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Neuropeptide Regulation of Ion Channels and Food Intake
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
In both POMC and AgRP neurons, KATP channels are modulated by ATP as well as leptin and insulin. Insulin activates KATP channels on AgRP neurons by stimulating the phosphoinositide 3-kinase (PI3K) signaling pathway (Qiu et al. 2014). Leptin also utilizes the PI3K pathway to hyperpolarize cells via the activation of KATP channels (Belgardt, Okamura, and Bruning 2009). In orexin neurons, leptin electrically silences the cell via indirect activation of KATP channels (Goforth et al. 2014). In addition to receptors for peripherally secreted peptides, some neuropeptide receptors are also coupled to KATP channels for the modulation of neuronal activity in the nervous system. In the arcuate nucleus of the hypothalamus, GLP-1 receptor activation by the selective agonist liraglutide inhibits NPY neurons through activation of protein kinase A (PKA)-dependent KATP channels (He et al. 2019). In the dorsal motor nucleus of the vagus, activation of MC4R by agonist MTII and THIQ hyperpolarizes cholinergic neurons through activating KATP channels (Sohn et al. 2013). Also, KATP channels are required for GLP-1 modulation of peripheral cells (Light et al. 2002; Aizawa et al. 1998).
1,3-Diphenyl-2-Propene-1-One-Based Natural Product Antidiabetic Molecules as Inhibitors of Protein Tyrosine Phosphatase-1B (PTP-1B)
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Vivek Asati
The kinase enzyme, phosphoinositide 3-kinases (PI3K) downstream the metabolic signaling by phosphorylating the substrate PI to phosphatidylinositol biphosphate (PIP2), thereby activates the protein 3-phosphoinositide-dependent protein kinase-1 (PDK1).16 This cascade activates protein kinase-B (PKB) which is a sole component in the enrichment of glucose uptake by stimulating insulin-dependent GLUT4 translocation (Fig. 7.1).17
Breast Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Amy Case, Gwenllian Edwards, Catherine Pembroke
PIK3CA mutations have been found in over 40% of estrogen receptor-positive breast cancers.168 PIK3CA encodes the alpha catalytic subunit of PI3K which is a component of phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathway, a pathway with a central role in cell growth, survival, and angiogenesis. Mutations in PIK3CA have been identified as a potential mechanism for endocrine resistance in estrogen receptor-positive breast cancers. Alpelisib is a PI3K inhibitor which has recently been studied in combination with fulvestrant in patients with advanced hormone receptor–positive breast cancers who have received prior treatment with an AI either in the adjuvant or advanced setting. This phase III, randomized study of 572 patients revealed that patients with an identified PIK3CA mutation had a PFS of 11.0 months in the alpelisib plus fulvestrant group compared with 5.7 months in the fulvestrant plus placebo group (HR for progression or death, 0.65; 95%CI, 0.50 to 0.85; p < 0.001). In the cohort without a PIK3CA mutation the hazard ratio was 0.85 (95%CI, 0.58 to 1.25).169 No trial data yet exist on whether the combined use of PIK3CA inhibitors with CDK4/6 inhibitors and AIs would have a synergistic anti-tumor effect.
RGS7 silence protects palmitic acid-induced pancreatic β-cell injury by inactivating the chemokine signaling pathway
Published in Autoimmunity, 2023
Yurong Zhu, Jun Li, Tao Ba, Yuan Sun, Xiangyun Chang
Chemokines can attract immune cells to inflammation sites due to their ability to induce directed chemotaxis of nearby responding cells [38,39]. Chemokines signaling participated in many physiological processes, such as cell migration [40–42], angiogenesis [43–45], cancer dissemination [46–48], and inflammatory response [49,50]. XCL1 and XCL2 are members of the C-chemokine subfamily, which promote inflammatory progression and are involved in a variety of inflammatory diseases [51,52]. Ras-associated protein 1A (Rap1A) is a type of small GTP-binding protein that belongs to the Ras subfamily [53], and plays an essential regulatory role in a variety of cellular processes, including proliferation [54]. PIK3R3 is one of the regulatory subunits of phosphoinositide 3-kinase, which notably affects cell genesis, proliferation, and apoptosis [55–57]. In this study, RGS7 activated the chemokine signaling pathway, showing as increased levels of RAP1A, XCL2, and XCL1, and decreased the levels of AKT3 and PIK3R3 in pancreatic β-cells. Furthermore, inhibition of RAP1A, the key gene of the chemokine signaling pathway, markedly eliminated the negative effect of RGS7 overexpression on pancreatic β-cells. These above data suggested that RGS7 silence protected pancreatic β-cells from PA by inactivating the chemokine signaling pathway.
Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Nehad M. El-Dydamony, Rana M. Abdelnaby, Rasha Abdelhady, Omaima Ali, Mohamed I. Fahmy, Rasha R. Fakhr Eldeen, Amira A. Helwa
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases consisting of three major classes that phosphorylate inositol phospholipids generating the second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3). Of interest is Class I which is frequently associated with cancer development containing four catalytic subunits p110α and p110β which are expressed in all tissues, p110γ, and p110δ which were reported to play an important role in haematological malignancies. The formed PIP3 activates the serine/threonine kinase AKT (PKB) which is considered a central node in this pathway allowing phosphorylation at Thr308 or Ser473 by phosphoinositide-dependent kinase (PDK1). Phosphorylated AKT (p-AKT) is involved in the deregulation of apoptosis, proliferation, and cell metastasis by modulating the phosphorylation of several downstream protein substrates that regulate cell growth.8,9 One of the important downstream proteins is cyclin D1 known to promote cell proliferation through mediating cell progression from G1-phase to S-phase. AKT is known to stabilise cyclin D1 through inactive phosphorylation of GSK3Κβ. This results in GSK3Κβ losing its kinase activity to phosphorylate Thr286 in cyclin D1 which in turn inhibits its cytoplasmic proteasomal degradation6 (Figure 1).
Duvelisib (Copiktra) in relapsed or refractory chronic lymphocytic leukemia: safety and efficacy
Published in Expert Review of Anticancer Therapy, 2021
Liana Nikolaenko, Tingting Liu, Alexey V. Danilov
While many patients with CLL embark on active surveillance following initial diagnosis, the majority eventually require therapy. The decision to initiate treatment is based on the presence of B symptoms, progressive lymphadenopathy, and/or cytopenias, per the IWCLL 2018 criteria [10]. Disease genetic characteristics, in particular, presence or absence of del(17p) or TP53 mutation, age, and performance status help in the selection process of treatment regimen. However, in the current era, novel targeted therapies are often employed across all CLL subtypes. For patients older than 65 years of age or with comorbidities (which constitute the majority of patients with CLL), the NCCN guidelines recommend a Bruton’s tyrosine kinase (BTK) inhibitor (ibrutinib or acalabrutinib) with or without obinutuzumab, an anti-CD20 monoclonal antibody. A combination of venetoclax, a small-molecule inhibitor selectively targeting the BCL-2 antiapoptotic protein, and obinutuzumab, is an alternative approach. In addition to the above, CIT including bendamustine with obinutuzumab or rituximab; or fludarabine, cyclophosphamide and rituximab (FCR) can be used for treatment of fit patients who lack TP53 aberrations. In the relapsed and/or refractory settings, treatment of CLL is expanded to include novel therapies targeting phosphoinositide 3-kinase (PI3K) pathway, including the small-molecule inhibitors idelalisib and duvelisib.