Displaying publications 1 - 20 of 99 in total

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  1. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy
    Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS, Heron SE, et al.
    Ann Neurol, 2016 Jan;79(1):120-31.
    PMID: 26505888 DOI: 10.1002/ana.24547
    Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy.
    Matched MeSH terms: TOR Serine-Threonine Kinases/metabolism*
  2. Lack of association between the LRRK2 A419V variant and Asian Parkinson's disease
    Gopalai AA, Lim SY, Aziz ZA, Lim SK, Tan LP, Chong YB, et al.
    Ann Acad Med Singap, 2013 May;42(5):237-40.
    PMID: 23771111
    INTRODUCTION: The G2385R and R1628P LRRK2 gene variants have been associated with an increased risk of Parkinson's disease (PD) in the Asian population. Recently, a new LRRK2 gene variant, A419V, was reported to be a third risk variant for PD in Asian patients. Our objective was to investigate this finding in our cohort of Asian subjects.

    MATERIALS AND METHODS: Eight hundred and twenty-eight subjects (404 PD patients, and 424 age and gender-matched control subjects without neurological disorders) were recruited. Genotyping was done by Taqman® allelic discrimination assay on an Applied Biosystems 7500 Fast Real-Time PCR machine.

    RESULTS: The heterozygous A419V genotype was found in only 1 patient with PD, compared to 3 in the control group (0.4% vs 1.3%), giving an odds ratio of 0.35 (95% confidence interval (CI), 0.01 to 3.79; P = 0.624).

    CONCLUSION: A419V is not an important LRRK2 risk variant in our Asian cohort of patients with PD. Our data are further supported by a literature review which showed that 4 out of 6 published studies reported a negative association of this variant in PD.

    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics*; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  3. The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals
    Tan HK, Moad AI, Tan ML
    Asian Pac J Cancer Prev, 2014;15(16):6463-75.
    PMID: 25169472
    The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.
    Matched MeSH terms: TOR Serine-Threonine Kinases/antagonists & inhibitors*; TOR Serine-Threonine Kinases/metabolism
  4. Mechanism of Chemoprevention against Colon Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/β-catenin Pathways
    Wee LH, Morad NA, Aan GJ, Makpol S, Wan Ngah WZ, Mohd Yusof YA
    Asian Pac J Cancer Prev, 2015;16(15):6549-56.
    PMID: 26434873
    The PI3K-Akt-mTOR, Wnt/β-catenin and apoptosis signaling pathways have been shown to be involved in genesis of colorectal cancer (CRC). The aim of this study was to elucidate whether combination of Gelam honey and ginger might have chemopreventive properties in HT29 colon cancer cells by modulating the mTOR, Wnt/β-catenin and apoptosis signaling pathways. Treatment with Gelam honey and ginger reduced the viability of the HT29 cells dose dependently with IC50 values of 88 mg/ml and 2.15 mg/ml respectively, their while the combined treatment of 2 mg/ml of ginger with 31 mg/ml of Gelam honey inhibited growth of most HT29 cells. Gelam honey, ginger and combination induced apoptosis in a dose dependent manner with the combined treatment exhibiting the highest apoptosis rate. The combined treatment downregulated the gene expressions of Akt, mTOR, Raptor, Rictor, β-catenin, Gsk3β, Tcf4 and cyclin D1 while cytochrome C and caspase 3 genes were shown to be upregulated. In conclusion, the combination of Gelam honey and ginger may serve as a potential therapy in the treatment of colorectal cancer through inhibiton of mTOR, Wnt/β catenin signaling pathways and induction of apoptosis pathway.
    Matched MeSH terms: TOR Serine-Threonine Kinases/genetics*; TOR Serine-Threonine Kinases/metabolism
  5. Fulltext Oral hyperpigmented lesions--a case study
    Kwa SK, Gupta ED
    Aust Fam Physician, 2013 Jul;42(7):490-1.
