Displaying publications 1 - 20 of 101 in total

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  1. Annona muricata leaves induce G₁ cell cycle arrest and apoptosis through mitochondria-mediated pathway in human HCT-116 and HT-29 colon cancer cells
    Zorofchian Moghadamtousi S, Karimian H, Rouhollahi E, Paydar M, Fadaeinasab M, Abdul Kadir H
    J Ethnopharmacol, 2014 Oct 28;156:277-89.
    PMID: 25195082 DOI: 10.1016/j.jep.2014.08.011
    ETHNOPHARMACOLOGICAL RELEVANCE: Annona muricata known as "the cancer killer" has been widely used in the traditional medicine for the treatment of cancer and tumors. The purpose of this study is to investigate the anticancer properties of ethyl acetate extract of Annona muricata leaves (EEAM) on HT-29 and HCT-116 colon cancer cells and the underlying mechanisms.
    MATERIALS AND METHODS: The effect of EEAM on the cell proliferation of HT-29 and HCT-116 cells was analyzed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay. High content screening system (HCS) was applied to investigate the cell membrane permeability, mitochondrial membrane potential (MMP), nuclear condensation and cytochrome c translocation from mitochondria to cytosol. Reactive oxygen species (ROS) formation, lactate dehydrogenase (LDH) release and activation of caspase-3/7, -8 and -9 were measured while treatment. Flow cytometric analysis was used to determine the cell cycle distribution and phosphatidylserine externalization. The protein expression of Bax and Bcl-2 was determined using immunofluorescence analysis. In addition, the potential of EEAM to suppress the migration and invasion of colon cancer cells was also examined.
    RESULTS: EEAM exerted significant cytotoxic effects on HCT-116 and HT-29 cells as determined by MTT and LDH assays. After 24 h treatment, EEAM exhibited the IC₅₀ value of 11.43 ± 1.87 µg/ml and 8.98 ± 1.24 µg/ml against HT-29 and HCT-116 cells, respectively. Flow cytometric analysis demonstrated the cell cycle arrest at G1 phase and phosphatidylserine externalization confirming the induction of apoptosis. EEAM treatment caused excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage and activation of the initiator and executioner caspases in both colon cancer cells. Immunofluorescence analysis depicted the up-regulation of Bax and down-regulation of Bcl-2 proteins while treated with EEAM. Furthermore, EEAM conspicuously blocked the migration and invasion of HT-29 and HCT-116 cells.
    CONCLUSIONS: These findings provide a scientific basis for the use of A. muricata leaves in the treatment of cancer, although further in vivo studies are still required.
    Matched MeSH terms: bcl-2-Associated X Protein/metabolism
  2. Fulltext The chemopotential effect of Annona muricata leaves against azoxymethane-induced colonic aberrant crypt foci in rats and the apoptotic effect of Acetogenin Annomuricin E in HT-29 cells: a bioassay-guided approach
    Zorofchian Moghadamtousi S, Rouhollahi E, Karimian H, Fadaeinasab M, Firoozinia M, Ameen Abdulla M, et al.
    PLoS One, 2015;10(4):e0122288.
    PMID: 25860620 DOI: 10.1371/journal.pone.0122288
    Annona muricata has been used in folk medicine for the treatment of cancer and tumors. This study evaluated the chemopreventive properties of an ethyl acetate extract of A. muricata leaves (EEAML) on azoxymethane-induced colonic aberrant crypt foci (ACF) in rats. Moreover, the cytotoxic compound of EEAML (Annomuricin E) was isolated, and its apoptosis-inducing effect was investigated against HT-29 colon cancer cell line using a bioassay-guided approach. This experiment was performed on five groups of rats: negative control, cancer control, EEAML (250 mg/kg), EEAML (500 mg/kg) and positive control (5-fluorouracil). Methylene blue staining of colorectal specimens showed that application of EEAML at both doses significantly reduced the colonic ACF formation compared with the cancer control group. Immunohistochemistry analysis showed the down-regulation of PCNA and Bcl-2 proteins and the up-regulation of Bax protein after administration of EEAML compared with the cancer control group. In addition, an increase in the levels of enzymatic antioxidants and a decrease in the malondialdehyde level of the colon tissue homogenates were observed, suggesting the suppression of lipid peroxidation. Annomuricin E inhibited the growth of HT-29 cells with an IC50 value of 1.62 ± 0.24 μg/ml after 48 h. The cytotoxic effect of annomuricin E was further substantiated by G1 cell cycle arrest and early apoptosis induction in HT-29 cells. Annomuricin E triggered mitochondria-initiated events, including the dissipation of the mitochondrial membrane potential and the leakage of cytochrome c from the mitochondria. Prior to these events, annomuricin E activated caspase 3/7 and caspase 9. Upstream, annomuricin E induced a time-dependent upregulation of Bax and downregulation of Bcl-2 at the mRNA and protein levels. In conclusion, these findings substantiate the usage of A. muricata leaves in ethnomedicine against cancer and highlight annomuricin E as one of the contributing compounds in the anticancer activity of A. muricata leaves.
