Helicteres L. SPECIES (Malvaceae SENSU LATO) AS SOURCE OF NEW DRUGS: A REVIEW

Abstract

Helicteres genus, Malvaceae, has pantropical distribution, encompasses about 60 species, 31 of them found in Brazil. Species belonging to this genus are used for treatment of various diseases and aroused scientific interest in search for bioactive compounds present in these plants. In this context, this review aims to provide a complete and concise overview of scientific advances in phytochemical and pharmacological studies of these species and their use by folk medicine. The presented data were collected from scientific databases, ‘Web of Science’, ‘Scifinder’, ‘Pubmed’, ‘Sciencedirect’, and ‘Google Scholar’, using the keyword ‘Helicteres’. The species H. isora and H. angustifolia, found in Asia, are the most explored scientifically, whereas studies of species of this genus found in Americas are still rare, being possible to highlight studies carried out in Brazil with H. velutina and H. eichleri. About 149 compounds were isolated and characterized in the genus, being emphasized terpenoids, flavonoids and lignoids. These species have demonstrated various pharmacological properties in vitro and in vivo, incluinding insecticide, antidiabetic, antitumor and hepatoprotective activities. The presented data show the importance of studies carried out isolating bioactive compounds from this genus that may be used in several diseases’ treatment or/as prototypes to development of new drugs.

Keywords:
Helicteres L.; secondary metabolite; ethnopharmacological relevance; scientific studies

INTRODUCTION

The use of natural products by mankind with the purpose of supplying physical and biological needs is an ancient practice, being the knowledge acquired transmitted throughout the generations.^1-3 Previous studies have allowed the association of chemical constituents present in the medicinal species and their respective pharmacological activities, based on experimental researches including knowledges of botany, chemistry, biochemistry and pharmacology, greatly contributing to the discovery of bioactive natural products.^4,5

In this context, species of Sterculiaceae clade, Malvaceae sensu lato, have aroused great interest in the scientific environment and stand out for their importance in industrial, economic, medicinal, food and ornamental production, as well their chemical and biological properties.^6,7

Among the genus belonging to this group, we highlight Helicteres L., whose biological and pharmacological effects of some species used in folk medicine were scientifically confirmed through the isolation, structural characterization and pharmacological activities developed by its secondary metabolites.⁸

Helicteres L. genus has pantropical distribuition, comprising approximately 60 species in America and Asia, with no species common to both continents. In Asia, the most studied species chemically and pharmacologically are H. isora, H. angustifolia and H. hirsute. China has about ten species, of which only one is endemic.⁹

In America, there are 38 species distributed from Mexico to Argentina, with no reports of occurence for Ecuador and Chile. Among the most scientifically studied species in the continent, we can highlight H. sacarolha, H. eichleri and H. velutina, the last two endemic in Brazil, which is considered the center of diversity of this genus in Americas, having a registered occurrence of 31 species, 23 of which are exclusive from cerrado, caatinga and dry forests.^10-12

Based on the presented data, the objective of this review is to make a survey about the traditional use of Helicteres genus species, as well as evaluating their chemical and pharmacological potential to show the importance of this genus and provide a basis for future research.

METHODOLOGY

Available information on traditional uses, phytochemical study, botanical characteristics and biological activities of Helicteres genus were collected from scientific databases: ‘Web of Science’, ‘Scifinder’, ‘Pubmed’, ‘Sciencedirect’, and ‘Google Scholar’, using articles, books, dissertations and theses published until July 2019, using the keyword ‘Helicteres’. This way, we came across 173 scientific papers. The interest in scientific studies focusing on species of this genus for the development of new drugs has increased over the years due to the promising results of the scientific studies conducted with Helicteres.

The study selection and data extraction were performed by one author (DAF) and confirmed by others (EBA, MSRS, MFVS). The extracted data were summarized in tabular form and a narrative description was used to provide a summary of updated information.

RESULTS AND DISCUSSION

Botanical profile and pollinatio

The Helicteres L. species are characterized morphologically as erect shrubs or sub-bushes, with showy, zygomorph, pedicellate flowers usually pendulous and odorless (Figure 1), with a long androgynophore and ten transverse stamens grafted in to a yellow to red corolla; fruits are distinct, spiral capsules.^13-15

Figure 1
Helicteres plants. A) H. isora, B) H. angustifolia, C) H. sacarolha, D) H. brevispera, E) H. grazumifolia¹⁵

Its showy flowers are strongly attracted to bats and hummingbirds, as described in studies with H. ovata,¹⁶H. brevispira, H. sacarolha,^17-19 and H. lhotzkyana.^14,20H. isora flowers, present at Asia, are large and open daily, being visited by birds and insects that assist in pollination during the day.²¹

Ethnopharmacological relevance

Almost all parts of Helicteres L. plants, including roots, bark and aerial parts, are reported to be traditionally used in several countries and tribes for therapeutic purposes (Table 1).

