scholarly journals Regulatory mechanisms for the expression and activity of platelet-derived growth factor receptor.

2003 ◽  
Vol 50 (3) ◽  
pp. 647-658 ◽  
Author(s):  
Keiko Funa ◽  
Hidetaka Uramoto
Keyword(s):  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Regulatory System ◽  
Growth And Survival ◽  
Over Expression ◽  
Sarcoma Virus ◽  
Simian Sarcoma Virus ◽  
Positive And Negative Feedback ◽  
Different Levels ◽  
Expression And Activity

PDGF is one of the most potent serum mitogens, and the signalling mechanism by way of its receptor tyrosine-kinase has been extensively studied since its first purification in 1979. The identification of homology between the simian sarcoma virus oncogene, v-sis, and the B-chain of PDGF, as well as the frequent over-expression of both the ligands and receptors in various tumours and stroma led to the proposal of the PDGF-mediated autocrine and paracrine hypothesis. Consistent with the important roles of PDGF in the growth and survival of cells, the expression and activity of PDGF receptors are tightly controlled by both positive and negative feedback mechanisms at different levels. The deregulation of the control system can result in serious pathological conditions such as chronic inflammation and tumours. Understanding the molecular mechanisms for the regulatory system and the signalling pathway of PDGF is essential in order to find effective therapies in the diseases where PDGF is involved.

scholarly journals EGFR Signaling and its inhibition by EGFR inhibitors in NSCLC

2014 ◽  
Vol 2 (4) ◽  
pp. 375-388
Author(s):  
Rajvi Patel
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intracellular Signaling ◽  
Growth Factor Receptor ◽  
The United States ◽  
Egfr Inhibitors ◽  
Growth And Survival ◽  
Over Expression ◽  
Epidermal Growth

Lung cancer is the third most cancer among the population. The American society’s estimation for lung cancer in the United States for 2014 states that about 2,24,210 people are suffering from the lung cancer and 1,59,260 deaths are occur from lung cancer. Among all the types of lung cancer, NSCLC (Non-Small cell Lung Cancer) represents 85% of the lung cancer. The estimated spread of NSCLC is 2,26,160 and 1,60,340 cases are of death in 2012. One of the risk factor for NSCLC is over expression of epidermal growth factor receptor (EGFR) and its intracellular signaling pathways. EGFR is over expressed in 40-80 % cases of NSCLC. EGFR belongs to the ErbB family of receptor tyrosinekinases (RTK) having molecular weight 170 to 185 kDa. Epidermal Growth Factor (EGF) binds to the EGFR at its extracellular domain and this binding leads to the homo or hetero dimerization and autophosphorylation of EGFR which initiates the several intracellular pathways. Several mutations in EGFR or in any of the proteins of the pathway leads to the growth and survival of the tumor cells. So in order to inhibit the growth of tumor cell, several EGFR inhibitors and targeted therapies are found to target the particular mutations.DOI: http://dx.doi.org/10.3126/ijasbt.v2i4.11263 Int J Appl Sci Biotechnol, Vol. 2(4): 375-388 

The Anti-Proliferative Activity of Anisosciadone: A New Guaiane Sesquiterpene from Anisosciadium lanatum

2019 ◽  
Vol 19 (9) ◽  
pp. 1114-1119 ◽  
Author(s):  
Ahmed A. Mahmoud ◽  
Wael M. El-Sayed
Keyword(s):  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Chemical Constituents ◽  
Spectroscopic Techniques ◽  
Significant Activity ◽  
Caspase 9 ◽  
P53 Expression ◽  
Expression And Activity

