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  • ||||||||||  nitroprusside / Generic mfg., tamoxifen / Generic mfg.
    Preclinical, Journal:  Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice. (Pubmed Central) -  Mar 28, 2024   
    We used mouse models of constitutive endothelial cell-specific Arf6 deletion (Arf6f/- Tie2Cre) and tamoxifen-inducible Arf6 knockout (Arf6f/f Cdh5CreER+)...The impairment in vasodilation was primarily due to attenuated insulin-stimulated NO bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside-mediated vasodilation...Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.
  • ||||||||||  Preclinical, Journal:  ARF6, a component of intercellular bridges, is essential for spermatogenesis in mice. (Pubmed Central) -  Jan 20, 2024   
    Furthermore, germ cell-specific inactivation using the Ddx4-CreERT2 results in the same testicular morphological phenotype, showing the germ cell-intrinsic requirement of ARF6. Therefore, ARF6 is essential for spermatogenesis in mice and this function is conserved from Drosophila to mammals.
  • ||||||||||  The roles of insulin in stimulating ARF6-Rac1-mediated neurite outgrowth (WCC Halls A-C) -  Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_12579;    
    The phosphorylation of FE65 S459 further tiggers ARF6-Rac1-mediated neurite outgrowth by potentiate FE65-ARF6 interaction. Our findings reveal a novel mechanism that insulin stimulates neurite outgrowth.
  • ||||||||||  NAV-2729 / Navigen
    Addiction to Small Gtpase ARF6-Mediated Sphingolipid Homeostasis By AML but Not the Host (SDCC - Halls G-H) -  Nov 3, 2023 - Abstract #ASH2023ASH_1789;    
    Our findings reveal a novel mechanism that insulin stimulates neurite outgrowth. Surprisingly, Tamoxifen-induced whole body KO of Arf6 in adult Arf6 f/f ;Rosa-CreERT 2 mice led to healthy and grossly normal mice with a normal lifespan...Both NAV-2729 and A6-4471 inhibited AML cell line proliferation and reduced primary AML cell colony formation in lower
  • ||||||||||  Review, Journal:  Arf6 as a therapeutic target: Structure, mechanism, and inhibitors. (Pubmed Central) -  Oct 6, 2023   
    In addition, Arf6 inhibitors and mechanism of action are listed in the table. This review further emphasizes the crucial roles in drug resistance and attempts to offer an outlook of Arf6 in cancer therapy.
  • ||||||||||  Journal:  Aging Differentially Affects Axonal Autophagosome Formation and Maturation. (Pubmed Central) -  Jul 19, 2023   
    Our data indicate that early aging does not negatively impact autophagic vesicle transport nor the later stages of autophagy. However, alterations in autophagic vesicle transport efficiency during late aging reveal that aging differentially impacts distinct aspects of neuronal autophagy.Abbreviations: ACAP3: ArfGAP with coiled-coil, ankyrin repeat and PH domains 3; ARF6: ADP-ribosylation factor 6; ATG: autophagy related; AVs: autophagic vesicles; DCTN1/p150: dynactin 1; DRG: dorsal root ganglia; GAP: GTPase activating protein; GEF: guanine nucleotide exchange factor; LAMP2: lysosomal-associated protein 2; LysoT: LysoTracker; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK8IP1/JIP1: mitogen-activated protein kinase 8 interacting protein 1; MAPK8IP3/JIP3: mitogen-activated protein kinase 8 interacting protein 3; mCh: mCherry; PE: phosphatidylethanolamine.
  • ||||||||||  NAV-2729 / Navigen
    Preclinical, Journal:  ARF6 is a host factor for SARS-CoV-2 infection in vitro. (Pubmed Central) -  Jun 25, 2023   
    By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but on cholesterol...In addition, pharmacological inhibition of ARF6 with the small molecule NAV-2729 showed a dose-dependent reduction of viral infection...This highlighted a role for ARF6 in multiple cell contexts. Together, these experiments point to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2.
  • ||||||||||  Journal:  Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis. (Pubmed Central) -  May 14, 2023   
    Our findings suggest that the atheroprotection afforded by Arf6 heterozygosity may result from reduced immune cell migration (all p?0.005) as well as endothelial and vascular smooth muscle cell proliferation (both p?0.001) but independent of changes in circulating lipids (all p?0.40). These findings demonstrate a critical role for Arf6 in the development and severity of atherosclerosis and suggest that Arf6 inhibition can be explored as a novel therapeutic strategy for the treatment of atherosclerotic CVD.
  • ||||||||||  doxorubicin hydrochloride / Generic mfg.
