant P. falciparum strain (CQS D10) and exhibited good activity at low concentrations, with an IC50 value of 2.34 µg/mL against a value of 28.07 nM for CQ (chloroquine) as a positive control [105]. These results are similar to the findings of a study in which 11-O-galloylbergenin was isolated from all parts of the plants of the species M. philippensis [49]. Other derivatives of natural bergenin had their IC50 determined against P. falciparum, namely, 4-O-(3′-O-methylgalloyl) norbergenin (IC50 of 0.6 µg/mL) [36], 4-O-galloylnorbergenin (IC50 3.9 µg/mL) [36], and 11-O-p-hydroxybenzoylnorbergenin (IC50 of 4.9 μg/mL) [36].
The in vivo antimalarial activity of bergenin was also evaluated (Table 2). Experimental models have used animals such as rats and mice infected with P. berghei [106]. P. berghei is a parasite that infects rodents and was discovered in the 90s in Congo. Since then, it has been widely used for experimental infections, which are considered models for biological and therapeutic studies [106]. Thirteen mice experimentally infected with P. berghei, with parasitemia of 35%, were treated with 800 mg/kg/day (100 µL twice daily) of bergenin (isolated from the leaves of R. aesculifolia) for 4 to 6 days intragastrically, and the findings showed that bergenin decreased parasitemia from 35 to 27%. These data indicate that bergenin suppresses the growth of P. berghei in vivo [6]. Singh et al. [39] experimentally induced P. berghei infection intraperitoneally in mice and, after 7 days of infection, treated with bergenin (isolated from F. virosa leaves) at concentrations of 25 to 100 mg/kg for 8 days, it caused an 85.13% suppression of parasitemia on the eighth day at a concentration of 100 mg/kg bergenin. These results are similar to the findings of Gorky et al. [15].
On the other hand, Da Silva et al. [107], in vitro experiments using bergenin (isolated from H. balsamifera leaves) against P. falciparum, found no activity (Table 2), but in vivo experiments found moderate efficacy in inhibiting the growth of P. berghei (IC50 of 146.87 mg/kg), which suggests that more studies should be done to determine the concentrations for successful parasitic inhibitions.
Table 2. Summary of studies regarding the antimalarial activity of bergenin and its derivatives. In vitro tests were carried out against P. falciparum and in vivo (in mice) against P. berghei.
Table 2. Summary of studies regarding the antimalarial activity of bergenin and its derivatives. In vitro tests were carried out against P. falciparum and in vivo (in mice) against P. berghei.
Compound NameSource of IsolationAssay Type, IC50CytotoxicityReference
CLCV
BergeninEthanolic extract of the rhizome of W. bignoniain vitro, 5.0 µg/mLHeLa and dermal fibroblastsNC[15]
BergeninLeaves of F. virosain vitro, 8.07 µg/mLMurine intraperitoneal macrophagesNC[39]
BergeninMethanolic extract of the stem bark of D. sanza-minikain vitro, 0.6 µg/mLNDND[36]
BergeninLeaves of H. balsamiferain vitro, SANDND[107]
BergeninEthanolic extract of the rhizome of B. ciliatain vitro, 5.0 µg/mLHeLa and dermal fibroblastsNC[15]
BergeninRhizome of B. ciliatain vivo -mice, 50 mg/kgHeLa and dermal fibroblastsNC[15]
BergeninLeaves of R. aesculifolia in vitro, 14.1 µg/mLHeLa and HepG2NC[6]
BergeninLeaves of R. aesculifoliain vivo -mice, 800 mg/kg)HeLa and HepG2NC[6]
BergeninRoots of B. ligulatain vitro, 2.41 µg/mLNDND[105]
BergeninWhole plant of M. philippensisin vitro, 6.92 µMNDND[49]
11-O-GalloylbergeninRoots of B. ligulatain vitro, 2.34 µg/mL)NDND[108]
4-O-(3′-Methylgalloyl)norbergeninMethanolic extract of the stem bark of D.sanza-minikain vitro, 0.6 µg/mLNDND[36]
4-O-GalloylnorbergeninMethanolic extract of the stem bark of Diospyros sanza-minikain vitro, 3.9 µg/mLNDND[36]
11-O-p- HydroxybenzoylnorbergeninMethanolic extract of the stem bark of Diospyros sanza-minikain vitro, 4.9 µg/mLNDND[36]
11-O-GalloylbergeninWhole plant of M. philippensisin vitro, 7.85 µMNDND[49]
BergeninExtract of the aerial part of M. erythrophyllain vitro, 7.43 µg/mLRaw 264.7 macrophage cellsNC[37]
BergeninLeaves of F. virosain vivo -mice,100 mg/Kg)Murine intraperitoneal macrophagesNC[49]
BergeninLeaves of H. balsamiferain vivo -mice, 146.87 mg/kgNDND[107]
BergeninEthanolic extract of the rhizome of W. bignoniain vivo -mice, 50 mg/kgHeLa and dermal fibroblastsNC[15]
Abbreviation: NC: no cytotoxicity, ND: no cytotoxicity determined, NA: no activity, CL: cell line, CV: cell viability.

5.2. Antileishmanial Activity

The antileishmanial activity of bergenin has been reported in six in vitro studies and in one in vivo study. Crude extracts/fractions of the aerial parts of M. erythrophylla have shown an inhibitory effect against Leishmania donovani, which is the etiological agent of visceral leishmaniasis, in a resazurin colorimetric test [37]. The extracts were incubated together with visceral leishmaniasis 1S (MHOM/SD/62/1S) promastigotes at concentrations of 0.16 to 100 µg/mL, in triplicate, followed by the addition of resazurin and amphotericin B (10–0.016 µg/mL), was used as the positive control. The results indicated that the crude extract had a moderate effect on antileishmanial activity (IC50 of 61.6 µg/mL), and the hexane fraction showed good antileishmanial activity (IC50 of 31.06 µg/mL) when compared with the reference drug, which was the positive control amphotericin B (IC50 of 0.11 µM) [37]. Kaur and Kaur [103] reported antileishmanial activity of the ethanolic extract of B. ligulata root against L. donovani after finding satisfactory parasitic inhibition (IC50 of 22.70 µg/mL), and phytochemical data revealed that the main compound in B. ligulata is bergenin, which suggests that the antileishmanial activity of these extracts is due to this compound [103]. Keshav et al. [62] reported that hydroxyethanolic extract of C. microphyllum showed good activity against sensitive and resistant strains of L. donovani, with an IC50 of 14.40 µg/mL and 23.03 µg/mL, respectively. Kabran et al. [51] reported that bergenin isolated from leaves of M. oppositifolius had an effect against L. donovani (IC50 of 73.3 µM).
Bergenin isolated from aerial parts of M. erythrophylla showed an inhibitory effect against L. donovani in resazurin colorimetric tests [37]. Bergenin was incubated together with protozoa, in triplicate, at concentrations of 0.08 to 50 µg/mL. Amphotericin B (10–0.016 µg/mL) was used as a positive control; the results showed the promising effects of bergenin against L. donovani (IC50 of 53.7 µM) [37].
Antileishmanial activity was also evaluated in vivo. Kaur and Kaur [103] reported that ethanolic extract of B. ligulata root had an antileishmanial effect in inbred BALB/c mice infected intracardially with 107 promastigotes. In the study, 48 mice were divided into two groups, an uninfected group, and an infected group, and the infected groups had inflammation in the liver and spleen triggered by the recruitment of the inflammatory cytokines: interleukin 12 (IL-12), interleukin 4 (IL-4), interleukin 10 (IL-10) and interferon-gamma (IFN- γ). The infected group was treated with the ethanolic extract of B. ligulata orally at concentrations of 500 and 1000 mg/kg for 15 days, and the mice were euthanized at 1, 7, 14, and 21 days post-treatment. The spleen and liver were removed, then centrifuged, and the homogenate was used to quantify the parasitemia and determine the immune response by the parasite-specific enzyme-linked IgG1 and IgG2a isotopes, delayed-type hypersensitivity (DTH) responses, and the effect of recruited cytokines. The results indicated that the treatment with the extracts rich in bergenin at both concentrations tested significantly reduced the parasitic load, corresponding to 91.1% and 95.6%, respectively. The treatment with the extracts induced the IgG2a antibody response, which is considered an indicator of the Th1 type of immune response, thus contributing to parasitic reduction. The treatment also triggered inhibition of the Th2 activation pathway by reducing the production of inflammatory cytokines, especially IFN- γ at 5001.61 to 175.21 pg/mL, which contributed to the reduction of inflammation of the internal organs of infected mice [103].

5.3. Trypanocidal Activity

The trypanocidal activity was mainly evaluated using bergenin-rich extracts, with four in vitro studies and one in vivo study. Ethanolic extract of leaves of C. pluviosa rich in bergenin showed trypanocidal activity against Trypanosoma cruzi in vitro [72]. The extracts were incubated at concentrations of 10 to 500 µg/mL together with the parasitic suspension of T. cruzi in the infective trypomastigote form (2 × 105/0.1 mL) in LIT (liver infusion tryptose) culture medium and, after 24 h, the suspension was microscopically quantified. The results indicated that the ethanolic extract of C. pluviosa showed good activity against the development of trypomastigotes of T. cruzi (IC50 of 55 µg/mL). Nyasse et al. [109] reported that bergenin isolated from F. virosa leaves also exhibited inhibitory activity in the growth of T. brucei in the bloodstream (trypomastigotes), with an IC50 value of 1 mM. Growth inhibition is achieved by inhibiting three glycolytic enzymes of the parasite: GAPDH (glyceraldehyde-3-phosphate dehydrogenase), PFK (phosphofructokinase), and PGK (phosphoglycerate kinase), which leads to the death of the parasite. Melos and Echearria [110] reported that trypanosomatids are highly dependent on glycolysis for ATP production, and, as many glycolytic enzymes have their own characteristics, they are considered to be potential targets for new chemotherapeutic agents.
Nyunt et al. [111] reported the trypanocidal activity of 11-O-acetylbergenin (isolated from the methanolic extract of V. repens) against Trypanosoma evansi trypomastigotes in vitro. 11-O-acetylbergenin was incubated in 96-well plates along with T. evansi in the trypomastigote form. Subsequently, the activity was determined by counting the number of parasites using a Neubauer hemocytometer. The findings indicated that 11-O-acetylbergenin inhibited (IC50 of 0.17 mM) the growth of T. evansi, thus suggesting trypanocidal activity.
The trypanocidal activity of the ethanolic extract of the stem bark of S. gabonensis was investigated in rats infected with Trypanosoma congolense. Twenty albino rats in four groups (A, B, C, and D) of five rats were injected intraperitoneally with 0.5 mL of blood infected with T. congolese. A further ten rats (E and F) were not infected with the parasite. All the infected animals developed the following clinical manifestations: varying degrees of lethargy, mucosa, rough fur, reduced appetite, and depression. Groups A, B, and C were treated with the ethanolic extract of S. gabonensis from the stock solution orally via water intake. Group A received 0.5 mg/kg, Group B received 1 mg/kg, and Group C received 3.5 mg/kg; however, Group D did not receive any treatment, Group E received treatment with the stock solution (0.5 mg/kg) and Group F did not receive any treatment. The results show that the treated infected groups (A, B, and C) had a mortality rate of 40 to 80% with 13 to 32 days of survival, while the infected Group (D), which received no treatment, had a mortality rate of 100% with 12 to 23 days of survival. The other negative control groups did not suffer any impact. These results suggest that treatment with ethanolic extract of the stem bark of S. gabonensis, which is rich in bergenin, reduced the growth of T. congolense and prolonged the lifespan of the infected rats [69].

5.4. Antiviral Activity

Bergenin has shown promise in studies focused on antiviral activity since it was discovered that extracts of species of the genus Bergenia exert immunostimulating activity in response to viruses and pathogenic microorganisms after their invasion of biological systems [112]. In this context, it is reported that bergenin can induce the transmembrane glycoprotein CD64, which has an important role in the humoral immune response, using an Fc receptor that binds to monomeric antibodies such as IgG [113]. To date, about 8 in vitro studies have been performed, though no study evaluated in vivo conditions.
The methanolic extract of A. rivularis showed an antiviral effect against herpes simplex virus type 1 (HSV-1) and influenza A via a dye-uptake assay in HSV-1/Vero cell systems and influenza A virus/MDCK [85]. The cells were incubated together with the viruses in different concentrations of extracts (6.25 to 100 µg/mL), and the results revealed that the extracts exhibited good antiviral activity with consequent destruction of HSV-1 and influenza A viruses IC50 of 6.25 µg/mL. These results suggest that extracts of A. rivularis exerted antiviral activity due to the presence of secondary metabolites since phytochemical investigations of the plant showed the presence of bergenin, flavonoids, and terpenoids [114]. Under the same conditions, Rajbhandar et al. [9] evaluated bergenin isolated from the rhizome of A. rivularis; however, they only tested the antiherpes activity, and the results were similar. Bergenin exhibited good activity against the herpes virus (IC50 of 6.25 µg/mL), proving that bergenin has this potential and can be explored further.
Zuo et al. [88] evaluated bergenin isolated from the aqueous ethanolic extract of the aerial parts of S. melanocentra against the NS3 serine protease of the hepatitis C virus (HCV) in an enzyme-linked immunosorbent assay (ELISA). HCV is an enveloped virus with positive-stranded genomic RNA that encodes a polyprotein that is cleaved by the NS3 serine protease, thus allowing the development of HCV [115] and, therefore, has been targeted for the development of new therapies for HCV infection. In the study, bergenin was incubated along with NS3 serine protease, and the results indicated that bergenin significantly inhibited NS3 serine protease (IC50 of 27.7 μg/mL).
Piacente et al. [116] evaluated the methanolic extract of aerial parts of A. japonica (the main constituent of bergenin) against the HIV virus in vitro and showed a moderate effect. However, when they tested bergenin and norbergenin isolated from the same extracts, both compounds showed weak antiHIV activity. The methanolic extract of the roots and bark of P. africanum was evaluated for its activity against HIV-1 reverse transcriptase (RT) [117]. Drugs that fight the HIV virus act as inhibitors of the reverse transcriptase, integrase, and protease enzymes. However, by inhibiting these enzymes, drugs prevent the multiplication of the virus in host cells. Reverse transcriptase is an enzyme that performs reverse transcription by producing DNA from RNA. It is also called RNA-dependent DNA polymerase. Therefore, the extracts incubated with this enzyme showed an inhibitory effect (IC50 of 3.5 µg/mL) against the DNA-dependent RNA polymerase activity (RDDP) of RT; however, bergenin isolated from the same extract had no effect against the same enzyme at concentrations tested up to 100 µM [117].

