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Fulltext The growth suppressing effects of girinimbine on HepG2 involve induction of apoptosis and cell cycle arrest

Syam S, Abdul AB, Sukari MA, Mohan S, Abdelwahab SI, Wah TS

Molecules, 2011 Aug 23;16(8):7155-70.
PMID: 21862957 DOI: 10.3390/molecules16087155

Murraya koenigii is an edible herb widely used in folk medicine. Here we report that girinimbine, a carbazole alkaloid isolated from this plant, inhibited the growth and induced apoptosis in human hepatocellular carcinoma, HepG2 cells. The MTT and LDH assay results showed that girinimbine decreased cell viability and increased cytotoxicity in a dose-and time-dependent manner selectively. Girinimbine-treated HepG2 cells showed typical morphological features of apoptosis, as observed from normal inverted microscopy and Hoechst 33342 assay. Furthermore, girinimbine treatment resulted in DNA fragmentation and elevated levels of caspase-3 in HepG2 cells. Girinimbine treatment also displayed a time-dependent accumulation of the Sub-G(0)/G(1) peak (hypodiploid) and caused G(0)/G(1)-phase arrest. Together, these results demonstrated for the first time that girinimbine could effectively induce programmed cell death in HepG2 cells and suggests the importance of conducting further investigations in preclinical human hepatocellular carcinoma models, especially on in vivo efficacy, to promote girinimbine for use as an anticancer agent against hepatocellular carcinoma.
Zerumbone induces apoptosis in T-acute lymphoblastic leukemia cells

Abdelwahab SI, Abdul AB, Mohan S, Taha MM, Syam S, Ibrahim MY, et al.

Leuk. Res., 2011 Feb;35(2):268-71.
PMID: 20708800 DOI: 10.1016/j.leukres.2010.07.025

Zerumbone (ZER) is a potential anticancer natural compound, isolated from Zingiber zerumbet Smith. In this investigation, the anticancer properties of ZER were evaluated on cancer cells of T-acute lymphoblastic leukemia, CEM-ss. The results showed that ZER has cytotoxic effect against CEM-ss cells with an IC(50) of 8.4 ± 1.9 μg/ml (coefficient of variation < 30%). Comparatively, 5-fluorouracil (positive control), imposed an inhibitory effect on CEM-ss cells with an IC(50) of 1.94 ± 0.06 μg/ml. Scanning electron microscopy (SEM) results revealed abnormalities such as membrane blebbing, holes and cytoplasmic extrusions, all of which are characteristics of apoptosis. In addition, ZER has increased the number of TUNEL-positive stain and the cellular level of caspase-3, the hallmarks of apoptosis, on treated CEM-ss cells. It could be concluded that, ZER was able to produce apoptosis on T-acute lymphoblastic leukemia, CEM-ss. The current findings suggest that ZER might be helpful for improving the usefulness of anticancer agents in the therapy of leukemia.
Fulltext In Vitro Ultramorphological Assessment of Apoptosis on CEMss Induced by Linoleic Acid-Rich Fraction from Typhonium flagelliforme Tuber

Mohan S, Bustamam A, Ibrahim S, Al-Zubairi AS, Aspollah M, Abdullah R, et al.

Evid Based Complement Alternat Med, 2011;2011:421894.
PMID: 21785623 DOI: 10.1093/ecam/neq010

The plant Typhonium flagelliforme, commonly known as "rodent tuber" in Malaysia, is often used as a health supplement and traditional remedy for alternative cancer therapies, including leukemia. This study aimed to evaluate in vitro anti-leukemic activity of dichloromethane extract/fraction number 7 (DCM/F7) from T. flagelliforme tuber on human T4 lymphoblastoid (CEMss) cell line. The DCM extract of tuber has been fractionated by column chromatography. The obtained fractions were evaluated for its cytotoxicity toward CEMss cells as well as human primary blood lymphocytes (PBLs). Assessment of apoptosis produced by the most active fraction was evaluated by various microscopic techniques and further confirmation of apoptosis was done by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Phytochemical screening was done by gas chromatography-mass spectrometry (GC-MS). The results shows that 7 out of 12 fractions showed significant cytotoxicity against the selected cell line CEMss, in which fractions DCM/F7, DCM/F11 and DCM/F12 showed exceptional activity with 3, 5 and 6.2 μg ml(-1), respectively. Further studies in the non-cancerous PBL exhibited significant selectivity of DCM/F7 compared to other fractions. Cytological observations showed chromatin condensation, cell shrinkage, abnormalities of cristae, membrane blebbing, cytoplasmic extrusions and formation of apoptotic bodies as confirmed collectively by double-staining of acridine orange (AO)/propidium iodide (PI), SEM and TEM. In addition, DCM/F7 has increased the cellular DNA breaks on treated cells. GC-MS revealed that DCM/F7 contains linoleic acid, hexadecanoic acid and 9-hexadecanoic acid. The present results indicate that T. flagelliforme possess a valuable anti-leukemic effect and was able to produce distinctive morphological features of cell death that corresponds to apoptosis.
Fulltext Antiapoptotic and Antioxidant Properties of Orthosiphon stamineus Benth (Cat's Whiskers): Intervention in the Bcl-2-Mediated Apoptotic Pathway

