Orthosiphon stamineus : Ethnopharmacology, Extraction & Bioprocesses and Anti-Cancer activities
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Transcript of Orthosiphon stamineus : Ethnopharmacology, Extraction & Bioprocesses and Anti-Cancer activities
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Orthosiphon stamineus : Ethnopharmacology, Extraction &
Bioprocesses and Anti-Cancer activities
(Paper Review)
Submitted By
Qabas Marwan Abdulazeez
Metric No: G1223171
M. Sc. Student
Department of Biotechnology Engineering
Date of Submission: 15th May 2014
Submitted To
Assoc. Prof. Azura BT. Amid
Department of Biotechnology Engineering
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ABSTRACT
Ethnopharmacological relevance: Orthosiphon stamineus is a medicinal herb belong to
the family Lamiaceae. It is a widely used in several countries (especially in Indonesia and
Malaysia) as traditional medicine. It was known as Java tea or Misai Kuching. This
plant has several activities, such as antioxidant, antibacterial, diuretic and anticancer.
Because of those properties, O. stamineus is potential to be developed as a new source of
drugs and to treat some critical human diseases
Aim of the review: The present paper reviewed the ethnopharmacology, extraction &
bioprocesses anti-cancer activities.
Materials and methods: Information on O. stamineus was gathered via the Internet using
Google Scholar and libraries. Additionally, information also was obtained from some
electronic books. The keywords applied on Google was Orthosiphon stamineus, java tea,
Misai Kuching, O. stamineus extraction, O. stamineus anti-cancer.
Results: More than 116 chemical compounds have been isolated, and the main
compositions are essential oils, organic acids and flavones, etc. Orthosiphon stamineus
and its active principles possess wide pharmacological actions, such as anti-cancer,
antibacterial, anti-oxidative and Diuretic activities.
Conclusions: As an important traditional Malaysian and Indonesian medicine, further
studies on O. stamineus can lead to the development of new drugs and therapeutics for
various diseases, and how to utilize it better should be paid more attentions.
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CONTENTS
1. Introduction 1
2. Ethnopharmacology Studies and Activities 3
2.1 Anti-oxidant Activity 3
2.2 Diuretic Activity 5
2.3 Anti-cancer Activity 5
2.4 Anti-diabetic 7
2.5 Anti-Fungal Agents 8
2.6 Other Activities 9
3. Extraction & Bioprocesses 10
4. Chemical Compounds 10
5. Conclusion 15
6. References 16
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1. Introduction
Orthosiphon stamineus plant is a popular medicinal plant in Southeast Asia. It is
widely used for treatment of kidney, bladder inflammation, gout and diabetes (Akowuah,
Ismail, Norhayati, & Sadikun, 2005), especially those affecting the urinary tract, diabetes
mellitus, hypertension, rheumatism, tonsillitis and menstrual disorder (Awale, et al.,
2003). Several compounds have been isolated from this plant which includes sinensetin,
an important flavonoid having an antioxidation property. It has high chemo-sensitizing
effect which is used to synthesize multi-drug resistance (MDR) cell for anticancer drugs
(Ahmad, et al., 2008).
Although it was first introduced to the European consumers as an herbal tea in the
20th century, this species was only became popular, particularly in Indonesia and
Malaysia in the last few decades. In Malaysia, it has been used in traditional medicine to
treat diseases of the urinary system (Adam, et al., 2009), and used as diuretic, and to treat
rheumatism, abdominal pain, kidney and bladder inflammation, edema, gout and
hypertension (Abdul Majid, 2010). It is believed that the bioactive compounds contained
in the leaves of O. stamineus exert the effects as an antiallergic, antihypertensive, anti-
inflammatory, antioxidant , and diuretic properties (Abdullah, Shaari, & Azimi, 2012).