Table 1
Species of Helicteres genus and their uses in folk medicine

Scientific name/ Popular name	Medicinal parts	Traditional use	Therapeutic indications	References
H. isora / "Ulet-Ulet"	RT and BK	Decoction Juice Paste Extract	Anthelmintic Snake bites Chronic nephritis Gastric ulcers Antidiabetic Expectorant Astringent Anticolagogue Antiasthmatic Intestinal infections	22-24,27-34
	FR	Pod extracts	Anthelmintic Intestinal infections Vermifuges Antiflatulence Antispasmodic Astringent Antidiarrheal Antidysenteric Antipyretic	22,24,27,29-32, 34-38
	LV	Paste	Tanning	30,39
H. angustifolia / "Shan-Zhi-Ma"	RT and ST	Tea Medicinal liquor	Analgesic Anti-inflammatory Antibacterial Antiviral Antitumoral	25,40-42
H. sacarolha / "Sacarolha"	RT and LV	Decoction Infusion Maceration	Antihypertensive Antiulcerogenic Antisyphilitic Hepatoprotective Anti-inflammatory Amenorrhea Blood clearance	8,25,43
H. ovata	*	*	Antisyphilitic Blood clearance	21,25
H. hirsuta	RT	Decoction	Treatment of uterus pain Antimalarial Antidiabetic	44,45
H. velutina / "Pitó"	AP	*	Insect repellent	26

• ^*
  not reported in the literature. RT: Roots; BK: Barks; FR: Fruits; LV: Leaves; ST: Stems; AP: Aerial Parts.

The juice of H. isora root is used in Tradicional Chinese Medicine for diabetes treatment, while fruit extract is used in various intestinal disorders to relieve colic and as an anthelmintic medicine against tapeworm.^22-24

The root tea of H. angustifolia is used to treat influenza symptoms and to inhibit tumor growth.²⁵H. sacarolha preparations with roots and leaves, in form of decoction, infusion or maceration, are used for liver complications, ovarian inflammation, amenorrhea and blood purification,⁸ while the aerial parts of H. velutina are used by indigenous tribe Pankarare/Brazil as insect repellent.²⁶

Ethnopharmacological research with species of this genus acts as a subsidy to the pharmaceutical interest and registration of the empirical uses of medicinal plants in traditional communities associated with chemical-pharmacological tests generates useful knowledges to lead to the development of new drugs.

Phytochemistry profile

In literature, 46 references on the phytochemistry field with species of Helicteres genus were found, 39 of which referring to the studies with H. isora and H. angustifolia. Furthemore, papers reporting research in this area with the species H. hirsute,^38,46H. vegae,⁴⁷H. velutina¹² and H. eichleri⁴⁸ were found, 149 compounds were isolated and identified from Helicteres (Table 2) among the most reported classes. All substances are compiled in the Table 2 (compounds) and Figure 2 (structures).