    PMID: 23826603
    An overweight woman, aged 58 years, presented for follow up of hypertension, diabetes and dyslipidaemia. She was noted to have hyperpigmented brown macules on the inner surface of the lower lip and buccal mucosa (Figure 1). She stated that she had first noticed these lesions when aged in her 40s. Her mother died at age 58 years from gastric cancer with extensive metastases, and her brother died at age 45 years from colon cancer with spread to the liver and lungs.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics
  6. Fulltext DRD and GRIN2B polymorphisms and their association with the development of impulse control behaviour among Malaysian Parkinson's disease patients
    Zainal Abidin S, Tan EL, Chan SC, Jaafar A, Lee AX, Abd Hamid MH, et al.
    BMC Neurol, 2015;15:59.
    PMID: 25896831 DOI: 10.1186/s12883-015-0316-2
    Impulse control disorder (ICD) and behaviours (ICB) represent a group of behavioural disorders that have become increasingly recognised in Parkinson's disease (PD) patients who previously used dopaminergic medications, particularly dopamine agonists and levodopa. It has been suggested that these medications can lead to the development of ICB through the abnormal modulation of dopaminergic transmission and signalling in the mesocorticolimbic dopaminergic system. Several studies have reported an association between polymorphisms in the dopamine receptor (DRD) and N-methyl-D-aspartate 2B (GRIN2B) genes with the development of ICB in PD (PD-ICB) patients. Thus, this study aimed to investigate the association of selected polymorphisms within the DRD and GRIN2B genes with the development of ICB among PD patients using high resolution melt (HRM) analysis.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics
  7. Fulltext LRRK2 G2385R and R1628P mutations are associated with an increased risk of Parkinson's disease in the Malaysian population
    Gopalai AA, Lim SY, Chua JY, Tey S, Lim TT, Mohamed Ibrahim N, et al.
    Biomed Res Int, 2014;2014:867321.
    PMID: 25243190 DOI: 10.1155/2014/867321
    The LRRK2 gene has been associated with both familial and sporadic forms of Parkinson's disease (PD). The G2019S variant is commonly found in North African Arab and Caucasian PD patients, but this locus is monomorphic in Asians. The G2385R and R1628P variants are associated with a higher risk of developing PD in certain Asian populations but have not been studied in the Malaysian population. Therefore, we screened the G2385R and R1628P variants in 1,202 Malaysian subjects consisting of 695 cases and 507 controls. The G2385R and R1628P variants were associated with a 2.2-fold (P = 0.019) and 1.2-fold (P = 0.054) increased risk of PD, respectively. Our data concur with other reported findings in Chinese, Taiwanese, Singaporean, and Korean studies.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics*
  8. Fulltext Induction of Endoplasmic Reticulum Stress Pathway by Green Tea Epigallocatechin-3-Gallate (EGCG) in Colorectal Cancer Cells: Activation of PERK/p-eIF2α/ATF4 and IRE1α
    Md Nesran ZN, Shafie NH, Ishak AH, Mohd Esa N, Ismail A, Md Tohid SF
    Biomed Res Int, 2019;2019:3480569.
    PMID: 31930117 DOI: 10.1155/2019/3480569
    Epigallocatechin-3-gallate (EGCG) is the most abundant bioactive polyphenolic compound among the green tea constituents and has been identified as a potential anticancer agent in colorectal cancer (CRC) studies. This study was aimed to determine the mechanism of actions of EGCG when targeting the endoplasmic reticulum (ER) stress pathway in CRC. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed on HT-29 cell line and normal cell line (3T3) to determine the EGCG toxicity. Next, western blot was done to observe the expression of the related proteins for the ER stress pathway. The Caspase 3/7 assay was performed to determine the apoptosis induced by EGCG. The results demonstrated that EGCG treatment was toxic to the HT-29 cell line. EGCG induced ER stress in HT-29 by upregulating immunoglobulin-binding (BiP), PKR-like endoplasmic reticulum kinase (PERK), phosphorylation of eukaryotic initiation factor 2 alpha subunit (eIF2α), activating transcription 4 (ATF4), and inositol-requiring kinase 1 alpha (IRE1α). Apoptosis was induced in HT-29 cells after the EGCG treatment, as shown by the Caspase 3/7 activity. This study indicates that green tea EGCG has the potential to inhibit colorectal cancer cells through the induction of ER stress.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/metabolism*
  9. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase
    Merlot AM, Shafie NH, Yu Y, Richardson V, Jansson PJ, Sahni S, et al.
