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Basic Thermal Physiology: What Processes Lead to the Temperature Distribution on the Skin Surface
Published in Kurt Ammer, Francis Ring, The Thermal Human Body, 2019
According to the current theory, active cutaneous vasodilation is based on the action of transmitter substances, released from sympathetic nerve terminals, on endothelial cells and smooth muscle cells of blood vessels [13]. Three transmitter substances acetylcholine (Ach), the vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are involved. Ach binds to a muscarinic receptor- 3 (M3) at the endothelial cells, while PACAP connects to the pituitary adenylate cyclase-activating peptide 1 receptor (PAC1) or the vasoactive intestinal peptide receptor 1 or 2 (VPAC1 or VPAC2 of smooth muscle cells. VIP binds also to the muscle cell via VPAC1 or VPAC2 and seems to act on mast cells to release histamine that binds via histamine-1 receptors (H1) to endothelial cells.
Pathological Evaluation and Biochemical Characterization of Peptide Receptors Other Than Somatostatin Receptors as Potential Tumor Targets for Radionuclide Diagnosis and Therapy
Published in Marco Chinol, Giovanni Paganelli, Radionuclide Peptide Cancer Therapy, 2016
Giuseppe Pelosi, Michelle Masullo, Giuseppe Viale
Despite the considerable knowledge on VIP/PACAP receptors and mRNA expression in neoplasms gathered from the evaluation of tumor cell lines (94–96), relatively few studies are available thus far concerning human tumors (34). VPAC1 receptor has been found in a variety of carcinomas of the lung, stomach, colonrectum, breast, prostate, pancreas, liver, and urinary bladder (34), as well as in most ileal and bronchial carcinoids, insulinomas, gastrinomas, glucagonomas, and VIPomas (5), whereas VPAC2 receptors are distributed in mesenchymal neoplasms, such as leiomyomas (11), and gastrointestinal stromal tumors (97), in meningiomas, and less frequently in carcinoids, insulinomas, gastric and breast cancer, and pheochromocytoma (34). PAC1 receptor expression is more ubiquitous, being especially encountered in neoplasms of neuroendocrine lineage, such as gliomas, neuroblastomas, pituitary adenomas (98,99), and paragangliomas (11), but also in non-neuroendocrine tumors, such as endometrial carcinoma (11), meningioma, and breast cancer, and rarely in cancers of the stomach, liver, colon-rectum, thyroid, and prostate (34). A uniformly abundant expression of all the VIP/PACP receptor subtypes is an exclusive feature of glioblastomas (34), whereas medullary carcinomas of the thyroid are among the rare tumors not expressing any type of VIP/PACAP receptors (100).
Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Asmaa E. Kassab, Ehab M. Gedawy, Mohammed I. A. Hamed, Ahmed S. Doghish, Rasha A. Hassan
One of the hallmarks of cancer is the ability of cancer cells to avoid apoptosis, permitting unchecked proliferation3. Therefore, reactivation of apoptosis in cells with defective apoptotic pathways is a promising anticancer strategy. Compounds such as Bcl-2 inhibitors (ABT-737), XIAP inhibitors (SM-164), and p53-MDM2 disruptors (Nutlins), act specifically on proteins within the apoptotic cascade, actuating apoptosis and driving to death of cancer cells4–6. Although tolmetin showed minor activity, tolmetin hydrazone and thiosemicarbazide derivatives Ia and Ib (Figure 1) exhibited anticancer activity against colon (HT-29) and prostate (PC-3) cancer cell lines, respectively, due to the activation of caspase-8 and caspase-9 involved in the apoptotic pathway7,8. Moreover, procaspase-3 levels are elevated in certain cancers, including lymphomas, leukemias, melanomas, pancreatic, liver, lung, breast, and colon cancers9–14. Procaspase-Activating Compound-1 (PAC-1, Figure 1) reinforces the enzymatic activity of procaspase-3 in vitro, induces apoptotic cell death in cancer cells15. Structure-activity relationship (SAR) studies revealed that the activity of PAC-1 in vitro and in cell culture is dependent on the presence of the o-hydroxy N-acyl hydrazone moiety (highlighted in Figure 1), a structural motif known to participate in Zn2+ metal chelation16,17.
Diagnosis of platelet function disorders: A standardized, rational, and modular flow cytometric approach
Published in Platelets, 2018
Oliver Andres, Katja Henning, Gabriele Strauß, Annerose Pflug, Georgi Manukjan, Harald Schulze
Since platelets of patients with AML under induction therapy exhibit a known hyporeactivity [18], we investigated a cohort of 15 adult patients in this treatment phase. Even though these patients showed broad variation in platelet size (FSC) and granularity (SSC), platelets seemed to be overall faintly smaller and less granulated (Figure 4A). Expression of the platelet fibrinogen, laminin and fibronectin receptors was markedly decreased in most patients. The GPIb-IX-V complex was less affected and showed normal expression levels in the majority of patients (Figure 4A). However, in comparison to healthy individuals, platelets of these patients were generally hyporeactive as neither ADP nor TRAP6 were capable to induce adequate neo-exposition of CD62P and CD63 nor activated CD41/CD61 as shown by reduced PAC-1 antibody binding (Figure 4B). In five patients, suboptimal doses of TRAP6 did not result in any PAC-1 binding. As platelet calcium mobilization was normal in all four tested individuals, hyporeactivity could not be attributed to early signaling pathways (Figure 4C left). Mepacrine loading was significantly decreased in each of the three investigated patients, whereas mepacrine release appeared intact (Figure 4C right).
Design, synthesis, and evaluation of novel N'-substituted-1-(4-chlorobenzyl)-1H-indol-3-carbohydrazides as antitumor agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Le Cong Huan, Duong Tien Anh, Pham-The Hai, Lai Duc Anh, Eun Jae Park, A Young Ji, Jong Soon Kang, Do Thi Mai Dung, Dao Thi Kim Oanh, Truong Thanh Tung, Dinh Thi Thanh Hai, Sang-Bae Han, Nguyen-Hai Nam
As can be observed in Figure 3, 4b, 4f, 4g, and 4i were identified as potential procaspase-activating compounds, with activity up to 150–300 times higher than PAC-1. They also showed good cytotoxicity against three cancer cell lines (SW620, PC3, and NCI-H23), especially 4f with IC50 of 0.005–0.011 µM which is significantly higher than that of PAC-1. These compounds are therefore considered as potential hit compounds and needed to be explored for their structure–activity relationships that are useful for further hit-to-lead optimisation. To do so, these four derivatives were docked into the active site of procaspase enzymes taking into account the studies reported elsewhere.