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Computational Biology and Bioinformatics in Anti-SARS-CoV-2 Drug Development
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Cathepsin L, which is involved in SARS-CoV-2 endocytosis entry [112], serves as one more potential therapeutic option for COVID-19 [113]. The main entry pathway for SARS-CoVs is receptor-mediated endocytosis, in which adaptor-associated kinase 1 (AAK1) and cyclin G-associated kinase (GAK) play key roles in receptor-mediated endocytosis and clathrin-mediated trafficking, respectively. Since AAK1 and GAK regulate intracellular viral trafficking during entry, assembly, and release of RNA viruses, inhibition of their activity represents a promising therapy for COVID-19 [87]. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2) synthesized in late endosomes by the phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates the dynamic process of endosome maturation [114, 115]. Therefore, inhibition of PIKfyve represents a useful strategy to modulate infection by SARS-CoV-2 and viruses that enter through endocytosis [116].
Regulation of Growth of Airway Smooth Muscle by Second Messenger Systems
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
To date, two phosphoinositide (PI) pathways have been characterized. In the canonical PI pathway, activation of phosphatidylinositol-specific PLC hydrolyzes PIP2 to IP3 and DAG. In the 3-phosphoinositide pathway, activation of phosphatidylinositol 3-kinase (PtdIns 3-kinase), which may be regulated by protein tyrosine kinase activation, phosphorylates phosphatidylinositides at the D3 position of the inositol ring and leads to the formation of phosphatidylinositol 3-phosphate, phosphatidylinositol 3,4-bisphosphate and PtdIns 3,4,5-P3 (Figure 2).29–32
Endolysosomal Patch Clamping
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Cheng-Chang Chen, Christian Grimm, Christian Wahl-Schott, Martin Biel
The endolysosomal system is a series of membrane-bound organelles which is required for maintaining physiological functions of the cell, including transport of cargo molecules from the extracellular environment into the intracellular space (endocytosis) and vice versa (exocytosis and recycling). Endolysosomes are highly dynamic and belong to the smallest organelles in the cell. The size of these intracellular organelles is between 100 nm and 1,000 nm in diameter. Endolysosomal organelles are categorized into different subgroups including recycling endosomes (RE), early endosomes (EE), late endosomes (LE) and lysosomes (LY). It is widely accepted that phagosomes, autophagosomes, secretory vesicles, melanosomes (in melanocytes) and synaptic vesicles (in neurons) are also closely associated with the endolysosomal system. The endolysosomes can be classified by their specific membrane proteins, such as Ras-related proteins (Rab). For example, Rab11 is one of the most common membrane proteins of recycling endosomes; EEA1 and Rab5 proteins usually localize to early endosomes; Rab7 and Rab9 proteins are mainly localized on late endosomes and lysosomes. Likewise, different lipid compositions have also been assessed to identify individual stages of endolysosomes, e.g. phosphoinositides, such as phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], are thought to be mainly localized to LE/LY, and phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] are primarily found on EE and the plasma membrane (Li et al., 2013). In the maturation pathway of endolysosomes, the pH in the lumen decreases gradually from neutral to acidic and from EE to LE/LY. After acidification of the luminal environment, endocytosed materials are degraded by hydrolytic cleavage in lysosomes.
Investigate the role of PIK3CA gene expression in colorectal polyp development
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Ameer Ali Imarah, Rana Ahmed Najm, Haider Ali Alnaji, Saleem Khteer Al-Hadraawy, Abbas F. Almulla, Hussein Raof Al-Gazali
When colonic adenomas grow larger than 2 centimeters in diameter, they can be a precursor to colorectal adenocarcinoma, making them therapeutically significant [8]. The severity of this type of polyps came from the ability to cumulate mutations associated with cell cycle control over years [1] and PIK3CA, one of these genes [9]. The phosphatidylinositol 3-kinases (PI3Ks) are involved in signaling pathways important for tumorigenesis, including those involved in apoptosis, proliferation, and migration [10]. Phosphoinositide-3-kinase, catalytic alpha polypeptide (PIK3CA), is an integral member of the lipid kinase family, encoding the p110 catalytic subunit of the kinase [11]. PIK3CA gene is located on chromosome 3 long arm (3q26.32) and is involved in cell control via expression to catalytic subunit p110 in phosphatidylinositol 3 Kinase. Phosphoinositide 3 The kinase enzyme interacts with phosphatidylinositol-3-phosphate, a membrane component, to catalyze the phosphorylation of AKT, which then activates the signaling pathway. Because the activation of this pathway depends on outside signals like growth factors, this gene is classified as a proto-oncogene [12].
Dexpanthenol may protect the brain against lipopolysaccharide induced neuroinflammation via anti-oxidant action and regulating CREB/BDNF signaling
Published in Immunopharmacology and Immunotoxicology, 2022
Gülin Ozdamar Unal, Halil Asci, Yalcın Erzurumlu, Ilter Ilhan, Nursel Hasseyid, Ozlem Ozmen
In this study, the effect of dexpanthenol, a PA derivative, on neuroinflammation in brain, cerebellum, and hippocampus tissues secondary to systemic inflammation was investigated by evaluating diverse parameters. It is a known fact that in the case of LPS-induced sepsis, infiltration of the BBB by inflammatory cells can cause damage to brain tissues such as the cortex, cerebellum, and hippocampus by increasing the permeability of this barrier [16]. It can increase the synthesis of proinflammatory cytokines from cells by activating intracellular mechanisms such as NF-kappa B (NF-kB)or MAPK signaling mediated by TLR-4, which is the cell surface receptor of LPS transported to the brain tissue through blood [17,18]. To prevent these damages, the body has antioxidant and anti-inflammatory natural response mechanism [19]. For instance, it reduces oxidative stress by increasing the level of antioxidant enzymes such as superoxide dismutase, catalase and reduces neuroinflammation by increasing brain tissue-specific CREB-mediated BDNF levels. Phosphatidylinositol 3-phosphate (PI3K) induction can modulate BDNF related gene regulation by activating NF-kB and CREB transcription factors as neurogenesis and suppression of inflammation (Figure 7) [3].
An evaluation of buparlisib for the treatment of head and neck squamous cell carcinoma
Published in Expert Opinion on Pharmacotherapy, 2021
Nicholas Lenze, Bhisham Chera, Siddharth Sheth
PI3K enzymes are categorized into three classes according to structure, substrate preference, and function. Class I PI3Ks are heterodimers consisting of a regulatory subunit and a catalytic subunit. These are further subcategorized by their catalytic subunits: class IA (PI3Kα, PI3Kβ, PI3Kδ) or class IB (PI3Kγ) [9,10]. Class IA consists of three catalytic subunits isoforms (p110α, p110β, and p110δ) which are encoded by PIK3CA, PIK3CB, and PIK3CD, respectively. Class IA has five variants of the regulatory subunit: p85α, p55α, p50α, p85β, and p55δ. Class IB consists of the catalytic subunit (p110γ), which is encoded by PIK3CG. Class IB has two variants of the regulatory subunit: p101 and p76. Class II PI3Ks are monomers of catalytic isoforms and lack regulatory subunits. Class II PI3Ks are involved in angiogenesis, endocytosis, and insulin stimulation [11]. Class III PI3Ks are heterodimers of the catalytic regulatory subunit, and they convert phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI3P). The Class III PI3Ks function in autophagy induction [12].