    Biochem Pharmacol, 2016 06 01;109:27-47.
    PMID: 27059255 DOI: 10.1016/j.bcp.2016.04.001
    The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP); (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing; (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)); (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP); and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics*; Protein-Serine-Threonine Kinases/metabolism
  10. Fulltext The role of autophagy-related proteins in the pathogenesis of neuromyelitis optica spectrum disorders
    Guo HL, Shen XR, Liang XT, Li LZ
    Bioengineered, 2022 Jun;13(6):14329-14338.
    PMID: 36694421 DOI: 10.1080/21655979.2022.2084273
    This study aimed to investigate the expression of autophagy-related proteins in a mouse model of neuromyelitis optica (NMO). Mice were assigned to one of four groups: an animal experimental model group (NMO-EAE group, given with exogenous IL-17A), Interleukin-17 monoclonal antibody intervention group (NMO-EAE_0IL17inb), No exogenous interleukin-17 enhanced immune intervention group (NMO-EAE_0IL17), and a control group. Behavioral scores were assessed in each group, and the protein expressions of sequestosome 1 (P62), Beclin-1, the mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K-I), and LC3II/LC3I were detected using Western blotting. In the NMO-EAE_0IL17 group, the expression of Beclin-1 decreased, the LC3II/LC3I ratio was lower, and the expressions of P62, mTOR, and PI3K-I increased; after administration of IL-17A inhibitor into the brain tissue, however, the expression of Beclin-1 increased significantly, along with the LC3II/LC3I ratio, while the expressions of P62, mTOR and PI3K-I protein decreased significantly. In terms of behavioral scores, the scores of optic neuritis and myelitis were more serious, onset occurred earlier and the progress was faster, after the administration of IL-17A. In the mechanism of NMO animal model, IL-17A may regulate autophagy and affect the disease process through the activation of the PI3K-mTOR signaling pathway.
    Matched MeSH terms: TOR Serine-Threonine Kinases/genetics; TOR Serine-Threonine Kinases/metabolism
  11. The roles of MTOR and miRNAs in endothelial cell senescence
    Khor ES, Wong PF
    Biogerontology, 2020 10;21(5):517-530.
    PMID: 32246301 DOI: 10.1007/s10522-020-09876-w
    Accumulation of senescent cells in vascular endothelium is known to contribute to vascular aging and increases the risk of developing cardiovascular diseases. The involvement of classical pathways such as p53/p21 and p16/pRB in cellular senescence are well described but there are emerging evidence supporting the increasingly important role of mammalian target of rapamycin (MTOR) as driver of cellular senescence via these pathways or other effector molecules. MicroRNAs (miRNAs) are a highly conserved group of small non-coding RNAs (18-25 nucleotides), instrumental in modulating the expression of target genes associated with various biological and cellular processes including cellular senescence. The inhibition of MTOR activity is predominantly linked to cellular senescence blunting and prolonged lifespan in model organisms. To date, known miRNAs regulating MTOR in endothelial cell senescence remain limited. Herein, this review discusses the roles of MTOR and MTOR-associated miRNAs in regulating endothelial cell senescence, including the crosstalk between MTOR Complex 1 (MTORC1) and cell cycle pathways and the emerging role of MTORC2 in cellular senescence. New insights on how MTOR and miRNAs coordinate underlying molecular mechanisms of endothelial senescence will provide deeper understanding and clarity to the complexity of the regulation of cellular senescence.
    Matched MeSH terms: TOR Serine-Threonine Kinases/physiology*
  12. Fulltext Unravelling the genetic links between Parkinson's disease and lung cancer
    Leong YQ, Koh RY, Chye SM, Ng KY
    Biol Chem, 2023 May 25;404(6):551-567.