Table 2
Isolated compounds from Helicteres genus

Nº	Name	Source	Literature
Terpenoids
1	Cucurbitacin B	RT of H.i.	24,49
2	Cucurbitacin B 2-sulfate	RT of H.a.	50
3	Isocucurbitacin B	RT of H.i.	24,49
4	Cucurbitacin D	RT of H.a.	50-53
5	Cucurbitacin E
6	Cucurbitacin G 2-O-β-D-glucopyranoside
7	Cucurbitacin I
8	Cucurbitacin J
9	Isocurcubitacin D
10	Hexanorcucurbitacin I
11	Lup-20(29)-em-3β-ol	RT of H.h. AP of H.e.	48,54
12	Betulinic acid	RT of H.i., H.a. and H.h.	51,54,55
13	3β-benzoylbetulinic acid	RT of H.h.	54
14	Betulinic acid methyl ester
15	3β-O (trans-coumaroyl) betulinic acid	RT of H.a.	44
16	Pyracrenic acid	RT of H.a. and H.h.	53
17	3β-O-(trans-feruloyl) betulinic acid	RT of H.a.	44
18	3β-O-(trans-coumaroyl) botulin
19	3β-O-(cis-coumaroyl) botulin
20	3β-O-(trans-caffeoyl) betulin
21	3β-O-(trans-feruloyl) betulin
22	3β-acetoxybetulinic acid	RT of H.a. AP of H.h.	52,56
23	3-acetoxybetulin	RT of H.a.	35,44,51,53,55
24	3β-27-diacetoxy-lup-20(29)en-28-oic methyl ester
25	3β-acetoxy-27-benzoyloxylup-20(29)-en-28-oic acid
26	3β-acetoxylup-20(29)-en-28-ol
27	3β-hydroxylup-20(29)-en-28-oic acid 3-caffeate
28	3β-hydroxy-27-benzoyloxylup-20(29)-en-28-oic acid
29	3β-hydroxy-27-benzoyloxylup-20(29)-en-28-oic acid methyl ester
30	Methyl helicterate
31	3β-acetoxy-27-[(E)-cinnamoyloxy]lup-20(29)-en-28-oic acid methyl ester
32	3β-acetoxy-27-[(4-hydroxybenzoyl)oxy]lup-20(29)-en-28-oic acid
33	Cylicodiscic acid
34	Simiarenol	AP of H.h.	56
35	Isorin	RT and FR of H.i.	55,57
36	3β-hydroxyolean-12-en-27-benzoyloxy-28-oate	RT of H.a.	44,58-60
37	3β-O-(p-hydroxy-(E)-cinnamoyl)-12 oleanen-28-oic acid
38	Helicterilic acid
39	3β-acetoxy-27-[(4-hydroxybenzoyl)oxy]olean-12-en-28-oic acid methyl ester
40	3β-acetoxy-27-(benzoyloxy)olean-12-en-28-oic acid methyl ester
41	Ursolic acid	RT of H.a. AP of H.e.	48,61
42	3α-hydroxy-urs-12-en-28-oic acid	AP of H.e.	48
43	3α-hydroxy-olean-12-en-28-oic acid
44	Micromeric acid
45	Oleanolic acid	RT of H.i., H.a. AP of H.vel.	12,62,63
46	3β-acethoxy-olean-12-en-28-oic acid	AP of H.vel.	12
47	3β-sterearyloxy-olean-12-ene
48	10-methyl, 4-isopropenyl, dodecahydro-ethanophenanthrene	RT of H.i.	64
49	Methyl helicterilate	RT of H.a.	65
Steroids
50	β-sitosterol glucoside	RT of H.i., H.a. AP of H.vel.	12,24,66
51	β-sitosterol	RT of H.i., H.a. AP of H.e.	24,48,67,68
52	Stigmasterol	RT of H.h. AP of H.e.	48,54
53	Heligenin A	RT of H.a.	51,52,66
54	Heligenin B
55	2α,7β,20α-Trihydroxy-3β,21-dimethoxy-5-pregnen
56	3β-ergost-5-en-3-ol
Flavonoids
57	Kaempferol-3-O-galactoside		69
58	Herbacetin-8-O-glucuronide
59	7-O-methylisoscutellarein	AP of H.h.	54,56,70
60	7,4'-di-O-methylisoscutellarein
61	Isoscutellarein 4'-methyl ether 8-O-β-D-glucopyranoside
62	Isoscutellarein 4'-methyl ether 8-O-β-D-glucuronide 6''-n-butyl ester	FR of H.i.	36
63	Isoscutellarein 4'-methyl ether 8-O-β-D-glucuronide
64	Isoscutellarein 4'-methyl ether 8-O-β-D-glucuronide 2''-sulfate
65	Isoscutellarein 4'-methyl ether 8-O-β-D-glucuronide 2'',4''-disulfate
66	Isoscutellarein 8-O-β-D-glucuronide 2'',4''-disulfate
67	Kaempferol-3-O-β-d-glucopyranoside	FR of H.i. RT of H.a.	51,55,57
68	Kaempferol	FR of H.i. AP of H.vel.	12,57
69	Tiliroside	FR of H.i. RT of H.a. AP of H.vel.	12,52,55,57
70	5,7,8-trihydroxy-4¢-methoxyflavone	FR of H.i. AP of H.a.	55,57
71	3',5,7,8-tetrahydroxy-4'-methoxyflavone	FR of H.i.	71
72	Takakin 8-O-β-D-glucuronide 6-methyl ester	RT of H.a.	72
73	Takakin 8-O-β-D-glucuronide 2-sodium sulfate
74	Takakin 8-O-β-D-glucuronide
75	8-O-β-D-glucuronyl-hypolaetin 4'-methyl ether
76	5,8-dihydroxy-7,4'-dimethoxyflavone	LV of H.i. RT of H.a. AP of H.vel. and H.h.	12,51,54,69
77	Tricin	RT of H.a.	66
78	7,4'-di-O-metil-8-O-sulphate flavone	AP of H.vel.	12
79	5,4'-di-hydroxy-7-methoxy-8-O-sulphate flavone
80	5,6-di-hydroxy-7,4'-methoxy-8-O-sulphate flavone
81	Hesperidin	FR of H.i.	36,55,57
82	Viscumside A
83	3',5,7,8-tetrahydroxy-4'-methoxyflavone 8-O-β-d-glucopyranosiduronic acid methyl ester
84	4',5,7,8-tetrahydroxyflavone 8-O-β-D-glucopyranosiduronic acid methyl ester
Compounds Phenolics
85	Rosmarinic acid	FR of H.i. RT of H.a., H.veg. AP of H.e.	36,55
86	4'-O-β-D-glucopyranosyl rosmarinic acid	FR of H.i.	38
87	4,4'-O-di-β-D-glucopyranosyl rosmarinic acid
88	4'-O-β-D-glucopyranosyl isorinic acid
89	3'-O-(8"-Z-caffeoyl) rosmarinic acid	LV of H.veg.	47
90	3-(3,4-dimethoxyphenyl)-2-propenal	RT of H.a.	51,52
91	Catechol	RT of H.i.	24
92	4-hydroxybenzoic acid	RT of H.h.	54
Compounds Phenolics
93	3,4-dihydroxybenzoic acid methyl ester	RT of H.h.	54
94	4-hydroxy-3,5-dimethoxybenzoic acid
95	Syringic acid-4-O-α-L-rhamnopyanoside	RT of H.a.	52
96	Protocatechuic aldehyde
97	Gallic acid	RT of H.i.	24
98	Vanillin	LV of H.i.	24
99	Coniferyl alcohol	RT of H.a.	52
100	Caffeic acid	RT of H.i.	24
101	p-Coumaric acid	LV of H.i.	24
102	Methyl caffeate	AP of H.h.	54
Lignoids
103	Lariciresinol	RT of H.a.	51,57
104	Hedyotol C 7"-O-β-D-glucopyranoside
105	Hedyotol D 7"-O-β-D-glucopyranoside
106	(+)-pinoresinol	RT of H.a., H.h. AP of H.vel.	12,46
107	(+/-)-medioresinol	RT of H.a. and H.h.	46,51
108	(+/-)-syringaresinol
109	(-)-boehmenan
110	(-)-boehmenan H
111	(+/-)-trans-dihydrodiconiferyl alcohol	RT of H.a. FR of H.i.	46,51,73
112	(7S,8R)-Urolignoside	RT of H.a.	52
113	(7S,8R)-Dihydrodehydrodiconiferyl alcohol	RT of H.a. and H.h.	12,57
114	Helisorin	FR of H.i.	73,74
115	Helicterins C
116	Helicterins E
117	Helicterins D
118	Helicterins F
119	Helicterins A
120	Helicterins B
121	Helisterculins A
122	Helisterculins B
Quinones
123	Perezone	RT of H.a.	40,42,57,66,75
124	2,​6-​Dimethoxy-​p-​benzoquinone
125	8-acetyl-9-hydroxy-3-methoxy-7-methyl-1-phenalenon
126	Heliquinone
127	Heliquinone methyl ether
128	Mansonone F
129	Mansonone E
130	Mansonone H
131	Mansonone M
132	6-[2-(5-acetyl-2,7-dimethyl-8-oxo-bicyclo[4.2.0]octa-1,3,5-trien-7-yl)-2-oxo-ethyl]-3,9-dimethylnaphtho[1,8-bc]pyran-7,8-dione
Other compounds
133	Malatyamine ethyl ester (Amine)	RT of H.i.	53,76-79
134	Diosgenin (Saponin)
135	6,7-dihydroxy-3,8,11-trimethylcyclohexo-[d,e]-coumarin	RT of H.a.	51,64
136	6,7,9α-trihydroxy-3,8,11α-trimethylcyclohexo-[d,e]-coumarin (Coumarin)
137	Tetratriacontanol (Alcohol)	LV of H.i.	67
138	Tetratriacontanoic acid (Fatty acid)
139	Palmitic acid (Fatty acid)	LV of H.i. AP of H.vel	12,24
140	Aliphatic alcohol decanol (Alcohol)	AP of H.vel. and H.e.	12,48
141	Helicterone A (Alkaloid)	RT of H.a.	52
142	Yohimbine (Alkaloid)	FR of H.i.	80
143	Pheophytin A	RT of H.i. AP of H.vel.	12,81
144	Pheophytin B
145	132-hydroxy-(132-R)-pheophytin a	AP of H.vel.	12
146	132-hydroxy-(132-S)-pheophytin a
147	Ellagic acid (Tannin)	RT of H.i.	82,83
148	3,6,9-trimethyl-pyrano[2,3,4-de]chromen-2-one (Lactone)	RT of H.a.	75
149	4-4'-sulfinylbis(2-(tert-butyl)-5-methylphenol	AP of H.h.	56,70

