scholarly journals Mel1c Mediated Monochromatic Light-Stimulated IGF-I Synthesis through the Intracellular Gαq/PKC/ERK Signaling Pathway

2019 ◽  
Vol 20 (7) ◽  
pp. 1682
Author(s):  
Shujie Ning ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong ◽  
Yaoxing Chen
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Monochromatic Light ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Erk Signaling ◽  
Sham Operation ◽  
Intracellular Signaling Pathway ◽  
Igf I

Previous studies have demonstrated that monochromatic light affects plasma melatonin (MEL) levels, which in turn regulates hepatic insulin-like growth factor I (IGF-I) secretion via the Mel1c receptor. However, the intracellular signaling pathway initiated by Mel1c remains unclear. In this study, newly hatched broilers, including intact, sham operation, and pinealectomy groups, were exposed to either white (WL), red (RL), green (GL), or blue (BL) light for 14 days. Experiments in vivo showed that GL significantly promoted plasma MEL formation, which was accompanied by an increase in the MEL receptor, Mel1c, as well as phosphorylated extracellular regulated protein kinases (p-ERK1/2), and IGF-I expression in the liver, compared to the other light-treated groups. In contrast, this GL stimulation was attenuated by pinealectomy. Exogenous MEL elevated the hepatocellular IGF-I level, which is consistent with increases in cyclic adenosine monophosphate (cAMP), Gαq, phosphorylated protein kinase C (p-PKC), and p-ERK1/2 expression. However, the Mel1c selective antagonist prazosin suppressed the MEL-induced expression of IGF-I, Gαq, p-PKC, and p-ERK1/2, while the cAMP concentration was barely affected. In addition, pretreatment with Ym254890 (a Gαq inhibitor), Go9863 (a PKC inhibitor), and PD98059 (an ERK1/2 inhibitor) markedly attenuated MEL-stimulated IGF-I expression and p-ERK1/2 activity. These results indicate that Mel1c mediates monochromatic GL-stimulated IGF-I synthesis through intracellular Gαq/PKC/ERK signaling.

scholarly journals Development of Single-Molecule Electrical Identification Method for Cyclic Adenosine Monophosphate Signaling Pathway

Nanomaterials ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 784
Author(s):  
Yuki Komoto ◽  
Takahito Ohshiro ◽  
Masateru Taniguchi
Keyword(s):  
Machine Learning ◽  
Signaling Pathway ◽  
Single Molecule ◽  
Intracellular Signaling ◽  
Second Messengers ◽  
Electrical Conductance ◽  
Structural Difference ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Intracellular Signaling Pathway

Cyclic adenosine monophosphate (cAMP) is an important research target because it activates protein kinases, and its signaling pathway regulates the passage of ions and molecules inside a cell. To detect the chemical reactions related to the cAMP intracellular signaling pathway, cAMP, adenosine triphosphate (ATP), adenosine monophosphate (AMP), and adenosine diphosphate (ADP) should be selectively detected. This study utilized single-molecule quantum measurements of these adenosine family molecules to detect their individual electrical conductance using nanogap devices. As a result, cAMP was electrically detected at the single molecular level, and its signal was successfully discriminated from those of ATP, AMP, and ADP using the developed machine learning method. The discrimination accuracies of a single cAMP signal from AMP, ADP, and ATP were found to be 0.82, 0.70, and 0.72, respectively. These values indicated a 99.9% accuracy when detecting more than ten signals. Based on an analysis of the feature values used for the machine learning analysis, it is suggested that this discrimination was due to the structural difference between the ribose of the phosphate site of cAMP and those of ATP, ADP, and AMP. This method will be of assistance in detecting and understanding the intercellular signaling pathways for small molecular second messengers.

Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2127-2134 ◽  
Author(s):  
Derek S. Sim ◽  
Glenn Merrill-Skoloff ◽  
Barbara C. Furie ◽  
Bruce Furie ◽  
Robert Flaumenhaft
Keyword(s):  
Vascular Injury ◽  
Intracellular Signaling ◽  
Thrombus Formation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
In Vivo Model ◽  
The Status ◽  
Platelet Accumulation ◽  
Camp Levels

Abstract Platelet accumulation at sites of vascular injury is the primary event in arterial thrombosis. Initial platelet accrual into thrombi is mediated by interactions of platelet adhesion receptors with ligands on the injured endothelium or in the sub-endothelial matrix. The role of intracellular signals in initial platelet accumulation at sites of endothelial injury, however, is the subject of debate. We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3′,5′-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation. These studies demonstrate that elevation of basal cAMP levels results in an overall decline in platelet accumulation at the site of vascular injury. In particular, the initial rate of accumulation of platelets is inhibited by elevation of cAMP. Analysis of the kinetics of individual platelets at injury sites using intravital microscopy demonstrates that cAMP directs the rate at which platelets attach to and detach from thrombi. These studies demonstrate that cAMP in circulating platelets controls attachment to and detachment from sites of arteriolar injury. Thus, the status of the intracellular signaling machinery prior to engagement of platelet receptors influences the rate of platelet accumulation during thrombus formation.

scholarly journals Cilostazol Improves Hyperglycemia-Induced Impairment of Angiogenesis by Stimulating Adiponectin/Adiponectin Receptor1/Sirtuin1

2021 ◽  
Author(s):  
Shih-Ya Tseng ◽  
Hsien-Yuan Chang ◽  
Yi-Heng Li ◽  
Ting-Hsing Chao
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Antiplatelet Agent ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Sirtuin 1

Abstract Background: Cilostazol is an antiplatelet agent with vasodilating effects that functions by increasing the intracellular concentration of cyclic adenosine monophosphate. However, the effect of cilostazol on adiponectin is still unclear. Purpose: We investigated the effects of cilostazol on adiponectin/adiponectin receptors and the Sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) signaling pathway to prevent high glucose (HG)-induced impairment of angiogenesis in vitro and in vivo. Methods and Results: Human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HASMCs) were cocultured in HG conditions. Adiponectin concentrations in the supernatant were significantly increased when HASMCs were treated with cilostazol but not significantly changed when only HUVECs were treated with cilostazol. Cilostazol treatment restored the expression of the adipoR1 and SIRT1 proteins and upregulated the phosphorylation of AMPKa1 in the HUVECs treated with HG but not adipoR2. Cilostazol prevented apoptosis and stimulated proliferation, chemotactic motility and capillary-like tube formation in HG-treated HUVECs through the adipoR1/AMPK/SIRT1 signaling pathway. In cilostazol-treated mice, recovery of the blood flow ratio after hindlimb ischemia and circulating CD34+CD45dim cells were significantly attenuated by adipoR1 knockdown but not adipoR2 knockdown. The expression of SIRT1, phosphorylation of AMPKa1/acetyl-CoA carboxylase and Akt/endothelial nitric oxide synthase in ischemic muscles were significantly attenuated by gene knockdown of adipoR1. Conclusions: Cilostazol prevents HG-induced endothelial dysfunction in vascular endothelial cells and enhances angiogenesis in hyperglycemic mice by upregulating the expression of adiponectin/adipoR1 and its SIRT1/AMPK downstream signaling pathway.

scholarly journals Intracellular signaling pathway in dendritic cells and antigen transport pathway in vivo mediated by an OVA@DDAB/PLGA nano-vaccine

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shulan Han ◽  
Wenyan Ma ◽  
Dawei Jiang ◽  
Logan Sutherlin ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Ammonium Bromide ◽  
Transport Pathway ◽  
Antigen Uptake ◽  
Intracellular Signaling Pathway ◽  
Antigen Transport

