Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure
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PROVIDER: PRJNA1005312 | ENA |
REPOSITORIES: ENA
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Project description:In acute liver failure (ALF), liver regeneration deficiency is frequently observed, which is the leading cause of ALF and has a high mortality rate. If not treated promptly, ALF may lead to the need for a liver transplant due to limited treatment options. Here, we report the discovery of a 4-guanidino-n-butyl syringate (Leonurine), which has a hepatoprotective effect and can promote regeneration in mouse liver and human embryonic stem cell-induced liver organoids after acute liver injury (ALI). Leonurine demonstrated excellent safety and pharmacokinetics in vivo and was able to significantly reduce mortality in mice after administration of a lethal 24-hour dose of thioacetamide (TAA) or acetaminophen (APAP), which is fully protective compared to treatment with N-acetyl cysteine (NAC) loss of protection. We have synthesized a Leonurine biotinylation probe and have identified adiponectin receptor 2 (AdipoR2), a progesterone and adiponectin receptor family member, as a selective binding partner of Leonurine with a dissociation constant at micromolar levels. Depleting nitric oxide (NO) levels in hepatocytes is the leading cause of liver regeneration deficiency following ALI. The reduction of AdipoR2-Calmodulin (CaM)-endothelial nitric oxide synthase (NOS3) complex activity decreased NO production in hepatocytes, a significant contributor to the ALF phenotype induced by liver regeneration deficiency. Leonurine can form a guanidine-arginine pairing with the AdipoR2 arginine 335 (R335) site to enhance the activity level of AdipoR2 and increase the NO content in hepatocytes, promoting liver regeneration, and quickly antagonize ALF. The oxygen atom of AdipoR2 tyrosine 274 (Y274) interacts with the oxygen atom of Leonurine through hydrogen bonds, significantly enhancing the hydrophobicity of AdipoR2 arginine 275 (R275) residue, thereby activating its surface activity, reducing the molecular switch stability of R275 and aspartate 117 (D117) configurations, which increased the hydrophilic effect, thus regulating Ca2+ inflow but not significantly affecting the AMP level of hepatocytes and finally increasing CaM activity to upregulate the activity of the AdipoR2-CaM-eNOS complex, resulting in increased NO production. In vitro, the knockdown of AdipoR2 or the introduction of a mutant that does not bind to Leonurine blunts the effect of Leonurine's up-regulation of AdipoR2-CaM-eNOS complex activity. In vivo, the knock-out of AdipoR2 or NOS3 eliminated liver protection and regeneration, which Leonurine mediates. The evidence suggests that Leonurine possesses therapeutic benefits for patients without significant adverse effects. Our findings indicate that Leonurine possesses the potential to provide a rapid-acting treatment for the exercise of therapeutic benefits in ALF.
2024-11-09 | GSE240824 | GEO
Project description:To identify direct CaMKII-dependent downstream genes of H3S28p we used chromatin-immunoprecipitation followed by massive parallel DNA sequencing (ChIPseq) analysis of isolated adult murine cardiomyocytes from CamKII WT as well as from CaMKIIγ/CaMKIIδ double knockout (DKO) . DKO and WT cells were subjected to long-term Iso treatment for 24 h to maximize CaMKII-dependent H3S28p.
2019-06-13 | E-MTAB-8011 | biostudies-arrayexpress
Project description:Tetradesmus sp.198
| PRJNA1137156 | ENA
Project description:MLC1 is membrane protein highly expressed by brain perivascular astrocytes. Mutations in MLC1 account for megalencephalic leukoencephalopathy with subcortical cysts (MLC), an incurable leu-kodystrophy characterized by macrocephaly, brain edema and cysts, myelin vacuolation and as-trocyte swelling, that cause cognitive and motor dysfunctions. MLC pathological models demon-strated that in astrocytes MLC1 mutations affect the swelling-activated Cl- currents (ICl,swell) medi-ated by volume-regulated anion channel (VRAC) and the consequent regulatory volume decrease (RVD), and also induce the abnormal activation of intracellular signaling pathways linked to in-flammation/osmotic stress. Despite this knowledge, MLC1 function and MLC molecular pathogen-esis are still elusive. Following the observations that calcium regulates all the MLC1-modulated processes and that intracellular Ca2+ homeostasis is altered in MLC1-defective cells, we applied biochemistry, molecular biology, video imaging, electrophysiology and proteomic techniques on cultured human and mouse astrocytes to study MLC1/calcium signaling relationships. We revealed that MLC1 binds the Ca2+ effector proteins calmodulin (CaM) and Ca2+/CaM-dependent protein ki-nase II (CaMKII) and, as result, changes its assembly, localization and functional properties in re-sponse to Ca2+ influx or release. Noteworthy, CaM binding to the COOH terminal promotes MLC1 trafficking to the plasma membrane, while CaMKII phosphorylation of the NH2 end potentiates MLC1 activation of ICl,swell, that are critically important for RVD. Overall, our results show that MLC1 is a Ca2+-regulated protein linking VRAC function and volume regulation to Ca2+ signaling in astro-cytes, opening new avenues to clarify the defective molecular pathways of MLC and other diseas-es where astrocyte swelling and brain edema underlie the pathological process. In this contest we submit here the MS data showing MLC phosphorylation on Threonine 17.
