Monoamine-activated alpha 2-macroglobulin inhibits neurite outgrowth, survival, choline acetyltransferase, and dopamine concentration of neurons by blocking neurotrophin-receptor (trk) phosphorylation and signal transduction.
Humans; Animals; Cell Survival/drug effects; Phosphorylation/drug effects; Signal Transduction/*drug effects; Infant; Neurons/physiology; Rats; Species Specificity; Choline O-Acetyltransferase/metabolism; Dopamine/metabolism; alpha-Macroglobulins/*pharmacology; Biogenic Monoamines/*pharmacology; Neurites/physiology; Prosencephalon/cytology/*physiology; Receptor Protein-Tyrosine Kinases/*drug effects; Newborn; Receptors; Nerve Growth Factor/*drug effects
Koo P H; Liebl D J; Qiu W S; Hu Y Q; Dluzen D E
Annals of the New York Academy of Sciences
1994
1994-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Antitumor effect of novel gallium compounds and efficacy of nanoparticle-mediated gallium delivery in lung cancer.
Antineoplastic Agents/*administration & dosage/chemistry/pharmacokinetics; Biocompatible Materials/administration & dosage/chemistry/pharmacokinetics; Cell Line; Cell Survival/drug effects; Coordination Complexes/*administration & dosage/chemistry/pharmacokinetics; Drug Carriers/administration & dosage/chemistry; Drug Stability; Endocytosis/drug effects; Gallium/*administration & dosage/chemistry/pharmacokinetics; Hemolysis/drug effects; Humans; Lung Neoplasms/*drug therapy/metabolism; Materials Testing; Membrane Potential; Mitochondrial/drug effects; Nanoparticles/*administration & dosage/chemistry; Particle Size; Platelet Aggregation/drug effects; Reactive Oxygen Species/metabolism; Transferrin/chemistry/pharmacology; Tumor
The widespread application of gallium (Ga) in cancer therapy has been greatly hampered by lack of specificity resulting in poor tumor accumulation and retention. To address the challenge, two lipophilic gallium (III) compounds (gallium hexanedione; GaH and gallium acetylacetonate; GaAcAc) were synthesized and antitumor studies were conducted in human lung adenocarcinoma (A549) cells. Nanoparticles (NPs) containing various concentrations of the Ga compounds were prepared using a binary mixture of Gelucire 44/14 and cetyl alcohol as matrix materials. NPs were characterized based on size, morphology, stability and biocompatibility. Antitumor effects of free or NP-loaded Ga compounds were investigated based on cell viability, production of reactive oxygen species and reduction of mitochondrial potential. Compared to free Ga compounds, cytotoxicity of NP-loaded Ga (5-150 microg/ml) was less dependent on concentration and incubation time (exposure) with A549 cells. NP-mediated delivery (5-150 microg Ga/ml) enhanced antitumor effects of Ga compounds and the effect was pronounced at: (i) shorter incubation times; and (ii) at low concentrations of gallium (approximately 50 microg/ml) (p \textless 0.0006). Additional studies showed that
Wehrung Daniel; Oyewumi Moses O
Journal of biomedical nanotechnology
2012
2012-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jbn.2012.1361" target="_blank" rel="noreferrer noopener">10.1166/jbn.2012.1361</a>
Butein Activates Autophagy Through AMPK/TSC2/ULK1/mTOR Pathway to Inhibit IL-6 Expression in IL-1beta Stimulated Human Chondrocytes.