Background: The increase in cancer rate and the development of resistant tumors require a continuous search for new anticancer agents. Aims: This study aimed to analyze and identify the chemical constituents of Anisosciadium lanatum, and to investigate the antiproliferative activity of the identified constituents against various human cell lines (HepG2, MCF7, HT29, A549, and PC3) along with the possible molecular mechanisms involved. Methods: The structure of the isolated compounds was determined by spectroscopic techniques including HRFABMS, GC-MS, IR, and 400 MHz 1D and 2D NMR analyses (1H, 13C NMR, DEPT, 1H-1H COSY, HMQC, HMBC and NOESY). The antiproliferative activity and IC50 value of the isolated compounds were measured and compared to doxorubicin. Results: A new guaiane sesquiterpene containing a rare epoxide structural element, 10β,11β−epoxy−1α,4β,5β,7αΗ- guaiane-9-one, anisosciadone (1), and stigmasterol (2) have been isolated from the plant. Anisosciadone (1) showed a significant antiproliferative activity against liver, colon, and lung cells only, while stigmasterol (2) had a significant activity against liver, colon, and breast cells. Both 1 and 2 caused no cytotoxicity to normal fibroblasts. Anisosciadone elevated the expression and activity of Caspase 3 as well as p53 expression without affecting Caspase 9 in HepG2 cells. It also caused ~ 50% downregulation in cdk1 expression. Conclusion: Taken together, anisosciadone was specific in action against cancer cells and induced apoptosis in liver cells. It also has a unique feature by elevating the expression and activity of Caspase 3 without affecting the initiator Caspase 9. Therefore, anisosciadone deserves more investigation as a targeted therapy for cancer.

scholarly journals Circular RNA AFF4 modulates osteogenic differentiation in BM-MSCs by activating SMAD1/5 pathway through miR-135a-5p/FNDC5/Irisin axis

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Chao Liu ◽  
An-Song Liu ◽  
Da Zhong ◽  
Cheng-Gong Wang ◽  
Mi Yu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Regulatory System ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Integrin Αv

AbstractBone marrow-derived mesenchymal stem cells (BM-MSCs), the common progenitor cells of adipocytes and osteoblasts, have been recognized as the key mediator during bone formation. Herein, our study aim to investigate molecular mechanisms underlying circular RNA (circRNA) AFF4 (circ_AFF4)-regulated BM-MSCs osteogenesis. BM-MSCs were characterized by FACS, ARS, and ALP staining. Expression patterns of circ_AFF4, miR-135a-5p, FNDC5/Irisin, SMAD1/5, and osteogenesis markers, including ALP, BMP4, RUNX2, Spp1, and Colla1 were detected by qRT-PCR, western blot, or immunofluorescence staining, respectively. Interactions between circ_AFF4 and miR-135a-5p, FNDC5, and miR-135a-5p were analyzed using web tools including TargetScan, miRanda, and miRDB, and further confirmed by luciferase reporter assay and RNA pull-down. Complex formation between Irisin and Integrin αV was verified by Co-immunoprecipitation. To further verify the functional role of circ_AFF4 in vivo during bone formation, we conducted animal experiments harboring circ_AFF4 knockdown, and born samples were evaluated by immunohistochemistry, hematoxylin and eosin, and Masson staining. Circ_AFF4 was upregulated upon osteogenic differentiation induction in BM-MSCs, and miR-135a-5p expression declined as differentiation proceeds. Circ_AFF4 knockdown significantly inhibited osteogenesis potential in BM-MSCs. Circ_AFF4 stimulated FNDC5/Irisin expression through complementary binding to its downstream target molecule miR-135a-5p. Irisin formed an intermolecular complex with Integrin αV and activated the SMAD1/5 pathway during osteogenic differentiation. Our work revealed that circ_AFF4, acting as a sponge of miR-135a-5p, triggers the promotion of FNDC5/Irisin via activating the SMAD1/5 pathway to induce osteogenic differentiation in BM-MSCs. These findings gained a deeper insight into the circRNA-miRNA regulatory system in the bone marrow microenvironment and may improve our understanding of bone formation-related diseases at physiological and pathological levels.

scholarly journals MODL-12. DEVELOPMENT OF A NOVEL IMMUNOCOMPETENT MOUSE MODEL FOR DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii413-iii413
Author(s):  
Maggie Seblani ◽  
Markella Zannikou ◽  
Katarzyna Pituch ◽  
Liliana Ilut ◽  
Oren Becher ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mouse Model ◽  
Growth Factor Receptor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Time Of Application ◽  
Tumor Associated Antigen ◽  
Sarcoma Virus

Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor affecting young children. Immunotherapies hold promise however the lack of immunocompetent models recreating a faithful tumor microenvironment (TME) remains a challenge for development of targeted immunotherapeutics. We propose to generate an immunocompetent DIPG mouse model through induced overexpression of interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen overexpressed by glioma cells. A model with an intact TME permits comprehensive preclinical assessment of IL13Rα2-targeted immunotherapeutics. Our novel model uses the retroviral avian leucosis and sarcoma virus (RCAS) for in vivo gene delivery leading to IL13Rα2 expression in proliferating progenitor cells. Transfected cells expressing IL13Rα2 and PDGFB, a ligand for platelet derived growth factor receptor, alongside induced p53 loss via the Cre-Lox system are injected in the fourth ventricle in postnatal pups. We validated the expression of PDGFB and IL13Rα2 transgenes in vitro and in vivo and will characterize the TME through evaluation of the peripheral and tumor immunologic compartments using immunohistochemistry and flow cytometry. We confirmed expression of transgenes via flow cytometry and western blotting. Comparison of survival dynamics in mice inoculated with PDGFB alone with PDGFB+IL13Rα2 demonstrated that co-expression of IL13Rα2 did not significantly affect mice survival compared to the PDGFB model. At time of application, we initiated experiments to characterize the TME. Preliminary data demonstrate establishment of tumors within and adjacent to the brainstem and expression of target transgenes. Preclinical findings in a model recapitulating the TME may provide better insight into outcomes upon translation to clinical application.

scholarly journals Natural Disruption of Two Regulatory Networks in Serotype M3 Group A Streptococcus Isolates Contributes to the Virulence Factor Profile of This Hypervirulent Serotype

2014 ◽  
Vol 82 (5) ◽  
pp. 1744-1754 ◽  
Author(s):  
Tram N. Cao ◽  
Zhuyun Liu ◽  
Tran H. Cao ◽  
Kathryn J. Pflughoeft ◽  
Jeanette Treviño ◽  
...  
Keyword(s):  
Virulence Factor ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Group A Streptococcus ◽  
Regulatory System ◽  
Mrna Levels ◽  
Bacterial Strains ◽  
Content Type ◽  
Small Regulatory Rna ◽  
Group A

ABSTRACTDespite the public health challenges associated with the emergence of new pathogenic bacterial strains and/or serotypes, there is a dearth of information regarding the molecular mechanisms that drive this variation. Here, we began to address the mechanisms behind serotype-specific variation between serotype M1 and M3 strains of the human pathogenStreptococcus pyogenes(the group AStreptococcus[GAS]). Spatially diverse contemporary clinical serotype M3 isolates were discovered to contain identical inactivating mutations within genes encoding two regulatory systems that control the expression of important virulence factors, including the thrombolytic agent streptokinase, the protease inhibitor-binding protein-G-related α2-macroglobulin-binding (GRAB) protein, and the antiphagocytic hyaluronic acid capsule. Subsequent analysis of a larger collection of isolates determined that M3 GAS, since at least the 1920s, has harbored a 4-bp deletion in thefasCgene of thefasBCAXregulatory system and an inactivating polymorphism in therivRregulator-encoding gene. ThefasCandrivRmutations in M3 isolates directly affect the virulence factor profile of M3 GAS, as evident by a reduction in streptokinase expression and an enhancement of GRAB expression. Complementation of thefasCmutation in M3 GAS significantly enhanced levels of the small regulatory RNA FasX, which in turn enhanced streptokinase expression. Complementation of therivRmutation in M3 GAS restored the regulation ofgrabmRNA abundance but did not alter capsule mRNA levels. While important, thefasCandrivRmutations do not provide a full explanation for why serotype M3 strains are associated with unusually severe invasive infections; thus, further investigation is warranted.

scholarly journals Expression of Phosphocitrate-Targeted Genes in Osteoarthritis Menisci

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Yubo Sun ◽  
David R. Mauerhan ◽  
Nury M. Steuerwald ◽  
Jane Ingram ◽  
Jeffrey S. Kneisl ◽  
...  
Keyword(s):  
Immune System ◽  
Molecular Mechanisms ◽  
Fibroblast Growth Factor Receptor ◽  
Collagen Type ◽  
Skeletal Development ◽  
Growth Factor Receptor ◽  
Type Ii ◽  
Immune System Activation ◽  
System Activation ◽  
Disease Modifying