    PMID: 36634094 DOI: 10.1515/hsz-2022-0228
    Increase evidence from epidemiological studies have shown an inverse association between Parkinson's disease (PD) and lung cancer. PD and lung cancer are both geriatric diseases, where these two diseases are sharing some common genetic determinants. Several PD-associated genes including alpha synuclein (SNCA), PTEN-induced kinase 1 (PINK1), parkin, parkinsonism associated deglycase (DJ-1), leucine-rich repeat kinase 2 (LRRK2), F-box protein 7 (FBXO7) and ubiquitin C-terminal hydrolase L1 (UCHL1) were reported to have altered expressions in lung cancer patients. This indicates that certain PD-associated genes might be important in conferring anticancer effects. This review aims to depict the physiological functions of these genes, and discuss the putative roles of these PD-associated genes in lung cancer. The understanding of the roles of these genes in the lung cancer progression might be important in the identification of new treatment targets for lung cancer. Gene therapy that aims to alter the expressions of these genes could be developed for future anticancer therapy. As a result, studying the roles of these genes in lung cancer may also help to understand their involvements as well as their roles in the pathogenesis of PD.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics
  13. Fulltext Natural sources, biological effects, and pharmacological properties of cynaroside
    Bouyahya A, Taha D, Benali T, Zengin G, El Omari N, El Hachlafi N, et al.
    Biomed Pharmacother, 2023 May;161:114337.
    PMID: 36812715 DOI: 10.1016/j.biopha.2023.114337
    Cynaroside is a flavonoid, isolated from several species belonging to the Apiaceae, Poaceae, Lamiaceae, Solanaceae, Zingiberaceae, Compositae and other families and it can be extracted from seeds, roots, stems, leaves, barks, flowers, fruits, aerial parts, and the whole plant of these species. This paper discloses the current state of knowledge on the biological/pharmacological effects and mode of action to better understand the numerous health benefits of cynaroside. Several research works revealed that cynaroside could have beneficial effects on various human pathologies. Indeed, this flavonoid exerts antibacterial, antifungal, antileishmanial, antioxidant, hepatoprotective, antidiabetic, anti-inflammatory, and anticancer effects. Additionally, cynaroside exhibits its anticancer effects by blocking MET/AKT/mTOR axis by decreasing the phosphorylation level of AKT, mTOR, and P70S6K. For antibacterial activity, cynaroside reduces biofilm development of Pseudomonas aeruginosa and Staphylococcus aureus. Moreover, the incidence of mutations leading to ciprofloxacin resistance in Salmonella typhimurium was reduced after the treatment with cynaroside. In addition, cynaroside inhibited the production of reactive oxygen species (ROS), which reduced the damage to mitochondrial membrane potential caused by hydrogen peroxide (H2O2). It also enhanced the expression of the anti-apoptotic protein Bcl-2 and lowered that of the pro-apoptotic protein Bax. Cynaroside abrogated the up-regulation of c-Jun N-terminal kinase (JNK) and p53 protein expression triggered by H2O2. All these findings suggest that cynaroside could be used to prevent certain human diseases.
    Matched MeSH terms: TOR Serine-Threonine Kinases
  14. Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73
    Wong SW, Tiong KH, Kong WY, Yue YC, Chua CH, Lim JY, et al.
    Breast Cancer Res Treat, 2011 Jul;128(2):301-13.
    PMID: 20686837 DOI: 10.1007/s10549-010-1055-0
    Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; TOR Serine-Threonine Kinases/genetics; TOR Serine-Threonine Kinases/metabolism
  15. Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma
    Khor TO, Gul YA, Ithnin H, Seow HF
    Cancer Lett, 2004 Jul 16;210(2):139-50.