Orthosphon stamineus is a perennial herb. It attains 0.3-1.5 m high and having 4-
angle stem. Leaves are simple, opposite, ovate-oblong-lanceolate, elliptic or rhamboid,
which have 2-4 cm wide and 4-7 cm long. The flowers are white, blue or violet. When
the flowers open, stamens and pistil extend out far beyond the petals, which create "cat's
whiskers" effect. This plant needs full sun and a moist garden soil for growing and
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flowering. However, it grows perfectly under light shade and warmer climates (Adnyana
, Setiawan , & Insanu, 2013) . O. stamineus has many other names, include: Orthosiphon
aristatus, Orthosiphon spicatus, Orthosiphon blaetter, kutum, mamam, bunga laba-laba,
remuk jung, remujung, kumis ucing, songot koceng, sesalaseyan (Java), java tea, cats
whisker, Indian kidney tea (English), mao xu cao (China), misai kucing, ruku hutan
(malaysia), kabling gubat, kabling parang (Philippine), se-cho, myit-shwe (Myanmar),
rau-meo (Vietnam), neko no hige (Japan), katzenbart (Germany) and yaa-nuad-maew, pa-
yab-mek (Thailand). (Abdul Majid, 2010) (Anonymous, 1967).
Figure (1): Orthosiphon stamineus (Misai kucing).
Source : http://bestfarms.com.my/wp-content/uploads/2011/07/bunga_misai_kucing.jpg
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2. Ethnopharmacology Studies and Activities
O. Stamineus has been traditionally used for many diseases, especially in South
East Asian countries like: Indonesia, Malaysia, Thailand, Vietnam and Myanmar. It is
also recognized in European country, such as Holland, France and England to be
consumed as a herbal product. The leaves of this plant have been used in Indonesia for
diuretic, preventing and treating rheumatism, diabetes mellitus, hypertension, tonsillitis,
epilepsy, menstrual disorder, gonorrhoea, syphilis, renal calculi, gallstone, acute and
chronic nephritis, gout arthritis, and antipyretic.
Many of the beneficial effects of O. Stamineus consumption have been attributed
to the pharmacological actions of these major constituents (Pan, et al., 2011). In Vietnam,
the aerial part is used for treating urinary lithiasis, edema, eruptive fever, influenza,
hepatitis, jaundice and biliary lithiasis (Anonymous, 1967), while in Malaysia and
Thailand, the leaves are used for diuretic, kidney tonic, and cystotonic medicines
(Adnyana , Setiawan , & Insanu, 2013).
Many Ethnopharmacological Activities for O. Stamineus have been discovered
by many studies, the most important activities are :
2.1 Anti-oxidant Activity
Recently, there has been considerably interest in finding naturally occurring
antioxidants to replace synthetic antioxidants in foods and medicinals. Several studies
have analyzed the antioxidant potential of a variety of herbs. Among the different parts of
plants studied, the leaves of O. stamineus are reported to have extracts with free radical-
scavenging activity (Akowuah, Zhari, Norhayati, Sadikun, & Khamsah, 2004) .
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The highest antioxidant activity was found in acetone extract. Other report
observed that there were variations in total phenolic compounds, ranging from 6.7 to 10.1
mg caffeic acid/g dry weight of the methanol extract. Some studies also proved using
different in vitro method (superoxide scavenging and xanthine oxidase) that O. stamineus
extract showed potential antioxidant activity (Adnyana , Setiawan , & Insanu, 2013).
(Akowuah, Zhari, Norhayati, Sadikun, & Khamsah, 2004) study reported that
until now, Twenty phenolic compounds were isolated, including nine lipophilic flavones,
two flavonol glycosides, and nine caffeic acid derivatives, such as rosmarinic acid and
2,3- dicaffeoyltartaric acid, were identified and quantified by HPLC analysis.
More than fifty compounds were isolated from O. Stamineus. They were tested
their antioxidant activity using inhibition of NO production in LPS-activated
machropage-like J774.1 cells. Siphonol A C and E, 2-O-deacethylorthosiphol J,
orthosiphol A, B, D, H, K, M, N, O, X, Y staminol A, neoorthosiphol B, Staminols C and
D, orthosiphonones C and D and 14-deoxo-14-O-acetylorthosiphol Y,
nororthosiphonolide A, orthosiphonone A, secoorthosiphols B and C and 3-O-
deacetylorthosiphol I showed stronger antioxidative activity than NG-monomethyl-L-
arginine as positive control. 2-O-deacetylorthosiphonone I, showed the most potent
activity, with an IC50 value of 35.0 M. (Adnyana , Setiawan , & Insanu, 2013). The
plants strong anti-oxidant action is what makes many researchers to explore the potential
pharmacological properties of this plant (Abdul Majid, 2010).