• H.i.H. isora; H.a.H. angustifolia; H.vel.H. velutina; H.h.H. hirsuta; H.veg.H. vegae; H.e.H. eichleri. RT: Roots; AP: Aerial Parts; FR: Fruits; LV: Leaves.

Figure 2
Compounds isolated from Helicteres species

Terpenoids and steroids

Terpenoids and its oxygenated, acetylated and dehydrogenated derivatives are hydrocarbons of plant origin.⁸⁴ Many of these molecules have biological activities that are used for the treatment of human diseases. These molecules have led to six major classes of drugs in the last century: steroids, tocopherols, texanes, artemisinins, ingenans and cannabinoids.^85,86

Fifty terpenoids were isolated and identified from H. isora, H. angustifolia, H. hirsuta, H. eichleri and H. velutina, evidencing this class as the predominant compounds in Helicteres genus (Table 2). In a preliminary bioassay, cucurbitacins D (4) and J (8) exhibited significant inhibitory activities against hepatocellular carcinoma and malignant melanoma cells in vitro.⁵¹

Compounds 3β-O (trans-coumaroyl) betulinic acid (15), pyracrenic acid (16), 3β-acetoxy-27-[(4-hydroxybenzoyl)oxy]lup-20(29)-en-28-oic acid (32) and 3β-acetoxy-27-[(4-hydroxybenzoyl)oxy]olean-12-en-28-oic acid methyl (39), showed significant cytotoxic activities against human colorectal cancer and human gastric cancer cell lines in vitro.⁴⁴ The compound 10-methyl, 4-isopropenyl, dodecahydro-ethanophenanthrene (48) exhibited considerable antimicrobial and antispasmodic activities.⁶⁴

Steroids are one of the less widespread classes in isolated from species of Helicteres genus, with only seven representatives (50-56).

Phytosteroids are steroidal substances extracted from plant species, the most common being β-sitosterol (51) and Stigmasterol (52). This class of substances has carbonic skeleton formed by the cyclopentanoperhydrophenanthrenic ring,⁸⁷ highlightin the β-sitosterol, which presented antimicrobial and larvicidal activities.^88,89

Flavonoids and phenolic compounds

Flavonoids represent one of the most important and diverse groups of phenolic compounds among natural products.^90,91 Among the phytotherapics currently studied, flavonoids have been highlighted due to their wide range of biological and/or pharmacological actions demonstrated under both experimental and human conditions.⁹²

Twenty-nine flavonoids were isolated from Helicteres genus, with emphasis on heterosides (69),^36,71 sulphated (78-80) and heterosides glycosulphated (65-67).^12,36 Among those compounds, tiliroside (70) and 7,4′-di-O-methyl-8-O-sulphate flavone (78) have larvicidal activity against Aedes aegypti,⁸⁸ while 7,4’-O-methylisoscutellarein (60) have shown anti-inflammatory activity by inhibiting neutrophil recruitment and decreasing IL-1β and TNF-α production in vitro.⁹³

Besides the flavonoids, it was possible to identify 18 phenolic compounds (85-102) with different nuclei, among them rosmarinic acid (85) isolated from H. isora fruits, H. angustifolia and H. vegae roots and H. eichleri aerial parts. Scientific studies of this substance have proven its antioxidant, anti-inflammatory, antifibrosis, hepatoprotective and antineoplasic activities.⁹⁴

