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Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
What other sites could be involved in altered insulin secretion? There have been a number of suggestions. There is an overall decrease in islet mitochondrial DNA content, but no major deletions or restriction fragment polymorphisms,324 and it was suggested that reduced levels may occur as a consequence of the disturbed metabolic environment. Roles for reductions in ADP-ribosyl cyclase activity and intracellular cyclic ADP-ribose levels,325and reduced expression of a Ca2+-ATPase, SERCA-3, which is involved in the active uptake of cytosolic Ca2+ into the endoplasmic reticulum, have also been reported.326 Additionally, Leckstrom et al.327 showed that the plasma islet amyloid polypeptide (IAPP)/insulin ratio was higher in GK rats after glucose injection, equivalent to a relative hypersecretion of IAPP. Increased amounts of islet IGF II mRNA and a high-molecular-weight IGF II peptide were found in the 2- and 6-month-old GK rats compared with 1-month-old rats.328 The authors suggested that it could have resulted in the development of fibrosis, and the Nidd/gk1 region of rat chromosome 1, identified by Gauguier et al.303 as a susceptibility locus, contains the IGF II gene. The hyperglycemic-hyperinsulinemic pattern observed in GK rats is also associated with hepatic glucose overproduction, decreased responsiveness to insulin in the basal state, and moderate insulin resistance in muscles and adipose tissues, present by 8 weeks of age in GK females. The origin of insulin resistance has been associated with decreased receptor number.329 However, there is probably also a deficiency in the signal-transduction pathways. Farese et al.330 suggested that diabetic GK rats have a defect in synthesizing or releasing functional chiro-inositol-containing inositol phosphoglycan in adipocytes, and that defective IPG-regulated intracellular glucose metabolism contributes to insulin resistance.
The plant hormone abscisic acid stimulates megakaryocyte differentiation from human iPSCs in vitro
Published in Platelets, 2022
Weihua Huang, Haihui Gu, Zhiyan Zhan, Ruoru Wang, Lili Song, Yan Zhang, Yingwen Zhang, Shanshan Li, Jinqi Li, Yan Zang, Yanxin Li, Baohua Qian
It is generally known that the ERK1/2 pathway is associated with the promotion of cell proliferation[20] and a reduction in apoptosis[39], depending on the cell type and conditions[23]. Some studies have suggested that activation of the ERK 1/2 pathway is required for MK differentiation and the early stages of thrombopoiesis[40, 41]. IGF-1[42] and melatonin[40] function through both ERK1/2 and Akt signaling to promote MK differentiation and proplatelet and platelet release. The intracellularly produced second messengers PKA and cADPR, which are generated by the ABA signaling cascade, promote stem cell precursor expansion downstream of ERK1/2 activation [23]. Additionally, ABA triggers the LANCL2-induced signaling cascade to activate the activation of PKA and the ADP-ribosyl cyclase CD38 [23, 26]. In the presence of ABA from days 0 to 14, we found enhanced activation of AKT and ERK1/2 signaling (Figure 4) involved in HPC and MK differentiation. However, this phosphorylation was significantly inhibited by the PKA inhibitor H89.
CD38: targeted therapy in multiple myeloma and therapeutic potential for solid cancers
Published in Expert Opinion on Investigational Drugs, 2020
Ying Jiao, Ming Yi, Linping Xu, Qian Chu, Yongxiang Yan, Suxia Luo, Kongming Wu
CD38 is identified to have three enzyme activities, NAD+ glycohydrolase (NADase), ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase in 1994 [55], which accounts for the balance of NAD pool. NAD (nicotinamide adenine dinucleotide) is an important coenzyme that regulates various metabolic processes, including glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. As NADase, the main function, CD38 plays an indispensable role in catalyzing the majority of β-NAD and β-NAD derivatives, such as β-NADP and β-NMN, rather than α- NAD or NADH to produce nicotinamide (NAM) and almost stoichiometric ADPR [56,57]. Presented as ADP-ribosyl cyclase, the secondary function, CD38 can convert β-NAD and β-NAD derivatives to cyclic ADP ribosyl (cADPR) and nicotinamide [58]. Furthermore, it can convert cADPR into ADPR as cADPR hydrolase [59]. Both ADPR and cADPR, the second messengers, are involved in calcium signaling to regulate calcium mobilization [60–62]. A study indicates that adenosine catalyzed by CD38 inhibits CD8+ T cell and CD4+ T cell proliferation through the interaction with the specific adenosine receptors on T cells [63].
Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells
Published in OncoImmunology, 2019
Fabio Morandi, Danilo Marimpietri, Alberto L. Horenstein, Maria Valeria Corrias, Fabio Malavasi
Metastatic NB cells in the BM exploit different mechanisms to escape the control of the immune system. The most known are downregulation of HLA molecules along with the expression and/or release of inhibitory molecules (i.e., HLA-G, MICA, B7H3 and calprotectin among the others.9,12,13 However, one of the strategies adopted by different human tumors [i.e. breast cancer,14 melanoma,15,16 prostate cancer,17 and gastric carcinom18] to impair the anti-tumor immune response relays on the local production of the immunosuppressive adenosine (ADO). Extracellular ADO is generated by a set of adenosinergic ectoenzymes, ruling the classical (the first to be identified) and alternative pathways. The first one relies on the metabolism of adenosine 5ʹ-triphosphate (ATP), metabolized by CD39, an ecto-nucleoside-triphosphate-diphosphohydrolase. ATP is converted to adenosine 5ʹ-diphospate (ADP), and the latter molecule into adenosine 5ʹ-monophospate (AMP).19 The alternative pathway starts from the metabolism of nicotinamide adenine dinucleotide (NAD+) operated by CD38, an ectoenzyme with ADP-ribosyl-cyclase/cyclic ADP ribose-hydrolase enzymatic activities, that converts NAD+ to adenosine diphosphate ribose (ADPR).20 The latter molecule may be converted to AMP in the presence of CD203a(PC-1) (an ectonucleotide-pyrophosphatase-phosphodiesterase-1). The same enzyme can also convert ATP to AMP. The two pathways converge to the action of CD73, a 5ʹ-nucleotidase, which converts AMP to AD.21,22