Abdelwahab SI, Mohan S, Mohamed Elhassan M, Al-Mekhlafi N, Mariod AA, Abdul AB, et al.

Evid Based Complement Alternat Med, 2011;2011:156765.
PMID: 21234328 DOI: 10.1155/2011/156765

Antiapoptotic and antioxidant activities of aqueous-methanolic extract (CAME) of Orthosiphonstamineus Benth(OS), and its hexane (HF), chloroform (CF), n-butanol (NBF), ethyl acetate (EAF) and water (WF) fractions were investigated. Antioxidant properties were evaluated using the assays of Folin-Ciocalteu, aluminiumtrichloride, β-carotene bleaching and DPPH. The role of OS against hydrogen peroxide induced apoptosis on MDA-M231 epithelial cells was examined using MTT assay, phase contrast microscope, colorimetric assay of caspase-3, western blot and quantitative real-time PCR. Results showed that EAF showed the highest total phenolic content followed by CAME, NBF, WF, CF and HF, respectively. Flavonoid content was in the order of the CF > EAF > HF > CAME > NBF > WF. The IC(50) values on DPPH assay for different extract/fractions were 126.2 ± 23, 31.25 ± 1.2, 15.25 ± 2.3, 13.56 ± 1.9, 23.0 ± 3.2, and 16.66 ± 1.5 μg/ml for HF, CF, EAF, NBF, WF and CAME, respectively. OSreduced the oxidation of β-carotene by hydroperoxides. Cell death was dose-dependently inhibited by pretreatment with OS. Caspase-3 and distinct morphological features suggest the anti-apoptotic activities of OS. This plant not only increased the expression of Bcl-2, but also decreased Bax expression, and ultimately reduced H(2)O(2)-induced apoptosis. The current results showed that phenolics may provide health and nutritional benefits.
Fulltext Eleucine indica Possesses Antioxidant, Antibacterial and Cytotoxic Properties

Al-Zubairi AS, Abdul AB, Abdelwahab SI, Peng CY, Mohan S, Elhassan MM

Evid Based Complement Alternat Med, 2011;2011:965370.
PMID: 19617201 DOI: 10.1093/ecam/nep091

The use of evidence-based complementary and alternative medicine is increasing rapidly. Eleucine indica (EI) is traditionally used in ailments associated with liver and kidneys. The therapeutic benefit of the medicinal plants is often attributed to their antioxidant properties. Therefore, the aim of this study was to screen the hexane, dicholoromethane, ethyl acetate (EA) and methanol extracts (MeTH) of EI for their antioxidant, antibacterial and anti-cancer effects using total phenolic contents (TPCs) and DPPH, disc diffusion method and MTT cytotoxicity assays, respectively. The MeTH was showed to have the highest TPC and scavenging activity (77.7%) on DPPH assay, followed by EA (64.5%), hexane (47.19%) and DCM (40.83%) extracts, whereas the MeTH showed no inhibitory effect on all tested bacteria strains. However, the EA extract exhibited a broad spectrum antibacterial activity against all tested bacteria except Bacillus subtilis, in which this bacterium was found to be resistant to all EI extracts. Meanwhile, hexane extract was demonstrated to have a remarkable antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, while the dicholoromethane extract did not exhibit significant activity against P. aeruginosa. None of the extracts showed significant cytotoxic activity towards MCF-7, HT-29 and CEM-SS human cancer cell lines after 72 h incubation time (IC(50) > 30 μg/ml). These results demonstrate that the extract prepared from the EI possesses antioxidant activity in vitro in addition to antibacterial properties. Further investigations are needed to verify the antioxidant effects in vitro and in vivo.
Typhonium flagelliforme inhibits the proliferation of murine leukemia WEHI-3 cells in vitro and induces apoptosis in vivo

Mohan S, Abdul AB, Abdelwahab SI, Al-Zubairi AS, Aspollah Sukari M, Abdullah R, et al.