Some studies also report the compounds quantification in species of Helicteres genus, among which are total phenolic content, flavonoids and condensed tannins of H. vegae.⁴⁷ It was also accomplished the phenolics, flavonoids and saponins quantification of H. hirsuta^45,95,96 and H. isora, to evaluate their antioxidant potential.^97-99

Lignoids

Twenty-one lignoids were isolated and identified from H. isora, H. angustifolia, H. hirsuta and H. velutina species, most of them found in the roots and fruits. Yin et al. (2016)⁵⁷ isolated two benzofuran lignans of H. angustifolia that were evaluated for anti-complementary activity in vitro and showed potent activity when compared to heparin (positive control). Tezuka et al. (2000)⁷⁴ isolated and identified six dimeric neolignans from fruits of H. isora: Helicterins B (120), C (115), D (117), E (116) and F (118), which showed mild inhibitory activity against avian myeloblastosis virus reverse transcriptase (AMV-RT), having an emphasis on the inhibitory activity of Helicterins A (119), which was identical to the antineoplasic drug doxirubicin, with an IC₅₀ of 66 µM. This can be of interest for the development of new therapeutic alternatives.

Quinones

Quinones are structurally characterized as cyclic α, β-dienics, and have considerable toxicological and pharmacological interests due to their biooxidation-reduction properties and ability to catalyze biological electrical transfer.¹⁰⁰ However, biological studies involving isolated quinones of Helicteres species are scarce, as it is necessary to investigate possible biological actions not yet explored. So far, ten quinones have been isolated and identified in the studied genus (123-132), and the compounds that best represent this class were sesquiterpene quinones and O-benzoquinones, isolated from H. angustifolia roots.^40,42,51

Other compounds

Beyond to previously detailed compounds, other classes of metabolites, such as amines, saponins, lactones, coumarins, alcohols, fatty acids, alkaloids, pheophytins and tannins (133-149) (Table 2, Figure 1), were less frequently detected in this genus.

Aleykutty & Akhila (2012),⁸⁰ by means of a computational approach, predicted the antidiabetic potential of the chemical constituents identified in H. isora, especially the indolalkylamine, Yohimbine (142), which presented the best binding energy with the enzyme aldose reductase and the insulin receptor protein, pharmacological targets for glycemic control.

Pharmacology study

Pharmacological potential of Helicteres species has gained prominence, especially with H. isora and H. angustifolia, that have a long history of use in traditional Chinese medicine. Researches have been developed about antidiabetic, antiulcerogenic and antitumor activities within Helicteres species in order to confirm the activities reported by folk medicine (Table 3).

Table 3
In vitro, in vivo, ex vivo and in silico biological studies reported from Helicteres genus

