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Recent Developments in Therapies and Strategies Against COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Misbah Hameed, M. Zia-Ul-Haq, Marius Moga
Baricitinib inhibits Janus kinase 1 and 2. It has a role in triggering effect on cytokine-induced phosphorylation of STAT, which when transported to nuclear region, regulates gene transcription. Member of this family includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2) [40]. Studies reported that it activates different cytokines which stops the phosphorylation of STATs and causes temporary changes in neutrophil and lymphocyte numbers [10]. AP2-associated protein kinase 1 (AAK1) is an important manager of clathrin-mediated endocytosis and its disruption can restrict the passage of the virus into the host cells and further accumulation of virus intracellular. In a trial (NCT04321993) Baricitinib was suggested to be effective in COVID-19 patients showing acute respiratory disease as it will help reduce the entry of virus and also reduce the associated inflammation. It has also been used in combination with antivirals like ritonavir, Remdesivir, and lopinavir. The combination is suggested to be more effective as it will decrease viral infectivity by interfering with its entrance into the cells as well as reduce viral replication and will increase the host inflammatory response.
Newer Agents in Systemic Treatment
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Rachita Dhurat, Shilpi Agarwal
Currently, four important members of the JAK family are known. Janus kinase 1 and Janus kinase 2 are involved in host defense, hematopoiesis, neural development, and growth. Janus kinase 3 and tyrosine kinase 2 have a role in the immune response [32].
Interferon Alpha
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Jason Grebely, Gregory Dore, William Sievert
In brief, endogenous interferon alpha binding to cell-surface receptors leads to dimerization and activation of a cell signaling cascade (Feld and Hoofnagle, 2005). Janus-activated kinase 1 (Jak1) and tyrosine kinase 2 (Tyk2) are activated, and they phosphorylate STAT1 and STAT2. After dimerization, the activated STAT1/2 complex is then translocated to the nucleus, binding to IFN regulatory factor 9 (IRF-9), leading to the induction of multiple ISGs (Feld and Hoofnagle, 2005). Expression of ISGs in cells result in a positive feedback loop, which leads to the further production of endogenous interferon alpha (Feld and Hoofnagle, 2005). Interferon alpha also induces the expression of genes involved in the immune response, resulting in the activation of natural killer cells, maturation of dendritic cells, proliferation of memory T-cells and prevention of T-cell apoptosis (Tilg, 1997).
New synthetic pharmacotherapeutic approaches to the treatment of moderate-to-severe plaque psoriasis in adults
Published in Expert Opinion on Pharmacotherapy, 2023
Rithi J. Chandy, Sarah G. Bridgeman, Brandon M. Godinich, Steven R. Feldman
Deucravacitinib is a new oral synthetic pharmacotherapeutic treatment for moderate-to-severe plaque psoriasis in adults. Tyrosine kinase 2 (TYK2), a member of the JAK family, is involved in cytokine signaling through mediating intracellular components of adaptive and innate immune responses. TYK2 is therapeutically targeted for plaque psoriasis because of the linkage with the main psoriatic pathogenic pathways – the IL-23/IL-17 axis [45–49]. Deucravacitinib is a TYK2 allosteric inhibitor that binds to an inactive pseudokinase catalyst domain resulting in the inhibition of receptor-mediated stimulation of TYK2 and downstream inactivity which is unlike other TYK2 inhibitors who have competitive enzyme kinetics [12,45,46,50,51]. Deucravacitinib received its first approval in the United States for the treatment of moderate-to-severe plaque psoriasis on September 9th, 2022. The recommended daily dosage is 6 mg administered orally.
PTK2 regulates tau-induced neurotoxicity via phosphorylation of p62 at Ser403
Published in Journal of Neurogenetics, 2023
Shinrye Lee, Myungjin Jo, Younghwi Kwon, Yu-Mi Jeon, Seyeon Kim, Kea Joo Lee, Hyung-Jun Kim
PTK2 (protein tyrosine kinase 2) plays an essential role in regulating cell proliferation, survival, and migration (Armendáriz, Masdeu, Soriano, Ureña, & Burgaya, 2014). The tyrosine phosphorylation sites in PTK2 are Y397, 407, 576, 577, 861, and 925. Initiation of PTK2 activation requires autophosphorylation at Y397 and subsequent phosphorylation of other residues in PTK2 by SRC protein family members to activate the PTK2 downstream signaling pathway (Hanks, Ryzhova, Shin, & Brábek, 2003; Rasmussen, Müller, Jørgensen, Pedersen, & Hoffmann, 2015). Previous studies have indicated that PTK2 plays a critical role in the deposition of ubiquitinated aggregates and in neurotoxicity induced by UPS impairment through regulation of the TBK1-p62 pathway in TDP-43 proteinopathies (Lee, Jeon, et al.,2020).
Emerging protein kinase inhibitors for the treatment of rheumatoid arthritis
Published in Expert Opinion on Emerging Drugs, 2021
Penélope Esther Palominos, Ilka Benedet Lineburger, Ricardo Machado Xavier
The Janus Kinase (JAK) family is composed by four members: JAK 1, JAK 2, JAK 3 and tyrosine kinase 2 (TYK 2) [30]. When a type I or type II cytokine binds to its receptor, JAKs become activated and phosphorylate the receptor; subsequently, a signal transducer and activator of transcription (STAT protein) is recruited to the site, phosphorylated and activated, and finally, the STAT dimers translocate to the nucleus and regulate gene expression. This is often called the JAK-STAT pathway in the signaling cascade [31]. Diverse cytokine receptors use distinct combination of JAKs to activate different programs in cells [32]. In RA, IL-6 is a key pro-inflammatory cytokine and activates the acute-phase response, lymphocyte growth and activation and bone resorption through JAK 1 and JAK 2. Thus, the mitigation of IL-6 inflammatory effects through JAKs inhibition has the potential to limit inflammatory clinical manifestations and radiographic progression in RA patients.