AMP-Activated Protein Kinases/metabolism; AMPK; Articular/cytology/pathology; Autophagy; Autophagy-Related Protein 5/antagonists & inhibitors/genetics/metabolism; Autophagy-Related Protein-1 Homolog/metabolism; Autophagy/*drug effects; Butein; Cartilage; Cell Survival/drug effects; Cells; Chalcones/*pharmacology; Chondrocytes/cytology/drug effects/metabolism; Cultured; Humans; Inflammation; Interleukin-1beta/*pharmacology; Interleukin-6/genetics/*metabolism; Intracellular Signaling Peptides and Proteins/metabolism; mTOR; Osteoarthritis; Osteoarthritis/metabolism/pathology; Phosphorylation/drug effects; Reactive Oxygen Species/metabolism; RNA; RNA Interference; Signal Transduction/*drug effects; Small Interfering/metabolism; TOR Serine-Threonine Kinases/metabolism; TSC2; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins/metabolism; ULK1
BACKGROUND/AIMS: Butein (2',3,4,4'-Tetrahydroxychalcone), a polyphenol produced by several plants including Butea monoserpma, has been reported to exert potent anti-inflammatory activity but the mechanism remains unknown. In the present work we investigated the mechanism of Butein-mediated suppression of IL-6 expression in normal and human osteoarthritis (OA) chondrocytes under pathological conditions. METHODS: Expression level of interleukin-6 (IL-6) protein in OA cartilage was analyzed by immunohistochemistry using a validated antibody. Chondrocytes derived from normal or OA cartilage by enzymatic digestion were pretreated with Butein followed by stimulation with interleukin-1beta (IL-1beta) and the levels of IL-6 mRNA were quantified by TaqMan assay and the protein levels were measured by Western immunoblotting. Autophagy activation was determined by Western blotting and confocal microscopy. Autophagy was inhibited by siRNA mediated knockdown of ATG5. RESULTS: Expression of IL-6 protein was high in the OA cartilage compared to smooth cartilage from the same patient. OA chondrocytes and cartilage explants stimulated with IL-1beta showed high level expression of IL-6 mRNA and protein. Butein increased the phosphorylation of AMPKalphaThr-172, TSC2Ser-1387 and ULK1Ser-317 and inhibited the phosphorylation of mTORSer-2448 and its downstream target p70S6K and increased autophagy flux that correlated with the suppression of the IL-1beta mediated expression of IL-6 in normal and OA chondrocytes. In OA chondrocytes with siRNA-mediated knockdown of ATG5 expression, treatment with Butein failed to activate autophagy and abrogated the suppression of IL-1beta induced IL-6 expression. CONCLUSION: Our findings demonstrate for the first time that Butein activate autophagy in OA chondrocytes via AMPK/TSC2/ULK1/mTOR pathway. Additionally, activation of autophagy was essential to block the IL-1beta-induced expression of IL-6 in OA chondrocytes. These data support further studies to evaluate the use of Butein or compounds derived from it for the management of OA.
Ansari Mohammad Y; Ahmad Nashrah; Haqqi Tariq M
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
2018
2018
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1159/000493225" target="_blank" rel="noreferrer noopener">10.1159/000493225</a>
Mechanisms of Chinese Medicine Xinmailong's protection against heart failure in pressure-overloaded mice and cultured cardiomyocytes.
Animal; Animals; Cardiac/cytology/*drug effects/metabolism; Cell Nucleus/metabolism; Cell Survival/drug effects; Cells; Chinese Herbal/*administration & dosage/pharmacology; Constriction; Cultured; Disease Models; Drugs; Echocardiography; GABA Plasma Membrane Transport Proteins/*metabolism; Gene Expression Regulation/drug effects; Glycogen Synthase Kinase 3 beta/metabolism; Heart Failure/etiology/metabolism/physiopathology/*prevention & control; Humans; MAP Kinase Signaling System/drug effects; Mice; Myocytes; Pathologic; Phosphorylation; Proto-Oncogene Proteins c-akt/metabolism; Rats
Patients with heart failure (HF) have high mortality and mobility. Xinmailong (XML) injection, a Chinese Medicine, is clinically effective in treating HF. However, the mechanism of XML's effectiveness on HF was unclear, and thus, was the target of the present study. We created a mouse model of pressure-overload-induced HF with transverse aortic constriction (TAC) surgery and compared among 4 study groups: SHAM (n = 10), TAC (n = 12), MET (metoprolol, positive drug treatment, n = 7) and XML (XML treatment, n = 14). Dynamic changes in cardiac structure and function were evaluated with echocardiography in vivo. In addition, H9C2 rat cardiomyocytes were cultured in vitro and the phosphorylation of ERK1/2, AKT, GSK3beta and protein expression of GATA4 in nucleus were detected with Western blot experiment. The results showed that XML reduced diastolic thickness of left ventricular posterior wall, increased ejection fraction and fraction shortening, so as to inhibit HF at 2 weeks after TAC. Moreover, XML inhibited the phosphorylation of ERK1/2, AKT and GSK3beta, subsequently inhibiting protein expression of GATA4 in nucleus (P \textless 0.001). Together, our data demonstrated that XML inhibited the TAC-induced HF via inactivating the ERK1/2, AKT/GSK3beta, and GATA4 signaling pathway.
Qi Jianyong; Yu Juan; Tan Yafang; Chen Renshan; Xu Wen; Chen Yanfen; Lu Jun; Liu Qin; Wu Jiashin; Gu Weiwang; Zhang Minzhou
Scientific reports
2017
2017-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/srep42843" target="_blank" rel="noreferrer noopener">10.1038/srep42843</a>
Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1.
