Double Edge Sword Behavior of Carbendazim: A Potent Fungicide With Anticancer Therapeutic Properties

2018 ◽  
Vol 18 (1) ◽  
pp. 38-45 ◽  
Author(s):  
Karan Goyal ◽  
Ajay Sharma ◽  
Ridhima Arya ◽  
Rohit Sharma ◽  
Girish K. Gupta ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Potential Role ◽  
Anticancer Agent ◽  
Significant Proportion ◽  
Dual Role ◽  
Pharmacokinetic Studies ◽  
Phase I Clinical Trials ◽  
Discovery Research ◽  
Drug Discovery Research

Background: A number of benzimidazole derivatives such as benomyl and carbendazim have been known for their potential role as agricultural fungicides. Simultaneously carbendazim has also been found to inhibit proliferation of mammalian tumor cells specifically drug and multidrug resistant cell lines. Objective: To understand the dual role of Carbendazim as a fungicide and an anticancer agent, the study has been planned referring to the earlier studies in literature. Results: Studies carried out with fungal and mammalian cells have highlighted the potential role of carbendazim in inhibiting proliferation of cells, thereby exhibiting therapeutic implications against cancer. Because of its promising preclinical antitumor activity, Carbendazim had undergone phase I clinical trials and is under further clinical investigations for the treatment of cancer. A number of theoretical interactions have been pinpointed. There are many anticancer drugs in the market, but their usefulness is limited because of drug resistance in a significant proportion of patients. The hunger for newer drugs drives anticancer drug discovery research on a global platform and requires innovations to ensure a sustainable pipeline of lead compounds. Conclusion: Current review highlights the dual role of carbendazim as a fungicide and an anticancer agent. Further, the harmful effects of carbendazim and emphasis upon the need for more pharmacokinetic studies and pharmacovigilance data to ascertain its clinical significance, have also been discussed.

scholarly journals The role of cytochrome c in caspase activation in Drosophila melanogaster cells

2002 ◽  
Vol 156 (6) ◽  
pp. 1089-1098 ◽  
Author(s):  
Loretta Dorstyn ◽  
Stuart Read ◽  
Dimitrios Cakouros ◽  
Jun R. Huh ◽  
Bruce A. Hay ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Mammalian Cells ◽  
Significant Proportion ◽  
Ectopic Expression ◽  
Caspase Activation ◽  
Cytochrome C Release ◽  
Cell Extracts ◽  
Effector Caspase ◽  
Drosophila Cells

The release of cytochrome c from mitochondria is necessary for the formation of the Apaf-1 apoptosome and subsequent activation of caspase-9 in mammalian cells. However, the role of cytochrome c in caspase activation in Drosophila cells is not well understood. We demonstrate here that cytochrome c remains associated with mitochondria during apoptosis of Drosophila cells and that the initiator caspase DRONC and effector caspase DRICE are activated after various death stimuli without any significant release of cytochrome c in the cytosol. Ectopic expression of the proapoptotic Bcl-2 protein, DEBCL, also fails to show any cytochrome c release from mitochondria. A significant proportion of cellular DRONC and DRICE appears to localize near mitochondria, suggesting that an apoptosome may form in the vicinity of mitochondria in the absence of cytochrome c release. In vitro, DRONC was recruited to a >700-kD complex, similar to the mammalian apoptosome in cell extracts supplemented with cytochrome c and dATP. These results suggest that caspase activation in insects follows a more primitive mechanism that may be the precursor to the caspase activation pathways in mammals.

scholarly journals Cryo-EM structure of a single-chain β1–adrenoceptor – AmpC β-lactamase fusion protein

2021 ◽  
Author(s):  
Gabriella Collu ◽  
Inayathulla Mohammed ◽  
Aleix Lafita ◽  
Tobias Bierig ◽  
Emiliya Poghosyan ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Mammalian Cells ◽  
Data Bank ◽  
Single Chain ◽  
Intracellular Loop ◽  
Class A ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Wide Range ◽  
G Protein Coupled

The insertion of fusion proteins has enabled the crystallization of a wide range of G–protein–coupled receptors (GPCRs). Here, we explored the possibility of using a larger fusion protein, inserted into the third intracellular loop (ICL3) of β1-adrenoceptor (β1AR) via rigid chimeric helix fusions. The aim was to engineer a single–chain fusion protein that comprises sufficient mass and rigidity to allow single–particle cryo–EM data collection, without depending on binding proteins, such as G–proteins or nanobodies. Through parsing of the protein data bank (PDB), we identified the protein AmpC–β–lactamase as a suitable candidate. Both termini of this protein are α–helical and the helices are antiparallel to each other. The distance between their centroids measures ≈11 Å. Such a geometry is ideal to design extended chimeric helices with transmembrane (TM) helices 5 and 6 of β1AR, and the insertion of the protein adds ≈39 kDa of mass to the receptor. We expressed the β1AR – AmpC β–lactamase fusion protein in mammalian cells. The binding of the antagonists propranolol and cyanopindolol to the purified fusion protein was confirmed by CPM–based thermofluor assays. The cryo–EM structure was solved to a nominal overall resolution of 3.6 Å and the seven helix architecture and helix eight were clearly resolved. Superimposition of the structure with known X–ray crystal structures of β1AR suggests that the protein is in its inactive conformation. The fusion protein described here provides a basis for high–throughput structure elucidation of class A GPCRs by cryo–EM for drug discovery research as well as for the elucidation of inactive state or wild–type GPCR structures. The fusion protein geometry theoretically fits a wide range of class A GPCRs and therefore can be applied to a multitude of receptors.