    Matched MeSH terms: bcl-2-Associated X Protein/genetics; bcl-2-Associated X Protein/metabolism
  3. GC-MS metabolomics revealed protocatechuic acid as a cytotoxic and apoptosis-inducing compound from black rice brans
    Yuliana ND, Tuarita MZ, Khatib A, Laila F, Sukarno S
    Food Sci Biotechnol, 2020 Jun;29(6):825-835.
    PMID: 32523792 DOI: 10.1007/s10068-019-00725-2
    GC-MS metabolomics was used to discriminate the phytochemicals profile of Indonesian white, red, and black rice brans, and Japanese white rice brans. This technique was used for the first time to identify compounds in rice brans having cytotoxic activity against WiDr colon cancer cells. Orthogonal Projection to the Latent Structure (OPLS) analysis showed that protocatechuic acid (PA) was a discriminating factor found in black rice brans which strongly correlated with its cytotoxicity (IC50 8.53 ± 0.26 µM). Real time-PCR data demonstrated that PA cytotoxicity at different concentrations (1, 5, 10, 25 and 50 µg/mL) was mediated through different pathways. Bcl-2 expression was downregulated at all tested concentrations indicating apoptosis stimulation. At 1-10 ppm concentration, PA activated both intrinsic and extrinsic apoptosis pathways since the expression of p53, Bax, caspase-8, and caspase-9 were upregulated. At a higher dose (25 and 50 µg/mL), PA possibly involved in pyroptosis-mediated pro-inflammatory cell death by upregulating the expression of caspase-1 and caspase-7.
    Matched MeSH terms: bcl-2-Associated X Protein
  4. Fulltext Molecular attributes and apoptosis-inducing activities of a putative serine protease isolated from Tiger Milk mushroom (Lignosus rhinocerus) sclerotium against breast cancer cells in vitro
    Yap HYY, Tan NH, Ng ST, Tan CS, Fung SY
    PeerJ, 2018;6:e4940.
    PMID: 29888137 DOI: 10.7717/peerj.4940
    Background: The highly valued medicinal tiger milk mushroom (also known as Lignosus rhinocerus) has the ability to cure numerous ailments. Its anticancer activities are well explored, and recently a partially purified cytotoxic protein fraction termed F5 from the mushroom's sclerotial cold water extract consisting mainly of fungal serine proteases was found to exhibit potent selective cytotoxicity against a human breast adenocarcinoma cell line (MCF7) with IC50 value of 3.00 μg/ml. However, characterization of its cell death-inducing activity has yet to be established.

    Methods: The mechanism involved in the cytotoxic activities of F5 against MCF7 cells was elucidated by flow cytometry-based apoptosis detection, caspases activity measurement, and expression profiling of apoptosis markers by western blotting. Molecular attributes of F5 were further mined from L. rhinocerus's published genome and transcriptome for future exploration.

    Results and Discussion: Apoptosis induction in MCF7 cells by F5 may involve a cross-talk between the extrinsic and intrinsic apoptotic pathways with upregulation of caspase-8 and -9 activities and a marked decrease of Bcl-2. On the other hand, the levels of pro-apoptotic Bax, BID, and cleaved BID were increased accompanied by observable actin cleavage. At gene level, F5 composed of three predicted non-synonymous single nucleotide polymorphisms (T > C) and an alternative 5' splice site.

    Conclusions: Findings from this study provide an advanced framework for further investigations on cancer therapeutics development from L. rhinocerus.

    Matched MeSH terms: bcl-2-Associated X Protein
  5. Fulltext Gastroprotective Effects of Lion's Mane Mushroom Hericium erinaceus (Bull.:Fr.) Pers. (Aphyllophoromycetideae) Extract against Ethanol-Induced Ulcer in Rats
    Wong JY, Abdulla MA, Raman J, Phan CW, Kuppusamy UR, Golbabapour S, et al.
    Evid Based Complement Alternat Med, 2013;2013:492976.