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2.2 Diuretic Activity
One of earlier research works reported that, because of the high content of
potassium, inositol and lipophilic flavones in the leaves of O. stamineus it possesses
strong diuretic activity. (Abdul Majid, 2010). Diuretic activity of hydroalcohol extract
from aerial parts of O. stamineus was reported. At a dose of 50 mg/kg, this extract
showed similar effect with hydrochlorotiazide at a dose of 10 mg/kg (Beaux, Fleurentin,
& Mortier, 1999). Other studies reported that an aqueous extract and leaves tincture
enhanced ion excretion of rats which were not due to the potassium content of the starting
material (Englert & Harnischfeger, 1992) (Cicero, Sando, Izzo, Vasta, Trimarco, &
Borghi, 2012)..
A study for (Kannappan, Madhukar, Marymmal, Sindhura, & Mannavalan, 2012)
showed that the administration of methanol extract at doses of 100 and 200 mg/kg bw
significantly decreased serum creatinine levels, blood urea, urinary protein and extent
renal damage after 10 days administration.
The results of (Arafat, Tham, Sadikun, Zhari, Haughton, & Asmawi, 2008) study
showed that, sodium and potassium excretion increased significantly (p < 0.05 and
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2012). Sinensetin has a wide range of biological activities such as antibacterial,
antifungal, antitumor, anticancer, prostaglandin binding and insect antifeedant (Hossain
& Ismail, 2012).
Many studies investigated about the Sinensetin in O. stamineus and the
Anticancer Activity, especially for breast cancer. Over 60% of breast cancer cases are
Estrogen Receptor (ER+) positive which is highly dependent on estrogen for growth.
Tamoxifen is a potent antagonist of ER and has been approved to be the first line anti-
estrogen therapy since the early 1970s . However, most tamoxifen sensitive breast cancer
cases succumb to tamoxifen resistance leading to poor prognosis . The resistance that is
developed is mainly due to cross-talk between ER and type 1 tyrosine kinase receptors,
including Epidermal Growth Factor Receptor (EGFR) and human epidermal growth
factor receptor 2 (HER2). These two cytokines are forund to be up-regulated during
tamoxifen treatment leading to further progression of breast cancer. In addition, up-
regulation of bcl-2 and cycloxigenase-2 (COX-2), which are key players in tenor
development, also contribute to tamoxifen resistance (Sahib, Ismail, Othman, & Abdul
Majid, 2009). O. stamineus as Synergistic enhancer to tamoxifen, it may probably exert
the anti-estogenic effect (Abdul Majid, 2010). In (Dolekov, Rrov, Grz, Vondrusov,
Strnad, & Krytof, 2012) study, the antiproliferative properties of a chloroform extract of
the leaves of O.stamineus and of pure eupatorin. The compound was able to reduce the
number of viable cancer cells to the same extent as the extract, with IC50 values in
micromolar range.
Recently, methanolic extract of O. stamineus was found to have potent anti-
angiogenic activity in vitro. However, molecular modeling data and immune-
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histochemical analysis reveal that this activity occurs due to direct inhibition of the
Vascular Endothelial Growth Factor Receptors (VEGFR). Previous studies have shown
that (VEGFR) are present on the surface of hormone sensitive breast cancer cell line
MCF-7. (Sahib, Ismail, Othman, & Abdul Majid, 2009).
2.4 Anti-diabetic
In (Sriplang, Adisakwattana, Rungsipipat, & Yibchok-anun, 2007) study, when
oral glucose tolerance is tested, the water extract at doses of 0.21.0 g/kg significantly
decreased plasma glucose concentration in dose-dependent manner for both normal and
diabetic rats. At a dose of 1.0 g/kg showed similar effect with glibenclamide (5 mg/kg).
In diabetic rats, after they were given the extract orally (0.5 g/kg) for 14 days, plasma
glucose concentrations were reduced significantly. In addition, plasma triglyceride
concentration was also lower in the extract-treated diabetic rats than that of untreated
group.
