Displaying publications 21 - 40 of 248 in total

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  1. Fulltext (E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) induces cytoprotection in CCD18-Co human colon fibroblast cells through Nrf2/ARE pathway activation
    Tan HH, Thomas NF, Inayat-Hussain SH, Chan KM
    Sci Rep, 2021 02 26;11(1):4773.
    PMID: 33637843 DOI: 10.1038/s41598-021-83163-7
    Cytoprotection involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an important preventive strategy for normal cells against carcinogenesis. In our previous study, the chemopreventive potential of (E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) has been elucidated through its cytoprotective effects against DNA and mitochondrial damages in the human colon fibroblast CCD-18Co cell model. Therefore this study aimed to investigate the molecular mechanisms underlying BK3C231-induced cytoprotection and the involvement of the Nrf2/ARE pathway. The cells were pretreated with BK3C231 before exposure to carcinogen 4-nitroquinoline N-oxide (4NQO). BK3C231 increased the protein expression and activity of cytoprotective enzymes namely NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), as well as restoring the expression of glutamate-cysteine ligase catalytic subunit (GCLC) back to the basal level. Furthermore, dissociation of Nrf2 from its inhibitory protein, Keap1, and ARE promoter activity were upregulated in cells pretreated with BK3C231. Taken together, our findings suggest that BK3C231 exerts cytoprotection by activating the Nrf2 signaling pathway which leads to ARE-mediated upregulation of cytoprotective proteins. This study provides new mechanistic insights into BK3C231 chemopreventive activities and highlights the importance of stilbene derivatives upon development as a potential chemopreventive agent.
    Matched MeSH terms: Signal Transduction/drug effects
  2. Fulltext An Insight into the Anti-Angiogenic and Anti-Metastatic Effects of Oridonin: Current Knowledge and Future Potential
    Abdullah NA, Md Hashim NF, Ammar A, Muhamad Zakuan N
    Molecules, 2021 Feb 03;26(4).
    PMID: 33546106 DOI: 10.3390/molecules26040775
    Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted anti-cancer therapy is increasingly used with conventional therapy to improve patients' outcomes in advanced and metastatic tumors. However, due to the complexity of cancer biology and metastasis, it is urgent to develop new agents and evaluate the anti-cancer efficacy of available treatments. Many phytochemicals from medicinal plants have been reported to possess anti-cancer properties. One such compound is known as oridonin, a bioactive component of Rabdosia rubescens. Several studies have demonstrated that oridonin inhibits angiogenesis in various types of cancer, including breast, pancreatic, lung, colon and skin cancer. Oridonin's anti-cancer effects are mediated through the modulation of several signaling pathways which include upregulation of oncogenes and pro-angiogenic growth factors. Furthermore, oridonin also inhibits cell migration, invasion and metastasis via suppressing epithelial-to-mesenchymal transition and blocking downstream signaling targets in the cancer metastasis process. This review summarizes the recent applications of oridonin as an anti-angiogenic and anti-metastatic drug both in vitro and in vivo, and its potential mechanisms of action.
    Matched MeSH terms: Signal Transduction/drug effects
  3. Garlic flavonoids alleviate H2 O2 induced oxidative damage in L02 cells and induced apoptosis in HepG2 cells by Bcl-2/Caspase pathway
    Gao X, Yanan J, Santhanam RK, Wang Y, Lu Y, Zhang M, et al.
    J Food Sci, 2021 Feb;86(2):366-375.
    PMID: 33448034 DOI: 10.1111/1750-3841.15599
    Liver damage is a common liver disorder, which could induce liver cancer. Oral antioxidant is one of the effective treatments to prevent and alleviate liver damage. In this study, three flavonoids namely myricetin, isoquercitrin, and isorhamnetin were isolated and identified from Laba garlic. The isolated compounds were investigated on the protective effects against H2 O2 -induced oxidative damages in hepatic L02 cells and apoptosis inducing mechanism in hepatic cancer cells HepG2 by using MTT assay, flow cytometry and western blotting analysis. Myricetin, isoquercitrin, and isorhamnetin showed proliferation inhibition on HepG2 cells with IC50 value of 44.32 ± 0.213 µM, 49.68 ± 0.192 µM, and 54.32 ± 0.176 µM, respectively. While they showed low toxicity on normal cell lines L02. They could significantly alleviate the oxidative damage towards L02 cells (P < 0.05), via inhibiting the morphological changes in mitochondria and upholding the integrity of mitochondrial structure and function. The fluorescence intensity of L02 cells pre-treated with myricetin, isoquercitrin, and isorhamnetin (100 µM) was 89.23 ± 1.26%, 89.35 ± 1.43% and 88.97 ± 0.79%, respectively. Moreover, the flavonoids could induce apoptosis in HepG2 cells via Bcl-2/Caspase pathways, where it could up-regulate the expression of Bax and down-regulate the expression of Bcl-2, Bcl-xL, pro-Caspase-3, and pro-Caspase-9 proteins in a dose dependent manner. Overall, the results suggested that the flavonoids from Laba garlic might be a promising candidate for the treatment of various liver disorders. PRACTICAL APPLICATION: Flavonoids from Laba garlic showed selective toxicity towards HepG2 cells in comparison to L02 cells via regulating Bcl-2/caspase pathway. Additionally, the isolated flavonoids expressively barred the oxidative damage induced by H2 O2 in L02 cells. These results suggested that the flavonoids from laba garlic could be a promising agent towards the development of functional foods.
    Matched MeSH terms: Signal Transduction/drug effects
  4. Roles of Rho‑associated kinase in lung cancer (Review)
    Zakaria MA, Rajab NF, Chua EW, Selvarajah GT, Masre SF
    Int J Oncol, 2021 02;58(2):185-198.
    PMID: 33491756 DOI: 10.3892/ijo.2020.5164
    Lung cancer is one of the most lethal forms of cancer known to man, affecting millions of individuals worldwide. Despite advancements being made in lung cancer treatments, the prognosis of patients with the disease remains poor, particularly among patients with late‑stage lung cancer. The elucidation of the signaling pathways involved in lung cancer is a critical approach for the treatment of the disease. Over the past decades, accumulating evidence has revealed that Rho‑associated kinase (ROCK) is overexpressed in lung cancer and is associated with tumor growth. The present review discusses recent findings of ROCK signaling in the pathogenesis of lung cancer that were conducted in pre‑clinical studies. The significant role of ROCK in cancer cell apoptosis, proliferation, migration, invasion and angiogenesis is discussed. The present review also suggests the use of ROCK as a potential target for the development of lung cancer therapies, as ROCK inhibition can reduce multiple hallmarks of cancer, particularly by decreasing cancer cell migration, which is an initial step of metastasis.
    Matched MeSH terms: Signal Transduction/drug effects
  5. Lignans and Polyphenols of Phyllanthus amarus Schumach and Thonn Induce Apoptosis in HCT116 Human Colon Cancer Cells through Caspases-Dependent Pathway
    Mohamed SIA, Jantan I, Nafiah MA, Seyed MA, Chan KM
    Curr Pharm Biotechnol, 2021;22(2):262-273.
    PMID: 32532192 DOI: 10.2174/1389201021666200612173029
    BACKGROUND: The anticancer effects of Phyllanthus amarus extract on various cancer cells have been investigated, however, the effects of its major constituents on HCT116 human colorectal cancer cells have not been reported.

