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  1. Article ; Online: Observation on the ice crystal formation process of large yellow croaker (Pseudosciaena crocea) and the effect of multiple cryoprotectants pre-soaking treatments on frozen quality.

    Yang, Zhikang / Ye, Guosen / Yang, Dazhang / Xie, Jing / Huo, Yilin

    Cryobiology

    2023  Volume 113, Page(s) 104580

    Abstract: By observing the formation behavior of ice crystals, the quality of food products under different freezing conditions can be intuitively judged. In this paper, large yellow croaker was taken as the research object, and a novel cryomicroscopic system was ... ...

    Abstract By observing the formation behavior of ice crystals, the quality of food products under different freezing conditions can be intuitively judged. In this paper, large yellow croaker was taken as the research object, and a novel cryomicroscopic system was developed to directly observe the structure of ice crystals during the freezing process. The cryoprotective effects of 4% sucrose +4% sorbitol (SU + SO), 4% xylo-oligosaccharide (XO), 4% xylo-oligosaccharide + 0.3% tetrasodium pyrophosphate (XO + TSPP) and 0.2% antifreeze protein (AFP) at different freezing temperatures were investigated. And the evaluation indicators, such as cell deformation degree, equivalent diameters, roundness, elongation and fractal dimension were introduced to quantify the damage of ice crystals to muscle tissues and fibers. The results indicate that reducing the freezing temperature and adding cryoprotectants can improve the quality of large yellow croaker. AFP has the best cryoprotective effect, with a reduction in cell deformation degree of 54.78% and 67.83% compared to the Control group at -5 °C and -20 °C, respectively. SU + SO and XO have the equivalent antifreeze effect, which is slightly inferior to XO + TSPP. In addition, physical parameters of large yellow croaker samples were measured to verify the influence of ice crystal structure on product quality. Therefore, direct observation of the ice crystal formation process and evaluation of ice crystal structure can accurately reflect the quality of frozen products, which is of great significance for the development of refrigeration and preservation technology.
    MeSH term(s) Animals ; Freezing ; Cryoprotective Agents/pharmacology ; Cryoprotective Agents/chemistry ; Ice ; alpha-Fetoproteins ; Cryopreservation/methods ; Perciformes ; Antifreeze Proteins/pharmacology ; Oligosaccharides/chemistry
    Chemical Substances Cryoprotective Agents ; Ice ; alpha-Fetoproteins ; Antifreeze Proteins ; Oligosaccharides
    Language English
    Publishing date 2023-08-23
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 80098-3
    ISSN 1090-2392 ; 0011-2240
    ISSN (online) 1090-2392
    ISSN 0011-2240
    DOI 10.1016/j.cryobiol.2023.104580
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  2. Article ; Online: Evaluation of GSK2789917-induced TRPV4 inhibition in animal models of fluid induced lung injury.

    Bihari, Shailesh / Costell, Melissa H / Bouchier, Tara / Behm, David J / Burgert, Mark / Ye, Guosen / Bersten, Andrew D / Puukila, Stephanie / Cavallaro, Elena / Sprecher, Dennis L / Dixon, Dani-Louise

    Naunyn-Schmiedeberg's archives of pharmacology

    2023  

    Abstract: Administration of bolus intravenous fluids, common in pre-hospital and hospitalised patients, is associated with increased lung vascular permeability and mortality outside underlying disease states. In our laboratory, the induction of lung injury and ... ...

    Abstract Administration of bolus intravenous fluids, common in pre-hospital and hospitalised patients, is associated with increased lung vascular permeability and mortality outside underlying disease states. In our laboratory, the induction of lung injury and oedema through rapid administration of intravenous fluid in rats was reduced by a non-specific antagonist of transient receptor potential vanilloid 4 (TRPV4) channels. The aims of this study were to determine the effect of selective TRPV4 inhibition on fluid-induced lung injury (FILI) and compare the potency of FILI inhibition to that of an established model of TRPV4 agonist-induced lung oedema. In a series of experiments, rats received specific TRPV4 inhibitor (GSK2789917) at high (15 μg/kg), medium (5 μg/kg) or low (2 μg/kg) dose or vehicle prior to induction of lung injury by intravenous infusion of TRPV4 agonist (GSK1016790) or saline. GSK1016790 significantly increased lung wet weight/body weight ratio by 96% and lung wet-to-dry weight ratio by 43% in vehicle pre-treated rats, which was inhibited by GSK2789917 in a dose-dependent manner (IC
    Language English
    Publishing date 2023-11-15
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 121471-8
    ISSN 1432-1912 ; 0028-1298
    ISSN (online) 1432-1912
    ISSN 0028-1298
    DOI 10.1007/s00210-023-02821-x
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  3. Article ; Online: Design and Optimization of an Acyclic Amine Series of TRPV4 Antagonists by Electronic Modulation of Hydrogen Bond Interactions.

