scholarly journals Inhibition of Bruton's tyrosine kinase activity attenuates trauma-induced multiple organ dysfunction in rats

2021 ◽  
Author(s):  
Nikita M Patel ◽  
Filipe RMB Oliveira ◽  
Hanna Pillmann Ramos ◽  
Eleonora Aimaretti ◽  
Gustavo Ferreira Alves ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Tyrosine Kinase ◽  
Organ Dysfunction ◽  
Multiple Organ ◽  
Organ Injury ◽  
Bruton’S Tyrosine Kinase ◽  
Multiple Organ Dysfunction ◽  
Bruton's Tyrosine Kinase ◽  
Rat Models ◽  
Btk Inhibitors

Objective: The aim of this study was to investigate (a) the potential of the Bruton's tyrosine kinase (BTK) inhibitors (BTKi) acalabrutinib and fenebrutinib to reduce multiple organ dysfunction syndrome (MODS) in acute and chronic hemorrhagic shock (HS) rat models and (b) whether treatment with either acalabrutinib or fenebrutinib attenuates BTK, NF-κB and NLRP3 activation in HS. Background: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. The protein BTK is known to play a role in the activation of the NLRP3 inflammasome, which is a key component of the innate inflammatory response. However, its role in trauma-hemorrhage is unknown. Methods: Acute and chronic HS rat models were performed to determine the influence of acalabrutinib or fenebrutinib on MODS. The activation of BTK, NF-κB and NLRP3 pathways were analyzed by western blot in the kidney. Results: We demonstrated that (a) HS caused organ injury and/or dysfunction and hypotension (post resuscitation) in rats, while (b) treatment of HS-rats with either acalabrutinib or fenebrutinib attenuated the organ injury and dysfunction in acute and chronic HS models and (c) reduced the activation of BTK, NF-κB and NLRP3 pathways in the kidney. Conclusion: Our results point to a role of BTK in the pathophysiology of organ injury and dysfunction caused by trauma/hemorrhage and indicate that BTK inhibitors may be repurposed as a potential therapeutic approach for MODS after trauma and/or hemorrhage.

scholarly journals Inhibition of Bruton's Tyrosine Kinase Activity Attenuates Hemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Nikita M. Patel ◽  
Filipe R. M. B. Oliveira ◽  
Hanna Pillmann Ramos ◽  
Eleonora Aimaretti ◽  
Gustavo Ferreira Alves ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Hemorrhagic Shock ◽  
Organ Dysfunction ◽  
Kinase Activity ◽  
Multiple Organ ◽  
Bruton’S Tyrosine Kinase ◽  
Multiple Organ Dysfunction ◽  
Tyrosine Kinase Activity ◽  
Bruton's Tyrosine Kinase

scholarly journals Observations on the use of Bruton’s tyrosine kinase inhibitors in SAR-CoV-2 and cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Brooke Benner ◽  
William E. Carson
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Innate Immune ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Process Understanding ◽  
Btk Inhibitors ◽  
Severe Lung Disease ◽  
Pro Inflammatory Cytokines ◽  
Severe Lung

AbstractBruton’s tyrosine kinase (BTK) inhibitors, drugs utilized in cancer, are being repurposed for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (COVID-19). Recently, BTK inhibitors acalabrutinib and ibrutinib have been found to protect against pulmonary injury in a small group of patients infected with SARS-CoV-2. The high levels of pro-inflammatory cytokines found in the circulation of COVID-19 patients with severe lung disease suggest the involvement of the innate immune system in this process. Understanding the potential mechanism of action of BTK inhibition in SARS-CoV-2 is clearly of importance to determine how acalabrutinib, ibrutinib and possibly other BTK inhibitors may provide protection against lung injury.

scholarly journals DESIGN AND SYNTHESIS OF SOME NEWER IMIDAZOLYL HETEROCYCLES AS POTENT BTK INHIBITORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

2017 ◽  
Vol 9 (3) ◽  
pp. 80
Author(s):  
R. Priyadarsini ◽  
Anandhan Menaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Hydrogen Bond ◽  
Molecular Docking ◽  
Tyrosine Kinase ◽  
Pharmacophore Model ◽  
Spectral Studies ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Hydrogen Bond Acceptor ◽  
Btk Inhibitors

Objective: The rheumatoid arthritis as a global health problem over the past few decades, Emphasizes the need for discovery of new therapeutic disease modifying anti-rheumatoid Arthritis drugs (DMARD’s). Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor, tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in the development, differentiation and proliferation of B-lineage cells, thus making BTK an efficient therapeutic target for the treatment of rheumatoid arthritis. This prompted us to synthesise a novel series of Imidazolyl Heterocycles as potent BTK (Bruton’s Tyrosine Kinase) inhibitors with alleged Anti-Rheumatoid Arthritis properties. Methods: Newer BTK inhibitors containing one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) and three hydrophobic features based on that pharmacophore model for BTK were designed. The designed compounds were sorted by applying ADMET properties, Lipinski rule of five, molecular docking and Novelty prediction to refine the designed ligands. Finally, different five compounds containing Imidazole as the heterocyclic nucleus have been synthesized and characterized by different analytical methods like Chromatographic data, Elemental analysis and Spectral studies by IR, 1H NMR, 13C NMR, GC-MS. Molecular docking studies were performed against BTK using GLIDE 10.2. Results: Several important hydrogen bonds with BTK were revealed, which include the gatekeeper residue Glu475 and Met477 at the hinge region. Conclusion: Overall, this study suggests that the proposed ligands are found to be more effective BTK inhibitor as Anti-Rheumatoid arthritis agents.