    OBJECTIVE: In the present study, we investigated the cytotoxic effect of 80% ethanol extract of P. amarus and its marker constituents (phyllanthin, hypophyllanthin, gallic acid, niranthin, greraniin, phyltetralin, isolintetralin, corilagin and ellagic acid) on HCT116 and their underlying mechanisms of action.

    METHODS: Their antiproliferative and apoptotic effects on HCT 116 were performed using MTT assay and flow cytometric analysis, respectively, while caspases 3/7, 8 and 9 activities were examined using the colorimetric method. The expression of cleaved poly ADP ribose polymerase enzyme (PARP) and cytochrome c proteins was investigated by the immune-blot technique.

    RESULTS AND DISCUSSION: HPLC and LC-MS/MS analyses demonstrated that the extract contained mainly lignans and polyphenols. The plant samples markedly suppressed the growth and expansion of HCT116 cells in a concentration- and time-dependent manner with no toxicity against normal human fibroblast CCD18 Co. P. amarus extract, phyllanthin and gallic acid induced mode of cell death primarily through apoptosis as confirmed by the exteriorization of phosphatidylserine. Caspases 3/7, 8, and 9 activities increased in a concentration-dependent manner following 24h treatment. The expressions of cleaved PARP (Asp 214) and cytochrome c were markedly upregulated.