    PMID: 15183529
    The enhancement of cell proliferation and promotion of cell survival via the inhibition of apoptosis is thought to be the key to the initiation and progression of cancers. The phosphatidylinositol-3 kinase (PI3K)/Akt is an important survival signal pathway that has been shown to be crucial in the regulation of balance between pro-apoptotic and survival (anti-apoptotic) signal. In this study, the expression of phosphorylated Akt at Thr308 and Ser473, BCL-2-antagonist of cell death (BAD) at Ser136 and glycogen synthase kinase-3beta (GSK-3beta) at Ser9 in 47 paraffin-embedded human colorectal carcinoma (CRC) tissues were determined by immunohistochemical staining in order to dissect the alterations in the signal transduction pathways in CRC. Our results showed that there was a significant increase in the expression of these biomolecules in CRC tissues compared to the apparently normal adjacent tissues. The frequency of increased expression in tumor colonic mucosa were as follows: p-Akt1/2/3 (Thr308) = 16/47 (34%); p-Akt1 (Ser473) = 21/47 (44.7%); phospho-BAD (p-BAD) Ser136 = 27/47 (57.4%) and phospho-GSK-3beta (p-GSK-3beta) = 21/47 (44.7%). Analysis of the total p-Akt1 (Ser473), p-Akt1/2/3 (Thr308), p-GSK-3beta (Ser9) and p-BAD (Ser136) score found that there was a statistically significant relationship with each other. A statistically significant positive linear relationship was found between total p-Akt (Ser473) score and total p-GSK-3beta (Ser9) score as well as with total p-BAD (Ser136) score. On the other hand, total p-Akt1/2/3 (Thr308) scores had a statistically significant positive linear relationship with p-GSK-3beta (Ser9) only. The Akt targets, p-GSK-3beta (Ser9) and p-BAD (Ser136) were positively correlated to each other. There was no significant correlation between clinico-pathological data with total p-Akt1 (Ser473), p-Akt1/2/3 (Thr308), p-GSK-3beta (Ser9) and p-BAD (Ser136) score except for age. The total scores of p-GSK-3beta were found to be higher in patients in the age group of greater than 60. This is the first report of p-Akt1/2/3 (Thr308) and p-BAD (Ser136) expression in primary colorectal tumor tissue. Our data further supports the role of PI3K/Akt signaling pathways in the pathogenesis of CRC and contributes to the identification of target molecules in the signal transduction pathway for cancer therapy.
    Matched MeSH terms: Threonine/chemistry; Protein-Serine-Threonine Kinases/biosynthesis*; Protein-Serine-Threonine Kinases/metabolism*
  16. In vitro anticancer properties and biological evaluation of novel natural alkaloid jerantinine B
    Qazzaz ME, Raja VJ, Lim KH, Kam TS, Lee JB, Gershkovich P, et al.
    Cancer Lett, 2016 Jan 28;370(2):185-97.
    PMID: 26515390 DOI: 10.1016/j.canlet.2015.10.013
    Natural products play a pivotal role in medicine especially in the cancer arena. Many drugs that are currently used in cancer chemotherapy originated from or were inspired by nature. Jerantinine B (JB) is one of seven novel Aspidosperma indole alkaloids isolated from the leaf extract of Tabernaemontana corymbosa. Preliminary antiproliferative assays revealed that JB and JB acetate significantly inhibited growth and colony formation, accompanied by time- and dose-dependent apoptosis induction in human cancer cell lines. JB significantly arrested cells at the G2/M cell cycle phase, potently inhibiting tubulin polymerisation. Polo-like kinase 1 (PLK1; an early trigger for the G2/M transition) was also dose-dependently inhibited by JB (IC50 1.5 µM). Furthermore, JB provoked significant increases in reactive oxygen species (ROS). Annexin V+ cell populations, dose-dependent accumulation of cleaved-PARP and caspase 3/7 activation, and reduced Bcl-2 and Mcl-1 expression confirm apoptosis induction. Preclinical in silico biopharmaceutical assessment of JB calculated rapid absorption and bioavailability >70%. Doses of 8-16 mg/kg JB were predicted to maintain unbound plasma concentrations >GI50 values in mice during efficacy studies. These findings advocate continued development of JB as a potential chemotherapeutic agent.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/antagonists & inhibitors
  17. Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition
    Hossan MS, Chan ZY, Collins HM, Shipton FN, Butler MS, Rahmatullah M, et al.
    Cancer Lett, 2019 07 01;453:57-73.