5.5. Antibacterial Activity

The antibacterial activity of bergenin has been reported in 15 in vitro studies and 4 in vivo studies. Liu et al. [82] reported that the methanolic extract of leaves of B. purpurascens showed antibacterial activity against strains that commonly cause respiratory infections: Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Enterobacter cloacae. The bacteria were incubated in triplicate along with the extracts at concentrations of 0.8 to 512 µg/mL using the agar well diffusion method, with resazurin as the dye added to each well. The results showed that the extract of B. purpurascens inhibited the growth of all strains, with IC50 ranging from 27 to 280 µg/mL. Other studies with the same approach using extracts that have bergenin had satisfactory results in vitro: methanol extracts of flowers of four angiosperm plant species Wendlandia thyrsoidea, Olea dioica, Lagerstroemia speciosa, and Bombax malabaricum against S. aureus, Bacillus cereus, Vibrio cholerae and E. coli, IC50 ranging from 1.2 to 3.8 µg/mL [14]; ethanol extract of C. corean against resistant strains of S. aureus, IC50 of 20 µg/mL [118]; methanolic extract of the rhizome of B. ligulata against E. coli and S. aureus, IC50 of 250 µg/mg [119]; methanolic extract of the rhizome of A. rivularis against E. coli, IC50 of 100 µg/mL [120].
Bergenin isolated from the ethanolic extract of P. roxburghii was tested in vitro using the agar well diffusion method [82] against Gram-positive (+) (S. aureus and E. faecalis) and Gram-negative (-) bacteria (P. aeruginosa, K. pneumoniae, S. typhi, E. coli, Acenatobacter sp., and Proteus sp.) [121]. The findings indicated that bergenin had a significant effect against the bacteria E. coli (−), K. pneumoniae (−), and P. aeruginosa (−) (IC50 ranging from 0.78 to 1.56 µg/mL); however, it had a weak effect against the bacteria S. typhi (−), Acenatobacter sp. (−), E. Proteus sp. (−), E. phaeacalis (+) and S. aureus (+) (IC50 ranging from 3.125 to 6.25 µg/mL) [122]. Nyemb et al. [123] reported that bergenin isolated from C. populnea roots had an inhibitory effect against four strains of Gram-negative bacteria in vitro: S. typhi (ATCC6539), S. typhi (isolated), P. aeruginosa (ATCC9721) and E. coli (isolated), IC50 ranging from 8 to 64 µg/mL. These results suggest that bergenin is able to easily cross the complex and multilayer lipopolysaccharide cell walls of Gram-negative bacteria. In doing so, it weakens them, causing lysis and consequent death [123]. However, some studies with bergenin had negative results [124,125]. Silva et al. [67] reported that bergenin isolated from the ethyl acetate fraction of E. uchi bark had no inhibitory effect against Gram-positive and Gram-negative bacteria. Similarly, Raj et al. [125] reported that bergenin isolated from crude methanolic extract of P. pterocarpum flowers had no inhibitory effect against bacteria.
Semisynthetic derivatives of bergenin isolated from the root of P. dubium [122] showed antibacterial activity in vitro using the agar diffusion method. 8,10-dihexyl-bergenin (1a), 8,10-didecyl-bergenin (1b), 8,10-ditetradecyl-bergenin (1c), 8,10-dimethylbergenin (1d), 8-methylbergenin, and 8,10-dioctyl-bergenin (1e) (Figure 2) exhibited antibacterial activity against S. aureus, B. subtilis, E. coli, and K. pneumoniae, with a minimum inhibitory concentration (MIC) of 5.1–6.2 mM [126], which suggests that pure bergenin can be transformed into a potent antibacterial agent [126]. 8,10-dibenzoylbergenin (1f) (IC50 of 125 µg/mL) was shown to be better antibacterial than bergenin (IC50 of 250 µg/mL) in an in vitro assay against S. aureus, which indicates that it is also a potential antibacterial derivative of bergenin [127].
Antibacterial activity was also determined in vivo. Liu et al. [82] evaluated the antibacterial activity of the methanolic extract of P. roxburghii (bergenin being the main constituent) against S. aureus in a neonatal Wister rat model. S. aureus is a bacterium of the Gram-positive cocci group that is part of the human microbiota, but that can cause diseases ranging from a simple infection, such as pimples and boils, to more serious ones, such as pneumonia and meningitis. Ten newborn rats were divided into four groups in which they received the treatments together with the S. aureus bacteria orally for four days in a row: Group I received saline, Group II received normal saline plus 2 mL of S. aureus, Group III received 50 mg of the extract plus 2 mL of S. aureus and Group IV received 100 mg of the extract plus 2 mL of S. aureus. The survival and weight of the rats were monitored for 9 days. The results showed that the survival rate of Group I was 80%. Infection with S. aureus led to mortality and reduced the survival % to 34.28% in Group II. However, in Groups III and IV, the percentage of survival was 48.57 and 60%, respectively, suggesting that extracts of B. purpurascens could reduce mortality caused by infection with S. aureus in newborn rats [82]. Kumar et al. [128] evaluated bergenin as an adjuvant immunotherapeutic agent for tuberculosis in mice. Mice were infected with 15 mL of M. tb H37Rv suspension using a Madison aerosol chamber, which targets the lungs and spleen. Days later, they were treated intraperitoneally with 4 mg of bergenin for 45 days. Then, the mice were euthanized, and the spleen and lung organs were removed. The results indicated that adjuvant therapy with bergenin protects mice against tuberculosis (IC50 4 mg). It is suggested that this treatment induces the adaptive immune response by inducing memory T cells (CD8+ T, CD62L1o, and CD44hi), which can provide lasting protection against pathogens. This knowledge could be used to potentiate the BCG vaccine for TB [128]. Dias et al. [129] reported that the ethyl acetate leaf extract (EALE) of H. balsamifera (bergenin being the main constituent) had an effect on the inhibition of S. aureus in mealworms. The larvae were divided into three groups: Group I larvae infected with a lethal dose of S. aureus without treatment, Group II uninfected larvae plus treatment with 3 mg of EALE, and Group III larvae infected with a lethal dose of S. aureus plus treatment with 3 mg of EALE. The findings indicated that Group I had a mean lifespan of 1 day, Group II had no decrease in its lifespan and Group III had a prolonged lifespan (5 to 6 days), and, at the end of the evaluation, 50% of the larvae were still alive, indicating that EALE) inhibits the growth of S. aureus [130].

5.6. Antifungal Activity

The antifungal activity of bergenin has been reported in five in vitro studies. Bergenin isolated from the ethyl acetate fraction of E. uchi bark was tested against Candida albicans, Candida tropicalis, Candida guilliermondii, Aspergillus flavus, Aspergillus nidulans, and Aspergillus niger using the well agar diffusion method [67]. The fungi were coated in triplicate along with bergenin in different concentrations, and resazurin was added to each well as a dye. The results indicated that the presence of bergenin inhibits the growth of the yeasts C. albicans (IC50 of 14.9 µM), C. guilliermondii (IC50 of 28.8 µM), and C. tropicalis (IC50 of 14.9 µM) but has lower activity against the filamentous fungi A. falvus (IC50 of 1093.0 µM), A. niger (IC50 of 476.1 µM), A. nidulans (IC50 of 951.9 µM) [67]. Raj et al. [125] reported that bergenin isolated from the crude methanolic extract of P. pterocarpum flowers had an inhibitory effect against Trichophyton mentagrophytes (IC50 of 250 µg/mL), Epidermophyton floccosum (IC50 of 500 µg/mL), Trichophyton rubrum (IC50 of 500 µg/mL), Aspergillus niger (IC50 of 500 µg/mL), and Botrytis cinerea (IC50 of 250 µg/mL). Rolta et al. [119] reported that bergenin isolated from the methanolic extract of the rhizome of B. ligulata had an inhibitory effect against two Candida sp. resistant strains: C. albicans (MTCC277) and C. albicans (ATCC90028), both with IC50 of 250 µg/mL. Pavithra et al. [14] reported that methanol extracts of flowers from four angiosperm plant species, W. thyrsoidea, O. dioica, L. speciosa, and B. malabaricum hadn’t inhibitory effect against C. albicans. These results suggest that further studies should be carried out in order to determine a good inhibitory concentration, and this observation was also made by Nyemb et al. [123].

5.7. Anti-inflammatory Activity

Several studies have evaluated the anti-inflammatory activity of bergenin, 16 in vitro and 12 in vivo. In all studies, bergenin showed that it has optimal cell viability (Table 3). Nunumura et al. [131] reported the anti-inflammatory activity of bergenin (0.01–1000 µM isolated from the trunk bark of E. uchi) against three enzymes in vitro, namely, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and phospholipase A2 (PLA2). The effects of bergenin against COX-1 and COX-2 were determined by measuring the levels of prostaglandin E2 (PGE2), and the effects against PLA2 were determined by measuring its concentration by means of HPGP (1 hexadecanoyl-2-10-pyrenyldecanoyl-sn-glycero-3-phosphoglycerol). The results showed that bergenin selectively inhibited COX-2 (IC50 of 1.2 µM), though it was poorly active against PLA2 (IC50 of 156.6 µM) and was not able to inhibit COX-1 (IC50 of 107.2 µM). These results corroborate the findings of Li et al. [129] (IC50 of 100 µM) and De Oliveira et al. [132] (IC50 of 1.2 µM). However, Jachak et al. [66] had a satisfactory result in COX-1 inhibition (IC50 of 70.54 µM) and demonstrated that bergenin inhibits both COX-1 and COX-2. COX-1 and COX-2 enzymes convert arachidonic acid to prostaglandin E2; thus, its inhibition can cause relief in inflammatory symptoms, as occurs with ibuprofen and celecoxib [133]. Bergenin showed an anti-inflammatory effect in human immortalized keratinocytes (HaCaT) [134] induced by interferon (TNF-α). These were treated with bergenin at concentrations of 0.01 to 200 µM, and the results show that bergenin (IC50 of 50 µM) triggers activation of the Nrf2 (erythroid-derived nuclear factor 2) pathway and inactivation of the NF-κB (nuclear factor k-b) pathway, inducing upregulation of IL-6 and IL-8 in HaCa. In other words, it reduces the levels of IL-6 and IL-8 and demonstrates an anti-inflammatory effect since blocking the expression levels of these two cytotoxins reduces inflammation. These results are similar to the findings of Chen et al. [135] and suggest that bergenin (IC50 of 100 µM) inhibits the pro-inflammatory response induced by TNF-α by blocking the NF-κB signaling pathway.
Shah et al. [126] isolated bergenin from the crude extract of M. philippenensis and then subjected it to chemical derivatization, obtaining 16 different synthetic derivatives. They subsequently tested its anti-inflammatory activity in vitro. Bergenin and its derivatives were incubated with macrophages treated with LPs (lipopolysaccharides) to determine whether bergenin could activate the iNO pathway for nitric oxide (NO) production and inhibit TNF-α production to normalize the cells. The results showed that only compounds 1g (IC50 of 322.1 µM) and 1h (IC50 of 253.2 µM) showed significant activity for NO production (Figure 2). Jungo et al. [136] also obtained good results, which suggests that the suppression of inflammatory cytokines may be associated with excessive production of NO (IC50 of 30 µM).
In vivo studies have determined the anti-inflammatory activity of bergenin in edema of the paw, ear, intestine, lungs, and mammary glands of experimentally induced rats and mice. Male BALB/c mice were experimentally induced into acute pulmonary injury/edema by intranasal inhalation of LPs. The mice showed histological changes, with increases in the activity of myeloperoxidases (MPO) in lung tissues and inflammatory cells (BALF) and decreases in cytokines (in BALF and serum) and, after 12 h, were treated with bergenin at concentrations of 50, 100 and 200 mg/kg. The results indicated that bergenin (IC50 of 50 mg/kg) repaired the injured tissue and normalized the edema at all concentrations tested: decreased MPO activity (decumulated neutrophils in lung tissues), decreased inflammatory cells (neutrophils and macrophages in BALF), increased production of inflammatory cytokines (IL-1β and IL-6 in BALF, IL-1β, TNF-α and IL-6 in LPA serum), markedly inhibited the phosphorylation of NF-kB p65. However, it inhibited the expression of MyD88 (myeloid differentiation factor 88) though not the expression of NF-κB p65 in lung tissues, which indicates that bergenin partially suppresses its production. In addition, bergenin also inhibited nuclear translocation and phosphorylation of NF-κB p65 stimulated by LPs in Raw264 cells, indicating that bergenin has anti-inflammatory effects in LPS-induced pulmonary edema [109].
Wistar rats were induced to acute ulcerative colitis by TNBS (2,4,6-trinitrobenzenesulfonic acid), causing an intestinal inflammation with tissue damage, and were subsequently treated with bergenin at concentrations of 12 to 100 mg/kg/day [137]. The results indicated that bergenin (IC50 of 25mg/kg) decreased the signs of macroscopic and microscopic colitis damage and reduced the degree of neutrophilic infiltration in the colon tissue. In addition, it was able to negatively regulate the expression of COX-2, iNOS, IkB-α, and pSTAT3 proteins (phosphorylated transducer and activator of immunohistochemical expression of expression-3) as well as activating inflammasome signaling pathways [137]. This pathway consists of an intracellular multiprotein complex that acts in the activation of enzymes of the cysteine-aspartate proteases (CASPASES) family as an essential structure for the regulation of immunity under physiological conditions and in recognition of danger signals with subsequent recruitment of cytokines that will normalize inflammation [138] The findings did not differ from those of Wang et al. [139] who tested bergenin isolated from the herb S. stolonifera. Gao et al. [10] reported that bergenin plays an anti-inflammatory role through the modulation of MARPK and NF-kB signaling pathways in an LP-induced mammary gland mastitis mouse model. Mice with mastitis induced in the mammary gland showed an excessive concentration of the pro-inflammatory cytokines NO, TNF-α, IL-1β, and IL-6, but only after treatment with bergenin. The results suggest that bergenin reduced the expression of pro-inflammatory cytokines, NO, TNF-α, IL-1β, and IL-6 by inhibiting the activation of the signaling pathways NF-kB and MAPKs, resulting in tissue normalization. These two pathways are responsible for the expression of inflammatory processes [140]. Inhibition of these two pathways was also observed in BALB/c rats (IC50 of 10 µM) with inflammation caused by Klebsiella pneumonia [141]. Souza et al. [142] reported that the phenolic extract of the stem bark of E. uchi (the main constituent being bergenin) had an anti-inflammatory effect in the edema of mice paws induced by intraplantar injection of carrageenan. Carrageenan is an inflammatory agent and produces inflammation by releasing prostaglandins, causing the formation of edema [143]. The results suggested that the phenolic extracts normalized edema by inhibiting COX-2, the main COX isoform induced during inflammation, to regulate the production of prostaglandins at the site of inflammation [128]. These results are similar to the findings of Borges [142], who tested acetylbergenin isolated from the stem bark of E. uchi in a paw edema model in rats induced experimentally by intraplantar injection of 100 µL of 1% carrageenan in the right paw of rats of the MacCoy lineage. Bergenin had an anti-inflammatory effect in a model of inflammation induced by Freund’s complete adjuvant (FCA) [73,144]. Mice were experimentally induced into edema by injection of FCA in the plantar region of the right paw. After this procedure, the recruitment of pro-inflammatory cytokines in the site was observed. The treatment with bergenin determined the suppression (IC50 of 12.5 mg/kg) of IL-1β, TNF-α, and IL-10 levels and normalized the tissues, suggesting that the anti-inflammatory effect of bergenin may be closely linked to the inhibition of these inflammatory cytokines [145]. It is known that they precede the release of the final mediators of hyperalgesia, i.e., prostaglandins and sympathetic amines [146]. These results are similar to the findings of Bharate et al. [22], who tested bergenin-rich extracts of B. ciliata.
Male Sprague-Dawley rats were experimentally exposed to tobacco smoke and developed chronic bronchitis. Later, they were treated with bergenin (87 mg/kg) and dexamethasone (0.2 mg/kg). The results indicated that both compounds suppressed inflammatory cell infiltration and inhibited mucus secretion, in addition to reducing white blood cells in BALF [147]. The authors suggest that the anti-inflammatory mechanism of action of bergenin may be associated with the alteration of branched-chain amino acid (BCAA) metabolism, glycine, serine, and threonine metabolism, and glycolysis to treat chronic bronchitis. It has been proven that these metabolic changes have an influence on the inflammatory response [148].
Table 3. Studies related to the anti-inflammatory activity of bergenin and its derivatives.
Table 3. Studies related to the anti-inflammatory activity of bergenin and its derivatives.
Compound NameSource of IsolationType of Assay, IC50CytotoxicityReference
CLCV
BergeninTrunk bark of E. uchiin vitro, 1.2 µMNCNC[131]
BergeninBergenia spp.in vivo -mice, 50 mg/kgRaw264.7 cellsNC[109]
BergeninNIin vitro, 50 µMCCK8CellsNC[134]
BergeninPeltophorum spp.in vivo -rats, 25 mg/kgNDND[137]
BergeninNIin vitro, 10 µMRaw264.7 cellsNC[141]
BergeninTrunk bark of E. uchiin vivo -mice, 100 mg/kgNDND[143]
BergeninNIin vivo -rats, 50 mg/kgNDND[138]
BergeninBark, leaf, and branches of E. uchiin vitro, 1.2 µMNDND[132]
AcetylbergeninStem bark of E. uchiin vivo -rats, 6.8 mg/kgNDND[144]
BergeninStem bark of C. gardnerianumin vivo -mice,12.5 mg/kgBALB/c mice splenocytesNC[73]
BergeninCrude extract of M. philippenensisin vitro, 303.12 µMNINC[126]
HeptylbergeninCrude extract of M. philippenensisin vitro, 212.95 µMNINC[126]
OctylbergeninCrude extract of M. philippenensisin vitro, 269.99 µMNINC[126]
EthylbergeninCrude extract of M. philippenensisin vitro, 322.09 µMNINC[126]
PropylbergeninCrude extract of M. philippenensisin vitro, 303.12 µMNINC[126]
BergeninS. stoloniferain vivo- mice, 100 mg/kgRAW264.7 cellsNC[139]
BergeninS. stolonifera herbin vitro, 0.1 µMRAW264.7CellsNC[139]
BergeninNIin vivo -rats, 87 mg/kgNDND[147]
BergeninNIin vitro, 100 µMCCK-8NC[135]
BergeninNIin vitro, 30 µMNDND[136]
BergeninStem bark of C. gardnerianumin vivo -rats, 25 mg/kgMacrophagesNC[149]
BergeninRhizome of Bergenia spp.in vitro, 7.29 μMINS-1E rat insulinoma cellsNC[150]
BergeninExtract of B. ciliatain vitro, 12.5 μg/mLTHP-1NC[22]
BergeninExtract of B. ciliatain vivo -mice, 100 mg/kgTHP-1NC[22]
11-O-(40-O-Methylgalloyl)-bergeninMethanolic extract of S. atratain vitro, 100 μgNDND[129]
BergeninEthanolic extract of dry leaves of T. procumbensin vitro, 70.54 µMNDND[66]
BergeninEthanolic extract of dry leaves of T. procumbensin vivo -rats, 200 mg/kgNDND[66]
11-O-GalloylbergeninEthanolic extract of M. philippinensisin vivo -rats, 20 mg/kgLCMK-2 monkey kid-ney epithelial cells and mice hepatocytesNC[151]
AcetylbergeninStem bark of E. uchiin vivo -rats, 6.8 mg/kgNDND[152]
Abbreviation: NC: no cytotoxicity, ND: no cytotoxicity determined, NA: no activity, CL: cell line, CV: cell viability, NI: Uninformed.

