scholarly journals Shedding Light on the Inhibitory Mechanisms of SARS-CoV-1/CoV-2 Spike Proteins by ACE2-Designed Peptides

2021 ◽  
Vol 61 (3) ◽  
pp. 1226-1243
Author(s):  
Frederico Campos Freitas ◽  
Paulo Henrique Borges Ferreira ◽  
Denize Cristina Favaro ◽  
Ronaldo Junio de Oliveira
Keyword(s):  
Inhibitory Mechanisms ◽  
Spike Proteins

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

scholarly journals Inhibitory Mechanisms in the Processing of Negations: A Neural Reuse Hypothesis

2021 ◽  
Author(s):  
David Beltrán ◽  
Bo Liu ◽  
Manuel de Vega
Keyword(s):  
Cognitive Control ◽  
Response Inhibition ◽  
Cognitive Functions ◽  
Functional Relation ◽  
Control Mechanisms ◽  
Inhibitory Effects ◽  
General Domain ◽  
Inhibitory Mechanisms ◽  
Neural Reuse ◽  
Theoretical Foundations

AbstractNegation is known to have inhibitory consequences for the information under its scope. However, how it produces such effects remains poorly understood. Recently, it has been proposed that negation processing might be implemented at the neural level by the recruitment of inhibitory and cognitive control mechanisms. On this line, this manuscript offers the hypothesis that negation reuses general-domain mechanisms that subserve inhibition in other non-linguistic cognitive functions. The first two sections describe the inhibitory effects of negation on conceptual representations and its embodied effects, as well as the theoretical foundations for the reuse hypothesis. The next section describes the neurophysiological evidence that linguistic negation interacts with response inhibition, along with the suggestion that both functions share inhibitory mechanisms. Finally, the manuscript concludes that the functional relation between negation and inhibition observed at the mechanistic level could be easily integrated with predominant cognitive models of negation processing.

scholarly journals Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 561
Author(s):  
Anca Bobircă ◽  
Florin Bobircă ◽  
Ioan Ancuta ◽  
Alesandra Florescu ◽  
Vlad Pădureanu ◽  
...  
Keyword(s):  
Immune System ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Multidisciplinary Approach ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Cancer Cell Growth ◽  
Inhibitory Mechanisms ◽  
Checkpoint Inhibitor Therapy

The advent of immunotherapy has changed the management and therapeutic methods for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, which works by interfering with cancer cell growth via various pathways and stages of the cell cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape the immune system and combat cell proliferation. The widespread use of immune checkpoint inhibitors (ICIs) over the past 10 years has presented valuable information on the profiles of toxic adverse effects. The attenuation of T-lymphocyte inhibitory mechanisms by ICIs results in immune system hyperactivation, which, as expected, is associated with various adverse events defined by inflammation. These adverse events, known as immune-related adverse events (ir-AEs), may affect any type of tissue throughout the human body, which includes the digestive tract, endocrine glands, liver and skin, with reports of cardiovascular, pulmonary and rheumatic ir-AEs as well. The adverse events that arise from ICI therapy are both novel and unique compared to those of the conventional treatment options. Thus, they require a multidisciplinary approach and continuous updates on the diagnostic approach and management.

scholarly journals Comparison of Ferroptosis-Inhibitory Mechanisms between Ferrostatin-1 and Dietary Stilbenes (Piceatannol and Astringin)

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1092
Author(s):  
Ban Chen ◽  
Xican Li ◽  
Xiaojian Ouyang ◽  
Jie Liu ◽  
Yangping Liu ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Ultra Performance Liquid Chromatography ◽  
Mass Spectrometry Analysis ◽  
Death Process ◽  
High Electron ◽  
Hydrogen Atoms ◽  
Spectrometry Analysis ◽  
Inhibitory Mechanisms ◽  
Quantum Chemistry Calculations ◽  
Transfer Potential

Synthetic arylamines and dietary phytophenolics could inhibit ferroptosis, a recently discovered regulated cell death process. However, no study indicates whether their inhibitory mechanisms are inherently different. Herein, the ferroptosis-inhibitory mechanisms of selected ferrostatin-1 (Fer-1) and two dietary stilbenes (piceatannol and astringin) were compared. Cellular assays suggested that the ferroptosis-inhibitory and electron-transfer potential levels decreased as follows: Fer-1 >> piceatannol > astringin; however, the hydrogen-donating potential had an order different from that observed by the antioxidant experiments and quantum chemistry calculations. Quantum calculations suggested that Fer-1 has a much lower ionization potential than the two stilbenes, and the aromatic N-atoms were surrounded by the largest electron clouds. By comparison, the C4′O-H groups in the two stilbenes exhibited the lowest bond disassociation enthalpies. Finally, the three were found to produce corresponding dimer peaks through ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry analysis. In conclusion, Fer-1 mainly depends on the electron transfer of aromatic N-atoms to construct a redox recycle. However, piceatannol and astringin preferentially donate hydrogen atoms at the 4′-OH position to mediate the conventional antioxidant mechanism that inhibits ferroptosis, and to ultimately form dimers. These results suggest that dietary phytophenols may be safer ferroptosis inhibitors for balancing normal and ferroptotic cells than arylamines with high electron-transfer potential.