Abstract Background Poly(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles have potential applications as a vaccine adjuvant and delivery system due to its unique advantages as biodegradability and biocompatibility. Experimental We fabricated cationic solid lipid nanoparticles using PLGA and dimethyl-dioctadecyl-ammonium bromide (DDAB), followed by loading of model antigen OVA (antigen ovalbumin, OVA257-264) to form an OVA@DDAB/PLGA nano-vaccine. And we investigated the intracellular signaling pathway in dendritic cells in vitro and antigen transport pathway and immune response in vivo mediated by an OVA@DDAB/PLGA nano-vaccine. Results In vitro experiments revealed that the antigen uptake of BMDCs after nanovaccine incubation was two times higher than pure OVA or OVA@Al at 12 h. The BMDCs were well activated by p38 MAPK signaling pathway. Furthermore, the nano-vaccine induced antigen escape from lysosome into cytoplasm with 10 times increased cross-presentation activity than those of OVA or OVA@Al. Regarding the transport of antigen into draining lymph nodes (LNs), the nano-vaccine could rapidly transfer antigen to LNs by passive lymphatic drainage and active DC transport. The antigen+ cells in inguinal/popliteal LNs for the nano-vaccine were increased over two folds comparing to OVA@Al and OVA at 12 h. Moreover, the antigen of nano-vaccine stayed in LNs for over 7 days, germinal center formation over two folds higher than those of OVA@Al and OVA. After immunization, the nano-vaccine induced a much higher ratio of IgG2c/IgG1 than OVA@Al. It also effectively activated CD4+ T, CD8+ T and B cells for immune memory with a strong cellular response. Conclusion These results indicated that DDAB/PLGA NP was a potent platform to improve vaccine immunogenicity by p38 signaling pathway in BMDCs, enhancing transport of antigens to LNs, and higher immunity response. Graphical Abstract

scholarly journals Highly sensitive genetically-encoded sensors for population and subcellular imaging of cAMP in vivo

2021 ◽  
Author(s):  
Crystian I Massengill ◽  
Landon Bayless-Edwards ◽  
Cesar C Ceballos ◽  
Elizabeth R Cebul ◽  
Maozhen Qin ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Fluorescence Lifetime Imaging ◽  
Lifetime Imaging ◽  
Highly Sensitive ◽  
Increased Sensitivity ◽  
Resolution Imaging

AbstractCyclic adenosine monophosphate (cAMP) integrates information from diverse G protein-coupled receptors, such as neuromodulator receptors, to regulate pivotal biological processes in a cellular- and subcellular-specific manner. However, in vivo cellular-resolution imaging of cAMP dynamics in neurons has not been demonstrated. Here, we screen existing genetically-encoded cAMP sensors, and further develop the best performer to derive three improved variants, called cAMPFIREs. These sensors exhibit up to ten-fold increased sensitivity to cAMP and a corrected, cytosolic distribution. cAMPFIREs are compatible with both ratiometric and fluorescence lifetime imaging, and can detect cAMP dynamics elicited by norepinephrine at physiologically-relevant, nanomolar concentrations. Imaging of cAMPFIREs in awake mice reveals tonic levels of cAMP in cortical neurons that are associated with wakefulness, and are differentially regulated in different subcellular compartments. Furthermore, enforced locomotion elicits neuron-specific, bidirectional cAMP dynamics, in part, mediated by norepinephrine. Finally, cAMPFIREs also function in Drosophila, suggesting that they have broad applicability for studying intracellular signaling in vivo.

scholarly journals Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain

2021 ◽  
Vol 17 ◽  
pp. 174480692110033
Author(s):  
Travis Okerman ◽  
Taylor Jurgenson ◽  
Madelyn Moore ◽  
Amanda H Klein
Keyword(s):  
Spinal Cord ◽  
Sciatic Nerve ◽  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Morphine Tolerance ◽  
Spinal Nerve ◽  
Intracellular Signaling Pathway ◽  
Spinal Cord Dorsal ◽  
Phosphoinositide 3 Kinase ◽  
Induced Tolerance

Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.

scholarly journals Intracellular Signaling Pathway Activation via TGF-β Differs in the Anterior and Posterior Axis During Palatal Development

2016 ◽  
Vol 25 (2) ◽  
pp. 195-204
Author(s):  
Arisa Higa ◽  
Kyoko Oka ◽  
Michiko Kira-Tatsuoka ◽  
Shougo Tamura ◽  
Satoshi Itaya ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Intracellular Signaling Pathway ◽  
Pathway Activation ◽  
Palatal Development

scholarly journals Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Kaley M. Wilburn ◽  
Christine R. Montague ◽  
Bo Qin ◽  
Ashley K. Woods ◽  
Melissa S. Love ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Adenylyl Cyclase ◽  
Cholesterol Metabolism ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Signaling ◽  
Camp Synthesis ◽  
Pharmacokinetic Properties ◽  
Bacterial Utilization

There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3’, 5’-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required for cholesterol metabolism. Finally, in this work the pharmacokinetic properties of Rv1625c agonists are optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a novel role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.

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