    CONCLUSION: P. amarus extract, phyllanthin and gallic acid exhibited an apoptotic effect on HCT116 cells through the caspases-dependent pathway.

    Matched MeSH terms: Signal Transduction/drug effects
  6. Selective targeting of cancer signaling pathways with nanomedicines: challenges and progress
    Barkat HA, Das SS, Barkat MA, Beg S, Hadi HA
    Future Oncol, 2020 Dec;16(35):2959-2979.
    PMID: 32805124 DOI: 10.2217/fon-2020-0198
    Cancer is one of the leading causes of death worldwide. Regardless of advances in understanding the molecular mechanics of cancer, its treatment is still lacking and the death rates for many forms of the disease remain the same as six decades ago. Although a variety of therapeutic agents and strategies have been reported, these therapies often failed to provide efficient therapy to patients as a consequence of the inability to deliver right and adequate chemotherapeutic agents to the right place. However, the situation has started to revolutionize substantially with the advent of novel 'targeted' nanocarrier-based cancer therapies. Such therapies hold great potential in cancer management as they are biocompatible, tailored to specific needs, tolerated and deliver enough drugs at the targeted site. Their use also enhances the delivery of chemotherapeutics by improving biodistribution, lowering toxicity, inhibiting degradation and increasing cellular uptake. However, in some instances, nonselective targeting is not enough and the inclusion of a ligand moiety is required to achieve tumor targeting and enhanced drug accumulation at the tumor site. This contemporary review outlines the targeting potential of nanocarriers, highlighting the essentiality of nanoparticles, tumor-associated molecular signaling pathways, and various biological and pathophysiological barriers.
    Matched MeSH terms: Signal Transduction/drug effects
  7. Cytoprotective effects of antioxidant supplementation on mesenchymal stem cell therapy
    Panahi M, Rahimi B, Rahimi G, Yew Low T, Saraygord-Afshari N, Alizadeh E
    J Cell Physiol, 2020 10;235(10):6462-6495.
    PMID: 32239727 DOI: 10.1002/jcp.29660
    Mesenchymal stem cells (MSCs) are earmarked as perfect candidates for cell therapy and tissue engineering due to their capacity to differentiate into different cell types. However, their potential for application in regenerative medicine declines when the levels of the reactive oxygen and nitrogen species (RONS) increase from the physiological levels, a phenomenon which is at least inevitable in ex vivo cultures and air-exposed damaged tissues. Increased levels of RONS can alter the patterns of osteogenic and adipogenic differentiation and inhibit proliferation, as well. Besides, oxidative stress enhances senescence and cell death, thus lowering the success rates of the MSC engraftment. Hence, in this review, we have selected some representatives of antioxidants and newly emerged nano antioxidants in three main categories, including chemical compounds, biometabolites, and protein precursors/proteins, which are proved to be effective in the treatment of MSCs. We will focus on how antioxidants can be applied to optimize the clinical usage of the MSCs and their associated signaling pathways. We have also reviewed several paralleled properties of some antioxidants and nano antioxidants which can be simultaneously used in real-time imaging, scaffolding techniques, and other applications in addition to their primary antioxidative function.
    Matched MeSH terms: Signal Transduction/drug effects
  8. Beyond lipid-lowering: role of statins in endometrial cancer
    Hafizz AMHA, Zin RRM, Aziz NHA, Kampan NC, Shafiee MN
    Mol Biol Rep, 2020 Oct;47(10):8199-8207.
    PMID: 32897522 DOI: 10.1007/s11033-020-05760-5
    As the obesity rates dramatically increased across the globe, the risk of endometrial cancer (EC) has substantially increased. Measures to improve the EC outcome is utmost important, especially data have shown that women at their reproductive age are commonly affected. No doubt, surgical intervention is a standard treatment for EC. However, the fact that this cancer could arise from metabolic diseases, additional therapy by lipid-lowering agent could be utilized to change the tumour environment. We review available evidence to support the use of this agent in the clinical setting. We search available evidence on the use of statin in EC, in various settings including cell lines, animal and human study. The possible actions at different molecular pathways leading to cellular changes and proliferation of cell were evaluated. The venture in drug repositioning of statins as a chemo-preventive potential agent in EC has gained attention in gynaecological oncology practice worldwide. Lipid-lowering effect by statins may exerted a chemoprotective effect in EC, but there is still lack of evidence on statins use to improve prognosis and survival in EC. Through the cholesterol-lowering effect of statins; theoretically, it could inhibit cell growth, proliferation, migration, and lead to apoptosis. Epidemiological studies suggested that statins may improve survival rate among EC patients. However, some evidence revealed the effects were only more prominent in type II EC. Notwithstanding that several studies also showed no benefit of statins in EC. Hence we highlight the limitations of these studies in this review. In line with recent literature on the topic, statins may play a role in EC management. Future studies for a proper systematic review and randomized controlled study are needed to answer some uncertainties of statins effect in EC.
    Matched MeSH terms: Signal Transduction/drug effects
  9. Fulltext Targeting the B-cell lymphoma 2 anti-apoptotic proteins for cervical cancer treatment
    Abdul Rahman SF, Xiang Lian BS, Mohana-Kumaran N
    Future Oncol, 2020 Oct;16(28):2235-2249.
    PMID: 32715755 DOI: 10.2217/fon-2020-0389