In vitro inhibitory mechanisms and molecular docking of 1′-S-1′-acetoxychavicol acetate on human cytochrome P450 enzymes

Phytomedicine ◽  
2017 ◽  
Vol 31 ◽  
pp. 1-9 ◽  
Author(s):  
A.K.M. Mahmudul Haque ◽  
Kok Hoong Leong ◽  
Yoke Lin Lo ◽  
Khalijah Awang ◽  
Noor Hasima Nagoor
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Cytochrome P450 Enzymes ◽  
Inhibitory Mechanisms ◽  
Human Cytochrome

scholarly journals Nanobiocide Based-Silver Nanomaterials Upon Coronaviruses: Approaches for Preventing Viral Infections

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Kamyar Khoshnevisan ◽  
Hassan Maleki ◽  
Hadi Baharifar
Keyword(s):  
Viral Entry ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Antiviral Agents ◽  
Long Term Stability ◽  
Silver Nanomaterials ◽  
Inhibitory Mechanisms ◽  
Low Toxicity ◽  
Nano Graphene

Abstract The effectiveness of silver nanomaterials (AgNMs), as antiviral agents, has been confirmed in humans against many different types of viruses. Nanobiocides-based AgNMs can be effectively applied to eliminate coronaviruses (CoVs), as the cause of various diseases in animals and humans, particularly the fatal human respiratory infections. Mostly, these NMs act effectively against CoVs, thanks to the NMs’ fundamental anti-viral structures like reactive oxygen species (ROS), and photo-dynamic and photo-thermal abilities. Particularly, the antiviral activity of AgNMs is clarified under three inhibitory mechanisms including viral entry limitation, attachment inhibition, and viral replication limitation. It is believed that nanobiocide with other possible materials such as TiO2, silica and, carbon NMs exclusively nano-graphene materials can emerge as a more effective disinfectant for long-term stability with low toxicity than common disinfectants. Nanobiocides also can be applied for the prevention and treatment of viral infections specifically against COVID-19. Graphic Abstract

scholarly journals Preparing to React: A Behavioral Study on the Interplay between Proactive and Reactive Action Inhibition

2021 ◽  
Vol 11 (6) ◽  
pp. 680
Author(s):  
Stefania C. Ficarella ◽  
Andrea Desantis ◽  
Alexandre Zénon ◽  
Boris Burle
Keyword(s):  
Ad Hoc ◽  
Motor Preparation ◽  
Proactive Inhibition ◽  
False Alarms ◽  
Control Mechanisms ◽  
Reactive Inhibition ◽  
Inhibitory Mechanisms ◽  
Motor Activities ◽  
Errors Analysis ◽  
Action Inhibition

Motor preparation, based on one’s goals and expectations, allows for prompt reactions to stimulations from the environment. Proactive and reactive inhibitory mechanisms modulate this preparation and interact to allow a flexible control of responses. In this study, we investigate these two control mechanisms with an ad hoc cued Go/NoGo Simon paradigm in a within-subjects design, and by measuring subliminal motor activities through electromyographic recordings. Go cues instructed participants to prepare a response and wait for target onset to execute it (Go target) or inhibit it (NoGo target). Proactive inhibition keeps the prepared response in check, hence preventing false alarms. Preparing the cue-coherent effector in advance speeded up responses, even when it turned out to be the incorrect effector and reactive inhibition was needed to perform the action with the contralateral one. These results suggest that informative cues allow for the investigation of the interaction between proactive and reactive action inhibition. Partial errors’ analysis suggests that their appearance in compatible conflict-free trials depends on cue type and prior preparatory motor activity. Motor preparation plays a key role in determining whether proactive inhibition is needed to flexibly control behavior, and it should be considered when investigating proactive/reactive inhibition.

scholarly journals Clinical and economic aspects of the use of rituximab in non-Hodgkin's lymphoma

2014 ◽  
Vol 50 (3) ◽  
pp. 445-455
Author(s):  
Camila Bezerra Melo Figueirêdo ◽  
Joelma Rodrigues de Souza ◽  
Daniel Handerson Galindo Soares ◽  
Caio Cesar de Andrade Rodrigues Silva ◽  
Virginia Maria Barros de Lorena
Keyword(s):  
B Cells ◽  
Hodgkin’S Lymphoma ◽  
Clinical Results ◽  
Cost Utility ◽  
Hodgkin's Lymphoma ◽  
Clinical Tests ◽  
Viable Option ◽  
Non Hodgkin’S Lymphoma ◽  
Inhibitory Mechanisms ◽  
Non Hodgkin's Lymphoma

Non-Hodgkin's lymphoma (NHL) consists of a group of neoplasias involving mainly B cells and represents 90% of all lymphomas. The current available therapy is based on chemotherapy associated with the monoclonal antibody rituximab (Mab Thera(r)), which targets the CD20 protein, present in over 80% of NHL mature B cells. Recent clinical reports show a preference for combining the benefits of immunotherapy and adjuvant chemotherapy, thus generating safe and effective alternative treatments. The current review aimed at evaluating various aspects related to the use of rituximab for NHL, highlighting the possible inhibitory mechanisms of cell proliferation, the achieved clinical results, and the expected clinical and economic outcomes of treatments. The results from clinical tests indicate the need for a better understanding of the critical mechanisms of action of this antibody, which may maximize its therapeutic efficacy. This therapy not only represents a viable option to treat most types of NHLs, especially when associated with conventional chemotherapy, but also offers cost-utility and cost-effectiveness advantages.

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