5.8. Antioxidant Activity

Bergenin isolated from parts of different plant species has shown good antioxidant activity in 33 in vitro and 4 in vivo studies (Table 4). Bergenin has shown an in vitro effect on free radical scavenging in assays with the DPPH(2,2-diphenyl-1-picrylhydrazylhydrate) radical. The DPPH free radical method is an antioxidant assay based on electron transfer that yields a violet solution in ethanol [153]. The IC50 for free radical scavenging DPPH in vitro was determined as 0.7–165.35 µg/mL [49,66,73,109,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158] and 951 µM [46]. The presence of bergenin reduces free radicals and gives rise to a colorless ethanol solution [159], indicating that it may be potentially useful for various pathological conditions associated with the devastating effects of oxygen-reactive species [124]. Studies with the same approach also evaluated the antioxidant potential using bergenin derivatives for DPPH free radical scavenging and presented a satisfactory IC50, i.e., 11-O-galloylbergenin IC50 of 5.39–7.45 µg/mL [105,108], hydroxybenzoyl-bergenin IC50 of 7.45 µg/mL [160], with the exception of diethyl ether of bergenin IC50 of 400 µg/mL [154]. Bergenin also exhibited antioxidant activity in vitro in hydrogen peroxide radical scavenging activity (H2O2) IC50 of 32.54 μg/mL [73]; in superoxide radical scavenging activity IC50 of 0.25–100 μg/mL [47,66,73]; in ABTS radical scavenging activity IC50 of 31.56–75.06 μg/mL [66,73] and 0.08 mg/mL [155]; in lipid peroxidation scavenging activity (LP) IC50 of 365.12 μg/mL [73]; in nitric oxide, radical scavenging activity (NO) IC50 of 2.98–785.63 μg/mL [73,155] and 0.35 mg/mL [47]; in hydroxyl radical scavenging activity (HO) IC50 of 0.12 mg/mL [48], 8.48 μg/mL [155]; in the radical NADH IC50 of 1 mg/g [156] and in the radical FRAP IC50 of 0.4 mg/g [156].
Bergenin exhibited antioxidant activity in HepG2 cells that were induced to oxidative damage by sodium selenite in vitro [161]. The cells treated with sodium selenium caused an oxidative-antioxidant imbalance that damaged them as it decreased antioxidant enzymes, which allowed the proliferation of free radicals that, in turn, triggered pro-inflammatory cascades and induced the damage. HepG2 was co-incubated with sodium selenite (10 µM) and bergenin (75, 150, and 300 µM) for 24 h. The results indicated that bergenin (IC50 of 75 µM) exerted protective effects against oxidative stress induced by sodium selenite in HepG2 cells since it sequesters free radicals and normalizes the oxidative stress balance. Similar protection was observed in PC12 cells, a cell line derived from a pheochromocytoma of the adrenal medulla of rats, with norbergenin derivatives isolated from D. crassiflora stems (IC50 of 0.1 and 10 µM) [162].
BALB/c mice immunosuppressed by cyclophosphamide (Cy) experimentally induced a decrease in the action of enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)], which are important in response to oxidative stress and accelerate the formation of free radicals and, consequently, the spleen and thymus suffered lesions [163]. Manente et al. [164] reported that oxidative cell damage is a major side effect of chemotherapy drugs, including cyclophosphamide. Cyclophosphamide disrupts the redox balance and causes tissue damage; however, after treatment with bergenin, the results suggested that bergenin (IC50 of 20 mg/kg) reversed the Cy-induced decrease in total antioxidant capacity, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities. This improved humoral and cellular immune functions and increased antioxidant activity. This effect is justified by the fact that bergenin acts as a free radical scavenger or a redox-regulating agent, effectively avoiding Cy-induced oxidative stress injury by increasing antioxidant enzymes and oxidative-reducing enzymes [163]. These enzymes, when increased at the site of injury, convert harmful oxygen into less-reactive hydrogen peroxide, catalyzing the dismutation of superoxide into oxygen and hydrogen peroxide [164]. Lee et al. [165] reported that bergenin had an antioxidant effect in mice treated with morphine. Morphine treatment induced oxidative stress by decreasing antioxidant enzymes and causing the proliferation of free radicals, and this allowed inflammation of the brain since oxidative stress and inflammation are interdependent. Free radicals activate pro-inflammatory genes that trigger a cascade of progressive inflammation; however, treatment with bergenin (IC50 of 20 mg/kg) had an antioxidant effect and played a role in antinarcotic effects through adaptation to morphine-induced oxidative stress in the brain. Sriset et al. [162 reported that bergenin attenuates sodium selenite-induced hepatotoxicity by improving hepatic oxidant-antioxidant balance in ICR mice. Mice were orally administered sodium selenite (4 m/kg), which caused liver damage through oxidative-antioxidant imbalance. This is because there is an increase in plasma levels of enzymes aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, and there is an increased proliferation of reactive oxygen species by decreasing antioxidant enzymes, resulting in lipid peroxidation in plasma. After treatment with bergenin, the results indicated that bergenin (IC50 of 10 mg) restored normal tissue damaged by the antagonistic effect exhibited by sodium selenite. The effect of bergenin on membrane lipid peroxidation and ascorbic acid level in tissues was studied using pathogen-free weaned rats as the experimental animal and 2,4-dinitrophenyl hydrazine (2,4-DNPH) as the experimental oxidant [166,167]. Lipid peroxidation was experimentally induced with 2,4-DNPH via the intraperitoneal route, which allowed a greater proliferation of reactive oxygen species and triggered processes that led to tissue damage by oxidative-antioxidant imbalance. In this context, three primary antioxidant enzymes were analyzed, namely catalase, superoxide dismutase (SOD), and glutathione peroxidase, and two non-enzymatic antioxidants, namely vitamin E (α-tocopherol) and vitamin C (ascorbic acid). After treatment with bergenin isolated from S. gabonensis stem bark extract (main constituent being bergenin), the results indicated that the bark extract (IC50 of 2.8 mg/100 g) exhibited divergent effects on antioxidant enzymes: impaired the enzyme-inducing action of 2,4-DNPH on liver and red blood cell catalase, reduced the depressant effect of SOD, and neither 2,4-DNPH nor the extract had any measurable effect on glutathione peroxidase. The bark extract also exerted a sparing effect on tissue antioxidant vitamins, ascorbic acid, and vitamin E, effectively inhibiting their depletion by 2,4-DNPH in the liver, red blood cells, and brain. These results suggest that the antioxidant mechanism of action of the bark extract against membrane peroxidation is multifactorial/multisystem, involving catalase inhibition, enhancing the SOD capacity of the liver and red blood cells, and sparing tissue depletion/use of vitamins C (ascorbic acid) and E (α-tocopherol) [166].
Table 4. Studies relating to the antioxidant activity of bergenin and its derivatives.
Table 4. Studies relating to the antioxidant activity of bergenin and its derivatives.
Compound NameSource of IsolationType of Assay + IC50CytotoxicityReference
CLCV
BergeninRoots of B. ligulatain vitro/DPPH, 100 µg/mLNDND[105]
11-O-GalloylbergeninRoots of B. ligulatain vitro/DPPH, 7.45 µg/mLNDND[105]
BergeninExtracts of the aerial parts of B. ligulatain vitro/DPPH, 54 μg/mLNDND[108]
Hydroxybenzoyl-bergeninExtracts of the aerial parts of B. ligulatain vitro/DPPH, 7.45 μg/mLNDND[108]
11-O-GalloylbergeninExtracts of the aerial parts of B. ligulatain vitro/DPPH, 5.39 μg/mLNDND[108]
BergeninStem bark of P. pterocarpumin vitro/DPPH, 0.96 μg/mLNDND[154]
Bergenin diethyl etherStem bark of P. pterocarpumin vitro/DPPH, 400 μg/mLNDND[154]
BergeninRoots of C. digynain vitro/DPPH, 165.35 μg/mLNDND[73]
BergeninFlowers of P. pterocarpumin vitro/DPPH, 1.95 μg/mLNDND[155]
BergeninEthanol extract from dried leaves of T. procumbensin vitro/DPPH, 20.42 μg/mLNDND[66]
BergeninStem bark of M. japonicusin vitro/DPPH, 951 μMNDND[46]
BergeninM. philippensisin vitro/DPPH, 99.807 μg/mLNDND[49]
11-O-GalloylbergeninM. philippensisin vitro/DPPH, 7.276 μg/mLNDND[49]
BergeninRhizome of B. ciliatain vitro/DPPH, 100 μg/mLNDND[157]
BergeninE. uchiin vitro/DPPH, 4.02 μg/mLNDND[158]
BergeninRhizome of B. ciliatain vitro/DPPH, 0.7 mg/gNDND[156]
BergeninAerial parts of T. labialisin vitro/DPPH, 100 μg/mLNDND[63]
BergeninBark, leaf, and branches of E. uchiin vitro/DPPH, 24.20 μg/mLJ774 cells of murine macrophagesNC[168]
BergeninEthanol extract from dried leaves of T. procumbensin vitro/H2O2, 100 μg/mLNDND[66]
BergeninRoots of C. digynain vitro/H2O2, 32.54 μg/mLNDND[73]
BergeninRoots of C. digynain vitro/H2O2, 75.06 μg/mLNDND[73]
BergeninM. repandusin vitro/H2O2, 0.25 mg/mLNDND[47]
BergeninRoots of C. digynain vitro/ABTS, 75.06 μg/mLNDND[73]
BergeninEthanol extract from dried leaves of T. procumbensin vitro/ABTS, 31.56 μg/mLNDND[66]
BergeninM. repandusin vitro/ABTS, 0.08 mg/mLNDND[47]
BergeninM. repandusin vitro/OH, 0.12 mg/mLNDND[47]
BergeninFlowers of P. pterocarpumin vitro/OH, 8.48 μg/mLNDND[155]
BergeninRhizome of B. crassifoliain vitro/FRAP, 0.4 mg/gNDND[156]
BergeninRhizome of B. ornatain vitro/NADH, 1 mg/gNDND[156]
BergeninRoots of C. digynain vitro/NO, 785.63 μg/mLNDND[73]
BergeninM. repandusin vitro/NO, 0.32 mg/mLNDND[47]
BergeninFlowers of P. pterocarpumin vitro/NO, 2.98 μg/mLNDND[155]
BergeninRoots of C. digynain vitro/PL, 365.12 μg/mLNDND[73]
BergeninNIin vitro, 75 μMHepG2NC[161]
BergeninNIin vivo -mice, 20 mg/kgSplenic NK and CTL cellsNC[163]
BergeninNIin vivo -mice, 20 mg/kgNINI[165]
BergeninNIin vivo -mice, 10 mg/kgHepG2NC[161]
BergeninExtract of stem bark from S. gabonensisin vivo -mice, 2.8 mg/100 gNDND[166]
4-O-p-HydroxybenzoylnorbergeninLeaves of D. gilletiiin vitro/DPPH, 8.2 μg/mLNDND[169]
MethylbergeninWhole plant of A. japonicain vitro/NO, 38.4 μg/mLHepG-2NC[170]
Abbreviation: NC: no cytotoxicity, ND: no cytotoxicity determined, NA: no activity, CL: cell line, CV: cell viability, NI: Uninformed.

5.9. Antinociceptive Activity

The antinociceptive activity is linked to the analgesic activity of bergenin, blocks the sensory neurons, and gives the sensation of pain relief in vivo. Obviously, all the studies presented in the previous sections, especially the anti-inflammatory and antioxidant activities, show the ability of bergenin to restore the normality of inflamed tissue or an organ or to restore the antioxidant oxidant balance and cause the mice or rats to feel pain relief. Ethanolic extract of D. dentatus leaves, which are rich in bergenin, showed antinociceptive activity in male Swiss mice. The mice were induced by formalin intraperitoneally, causing joint inflammation, knee edema, leukocyte infiltration, hyperalgesia, and sensation of excessive cold; however, oral treatment with the extract (100 and 300 mg/kg) reduced leukocyte infiltration and normalized the injured tissues, which consequently significantly inhibited nociceptive sensitivity and sensitivity to cold (IC50 of 100 mg/kg). The results suggest that the ethanolic extract could interfere with the peripheral and central pain mechanisms of nociception induced by formalin [171]. Bharate et al. [22] reached the same conclusion using the ethanolic extract of the rhizome of bergenin-rich B. ciliate (IC50 of 2 g/kg) in rats induced to nociception by acetic acid and the formalin-induced paw-licking method and suggested that upregulation of inflammation is inversely proportional to antinociceptive activity, i.e., the bergenin contained in the extract enables inhibition of both nociceptive response phases as anti-inflammatory processes are activated. Souza et al. [143] reported that the extract of the bark of E. uchi presented good antinociceptive activity (IC50 of 100 mg/kg) in the test of abdominal contortions induced by acetic acid. They suggested that the mechanism of action is associated with the inhibition of the formation of pro-inflammatory mediators. Paulino et al. [62] claim that bergenin has the potential to exert antinociceptive activity and may affect the opioid system. Opioids act by promoting the opening of potassium channels and inhibiting the opening of voltage-gated calcium channels, thus causing hyperpolarization and reduced neuronal excitability. In addition, there is a reduction in the release of transmitters (by inhibiting the entry of Ca2+), blocking the sensation of pain.
Bergenin isolated from the rhizome of B. ciliata showed antinociceptive activity (IC50 of 10 mg/kg) by normalizing the antioxidant oxidative balance and de-accumulation of IL-2 in an induced hyperoxaluric rat model [172]. Semisynthetic acetylbergenin, the product of acetylation of bergenin isolated from the cortex of E. uchi, also showed good antinociceptive activity in Swiss albino rats with abdominal contraction [173]. The abdominal contraction was induced in rats by intraperitoneal injection with 0.6% acetic acid triggering contractions, thereby raising levels of prostaglandin E2, which triggers local inflammatory processes by raising COX-2, in addition to interfering with nociceptive mechanisms causing extreme pain in rats; however, treatment with bergenin (IC50 of 6.8 mg/kg) normalized inflammation and inhibited nociception induced by acetic acid.

5.10. AntiArthritic Activity

Bergenin has been studied in order to verify its antiarthritic potential. In rat or mouse models that experimentally induced inflammation in the joints, seven studies were able to discriminate antiarthritic activity in vivo. Branquinho et al. [171] reported the activity of the ethanolic extract of leaves of D. dentatus, which are rich in bergenin, in male Swiss mice against rheumatoid arthritis. In the study, mice were experimentally induced to joint inflammation (including knee edema, leukocyte infiltration, and hyperalgesia) by zymosan through a single intraperitoneal dose of 200 µL. After treatment with the extract (0.3 to 30 mg/kg), the results suggested that the extract showed therapeutic action in rheumatoid arthritis and decreased the amount of inflammation through the de-accumulation of pro-inflammatory cytokines and by modulating the immune response in the cells. Bharat et al. [122] came to the same conclusion using the ethanolic extract of the rhizome of bergenin-rich B. ciliata (IC50 of 2 g/kg) in rats induced to arthritis using Mycobacterium.
Bergenin isolated from the rhizome of B. ciliata was shown to be a potent antiarthritic agent in an induced hyperoxaluric rat model [172]. Hyperoxaluria was induced using ethylene glycol, and this induction caused oxidative stress, especially in the joints, which caused a proliferation of pro-inflammatory cytokines, causing edema. However, treatment with bergenin (IC50 of 10 mg/kg) inhibited the proliferation of IL-β and sequestered reactive oxygen species, thus normalizing the joints. In the study by Jain et al. [174], bergenin and its derivatives exerted antiarthritic activity, possibly by inhibiting pro-inflammatory cytokines and producing TNF-α. Nazir et al. [175] reported that the effect of bergenin and norbergenin against adjuvant-induced arthritis, both at doses above 2 mg/kg, is achieved by possible modulation of the Th1/Th2 cytokine balance.
Methanolic extract of C. capitella and its metabolite 11-O-(4′-O-methyl galloyl)-bergenin, isolated from aerial parts, showed an antiarthritic effect on rat hind paws. Arthritis was induced by intraplantar injection of 0.1 mL of complete Freund’s adjuvant (CFA) into the subplantar tissue of the hind paw. CFA produced definitive edema within 24 h, with progressive arthritis on day 9 after inoculation according to the elevated levels of TNF-α, IL-1β, IL-6, and myeloperoxidase activity. There was also an increase in rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (antiCCP), which are considered predictors of severe arthritis. Subsequently, they were treated with the extract (250 mg/kg) and 11-O-(4′-O-methyl galloyl)-bergenin (5, 10, and 20 mg/kg). The findings indicated that both treatments inhibited the production of pro-inflammatory cytokines, and serum levels of RF and antiCCP were normalized, with an IC50 of 250 mg/kg for the extract and 20 mg/kg for 11-O-(4′-O-methyl galloyl)-bergenin [176].

5.11. Antiulcerogenic Activity

The antiulcerogenic activity of bergenin has been reported in several experimental ulcers. In this context, about six studies were carried out, one in vitro and five in vivo. Bergenin and norbergenin (isolated from the aqueous extract of M. japonicus) showed an inhibitory effect on the bovine adrenal tyrosine hydroxylase (TH) enzyme in vitro [177]. The increased activity of this enzyme is suggested to be related to the occurrence of gastric ulcers in patients stressed by the cold. The findings showed that bergenin and norbergenin inhibited TH activity by 12.2% and 51.0% at the concentration of 5 µg/mL, 16.1% and 51.6% at the concentration of 10 µg/mL, and 29.0% and 53.4% at the concentration of 20 µg/mL, respectively [177].
Male Donryu rats received treatment with bergenin (30 to 1000 mg/kg) orally and were subsequently placed in a cage and immersed up to the level of the xiphoid process in a water bath (23 °C) for 7 h, then euthanized. The stomach was removed and submerged in a formalin solution inducing inflammation, allowing the marking of the inner and outer layers of the gastric wall. Finally, the stomach was incised along the curvature, and the lesions were examined [178]. The results indicated that bergenin (IC50 30 mg/kg) inhibited the development of stress-induced gastric ulcers in rats. One of the mechanisms attributed to its effectiveness may be the inhibition of acetylcholine release, which induces acid secretion and improves gastric motility [178]. Oral administration of bergenin and norbergenin isolated from the leaves and roots of F. microcarpa and luvangetin showed significant protection against pyloric gastric ulcers in rats induced by aspirin and colds, suggesting that the gastroprotective effects of bergenin and norbergenin may be due to increased prostaglandin production [41].
Semisynthetic acetylbergenin (1i) isolated from E. uchi was effective in preventing gastric ulcers [152]. Acute gastric ulcer was induced by stress, according to Basile et al. [41]. Wistar rats were fasted with free access to water for 24 h, then treated with distilled water (0.5 mL), acetylbergenin (6.8 mg/kg), and indomethacin (10 mg/kg). Each animal was kept for 17 h in a container tube, which was immersed vertically until the water reached the neck region of the animal in a tank with running water at 25 °C. In addition, the rats were euthanized by CO2 inhalation. Their stomachs were immediately excised and opened by cutting along the largest curvature for examination of the inner wall, and the lesions were counted. The results indicated that treatment with indomethacin (10 mg/kg) produced more lesions when compared with acetylbergenin at a dose of 6.8 mg/kg, revealing that acetylbergenin has a protective effect [152].