    The B-cell lymphoma 2 (BCL-2) anti-apoptotic proteins have become attractive therapeutic targets especially with the development of BH3-mimetics which selectively target these proteins. However, it is important to note that expression levels of the anti-apoptotic proteins and their relevance in inhibiting apoptosis varies between different cell lineages. This addiction to certain anti-apoptotic proteins for survival, can be determined with various techniques and targeted effectively with selective BH3-mimetics. Studies have highlighted that anti-apoptotic proteins BCL-XL and MCL-1 are crucial for cervical cancer cell survival. Co-targeting BCL-XL and MCL-1 with selective BH3-mimetics yielded promising results in cervical cancer cell lines. In this review, we focus on the expression levels of the anti-apoptotic proteins in cervical cancer tissues and how to possibly target them with BH3-mimetics.
    Matched MeSH terms: Signal Transduction/drug effects
  10. Fulltext Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival
    Nalairndran G, Hassan Abdul Razack A, Mai CW, Fei-Lei Chung F, Chan KK, Hii LW, et al.
    J Cell Mol Med, 2020 Oct;24(20):12188-12198.
    PMID: 32926495 DOI: 10.1111/jcmm.15876
    Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome-wide lentiviral small-hairpin RNA (shRNA) library screen, we identified phosphoinositide-dependent kinase-1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock-down of endogenous human PDPK1 induced significant tumour-specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE-1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid-regulated kinase 3 (SGK3). Knock-down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock-down. Importantly, PDPK1 inhibitors (GSK2334470 and BX-795) significantly reduced tumour-specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1-SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa.
    Matched MeSH terms: Signal Transduction/drug effects
  11. Molecular process of glucose uptake and glycogen storage due to hamamelitannin via insulin signalling cascade in glucose metabolism
    Issac PK, Guru A, Chandrakumar SS, Lite C, Saraswathi NT, Arasu MV, et al.
    Mol Biol Rep, 2020 Sep;47(9):6727-6740.
    PMID: 32809102 DOI: 10.1007/s11033-020-05728-5
    Understanding the mechanism by which the exogenous biomolecule modulates the GLUT-4 signalling cascade along with the information on glucose metabolism is essential for finding solutions to increasing cases of diabetes and metabolic disease. This study aimed at investigating the effect of hamamelitannin on glycogen synthesis in an insulin resistance model using L6 myotubes. Glucose uptake was determined using 2-deoxy-D-[1-3H] glucose and glycogen synthesis were also estimated in L6 myotubes. The expression levels of key genes and proteins involved in the insulin-signaling pathway were determined using real-time PCR and western blot techniques. The cells treated with various concentrations of hamamelitannin (20 µM to 100 µM) for 24 h showed that, the exposure of hamamelitannin was not cytotoxic to L6 myotubes. Further the 2-deoxy-D-[1-3H] glucose uptake assay was carried out in the presence of wortmannin and Genistein inhibitor for studying the GLUT-4 dependent cell surface recruitment. Hamamelitannin exhibited anti-diabetic activity by displaying a significant increase in glucose uptake (125.1%) and glycogen storage (8.7 mM) in a dose-dependent manner. The optimum concentration evincing maximum activity was found to be 100 µm. In addition, the expression of key genes and proteins involved in the insulin signaling pathway was studied to be upregulated by hamamelitannin treatment. Western blot analysis confirmed the translocation of GLUT-4 protein from an intracellular pool to the plasma membrane. Therefore, it can be conceived that hamamelitannin exhibited an insulinomimetic effect by enhancing the glucose uptake and its further conversion into glycogen by regulating glucose metabolism.
    Matched MeSH terms: Signal Transduction/drug effects
  12. Fractalkine (CX3CL1) signaling and neuroinflammation in Parkinson's disease: Potential clinical and therapeutic implications
    Angelopoulou E, Paudel YN, Shaikh MF, Piperi C
    Pharmacol Res, 2020 08;158:104930.
    PMID: 32445958 DOI: 10.1016/j.phrs.2020.104930
    Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD) with the dysregulation of microglial activity being tightly linked to dopaminergic degeneration. Fractalkine (CX3CL1), a chemokine mainly expressed by neurons, can modulate microglial activity through binding to its sole G-protein-coupled receptor (CX3CR1), expressed by microglia. Fractalkine/CX3CR1 signaling is one of the most important mediators of the communication between neurons and microglia, and its emerging role in neurodegenerative disorders including PD has been increasingly recognized. Pre-clinical evidence has revealed that fractalkine signaling axis exerts dual effects on PD-related inflammation and degeneration, which greatly depend on the isoform type (soluble or membrane-bound), animal model (mice or rats, toxin- or proteinopathy-induced), route of toxin administration, time course and specific brain region (striatum, substantia nigra). Furthermore, although existing clinical evidence is scant, it has been indicated that fractalkine may be possibly associated with PD progression, paving the way for future studies investigating its biomarker potential. In this review, we discuss recent evidence on the role of fractalkine/CX3CR1 signaling axis in PD pathogenesis, aiming to shed more light on the molecular mechanisms underlying the neuroinflammation commonly associated with the disease, as well as potential clinical and therapeutic implications.
    Matched MeSH terms: Signal Transduction/drug effects*
  13. Berberine and musculoskeletal disorders: The therapeutic potential and underlying molecular mechanisms
    Wong SK, Chin KY, Ima-Nirwana S
    Phytomedicine, 2020 Jul 15;73:152892.
    PMID: 30902523 DOI: 10.1016/j.phymed.2019.152892
    BACKGROUND: Musculoskeletal disorders are a group of disorders that affect the joints, bones, and muscles, causing long-term disability. Berberine, an isoquinoline alkaloid, has been previously established to exhibit beneficial properties in preventing various diseases, including musculoskeletal disorders.