Phosphocitrate (PC) inhibited calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms remain elusive. This study sought to determine PC targeted genes and the expression of select PC targeted genes in OA menisci to test hypothesis that PC exerts its disease modifying activity in part by reversing abnormal expressions of genes involved in OA. We found that PC downregulated the expression of numerous genes classified in immune response, inflammatory response, and angiogenesis, including chemokine (C-C motif) ligand 5, Fc fragment of IgG, low affinity IIIb receptor (FCGR3B), and leukocyte immunoglobulin-like receptor, subfamily B member 3 (LILRB3). In contrast, PC upregulated the expression of many genes classified in skeletal development, including collagen type II alpha1, fibroblast growth factor receptor 3 (FGFR3), and SRY- (sex determining region Y-) box 9 (SOX-9). Immunohistochemical examinations revealed higher levels of FCGR3B and LILRB3 and lower level of SOX-9 in OA menisci. These findings indicate that OA is a disease associated with immune system activation and decreased expression of SOX-9 gene in OA menisci. PC exerts its disease modifying activity on OA, at least in part, by targeting immune system activation and the production of extracellular matrix and selecting chondroprotective proteins.

Antiepileptic and Antidepressant Drugs Used in the Treatment of Pain

2017 ◽  
Author(s):  
Lucia Daiana Voiculescu
Keyword(s):  
Serotonin Syndrome ◽  
Molecular Mechanisms ◽  
Tricyclic Antidepressants ◽  
Antidepressant Drugs ◽  
First Line ◽  
Off Label ◽  
First Line Therapy ◽  
Line Therapy ◽  
Pain Pathways ◽  
Different Levels

Antiepileptics and antidepressants are two categories of drugs frequently used as adjuvant analgesics. They interfere with the pain pathways at different levels through complex and not always well-defined molecular mechanisms. Although only a few have been licensed for use in the treatment of certain types of pain, anticonvulsants and antidepressants are widely prescribed off-label for pain associated with a variety of conditions. Most solid data come from experience with their use for postherpetic neuralgia, pain associated with diabetic neuropathy, and fibromyalgia. Anticonvulsants and antidepressant drugs are frequently used as first-line therapy in the treatment of pain, especially neuropathic type. Key words: antidepressant drugs, antiepileptic drugs, carbamazepine, gabapentinoids, neuropathic pain, off-label use, serotonin-norepinephrine reuptake inhibitors, serotonin syndrome, tricyclic antidepressants, use in specific populations

Down regulation of Pinkbar/pAKT and MMP2/MMP9 expression in MDA-MB-231 breast cancer cells as potential targets in cancer therapy by hAMSCs secretome

2021 ◽  
Author(s):  
Termeh Shakery ◽  
Fatemeh Safari
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
3D Cell Culture ◽  
Therapeutic Effects ◽  
Down Regulation ◽  
Egfr Signaling Pathway

Breast cancer (BC) is one of the most causes of cancer-related death among women worldwide. Cancer therapy based on stem cells was considered as a novel and promising platform. In present study, we explored the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through Pinkbar (planar intestinal-and kidney-specific BAR domain protein), pAKT, and matrix metalloproteinases including MMP2, MMP9 on MDA-MB-231 breast cancer cells. To do so, we employed a co-culture system using 6 well plates transwell with a diameter of 0.4 μm pore sized. After 72h hAMSCs-treated MDA-MB-231 breast cancer cells, the expression of Epidermal growth factor receptor (EGFR), and c-Src (a key mediator in EGFR signaling pathway), Pinkbar, pAKT, MMP2, and MMP9 was analyzed by using quantitative real time PCR (qRT-PCR) and western blot methods. Based on using 2D and 3D cell culture models, the significant reduction of tumor cell growth and motility through down regulation of EGFR, c-Src, Pinkbar, pAKT, MMP2, and MMP9 in MDA-MB-231 breast cancer cells was shown. Also, the induction of cellular apoptosis also found. Our finding indicates that the hAMSCS secretome has therapeutic effects on cancer cells. To identify the details of the molecular mechanisms, more experiments will be required.

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