5.12. Antidiabetic/Antiobesity Activity

Antidiabetic/antiobesity activity was investigated in eight in vivo studies. The alcoholic extract of C. digyna root rich in bergenin showed an antidiabetic effect in diabetic rats induced by streptozotocin-nicotinamide. The rats received a single dose of streptozotocin-nicotinamide (65 mg/kg) intraperitoneally, which induced fatal hypoglycemia due to the massive release of pancreatic insulin. After 6 h, the rats received 10% glucose solution and continued receiving more glucose by injection until reaching a glucose level of 200 mg/dL in fasting. Treatment with the extract (250 to 750 mg/kg) for 14 days reduced dose-dependent blood glucose levels from 200 mg/dL to 146.33 mg/dL (IC50 of 250 mg/kg), and it was also noted that it was able to reduce the body weight of the rats [179]. Hyperglycemia is recognized as a common complication of diabetes mellitus. Reduced insulin secretion causes a variety of disruptions in metabolic and regulatory mechanisms that lead to lipid accumulation. Bergenin significantly reduces triacylglycerols and total cholesterol in diabetic rats. The lipid-lowering effect of bergenin and other antidiabetic drugs reduces the risk of vascular complications [179]. San et al. [91] reported that the methanolic extract of the root of C. javana affected glucose uptake (100 µg/mL) in L6 skeletal muscle cells according to the reported methods [91,180].
Rats fed a hyperglycemic diet increased blood glucose to 220 mg/dL and developed type 2 diabetes, then received intragastric treatment with bergenin (10, 20, 40 mg/kg) or metformin (25 mg/kg) as the positive control from 8 to 16 weeks [181]. Treatment with bergenin (10, 20, 40 mg/kg) significantly reduced the concentration of glucose in the blood from 220 to 86.19 mg/dL against 80.45 mg/dL of metformin. Bergenin significantly improved the insulin sensitivity index, reduced liver damage and oxidative changes, and brought antioxidants and lipids back to normal, suggesting that bergenin can be used as a functional drug or as an adjunct in the management of insulin resistance and associated fatty liver disease [181]. Other studies have also determined the IC50 for the inhibition of the development of type 2 diabetes with antiobesity consequences; namely, bergenin isolated from the methanolic extract of F. racemosa (IC50 of 200 mg/kg) [182] and bergenin isolated from the rhizomes of B. crassifolia (IC50 of 100 mg/kg) [183].
Methoxybergenin, a natural derivative isolated from the stem bark of V. pauciflora, showed an antidiabetic effect in diabetic Wistar rats induced via alloxan [184]. Twenty-five Wistar rats with a body weight of 100 g, presenting a normal glycemia (50–125 mg/dl), were induced via alloxan at a dose of 150 mg/kg intraperitoneally, which subsequently presented an elevation of the blood glucose level (440 mg/dL), thus damaging the production of insulin by the cells of the pancreas. Treatment with methoxybergenin after 21 days of treatment exhibited good antidiabetic activity (IC50 of 191 mg/200 g), and this inhibition allowed the reduction of the body weight of the rats, which suggests antiobesity activity [184].
Kumar et al. [185] reported that bergenin isolated from the methanolic extract of M. philippinensis showed moderate antiglycation activity (IC50 of 186.73 µg/mL), which suggests participation in glycemic regulation. This effect allows sugar molecules not to be fixed in large quantities in proteins, especially hemoglobin, in addition to avoiding increased oxidative stress. The same was observed with respect to 11-O-galloylbergenin isolated from the ethyl acetate fraction of P. peltatum (IC50 of 0.1 µg/mL) [186].

5.13. AntiArrhythmic Activity

Studies on the antiarrhythmic activity of bergenin are scarce; however, only one study undertook this assessment [7]. Bergenin isolated from the aerial parts of F. virosa was investigated for its antiarrhythmic effects at concentrations of 0.2 mg/kg, 0.4 mg/kg, and 0.8 mg/kg, and showed distinct therapeutic effects on arrhythmias induced by barium chloride (BaCl2) in rats. At concentrations of 0.4 mg/kg and 0.8 mg/kg, bergenin significantly countered arrhythmias induced by coronary artery ligation and reperfusion. At a concentration of 0.8 mg/kg, bergenin raised the atrial fibrillation threshold in rabbits from 1.34 mV to 1.92 mV, suggesting that bergenin has the potential to treat cardiac arrhythmias [7]. According to Filho et al. [187], the elevation of the atrial fibrillation threshold allows the electric current to travel with sufficient intensity to contract the muscles of the ventricles and cause involuntary systole.

5.14. Anticancer Activity

The anticancer activity of bergenin has been reported in 13 in vitro studies and 2 in vivo studies. Bergenin-rich E. agallocha leaf extract showed anticancer activity in a cervical cancer cell line (SiHa HPV 16+) [45]. The extract was matched with a cancer cell line and peripheral healthy blood mononuclear cells (PBMC) using an MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to assess its cytotoxicity. The findings indicated that bergenin-rich extracts exhibited remarkable activity against the SiHa cell line (IC50 of 15.538 µg/mL), whereas for healthy cells (PBMC), the extracts induced cell proliferation, suggesting that they do not produce cytotoxicity in normal healthy cells. The mechanism of action of this effect may be associated with blocking the action of the GLI-related protein (glioma-associated oncogene homolog). GLI is a transcriptional effector involved in developing tumors; thus, blocking its action leads to the inhibition of its translocation to the nucleus [188]. Konoshima et al. [160] describe GLI as an effective inhibitor of the Hedgehog, a signaling pathway in cancer therapy. Bergenin has shown effects on human colorectal adenocarcinoma cell line HCT116 [189]. Bergenin markedly inhibited (IC50 of 30 µM) the growth of HCT116 cells with cellular apoptosis of up to 5.21%. When the influence of bergenin on the cell cycle was evaluated, it was found that it increased the number of cells in the Gap 1 (G1) phase with a decrease in the percentage of cells in the synthesis phase (S) in 24 h, showing that bergenin can lead to DNA damage in HCT116 cells by increasing the phosphorylation of the histone variant H2AX in Ser139 and generation of reactive oxygen species (ROS). The canonical PI3K/AKT/mTOR signaling pathway emerges as a critical regulator of the cell proliferation pathway [190]. This pathway is very important and is involved in the regulation of cell proliferation, cell cycle progression, apoptosis, and morphogenesis in different organs [191,192]. Bergenin, isolated from the bark of F. religiosa, F. virens, F. glomerata, F. benghalensis, and T. pulpunea, showed effects on cervical cancer lines of Hela and SiHa cancer cells (IC50 of 125.8 and 96.0 µg/mL respectively) using an MTT assay [42]. Newell et al. [77] reported anticancer activity of bergenin isolated from the seed of five Ardisia species, namely A. japonica, A. escallonioides, A. mamillata, A. crenata, and A. compressa, with the inhibition of human topoisomerase II enzyme and cytotoxicity in human liver cancer cells (HepG2) in vitro. The findings indicated that bergenin showed catalytic inhibition of topoisomerase II (IC50 of 18 µM) and cytotoxicity (IC50 of 18 µM) against HepG2 cells, and it was found that bergenin showed a tendency to accumulate cells in the G1 phase and reduction of G2/M leading to apoptosis of malignant cells.
Bergenin (isolated from the herb B. purpurascens) inhibited the activity of human hepatic cytochrome P450 enzymes (CYP), CYP3A4, 2E1, and 2C9, with IC50 values of 14.39, 22.83, and 15.11 µM, respectively [193]. Enzyme kinetics studies showed that bergenin was not only a non-competitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP2E1 and CYP2C9. These enzymes at high levels may favor extrinsic factors (e.g., alcohol and tobacco consumption), triggering the development of oral cancer [193].
Bulugahapitiya et al. [40] reported anticancer activity of ethyl acetate extract (EtOAc) from F. leucopyrus leaves, bergenin and bergenin diastereomer (at C-9 and C-14) both isolated from EtOAc, against human ovarian carcinoma. Anticancer activity was evaluated using cell proliferation assays (MTS) and human telomerase reverse transcriptase (hTERT) in human ovarian carcinoma (A 2780). The MTS assay showed significant antiproliferation activity with an IC50 of 36.35, 12.36, and 48.53 µg/mL for EtOAc, bergenin, and bergenin diastereoisomer, respectively. A rapid depletion of the hTERT content in human ovarian cancer cells was observed for the bergenin diastereomer in the concentration range of 50–200 µg/mL. The findings suggested the anticancer activity of F. leucopyrus leaves against human ovarian cancer, and bergenin and its isomer were identified as the compounds responsible for the anticancer activity of this plant. It can effectively inhibit the proliferation of cancer cells and inhibit the human telomerase reverse transcriptase enzyme, which is directly responsible for the activation of cancer cell telomerase [194]. These results resemble the findings of Mettihewa et al. [195]. Bergenin, isolated from S. stolonifera, was shown to induce apoptosis (IC50 of 6.1 µM) in BGC-823 carcinoma cells in an MTT assay [196].
Esterified bergenin 5c (11-hydroxyl-modified bergenin), a semisynthetic derivative of bergenin, was evaluated for its antitumor properties in vitro and in vivo [197]. The findings showed that it trapped HepG2 cells (IC50 of 4.23 ± 0.79 mM) in the G2/M phase and induced cell apoptosis. In addition, compound 5c suppresses (IC50 30 mg/kg) tumor growth in Heps xenograft-bearing mice with low toxicity. Liu et al. [198] reported that the methanolic extract, which is rich in bergenin and norbergenin, from S. stolonifera showed an antitumor effect, and its lung tumor inhibition rate can reach 49.2% (IC50 of 5.150 mg/g). The extract showed some capacity in the recovery of the immune system and hematological system of Lewis mice, in addition to causing necrosis in tumor cells and decreased macrophage density to inhibit the growth of lung tumors [198]. De-Biao et al. [199] reported anticancer activity of 3, 4, 11-trihydroxyl modified bergenin derivatives in an MTT assay in the inhibition of DU-145 and BGC-823 cells, with significant inhibitions of compounds 3a to 7a (3, 4, 11-trihydroxyl modified derivatives of bergenin). IC50 ranged from 20.89–100 µM for DU-145 and 23.99–100 µM.
11-O-Galloylbergenin, a natural bergenin derivative isolated from leaves of C. coreana, was shown to be a potent antitumor agent in human osteosarcoma cells (MG63 cells) in an MTT assay. The findings showed that it inhibited the proliferation of MG63 cells and induced cellular apoptosis. This phenomenon was accompanied by the upregulation of the p53 and p21 genes [200]. The p53 gene encodes the tumor suppressor protein p53, which plays a significant role in tumor development and regulates the cell cycle and apoptosis, especially in the early events of osteosarcoma tumorigenesis [200].

5.15. Hepatoprotective Activity

In three in vitro studies and seven in vivo studies, bergenin showed hepatoprotective activity. Bergenin isolated from the cortex of M. japonicus exhibited good hepatoprotective activity by removing hepatotoxicity in a rat liver-cell assay induced by carbon tetrachloride (CCl4) [201]. Hepatocytes were isolated from rats using the method of Berry and Friend [202] and were then cultured [198]. After one day of plating, they were exposed to CCl4 (10 mM), which induced hepatotoxicity by metabolic activation. In other words, CCl4 is metabolically activated by cytochrome P-450-dependent mixed oxidase in the endoplasmic reticulum to form a trichloromethyl free radical (CCl3), which, combined with lipids and proteins in the presence of oxygen to induce lipid peroxidation [203], results in changes in the structures of the endoplasmic reticulum system and other membranes, loss of metabolic enzyme activation, reduced protein synthesis, and loss of glucose-6-phosphatase activation, thus leading to liver damage [204]. However, treatment with bergenin (IC50 of 300 μM) lowered the activity of enzymes whose high levels indicate liver damage, namely pyruvic transaminase (GPT) sorbitol dehydrogenase (SDH) [201]; both enzymes are also associated with lipid peroxidation [205]. In vivo studies positively confirmed the hepatoprotective activity in rats with experimentally induced hepatotoxicity by CCl4, and the IC50 was determined. Bergenin isolated from the cortex of M. japonicus exhibited a hepatoprotective effect in rats (IC50 of 50 mg/kg) and normalized the decreased activities of glutathione S-transferase and glutathione reductase, in addition to significantly preventing the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver [206]. Bergenin isolated from the herb S. stolonifera exhibited (IC50 of 100 mg/kg) a hepatoprotective effect and detoxified liver cells [206]; bergenin isolated from the extract of P. pterocarpum showed a hepatoprotective effect in albino rats (IC50 of 100 mg/kg) reducing excessive levels of the enzymes alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (γ-GT), direct bilirubin (DB) and total bilirubin (TB) [207,208]; bergenin and 11-O-galloylbergenin, isolated from the leaves of A. edulis, have remarkable antihepatotoxic activity against CCl4 and galactosamine cytotoxicity in cultured primary rat hepatocytes (IC50 of 100 mg/kg) [122]. Mondal et al. [209] reported that the hepatoprotective capacity of bergenin could also be related to the fact that it can sequester free radicals and restore the antioxidant oxidant balance.
The hepatoprotective effects of acetylbergenin have been examined against D-galactosamine (GalN). Ga1N induced liver damage in rats, compared to previously reported bergenin [137]. Acetylbergenin was synthesized from the acetylation of bergenin, isolated from M. japonicus, to increase lipophilic and physiological activities. Acetylbergenin was administered orally once daily for 7 days, and then GalN (400 mg/kg) was injected at 24 h and 96 h after the final acetylbergenin administration. Acetylbergenin reduced elevated serum enzymatic activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase, glutamyltransferase, and GalN-induced hepatic malondialdehyde formation. Acetylbergenin also significantly restored GalN-induced decreased glutathione levels and decreased glutathione S-transferase and glutathione reductase activities to normalization. Therefore, these results suggest that acetylbergenin has hepatoprotective effects against GalN-induced hepatotoxicity by inhibiting lipid peroxidation and maintaining an adequate level of GSH for xenobiotic detoxification as its underlying hepatoprotective mechanisms. In addition, lipophilic acetylbergenin showed more activity in hepatoprotection than the much less lipophilic bergenin that was previously reported [210].

5.16. Neuroprotective Activity

The neuroprotective activity of bergenin has been reported in two in vitro studies. Bergenin showed neuroprotective activity against Alzheimer’s disease (AD) [211], a chronic progressive neurodegenerative disease, which often occurs in the elderly and negatively affected intellectual abilities and cognitive processes. Human neuroblastoma cell lines (SH-SY5Y) were treated in an MTT assay with N-methyl D-aspartate (NMDA) at the concentration of 2.5 mM per 24 h, which led to reduced cell viability (49.33%). In this context, this concentration was selected to induce cytotoxicity in SH-SY5Y, along with pretreatment with bergenin (5 to 50,000 nM) in an MTT assay. The findings revealed that pretreatment with bergenin led to NMDA concentration-dependent reversal in the concentration range of 5–500 nM. Bergenin at 500 nM led to the greatest increase in cell survival—up to 81.754% [211]. Takahashi et al. [46] reported the neuroprotective activity of norbergenin derivatives isolated from the methanolic extract of the bark of M. japonicus, and this suggests that it is closely related to their ability to sequester reactive oxygen species and thus restore antioxidant oxidative balance.
Suzuki et al. [212] reported the protective effect of norbergenin-11-caproate (a semisynthetic derivative of norbergenin isolated from M. japonicus) against cell damage in human neuroblastoma IMR-32 cells treated with tunicamycin. When IMR-32 cells were treated with tunicamycin, their viability in an MTT assay was decreased in a dose-dependent manner (0.01–1 μM). Treatment with norbergenin-11-caproate (10 mM) showed complete protection against the cell growth inhibitory effect of tunicamycin but did not inhibit the induction of Bip/GRP78 mRNA, suggesting the therapeutic potential of this derivative.

5.17. Cardioprotective Activity

Studies on the cardioprotective activity of bergenin are scarce, with only one study investigating this effect. Thirty rats were experimentally induced to myocardial infarction by isoproterenol (ISO), which sharply increased the ST and deep Q wave, in addition to causing leakage of cardiac marker enzymes, such as cTnI (cardiac troponin I), CPK (creatine phosphokinase), CK-MB (creatine kinase MB isoenzyme), LDH (lactate dehydrogenase), ALT (alanine aminotransferase) and AST (aspartate aminotransferase), from cardiac tissue to circulation, cell membrane rupture, hypoxia, and cardiac hypertrophy. Subsequently, they were treated twice within 24 h with bergenin at doses of 1 and 3 mg/kg via injection for 5 days to determine the cardioprotective response. The results indicated that bergenin (IC50 of 1 mg/kg) sharply restricted ST segment elevation induced by isoproterenol, Q wave, and ECG pattern, indicating that it has protective effects on the cell membrane since it prevents the extension of myocardial damage (induced by ISO) by strengthening the myocardial cell membrane and tissue architecture, and also normalizes marker enzymes [211].