    PURPOSE: This review article aims to recapitulate the therapeutic potential of berberine and its mechanism of action in treating musculoskeletal disorders.

    METHODS: A wide range of literature illustrating the effects of berberine in ameliorating musculoskeletal disorders was retrieved from online electronic databases (PubMed and Medline) and reviewed.

    RESULTS: Berberine may potentially retard the progression of osteoporosis, osteoarthritis and rheumatoid arthritis. Limited studies reported the effects of berberine in suppressing the proliferation of osteosarcoma cells. These beneficial properties of berberine are mediated in part through its ability to target multiple signaling pathways, including PKA, p38 MAPK, Wnt/β-catenin, AMPK, RANK/RANKL/OPG, PI3K/Akt, NFAT, NF-κB, Hedgehog, and oxidative stress signaling. In addition, berberine exhibited anti-apoptotic, anti-inflammatory, and immunosuppressive properties.

    CONCLUSION: The current evidence indicates that berberine may be effective in preventing musculoskeletal disorders. However, findings from in vitro and in vivo investigations await further validation from human clinical trial.

    Matched MeSH terms: Signal Transduction/drug effects
  14. Melatonin inhibits high glucose-induced ox-LDL/LDL expression and apoptosis in human umbilical endothelial cells
    Tiong YL, Ng KY, Koh RY, Ponnudurai G, Chye SM
    Horm Mol Biol Clin Investig, 2020 Jun 29;41(4).
    PMID: 32598308 DOI: 10.1515/hmbci-2020-0009
    BACKGROUND: Cardiovascular disease (CVD) is one of the major cause of mortality in diabetic patients. Evidence suggests that hyperglycemia in diabetic patients contributes to increased risk of CVD. This study is to investigate the therapeutic effects of melatonin on glucose-treated human umbilical vein endothelial cells (HUVEC) and provide insights on the underlying mechanisms.