    Journal:  Fine-Tuned Polymer Nanoassembly for Co-Delivery of Chemotherapeutic Drug and siRNA. (Pubmed Central) -  Jan 15, 2023   
    Furthermore, the as-obtained polymersome could efficiently co-deliver doxorubicin hydrochloride (DOX) as a hydrophilic chemotherapeutic model and siRNA against ADP-ribosylation factor 6 (siArf6) as an siRNA model into cancer cell via lysosomal pH-triggered payload release...PC-3 prostate cell was synergistically killed by the DOX- and siArf6-coloading polymersome (namely PLD@DOX/siArf6). PLD@DOX/siArf6 may serve as a robust nanomedicine for anti-cancer therapy.
  • ||||||||||  Review, Journal:  Orchestration of mesenchymal plasticity and immune evasiveness via rewiring of the metabolic program in pancreatic ductal adenocarcinoma. (Pubmed Central) -  Nov 22, 2022   
    In this review, we summarize our recent understanding of how PDAC cells acquire and augment mesenchymal features via metabolic and immunological changes during tumor progression, and how mesenchymal malignancies induce metabolic network rewiring and facilitate an immune evasive TME. In addition, we also present our recent findings on the interesting relevance of the small G protein ADP-ribosylation factor 6-based signaling pathway driven by KRAS/TP53 mutations, inflammatory amplification signals mediated by the proinflammatory cytokine interleukin 6 and RNA-binding protein ARID5A on PDAC metabolic reprogramming and immune evasion, and finally discuss potential therapeutic strategies for the quasi-mesenchymal subtype of PDAC.
  • ||||||||||  Biomarker, Journal:  Application of an antibody microarray for serum protein profiling of coronary artery stenosis. (Pubmed Central) -  Oct 14, 2022   
    Cadherin-P, interleukin-5, glutathione S-transferase Mu, and neuronal nitric oxide synthase were sex-independently increased in Group A compared with those in group B. The microarray data on cadherin-P were externally validated in an independent group D using ELISA. Fibroblast growth factor-1, FGF-2, collagen II, granulocyte-macrophage colony-stimulating factor, IL-1 alpha, angiopoietin-2, granulocyte colony-stimulating factor, lymphocyte cell-specific protein tyrosine kinase, and IkappaB kinase b were increase in men in group A compared with group B. Cyclin-dependent kinase 1, DNA fragmentation factor subunit alpha DFF45/ICAD, adenovirus type 2 E1A, calponin, ADP-ribosylation factor-6, muscle-specific actin, thyroid hormone receptor alpha, and alpha-methylacyl-CoA racemase were specifically increased in women in Group A compared with group B. Alterations in the levels of specific proteins may point to the signaling pathways contributing to coronary atherosclerosis, and these proteins will be useful biomarkers for the progression of cardiovascular diseases.
  • ||||||||||  Journal:  The Arf6/PIP5K pathway activates IKACh in cigarette smoke mediated atrial fibrillation. (Pubmed Central) -  Sep 24, 2022   
    In HEK293 cells stably transfected with Kir3.1 and Kir3.4, the molecular correlates of I, CS exposure increased the expression of the Kir3.1 and Kir3.4 proteins at the cell surface, activated Arf6 and increased the I current. Inhibition of PIP5K, or of Kir3.1/Kir3.4 trafficking via Arf6 abrogated the CS effects on I. Cigarette smoke modifies the atrial electrophysiological substrate, leading to arrhythmogenesis, in part, through I activation via an Arf6/PIP5K dependent pathway.
  • ||||||||||  Journal:  AMPK promotes Arf6 activation in a kinase-independent manner upon energy deprivation. (Pubmed Central) -  Sep 20, 2022   
    We further identified the binding motif in the C-terminal regulatory domain of AMPK that is responsible for promoting Arf6 activation and thus inducing cell migration and invasion. These findings reveal a noncanonical role of AMPK in which its C-terminal regulatory domain serves as a GEF for Arf6 during energy deprivation.
  • ||||||||||  Journal:  CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway. (Pubmed Central) -  Apr 12, 2022   
    Moreover, recipient MCF-7 cells could effectively uptake these miR-760-rich exosomes that significantly promoted proliferation, tumor growth in vivo, migration, invasion, and chemoresistance by activating ARF6-mediated Src/PI3K/Akt signaling and the epithelial-mesenchymal transition (EMT) pathway. Together, our results support that exosomal miR-760 secreted by CCL18-stimulated high metastatic BC cells promoted the malignant behaviors in low metastatic BC cells by up-regulating the ARF6-mediated Src/PI3K/Akt signaling pathway.