Acetylation/drug effects; Animals; Butyrates/pharmacology; Cell Line; Cell Survival/drug effects; Dopamine Plasma Membrane Transport Proteins/*metabolism; Dopamine transporter; Dopaminergic Neurons/cytology/drug effects/metabolism; Dose-Response Relationship; Drug; Epigenesis; Epigenetics; Genetic; Genetic/drug effects; Group A; HDAC; Histone deacetylase; Histone Deacetylase Inhibitors/*pharmacology; Histone Deacetylases/metabolism; Histones/*drug effects/metabolism; Homeodomain Proteins/metabolism; Hydroxamic Acids/pharmacology; Member 2/*metabolism; Messenger/metabolism; Nuclear Receptor Subfamily 4; Nurr1; Pitx3; Promoter Regions; Rats; RNA; Transcription Factors/metabolism; Valproate; Valproic Acid/*pharmacology
The dopamine transporter (DAT) is the key regulator of dopaminergic transmission and is a target of several xenobiotics, including pesticides and pharmacological agents. Previously, we identified a prominent role for histone deacetylases in the regulation of DAT expression. Here, we utilized a rat dopaminergic cell line (N27) to probe the responsiveness of DAT mRNA expression to inhibitors of histone acetylation. Inhibition of histone deacetylases (HDACs) by valproate, butyrate and Trichostatin A led to a 3-10-fold increase in DAT mRNA expression, a 50% increase in protein levels, which were accompanied by increased H3 acetylation levels. To confirm the mechanism of valproate-mediated increase in DAT mRNA, chromatin immunoprecipitation (ChIP) assays were used and demonstrated a significant increase in enrichment of acetylation of histone 3 on lysines 9 and 14 (H3K9/K14ac) in the DAT promoter. Expression of Nurr1 and Pitx3, key regulators of DAT expression, were increased following valproate treatment and Nurr1 binding was enriched in the DAT promoter. Together, these results indicate that histone acetylation and subsequent enhancement of transcription factor binding are plausible mechanisms for DAT regulation by valproate and, perhaps, by other xenobiotics.
Green Ashley L; Zhan Le; Eid Aseel; Zarbl Helmut; Guo Grace L; Richardson Jason R
Neuropharmacology
2017
2017-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuropharm.2017.07.020" target="_blank" rel="noreferrer noopener">10.1016/j.neuropharm.2017.07.020</a>
Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells.
Aorta/pathology; Apoptosis/drug effects; Atherosclerosis/*drug therapy/metabolism/pathology/physiopathology; Cell Line; Cell Survival/drug effects; Cytoprotection; Endothelium; Free Radical Scavengers/*pharmacology; Humans; Mitochondria/drug effects/metabolism/pathology; Oxidative Stress/drug effects; Reperfusion Injury/*drug therapy/metabolism/pathology/physiopathology; Superoxides/metabolism; Vascular/*drug effects/metabolism/pathology; Vitamin B 12/*pharmacology; Vitamin B Complex/*pharmacology
Superoxide (O(2)(*-)) is implicated in inflammatory states including arteriosclerosis and ischemia-reperfusion injury. Cobalamin (Cbl) supplementation is beneficial for treating many inflammatory diseases and also provides protection in oxidative-stress-associated pathologies. Reduced Cbl reacts with O(2)(*-) at rates approaching that of superoxide dismutase (SOD), suggesting a plausible mechanism for its anti-inflammatory properties. Elevated homocysteine (Hcy) is an independent risk factor for cardiovascular disease and endothelial dysfunction. Hcy increases O(2)(*-) levels in human aortic endothelial cells (HAEC). Here, we explore the protective effects of Cbl in HAEC exposed to various O(2)(*-) sources, including increased Hcy levels. Hcy increased O(2)(*-) levels (1.6-fold) in HAEC, concomitant with a 20% reduction in cell viability and a 1.5-fold increase in apoptotic death. Pretreatment of HAEC with physiologically relevant concentrations of cyanocobalamin (CNCbl) (10-50nM) prevented Hcy-induced increases in O(2)(*-) and cell death. CNCbl inhibited both Hcy and rotenone-induced mitochondrial O(2)(*-) production. Similarly, HAEC challenged with paraquat showed a 1.5-fold increase in O(2)(*-) levels and a 30% decrease in cell viability, both of which were prevented with CNCbl pretreatment. CNCbl also attenuated elevated O(2)(*-) levels after exposure of cells to a Cu/Zn-SOD inhibitor. Our data suggest that Cbl acts as an efficient intracellular O(2)(*-) scavenger.
Moreira Edward S; Brasch Nicola E; Yun June
Free radical biology & medicine
2011
2011-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.freeradbiomed.2011.05.034" target="_blank" rel="noreferrer noopener">10.1016/j.freeradbiomed.2011.05.034</a>
Screening and identification of novel compounds with potential anti-proliferative effects on gallium-resistant lung cancer through an AXL kinase pathway.
Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology; Antitumor; AXL; Cell Line; Cell Proliferation/drug effects; Cell Survival/drug effects; Dose-Response Relationship; Drug; Drug Resistance; Drug Screening Assays; Gallium; Gallium-resistance; Gallium/pharmacology; Humans; Lung cancer; Lung Neoplasms/drug therapy/*enzymology/*pathology; Molecular Structure; Naphthalenes/chemistry/*pharmacology; Neoplasm/drug effects; Proto-Oncogene Proteins/*antagonists & inhibitors/metabolism; Pyrazoles/chemistry/*pharmacology; Quinolines/chemistry/*pharmacology; Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism; Structure-Activity Relationship; Tetrazoles/chemistry/*pharmacology; Tumor; Virtual screening
The clinical application of gallium compounds as anticancer agents is hampered by development of resistance. As a potential strategy to overcome the limitation, eight series of compounds were identified through virtual screening of AXL kinase homology model. Anti-proliferative studies were carried using gallium-sensitive (S) and gallium-resistant (R) human lung adenocarcinoma (A549) cells. Compounds 5476423 and 7919469 were identified as leads. The IC50 values from treating
Oyewumi Moses O; Alazizi Adnan; Liva Sophia; Lin Li; Geldenhuys Werner J
Bioorganic & medicinal chemistry letters
2014
2014-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2014.07.072" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2014.07.072</a>
Serotonin-activated alpha 2-macroglobulin inhibits neurite outgrowth and survival of embryonic sensory and cerebral cortical neurons.
Afferent/drug effects/ultrastructure; alpha-Macroglobulins/metabolism/*pharmacology; Animals; Bovine/pharmacology; Cell Survival/drug effects; Cells; Chick Embryo; Cultured; Frontal Lobe/*cytology/embryology; Ganglia; Humans; Nerve Growth Factors/*antagonists & inhibitors/pharmacology; Neurites/drug effects/ultrastructure; Neurons; Neurons/*drug effects/ultrastructure; Protein Binding; Rats; Serotonin/metabolism/*pharmacology; Serum Albumin; Spinal/*cytology/embryology
Methylamine-modified alpha-2-macroglobulin (MA-alpha 2M) has been recently shown to inhibit the biological activity of beta-nerve growth factor (NGF) in promoting neurite outgrowth by embryonic dorsal root ganglia in culture (Koo PH, Liebl DJ, J Neurosci Res 31:678-692, 1992). The objectives of this study are to determine whether alpha 2M can also be modified by larger aromatic biogenic amines such as
Liebl D J; Koo P H
Journal of neuroscience research
1993
1993-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jnr.490350207" target="_blank" rel="noreferrer noopener">10.1002/jnr.490350207</a>
Synthesis and Biological Evaluation of Pentacycloundecylamines and Triquinylamines as Voltage-Gated Calcium Channel Blockers.
Alicyclic/chemical synthesis/*chemistry/pharmacology; Amines/chemical synthesis/*chemistry/pharmacology; Animals; Apoptosis/drug effects; Calcium Channel Blockers/chemical synthesis/*chemistry/pharmacology; Calcium Channels; Calcium/*metabolism; Cell Survival/drug effects; Hydrocarbons; Hydrogen Peroxide/pharmacology; L-Lactate Dehydrogenase/metabolism; L-type calcium channel (LTCC) blockers; L-Type/*metabolism; Multifunctional drugs; Neurodegeneration; PC12 Cells; Pentacycloundecylamine; Quinones/chemical synthesis/*chemistry/pharmacology; Rats; Structure-Activity Relationship; Triquinylamine
Preclinical studies for neurodegenerative diseases have shown a multi-targeted approach to be successful in the treatment of these complex disorders with several pathoetiological pathways. Polycyclic compounds, such as NGP1-01 (7a), have demonstrated the ability to target multiple mechanisms of the complex etiology and are referred to as multifunctional compounds. These compounds have served as scaffolds with the ability to attenuate Ca(2+) overload and excitotoxicity through several pathways. In this study, our focus was on mitigating Ca(2+) overload through the L-type calcium channels (LTCC). Here, we report the synthesis and biological evaluation of several novel polycyclic compounds. We determined the IC50 values for both the pentacycloundecylamines and the triquinylamines by means of a high-throughput fluorescence calcium flux assay utilizing Fura-2/AM. The potential of these compounds to offer protection against hydrogen peroxide-induced cell death was also evaluated. Overall,
Young Lois-May; Geldenhuys Werner J; Domingo Olwen C; Malan Sarel F; Van der Schyf Cornelis J
Archiv der Pharmazie
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/ardp.201500293" target="_blank" rel="noreferrer noopener">10.1002/ardp.201500293</a>