6. Conclusions and Future Perspective

Because it is a secondary metabolite with immeasurable pharmacological potential and because it is distributed in many plant species (at least 112 species belonging to 34 families), bergenin has aroused the interest of researchers in the medical and biotechnological fields. Both its derivatives (natural and semisynthetic) and its extracts are well studied, with phytochemical confirmation of its highest concentration, and in none of the studies has it been observed to be cytotoxic to healthy cells. At least 17 activities were well studied, of which we can highlight the following: antimalarial, antileishmanial, trypanocidal, antiviral, antibacterial, anti-inflammatory, antioxidant, antinociceptive, antiarthritic, antiulcerogenic, antidiabetic, anticancer and hepatoprotective activities. However, it is emphasized that more studies should be carried out in order to further explore its pharmacological potential, especially the unraveling of the different mechanisms of action against infectious-contagious pathogens that are part of tropical and neglected infectious diseases and which have wide worldwide distribution such as malaria and leishmaniasis. For activities whose mechanisms of action are already well known, such as anti-inflammatory and antioxidant activities, there may be interest in the production of synthetic derivatives, with conducting of preclinical and clinical studies, since in preclinical studies in vitro and in vivo (in mice) with natural bergenin as well as its semisynthetic derivatives, it has been shown to be safe.

Author Contributions

Z.M.S., W.M.M., H.H.F.K., and G.C.d.M. conceived the main idea of this work. All authors designed and wrote most of this review’s topics. Z.M.S., M.N.Y., E.L.d.S., A.C.G.d.A., Y.O.C., E.V.C., F.M.A.d.S., and J.F.T. elaborated the figures of this review article. All authors corrected the manuscript and provided important contributions during the development of this work. All authors contributed to the article and approved the final submitted version. All authors have read and agreed to the published version of the manuscript.