    MATERIALS AND METHODS: Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Reactive oxygen species (ROS) and membrane potential was detected using 2',7'-dichlorofluorescein diacetate and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1) dye staining, respectively. While, cell apoptosis was determined by Annexin-V staining and protein expression was measured using Western blot.

    RESULTS: Our results suggested that melatonin inhibited glucose-induced ROS elevation, mitochondria dysfunction and apoptosis on HUVEC. Melatonin inhibited glucose-induced HUVEC apoptosis via PI3K/Akt signaling pathway. Activation of Akt further activated BcL-2 pathway through upregulation of Mcl-1 expression and downregulation Bax expression in order to inhibit glucose-induced HUVEC apoptosis. Besides that, melatonin promoted downregulation of oxLDL/LOX-1 in order to inhibit glucose-induced HUVEC apoptosis.

    CONCLUSIONS: In conclusion, our results suggested that melatonin exerted vasculoprotective effects against glucose-induced apoptosis in HUVEC through PI3K/Akt, Bcl-2 and oxLDL/LOX-1 signaling pathways.

    Matched MeSH terms: Signal Transduction/drug effects
  15. Miltefosine suppression of Pten null T-ALL leukemia via β-catenin degradation through inhibition of pT308-Akt and TGFβ1/Smad3
    Zhang Y, Lee S, Xu W
    Biochem Biophys Res Commun, 2020 04 16;524(4):1018-1024.
    PMID: 32063363 DOI: 10.1016/j.bbrc.2020.02.021
    Pten deletion in the hematopoietic stem cells (HSC) causes a myeloproliferative disorder, which may subsequently develop into a T-cell acute lymphoblastic leukemia (T-ALL). β-catenin expression was dramatically increased in the c-KitmidCD3+Lin- leukemia stem cells (LSC) and was critical for T-ALL development. Therefore, the inactivation of β-catenin in LSC may have a potential to eliminate the LSC. In this study, we investigated the mechanism of enhancement of the β-catenin expression and subsequently used a drug to inactivate β-catenin expression in T-ALL. Western blot (WB) analysis revealed an increased level of β-catenin in the leukemic cells, but not in the pre-leukemic cells. Furthermore, the WB analysis of the thymic cells from different stages of leukemia development showed that increased expression of β-catenin was not via the pS9-GSK3β signaling, but was dependent on the pT308-Akt activation. Miltefosine (Hexadecylphosphocholine) is the first oral anti-Leishmania drug, which is a phospholipid agent and has been shown to inhibit the PI3K/Akt activity. Treatment of the PtenΔ/Δ leukemic mice with Miltefosine for different durations demonstrated that the pT308-Akt and the β-catenin expressions were inhibited in the leukemia blast cells. Miltefosine treatment also suppressed the TGFβ1/Smad3 signaling pathway. Analysis of TGFβ1 in the sorted subpopulations of the blast cells showed that TGFβ1 was secreted by the CD3+CD4- subpopulation and may exert effects on the subpopulations of both CD3+CD4+ and CD3+CD4- leukemia blast cells. When a TGFβR1 inhibitor, SB431542 was injected into the PtenΔ/Δ leukemic mice, the Smad3 and β-catenin expressions were down-regulated. On the basis of the results, we conclude that Miltefosine can suppress leukemia by degrading β-catenin through repression of the pT308-Akt and TGFβ1/Smad3 signaling pathways. This study demonstrates a possibility to inhibit Pten loss-associated leukemia genesis via targeting Akt and Smad3.
    Matched MeSH terms: Signal Transduction/drug effects*
  16. Fulltext Lysine-Specific Demethylase-1 Deficiency Increases Agonist Signaling Via the Mineralocorticoid Receptor
    Treesaranuwattana T, Wong KYH, Brooks DL, Tay CS, Williams GH, Williams JS, et al.
    Hypertension, 2020 04;75(4):1045-1053.
    PMID: 32160100 DOI: 10.1161/HYPERTENSIONAHA.119.13821
    LSD1 (lysine-specific demethylase-1) is an epigenetic regulator of gene transcription. LSD1 risk allele in humans and LSD1 deficiency (LSD1+/-) in mice confer increasing salt-sensitivity of blood pressure with age, which evolves into salt-sensitive hypertension in older individuals. However, the mechanism underlying the relationship between LSD1 and salt-sensitivity of blood pressure remains elusive. Here, we show that LSD1 genotype (in humans) and LSD1 deficiency (in mice) lead to similar associations with increased blood pressure and urine potassium levels but with decreased aldosterone levels during a liberal salt diet. Thus, we hypothesized that LSD1 deficiency leads to an MR (mineralocorticoid receptor)-dependent hypertensive state. Yet, further studies in LSD1+/- mice treated with the MR antagonist eplerenone demonstrate that hypertension, kaliuria, and albuminuria are substantially improved, suggesting that the ligand-independent activation of the MR is the underlying cause of this LSD1 deficiency-mediated phenotype. Indeed, while MR and epithelial sodium channel expression levels were increased in LSD1+/- mouse kidney tissues, aldosterone secretion from LSD1+/- glomerulosa cells was significantly lower. Collectively, these data establish that LSD1 deficiency leads to an inappropriate activation and increased levels of the MR during a liberal salt regimen and suggest that inhibiting the MR pathway is a useful strategy for treatment of hypertension in human LSD1 risk allele carriers.
    Matched MeSH terms: Signal Transduction/drug effects
  17. Blood pressure lowering effect and vascular activity of Phyllanthus niruri extract: The role of NO/cGMP signaling pathway and β-adrenoceptor mediated relaxation of isolated aortic rings
    Bello I, Usman NS, Dewa A, Abubakar K, Aminu N, Asmawi MZ, et al.
    J Ethnopharmacol, 2020 Mar 25;250:112461.
    PMID: 31830549 DOI: 10.1016/j.jep.2019.112461
    ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus niruri have a long history of use in the traditional treatment of various ailments including hypertension. Literature reports have indicated that it is a potent antihypertensive herbal medication used traditionally.