  • ||||||||||  Journal:  A polymer‑calcium phosphate nanocapsule for RNAi-induced oxidative stress and cascaded chemotherapy. (Pubmed Central) -  Dec 28, 2021   
    Blocking Arf6 signal pathway of cancer cells led to their mitochondrial aggregation and subsequently induced a burst of ROS for oxidative catastrophe, which further triggered the cascaded CPT chemotherapy via the breakage of ROS-labile dithioketal linker. This strategy of RNAi-induced oxidative catastrophe and cascaded chemotherapy resulted in a significant combination effect on cancer cell killing and tumor growth inhibition in mice with low side effects, and provided a promising paradigm for precise cancer therapy.
  • ||||||||||  Journal:  IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex. (Pubmed Central) -  Dec 2, 2021   
    Whole cell electrophysiological recording identified that synaptic transmissions mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), N-methyl-D-aspartate receptor (NMDAR), and γ-aminobutyric acid receptor (GABAR) were significantly decreased in pyramidal neurons in layer 5 of the mPFC in IQSEC2 KO mice. Reexpression of IQSEC2 isoform 1 in the mPFC of IQSEC2 KO mice using adeno-associated virus (AAV) rescued both synaptic and social deficits, suggesting that impaired synaptic function in the mPFC is responsible for social deficits in IQSEC2 KO mice.
  • ||||||||||  NAV-2729 / Navigen
    Journal:  ADP ribosylation factor 6 promotes contraction and proliferation, suppresses apoptosis and is specifically inhibited by NAV2729 in prostate stromal cells. (Pubmed Central) -  Nov 12, 2021   
    Significance Statement By knockout of ARF6 in prostate stromal cells, we demonstrate an involvement of ARF6 in promotion of prostate smooth muscle contraction and stromal growth, and define concentration ranges for their ARF6-specific inhibition by NAV2729. Besides the context of benign prostatic hyperplasia and lower urinary tract symptoms, analog ARF6 functions in contraction and growth appear possible in other smooth muscle-rich organs, which merits further attention considering the high clinical relevance of smooth muscle-based diseases.
  • ||||||||||  Review, Journal:  EFA6 in Axon Regeneration, as a Microtubule Regulator and as a Guanine Nucleotide Exchange Factor. (Pubmed Central) -  Nov 4, 2021   
    EFA6 inhibition could be a promising therapeutic strategy to promote axon regeneration and functional recovery after axon injury. This review summarizes the inhibitory role on axon regeneration through regulating microtubule dynamics and through affecting ARF6 (ADP-ribosylation factor 6) GTPase-mediated integrin transport.
  • ||||||||||  Journal:  Density Gradient Ultracentrifugation for Investigating Endocytic Recycling in Mammalian Cells. (Pubmed Central) -  Oct 20, 2021   
    The isolated fractions were subjected to standard Western blotting for analyzing their protein contents. By employing this method, we identified that the plasma membrane targeting of engulfment and cell motility 1 (ELMO1), a Ras-related C3 botulinum toxin substrate 1 (Rac1) guanine nucleotide exchange factor, is through ARF6-mediated endocytic recycling.
  • ||||||||||  Journal:  Long Non-Coding RNA MDFIC-7 Promotes Chordoma Progression Through Modulating the miR-525-5p/ARF6 Axis. (Pubmed Central) -  Oct 9, 2021   
    Our findings demonstrate that lncRNA MDFIC-7 acts as a molecular sponge to competitively bind to miR-525-5p and promote expression of ARF6. The lncRNA MDFIC-7/miR-525-5p/ARF6 axis regulates chordoma progression and the Warburg effect in chordoma, suggesting that lncRNA MDFIC-7 and miR-525-5p could be promising therapeutic targets for the treatment of chordoma.
  • ||||||||||  Journal:  Discovery of a dual Ras and ARF6 inhibitor from a GPCR endocytosis screen. (Pubmed Central) -  Aug 19, 2021   
    In silico modeling and in vitro studies reveal a unique binding modality of Rasarfin within the SOS-binding domain of Ras. Our findings unveil a class of dual small G protein inhibitors for receptor trafficking and signaling, useful for the inhibition of oncogenic cellular responses.
  • ||||||||||  Preclinical, Journal:  Preserving Vascular Integrity Protects Mice Against Multidrug-Resistant Gram-Negative Bacterial Infection. (Pubmed Central) -  Jun 22, 2021   
    Finally, we show that the mechanism of protection elicited by these small molecule inhibitors is by restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of TLR4/MyD88/ARNO/ARF6 pathway. By targeting the host's vasculature with small molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and re-emerging pathogens.