    PMID: 24302966 DOI: 10.1155/2013/492976
    Hericium erinaceus is a famous tonic in oriental medicine. The gastroprotective effects of aqueous extract of H. erinaceus against ethanol-induced ulcers in Sprague Dawley rats were investigated. The possible involvements of lipid peroxidation, superoxide dismutase, and catalase were also investigated. Acute toxicity study was performed. The effects of aqueous extract of H. erinaceus on the ulcer areas, ulcer inhibition, gastric wall mucus, gross and histological gastric lesions, antioxidant levels, and malondialdehyde (MDA) contents were evaluated in ethanol-induced ulcer in vivo. In acute toxicity study, a high dose of 5 g/kg did not manifest any toxicological signs in rats. The extract promoted ulcer protection as ascertained by a significant reduction of the ulcer area. Furthermore, it exhibited a significant protection activity against gastric mucosal injury by preventing the depletion of antioxidant enzymes. The level of MDA was also limited in rat stomach tissues when compared with the ulcer control group. Immunohistochemistry showed upregulation of HSP70 protein and downregulation of BAX protein in rats pretreated with the extract. The aqueous extract of H. erinaceus protected gastric mucosa in our in vivo model. It is speculated that the bioactive compounds present in the extract may play a major role in gastroprotective activity.
    Matched MeSH terms: bcl-2-Associated X Protein
  6. SRJ23, a new semisynthetic andrographolide derivative: in vitro growth inhibition and mechanisms of cell cycle arrest and apoptosis in prostate cancer cells
    Wong HC, Wong CC, Sagineedu SR, Loke SC, Lajis NH, Stanslas J
    Cell Biol Toxicol, 2014 Oct;30(5):269-88.
    PMID: 25070834 DOI: 10.1007/s10565-014-9282-5
    3,19-(3-Chloro-4-fluorobenzylidene)andrographolide (SRJ23), a new semisynthetic derivative of andrographolide (AGP), exhibited selectivity against prostate cancer cells in the US National Cancer Institute (NCI) in vitro anti-cancer screen. Herein, we report the in vitro growth inhibition and mechanisms of cell cycle arrest and apoptosis induced by SRJ23.
    Matched MeSH terms: bcl-2-Associated X Protein/metabolism
  7. Fulltext Phenolics Extracted from Jasminum sambac Mitigates Diabetic Cardiomyopathy by Modulating Oxidative Stress, Apoptotic Mediators and the Nfr-2/HO-1 Pathway in Alloxan-Induced Diabetic Rats
    Umar U, Ahmed S, Iftikhar A, Iftikhar M, Majeed W, Liaqat A, et al.
    Molecules, 2023 Jul 17;28(14).
    PMID: 37513325 DOI: 10.3390/molecules28145453
    Diabetes mellitus is a chronic metabolic disorder defined as hyperglycemia and pancreatic β-cell deterioration, leading to other complications such as cardiomyopathy. The current study assessed the therapeutic effects of phenolic acids extracted from Jasminum sambac phenols of leaves (JSP) against diabetes-induced cardiomyopathy in rats. The rats were divided into four groups, with each group consisting of 20 rats. The rats were given intraperitoneal injections of alloxan monohydrate (150 mg/kg) to induce diabetes. The diabetes-induced groups (III and IV) received treatment for six weeks that included 250 and 500 mg/kg of JSP extract, respectively. In the treated rats, the results demonstrated that JSP extract restored fasting glucose, serum glucose, and hyperlipidemia. Alloxan induced cardiomyopathy, promoted oxidative stress, and altered cardiac function biomarkers, including cardiac troponin I, proBNP, CK-MB, LDH, and IMA. The JSP extract-treated rats showed improved cardiac function indicators, apoptosis, and oxidative stress. In diabetic rats, the mRNA expression of caspase-3, BAX, and Bcl-2 was significantly higher, while Bcl-2, Nrf-2, and HO-,1 was significantly lower. In the treated groups, the expression levels of the BAX, Nrf-2, HO-1, Caspase-3, and Bcl-2 genes were dramatically returned to normal level. According to our findings, the JSP extract prevented cardiomyopathy and heart failure in the hyperglycemic rats by improving cardiac biomarkers and lowering the levels of hyperlipidemia, oxidative stress, apoptosis, hyperglycemia, and hyperlipidemia.
    Matched MeSH terms: bcl-2-Associated X Protein/metabolism
  8. Fulltext Induction of Apoptosis in MCF-7 Cells via Oxidative Stress Generation, Mitochondria-Dependent and Caspase-Independent Pathway by Ethyl Acetate Extract of Dillenia suffruticosa and Its Chemical Profile
    Tor YS, Yazan LS, Foo JB, Wibowo A, Ismail N, Cheah YK, et al.
    PLoS One, 2015;10(6):e0127441.