Other study showed antidiabetic effects of the petroleum, chloroform, methanol
and water extracts. Chloroform extract at a dose of 1 g/kg bw significantly reduced blood
glucose level. Further, this extract was fractionated and finally one subfraction showed
similar antidiabetic effect with metformin (Mohamed, Mohamed, Asmawi, Sadikun,
Ebrika, & Yam, 2011).
In (Mohamed, Yam, Ang, Mohamed, & Asmawi, 2013) study, the results showed
that, the chloroform sub-fraction 2 (Cf 2-b) of O.stamineus extract at a dose of 1 g/kg
twice daily on diabetic rats for 14 days showed a significant lowering (p < 0.05) of the
final blood glucose level compared to the pretreatment level.
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2.5 Anti-Fungal Agents
The increasing social and economic implications caused by fungi means there is a
constant striving to produce safer food crops and to develop new anti-fungal agents. In
general, plant-derived essential oils are considered as non-phytotoxic compounds and
potentially effective against plant pathogenic fungi. In recent years, interests have been
generated in the development of safer anti-fungal agents such as plant-based essential oils
and extracts to control phytopathogens in agriculture. Several publications have
documented the anti-fungal activities of essential oils and plant extracts. (Hossain, Ismail,
Rahman, & Kang, 2008).
In 1985, Gurin and Rveillre tested a hydro-alcoholic extract of Orthosiphon
stamineus (DER = 20%) against 9 fungal species. They showed it inhibited the spore
germination in 6 fungal species (Saccharomyces pastorius, Candida albicans, Rhizopus
nigricans, Penicillium digitatum, Fusarium oxysporum, Trichophyton mentagrophytes)
and delayed the growth of remaining species (Aspergillus fumigatus, Aspergillus niger,
Botrytis cinerea). The authors mentioned that the antifungal activity of Orthosiphon
stamineus had not been established before. Consequently, further research on this plant
had to be performed ((HMPC), 2010). The hydrodistillation of the leaves and stems of O.
stamineus gave dark yellowish oils with the major components of the oils having
oxygenated monoterpenes and sesquiterpenes, and their respective hydrocarbons
(Hossain, Ismail, Rahman, & Kang, 2008). Same study concluded that, the active
antimicrobial compounds of essential oils are terpenes derived from O. stamineus, which
are phenolic in nature, it would seem reasonable that their antimicrobial or anti-fungal
mode of action might be related to that of other compounds.
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2.6 Other Activities
O. stamineus as a remedy for kidney stones and gout Deposition of precipitates of
calcium oxalate crystals lead to the condition commonly known as kidney stones, which
can be easily diagnosed by radiological studies or ultrasound examination. This kind of
crystal is difficult to be dissolved and expelled successfully out from the body with
clinical therapy, however certain medications proved to be act as prophylactic agents in
preventing the calcium stones if they have a propensity to recur (Abdul Majid, 2010).
O. stamineus is listed in the French, Indonesia, Dutch, and Swiss pharmacopoeias
for conditions related to renal cleansing and function, and related disorders that include
nephritis, cystitis, and urethritis. In Europe, people use the leaves of O. stamineus extract
as a tonic for kidney and bladder stones, liver and gallbladder problems and urinary tract
infections. It is also used to reduce cholesterol and blood pressure. Researchers have
found it to be mildly antiseptic as well (Abdul Majid, 2010).
(Ho, Noryati, Sulaiman, & Rosma, 2010) study showed that the highest
concentration of rosmarinic acid had the best antibacterial and free radical scavenging
activities. This suggests that rosmarinic acid content is closely associated with
antibacterial and free radical scavenging activities of O.stamineus extracts.
The anti-hyperglycemic effect of O. stamineus was evaluated by (Sriplang,
Adisakwattana, Rungsipipat, & Yibchok-anun, 2007) study. It found the evidence of a
direct stimulatory effect of the Orthosiphon stamineus extract on insulin secretion from
the pancreatic beta cells.