Funding

This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES—Finance code 001) and by the Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM) (Pró-Estado Program-#002/2008, #007/2018, and #005/2019. We also would like to thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the productivity scholarships grants provided to W.M.M. (No. 309207/2020-7), to H.H.F.K. (No. 305942/2020-4), and to G.C.M. (No 315156/2021-0). The author H.H.F.K. also acknowledges FAPEAM for the PRODOC project (call 003/2022).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Okada, T.; Suzuki, T.; Hasobe, S.; Kisara, K. Studies on Bergenin (Report I). Antiulcerogenic activities of Bergenin. Folia Pharmacol. Jpn. 1973, 69, 369–378. [Google Scholar] [CrossRef]
  2. Bajracharja, G.B. Diversity, pharmacology and synthesis of bergenin and its derivatives: Potential materials for therapeutic usages. Sugar Wounds 2015, 101, 133–152. [Google Scholar] [CrossRef]
  3. Borges, L.P.; Amorim, V.A. Metabólitos secundários de plantas secondary plant metabolites. Rev. Agrotecnologia. Ipameri 2020, 11, 54–67. [Google Scholar]
  4. De Sá, B.M.; Estudo da Toxidade Não Clínica do Extrato Hidroetanolico das Cascas do Caule e de Endopleura uchi (Huber) Cuatrec. Dissertação de Mestrado, Programa de Pós-Graduação em Biodiversidade Tropical, Instituto de Pesquisas Cientificas Agropecuária do Amapá. 2014. Available online: http://repositorio.unifap.br:80/jspui/handle/123456789/484 (accessed on 9 August 2022).
  5. Marx, F.; Andrade, E.H.A.; Zoghbi, M.G.B.; Maia, J.G.S. Studies of edible Amazonian plants. Part 5: Chemical characterization of Amazonian Endopleura uchi fruits. Eur. Food Res. Technol. 2002, 214, 331–334. [Google Scholar] [CrossRef]
  6. Liang, J.; Li, Y.; Liu, X.; Huang, Y.; Shen, Y.; Wang, J.; Liu, Z.; Zhao, Y. In vivo and in vitro antimalarial activity of bergenin. Biomed. Rep. 2013, 1, 260–264. [Google Scholar] [CrossRef] [Green Version]
  7. Pu, H.-L.; Huang, X.; Zhao, J.-H.; Hong, A. Bergenin is the Antiarrhythmic Principle of Fluggea virosa. PubMed 2002, 68, 372–374. [Google Scholar] [CrossRef]
  8. Lee, Y.Y.; Jang, D.S.; Jin, J.L.; Yun-Choi, H.S. Anti-platelet aggregating and anti-oxidative activities of 11-O- (4′-O-methylgalloyl)-bergenin, a new compound isolated from Crassula cv. ‘Himaturi’. Planta Med. 2005, 71, 776–777. [Google Scholar] [CrossRef] [Green Version]
  9. Rajbhandari, M.; Lalk, M.; Mentel, R.; Lindequist, U. Antiviral Activity and Constituents of the Nepalese Medicinal Plant Astilbe rivularis. Rec. Nat. Prod. 2011, 5, 138–142. [Google Scholar]
  10. Gao, X.J.; Guo, M.Y.; Wang, T.C.; Cao, Y.G.; Zhang, N.S. Bergenin Plays an Anti-Inflammatory Role via the Modulation of MAPK and NF-κB Signaling Pathways in a Mouse Model of LPS-Induced Mastitis. Inflammation 2015, 38, 1142–1150. [Google Scholar] [CrossRef]
  11. Lu, S.; Zhang, G. Alkaloids from Gendarussa vulgaris Nees. Nat. Prod. Res. 2008, 22, 1610–1613. [Google Scholar] [CrossRef]
  12. Zhang, X.-H.; Zhou, T.; Xuan, L.-J. A dipeptide and two glycosides from Streptocaulon griffithii. J. Asian Nat. Prod. Res. 2008, 10, 891–896. [Google Scholar] [CrossRef]
  13. Su, Y.; Xu, J.-J.; Bi, J.-L.; Wang, Y.-H.; Hu, G.-W.; Yang, J.; Yin, G.-F.; Long, C.-L. Chemical constituents of Arisaema franchetianum tubers. J. Asian Nat. Prod. Res. 2013, 15, 71–77. [Google Scholar] [CrossRef] [PubMed]
  14. Pavithra, G.M.; Siddiqua, S.; Naik, A.S.; TR, P.K.; Vinayaka, K.S. Antioxidant and antimicrobial activity of flowers of Wendlandia thyrsoidea, Olea dioica, Lagerstroemia speciosa and Bombax malabaricum. J. Appl. Pharmac. Sci. 2013, 3, 114–120. [Google Scholar] [CrossRef]
  15. Gork, V.; Walter, N.S.; Chauhan, M.; Kaur, M.; Dhingra, N.; Bagai, U.; Kaur, S. Ethanol extract of Bergenia ciliata (Haw.) Sternb. (rhizome) impedes the propagation of the malaria parasite. J. Ethnopharmacol. 2021, 280, 114417. [Google Scholar] [CrossRef] [PubMed]
  16. Zhao, J.; Zeng, L.; Li, X.; Dong, X.; Yan, Y.; Cheng, Y.; Brachystemols, A. three new furan derivatives from Brachystemma calycinum. J. Asian Nat. Prod. Res. 2011, 13, 915–919. [Google Scholar] [CrossRef]
  17. Aiyar, S.N.; Jain, M.K.; Krishnamurti, M.; Seshadri, T.R. Chemical components of the roots of Connarus monocarpus. Phytochemistry 1964, 3, 335–339. [Google Scholar] [CrossRef]
  18. Zamarrud, A.I.; Hussain, H.; Ahmad, V.U.; Qaiser, M.; Amyn, A.; Mohammad, F.V. Two new antioxidant bergenin derivatives from the stem of Rivea hypocrateriformis. Fitoterapia 2011, 82, 722–725. [Google Scholar] [CrossRef]
  19. Venkateswarlu, K.; Satyalakshmi, G.; Suneel, K.; Reddy, T.S.; Raju, T.V.; Das, B.A. benzofuranoid and two clerodane diterpenoids from Pulicaria wightiana. Helv. Chim. Acta 2008, 91, 2081–2088. [Google Scholar] [CrossRef]
  20. Terracios Suculentas. Crassula ovata. Available online: https:terraciossuculentas.com.br (accessed on 26 June 2022).
  21. Zhang, S.; Wang, J.; Zhang, H. Chemical constituents of Tibetan medicinal herb Rhodiola kirilowii (Reg.) Reg. Zhongguo Zhong Yao Za Zhi 1991, 16, 483. [Google Scholar]
  22. Bharate, S.B.; Kumar, V.; Bharate, S.S.; Singh, B.; Singh, G.; Singh, A.; Gupta, M.; Singh, D.; Kumar, A.; Singh, S.; et al. Discovery and potential development of IIIM-160, a Bergenia ciliate-based anti-inflammatory and anti-arthritic botanical drug candidate. J. Integr. Med. 2019, 17, 192–204. [Google Scholar] [CrossRef]
  23. Flora e Fauna Web. Dipterocarpus grandflorus. Available online: https://www.nparks.gov.sg/florafaunaweb/flora/2/8/2857.Blanco. (accessed on 9 August 2022).
  24. Flora e Fauna Web. Dryobalanops aromatica C.F. Gaertn. Available online: https://www.nparks.gov.sg/florafaunaweb/flora/2/8/2862 (accessed on 9 August 2022).
  25. Ashton, P. Hopea utilis. IUCN Red listo f Treatened Species. Available online: https://iucnredlist.org/species/33023 (accessed on 18 June 2022).
  26. Flora e Fauna Web. Hopea sangal Korth. Available online: https://www.nparks.gov.sg/florafaunaweb/flora/2/9/2961 (accessed on 9 August 2022).
  27. Carruthers, W.R.; Hay, J.E.; Haynes, L.J. Isolation of bergenin from Shorea leprosula; identity of vakerin and bergenin. Chem. Ind. 1957, 1, 76–77. [Google Scholar]
  28. Mukherjee, H.; Ojha, D.; Bharitkar, Y.P.; Ghosh, S.; Mondal, S.; Kaity, S.; Dutta, S.; Samanta, A.; Chatterjee, T.K.; Chakrabarti, S.; et al. Evaluation of the wound healing activity of Shorea robusta, an Indian ethnomedicine, and its isolated constituent(s) in topical formulation. J. Ethnopharmacol. 2013, 149, 335–343. [Google Scholar] [CrossRef] [PubMed]
  29. Ito, T.; Tanaka, T.; Iinuma, M.; Iliya, I.; Nakaya, K.; Ali, Z.; Takahashi, Y.; Sawa, R.; Shirataki, Y.; Murata, J.; et al. New resveratrol oligomers in the stem bark of Vatica pauciflora. Tetrahedron 2003, 59, 5347–5363. [Google Scholar] [CrossRef]
  30. Royal Botanic Gardens. Vatica paucifora (Korth.) Blume. Available online: Https:Powo.science.kew.org/taxon (accessed on 22 June 2022).
  31. Ito, T.; Hara, Y.; Oyama, M.; Tanaka, T.; Murata, J.; Darnaedi, D.; Linuma, M. Occurrence of bergenin phenylpropanoates in Vatica bantamensis. Phytochem. Lett. 2012, 5, 743–746. [Google Scholar] [CrossRef]
  32. Seo, E.; Chai, H.; Constant, H.L.; Santisuk, T.; Reutrakul, V.; Beecher, C.W.W.; Farnsworth, N.R.; Cordell, G.A.; Pezzuto, J.M.; Kinghorn, D. Resveratrol tetramers from Vatica diospyroides. J. Org. Chem. 1999, 64, 6976–69783. [Google Scholar] [CrossRef]
  33. Song, X.; Chen, G.; Song, X.; Han, C.; Chen, S.; Weng, S. Study on the chemical constituents of leaves from Vatica mangachpoi Blanco. Linchan Huaxue Yu Gongye (Chem. Ind. Prod.) 2012, 32, 102–106. [Google Scholar]
  34. Mo, Z.; Chen, G.; Wang, J.; Wang, T.; Dai, C.; Yuan, Y. The extraction technology of bergenin fromleaf of Vatica mangachapoi Blanco. Shipin Keji (Food Sci. Technol.) 2012, 37, 207–209. [Google Scholar]
  35. Mishima, S.; Matsumoto, K.; Futamura, Y.; Araki, Y.; Ito, T.; Tanaka, T.; Iinuma, M.; Nozawa, Y.; Akao, Y. Antitumor effect of stilbenoids from Vateria indica against allografted sarcoma S-180 in animal model. J. Exp. Ther. Oncol. 2003, 3, 283–288. [Google Scholar] [CrossRef]
  36. Tangmouo, J.G.; Ho, R.; Matheeussen, A.; Lannang, A.M.; Komguem, B.B.M. Antimalarial activity of extract and norbergenina derivatives from the stem bark of Diospyros sanza-minika A. Chevalier (Ebenaceae). Phytother. Res. 2010, 24, 1676–1679. [Google Scholar] [CrossRef]
  37. Bouzeko, I.L.T.; Dongmo, F.L.M.; Ndontsa, B.L.; Ngansop, C.A.N.; Keumoe, R.; Bitchagno, G.T.M.; Jouda, J.B.; Mbouangouere, R.; Tchegnitegni, T.B.; Boyom, F.F.; et al. Chemical constituents of Mussaenda erythrophylla Schumach. & Thonn. (Rubiaceae) and their chemophenetic significance. Biochem. Syst. Ecol. 2021, 98, 1–6. [Google Scholar] [CrossRef]
  38. Olennikov, D.N.; Chekhirova, G.V. Galloylpicein and other phenolic compounds from Arctostaphylos uva-ursi. Chem. Nat. Prod. 2013, 49, 1–7. [Google Scholar] [CrossRef]
  39. Singh, S.V.; Manhas, A.; Kumar, Y.; Mishra, S.; Shanker, K.; Khan, F.; Srivastava, K.; Pal, A. Antimalarial activity and safety assessment of Flueggea virosa leaves and its major constituent with special emphasis on their mode of action. Biomed. Pharmacother. 2017, 89, 761–771. [Google Scholar] [CrossRef] [PubMed]
  40. Bulugahapitiya, V.P.; Munasinghe, M.M.A.B.; Hettihewa, L.M.; Kihara, N. Anti-cancer activity of Fluggea leucopyrus Willd (Katupila) against human ovarian carcinoma and characterization of active compounds. JSc EUSL 2020, 11, 12–26. [Google Scholar] [CrossRef]
  41. Basile, A.C.; Sertie, J.A.A.; Panizza, S.; Oshiro, T.T.; Azzolini, C.A. Pharmacological assay of Casearia sylvestris. I: Preventive anti-ulcer activity and toxicity of the leaf crude extract. J. Ethnopharmacol. 1990, 30, 185–197. [Google Scholar] [CrossRef]
  42. Aphale, S.; Pandita, S.; Raima, P.; Mishra, J.N.; Kaul-Ghanekar, R. Phytochemical Standardization of Panchavalkala: An Ayurvedic Formulation and Evaluation of its Anticancer Activity in Cervical Cancer Cell Lines. Pharmacogn. Mag. 2018, 14, 554–560. [Google Scholar]
  43. Thang, T.D.; Kuo, P.C.; Yu, C.S.; Shen, Y.C.; Hoa, L.T.M.; Thanh, T.V.; Kuo, Y.-H.K.; Yang, M.-L.; Wu, T.-S. Chemical constituents of the leaves of Glochidion obliquum and their bioactivity. Arch. Pharm. Res. 2011, 34, 383–389. [Google Scholar] [CrossRef]
  44. Takeda, Y.; Mima, C.; Masuda, T.; Hirata, E.; Takushi, A.; Otsuka, H. Glochidioboside, a glucoside of (7S,8R)-dihydrodehydrodiconiferyl alcohol from leaves of Glochidion obovatum. Phytochemistry 1998, 49, 2137–2139. [Google Scholar] [CrossRef]
  45. Sultana, T.; Mitra, A.K. das S. Evaluation of anti-cancer potential of Excoecaria agallocha (L.) leaf extract on human cervical cancer (SiHa) cell line and assessing the underlying mechanism of action. Future J. Pharm. Sci. 2022, 8, 1–18. [Google Scholar] [CrossRef]
  46. Takahashi, H.; Kosaka, M.; Watanabe, Y.; Nakade, K.; Fukuyama, Y. Synthesis and Neuroprotective Activity of Bergenin Derivatives with Antioxidant Activity. Bioorganic Med. Chem. 2003, 11, 1781–1788. [Google Scholar] [CrossRef]
  47. Sriset, Y.; Chatuphonprasert, W.; Jarkamjorn, K. In vitro antioxidant potential of Mallotus repandus (Willd.) Muell. Arg stem extract and its active constituent bergenin. Songklanakarin J. Sci. Technol. 2019, 43, 24–30. [Google Scholar]
  48. Riviere, C.; Hong, V.N.T.; Hong, Q.T.; Chataigne, G.; Hoai, N.N.; Dejaegher, B.; Tistaert, C.; Kim, T.N.T.; Heyden, Y.V.; Van, M.C.; et al. Mallotus species from Vietnamese mountainous areas: Phytochemistry and pharmacological activities. Phytochem. Ver. 2010, 9, 217–253. [Google Scholar] [CrossRef]
  49. Khan, H.; Amin, H.; Ullah, A.; Saba, S.; Rafique, J.; Khan, K.; Ahmad, N.; Badshah, S.L. Antioxidant and Antiplasmodial Activities of Bergenin and 11-O-Galloylbergenin Isolated from Mallotus philippensis. Oxidative Med. Cell. Longev. 2016, 1, 1–6. [Google Scholar] [CrossRef] [Green Version]
  50. Lalhelenmawia, H.; Chidambaran, K.; Brattacharjee, B.B.; Mandal, S.C. Antidiabetic Activity of Mallotus Roxburghianus Leaves in Diabetic Rats Induced by Streptozocin. Pharmacologyonline. 2007, 3, 244–254. [Google Scholar]
  51. Kabran, F.A.; Okpekon, T.A.; Roblot, F.; Seon-Meniel, B.; Leblanc, K.; Bories, C.; Champy, P.; Yolou, S.F.; Loiseau, P.M.; Djakouré, L.A.; et al. Bioactive phloroglucinols from Mallotus oppositifolius. Fitoterapia 2015, 107, 100–104. [Google Scholar] [CrossRef] [PubMed]
  52. Flowers of India. Chandada. Available online: http://www.flowersofindia.net/catalog/slides/Chandada.html (accessed on 9 August 2022).
  53. Tanaka, R.; Matsunaga, S. Triterpene dienols and other constituents from the bark of Phyllanthus flexuosus. Phytochemistry 1988, 27, 2273–2277. [Google Scholar] [CrossRef]
  54. Priya, O.S.; Viswanathan, M.B.G.; Balakrishna, K.; Venkatesan, M. Chemical constituents and in vitro antioxidant activity of Phyllanthus wightianus. Nat. Prod. Res. 2011, 25, 949–958. [Google Scholar] [CrossRef]
  55. Sanogo, R.; Vassallo, A.; Malafronte, N.; Imparato, S.; Russo, A.; Piaz, F.D. New phenolic glycosides from Securinega virosa and their antioxidant activity. Nat. Prod. Commun. 2009, 4, 1645–1650. [Google Scholar] [CrossRef] [Green Version]
  56. Schutz, B.; Orjala, J.; Sticher, O.; Rali, T. Dammarane triterpenes from the leaves of Secur. Melanthesoides. J. Nat. Prod. 1998, 61, 96–98. [Google Scholar] [CrossRef]
  57. Govaerts, R.; Frodin, D.G.; Radcliffe-Smith, A. World Checklist and Bibliography of Euphorbiaceae (and Pandaceae). Board Trust. R. Bot. Gard. 2000, 4, 1–1622. [Google Scholar]
  58. Peltophorum inerme. Available online: https://dgnurseries.com/product/peltophorum-inerme-2/ (accessed on 9 August 2022).
  59. Herabario Virtual Austral Americano Peltophorum inerme. Available online: https://herbariovaa.org/taxa/index.php?tid=44282 (accessed on 9 August 2022).
  60. Joshi, B.S.; Kamat, V.N. Identity of Peltophorum with bergenin. Nat. Chaften 1969, 56, 89–90. [Google Scholar]
  61. Peltophorum pterocarpum: Yellow Poinciana. Available online: https://edis.ifas.ufl.edu/publication/ST434 (accessed on 9 August 2022).
  62. Paulino, C.A.; Carvalho, C.B.; Almeida, B.C.; Chaves, M.H.; Almeida, F.R.C.; Brito, S.M.R.C. The stem bark extracts of Cenostigma macrophyllum attenuates tactile allodynia in streptozotocin-induced diabetic rats. Pharmcae. Biol. 2013, 51, 1243–1248. [Google Scholar] [CrossRef] [PubMed]
  63. Sridhar, C.; Krishnaraju, V.; Subbaraju, V. Antiinflammatory constituents of Teramnus labialis. Indian J. Pharm. Sci. 2006, 68, 111–114. [Google Scholar] [CrossRef] [Green Version]
  64. Kim, M.H.; Ha, S.Y.; Oh, M.H.; Kim, H.H.; Kim, S.R.; Lee, M.W. Anti-oxidative and anti-proliferative activity on human prostate cancer cells lines of the phenolic compounds from Corylopsis coreana Uyeki. Molecules 2013, 18, 4876–4886. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Hattori, S. Corylopsin, a crystalline constituent of the bark of Corylopsis spicata. Acta Phytochim. (Jpn) 1929, 4, 327–341. [Google Scholar]
  66. Jachak, S.M.; Gautam, R.; Selvam, C.; Madhan, H.; Srivastava, A.; Khan, T. Anti-inflammatory, cyclooxygenase inhibitory and antioxidant activities of standardized extracts of Tridax procumbens L. Fitoterapia 2011, 82, 173–177. [Google Scholar] [CrossRef] [PubMed]
  67. Da Silva, S.L.; De Oliveira, V.G.; Yano, T.; Nunomoura, R.C.S. Antimicrobial activity of bergenin from Endopleura uchi (Huber) Cuatrec. Acta Amaz. 2008, 39, 187–192. [Google Scholar] [CrossRef] [Green Version]
  68. Silva, R.; Oliveira, M.G.M.; Prado, T.C.; Souza, V.C. Humiriaceae in Flora of Brasil. Available online: http://reflora.jbrj.gov.br/reflora/floradobrasil/FB7974 (accessed on 20 August 2022).
  69. Nwosu, C.O.; Maduka, H.C.C.; Mahe, A.; Adamu, M.; Nwagbara, N.D. Reduction of effects on the haematology of rats infected with Trypanosoma congolense by ethanolic extrat of Sacoglottis gabonensis stem bark. Niger. J. Bot. 2010, 23, 41–54. [Google Scholar]
  70. Ozouga. Sacoglottis gabunensis. Available online: Https:Tropicaltimber.inf/pt-br/species (accessed on 20 June 2022).
  71. Patel, D.K.; Patel, K.; Kumar, R.; Gadewar, M.; Tahilyani, V. Pharmacological and analytical aspects of bergenin: A concise report. Asian Pac. J. Trop. Biomed. 2012, 1, 163–167. [Google Scholar] [CrossRef]
  72. Srinivasan, R.; Chandrasekar, M.J.N.; Nanjan, M.J.; Suresh, B. Antioxidant activity of Caesalpinia digyna root. J. Ethnopharmacol. 2007, 113, 284–291. [Google Scholar] [CrossRef]
  73. De Oliveira, C.M.S. Potencial Farmacológico da Bergenina para Controle da dor Inflamatória: Um Estudo Pré-Clínico. Dissertação de Mestrado. Curso de Pós-Graduação em Farmácia. Universidade da Bahia. 2010. Available online: https://repositorio.ufba.br/bitstream/ri/22567/1 (accessed on 20 June 2022).
  74. African plant Pentaclethra macrophylla. Available online: Https:En.m.wikipedia.org/wiki/Pentaclethramacrophylla (accessed on 26 June 2022).
  75. Gabriel, N.; Folefoc, J.P.B.; Zacharias, T.F.; Bernard, B. Constituents from the roots of Pentaclethra macrophylla. Biochem. Syst. Ecol. 2005, 33, 1280–1282. [Google Scholar]
  76. Li, R.W.; Leach, D.N.; Myers, S.P.; Lin, G.D.; Leach, G.J.; Waterman, P.G. A new anti-inflammatory glucoside from Ficus racemosa L. Planta Med. 2004, 70, 421–426. [Google Scholar] [PubMed]
  77. Newell, A.M.B.; Yousef, G.G.; Lila, M.A.; Ramirez-Mares, M.V.; Mejia, E.G.G. Comparative in vitro bioactivities of tea extracts from six species of Ardisia and their effect on growth inhibition of HepG2 cells. J. Ethnopharmacol. 2010, 130, 536–544. [Google Scholar] [CrossRef] [PubMed]