Leuk. Res., 2010 Nov;34(11):1483-92.
PMID: 20569984 DOI: 10.1016/j.leukres.2010.04.023

Typhonium flagelliforme (TF) is a tropical plant, traditionally used by the ethnic population of Malaysia for the cure of various cancers. This plant had shown to induce antiproliferative effect as well as apoptosis in cancer cells. However, there is no available information to address that TF affects murine leukemia cells in vitro and in vivo. Here, we investigated in vitro and in vivo effects of TF on murine leukemia WEHI-3 cells. It was found that the growth of leukemia cells in vitro was inhibited by the various extracts of TF. Among these fractions, the dichloromethane (DCM) tuber extracts of TF showed the lowest IC(50) (24.0 ± 5.2 μg/ml) and had demonstrated apoptogenic effect when observed under fluorescent microscope. We investigated the in vivo effects of DCM tuber extracts of TF on murine leukemia cells, and the results showed that the counts of immature granulocytes and monocytes were significantly decreased in peripheral blood of BALB/c leukemia mice after the oral administration of DCM tuber extracts of TF for 28 days with three doses (200, 400 and 800 mg/kg). These results were confirmed by observing the spleen histopathology and morphology of enlarged spleen and liver in leukemia mice when compared with the control. Furthermore, the cell death mechanism in the spleen tissue of treated mice was found via apoptosis.
Typhonium flagelliforme induces apoptosis in CEMss cells via activation of caspase-9, PARP cleavage and cytochrome c release: its activation coupled with G0/G1 phase cell cycle arrest

Mohan S, Abdul AB, Abdelwahab SI, Al-Zubairi AS, Sukari MA, Abdullah R, et al.

J Ethnopharmacol, 2010 Oct 5;131(3):592-600.
PMID: 20673794 DOI: 10.1016/j.jep.2010.07.043

The plant Typhonium flagelliforme (TF), commonly known as 'rodent tuber' in Malaysia, is often used as traditional remedy for cancer, including leukemia.
Regression of cervical intraepithelial neoplasia by zerumbone in female Balb/c mice prenatally exposed to diethylstilboestrol: involvement of mitochondria-regulated apoptosis

Abdelwahab SI, Abdul AB, Devi N, Taha MM, Al-zubairi AS, Mohan S, et al.

Exp. Toxicol. Pathol., 2010 Sep;62(5):461-9.
PMID: 19581075 DOI: 10.1016/j.etp.2009.06.005

Cervical cancer is the second most common cause of cancer death in women. We have demonstrated previously that zerumbone (ZER) has an anti-cancer effect towards human cervical cancer cells (HeLa).
Fulltext Potential chemoprevention of diethylnitrosamine-initiated and 2-acetylaminofluorene-promoted hepatocarcinogenesis by zerumbone from the rhizomes of the subtropical ginger (Zingiber zerumbet)

Taha MM, Abdul AB, Abdullah R, Ibrahim TA, Abdelwahab SI, Mohan S

Chem Biol Interact, 2010 Aug 05;186(3):295-305.
PMID: 20452335 DOI: 10.1016/j.cbi.2010.04.029

Zerumbone (ZER), a monosesquiterpene found in the subtropical ginger (Zingiber zerumbet Smith), possesses antiproliferative properties to several cancer cells lines, including the cervical, skin and colon cancers. In this study, the antitumourigenic effects of ZER were assessed in rats induced to develop liver cancer with a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and dietary 2-acetylaminofluorene (AAF) (0.02%). The rats also received intraperitoneal ZER injections at 15, 30 or 60 mg/kg body wt. twice a week for 11 weeks, beginning week four post-DEN injection. The hepatocytes of positive control (DEN/AAF) rats were smaller with larger hyperchromatic nuclei than normal, showing cytoplasmic granulation and intracytoplasmic violaceous material, which were characteristics of hepatocarcinogenesis. Histopathological evaluations showed that ZER protects the rat liver from the carcinogenic effects of DEN and AAF. Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (AP) and alpha-fetoprotein (AFP) were significantly lower (P<0.05) in ZER-treated than untreated rats with liver cancer. The liver malondialdehyde (MDA) concentrations significantly (P<0.05) increased in the untreated DEN/AAF rats indicating hepatic lipid peroxidation. There was also significant (P<0.05) reduction in the hepatic tissue glutathione (GSH) concentrations. The liver sections of untreated DEN/AAF rats also showed abundant proliferating cell nuclear antigen (PCNA), while in ZER-treated rats the expression of this antigen was significantly (P<0.05) lowered. By the TUNEL assay, there were significantly (P<0.05) higher numbers of apoptotic cells in DEN/AAF rats treated with ZER than those untreated. Zerumbone treatment had also increased Bax and decreased Bcl-2 protein expression in the livers of DEN/AAF rats, which suggested increased apoptosis. Even after 11 weeks of ZER treatment, there was no evidence of abnormality in the liver of normal rats. This study suggests that ZER reduces oxidative stress, inhibits proliferation, induces mitochondria-regulated apoptosis, thus minimising DEN/AAF-induced carcinogenesis in rat liver. Therefore, ZER has great potential in the treatment of liver cancers.
Fulltext Antidiarrhoeal Activity of Leaves of Melastoma malabathricum Linn