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3. Extraction & Bioprocesses
Leaf powder of Orthosiphon stamineus was extracted with the following solvents;
distilled water, 50% aqueous methanol, methanol, 70% aqueous acetone and chloroform,
at 2, 4 and 8 h, respectively, on a water bath at 40 C (Akowuah, Ismail, Norhayati, &
Sadikun, 2005). The plant was oven-dried at 40 C and the leaves were separated and
grounded into fine powder. The powdered material (360 g) was extracted sequentially by
adding 30 g in each flask with 200 mL of petroleum ether with continuous shaking for
8h. The residue will be dried and extracted successively with chloroform, methanol and
water. The extracts were concentrated under vacuum at 40 C and freeze dried under
vacuum (Sahib, Ismail, Othman, & Abdul Majid, 2009) (Hossain, Ismail, Rahman, &
Kang, 2008) (Adam, et al., 2009).
In some studies, the extraction process will be different from the others. For
example, in (Hossain & Ismail, 2012) study, the dry powder methanol will heat below 40
C with ultra-sonication for 30 min . (Abdullah, Shaari, & Azimi, 2012) study showed
that Stamineus leaves were dried by using three different methods; an oven at 40 oC,
under the shade and directly under the sun were dried for 4 days.
4. Chemical Compounds
Orthosiphon stamineus extractions were more than hundreds chemical
compounds, these compounds were reported and classified as terpenoids (monoterpenes,
diterpenes, triterpenes), polyphenols (lipophilic flavonoids and phenolic acids), saponins,
flavonoids, polyphenols (lipophilic flavonoids and phenolic acids), organic acids, etc, as
shown in Table (1). (Adnyana , Setiawan , & Insanu, 2013) (Rahman & Hossain, 2011).
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Table (1): Chemical compounds present in Orthosiphon stamineus Benth
NO Chemical compounds NO Chemical compounds
1 1-octen-3-ol 30 Betulinic acid
2 2,3-dicaffeoyltartaric acid 31 Borneol
3 2-O-deacetylorthosiphol J 32 Bornyl acetate
4 3-hydroxy-5,6,7,4-tetramethoxyflavone 33 Caffeic Acid
5 3-O-deacetylorthosiphol I 34 Caffeic acid depside A
6 4-hydroxy-5,6,7-trimethoxyflavone 35 Caffeic acid depside B
7 4,5,6,7-tetramethoxyflavone 36 Caffeic acid depside C
8 5,6-dihydroxy-7,4-dimethoxyflavone 37 Camphene
9 5,7,4'-Trimethylapigenin 38 Camphor
10 5,6,7,4-tetramethoxyflavone 39 Carotol
11 5,7,3',4'-tetramethylluteolin 40 Carvone
12 5-hydroxy-6,7,3',4-tetramethoxyflavone 41 Cis-Caryophyllene
13 6-hydroxyorthosiphol B 42 Caryophyllene oxide
14 6-hydroxy-5,7,4'-trimethoxyflavone 43 Cichoric acid
15 7,3,4-tri-O-methylluteolin 44 Cisimaritin
16 7-O-deacetylorthosiphol B 45 Eugenol
17 14-deoxo-14-O-acetylorthosiphol Y 46 Eupatorin
18 cadinol 47 Hederagenin
19 -humulene 48 Ladanein
20 -bourbonene 49 Limonene
21 caryophyllene 50 Luteolin
22 -elemene 51 Methylripariochromene A
23 -pinene 52 Neoorthosiphol A
24 sitosterol 53 Neoorthosiphol B
25 carryophylene 54 Neoorthosiphone A
26 -hydroxybetulinic acid 55 Norstaminol A
27 -cadinene 56 Norstaminol B
28 Acetovanillchromene 57 Norstaminol C
29 Aurantiamide acetate 58 Norstaminolactone A
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59 Nororthosiphonolide A 88 Orthosiphol Z
60 Norstaminone A 89 Orthosiphonone A
61 Oleanolic acid 90 Orthosiphonone B
62 Orthochromene A 91 Orthosiphonone C
63 Orthosiphol A 92 Orthosiphonone D
64 Orthosiphol B 93 Pillion
65 Orthosiphol C 94 Quercetin
66 Orthosiphol D 95 Rosmarinic acid
67 Orthosiphol E 96 Salvigenin
68 Orthosiphol F 97 Secoorthosiphol A
69 Orthosiphol G 98 Secoorthosiphol B
70 Orthosiphol H 99 Secoorthosiphol C
71 Orthosiphol I 100 Sinensetin
72 Orthosiphol J 101 Siphonol A
73 Orthosiphol K 102 Siphonol B
74 Orthosiphol L 103 Siphonol C
75 Orthosiphol M 104 Siphonol D
76 Orthosiphol N 105 Siphonol E