scholarly journals Proprotein cleavage of E-cadherin by furin in baculovirus over-expression system: potential role of other convertases in mammalian cells

FEBS Letters ◽  
1998 ◽  
Vol 438 (3) ◽  
pp. 306-310 ◽  
Author(s):  
Horst Posthaus ◽  
Claire M. Dubois ◽  
Marie-Hélène Laprise ◽  
Francine Grondin ◽  
Maja M. Suter ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Potential Role ◽  
Expression System ◽  
Over Expression ◽  
E Cadherin

scholarly journals Role of melatonin in the induction and maintenance of sleep

2002 ◽  
Vol 4 (4) ◽  
pp. 395-401
Keyword(s):  
Pineal Gland ◽  
Sleep Disorders ◽  
Significant Proportion ◽  
Aminobutyric Acid ◽  
Pharmacokinetic Studies ◽  
Rapid Eye Movement Sleep ◽  
Light Conditions ◽  
Human Volunteers ◽  
Physiological Sleep

Pharmacokinetic studies of melatonin in young and elderly human volunteers, and the measurement of hypnotic effects in chicks under alternate light-dark or permanent light conditions, show that melatonin is a bioprecursor of hypnotic acetyl metabolites produced by the enzymatic acetylation of both melatonin and 2-oxomelatonin under the control of serotonin N-acetyltransferases (NATs), which are present in the pineal gland. The acetyl metabolite of melatonin, which we call carbo2, is an N-acetyl-β-carboline. The electroencephalographs (EEG) architecture of the sleep produced by this compound is similar to thai of physiological sleep, and is characterized by the significant proportion of slow-wave deep sleep and rapid eye movement sleep. This is in sharp contrast to the EEG sleep architecture observed with GABAergic (GABA, γ-aminobutyric acid) compounds. Since insomnia and sleep disorders are believed to be due to a lack of NAT enzymes in the pineal gland, a new therapeutic approach of sleep disorders by administration of such hypnotic acetyl metabolites of melatonin, or synthetic analogs thereof, can be en visaged.

scholarly journals Myeloproliferative disorders

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2190-2198 ◽  
Author(s):  
Ross L. Levine ◽  
D. Gary Gilliland
Keyword(s):  
Potential Role ◽  
Significant Proportion ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Nonreceptor Tyrosine Kinase ◽  
Activating Mutation ◽  
Genetic Events ◽  
Improve Clinical Outcome ◽  
Stat Pathway

Abstract In 1951 William Dameshek classified polycythemia vera (PV), essential thombocytosis (ET), and primary myelofibrosis (PMF) as pathogenetically related myeloproliferative disorders (MPD). Subsequent studies demonstrated that PV, ET, and PMF are clonal disorders of multipotent hematopoietic progenitors. In 2005, a somatic activating mutation in the JAK2 nonreceptor tyrosine kinase (JAK2V617F) was identified in most patients with PV and in a significant proportion of patients with ET and PMF. Subsequent studies identified additional mutations in the JAK-STAT pathway in some patients with JAK2V617F− MPD, suggesting that constitutive activation of this signaling pathway is a unifying feature of these disorders. Although the discovery of mutations in the JAK-STAT pathway is important from a pathogenetic and diagnostic perspective, important questions remain regarding the role of this single disease allele in 3 related but clinically distinct disorders, and the role of additional genetic events in MPD disease pathogenesis. In addition, these observations provide a foundation for development of small molecule inhibitors of JAK2 that are currently being tested in clinical trials. This review will discuss our understanding of the pathogenesis of PV, ET, and PMF, the potential role of JAK2-targeted therapy, and the important unanswered questions that need to be addressed to improve clinical outcome.

Aptamers in Drug Design: An Emerging Weapon to Fight a Losing Battle

2019 ◽  
Vol 20 (16) ◽  
pp. 1624-1635
Author(s):  
Jobin Jose ◽  
Aaron Mathew Thomas ◽  
Darewin Mendonsa ◽  
Mohammad M. Al-Sanea ◽  
Md. Sahab Uddin ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Imaging Techniques ◽  
Polymer Materials ◽  
Recent Application ◽  
Preparation Methods ◽  
Discovery Research ◽  
Drug Discovery Research ◽  
Future Potential

Implementation of novel and biocompatible polymers in drug design is an emerging and rapidly growing area of research. Even though we have a large number of polymer materials for various applications, the biocompatibility of these materials remains as a herculean task for researchers. Aptamers provide a vital and efficient solution to this problem. They are usually small (ranging from 20 to 60 nucleotides, single-stranded DNA or RNA oligonucleotides which are capable of binding to molecules possessing high affinity and other properties like specificity. This review focuses on different aspects of Aptamers in drug discovery, starting from its preparation methods and covering the recent scenario reported in the literature regarding their use in drug discovery. We address the limitations of Aptamers and provide valuable insights into their future potential in the areas regarding drug discovery research. Finally, we explained the major role of Aptamers like medical imaging techniques, application as synthetic antibodies, and the most recent application, which is in combination with nanomedicines.

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