  78. Sumino, M.; Sekine, T.; Ruangrungsi, N.; Igarashi, K.; Ikegami, F. Ardisiphenols and other antioxidant principles from the fruits of Ardisia colorata. Chem. Pharm. Bull 2002, 50, 1484–1487. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Jain, M.K.; Gupta, K. Isolation of bergenin from Saxifraga ligulata Wall. J. Indian J. Chem. Soc. 1962, 39, 559–560. [Google Scholar]
  80. Kobayashi, H.; Mejia, E. The genus Ardisia: A novel source of health-promoting compounds and phytopharmaceuticals. J. Ethnopharmacol. 2005, 96, 347–354. [Google Scholar] [CrossRef]
  81. Mu, L.M.; Feng, J.Q.; Liu, P. A new bergenin derivative from the rhizome of Ardisia gigantifolia. PMID 2013, 27, 1242–1245. [Google Scholar] [CrossRef]
  82. Liu, B.; Wang, M.; Wang, X. Phytochemical analysis and antibacterial activity of methanolic extract of Bergenia purpurascens against common respiratory infection causing bacterial species in vitro and in neonatal rats. Microb. Pathog. 2018, 117, 315–319. [Google Scholar] [CrossRef]
  83. Chen, H.; Chen, T.; Li, J.X.; Xu, Q. Study on constituents in rhizome of Astilbe chinensis. Zhongguo Zhong Yao Za Zhi 2004, 29, 652–654. [Google Scholar]
  84. Mundo Ecologia. Tudo Sobre a Flor Astilbe; Características, Nome Científico e Fotos. Available online: Https:Mundoecologia.com.br (accessed on 22 June 2022).
  85. Rajbhandar, M.; Mentel, R.; Jha, P.K.; Chaudhary, R.P.; Bhattarai, S.; Gewali, M.B.; Karmacharya, N.; Hipper, M.; Lindequist, U. Antiviral activity of some plants used in Nepalese traditional medicine. Evid Based Complement Altern. Med. 2009, 6, 517–522. [Google Scholar] [CrossRef] [Green Version]
  86. Kimura, Y.; Sumiyoshi, M.; Sakanaka, M. Effects of Astilbe thunbergii rhizomes on wound healing: Part 1. Isolation of promotional effectors from Astilbe thunbergii rhizomes on burn wound healing. J. Ethnopharmacol. 2007, 109, 72–77. [Google Scholar] [CrossRef]
  87. Chauhan, S.K.; Singh, B.; Agrawal, S. Simultaneous determination of bergenin and gallic acid in Bergenia ligulata wall by high-performance thin-layer chromatography. J. AOAC Int. 2000, 83, 1480–1483. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Zuo, G.Y.; Li, Z.Q.; Chen, L.R.; Xu, X.J. In vitro anti-HCV activities of Saxifraga melanocentra and its related polyphenolic compounds. Antivir. Chem. Chemother. 2005, 16, 393–398. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Taneyama, M.; Yoshida, S.; Kobayashi, M.; Hasegawa, M. Isolation of norbergenin from Saxifraga stolonifera. Phytochemistry 1983, 22, 1053–1054. [Google Scholar] [CrossRef]
  90. Hoffmann, B.K.; Lotter, H.; Seligmann, O.; Wagner, H. Antihepatotoxic C-glycosylflavones from the leaves of Allophyllus edulis var. edulis and gracilis. Planta Med. 1992, 58, 544–548. [Google Scholar] [CrossRef] [PubMed]
  91. San, H.T.; Boonsnongcheep, P.; Putalun, W.; Sritularak, B.; Likhitwitayawuid, K. Bergenin from Cissus javana DC. (Vitaceae) root extractenhances glucose uptake by rat L6 myotubes. Trop. J. Pharm. Res. 2020, 19, 1081–1086. [Google Scholar] [CrossRef]
  92. Caldas, C.S.; Simone, C.A.; Pereira, M.A.; Malta, V.R.S.; Carvalho, R.L.P.; Da Silva, T.B.C.; Sant´ana, A.E.G.; Conserva, L.M. Bergenin monohydrate, a constituent of Humiria balsamifera, at 120K. Acta Crystallogr. 2002, 58, 609–611. [Google Scholar] [CrossRef]
  93. Rastogi, S.; Rawat, A.K.S. A comprehensive review on bergenin, a potencial hepatoprotective and antioxidative phytoconstituent. Herba Pol. 2008, 54, 66–79. [Google Scholar]
  94. Lu, X.; Wang, J. Advances in the study of Bergenia plants. Zhong Yao Cai 2003, 26, 58–60. [Google Scholar]
  95. Franz, G.; Grün, M. Chemistry, occurrence and biosynthesis of C-glycosyl compounds in plants. Planta Med. 1983, 47, 131–140. [Google Scholar] [CrossRef] [Green Version]
  96. Taneyama, M.; Yoshida, S. Studies on C-glycosides in higher plants. Bot. Mag. Tokyo 1979, 92, 69–73. [Google Scholar] [CrossRef]
  97. Rai, M.; Rai, A.; Mori, T.; Nakabayashi, R.; Yamamoto, M.; Nakamura, M.; Suzuki, H.; Saito, K.; Yamazaki, M. Gene-Metabolite Network Analysis Revealed Tissue-Specific Accumulation of Therapeutic Metabolites in Mallotus japonicus. Int. J. Mol. Sci. 2021, 22, 8835. [Google Scholar] [CrossRef] [PubMed]
  98. Saijo, R.; Nonaka, G.I.; Nishioka, I. Gallic acid esters of bergenin and norbergenin from Mallotus japonicus. Phytochemistry 1990, 29, 267–270. [Google Scholar] [CrossRef]
  99. Feng, W.S.; Li, Z.; Zheng, X.K.; Li, Y.J.; Su, F.Y.; Zhang, Y.L. Chemical constituents of Saxifraga stolonifera (L.). Meeb. Yao Xue Xue Bao (Acta Pharm. Sin.) 2010, 45, 742–746. [Google Scholar]
  100. Wang, G.C.; Liang, J.P.; Wang, Y.; Li, Q.; Ye, W.C. Chemical constituents from Flueggea virosa. Chin. J. Nat. Med. 2008, 6, 251–253. [Google Scholar] [CrossRef]
  101. Jia, Z.; Mitsunaga, K.; Koike, K.; Ohmoto, T. New bergenin derivatives from Ardisia crenata. Nat. Med. 1995, 49, 187–189. [Google Scholar]
  102. Tangmouo, J.G.; Ho, R.; Lannang, A.M.; Konguem, J.; Lontsi, A.T.; Lontsi, D.; Hostettmann, K. Norbergenin derivatives from the stem bark of Diospyros sanza-minika (Ebenaceae) and their radical scavenging activity. Phytochem. Lett. 2009, 2, 192–195. [Google Scholar] [CrossRef]
  103. Kaur, R.; Kaur, S. Evaluation of in vitro and in vivo antileishmanial potential of bergenin rich Bergenia ligulata (Wall.) Engl. root extract against visceral leishmaniasis in inbred BALB/c mice through immunomodulation. J. Tradit. Complement. Med. 2018, 8, 251–260. [Google Scholar] [CrossRef] [PubMed]
  104. Almeida, L.C.; Santos, E.; Santana, C.S.; Araújo, J.S.C.; Taranto, A.G.; Leite, F.H.A. Revisão de literatura sobre o mecanismo de ação da Artemisinina e dos endoperóxidos antimaláricos—parte II. Rev. Textura 2016, 9, 15–24. [Google Scholar] [CrossRef]
  105. Uddin, G.; Sadat, A.; Siddiqui, B. Comparative Antioxidant and Antiplasmodial Activities of 11-O-Galloylbergenin and Bergenin Isolated from Bergenia ligulata. Trop Biomed. 2014, 31, 143–148. [Google Scholar] [PubMed]
  106. Picote, S.; Bienvenu, A. Plasmodium. In Encyclopedia of Infection and Immunity; Elsevier: Amsterdam, The Netherlands, 2022; Volume 2, pp. 655–665. [Google Scholar] [CrossRef]
  107. Da Silva, T.B.C.; Alves, V.L.; Mendonça, L.V.H.; Conserva, L.M.; Da Rocha, E.M.M.; Lemos, R.P.L. Chemical Constituents and Preliminary Antimalarial Activity of Humiria balsamifera. Pharm. Biol. 2004, 42, 94–97. [Google Scholar] [CrossRef] [Green Version]
  108. Sadat, A.; Uddin, G.; Alam, M.; Ahmad, A.; Siddiqui, S. Structure activity relationship of bergenin, p-hydroxybenzoyl bergenin, 11-O-galloylbergenin as potent antioxidant and urease inhibitor isolated from Bergenia ligulata. Nat. Prod. Res. 2015, 29, 2291–2294. [Google Scholar] [CrossRef] [PubMed]
  109. Yang, S.; Yu, Z.; Wang, L.; Yuan, T.; Wang, X.; Zhang, X.; Wang, J.; Lv, Y.; Du, G. The natural product bergenin ameliorates lipopolysaccharide-induced acute lung injury by inhibiting NF-kappaB activation. J. Ethnopharmacol. 2017, 200, 147–155. [Google Scholar] [CrossRef] [PubMed]
  110. Melos, J.L.R.; Echevarria, A. Sistemas Enzimáticos de Tripanossomatídeos como Potenciais Alvos Quimioterápicos. Rev. Virtual Quim 2012, 4, 374–392. [Google Scholar]
  111. Nyunt, K.S.; Elkhateeb, A.; Tosa, Y.; Nabata, K.; Katakura, K.; Matsuura, H. Isolation of Antitrypanosomal Compounds from Vitis repens, a Medicinal Plant of Myanmar. Nat. Prod. Commun. 2012, 7, 609–610. [Google Scholar] [CrossRef] [Green Version]
  112. Tumová, L.; Hendrychová, H.; Vokurková, D. Immunostimulant Activity of Bergenia Extracts. Pharmacogn. Mag. 2017, 14, 328–332. [Google Scholar] [CrossRef]
  113. Horna, J.C.C. Biological Activities and Chemical Content of Glycyrrhiza species. Ph.D. Thesis, Faculty of Pharmacy, Hradec Kralove, Charles University, Staré MěSto, Czech Republic, 2010. [Google Scholar]
  114. Sastry, B.S.; Vykuntam, U.; Rao, E. Chemical examination of the aerial parts of Astilbe rivularis. Indian Drugs 1987, 24, 354–359. [Google Scholar]
  115. Hegde, V.R.; Pu, H.; Patel, M.; Das, P.R.; Butkiewicz, N.; Arreaza, G.; Gullo, V.P.; Chan, T.M. Two antiviral compounds from the plant Stylogne cauliflora as inhibitors of HCV NS3 protease. Bioorganic Med. Chem. Lett. 2003, 13, 2925–2928. [Google Scholar] [CrossRef]
  116. Piacente, S.; Pizza, C.; De Tommasi, N.; Mahmood, N. Constituents of Ardisia japonica and Their in Vitro Anti-HIV Activity. J. Nat. Prod. 1996, 59, 565–569. [Google Scholar] [CrossRef]
  117. Bessong, P.O.; Obi, C.L.; Andreola, M.L.; Rojas, L.B.; Pouysegu, L.; Igumbor, E.; Meyer, J.J.; Quideau, S.; Litvak, S. Evaluation of selected South African medicinal plants for inhibitory properties against human immunodeficiency virus type 1 reverse transcriptase and integrase. J. Ethnopharmacol. 2005, 99, 83–91. [Google Scholar] [CrossRef]
  118. Seo, J.-H.; Kim, J.-E.; Shim, J.-H.; Yoon, G.; Bang, M.-A.; Bae, C.-S.; Lee, K.-J.; Park, D.-H.; Cho, S.-S. HPLC Analysis, Optimization of Extraction Conditions and Biological Evaluation of Corylopsis coreana Uyeki Flos. Molecules 2016, 21, 94. [Google Scholar] [CrossRef] [PubMed]
  119. Rolta, R.; Goyal, M.; Sharma, D.; Bharaj, D.; Salaria, D.; Upadhyay, N.K.; Lal, U.R.; Dev, K.; Sourirajan, A. Bioassay Guided Fractionation of Phytocompounds from Bergenia ligulata: A synergistic approach to treat drug resistant bacterial and fungal pathogens. Pharmacol. Res. Mod. Chin. Med. 2022, 3, 1–11. [Google Scholar] [CrossRef]
  120. Adhikary, P.; Roshan, K.C.; Kayastha, D.; Thapa, D.; Shrestha, R.; Shrestha, T.M.; Gyawali, R. In Vitro Evaluation of Antimicrobial and Cytotoxic Potential of Dry Rhizome Extract of Astilbe Rivulari. Int. J. Pharmacogn. Phytochem. Res. 2012, 4, 122–126. [Google Scholar]
  121. Abbas, T.; Bhatti, A.A.; Saeed, A.; Tasleem, F.; Azhar, I.; Mehmood, Z.A. In vitro antibacterial activity of copper pod/yellow flame tree or peelagulmohar (Peltophorum roxburghii). Int. J. Curr. Res. 2015, 7, 14634–14639. [Google Scholar]
  122. Neto, O.C.S.; Teodoro, M.T.F.; Do Nascimento, B.O.; Cardoso, K.V.; Silva, E.O.; David, J.M.; David, J.P. Bergenin of Peltophorum dubium (Fabaceae) Roots and Its Bioactive Semi-Synthetic Derivatives. J. Braz. Chem. Soc. 2020, 31, 2644–2650. [Google Scholar] [CrossRef]
  123. Nyemb, J.N.; Djankou, M.T.; Talla, E.; Tchinda, A.T.; Ngoudjou, D.T.; Iqbai, J.; Mbafor, J.T. Antimicrobial, α-Glucosidase and Alkaline Phosphatase Inhibitory Activities of Bergenin, The Major Constituent of Cissus populnea Roots. Med. Chem. 2018, 8, 426–430. [Google Scholar] [CrossRef]
  124. Chauke, A.M.; Shai, L.J.; Mphahlele, P.M.; Mogale, M.A. Radical scavenging activity of selected medicinal plants from limpopo province of south Africa. Afr. J. Tradit. Complement. Altern. Med. 2012, 9, 426–430. [Google Scholar] [CrossRef] [Green Version]
  125. Raj, M.K.; Duraipandiyan, V.; Agustin, P.; Ignacimuthu, S. Antimicrobial activity of bergenin isolated from Peltophorum pterocarpum DC. Flowers. Asian Pac. J. Trop. Biomed. 2012, 1, 901–904. [Google Scholar] [CrossRef]
  126. Shah, M.R.; Arfan, M.; Amin, H.; Hussain, Z.; Qadir, M.I.; Choudhary, M.I.; VanDerveer, D.; Mesaik, M.A.; Soomro, S.; Jabeen, A.; et al. Synthesis of new bergenin derivatives as potent inhibitors of inflammatory mediators NO and TNF-α. Bioorganic Med. Chem. Lett. 2012, 22, 2744–2747. [Google Scholar] [CrossRef]
  127. De Freitas, F.A.; Araújo, R.C.; Soares, E.R.; Nunomura, R.C.S.; Da Silva, F.M.A.; Da Silva, S.R.S.; De Souza, A.Q.L.; De Souza, A.D.L.; Franco-Montalbán, F.; Acho, L.D.R.; et al. Biological evaluation and quantitative analysis of antioxidante compounds in pulps of the Amazonian fruits bacuri (Platonia insignis Mart.), ing_a (Inga edulis Mart.), and uchi (Sacoglottis uchi Huber) by UHPLC-ESI-MS/MS. J. Food Biochem. 2018, 42, 1–10. [Google Scholar] [CrossRef]
  128. Kumar, S.; Sharma, C.; Kaushik, S.R.; Kulshreshtha, A.; Chaturvedi, S.; Nanda, R.K.; Bhaskar, A.; Chattopadhyay, G.D.; Das, G.; Dwivwdi, V.P. The phytochemical bergenin as an adjunct immunotherapy for tuberculosis in mice. J. Biol. Chem. 2019, 294, 8555–8563. [Google Scholar] [CrossRef]
  129. Li, G.; Fang, Y.; Ma, Y.; Dawa, Y.; Wang, Q.; Gan, J.; Dang, J. Screening and Isolation of Potential Anti-Inflammatory Compounds from Saxifraga atrata via Affinity Ultrafiltration-HPLC and Multi-Target Molecular Docking Analyses. Nutrients 2022, 14, 2405. [Google Scholar] [CrossRef]
  130. Dias, E.d.J.S.; Filho, A.J.C.; Carneiro, F.J.C.; Da Rocha, C.Q.; Da Silva, L.C.N.; Santos, J.C.B.; Barros, T.F.; Santos, D.M. Antimicrobial Activity of Extracts from the Humiria balsamifera (Aubl). Plants 2021, 10, 1479. [Google Scholar] [CrossRef]
  131. Nunomura, R.C.S.; Oliveira, V.G.; Da Silva, S.L.; Nunomura, S.M. Characterization of Bergenin in Endopleura uchi Bark and its Anti-Inflammatory Activity. Braz. Chem. Soc. 2009, 20, 1060–1064. [Google Scholar] [CrossRef] [Green Version]
  132. De Oliveira, V.G.; Nunumura, R.C.S.; Nunumura, S.M. Estudo fitoquímico e de atividade biológica de Endopleura uchi. Universidade Federal do Amazonas—Instituto de Pesquisas da Amazonas. Química de Produtos Naturais. Available online: http://www.sbpcnet.org.br/livro/61ra/resumos/resumos/6902.htm (accessed on 5 September 2022).
  133. Larsen, A.K.; Skladanowski, A.; Bojanowski, K. The roles of DNA topoisomerase II during the cell cycle, Prog. Cell Cycle Res. 1996, 2, 229–239. [Google Scholar]
  134. Ye, X.; Ning, H. Bergenin attenuates TNF-α-induced oxidative stress and inflammation in HaCaT cells by activating Nrf2 pathway and inhibiting NF-κB pathway. Trop. J. Pharm. Res. 2022, 21, 1209–1213. [Google Scholar] [CrossRef]
  135. Zhou, B.X.; Wu, B.; Chen, M.; Chen, C.; Gao, Y.; Li, D.; Huang, D.; Chen, Z.; Zhao, X.; Huang, Q.; et al. Bergenin-activated SIRT1 inhibits TNF-α-induced proinflammatory response by blocking the NF-κB signaling pathway. Pulm. Pharmacol. Ther. 2020, 62, 101921. [Google Scholar]
  136. Jung, J.; Lim, E.; Kim, S.; Jung, M.; Oh, S. Practical Synthesis and Biological Evaluation of Bergenin Analogs. Chem. Biol. Drug Des. 2011, 109, 2270–2277. [Google Scholar] [CrossRef]
  137. De Oliveira, G.A.L.; De la Lastra, C.A.; Rosillo, M.A.; Martinez, M.L.C.; Sánchez-Hidalgo, M.; Medeiros, J.V.R.; Villegas, I. Preventive effect of bergenin against the development of TNBS-induced acute colitis in rats is associated with inflammatory mediators inhibition and NLRP3/ASC inflammasome signaling pathways. Chem. Biol. Interact. 2019, 297, 25–33. [Google Scholar] [CrossRef]
  138. Liu, T.; Zhang, L.; Joo, D.; Sun, S. NF-kB signaling in inflammation. Signal Transduct. Snd Target. Ther. 2017, 2, 1–9. [Google Scholar]
  139. Wang, K.; Li, Y.; Lv, Q.; Li, X.; Dai, Y.; Wei, Z. Bergenin, Acting as an Agonist of PPARγ, Ameliorates Experimental Colitis in Mice through Improving Expression of SIRT1, and Therefore Inhibiting NF-κB-Mediated Macrophage Activation. Front. Pharm. 2018, 8, 981. [Google Scholar] [CrossRef] [Green Version]
  140. Glezer, I.; Marcourakis, T.; Avella, M.; Gorenstein, C.; Scavone, C. O factor de transcricao NF-kapaB nos mecanismos moleculares de acção de psicofármacos. Rev Braz. J. Psychiatry 2000, 22, 26–30. [Google Scholar] [CrossRef] [Green Version]
  141. Tang, Q.; Wang, Q.; Sun, Z.; Kang, S.; Fan, Y.; Hao, Z. Bergenin Monohydrate Attenuates Inflammatory Response via MAPK and NF-κB Pathways Against Klebsiella pneumonia Infection. Front. Pharmacol. 2021, 12, 651–664. [Google Scholar] [CrossRef]
  142. Dutra, R.C.; Tavares, C.Z.; Ferraz, S.O.; Sousa, O.V.; Pimenta, D.S. Investigação das atividades analgésica e anti-inflamatória do extrato metanolico dos rizomas de Echinodorus grandiflorus. Ver. Bras. Farm. 2006, 16, 469–474. [Google Scholar] [CrossRef]
  143. Souza, M.K.J.; Soares, G.L.; Guilhon-Simplicio, F.; Perez, A.C.; Moura, C.C.V. Pharmacological evaluation of the antinociceptive and antiinflammatory activity of the species Endopleura Uchi. Enciclopedia Biosf. 2021, 18, 1–12. [Google Scholar] [CrossRef]
  144. Borges, J.C.M. Acetilbergenina: Obtenção e Avaliação das Atividades Antinociceptiva e Anti-Inflamatória. Dissertação de Mestrado. Programa de Pós-Graduação em Ciências Farmacêuticas. Instituto de Ciências da saúde. Universidade Federal do Pará. 2010. Available online: http://repositorio.ufpa.br:8080/jspui/handle/2011/5642 (accessed on 10 September 2022).
  145. Cunha, T.M.; Verri-Jr, W.A.; Silva, J.S.; Poole, S.; Cunha, F.Q.; Ferreira, S.H. A cascade of cytokines mediates mechanical inflamatory hypemociception in mice. Proc. Natl. Acad. Sci. USA 2005, 102, 1755–1760. [Google Scholar] [CrossRef] [Green Version]
  146. Verri-Jr, W.A.; Cunha, T.M.; Parada, C.A.; Poole, S.; Cunha, F.Q.; Ferreira, S.H. Hypemociceptive role of cytokines and chemokines: Targets for analgesic drug development? Pharmacol. Ther. 2006, 112, 116–138. [Google Scholar] [CrossRef]
  147. Ren, X.; Ma, S.; Wang, J.; Tian, S.; Fu, X.; Liu, X.; Li, Z.; Zhao, B.; Wang, X. Comparative effects of dexamethasone and bergenin on chronic bronchitis and their anti-inflammatory mechanisms based on NMR metabolomics. Mol. BioSystems 2016, 12, 1938–1947. [Google Scholar] [CrossRef]
  148. Sartori, T. Influência dos Aminoácidos de Cadeia Ramificada Sobre Aspectos Imunoregulatórios das Células Tronco Mesenquimais. Tese de Doutorado do Programa de Pós-Graduação em Farmácia. Universidade de São Paulo. 2020. Available online: https://www.teses.usp.br/teses/disponiveis/9/9142/tde-29062021-174755/pt-br.php (accessed on 25 September 2022). [CrossRef]