77 Orthosiphol O 106 Staminol A
78 Orthosiphol P 107 Staminol B
79 Orthosiphol Q 108 Staminol C
80 Orthosiphol R 109 Staminol D
81 Orthosiphol S 110 Staminolactone A
82 Orthosiphol T 111 Staminolactone B
83 Orthosiphol U 112 Tetramethylscutellarine
84 Orthosiphol V 113 Trans-ozic acid
85 Orthosiphol W 114 Ursolic acid
86 Orthosiphol X 115 Vomifoliol
87 Orthosiphol Y 116 16-hydroxy betulinic acid
Source : (Adnyana , Setiawan , & Insanu, 2013)
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Moreover, previous research have detected 69 chemical compounds in the
essential oil of leaves of O. Stamineus. They were:
Table (2): Chemical compounds in the essential oil of leaves of O. Stamineus
1-Octen-3-ol -Bourbene -Pinene
2-Methylnapthalene -Ionone Safranal
3-Octanol 2-Pentenyl furane Naphtalene
6-Trimethyl-2-cyclohexe-1 4-dione Isobornylacetate
8-Cineol 4-Heptenal Isomenthone
Benzaldehyde trans 2-Hexanal Heptenal
Borneol Dodecane Eugenol
Camphor 1-Methylnaphtalene -Muniolene
Carvone Cittonellol -Copaene
cis-2-Octenal Limonene Hexanal
cis-Caryophylene 4-dienal trans-Deca-2
Damascenone Dehydroionone cis-Linalooloxide
Geranylacetane -Terpineol Acetophenone
Hexahydrofamesylacetone Hexan-1-ol Germacrene
Linalool trans-Linalooloxide -Cadipene
Methylchavicol -Pinene,Tridecan -Cymene
Phenylacetaldehyde Caryophyllene oxide Camphene
trans- Anethol Germacrene D -Cyclocitral
trans cis-Octa-3-5-dien-2-one Decanal -Elemene
trans trans-Octa-3-5-dien-2-one 2-Amylfurane Menthone
trans-2-(cis)-6- Nonadienale Methyleugenol -Gubebene
Undecan Bornyl Acetate Perillen
-Carryophyllene -Humulene -Elemene
Source : (Hossain, Ismail, Rahman, & Kang, 2008)
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Figure (2): Structures of Orthosiphon stamineus active compounds: (A) rosmarinic acid,
(B) sinensetin, and (C) eupatorin . (Pan, et al., 2011) .
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5. Conclusion
As the above said, Orthosiphon stamineus was used and planted in Southeast
Asia. Recently,O. stamineus is widely used in many countries for treatment of kidney,
bladder inflammation, diabetes mellitus, hypertension, rheumatism, tonsillitis and
menstrual disorder. So, there are more potential utilization and development of O.
stamineus out of Asia, especially out of Malaysia.
Obviously, the chemical components and pharmacology activities of O. stamineus
have been studied, and many active compounds were isolated and identified. Of these,
due to the good antibacterial, anticancer, antioxidant and anti-tumor activities, methanol,
acetone and chloroform were used to extract the compound to characterize the quality of
O. stamineus. The different habitat, medicinal parts, extraction methods and solvents,
fresh flowers and dry flowers would result in the different chemical compositions and the
quality of O. stamineus. In Malaysia, O. stamineus was only used to treat some diseases.
But the results of phytochemical researches indicated that this plant capable to produce
many compounds with many activities, such as : anti-oxidant, diuretic, anti-cancer, anti-
diabetic, anti-fungal and anti-bacterial activities, production of essential oils, flavones,
iridoids and so more. these components can be the active parts to treat diseases.
In a word, phytochemical and pharmacological studies of O. stamineus have
received much interest, more and more extracts and active compounds have been isolated
and proved which has the anti-cancer, antiviral, antibacterial, antioxidant and enhance the
immune response effects, etc. Further research especially on in vitro/in vivo antibacterial
and anticancer effects should have priority.
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6. References
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