scholarly journals Sepsis, mitochondrial failure and multiple organ dysfunction

2014 ◽  
Vol 37 (2) ◽  
pp. 58 ◽  
Author(s):  
Josefina Duran-Bedolla ◽  
Marco A Montes de Oca-Sandoval ◽  
Vianey Saldaña-Navor ◽  
José A Villalobos-Silva ◽  
Maria Carmen Rodriguez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Organ Dysfunction ◽  
Physiological State ◽  
Redox Balance ◽  
Multiple Organ ◽  
Reactive Species ◽  
Systemic Inflammatory Response ◽  
Antioxidant Systems ◽  
Multiple Organ Dysfunction

Purpose: The purpose of this review is to consider the state of oxidative stress, failure of the antioxidant systems and mitochondrial failure as the main physiopathological mechanisms leading to multiple organ dysfunction during sepsis. Principal findings: Sepsis is a clinical syndrome caused by a severe infection that triggers an exaggerated inflammatory response. Involved in the pathogenesis of sepsis are the activation of inflammatory, immune, hormonal, metabolic and bioenergetic responses. One of the pivotal factors in these processes is the increase of reactive species accompanied by the failure of the antioxidant systems, leading to a state of irreversible oxidative stress and mitochondrial failure. In a physiological state, reactive species and antioxidant systems are in redox balance. The loss of this balance during both chronic and infectious diseases leads to a state of oxidative stress, which is considered to be the greatest promoter of a systemic inflammatory response. The loss of the redox balance, together with a systemic inflammatory response during sepsis, can lead to progressive and irreversible mitochondrial failure, energy depletion, hypoxia, septic shock, severe sepsis, multiple organ dysfunction and death of the patient. Conclusion: Knowledge of the molecular processes associated with the development of oxidative stress should facilitate the development of effective therapies and better prognosis for patients with sepsis and organ dysfunction.

scholarly journals Multiple Organ Dysfunction During Severe Malaria: The Role of the Inflammatory Response

10.5772/65348 ◽  
2016 ◽  
Author(s):  
Mariana Conceição de Souza ◽  
Tatiana Almeida Pádua ◽  
Maria das Graças Henriques
Keyword(s):  
Inflammatory Response ◽  
Severe Malaria ◽  
Organ Dysfunction ◽  
Multiple Organ ◽  
Multiple Organ Dysfunction

Bruton’s tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018)

2019 ◽  
Vol 29 (4) ◽  
pp. 217-241 ◽  
Author(s):  
Yifan Feng ◽  
Weiming Duan ◽  
Xiaochuan Cu ◽  
Chengyuan Liang ◽  
Minhang Xin
Keyword(s):  
Tyrosine Kinase ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Patent Review ◽  
Btk Inhibitors

Article Commentary: Sepsis, Systemic Inflammatory Response, and Multiple Organ Dysfunction: The Mystery Continues

2012 ◽  
Vol 78 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Donald E. Fry
Keyword(s):  
Clinical Trials ◽  
Inflammatory Response ◽  
Organ Dysfunction ◽  
Multiple Organ ◽  
Systemic Inflammatory Response ◽  
Invasive Infection ◽  
Multiple Organ Dysfunction ◽  
Human Sepsis ◽  
Critical Organ

Human sepsis is thought to be systemic inflammatory response syndrome (SIRS) that is activated by invasive infection. The multiple organ dysfunction syndrome (MODS) is the identified failure of critical organ function in patients that have sustained SIRS. Because SIRS and MODS are consequences of the excessive activation of inflammation, extensive research and numerous clinical trials have pursued treatments that would modify the inflammatory response. This presentation reviews the normal local mechanisms of inflammation and provides a theoretical framework for the transition of the inflammatory process to a systemic level. Clinical trials with biomodulators to block or inhibit inflammation have generally failed to improve the outcomes in patients with severe sepsis, septic shock, and MODS. The role of counter-inflammatory signaling and the newer concept of the cholinergic anti-inflammatory pathway are being investigated, and newer hypotheses are focusing upon the balancing of proinflammatory and counter-inflammatory mechanisms as important directions for newer therapies. It is concluded that failure to define novel and effective treatments reflects fundamental gaps in our understanding of inflammation and its regulation.

Sign in / Sign up

Export Citation Format

Share Document