    PMID: 26047480 DOI: 10.1371/journal.pone.0127441
    Dillenia suffruticosa, which is locally known as Simpoh air, has been traditionally used to treat cancerous growth. The ethyl acetate extract of D. suffruticosa (EADs) has been shown to induce apoptosis in MCF-7 breast cancer cells in our previous study. The present study aimed to elucidate the molecular mechanisms involved in EADs-induced apoptosis and to identify the major compounds in the extract. EADs was found to promote oxidative stress in MCF-7 cells that led to cell death because the pre-treatment with antioxidants α-tocopherol and ascorbic acid significantly reduced the cytotoxicity of the extract (P<0.05). DCFH-DA assay revealed that treatment with EADs attenuated the generation of intracellular ROS. Apoptosis induced by EADs was not inhibited by the use of caspase-inhibitor Z-VAD-FMK, suggesting that the cell death is caspase-independent. The use of JC-1 dye reflected that EADs caused disruption in the mitochondrial membrane potential. The related molecular pathways involved in EADs-induced apoptosis were determined by GeXP multiplex system and Western blot analysis. EADs is postulated to induce cell cycle arrest that is p53- and p21-dependent based on the upregulated expression of p53 and p21 (P<0.05). The expression of Bax was upregulated with downregulation of Bcl-2 following treatment with EADs. The elevated Bax/Bcl-2 ratio and the depolarization of mitochondrial membrane potential suggest that EADs-induced apoptosis is mitochondria-dependent. The expression of oxidative stress-related AKT, p-AKT, ERK, and p-ERK was downregulated with upregulation of JNK and p-JNK. The data indicate that induction of oxidative-stress related apoptosis by EADs was mediated by inhibition of AKT and ERK, and activation of JNK. The isolation of compounds in EADs was carried out using column chromatography and elucidated using the nuclear resonance magnetic analysis producing a total of six compounds including 3-epimaslinic acid, kaempferol, kaempferide, protocatechuic acid, gallic acid and β-sitosterol-3-O-β-D-glucopyranoside. The cytotoxicity of the isolated compounds was determined using MTT assay. Gallic acid was found to be most cytotoxic against MCF-7 cell line compared to others, with IC50 of 36 ± 1.7 μg/mL (P<0.05). In summary, EADs generated oxidative stress, induced cell cycle arrest and apoptosis in MCF-7 cells by regulating numerous genes and proteins that are involved in the apoptotic signal transduction pathway. Therefore, EADs has the potential to be developed as an anti-cancer agent against breast cancer.
    Matched MeSH terms: bcl-2-Associated X Protein/metabolism
  9. 7α-Hydroxy-β-Sitosterol from Chisocheton tomentosus Induces Apoptosis via Dysregulation of Cellular Bax/Bcl-2 Ratio and Cell Cycle Arrest by Downregulating ERK1/2 Activation
    Tasyriq M, Najmuldeen IA, In LL, Mohamad K, Awang K, Hasima N
    Evid Based Complement Alternat Med, 2012;2012:765316.
    PMID: 22997533
    In continuation of our interest towards the elucidation of apoptotic pathways of cytotoxic phytocompounds, we have embarked upon a study on the anticancer effects of 7α-hydroxy-β-sitosterol (CT1), a rare natural phytosterol oxide isolated from Chisocheton tomentosus. CT1 was found to be cytotoxic on three different human tumor cell lines with minimal effects on normal cell controls, where cell viability levels were maintained ≥80% upon treatment. Our results showed that cell death in MCF-7 breast tumor cells was achieved through the induction of apoptosis via downregulation of the ERK1/2 signaling pathway. CT1 was also found to increase proapoptotic Bax protein levels, while decreasing anti-apoptotic Bcl-2 protein levels, suggesting the involvement of the intrinsic pathway. Reduced levels of initiator procaspase-9 and executioner procaspase-3 were also observed following CT1 exposure, confirming the involvement of cytochrome c-mediated apoptosis via the mitochondrial pathway. These results demonstrated the cytotoxic and apoptotic ability of 7α-hydroxy-β-sitosterol and suggest its potential anti-cancer use particularly on breast adenocarcinoma cells.
    Matched MeSH terms: bcl-2-Associated X Protein
  10. Fulltext Phyllanthus Suppresses Prostate Cancer Cell, PC-3, Proliferation and Induces Apoptosis through Multiple Signalling Pathways (MAPKs, PI3K/Akt, NFκB, and Hypoxia)
    Tang YQ, Jaganath I, Manikam R, Sekaran SD
    Evid Based Complement Alternat Med, 2013;2013:609581.