Sunilson JA, Anandarajagopal K, Kumari AV, Mohan S

Indian J Pharm Sci, 2009 Nov;71(6):691-5.
PMID: 20376227 DOI: 10.4103/0250-474X.59556

The antidiarrhoeal effect of the water extract of Melastoma malabathricum Linn. (Melastomataceae) leaves were investigated by employing four experimental models of diarrhea in Swiss mice. Melastoma malabathricum water extract treated mice showed significant reduction in the fecal output and protected them from castor oil-induced diarrhoea. The extract also reduced the intestinal fluid secretion induced by magnesium sulphate and gastrointestinal motility after charcoal meal administration in the mice. No mortality and visible signs of general weakness was observed in the mice following the test extract administration up to 2000 mg/kg dose.
Fulltext In vitro ultramorphological assessment of apoptosis induced by zerumbone on (HeLa)

Abdel Wahab SI, Abdul AB, Alzubairi AS, Mohamed Elhassan M, Mohan S

J Biomed Biotechnol, 2009;2009:769568.
PMID: 19343171 DOI: 10.1155/2009/769568

Zerumbone (ZER), a potential anticancer compound, isolated from the fresh rhizomes of Zingiber zerumbet. In this investigation, the cytotoxic properties of ZER were evaluated, on cancer cells of human cervix (HeLa), breast and ovary, and normal cells of Chinese Hamster ovary, using MTT assay. Apoptogenic effects of ZER on HeLa were studied using fluorescence microscopy (AO/PI double staining), scanning and transmission electron microscopy (SEM and TEM), and colorimetric assay of the apoptosis promoter enzyme, caspase-3. The results of MTT assay showed that ZER has less effect on normal cells compared to cancer cells. The lowest IC(50) of ZER was observed on HeLa cells. Cytological observations showed nuclear and chromatin condensation, cell shrinkage, multinucleation, abnormalities of mitochondrial cristae, membrane blebbing, holes, cytoplasmic extrusions and formation of apoptotic bodies as confirmed collectively by double staining of AO/PI, SEM and TEM. Statistical analysis (two-tailed t-test) of differential counting of 200 cells under fluorescence microscope revealed significant difference in apoptotic cells populations between treated and untreated HeLa cells. In addition, ZER has increased the cellular level of caspase-3 on the treated HeLa cells. It could be concluded that ZER was able to produce distinctive morphological features of cell death that corresponds to apoptosis.
Modulation of intraocular pressure by unilateral and forced unilateral nostril breathing in young healthy human subjects

Mohan SM, Reddy SC, Wei LY

Int Ophthalmol, 2001;24(6):305-11.
PMID: 14750567

PURPOSE: To determine the effects of unilateral right/left nostril breathing (URNB/ULNB) and forced unilateral right/left nostril breathing (FURNB/FULNB) on intraocular pressure (IOP) and to examine the differences in the IOP during the various phases of nasal cycle.
METHODS: Young healthy volunteers of either sex aged between 19-24 years, participated in the sessions using URNB/ULNB (n = 52) and FURNB/FULNB (n = 28). The nostril dominance was calculated from signals recorded on the PowerLab equipment, representing pressure changes at the end of the nostrils during respiration. The IOP was measured with Tono-Pen. The subjects were divided into 4 groups viz. right nostril dominant (RND), left nostril dominant (LND), transitional right nostril dominant (TRND) and transitional left nostril dominant (TLND) groups. The IOP data 'before and after' URNB/ULNB or FURNB/FULNB were compared by using paired t-test. The baseline data of IOP between the groups were analysed by using independent samples t-test.
RESULTS: The URNB decreased the IOP in the LND and TLND (p < 0.01) and also in the RND (p < 0.05) groups but not significantly in the TRND group. The ULNB decreased the IOP in the RND group (p < 0.01) only. The FURNB significantly reduced the IOP (p < 0.05) only in the LND and RND groups. The FULNB decreased the IOP but not significantly. The baseline IOP did not differ significantly between the LND, RND, TLND and TRND groups.
CONCLUSION: The URNB/FURNB reduced the IOP, while ULNB/FULNB failed to increase the IOP significantly. It is suggested that the lowering of IOP by URNB indicated sympathetic stimulation.

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