    AIM OF THE STUDY: This study was carried out to investigate the antihypertensive and vasodilatory activity of four solvents extracts of P. niruri namely; petroleum ether (PEPN), chloroform (CLPN), methanol (MEPN) and water (WEPN), with the aim of elucidating the mechanism of action and identifying the phytochemical constituents.

    MATERIALS AND METHODS: Male Spontaneous Hypertensive Rats (SHRs) were given oral gavage of P. niruri extract daily for two weeks and the blood pressure was recorded in vivo. We also determine the vasodilation effect of the extracts on rings of isolated thoracic aorta pre-contracted with phenylephrine (PE, 1 μM). Endothelium-intact or endothelium-denuded aorta rings were pre-incubated with various antagonists like 1H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 μM) and Methylene blue (MB 10 μM), sGC inhibitors; Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 μM) a nitric oxide synthase (NOS) inhibitor; atropine (10 μM), a cholinergic receptor blocker; indomethacin (10 μM), a cyclooxygenase inhibitor and various K+ channel blockers such as glibenclamide (10 μM) and tetraethyl ammonium (TEA 10 μM) for mechanism study.

    RESULTS: SHRs receiving P. niruri extracts showed a significant decrease in their blood pressure (BP) when compared to the baseline value, with PEPN being more potent. The extracts (0.125-4 mg/mL) also induced vasorelaxation on endothelium-intact aorta rings. PEPN elicited the most potent maximum relaxation effect (Rmax). Mechanism assessment of PEPN showed that its relaxation effect is significantly suppressed in endothelium-denuded aorta rings. Pre-incubation of aorta rings with atropine, L-NAME, ODQ, indomethacin, and propranolol also significantly attenuated its relaxation effect. Conversely, incubation with TEA and glibenclamide did not show a significant effect on PEPN-induced relaxation.

    CONCLUSION: This study indicates that the antihypertensive activity of P. niruri extract is mediated by vasoactive phytoconstituents that dilate the arterial wall via endothelium-dependent pathways and β-adrenoceptor activity which, in turn, cause vasorelaxation and reduce blood pressure.