Species	Material used	Experimental model	Literature
Anti-inflammatory and Analgesic Activity
H.i.	Roots extracts	in vivo - antinociceptive	101
H.a.	Ethyl acetate extract	in vivo - anti-inflammatory and antipyretic	102,103
H.a.	n-butanolic fraction	in vivo - anti-inflammatory and analgesic	104
H.h.	Aerial parts extract	in vitro - COX1/COX2 inhibition	70
H.ga.	Aerial parts ethanolic extract	in vivo - acute inflammation	105
H.ga.	Leaves ethanolic extract	ex vivo - topical use	106
Antitumor and Cytotoxic Activity
H.i.	Fruits extract	in vitro - lung cancer	107,108
H.i.	Curcubitacin B and Isocurcubitacin B	not reported	109
H.i.	Stem hydroethanolic extract	in vivo - hepatocellular carcinoma	110
H.a.	Roots aqueous extract	in vitro - fibroblasts and osteosarcoma	111
H.a.	Triterpenes	in vitro - colorectal cancer	60
H.a.	Roots aqueous extract	in vivo - human fibrosarcoma	25
H.a.	Polysaccharides	in vivo - breast cancer	112
H.a.	2, 3, 3 β-O-[(E)-coumaroyl] betulinic acid and pyracrenic acid	in vitro - colorectal cancer	44
H.a.	Roots ethanolic and aqueous extract	in vitro - cell lines of lung cancer, colon and hepatocellular carcinoma	25,111
H.a.	Roots aqueous extract	in vitro - osteosarcoma and in vivo - pulmonary metastasis and subcutaneous xenograft	113
H.a.	Curcubitacin B and J	in vitro - hepatocellular carcinoma and malignant carcinoma	51
H.h.	(+/-)-pinoresinol	in vitro - lung and breast cancer	46
H.h.	Roots extract	in vitro - human KB cell lines	114
H.veg.	Leaves extract	in vitro - Salmonella typhimurium	47
H.s.	Leaves hydroethanolic extract	in vivo - ovarian cancer cell lineages	8
Hepatoprotective Activity
H.i.	Bark aqueous extract	in vivo - changes in liver enzymes	115
H.i.	Bark ethanolic extract	in vivo - changes in liver enzymes	116-118
H.a.	Aqueous extract	in vivo - inhibits hepatic fibrosis	119
H.a.	Methyl helicterate	in vivo - inhibits hepatic fibrosis	120,121
Antidiabetic and Hypolipidemic Activity
H.i.	Roots ethanolic extract	in vivo - sensitizing and hypolipidemic insulin	122
H.i.	n-butanolic fraction	in vivo - maintain normal glycemic levels	123
H.i.	Bark aqueous extract	in vivo - reduced blood glucose levels	30
H.i.	Bark aqueous extract	in vivo - reduction of peroxidation products	32
H.i.	Roots n-butanolic extract	in vivo - reduced glucose and total cholesterol	124
H.i.	Bark aqueous extract	in vivo - reduction of cholesterol, free fatty acids and triglycerides	31
H.i.	n-butanolic extract	in vivo - hypoglycemia	125
H.i.	Fraction rich in saponin	in vivo - decreased serum levels of lipids and glucose	126
H.i.	Stem extract	in vivo - glycogen and carbohydrate metabolism	127
H.i.	Bark aqueous extract	in vivo - decreased glucose levels	128
H.i.	Bark aqueous extract	in vivo - total blood glucose and lipids	127
H.i.	Fruits aqueous extract	in vitro - glucose uptake	129
H.i.	Fraction rich in saponin	in vitro - increases glycogen synthesis	130
H.i.	Fruits ethanolic extract	in vivo - stabilizes lipids levels	122
H.i.	Roots hydroethanolic extract and roots n-butanolic extract	in vivo - reduced glycemia, total cholesterol, triglycerides and urea	34
H.i.	Fruits aqueous extract	in vivo - increases glucose uptake and transport	131
H.i.	Stem extract	in vivo - normalizes glucose, urea and creatinine levels	88,116
H.i.	Bark aqueous extract	in vivo - antiperoxidative activity	88
H.i.	Isolated constituents	in silico - insulin receptors	79
H.i.	Roots extract	in vivo - reduction of plasma glycoproteins	132,133
H.i.	Roots extract	in vivo and in vitro - inhibition of a-amylase and reduction of glutathione	134,135
H.i.	Fruits aqueous extract	in vivo - hypoglycemia in patients with type II diabetes	22
H.i.	n-butanolic extract	in vivo - regulates blood glucose levels	136
H.i.	Fruits ethanolic extract	in vivo - regulates blood glucose levels	137
H.a.	Roots aqueous extract	in vivo - increases glucose uptake	138
H.a.	Roots ethanolic extract	in vivo - increases the uptake of glucose and adipocytes	139
H.a.	-	in vivo - inhibition of a-glicosidase	138,139
Antioxidant Activity
H.i.	Bark aqueous extract	in vitro - inhibition of peroxidation radicals	81
H.i.	Fruit hot aqueous extract	in vitro - inhibition of radicals H2O2 and NO	27
H.i.	Fruits phenolic extracts	in vitro - inhibition of radicals ABTS, Hydroxyl and DPPH	140
H.i.	Fruits aqueous extract	in vitro - inhibition of radicals DPPH and TBARS	129
H.i.	Fruits aqueous extract	in vitro - inhibition of radicals Hydroxyl, H2O2 and DPPH	141
H.i.	Fruits extract	in vitro - inhibition of radicals DPPH	107
H.i.	Fruits extract	in vitro - inhibition of radicals FRAP and DPPH	142,143
H.i.	Fruits extract	in vitro - inhibition of radicals DPPH and H2O2	107
H.i.	Fruits and barks extracts	in vitro - inhibition of lipid peroxidation	142
H.i.	Roots aqueous extract	in vitro - inhibition of radicals ABTS and DPPH	144
H.i.	Leaves, barks, roots and fruits extracts	in vitro - inhibition of radicals FRAP and DPPH	145
H.i.	Leaves and fruits extracts	in vitro - inhibition of radical DPPH	146
H.a.	Polysaccharides	in vitro - inhibition of radicals ABTS, Hydroxyl and DPPH	147-149
H.a.	Roots ethanolic and aqueous fractions	in vitro - inhibition of ABTS and DPPH	150
H.h.	Leaves extracts	in vitro - inhibition of radicals ABTS, DPPH and FRAP	148
H.h.	Fraction rich in saponin	in vitro - inhibition of radicals ABTS, DPPH, FRAP and CUPRAC	24,45,95,111, 151
H.h.	Stem and Leaves extracts	in vitro - inhibition of radicals, ABTS, DPPH and FRAP	45,95,96
H.veg.	Stem extracts	in vitro - inhibition of radicals, ABTS and DPPH	47
Antimicrobial and Antiviral Activity
H.i.	Fruits extracts	in vitro - E. coli, Staphylococcus epidermidis, Salmonella typhimurium and Proteus vulgaris	152
H.i.	Fruits acetone extracts	in vitro - Enterococcus faecalis, Escherichia coli and Bacillus cereus	153
H.i.	Leaves ethanolic extract	in vitro - Escherichia coli, Steptococcus and Salmonella	154
H.i.	Leaves and fruits extracts	in vitro - Staphylococcus aureus, Bacillus subtilis and B. coagulans; Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi; Bipolaris sorokiniana, Fusarium oxysporum f.sp. zingiberi, Colletotrichum capsici and Curvularia sp.	150
H.i.	Stem and leaves extracts	in vitro - E. coli, Pseudomonas, S. aureus, Bacillus subtillis, Aspergillus fumigatous, Aspergillus awamori, Rhizopus oryzae, Tricoderma viridae and Culmularia oryzae	155
H.i.	Fruits aqueous extract	in vitro - Pseudomonas aeruginosa	156
H.i.	Oleanolic acid	in vitro - S. aureus, E coli, P. aeruginosa, B. cereus and A. flavus	88
H.i.	b-sitosterol	in vitro -E. coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus cereus	88
H.i.	Barks and stems extracts	in vitro - Cryptococcus neoformans, Candida tropicalis, Trychophyton rubrum, Microsporum furfure and Epidermophyton floccosum	157
H.i.	Roots hydroethanolic extract	in vitro - Bacillus subtilis; Micrococcus luteus; S. aureus; E. coli; P. vulgaris; P. aeruginosa; S. typhimurium; A. niger; C. albicans and S. cerevisiae	101
H.i.	Fruits, barks and leaves extracts	in vitro - Escherichia coli, Salmonella typhii, Staphylococcus aureus, Corynebacteria diphtheriae and Nocardia sp.	158
H.i.	Leaves ethanolic extract	in vitro - Pseudomonas aeruginosa, Staphylococcus aureus and Aspergillus niger	159
H.i.	Fruits methanolic extract	in vitro - Candida albicans	148
H.i.	10-methyl, 4-isopropenyl, dodecahydro- ethanophenanthrene	not reported	65
H.a.	not reported	in vitro - E. coli	160
H.a.	Triterpenes	in vivo and in vitro - Hepatitis B	161
H.a.	Methyl helicterate	in vivo and in vitro - anti HBV	162,163
H.h.	Roots extract	in vitro - Staphylococcus aureus and Lactobacillus fermentum	114
H.h.	Saponin-enriched fractions	in vitro - E. coli and S. lugdunensis	164
H.gr	Aerial parts extract	in vitro - Bacillus subtilis; Micrococcus luteus; Enterobacter cloacae; Acinetobacter calcoaceticus; Aspergilus oryzae; Curvularia luneta; Mucor sp.	165
Other Activities
H.i.	Fruits extract	in vitro and in vivo - antispasmodic	37
H.i.	Fruits extract	in vitro - cardiotonics	166
H.i.	Fruits aqueous extract	in vivo - anthelminthic	167
H.i.	Fruits extract	in vivo - anthelminthic	144
H.i.	Bark methanolic extract	in vitro - cytoprotectors	168
H.i.	Bark aqueous extract	in vivo - acute oral toxicity	39
H.i.	10-methyl, 4-isopropenyl, dodecahydro- ethanophenanthrene	in vivo - antispasmodic	65
H.i.	Fruit extract	Demulcent and Astringent	169
H.a.	Terpenoids	in silico - ulcerative cults	170,171
H.a.	Leaves hydroethanolic extract	in vivo - acute and subchronic toxicity	8
H.vel.	Aerial parts extract	in vitro - Larvicidal activity against Aedes aegypti	12
H.vel.	Tiliroside and 7,4¢-di-O-methyl-8-O-sulphate flavone	in silico and in vitro - Larvicidal activity against Aedes aegypti	89
H.s.	Hydroethanolic extract	in vivo - gastroprotective	8
H.s.	Hydroethanolic extract	in vivo - acute and subchronic oral toxicity	8
H.e.	Aerial parts extract	in vitro - Larvicidal activity against Aedes aegypti	48
H.veg	Leaves and stem extracts	in vitro - Artemia salina eggs	47