    PMID: 23690850 DOI: 10.1155/2013/609581
    Phyllanthus is a traditional medicinal plant that has been found to have antihepatitis, antibacterial, and anticancer properties. The present studies were to investigate the in vitro molecular mechanisms of anticancer effects of Phyllanthus (P. amarus, P. niruri, P. urinaria, and P. watsonii) plant extracts in human prostate adenocarcinoma. The cancer ten-pathway reporter array was performed and revealed that the expression of six pathway reporters were significantly decreased (Wnt, NFκB, Myc/Max, hypoxia, MAPK/ERK, and MAPK/JNK) in PC-3 cells after treatment with Phyllanthus extracts. Western blot was conducted and identified several signalling molecules that were affected in the signalling pathways including pan-Ras, c-Raf, RSK, Elk1, c-Jun, JNK1/2, p38 MAPK, c-myc, DSH, β-catenin, Akt, HIF-1α, GSK3β, NFκB p50 and p52, Bcl-2, Bax, and VEGF, in treated PC-3 cells. A proteomics-based approach, 2D gel electrophoresis, was performed, and mass spectrometry (MS/MS) results revealed that there were 72 differentially expressed proteins identified in treated PC-3 cells and were involved in tumour cell adhesion, apoptosis, glycogenesis and glycolysis, metastasis, angiogenesis, and protein synthesis and energy metabolism. Overall, these findings suggest that Phyllanthus can interfere with multiple signalling cascades involved in tumorigenesis and be used as a potential therapeutic candidate for treatment of cancer.
    Matched MeSH terms: bcl-2-Associated X Protein
  11. Fulltext An Intrinsic Mitochondrial Pathway Is Required for Phytic Acid-Chitosan-Iron Oxide Nanocomposite (Phy-CS-MNP) to Induce G₀/G₁ Cell Cycle Arrest and Apoptosis in the Human Colorectal Cancer (HT-29) Cell Line
    Tan BL, Norhaizan ME, Chan LC
    Pharmaceutics, 2018 Oct 23;10(4).
    PMID: 30360519 DOI: 10.3390/pharmaceutics10040198
    Magnetic iron oxide nanoparticles are among the most useful metal nanoparticles in biomedical applications. A previous study had confirmed that phytic acid-chitosan-iron oxide nanocomposite (Phy-CS-MNP) exhibited antiproliferative activity towards human colorectal cancer (HT-29) cells. Hence, in this work, we explored the in vitro cytotoxicity activity and mechanistic action of Phy-CS-MNP nanocomposite in modulating gene and protein expression profiles in HT-29 cell lines. Cell cycle arrest and apoptosis were evaluated by NovoCyte Flow Cytometer. The mRNA changes (cyclin-dependent kinase 4 (Cdk4), vascular endothelial growth factor A (VEGFA), c-Jun N-terminal kinase 1 (JNK1), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase 9 (MMP9)) and protein expression (nuclear factor-kappa B (NF-κB) and cytochrome c) were assessed by quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. The data from our study demonstrated that treatment with Phy-CS-MNP nanocomposite triggered apoptosis and G₀/G₁ cell cycle arrest. The transcriptional activity of JNK1 and iNOS was upregulated after treatment with 90 μg/mL Phy-CS-MNP nanocomposite. Our results suggested that Phy-CS-MNP nanocomposite induced apoptosis and cell cycle arrest via an intrinsic mitochondrial pathway through modulation of Bax and Bcl-2 and the release of cytochrome c from the mitochondria into the cytosol.
    Matched MeSH terms: bcl-2-Associated X Protein
  12. ROS-Mediated Mitochondrial Pathway is Required for Manilkara Zapota (L.) P. Royen Leaf Methanol Extract Inducing Apoptosis in the Modulation of Caspase Activation and EGFR/NF-κB Activities of HeLa Human Cervical Cancer Cells
    Tan BL, Norhaizan ME, Chan LC
    Evid Based Complement Alternat Med, 2018;2018:6578648.
    PMID: 29977314 DOI: 10.1155/2018/6578648
    Manilkara zapota (L.) P. Royen (family: Sapotaceae) is commonly called sapodilla, or locally known as ciku. The detailed mechanisms underlying Manilkara zapota leaf methanol extract against HeLa human cervical cancer cells have yet to be investigated. Therefore, our present study is designed to investigate the ability to induce apoptosis and the underlying mechanisms of Manilkara zapota leaf methanol extract inducing cytotoxicity in HeLa cells. The apoptotic cell death was assessed using Annexin V-propidium iodide staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential activities were measured using dichlorodihydrofluorescein diacetate and MitoLite Orange, respectively, by NovoCyte Flow Cytometer. Bax and Bcl-2 expression were evaluated using Enzyme-Linked Immunosorbent Assay. Caspase-3 activity was determined using a colorimetric assay. The associated biological interaction pathways were evaluated using quantitative real-time PCR. Our data showed that HeLa cells were relatively more sensitive to Manilkara zapota leaf methanol extract than other cancer cell lines studied. Overall analyses revealed that Manilkara zapota leaf methanol extract can inhibit the viability of HeLa cells, induce mitochondrial ROS generation, and inhibit nuclear factor-kappa B (NF-κB) and epidermal growth factor receptor (EGFR) transcriptional activities. Our results suggested that Manilkara zapota leaf methanol extract might represent a potential anticervical cancer agent.