    Matched MeSH terms: Signal Transduction/drug effects
  18. The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions
    Wu H, Sun Y, Wong WL, Cui J, Li J, You X, et al.
    Eur J Med Chem, 2020 Mar 01;189:112042.
    PMID: 31958737 DOI: 10.1016/j.ejmech.2020.112042
    Transforming growth factor-β (TGF-β) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-β signaling pathway is a potential target for therapeutic intervention in the development of many diseases, such as fibrosis and cancer. Most currently available inhibitors of TGF-β signaling function as TGF-β receptor I (TβR-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-β receptor II (TβR-II) to interfere with the protein-protein interactions (PPIs) between TGF-β and its receptors. One compound, CJJ300, inhibited TGF-β signaling by disrupting the formation of the TGF-β-TβR-I-TβR-II signaling complex. Treatment of A549 cells with CJJ300 resulted in the inhibition of downstream signaling events such as the phosphorylation of key factors along the TGF-β pathway and the induction of EMT markers. Concomitant with these effects, CJJ300 significantly inhibited cell migration. The present study describes for the first time a designed molecule that can regulate TGF-β-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-β signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-β signaling and to design more potent TGF-β signaling antagonists.
    Matched MeSH terms: Signal Transduction/drug effects
  19. Potential Neuroprotective Effect of the HMGB1 Inhibitor Glycyrrhizin in Neurological Disorders
    Paudel YN, Angelopoulou E, Semple B, Piperi C, Othman I, Shaikh MF
    ACS Chem Neurosci, 2020 02 19;11(4):485-500.
    PMID: 31972087 DOI: 10.1021/acschemneuro.9b00640
    Glycyrrhizin (glycyrrhizic acid), a bioactive triterpenoid saponin constituent of Glycyrrhiza glabra, is a traditional medicine possessing a plethora of pharmacological anti-inflammatory, antioxidant, antimicrobial, and antiaging properties. It is a known pharmacological inhibitor of high mobility group box 1 (HMGB1), a ubiquitous protein with proinflammatory cytokine-like activity. HMGB1 has been implicated in an array of inflammatory diseases when released extracellularly, mainly by activating intracellular signaling upon binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). HMGB1 neutralization strategies have demonstrated disease-modifying outcomes in several preclinical models of neurological disorders. Herein, we reveal the potential neuroprotective effects of glycyrrhizin against several neurological disorders. Emerging findings demonstrate the therapeutic potential of glycyrrhizin against several HMGB1-mediated pathological conditions including traumatic brain injury, neuroinflammation and associated conditions, epileptic seizures, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Glycyrrhizin's effects in neurological disorders are mainly attributed to the attenuation of neuronal damage by inhibiting HMGB1 expression and translocation as well as by downregulating the expression of inflammatory cytokines. A large number of preclinical findings supports the notion that glycyrrhizin might be a promising therapeutic alternative to overcome the shortcomings of the mainstream therapeutic strategies against neurological disorders, mainly by halting disease progression. However, future research is warranted for a deeper exploration of the precise underlying molecular mechanism as well as for clinical translation.
    Matched MeSH terms: Signal Transduction/drug effects
  20. Modulation of cell signaling pathways by Phyllanthus amarus and its major constituents: potential role in the prevention and treatment of inflammation and cancer
    Harikrishnan H, Jantan I, Alagan A, Haque MA
    Inflammopharmacology, 2020 Feb;28(1):1-18.
    PMID: 31792765 DOI: 10.1007/s10787-019-00671-9
    The causal and functional connection between inflammation and cancer has become a subject of much research interest. Modulation of cell signaling pathways, such as those involving mitogen activated protein kinases (MAPKs), nuclear factor kappa β (NF-κB), phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt), and Wnt, and their outcomes play a fundamental role in inflammation and cancer. Activation of these cell signaling pathways can lead to various aspects of cancer-related inflammation. Hence, compounds able to modulate inflammation-related molecular targets are sought after in anticancer drug development programs. In recent years, plant extracts and their metabolites have been documented with potential in the prevention and treatment of cancer and inflammatory ailments. Plants possessing anticancer and anti-inflammatory properties due to their bioactive constituents have been reported to modulate the molecular and cellular pathways which are related to inflammation and cancer. In this review we focus on the flavonoids (astragalin, kaempferol, quercetin, rutin), lignans (phyllanthin, hypophyllanthin, and niranthin), tannins (corilagin, geraniin, ellagic acid, gallic acid), and triterpenes (lupeol, oleanolic acid, ursolic acid) of Phyllanthus amarus, which exert various anticancer and anti-inflammatory activities via perturbation of the NF-κB, MAPKs, PI3K/Akt, and Wnt signaling networks. Understanding the underlying mechanisms involved may help future research to develop drug candidates for prevention and new treatment for cancer and inflammatory diseases.
    Matched MeSH terms: Signal Transduction/drug effects*
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