2022-10-13 | PXD030549 | Pride
Project description:HepG2-NTCP_HA:HBc cells stably express HBV core antigen. Treatment of these cells with CAM-A compounds (but not CAM-E) induces the abnormal nuclear aggregation of core leading to cell death via apoptosis in a time dependent manner. The goal of this project is to determine the transcriptomic modifications induced by CAM-A treatment in these cell lines at day 2 and day 3 post-treatment.
2024-10-16 | GSE263292 | GEO
Project description:Effect of CaM overexpression on Arabidopsis transcriptome. Unlike animals, plants are immobile and cannot simply move away from unfavourable environments and thus have developed complex mechanisms to respond to and sense biotic and abiotic signals. These stimuli often lead to tightly controlled changes in cytoplasmic free calcium concentration [Ca2+]cyt termed "calcium signatures" which are thought to be, at least partly, responsible for the specificity of plant responses to the environment. However little is known about how exactly these calcium signatures are decoded into specific end-responses. Calmodulin (CaM) is the most well characterised Ca2+ binding protein and is the primary sensor of changing [Ca2+]. Upon binding Ca2+ CaM undergoes a conformational change allowing binding and activation of a wide variety of target proteins. In plants CaM exists in gene families encoding multiple isoforms. The expression of individual CaM genes can be differentially regulated and isoforms may be differentially localised. Furthermore specific isoforms can bind and activate different target proteins. These features of plant CaM allow the possibility of specificity during calcium signalling in response to specific stimuli. The effect of overexpression of four CaM protein isoforms on the Arabidopsis thaliana transcriptome will be investigated. Ten day old transgenic Arabidopsis seedlings (containing estradiol inducible CaM overexpression constructs) were induced for 9hrs in 5uM estradiol with appropriate water (0.025% DMSO) and empty vector controls.
2008-02-15 | E-NASC-65 | biostudies-arrayexpress
Project description:Pseudomonas putida strain:Rs-198 | isolate:Rs-198 Raw sequence reads
| PRJNA780237 | ENA
Project description:We previously found that mice with heterozygous knockout of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII HKO mice) show various dysregulated behaviors, including cyclic variations in locomotor activity (LA), suggesting that alpha-CaMKII HKO mice may serve as an animal model showing infradian oscillation of mood. We performed gene expression microarray analysis of dentate gyrus from alpha-CaMKII HKO mice. Mice were selected for the sampling such that their LA levels varied among the mice.
2016-03-29 | GSE68293 | GEO
Project description:Purpose: The goal of this study was to use deep sequencing to identify all splice variants of Calcium/calmodulin-dependent kinase II (CaMKII) expressed in the human hippocampus. Methods: Transcripts of CaMKII-encoding genes (CAMK2A, CAMK2B, CAMK2G, and CAMK2D) were sub-amplified by PCR from total RNA extracted from human hippocampal tissue samples from 3 donors. Illumina sequencing libraries were constructed by PCR from these initial pools of amplicons and sequenced on an Illumina MiSeq instrument. Sequencing reads passing quality controls were clustered on the basis of sequence identity or near-identity. Consensus sequences of clusters were mapped with known exons of CaMKII genes to identify the splice variant represented by each cluster. Donor 1 replicate 2, Donor 2, and Donor 3 libraries from genes CAMK2B, CAMK2G, and CAMK2D were first sequenced on a MiSeq Nano flow cell, then re-pooled for read balancing and sequenced again of a full-size MiSeq flow cell. For each library, reads from Nano and full-size flow cells were combined for subsequent analysis. Results: We perfomed the first comprehensive survey of CaMKII transcripts expressed in individual tissue samples (human hippocampus). We detected a total of 79 splice variants of the four human CaMKIIs: CaMKIIα (3), CaMKIIβ (30), CaMKIIγ (24), and CaMKIIδ (22), across tissue samples from 3 donors. This represents the vast majority of possible in-frame CaMKII splice variants (Sloutsky and Stratton, European Journal of Neuroscience, 2020; https://doi.org/10.1111/ejn.14761).
2020-07-21 | GSE154030 | GEO
Project description:We previously found that mice with heterozygous knockout of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII HKO mice) show various dysregulated behaviors, including cyclic variations in locomotor activity (LA), suggesting that alpha-CaMKII HKO mice may serve as an animal model showing infradian oscillation of mood. We performed gene expression microarray analysis of dentate gyrus from alpha-CaMKII HKO mice. Mice were selected for the sampling such that their LA levels varied among the mice. Dentate gyrus RNA isolated from alpha-CaMKII HKO mice.
2016-03-29 | E-GEOD-68293 | biostudies-arrayexpress