    Matched MeSH terms: bcl-2-Associated X Protein
  13. 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.
    Matched MeSH terms: bcl-2-Associated X Protein/genetics; bcl-2-Associated X Protein/metabolism
  14. Structural insight into tanapoxvirus mediated inhibition of apoptosis
    Suraweera CD, Anasir MI, Chugh S, Javorsky A, Impey RE, Hasan Zadeh M, et al.
    FEBS J, 2020 May 15.
    PMID: 32412687 DOI: 10.1111/febs.15365
    Premature programmed cell death or apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Tanapoxvirus (TANV) is a large double-stranded DNA virus belonging to the poxviridae that causes mild Monkeypox-like infections in humans and primates. TANV encodes for a putative apoptosis inhibitory protein 16L. We show that TANV16L is able to bind to a range of peptides spanning the BH3 motif of human pro-apoptotic Bcl-2 proteins, and is able to counter growth arrest of yeast induced by human Bak and Bax. We then determined the crystal structures of TANV16L bound to three identified interactors, Bax, Bim and Puma BH3. TANV16L adopts a globular Bcl-2 fold comprising 7 a-helices, and utilizes the canonical Bcl-2 binding groove to engage pro-apoptotic host cell Bcl-2 proteins. Unexpectedly, TANV16L is able to adopt both a monomeric as well as a domain-swapped dimeric topology where the a1 helix from one protomer is swapped into a neighbouring unit. Despite adopting two different oligomeric forms, the canonical ligand binding groove in TANV16L remains unchanged from monomer to domain-swapped dimer. Our results provide a structural and mechanistic basis for tanapoxvirus mediated inhibition of host cell apoptosis, and reveal the capacity of Bcl-2 proteins to adopt differential oligomeric states whilst maintaining the canonical ligand binding groove in an unchanged state.
    Matched MeSH terms: bcl-2-Associated X Protein
  15. Fulltext Evidence of the gastroprotective and anti- Helicobacter pylori activities of β-mangostin isolated from Cratoxylum arborescens (vahl) blume
    Sidahmed HM, Hashim NM, Mohan S, Abdelwahab SI, Taha MM, Dehghan F, et al.
    Drug Des Devel Ther, 2016;10:297-313.
    PMID: 26834460 DOI: 10.2147/DDDT.S80625
    PURPOSE: β-Mangostin (BM) from Cratoxylum arborescens demonstrated various pharmacological activities such as anticancer and anti-inflammatory. In this study, we aimed to investigate its antiulcer activity against ethanol ulcer model in rats.

    MATERIALS AND METHODS: BM was isolated from C. arborescens. Gastric acid output, ulcer index, gross evaluation, mucus production, histological evaluation using hematoxylin and eosin and periodic acid-Schiff staining and immunohistochemical localization for heat shock protein 70 (HSP70) and Bax proteins were investigated. Possible involvement of reduced glutathione, lipid peroxidation, prostaglandin E2, antioxidant enzymes, superoxide dismutase and catalase enzymes, radical scavenging, nonprotein sulfhydryl compounds, and anti-Helicobacter pylori were investigated.

    RESULTS: BM showed antisecretory activity against the pylorus ligature model. The pretreatment with BM protect gastric mucosa from ethanol damaging effect as seen by the improved gross and histological appearance. BM significantly reduced the ulcer area formation, the submucosal edema, and the leukocytes infiltration compared to the ulcer control. The compound showed intense periodic acid-Schiff staining to the gastric mucus layer and marked amount of alcian blue binding to free gastric mucus. BM significantly increased the gastric homogenate content of prostaglandin E2 glutathione, superoxide dismutase, catalase, and nonprotein sulfhydryl compounds. The compound inhibited the lipid peroxidation revealed by the reduced gastric content of malondialdehyde. Moreover, BM upregulate HSP70 expression and downregulate Bax expression. Furthermore, the compound showed interesting anti-H. pylori activity.

    CONCLUSION: Thus, it could be concluded that BM possesses gastroprotective activity, which could be attributed to the antisecretory, mucus production, antioxidant, HSP70, antiapoptotic, and anti-H. pylori mechanisms.

    Matched MeSH terms: bcl-2-Associated X Protein/genetics
  16. Anticancer Activity and Molecular Mechanism of Polyphenol Rich Calophyllum inophyllum Fruit Extract in MCF-7 Breast Cancer Cells
    Shanmugapriya, Chen Y, Kanwar JR, Sasidharan S
    Nutr Cancer, 2017 10 25;69(8):1308-1324.
    PMID: 29068745 DOI: 10.1080/01635581.2017.1367944
    This study was conducted to investigate the anticancer effects and mechanism of Calophyllum inophyllum fruit extract against MCF-7 cells. C. inophyllum fruit extract was found to have markedly cytotoxic effect against MCF-7 cells in a dose-dependent manner with the IC50 for 24 h of 23.59 µg/mL. Flow cytometry analysis revealed that C. inophyllum fruit extract mediated cell cycle at G0/G1 and G2/M phases, and MCF-7 cells entered the early phase of apoptosis. The expression of anti-apoptotic proteins Bcl-2 was decreased whereas the expression of the pro-apoptotic protein Bax, cytochrome C and p53 were increased after treatment. C. inophyllum fruit extract led to apoptosis in MCF-7 cells via the mitochondrial pathway in a dose dependent manner. This is evidenced by the elevation of intracellular ROS, the loss of mitochondria membrane potential (Δψm), and activation of caspase-3. Meanwhile, dose-dependent genomic DNA fragmentation was observed after C. inophyllum fruits extract treatment by comet assay. This study shows that C. inophyllum fruits extract-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3. C. inophyllum fruit extract could be an excellent source of chemopreventive agent in the treatment of breast cancer and has potential to be explored as green anticancer agent.
    Matched MeSH terms: bcl-2-Associated X Protein/genetics; bcl-2-Associated X Protein/metabolism
  17. Fulltext Pro-apoptotic effect of rice bran inositol hexaphosphate (IP6) on HT-29 colorectal cancer cells
    Shafie NH, Esa NM, Ithnin H, Saad N, Pandurangan AK
    Int J Mol Sci, 2013;14(12):23545-58.
    PMID: 24317430 DOI: 10.3390/ijms141223545
    Inositol hexaphosphate (IP6), or phytic acid is a natural dietary ingredient and has been described as a "natural cancer fighter", being an essential component of nutritional diets. The marked anti-cancer effect of IP6 has resulted in our quest for an understanding of its mechanism of action. In particular, our data provided strong evidence for the induction of apoptotic cell death, which may be attributable to the up-regulation of Bax and down-regulation of Bcl-xl in favor of apoptosis. In addition, the up-regulation of caspase-3 and -8 expression and activation of both caspases may also contribute to the apoptotic cell death of human colorectal adenocarcinoma HT-29 cells when exposed to IP6. Collectively, this present study has shown that rice bran IP6 induces apoptosis, by regulating the pro- and anti-apoptotic markers; Bax and Bcl-xl and via the activation of caspase molecules (caspase-3 and -8).
    Matched MeSH terms: bcl-2-Associated X Protein/genetics; bcl-2-Associated X Protein/metabolism
  18. Fulltext In Vitro and In Vivo Anticancer Activity of the Most Cytotoxic Fraction of Pistachio Hull Extract in Breast Cancer
    Seifaddinipour M, Farghadani R, Namvar F, Bin Mohamad J, Muhamad NA
    Molecules, 2020 Apr 13;25(8).
    PMID: 32295069 DOI: 10.3390/molecules25081776
    Pistacia (Pistacia vera) hulls (PV) is a health product that has been determined to contain bioactive phytochemicals which have fundamental importance for biomedical use. In this study, PV ethyl acetate extraction (PV-EA) fractions were evaluated with the use of an MTT assay to find the most cytotoxic fraction, which was found to be F13b1/PV-EA. After that, HPTLC was used for identify the most active compounds. The antioxidant activity was analyzed with DPPH and ABTS tests. Apoptosis induction in MCF-7 cells by F13b1/PV-EA was validated via flow cytometry analysis and a distinctive nuclear staining method. The representation of genes like Caspase 3, Caspase 8, Bax, Bcl-2, CAT and SOD was assessed via a reverse transcription (RT_PCR) method. Inhabitation of Tubo breast cancer cell development was examined in the BALB-neuT mouse with histopathology observations. The most abundant active components available in our extract were gallic acid and the flavonoid quercetin. The F13b1/PV-EA has antiradical activity evidence by its inhibition of ABTS and DPPH free radicals. F13b1/PV-EA displayed against MCF-7 a suppressive effect with an IC50 value of 15.2 ± 1.35 µg/mL. Also, the expression of CAT, SOD, Caspase 3, Caspase 8 and Bax increased and the expression of Bcl-2 decreased. F13b1/PV-EA dose-dependently inhibited tumor development in cancer-induced mice. Thus, this finding introduces F13b1/PV-EA as an effectual apoptosis and antitumor active agent against breast cancer.
    Matched MeSH terms: bcl-2-Associated X Protein/genetics; bcl-2-Associated X Protein/metabolism
  19. Fulltext Thymoquinone inhibits murine leukemia WEHI-3 cells in vivo and in vitro
    Salim LZ, Othman R, Abdulla MA, Al-Jashamy K, Ali HM, Hassandarvish P, et al.
    PLoS One, 2014;9(12):e115340.
    PMID: 25531768 DOI: 10.1371/journal.pone.0115340
    BACKGROUND: Thymoquinone is an active ingredient isolated from Nigella sativa (Black Seed). This study aimed to evaluate the in vitro and in vivo anti-leukemic effects of thymoquinone on WEHI-3 cells.

    METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxic effect of thymoquinone was assessed using an MTT assay, while the inhibitory effect of thymoquinone on murine WEHI-3 cell growth was due to the induction of apoptosis, as evidenced by chromatin condensation dye, Hoechst 33342 and acridine orange/propidium iodide fluorescent staining. In addition, Annexin V staining for early apoptosis was performed using flowcytometric analysis. Apoptosis was found to be associated with the cell cycle arrest at the S phase. Expression of Bax, Bcl2 and HSP 70 proteins were observed by western blotting. The effects of thymoquinone on BALB/c mice injected with WEHI-3 cells were indicated by the decrease in the body, spleen and liver weights of the animal, as compared to the control.

    CONCLUSION: Thymoquinone promoted natural killer cell activities. This compound showed high toxicity against WEHI-3 cell line which was confirmed by an increase of the early apoptosis, followed by up-regulation of the anti-apoptotic protein, Bcl2, and down-regulation of the apoptotic protein, Bax. On the other hand, high reduction of the spleen and liver weight, and significant histopathology study of spleen and liver confirmed that thymoquinone inhibited WEHI-3 growth in the BALB/c mice. Results from this study highlight the potential of thymoquinone to be developed as an anti-leukemic agent.

    Matched MeSH terms: bcl-2-Associated X Protein/metabolism
  20. Fulltext Mechanism of Hepatoprotective Effect of Boesenbergia rotunda in Thioacetamide-Induced Liver Damage in Rats
    Salama SM, Abdulla MA, Alrashdi AS, Hadi AH
    Evid Based Complement Alternat Med, 2013;2013:157456.
    PMID: 23997791 DOI: 10.1155/2013/157456
    Background. Researchers focused on developing traditional therapies as pharmacological medicines to treat liver cirrhosis. Objectives. Evaluating the hepatoprotective activity of Boesenbergia rotunda (BR) rhizome ethanolic extract on thioacetamide-induced liver cirrhosis in rats. Methods. Male Sprague-Dawley rats were intraperitoneally injected with 200 mg/kg TAA 3 times/week and daily oral administration of 250 mg/kg, 500 mg/kg of BR extract, and 50 mg/kg of the reference drug Silymarin for 8 weeks. At the end of the experiment, Masson's trichrome staining was used to measure the degree of liver fibrosis. Hepatic antioxidant enzymes (CAT and GPx), nitrotyrosine, cytochrome (P450 2E1), matrix metalloproteinase (MMP-2 and MMP-9), tissue inhibitor of metalloproteinase (TIMP-1), and urinary 8-hydroxyguanosine were measured. Serum levels of transforming growth factor TGF- β 1, nuclear transcription factor NF- κ B, proinflammatory cytokine IL-6, and caspase-3 were evaluated. Serum protein expression and immunohistochemistry of proapoptotic Bax and antiapoptotic Bcl-2 proteins were measured and confirmed by immunohistochemistry of Bax, Bcl-2, and proliferating cell nuclear antigen (PCNA). Results. BR treatment improved liver histopathology, immunohistochemistry, and biochemistry, triggered apoptosis, and inhibited cytokines, extracellular matrix proteins, and hepatocytes proliferation. Conclusion. Liver cirrhosis progression can be inhibited by the antioxidant and anti-inflammatory activities of BR ethanolic extract while preserving the normal liver status.
    Matched MeSH terms: bcl-2-Associated X Protein
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