    PMID: 30930233 DOI: 10.1016/j.canlet.2019.03.034
    Natural products possess a significant role in anticancer therapy and many currently-used anticancer drugs are of natural origin. Cerberin (CR), a cardenolide isolated from the fruit kernel of Cerbera odollam, was found to potently inhibit cancer cell growth (GI50 values 60% bioavailability and rapid absorption; doses of 1-10 mg/kg CR were predicted to maintain efficacious unbound plasma concentrations (>GI50 value). CR's potent and selective anti-tumour activity, and its targeting of key signalling mechanisms pertinent to tumourigenesis support further preclinical evaluation of this cardiac glycoside.
    Matched MeSH terms: TOR Serine-Threonine Kinases
  18. Fulltext Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation
    Tripathi M, Zhang CW, Singh BK, Sinha RA, Moe KT, DeSilva DA, et al.
    Cell Death Dis, 2016 12 08;7(12):e2513.
    PMID: 27929536 DOI: 10.1038/cddis.2016.374
    Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect. Moreover, HHcy increased unfolded protein response. Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.
    Matched MeSH terms: TOR Serine-Threonine Kinases/metabolism
  19. An overview of signaling pathways regulating YAP/TAZ activity
    Heng BC, Zhang X, Aubel D, Bai Y, Li X, Wei Y, et al.
    Cell Mol Life Sci, 2021 Jan;78(2):497-512.
    PMID: 32748155 DOI: 10.1007/s00018-020-03579-8
    YAP and TAZ are ubiquitously expressed homologous proteins originally identified as penultimate effectors of the Hippo signaling pathway, which plays a key role in maintaining mammalian tissue/organ size. Presently, it is known that YAP/TAZ also interact with various non-Hippo signaling pathways, and have diverse roles in multiple biological processes, including cell proliferation, tissue regeneration, cell lineage fate determination, tumorigenesis, and mechanosensing. In this review, we first examine the various microenvironmental cues and signaling pathways that regulate YAP/TAZ activation, through the Hippo and non-Hippo signaling pathways. This is followed by a brief summary of the interactions of YAP/TAZ with TEAD1-4 and a diverse array of other non-TEAD transcription factors. Finally, we offer a critical perspective on how increasing knowledge of the regulatory mechanisms of YAP/TAZ signaling might open the door to novel therapeutic applications in the interrelated fields of biomaterials, tissue engineering, regenerative medicine and synthetic biology.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/metabolism
  20. Fulltext Chemical composition and molecular structure of polysaccharide-protein biopolymer from Durio zibethinus seed: extraction and purification process
    Amid BT, Mirhosseini H, Kostadinović S
    Chem Cent J, 2012 Oct 14;6(1):117.
    PMID: 23062269 DOI: 10.1186/1752-153X-6-117
    BACKGROUND: The biological functions of natural biopolymers from plant sources depend on their chemical composition and molecular structure. In addition, the extraction and further processing conditions significantly influence the chemical and molecular structure of the plant biopolymer. The main objective of the present study was to characterize the chemical and molecular structure of a natural biopolymer from Durio zibethinus seed. A size-exclusion chromatography coupled to multi angle laser light-scattering (SEC-MALS) was applied to analyze the molecular weight (Mw), number average molecular weight (Mn), and polydispersity index (Mw/Mn).

    RESULTS: The most abundant monosaccharide in the carbohydrate composition of durian seed gum were galactose (48.6-59.9%), glucose (37.1-45.1%), arabinose (0.58-3.41%), and xylose (0.3-3.21%). The predominant fatty acid of the lipid fraction from the durian seed gum were palmitic acid (C16:0), palmitoleic acid (C16:1), stearic acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2), and linolenic acid (C18:2). The most abundant amino acids of durian seed gum were: leucine (30.9-37.3%), lysine (6.04-8.36%), aspartic acid (6.10-7.19%), glycine (6.07-7.42%), alanine (5.24-6.14%), glutamic acid (5.57-7.09%), valine (4.5-5.50%), proline (3.87-4.81%), serine (4.39-5.18%), threonine (3.44-6.50%), isoleucine (3.30-4.07%), and phenylalanine (3.11-9.04%).

    CONCLUSION: The presence of essential amino acids in the chemical structure of durian seed gum reinforces its nutritional value.

    Matched MeSH terms: Threonine
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