• H.i.H. isora; H.a.H. angustifolia; H.vel.H. velutina; H.h.H. hirsuta; H.veg.H. vegae; H.s.H. sacarolha; H.ga.H. gardineriana; H.e.H. eichleri; H.grH. grazumifolia.

Anti-inflammatory and analgesic activity

Natural products are widely used in folk medicine to treat inflammatory conditions, including fever, pain, migraine and arthritis, being targets for the development of new anti-inflammatory drugs.¹⁷² Studies with plant extracts have shown promissory activity.¹⁷³

H. isora root extract showed antinociceptive activity in mice.¹⁰¹H. angustifolia n-butanol fraction has anti-inflammatory and analgesic activity.¹⁰⁴ Non-clinical mice studies have showed through photoacoustic spectroscopy that H. gardneriana extract induces a significant reduction in the inflamed area.¹⁰⁶ Studies with extracts from the aerial parts of H. hirsute has been conducted in order to discover their mechanisms of action against inhibition of COX1 and COX2 in vitro⁷⁰ (Table 3).

Antitumor and cytotoxic activity

Cancer is one of the leading causes of mortality in the world. About 60% of current anticancer drugs are from natural origin, with emphasis on plant species that are rich in anticancer agents and can be used as an alternative to chemotherapeutic drugs as they are less toxic.¹⁷⁴ The effects of plant-derived natural products have been investigated to a large extent on cancer cell proliferation, survival, invasion and metastasis due to bioactivity and the diversity of their chemical constituents.^60,175

Helicteres are used to decrease tumor progression by folk medicine. In order to evaluate this activity, extracts, fractions and isolated substances have been studied through the evaluation of cytotoxic activity mainly in liver, lung, colon and breast cancers (Table 3).