  149. Villareal, C.F.; Santos, D.S.; Lauria, P.S.S.; Gama, K.B.; Espírito-Santo, R.F.; Juiz, P.J.L.; Alves, C.Q.; David, J.M.; Soares, M.B.P. Bergenin Reduces Experimental Painful Diabetic Neuropathy by Restoring Redox and Immune Homeostasis in the Nervous System. In. J. Mol. Sci 2020, 21, 4850. [Google Scholar] [CrossRef]
  150. Rajput, S.A.; Mirza, M.R.; Choudhary, M.I. Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells. PLoS ONE 2020, 12, e0241349. [Google Scholar] [CrossRef]
  151. Arfan, M.; Amin, H.; Khan, N.; Khan, I.; Saeed, M.; Khan, M.A.; Rehman, F.U. Analgesic and anti-inflammatory activities of 11-O-galloylbergenin. Ethnopharmacol. Commun. 2010, 131, 502–504. [Google Scholar] [CrossRef]
  152. Borges, C.M.J.; Aguiar, R.W.S.; Filho, H.S.R.; Guilhom, G.S.P. Anti-inflammatory and non ulcerogenic activities of acetylbergenin. Afr. J. Pharm. Pharmacol. 2017, 11, 402–410. [Google Scholar]
  153. Huang, D.J.; Ou, B.X.; Prior, R.L. The chemistry behind antioxidant capacity assays. J. Agrick. Food Chem. 2005, 53, 1841–1856. [Google Scholar] [CrossRef]
  154. Htwe, M.M.; Kyaw, Z.T.A.; Ngwe, H. A Study on Antioxidant Activity of Bergenin and its Derivative from the Bark of Peltophorum pterocarpum (DC.) K. Heyne (Pan-mèzali). 3rd Myanmar Korea Conf. Res. J. 2020, 3, 1667–1674. [Google Scholar]
  155. Subramanian, R.; Subbramaniyan, P.; Raj, V. Isolation of bergenin from Peltophorum pterocarpum flowers and its bioactivity. J. Basic Appl. Sci. 2015, 4, 256–261. [Google Scholar] [CrossRef] [Green Version]
  156. Hendrychova, H.; Martins, J.; Tumova, L.; Kcevar-Glavac, N. Bergenin Content and Free Radical Scavenging Activity of Bergenia Extracts. Nat. Prod. Commun. 2014, 10, 1273–1275. [Google Scholar] [CrossRef] [Green Version]
  157. Ravikanth, K.; Mehra, S.; Ganguly, B.; Sapra, S. Bergenin: Isolation from aqueous extract of Bergenia ciliata, antioxidant activity and in silico studies. Innov. Pharm. Pharm. 2020, 8, 10–14. [Google Scholar]
  158. Tacon, L.A.; Freitas, L.A.P. Box-Behnken design to study the bergenin content and antioxidant activity of Endopleura uchi bark extracts obtained by dynamic maceration. Rev. Bras. De Farmacogn. 2012, 23, 65–71. [Google Scholar] [CrossRef] [Green Version]
  159. Garcia, E.J.; Oldoni, T.L.C.; De Alencar, S.M.; Reis, A.; Loguercio, A.D.; Grande, R.H.M. Antioxidant activity by DPPY assay of potencial solution to be applied on bleached teeth. Braz. Dent. J. 2012, 23, 22–27. [Google Scholar] [CrossRef]
  160. Kinzler, K.W.; Vogelstein, B. The GLI gene encodes a nuclear protein, which binds specific sequences in the human genome. Mol. Cell Biol. 1990, 10, 634–642. [Google Scholar] [CrossRef]
  161. Sriset, Y.; Chatuphonprasert, W.; Jarukamjorn, K. Bergenin Attenuates Sodium Selenite-Induced Hepatotoxicity via Improvement of Hepatic Oxidant-Antioxidant Balance in HepG2 Cells and ICR Mice. J. Biol. Act. Prod. Nat. 2021, 11, 97–115. [Google Scholar] [CrossRef]
  162. Akak, C.M.; Nkengfack, A.E.; Tu, P. Norbergenin Derivatives from Diospyros crassiflora (Ebenaceae). Nat. Prod. Commun. 2013, 8, 1575–1578. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  163. Qi, Q.; Dong, Z.; Sun, Y.; Li, S.; Zhao, Z. Protective Effect of Bergenin against Cyclophosphamide-Induced Immunosuppression by Immunomodulatory Effect and Antioxidation in Balb/c Mice. Molecules 2018, 23, 2668. [Google Scholar] [CrossRef] [Green Version]
  164. Lima, G.P.C.; Superóxido Dismutase (SOD). Universidade Estadual Paulista: Laboratório de Química e Bioquímica Vegetal—LQBV 2017, 1–3. Available online: https://www.ibb.unesp.br (accessed on 1 October 2022).
  165. Yun, J.; Lee, Y.; Yun, K.; Oh, S. Bergenin decreases the morphine-induced physical dependence via antioxidative activity in mice. Arch. Pharm. Res. 2015, 38, 1248–1254. [Google Scholar] [CrossRef] [PubMed]
  166. Maduka, H.C.C.; Okoye, Z.S.C. The effect of Sacoglottis gabonensis stem bark extract, a Nigerian alcoholic beverage additive on the natural antioxidant defences during 2,4-dinitrophenyl hydrazine-induced membrane peroxidation in vivo. Vasc. Pharmmacology 2002, 39, 21–31. [Google Scholar] [CrossRef]
  167. Maduka, H.C.C.; Okoye, Z.S.C. Bergenin, an alcoholic beverage additive from Sacoglottis gabonensis as an antioxidant protectors of mammalian erythroytes against lysis by peroxylradicals. J. Med. Sci. 2000, 9, 88–92. [Google Scholar]
  168. Muniz, M.P.; Nunomura, S.M.; Lima, E.S.; De Almeida, P.D.O.; Nunomura, C.S. Quantification of bergenin, antioxidant activity and nitric oxide inhibition from bark, leaf and twig of Endopleura uchi. Quim. Nova 2020, 43, 413–418. [Google Scholar] [CrossRef]
  169. Tameye, N.S.J.; Akak, C.M.; Happi, G.M.; Frese, M.; Stammler, H.-G.; Neumann, B.; Lenta, B.N.; Sewald, N.; Nkengfack, A.E. Antioxidant norbergenin derivatives from the leaves of Diospyros gilletii De Wild (Ebenaceae). Phytochem. Lett. 2020, 36, 63–67. [Google Scholar] [CrossRef]
  170. Yu, K.-Y.; Wu, W.; Li, S.-Z.; Dou, L.-L.; Liu, L.-L.; Li, P.; Liu, E.-H. A new compound, methylbergenin along with eight known compounds with cytotoxicity and anti-inflammatory activity from Ardisia japônica. Nat. Prod. Res. 2017, 31, 2581–2586. [Google Scholar] [CrossRef]
  171. Branquinho, L.S.; Verdan, M.H.; Silva-Filho, S.E.; Oliveira, R.J.; Cardoso, C.A.L.; Arena, A.C.; Kassuya, C.A.L. Antiarthritic and Antinociceptive Potential of Ethanolic Extract from Leaves of Doliocarpus dentatus (Aubl.) Standl. in Mouse Model. Pharmacogn. Res. 2021, 13, 28–33. [Google Scholar]
  172. Aggarwal, D.; Gautam, D.; Sharma, M.; Singla, S.K. Bergenin attenuates renal injury by reversing mitochondrial dysfunction in ethylene glycol induced hyperoxaluric rat model. Eur. J. Pharmacol. 2016, 791, 611–621. [Google Scholar] [CrossRef]
  173. Borges, J.C.M.; Filho, H.d.S.R.; Gulhon, G.M.S.P.; Carvalho, J.C.T.; Santos, L.S.; Sousa, P.J.C. Antinociceptive Activity of Acetylbergenin in Mice. Lat. Am. J. Pharm 2011, 30, 1303–1308. [Google Scholar]
  174. Jain, S.K.; Singh, S.; Khajuria, A.; Guru, S.K.; Joshi, P.; Meena, S.; Nadkarni, J.R.; Singh, A.; Bharate, S.S.; Bhushan, S. Pyrano-isochromanones as IL-6 Inhibitors: Synthesis, in Vitro and in Vivo Antiarthritic Activity. J. Med. Chem. 2014, 57, 7085–7097. [Google Scholar] [CrossRef]
  175. Nazir, N.; Koul, S.; Qurishi, M.A.; Taneja, S.C.; Ahmad, S.S.; Bani, S.; Qazi, G.N. Immunomodulatory effect of bergenin and norbergenin against adjuvant-induced arthritis—A flow cytometric study. J. Ethnopharmacol. 2007, 112, 401–405. [Google Scholar] [CrossRef]
  176. El-hawary, S.S.; Mohammed, R.; Abouzid, S.; Ali, Z.Y.; Elwekeel, A. Anti-arthritic activity of 11-O-(4’-O-methyl galloyl)-bergenin and Crassula capitella extract in rats. J. Pharm. Pharmacol. 2016, 68, 834–844. [Google Scholar] [CrossRef]
  177. Zhang, Y.-H.; Fang, L.-H.; Lee, M.-H.; Ku, B.-S. Short communication: In vitro Inhibitory Effects of Bergenin and Norbergenin on Bovine Adrenal Tyrosine Hydroxylase. Phytother. Res 2003, 17, 967–969. [Google Scholar] [CrossRef]
  178. Abe, K.; Sakai, K.; Uchida, M. Effects of bergenin on experimental ulcers--prevention of stress induced ulcers in rats. Gen. Pharmacol. 1980, 11, 361–368. [Google Scholar] [CrossRef]
  179. Kumar, R.; Patel, D.K.; Prasad, S.K.; Sairam, K.; Hemalatha, S. Antidiabetic activity of alcoholic root extract of Caesalpinia digyna in streptozotocin-nicotinamide induced diabetic rats. Asian Pac. J. Trop. Biomed. 2012, 1, S934–S940. [Google Scholar] [CrossRef]
  180. Inthongkaew, P.; Chatsumpun, N.; Supasuteekul, C.; Kitisripanya, T.; Putalun, W.; Likhitwitayawuid, K.; Sritularak, B. α- Glucosidase and pancreatic lipase inhibitory activities and glucose uptake stimulatory effect of phenolic compounds from Dendrobium formosum. Rev. Bras. Farm. 2017, 27, 480–487. [Google Scholar] [CrossRef]
  181. Ambika, S.; Saravanan, R. Antihyperglycemic and antihyperlipidemic effect of bergenin on C57BL/6J mice with high fat-diet induced type 2 diabetes. J. Pharm. Res. 2016, 10, 126–132. [Google Scholar]
  182. Veerapur, V.P.; Prabhakar, K.R.; Thippeswamy, B.S.; Bansal, P.; Srinivasan, K.K.; Unnikrishnan, M.K. Antidiabetic effect of Ficus racemosa Linn. stem bark in high-fat diet and low-dose streptozotocin-induced type 2 diabetic rats: A mechanistic study. Food Chem. 2012, 132, 186–193. [Google Scholar] [CrossRef] [PubMed]
  183. Qiao, S.; Liu, R.; Lv, C.; Miao, Y.; Yue, M.; Tao, Y.; Wei, Z.; Xia, Y.X.; Dai, Y. Bergenin impedes the generation of extracellular matrix in glomerular mesangial cells and ameliorates diabetic nephropathy in mice by inhibiting oxidative stress via the mTOR/β-TrcP/Nrf2 pathway. Free Radic. Biol. Med. 2019, 145, 118–135. [Google Scholar] [CrossRef] [PubMed]
  184. Riris, I.D.; Napitupulu, M.A. Antidiabetic activity of methoxy bergenin isolated from ethanol extrat of raru stem bark (Vatica pauciflora Blume) in alloxan induced diabetic wistar rats. Asian J. Chem. 2017, 29, 870–874. [Google Scholar] [CrossRef]
  185. Kumar, T.V.; Tiwari, A.K.; Robinson, A.; Babu, K.S.; Kumar, R.S.C.; Kumar, D.A.; Zehra, A.; Rao, M. Synthesis and antiglycation potentials of bergenin derivatives. Bioorganic Med. Chem. Lett. 2011, 21, 4928–4931. [Google Scholar] [CrossRef]
  186. Habtemariam, S.; Cowley, R.A. Antioxidant and Anti-a-glucosidase Compounds from the Rhizome of Peltiphyllum peltatum (Torr.) Engl. Phytother. Res. 2012, 26, 1656–1660. [Google Scholar] [CrossRef]
  187. Filho, A.L.; Lorga, A.M.; Lopes, A.N.G.; De Paola, A.A.V.; Da Costa, A.N.; Péres, A.K.; Grupi, C.J.; Halperin, C.; Moreira, D.A.R.; Sousa, E.A.; et al. Diretriz de fibrilação atrial. Arq. Bras. Cardiol. 2003, 81, 1–23. [Google Scholar] [CrossRef]
  188. Konoshima, T.; Konishi, T.; Takasaki, M.; Yamazoe, K.; Tokuda, H. Antitumor-promoting activity of the diterpene from Excoecaria agallocha II. Biol. Pharm. Bull. 2001, 24, 1440–1442. [Google Scholar] [CrossRef] [Green Version]
  189. Gao, X.; Wang, Y.; Zhang, J.; Lin, L.; Yao, Q.; Xiang, G. Bergenin suppresses the growth of colorectal cancer cells by inhibiting PI3K/AKT/mTOR signaling pathway. Trop. J. Pharm. Res. 2017, 16, 2307–2313. [Google Scholar] [CrossRef]
  190. Marmol, I.; Sanchez-de-Diego, C.; Dieste, A.P.; Cerrada, E.; Yoldi, M.J.R. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int. J. Mol. Sci. 2017, 18, 197. [Google Scholar] [CrossRef] [Green Version]
  191. Courtney, K.D.; Corcoran, R.B.; Engelman, J.A. The PI3K pathway as drug target in human cancer. J. Clin. Oncol. 2010, 28, 1075–1083. [Google Scholar] [CrossRef] [Green Version]
  192. Hennessy, B.T.; Smith, D.L.; Ram, P.T.; Lu, Y.; Mills, G.B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 2005, 4, 988–1004. [Google Scholar] [CrossRef] [PubMed]
  193. Dong, G.; Zhou, Y.; Song, X. In vitro inhibitory effects of bergenin on human liver cytochrome P450 enzymes. Pharm. Biol. 2018, 56, 620–625. [Google Scholar] [CrossRef] [Green Version]
  194. Leão, R.; Apolónio, J.D.; Lee, D.; Figueiredo, A.; Tabori, U.; Castelo-Branco, P. Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: Clinical impacts in cancer. J. Biomed. Sci. 2018, 25, 1–12. [Google Scholar] [CrossRef]
  195. Hettihewa, L.M.; Munasinghe, M.M.A.B.; Bulugahapitiya, V.B.; Kihara, N. Dose dependent anti proliferative and cytotoxic effects of Flueggea leucopyrus Willd against human ovarian carcinoma; MTS and human telomerase enzyme inhibition. EJBPS 2015, 2, 14–18. [Google Scholar]
  196. Chen, Z.; Liu, Y.-M.; Yang, S.; Song, B.-A.; Xu, G.-F.; Bhadury, P.S.; Jin, L.-H.; Hu, D.-Y.; Liu, F.; Xue, W.; et al. Studies on the chemical constituents and anticancer activity of Saxifraga stolonifera (L) Meeb. Bioorganic Med. Chem. 2008, 16, 1337–1344. [Google Scholar] [CrossRef] [PubMed]
  197. Liang, C.; Pei, S.; Ju, W.; Jia, M.; Tian, D.; Tang, Y.; Mao, G. Synthesis and in vitro and in vivo antitumour activity study of 11-hydroxyl esterified bergenin/cinnamic acid hybrids. Eur. J. Med. Chem. 2017, 133, 319–328. [Google Scholar] [CrossRef]
  198. Liu, D.; Yang, P.; Zhang, Y. Water-soluble extract of Saxifraga stolonifera has anti-tumor effects on Lewis lung carcinoma-bearing mice. Bioorganic Med. Chem. Lett. 2016, 26, 4671–4678. [Google Scholar] [CrossRef]
  199. Yan, D.-B.; Zhang, D.-P.; Li, M.; Liu, W.-Y.; Feng, F.; Di, B.; Guo, Q.-L.; Xie, N. Synthesis and cytotoxic activity of 3, 4, 11-trihydroxyl modified derivatives of bergenin. Chin. J. Nat. Med. 2014, 12, 929–936. [Google Scholar] [CrossRef] [PubMed]
  200. Xu, H.; Zhu, X.; Bao, H.; Shek, T.W.; Huang, Z.; Wang, Y.; Wu, X.; Wu, Y.; Chang, Z.; Wu, S.; et al. Genetic and clonal dissection of osteosarcoma progression and lung metastasis. Int. J. Cancer 2018, 143, 1134–1142. [Google Scholar] [CrossRef]
  201. Kim, H.; Lim, H.; Chung, M.; Kim, Y.C. Antihepatotoxic activity of bergenin, the major constituent of Mallotus japonicus, on carbon tetrachloride-intoxicated hepatocytes. J. Ethnopharmacol. 2000, 69, 79–83. [Google Scholar] [CrossRef]
  202. Berry, M.N.; Friend, D.S. High-yield preparation of isolated rat liver parenchymal cells. J. Cell Biol. 1969, 43, 506–520. [Google Scholar] [CrossRef]
  203. Recknagel, R.O. A new direction in the study of carbon tetrachloride hepatotoxicity. Life Sci. 1983, 33, 401–408. [Google Scholar] [CrossRef] [PubMed]
  204. Recknagel, R.O.; Glende, E.A.; Hruszkewycz, A.M., Jr. Free Radicals in Biology; Academic Press: Cambridge, MA, USA, 1976; Volume 3, pp. 97–132. [Google Scholar]
  205. Boyer, T.D.; Vessey, D.A.; Holcomb, C.; Saley, N. Studies of the relationship between the catalytic activity and binding of non-substrate ligands by the glutathione S-transferases. Biochem. J. 1984, 217, 179–185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Lim, H.; Kim, H.; Choi, H.; Oh, S.; Choi, J. Hepatoprotective effects of bergenin, a major constituent of Mallotus japonicus, on carbon tetrachloride-intoxicated rats. J. Ethnopharmacol. 2000, 72, 469–474. [Google Scholar] [CrossRef]
  207. Rong-Hua, P.; Hong-Mei, H.; Yue, D.; Yu-Feng, X. Comparative pharmacokinetics of bergenin, a main active constituent of Saxifraga stolonifera Curt., in normal and hepatic injury rats after oral administration. Chin. J. Nat. Med. 2016, 14, 776–782. [Google Scholar] [CrossRef]
  208. Tasleem, F.; Mahmood, S.B.Z.; Imam, S.; Hameed, N.; Jafrey, R.; Azhar, I.; Gulzar, R.; Mahmoo, Z.A. Hepatoprotective effect of Peltophorum pterocarpum leaves extracts and pure compound against carbon tetra chloride induced liver injury in rats. Med. Res. Arch. 2017, 5, 1–14. [Google Scholar]
  209. Mondal, M.; Hossain, M.M.; Hasan, M.R.; Tarun, M.T.I.; Islam, M.A.F.; Choudhuri, M.S.K.; Islam, M.T.; Mubarak, M. Hepatoprotective and Antioxidant Capacity of Mallotus repandus Ethyl Acetate Stem Extract against D Galactosamine-Induced Hepatotoxicity in Rats. ACS Omega 2020, 5, 6523–6531. [Google Scholar] [CrossRef] [Green Version]
  210. Lim, H.K.; Kim, H.S.; Choi, H.S.; Oh, S.; Jang, C.G.; Shoi, J.; Kim, S.H.; Chang, M.J. Effects of acetylbergenin against d-galactosamine-induced hepatotoxicity in rats. Pharmacol. Res. 2000, 42, 472–474. [Google Scholar] [CrossRef] [PubMed]
  211. Ahmad, T.; Haq, I.U.; Khan, T.; Mahnashi, M.H.; Alasmary, M.Y.; Almedhesh, S.A.; Shehri, H.A.; Alshahrani, M.A.; Shah, A.J. Bergenin from Bergenia Species Produces a Protective Response against Myocardial Infarction in Rats. Processes 2022, 10, 1403. [Google Scholar] [CrossRef]
  212. Suzuki, S.; Okuse, Y.; Kawase, M.; Takiguchi, M.; Fukuyama, Y.; Takahashi, H.; Sato, M. A Norbergenin Derivative Inhibits Neuronal Cell Damage Induced by Tunicamycin. Biol. Pharm. Bull 2006, 29, 1335–1338. [Google Scholar] [CrossRef] [Green Version]
Figure 1. The biosynthesis of bergenin in plants is related to the gallic acid biosynthetic pathway.
Figure 1. The biosynthesis of bergenin in plants is related to the gallic acid biosynthetic pathway.
Biomolecules 13 00403 g001
Figure 2. (A) natural derivatives of bergenin isolated from different plant species and (B) semisynthetic derivatives obtained by modulation of bergenin in the laboratory.
Figure 2. (A) natural derivatives of bergenin isolated from different plant species and (B) semisynthetic derivatives obtained by modulation of bergenin in the laboratory.
Biomolecules 13 00403 g002
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Salimo, Z.M.; Yakubu, M.N.; da Silva, E.L.; de Almeida, A.C.G.; Chaves, Y.O.; Costa, E.V.; da Silva, F.M.A.; Tavares, J.F.; Monteiro, W.M.; de Melo, G.C.; et al. Chemistry and Pharmacology of Bergenin or Its Derivatives: A Promising Molecule. Biomolecules 2023, 13, 403. https://doi.org/10.3390/biom13030403

AMA Style

Salimo ZM, Yakubu MN, da Silva EL, de Almeida ACG, Chaves YO, Costa EV, da Silva FMA, Tavares JF, Monteiro WM, de Melo GC, et al. Chemistry and Pharmacology of Bergenin or Its Derivatives: A Promising Molecule. Biomolecules. 2023; 13(3):403. https://doi.org/10.3390/biom13030403

Chicago/Turabian Style

Salimo, Zeca M., Michael N. Yakubu, Emanuelle L. da Silva, Anne C. G. de Almeida, Yury O. Chaves, Emmanoel V. Costa, Felipe M. A. da Silva, Josean F. Tavares, Wuelton M. Monteiro, Gisely C. de Melo, and et al. 2023. "Chemistry and Pharmacology of Bergenin or Its Derivatives: A Promising Molecule" Biomolecules 13, no. 3: 403. https://doi.org/10.3390/biom13030403

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop