Displaying publications 1 - 20 of 110 in total

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  1. Kamarudin MN, Mohd Raflee NA, Hussein SS, Lo JY, Supriady H, Abdul Kadir H
    Drug Des Devel Ther, 2014;8:1765-80.
    PMID: 25336920 DOI: 10.2147/DDDT.S67980
    Alpha-lipoic acid, a potent antioxidant with multifarious pharmacological benefits has been reported to be neuroprotective in several neuronal models and used to treat neurological disorders such as Alzheimer's disease. Nonetheless, conclusive mechanisms of alpha-lipoic acid for its protective effects particularly in NG108-15 cells have never been investigated. In this study, the intricate neuroprotective molecular mechanisms by (R)-(+)-alpha-lipoic acid (R-LA) against H2O2-induced cell death in an in vitro model of neurodegeneration were elucidated. Pretreatment with R-LA (2 hours) significantly increased NG108-15 cell viability as compared to H2O2-treated cells and mitigated the induction of apoptosis as evidenced by Hoechst 33342/propidium iodide staining. R-LA (12.5-50 μM) aggrandized the reduced glutathione over glutathione disulfide ratio followed by a reduction in the intracellular reactive oxygen species level and an increase in mitochondrial membrane potential following H2O2 exposure. Moreover, pretreatment with R-LA stimulated the activation of PI3K-Akt through mTORC1 and mTORC2 components (mTOR, rictor and raptor) and production of antiinflammatory cytokine, IL-10 which led to the inactivation of glycogen synthase kinase-3β (GSK-3β) and reduction of both Bax/Bcl2 and Bax/Bcl-xL ratios, accompanied by inhibition of the cleaved caspase-3. Additionally, this observation was preceded by the suppression of NF-κβ p65 translocation and production of proinflammatory cytokines (IL-6 and TNF-α). The current findings accentuate new mechanistic insight of R-LA against apoptogenic and brain inflammatory factors in a neuronal model. These results further advocate the therapeutic potential of R-LA for the treatment of neurodegenerative diseases.
  2. Al-Wajeeh NS, Hajrezaie M, Al-Henhena N, Kamran S, Bagheri E, Zahedifard M, et al.
    Drug Des Devel Ther, 2017;11:995-1009.
    PMID: 28408799 DOI: 10.2147/DDDT.S107018
    Cibotium barometz is a pharmaceutical plant customarily used in traditional medicine in Malaysia for the treatment of different diseases, such as gastric ulcer. The gastroprotective effect of C. barometz leaves against ethanol-induced gastric hemorrhagic abrasions in Sprague Dawley rats has been evaluated in terms of medicinal properties. Seven groups of rats (normal control and ulcerated control groups, omeprazole 20 mg/kg, 62.5, 125, 250, and 500 mg/kg of C. barometz correspondingly) were used in antiulcer experiment and pretreated with 10% Tween 20. After 1 hour, the normal group was orally administered 10% Tween 20, whereas absolute alcohol was fed orally to ulcerated control, omeprazole, and experimental groups. Gastric's homogenate were assessed for endogenous enzymes activities. Stomachs were examined macroscopically and histologically. Grossly, the data demonstrated a significant decrease in the ulcer area of rats pretreated with plant extract in a dose-dependent manner with respect to the ulcerated group. Homogenates of the gastric tissue exhibited significantly increased endogenous enzymes activities in rats pretreated with C. barometz extract associated with the ulcerated control group. Histology of rats pretreated with C. barometz extract group using hematoxylin and eosin staining exhibited a moderate-to-mild disruption of the surface epithelium with reduction in submucosal edema and leucocyte infiltration in a dose-dependent manner. In addition, it showed heat shock protein70 protein up-expression and BCL2-associated X protein downexpression. These outcomes might be attributed to the gastroprotective and antioxidative effects of the plant.
  3. Albaayit SF, Abba Y, Rasedee A, Abdullah N
    Drug Des Devel Ther, 2015;9:3507-18.
    PMID: 26203223 DOI: 10.2147/DDDT.S84770
    Clausena excavata is a well-known plant used in folkloric medicine for the treatment of different ailments. This study aimed to determine the in vitro cytoxicity of its leaf solvent extracts as well as the in vivo wound healing and antioxidant activities of the methanolic extracts of C. excavata (MECE). HaCaT (keratocyte) and Vero cell lines were used for evaluation of the in vitro cytotoxic effects, while the in vivo wound healing and antioxidant activities were determined in skin wounds inflicted on rats. Twenty adult male Sprague-Dawley rats were divided into five groups of four animals each. Approximately 3.14 cm(2) excisional wound was inflicted on the nape of each rat following anesthesia. The treatment groups received topical application of MECE at 50 mg/mL (MECE-LD [low dose]), 100 mg/mL (MECE-MD [medium dose]), and 200 mg/mL (MECE-HD [high dose]), while the negative control group was treated with gum acacia in normal saline and the positive control group with intrasite gel. Wound contraction was evaluated on days 5, 10, and 15 after wound infliction, and tissue from wound area was collected at day 15 post-wound infliction for antioxidant enzyme evaluation and histopathological analyses. Generally, Vero cells were more resistant to the cytotoxic effects of the solvent extracts as compared with HaCaT cells. Chloroform (CH) and ethyl acetate (EA) extracts of C. excavata were toxic to HaCaT cells at 200 and 400 µg/mL, but the same concentrations showed higher (P<0.05) viability in Vero cells. There was significantly (P<0.01) greater wound contraction at days 10 and 15 post-wound infliction in all the treatment groups than in the control groups. Histopathologically, the MECE-HD-treated wound showed significantly (P<0.05) lesser inflammatory cell proliferation, degeneration, and distribution of granulation tissue than other groups. Similarly, the degree of collagen maturation, angiogenesis, and collagen distribution were significantly (P<0.05) lower in MECE-HD than in other groups. The MECE-HD, MECE-MD, and intrasite treatment groups showed a significantly (P<0.05) higher number of VEGF-positive and TGF-β1-positive cells in the skin wound than the control groups. The activities of superoxide dismutase and catalase were significantly (P<0.01) higher in the MECE-HD and intrasite treatment groups than in the other groups. Lipid peroxidase activity of the treated groups was significantly (P<0.01) lower than that in the control group. The study showed that MECE is a potent wound healing agent through anti-inflammatory and antioxidant effects that enhanced the rate of wound contraction, re-epithelialization, and collagen deposition. The effect of MECE is suggested to be due to its high polyphenolic compound content.
  4. Albaayit SF, Abba Y, Abdullah R, Abdullah N
    Drug Des Devel Ther, 2016;10:1973-86.
    PMID: 27366052 DOI: 10.2147/DDDT.S103993
    Clausena excavata is a natural herb with both antioxidant and anti-inflammatory properties. It has been used for decades in folkloric practice for the amelioration of various ailments. In this study, the gastroprotective activity of methanolic extract of C. excavata leaves (MECE) was determined in the Sprague Dawley rat ethanol-induced gastric ulcer model. Rats were pretreated with a single dose of vehicle (5% Tween 20), 20 mg/mL omeprazole, 400 and 200 mg/mL of MECE dissolved in 5% Tween 20. Ulcer was induced with 5 mL/kg of ethanol and stomach tissue was obtained after 1 hour. Histological examination was done on hematoxylin and eosin, periodic acid-Schiff, and immunochemically stained gastric mucosal tissues. Prostaglandin E2, superoxide dismutase, catalase, glutathione peroxidase, and lipid peroxidation levels of the gastric tissue homogenates were also determined. Significantly (P<0.05) smaller ulcer areas, less intense edema, and fewer leukocytes' infiltration were observed in MECE- and omeprazole-treated than in untreated gastric mucosa with ulcer. The gastric pH, mucus production, superoxide dismutase, catalase, and glutathione peroxidase contents increased, while the lipid peroxidation content decreased as a result of MECE treatment. Bcl-2-associated X protein was underexpressed, while heat shock protein 70 and transforming growth factor-beta protein were overexpressed in the ulcerated gastric mucosa tissues treated with omeprazole and MECE. Similarly, there was a reduction in the levels of tumor necrotic factor-alpha and interleukin-6, while the level of interleukin-10 was increased. This study showed that the gastroprotective effect of MECE is achieved through inhibition of gastric juice secretion and ulcer lesion development, stimulation of mucus secretion, elevation of gastric pH, reduction of reactive oxygen species production, inhibition of apoptosis in the gastric mucosa, and modulation of inflammatory cytokines.
  5. Ellulu MS, Rahmat A, Patimah I, Khaza'ai H, Abed Y
    Drug Des Devel Ther, 2015;9:3405-12.
    PMID: 26170625 DOI: 10.2147/DDDT.S83144
    Obesity is well associated as being an interfering factor in metabolic diseases such as hypertension and diabetes by increasing the secretion of proinflammatory markers from adipose tissue. Having healthy effects, vitamin C could work as an anti-inflammatory agent through its antioxidant capacity.
  6. Huri HZ, Ling DY, Ahmad WA
    Drug Des Devel Ther, 2015;9:4735-49.
    PMID: 26316711 DOI: 10.2147/DDDT.S87294
    PURPOSE: Cardiovascular disease (CVD) is a macrovascular complication in patients with type 2 diabetes mellitus (T2DM). To date, glycemic control profiles of antidiabetic drugs in cardiovascular (CV) complications have not been clearly elucidated. Therefore, this study was conducted retrospectively to assess the association of antidiabetic drugs and glycemic control with CV profiles in T2DM patients. The association of concurrent medications and comorbidities with glycemic control was also investigated.

    METHODS: A total of 220 T2DM patients from the University of Malaya Medical Centre, Malaysia, who had at least one CV complication and who had been taking at least one antidiabetic drug for at least 3 months, were included. The associations of antidiabetics, cardiovascular diseases, laboratory parameters, concurrent medications, comorbidities, demographics, and clinical characteristics with glycemic control were investigated.

    RESULTS: Sulfonylureas in combination (P=0.002) and sulfonylurea monotherapy (P<0.001) were found to be associated with good glycemic control, whereas insulin in combination (P=0.051), and combination biguanides and insulin therapy (P=0.012) were found to be associated with poor glycemic control. Stroke (P=0.044) was the only type of CVD that seemed to be significantly associated with good glycemic control. Other factors such as benign prostatic hyperplasia (P=0.026), elderly patients (P=0.018), low-density lipoprotein cholesterol levels (P=0.021), and fasting plasma glucose (P<0.001) were found to be significantly correlated with good glycemic control.

    CONCLUSION: Individualized treatment in T2DM patients with CVDs can be supported through a better understanding of the association between glycemic control and CV profiles in T2DM patients.

  7. Dorniani D, Hussein MZ, Kura AU, Fakurazi S, Shaari AH, Ahmad Z
    Drug Des Devel Ther, 2013;7:1015-26.
    PMID: 24106420 DOI: 10.2147/DDDT.S43035
    BACKGROUND: Iron oxide nanoparticles are of considerable interest because of their use in magnetic recording tape, ferrofluid, magnetic resonance imaging, drug delivery, and treatment of cancer. The specific morphology of nanoparticles confers an ability to load, carry, and release different types of drugs.

    METHODS AND RESULTS: We synthesized superparamagnetic nanoparticles containing pure iron oxide with a cubic inverse spinal structure. Fourier transform infrared spectra confirmed that these Fe3O4 nanoparticles could be successfully coated with active drug, and thermogravimetric and differential thermogravimetric analyses showed that the thermal stability of iron oxide nanoparticles coated with chitosan and 6-mercaptopurine (FCMP) was markedly enhanced. The synthesized Fe3O4 nanoparticles and the FCMP nanocomposite were generally spherical, with an average diameter of 9 nm and 19 nm, respectively. The release of 6-mercaptopurine from the FCMP nanocomposite was found to be sustained and governed by pseudo-second order kinetics. In order to improve drug loading and release behavior, we prepared a novel nanocomposite (FCMP-D), ie, Fe3O4 nanoparticles containing the same amounts of chitosan and 6-mercaptopurine but using a different solvent for the drug. The results for FCMP-D did not demonstrate "burst release" and the maximum percentage release of 6-mercaptopurine from the FCMP-D nanocomposite reached about 97.7% and 55.4% within approximately 2,500 and 6,300 minutes when exposed to pH 4.8 and pH 7.4 solutions, respectively. By MTT assay, the FCMP nanocomposite was shown not to be toxic to a normal mouse fibroblast cell line.

    CONCLUSION: Iron oxide coated with chitosan containing 6-mercaptopurine prepared using a coprecipitation method has the potential to be used as a controlled-release formulation. These nanoparticles may serve as an alternative drug delivery system for the treatment of cancer, with the added advantage of sparing healthy surrounding cells and tissue.

  8. Fani S, Kamalidehghan B, Lo KM, Hashim NM, Chow KM, Ahmadipour F
    Drug Des Devel Ther, 2015;9:6191-201.
    PMID: 26648695 DOI: 10.2147/DDDT.S87064
    A new monoorganotin Schiff base compound, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, (compound C1), was synthesized, and its structural features were investigated by spectroscopic techniques and single-crystal X-ray diffractometry. Compound C1 was exposed to several human cancer cell lines, including breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, ovarian adenocarcinoma cell lines Skov3 and Caov3, and prostate cancer cell line PC3, in order to examine its cytotoxic effect for different forms of cancer. Human hepatic cell line WRL-68 was used as a normal cell line. We concentrated on the MCF-7 cell line to detect possible underlying mechanism involvement of compound C1. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed the strongest cytotoxicity of compound C1 against MCF-7 cells, with a half maximal inhibitory concentration (IC50) value of 2.5±0.50 μg/mL after 48 hours treatment. The IC50 value was >30 μg/mL in WRL-68 cells. Induced antiproliferative activity of compound C1 for MCF-7 cells was further confirmed by lactate dehydrogenase, reactive oxygen species, acridine orange/propidium iodide staining, and DNA fragmentation assays. A significant increase of lactate dehydrogenase release in treated cells was observed via fluorescence analysis. Luminescent analysis showed significant growth in intracellular reactive oxygen species production after treatment. Morphological changes of necrosis and early and late apoptosis stages were observed in treated cells after staining with acridine orange/propidium iodide. DNA fragmentation was observed as a characteristic of apoptosis in treated cells. Results of the present study obviously reveal potential cytotoxic effects of compound C1 against human breast cancer MCF-7 cells.
  9. Abbaspour Babaei M, Kamalidehghan B, Saleem M, Huri HZ, Ahmadipour F
    Drug Des Devel Ther, 2016;10:2443-59.
    PMID: 27536065 DOI: 10.2147/DDDT.S89114
    c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence.
  10. Kamalidehghan B, Ghafouri-Fard S, Motevaseli E, Ahmadipour F
    Drug Des Devel Ther, 2018;12:1119-1133.
    PMID: 29765202 DOI: 10.2147/DDDT.S156826
    Background: Inhibition of prostate cancer stem cells (PCSCs) is an efficient curative maintenance protocol for the prevention of prostate cancer. The objectives of this study were to assess the efficiency of koenimbin, a major biologically active component of Murraya koenigii (L) Spreng, in the suppression of PC-3 cells and to target PC-3-derived cancer stem cells (CSCs) through apoptotic and CSC signaling pathways in vitro.

    Materials and methods: The antiproliferative activity of koenimbin was examined using MTT, and the apoptotic detection was carried out by acridine orange/propidium iodide (AO/PI) double-staining and multiparametric high-content screening (HCS) assays. Caspase bioluminescence assay, reverse transcription polymerase chain reaction (RT-PCR), and immunoblotting were conducted to confirm the expression of apoptotic-associated proteins. Cell cycle analysis was investigated using flow cytometry. Involvement of nuclear factor-kappa B (NF-κB) was analyzed using HCS assay. Aldefluor™ and prostasphere formation examinations were used to evaluate the impact of koenimbin on PC-3 CSCs in vitro.

    Results: Koenimbin remarkably inhibited cell proliferation in a dose-dependent manner. Koenimbin induced nuclear condensation, formation of apoptotic bodies, and G0/G1 phase arrest of PC-3 cells. Koenimbin triggered the activation of caspase-3/7 and caspase-9 and the release of cytochrome c, decreased anti-apoptotic Bcl-2 and HSP70 proteins, increased pro-apoptotic Bax proteins, and inhibited NF-κB translocation from the cytoplasm to the nucleus, leading to the activation of the intrinsic apoptotic pathway. Koenimbin significantly (P<0.05) reduced the aldehyde dehydrogenase-positive cell population of PC-3 CSCs and the size and number of PC-3 CSCs in primary, secondary, and tertiary prostaspheres in vitro.

    Conclusion: Koenimbin has chemotherapeutic potential that may be employed for future treatment through decreasing the recurrence of cancer, resulting in the improvement of cancer management strategies and patient survival.

  11. Al-Abboodi AS, Rasedee A, Abdul AB, Taufiq-Yap YH, Alkaby WAA, Ghaji MS, et al.
    Drug Des Devel Ther, 2017;11:3309-3319.
    PMID: 29200826 DOI: 10.2147/DDDT.S147626
    Introduction: Dentatin (DEN) (5-methoxy-2, 2-dimethyl-10-(1, 1-dimethyl-2propenyl) dipyran-2-one), a natural compound present in the roots of Clausena excavata Burm f, possesses pro-apoptotic and antiproliferative effects in various cancer cells. Because of its hydrophobicity, it is believed that its complexation with hydroxy-β-cyclodextrin (HPβCD) will make it a potent inhibitor of cancer cell growth. In the current work, the molecular mechanisms of apoptosis induced by DEN and DEN-HPβCD complex were demonstrated in human colon HT-29 cancer cells.

    Materials and methods: After the human colon HT-29 cancer cells were treated with DEN and DEN-HPβCD complex, their effects on the expression of apoptotic-regulated gene markers in mitochondria-mediated apoptotic and death receptor pathways were detected by Western blot analysis and reverse transcription polymerase chain reaction. These markers included caspases-9, 3, and 8, cytochrome c, poly (ADP-ribose) polymerase, p53, p21, cyclin A as well as the Bcl-2 family of proteins.

    Results: At 3, 6, 12, and 24 µg/mL exposure, DEN and DEN-HPβCD complex significantly affected apoptosis in HT-29 cells through the down-regulation of Bcl-2 and cyclin A in turn, and up-regulation of Bax, p53, p21, cytochrome c at both protein and mRNA levels. DEN and DEN-HPβCD complex also decreased cleaved poly (ADP-ribose) polymerase and induced caspases-3, -8, and -9.

    Conclusion: Results of this study indicate that the apoptotic pathway caused by DEN and DEN-HPβCD complex are mediated by the regulation of caspases and Bcl-2 families in human colon HT-29 cancer cells. The results also suggest that DEN-HPβCD complex may have chemotherapeutic benefits for colon cancer patients.

  12. Abdelgawad MA, Musa A, Almalki AH, Alzarea SI, Mostafa EM, Hegazy MM, et al.
    Drug Des Devel Ther, 2021;15:2325-2337.
    PMID: 34103896 DOI: 10.2147/DDDT.S310820
    Introduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.

    Methods: Three semi-synthetic series of compounds (C1-4, P1-4, and G1-4) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. (p-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.

    Results: Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC50: 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC50: 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC50 values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.

    Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.

  13. Ibrahim MY, Hashim NM, Mohan S, Abdulla MA, Kamalidehghan B, Ghaderian M, et al.
    Drug Des Devel Ther, 2014;8:1629-47.
    PMID: 25302018 DOI: 10.2147/DDDT.S66105
    Cratoxylum arborescens is an equatorial plant belonging to the family Guttiferae. In the current study, α-Mangostin (AM) was isolated and its cell death mechanism was studied. HCS was undertaken to detect the nuclear condensation, mitochondrial membrane potential, cell permeability, and the release of cytochrome c. An investigation for reactive oxygen species formation was conducted using fluorescent analysis. To determine the mechanism of cell death, human apoptosis proteome profiler assay was conducted. In addition, using immunofluorescence and immunoblotting, the levels of Bcl-2-associated X protein (Bax) and B-cell lymphoma (Bcl)-2 proteins were also tested. Caspaces such as 3/7, 8, and 9 were assessed during treatment. Using HCS and Western blot, the contribution of nuclear factor kappa-B (NF-κB) was investigated. AM had showed a selective cytotoxicity toward the cancer cells with no toxicity toward the normal cells even at 30 μg/mL, thereby indicating that AM has the attributes to induce cell death in tumor cells. The treatment of MCF-7 cells with AM prompted apoptosis with cell death-transducing signals. This regulated the mitochondrial membrane potential by down-regulation of Bcl-2 and up-regulation of Bax, thereby causing the release of cytochrome c from the mitochondria into the cytosol. The liberation of cytochrome c activated caspace-9, which, in turn, activated the downstream executioner caspace-3/7 with the cleaved poly (ADP-ribose) polymerase protein, thereby leading to apoptotic alterations. Increase of caspace 8 had showed the involvement of an extrinsic pathway. This type of apoptosis was suggested to occur through both extrinsic and intrinsic pathways and prevention of translocation of NF-κB from the cytoplasm to the nucleus. Our results revealed AM prompt apoptosis of MCF-7 cells through NF-κB, Bax/Bcl-2 and heat shock protein 70 modulation with the contribution of caspaces. Moreover, ingestion of AM at (30 and 60 mg/kg) significantly reduced tumor size in an animal model of breast cancer. Our results suggest that AM is a potentially useful agent for the treatment of breast cancer.
  14. Nordin N, Majid NA, Hashim NM, Rahman MA, Hassan Z, Ali HM
    Drug Des Devel Ther, 2015;9:1437-48.
    PMID: 25792804 DOI: 10.2147/DDDT.S77727
    Enicosanthellum pulchrum is a tropical plant from Malaysia and belongs to the Annonaceae family. This plant is rich in isoquinoline alkaloids. In the present study, liriodenine, an isoquinoline alkaloid, was examined as a potential anticancer agent, particularly in ovarian cancer. Liriodenine was isolated by preparative high-performance liquid chromatography. Cell viability was performed to determine the cytotoxicity, whilst the detection of morphological changes was carried out by acridine orange/propidium iodide assay. Initial and late apoptosis was examined by Annexin V-fluorescein isothiocyanate and DNA laddering assays, respectively. The involvement of pathways was detected via caspase-3, caspase-8, and caspase-9 analyses. Confirmation of pathways was further performed in mitochondria using a cytotoxicity 3 assay. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, while interruption of the cell cycle was used for final validation of apoptosis. The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and formation of apoptotic bodies. Early apoptosis was observed by Annexin V-fluorescein isothiocyanate bound to the cell membrane as early as 24 hours. Liriodenine activated the intrinsic pathway by induction of caspase-3 and caspase-9. Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased. DNA fragmentation occurred at 72 hours upon exposure to liriodenine. The presence of DNA fragmentation indicates the CAOV-3 cells undergo late apoptosis or final stage of apoptosis. Confirmation of apoptosis at the protein level showed overexpression of Bax and suppression of Bcl-2 and survivin. Liriodenine inhibits progression of the CAOV-3 cell cycle in S phase. These findings indicate that liriodenine could be considered as a promising anticancer agent.
  15. Yeap S, Akhtar MN, Lim KL, Abu N, Ho WY, Zareen S, et al.
    Drug Des Devel Ther, 2015;9:983-92.
    PMID: 25733816 DOI: 10.2147/DDDT.S65468
    Anthraquinones are an important class of naturally occurring biologically active compounds. In this study, anthraquinone derivative 1,3-dihydroxy-9,10-anthraquinone-2- carboxylic acid (DHAQC) (2) was synthesized with 32% yield through the Friedel-Crafts condensation reaction. The mechanisms of cytotoxicity of DHAQC (2) in human breast cancer MCF-7 cells were further investigated. Results from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that DHAQC (2) exhibited potential cytotoxicity and selectivity in the MCF-7 cell line, comparable with the naturally occurring anthraquinone damnacanthal. DHAQC (2) showed a slightly higher IC50 (inhibitory concentration with 50% cell viability) value in the MCF-7 cell line compared to damnacanthal, but it is more selective in terms of the ratio of IC50 on MCF-7 cells and normal MCF-10A cells. (selective index for DHAQC (2) was 2.3 and 1.7 for damnacanthal). The flow cytometry cell cycle analysis on the MCF-7 cell line treated with the IC50 dose of DHAQC (2) for 48 hours showed that DHAQC (2) arrested MCF-7 cell line at the G2/M phase in association with an inhibited expression of PLK1 genes. Western blot analysis also indicated that the DHAQC (2) increased BAX, p53, and cytochrome c levels in MCF-7 cells, which subsequently activated apoptosis as observed in annexin V/propidium iodide and cell cycle analyses. These results indicate that DHAQC (2) is a synthetic, cytotoxic, and selective anthraquinone, which is less toxic than the natural product damnacanthal, and which demonstrates potential in the induction of apoptosis in the breast cancer MCF-7 cell line.
  16. Abu N, Mohamed NE, Yeap SK, Lim KL, Akhtar MN, Zulfadli AJ, et al.
    Drug Des Devel Ther, 2015;9:1401-17.
    PMID: 25834398 DOI: 10.2147/DDDT.S67976
    Flavokawain B (FKB) is a naturally occurring chalcone that can be isolated through the root extracts of the kava-kava plant (Piper methysticum). It can also be synthesized chemically to increase the yield. This compound is a promising candidate as a biological agent, as it is reported to be involved in a wide range of biological activities. Furthermore, FKB was reported to have antitumorigenic effects in several cancer cell lines in vitro. However, the in vivo antitumor effects of FKB have not been reported on yet. Breast cancer is one of the major causes of cancer-related deaths in the world today. Any potential treatment should not only impede the growth of the tumor, but also modulate the immune system efficiently and inhibit the formation of secondary tumors. As presented in our study, FKB induced apoptosis in 4T1 tumors in vivo, as evidenced by the terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining of the tumor. FKB also regulated the immune system by increasing both helper and cytolytic T-cell and natural killer cell populations. In addition, FKB also enhanced the levels of interleukin 2 and interferon gamma but suppressed interleukin 1B. Apart from that, FKB was also found to inhibit metastasis, as evaluated by clonogenic assay, bone marrow smearing assay, real-time polymerase chain reaction, Western blot, and proteome profiler analysis. All in all, FKB may serve as a promising anticancer agent, especially in treating breast cancer.
  17. Ahmed S, Govender T, Khan I, Rehman NU, Ali W, Shah SMH, et al.
    Drug Des Devel Ther, 2018;12:255-269.
    PMID: 29440875 DOI: 10.2147/DDDT.S148912
    Background and aim: The challenges with current antimicrobial drug therapy and resistance remain a significant global health threat. Nanodrug delivery systems are playing a crucial role in overcoming these challenges and open new avenues for effective antimicrobial therapy. While fluticasone (FLU), a poorly water-soluble corticosteroid, has been reported to have potential antimicrobial activity, approaches to optimize its dissolution profile and antimicrobial activity are lacking in the literature. This study aimed to combine an experimental study with molecular modeling to design stable FLU nanopolymeric particles with enhanced dissolution rates and antimicrobial activity.

    Methods: Six different polymers were used to prepare FLU nanopolymeric particles: hydroxyl propyl methylcellulose (HPMC), poly (vinylpyrrolidone) (PVP), poly (vinyl alcohol) (PVA), ethyl cellulose (EC), Eudragit (EUD), and Pluronics®. A low-energy method, nanoprecipitation, was used to prepare the polymeric nanoparticles.

    Results and conclusion: The combination of HPMC-PVP and EUD-PVP was found most effective to produce stable FLU nanoparticles, with particle sizes of 250 nm ±2.0 and 280 nm ±4.2 and polydispersity indices of 0.15 nm ±0.01 and 0.25 nm ±0.03, respectively. The molecular modeling studies endorsed the same results, showing highest polymer drug binding free energies for HPMC-PVP-FLU (-35.22 kcal/mol ±0.79) and EUD-PVP-FLU (-25.17 kcal/mol ±1.12). In addition, it was observed that Ethocel® favored a wrapping mechanism around the drug molecules rather than a linear conformation that was witnessed for other individual polymers. The stability studies conducted for 90 days demonstrated that HPMC-PVP-FLU nanoparticles stored at 2°C-8°C and 25°C were more stable. Crystallinity of the processed FLU nanoparticles was confirmed using differential scanning calorimetry, powder X-ray diffraction analysis and TEM. The Fourier transform infrared spectroscopy (FTIR) studies showed that there was no chemical interaction between the drug and chosen polymer system. The HPMC-PVP-FLU nanoparticles also showed enhanced dissolution rate (P<0.05) compared to the unprocessed counterpart. The in vitro antibacterial studies showed that HPMC-PVP-FLU nanoparticles displayed superior effect against gram-positive bacteria compared to the unprocessed FLU and positive control.

  18. Ilangkovan M, Jantan I, Mesaik MA, Bukhari SN
    Drug Des Devel Ther, 2015;9:4917-30.
    PMID: 26347462 DOI: 10.2147/DDDT.S88189
    Phyllanthus amarus (family: Euphorbiaceae) is of immense interest due to its wide spectrum of biological activities. In the present study, the standardized 80% ethanol extract of P. amarus was investigated for its modulatory activity on various cellular immune parameters, including chemotaxis of neutrophils, engulfment of Escherichia coli by neutrophils, and Mac-1 expression, in leukocytes isolated from treated/nontreated Wistar-Kyoto rats. The detailed cell-mediated activity of P. amarus was also investigated, including analysis of the effects on T- and B-cell proliferation and CD4(+) and CD8(+) T-cell subsets in splenic mononuclear cells, and estimation of serum cytokine production by activated T-cells. The main components of the extract, phyllanthin, hypophyllanthin, corilagin, geraniin, ellagic acid, and gallic acid were identified and quantitatively analyzed in the extracts, using validated reversed-phase high-performance liquid chromatography (HPLC) methods. N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophils isolated from rats administered with the extract of P. amarus, at doses ranging from 100 to 400 mg/kg for 14 days, revealed a significant dose-dependent reduction in neutrophil migration (P<0.05). Similar patterns of inhibition were also observed in phagocytic activity and in fMLP-induced changes in expression of β2 integrin polymorphonuclear neutrophils. The results in P. amarus-treated rats also demonstrated a dose-dependent inhibition of both lipopolysaccharide-stimulated B-cell proliferation and concanavalin A-stimulated T-cell proliferation as compared with sensitized control. At a dose of 400 mg/kg (P<0.01), there was a significant decrease in the (%) expression of CD4(+) and CD8(+) in splenocytes and in serum cytokines of T helper (Th1) (IL-2 and IFN-γ) and Th2 (IL-4). In conclusion, P. amarus showed effective immunosuppressive activities in cellular immune response, by various immune regulatory mechanisms, and may be useful for improvement of immune-related disorders.
  19. Ahmad W, Jantan I, Kumolosasi E, Bukhari SN
    Drug Des Devel Ther, 2015;9:2961-73.
    PMID: 26089645 DOI: 10.2147/DDDT.S85405
    Tinospora crispa (TC) has been used in folkloric medicine for the treatment of various diseases and has been reported for several pharmacological activities. However, the effects of TC extract on the immune system are largely unknown. Therefore, the present study was aimed to investigate the immunomodulatory effects of a standardized 80% ethanol extract of the stem of TC on innate immune responses. Male Wistar Kyoto rats were treated daily at 100 mg/kg, 200 mg/kg, and 400 mg/kg doses of the extract for 21 days by oral gavage. The immunomodulatory potential of TC was evaluated by determining its effect on chemotaxis and phagocytic activity of neutrophils isolated from the blood of rats. To further elucidate the mechanism of action, its effects on the proliferation of T- and B-lymphocytes and T-lymphocytes subsets (CD4+ and CD8+) and on the secretion of Th1 and Th2 cytokines were also monitored. The main components of the extracts, syringin and magnoflorine, were identified and quantitatively analyzed in the extracts by using a validated reversed-phase high-performance liquid chromatography method. It was observed that the chemotactic activity of neutrophils obtained from extract-treated rats increased as compared to controls. A dose-dependent increase in the number of migrated cells and phagocytosis activity of neutrophils was observed. Dose-dependent increase was also observed in the T- and B-lymphocytes proliferation stimulated with concanavalin A (5 μg/mL) and lipopolysaccharide (10 μg/mL), and was statistically significant at 400 mg/kg (P>0.01). Apart from cell-mediated immune response, the concentrations of Th1 (TNF-α, IL-2, and IFN-γ) and Th2 (IL-4) cytokines were significantly increased in sera of rats treated with different doses as compared with the control group. From these findings, it can be concluded that TC possesses immunostimulatory activity and has therapeutic potential for the prevention of immune diseases.
  20. Arshad L, Jantan I, Bukhari SNA
    Drug Des Devel Ther, 2019;13:1421-1436.
    PMID: 31118577 DOI: 10.2147/DDDT.S185191
    Background: 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one (BBP), a novel synthetic curcumin analogue has been revealed to possess strong in vitro and in vivo immunosuppressive effects. Purpose: The aim of present study was to prepare and characterize BBP-encapsulated polylactic-co-glycolic acid-block-polyethylene glycol (PLGA-b-PEG) nanoparticles and to evaluate its in vivo efficacy against innate and adaptive immune responses. Methods: Male BALB/c mice were orally administered with BBP alone and BBP- encapsulated nanoparticles equivalent to 5, 10 and 20 mg/kg of BBP in distilled water for a period of 14 days. The immunomodulatory potential was appraised by determining its effects on non-specific and specific immune parameters. Results: The results showed that BBP was successfully encapsulated in PLGA-b-PEG polymer with 154.3 nm size and high encapsulation efficiency (79%) while providing a sustained release for 48 hours. BBP nanoparticles showed significant enhanced dose-dependent reduction on the migration of neutrophils, Mac-1 expression, phagocytic activity, reactive oxygen species (ROS) production, serum levels of ceruloplasmin and lysozyme, immunoglobulins and myloperoxidase (MPO) plasma levels when compared to unencapsulated BBP. Enhanced dose-dependent inhibition was also observed on lymphocyte proliferation along with the downregulation of effector cells expression and release of cytokines, and reduction in rat paw oedema in BBP nanoparticles treated mice. At higher doses the suppressive effects of the BBP nanoparticles on various cellular and humoral parameters of immune responses were comparable to that of cyclosporine-A at 20 mg/kg. Conclusion: These findings suggest that the immunosuppressive effects of BBP were enhanced as PLGA-b-PEG nanoparticles.
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