The acetone extract of H. isora fruits exhibited better cytotoxic activity in vitro against lung cancer cells.¹⁰⁷ Studies with the terpenes Helicteric acid (38), oleanolic acid (45) and betulinic acid (12) isolated from H. angustifolia have shown important anticancer activity and showed that compounds could decrease proliferation and induce apoptosis in HT-29 colorectal cancer cells in vitro.⁶⁰ A similar activity was developed by the compounds 2, 3, 3 β-O-[(E)-coumaroyl] betulinic acid (15) and pyracrenic acid (16).⁴⁴

In vivo studies revealed that hydroethanolic extract flavonoid-rich of H. sacarolha and phenolic compounds have good activity in ovarian cancer cell lineages, being non-toxic when ingested orally,⁸ while hidroethanolic stem bark extract of H. isora shows activity against hepatocellular carcinoma in mice.¹⁶⁷

Hepatoprotective activity

Extracts of several plant species have shown hepatoprotective activity^176-178 and approximately 100 of these species have been used in the preparation of over 700 herbal formulations that are available for use in prevention and treatment of liver disease.^179,180

The hepatic protection exerted by the H. isora and H. angustifolia species was also investigated in vivo, where the main parameters of alterations in liver enzymes production and serum markers are evaluated. H. isora bark ethanolic extract and H. angustifolia water extract demonstrated hepatoprotective activity against carbon tetrachloride induced liver damage in rats and mice, respectively.¹¹⁶ The methyl helicterate (30) isolated from H. angustifolia acts on carbon tetrachloride in induced hepatic fibrosis of rats, which may be associated with its free radical scavenging action and antioxidant activity. Another proposed mechanism of action of this substance would be the inhibits activation of hepatic stellate cells, modulating apoptosis and autophagy.^120,121

Antidiabetic and hypolipidemic activity

Available literature shows that various chemical compounds with antidiabetic properties have been identified in some plant species,^181,182 among which we can highlight some belonging to the Helicteres genus.

The ethanolic extract of H. isora roots causes significant reduction in glucose, triglyceride and insulin levels in mouse plasma, suggesting that it has insulin sensitizing and hypolipidemic activity with potential use in the treatment of type 2 diabetes.²⁸ Researches over this species have also proven the antidiabetic activity of the aqueous extracts of its peels, stem and fruits.^30,127,129

The extract and n-butanolic fractions of H. isora have shown good in vivo activity with antihyperglycemic activity, reducing glucose and total cholesterol levels.^123,124 Saponin-rich fractions also exhibit this activity in vitro and in vivo.^126,130 Molecular docking with insulin receptors was analyzed with compounds isolated from H. isora fruits,¹⁸³ and the results suggested that they may be useful for treating diabetes.

H. angustifolia roots aqueous and ethanolic extracts have also shown significant antidiabetic activity in vivo, significant alpha-glucosidase inhibitory and moderate enhanced glucose consumption activity, while having low cytotoxicity and acute toxicity.^138,139

Antioxidant activity

Antioxidants are important for preventing human diseases. Naturally occurring antioxidants such as ascorbic acid, vitamin E and phenolic compounds can reduce the oxidative damage associated with various diseases including cancer, cardiovascular disease, cataract, atherosclerosis, diabetes, arthritis, immune deficiency diseases and aging.²⁷

Evaluation of antioxidant activity of the species H. isora, H. angustifolia, H. hirsuta and H. vegae, mainly with respect to fruit extract,¹⁴¹ rich fractions of saponins²⁴ and polissacarids,¹⁴⁷ showed that they are capable of inhibiting in vitro peroxidation radicals such as DPPH (1,1-diphenyl-2-picryl-hydrazyl), H₂O₂ (Hydrogen peroxide), NO (Nitric Oxide), ABTS (2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)), TBARS (thiobarbituric acid-reactive substances), FRAP (ferric reducing antioxidant power) and CUPRAC (cupric reducing antioxidant capacity).

Antimicrobial and antiviral activity

In the current scenario, due to the various pathogenic microorganisms, infectious diseases are still one of the leading reasons behind the worldwide death rates.¹⁸⁴ The emergence of multiple commonly used antibiotic drug resistant bacteria is a severe health problem and major challenge for global drug discovery programs,¹⁵⁴ and the use of plant extracts and isolated compounds with known antimicrobial properties becomes an important alternative in therapeutic treatments.¹⁸⁵

H. isora and H. angustifolia organic extracts have been extensively studied for their potential to act as antimicrobial agents.¹⁵⁰ Among the isolated compounds, oleanolic acid (45)⁸⁸ and β-sitosterol (51)⁸⁸ showed good antibacterial activity, while methyl helicterilate compound (49) showed potential antiviral activity¹⁶² (Table 3).

Other activities

Other activities have been reported from Helicteres species. H. isora stems aqueous extract showed no toxicity when administered orally at concentrations of 100 and 200 mg/kg in rats.³⁹ Researchers also evaluate antispasmodic,³⁷ gastroprotective,⁸ anthelmintic¹⁶⁷ and larvicide against Aedes aegypti larvae^12,48 activities, among others. In addition, studies were also carried out to evaluate the nutritional value of H. isora fruits and stems.¹⁸⁶

CONCLUSIONS

Helicteres L. is one of the genera belonging to Sterculiaceae clade in Malvaceae family with several notable activities. Previous studies have revealed that terpenoids, flavonoids and lignoids are the dominant constituents of Helicteres species. However, information about this genus is scarce and not systematic. The in vitro and in vivo studies carried out to date prove traditional medicine reports regarding the activities of those species. However, pharmacological tests with isolated substances are still rare from this genus and its compounds, especially those unpublished in the literature, resulting in unexplored potentials.

Given the presented data, it is extremely important to continue exploring the chemical and biological potentials of these and other species present in the American and Asian flora, considering the need to find substances with biological activities that may be used for mankind benefit.

ACKNOWLEDGMENTS

The authors thank the Coordenação de Aperfeiçoamento do Ensino Superior (CAPES) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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Publication Dates

• Publication in this collection
  22 July 2020
• Date of issue
  June 2020

History

• Received
  11 Nov 2019
• Accepted
  12 Feb 2020
• Published
  20 Apr 2020