    Patterson, Jaclyn R / Terrell, Lamont R / Donatelli, Carla A / Holt, Dennis A / Jolivette, Larry J / Rivero, Ralph A / Roethke, Theresa J / Shu, Arthur / Stoy, Patrick / Ye, Guosen / Youngman, Mark / Lawhorn, Brian G

    Journal of medicinal chemistry

    2020  Volume 63, Issue 23, Page(s) 14867–14884

    Abstract: Investigation of TRPV4 as a potential target for the treatment of pulmonary edema associated with heart failure generated a novel series of acyclic amine inhibitors displaying exceptional potency and PK properties. The series arose through a scaffold ... ...

    Abstract Investigation of TRPV4 as a potential target for the treatment of pulmonary edema associated with heart failure generated a novel series of acyclic amine inhibitors displaying exceptional potency and PK properties. The series arose through a scaffold hopping approach, which relied on use of an internal H-bond to replace a saturated heterocyclic ring. Optimization of the lead through investigation of both aryl regions revealed approaches to increase potency through substituents believed to enhance separate intramolecular and intermolecular H-bond interactions. A proposed internal H-bond between the amine and neighboring benzenesulfonamide was stabilized by electronically modulating the benzenesulfonamide. In the aryl ether moiety, substituents para to the nitrile demonstrated an electronic effect on TRPV4 recognition. Finally, the acyclic amines inactivated CYP3A4 and this liability was addressed by modifications that sterically preclude formation of a putative metabolic intermediate complex to deliver advanced TRPV4 antagonists as leads for discovery of novel medicines.
    MeSH term(s) Animals ; Cytochrome P-450 CYP3A/metabolism ; Diamines/chemical synthesis ; Diamines/chemistry ; Diamines/metabolism ; Diamines/pharmacokinetics ; Drug Design ; Humans ; Hydrogen Bonding/drug effects ; Microsomes, Liver/metabolism ; Molecular Structure ; Protein Binding ; Rats ; Stereoisomerism ; Structure-Activity Relationship ; Sulfonamides/chemical synthesis ; Sulfonamides/chemistry ; Sulfonamides/metabolism ; Sulfonamides/pharmacokinetics ; TRPV Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/chemistry ; TRPV Cation Channels/metabolism
    Chemical Substances Diamines ; Sulfonamides ; TRPV Cation Channels ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55)
    Language English
    Publishing date 2020-11-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.0c01303
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  4. Article ; Online: Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4).

    Brnardic, Edward J / Ye, Guosen / Brooks, Carl / Donatelli, Carla / Barton, Linda / McAtee, Jeff / Sanchez, Robert M / Shu, Arthur / Erhard, Karl / Terrell, Lamont / Graczyk-Millbrandt, Grazyna / He, Yanan / Costell, Melissa H / Behm, David J / Roethke, Theresa / Stoy, Patrick / Holt, Dennis A / Lawhorn, Brian G

    Journal of medicinal chemistry

    2018  Volume 61, Issue 21, Page(s) 9738–9755

    Abstract: A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 ... ...

    Abstract A novel series of pyrrolidine sulfonamide transient receptor potential vanilloid-4 (TRPV4) antagonists was developed by modification of a previously reported TRPV4 inhibitor (1). Several core-structure modifications were identified that improved TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein. The new template was initially discovered as a minor regio-isomeric side product formed during routine structure-activity relationship (SAR) studies, and further optimization resulted in highly potent compounds with a novel pyrrolidine diol core. Further improvements in potency and pharmacokinetic properties were achieved through SAR studies on the sulfonamide substituent to give an optimized lead compound GSK3395879 (52) that demonstrated the ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. GSK3395879 is a tool for studying the biology of TRPV4 and an advanced lead for identifying new heart failure medicines.
    MeSH term(s) Administration, Oral ; Animals ; Biological Availability ; Drug Design ; Pyrrolidines/chemistry ; Rats ; Structure-Activity Relationship ; Sulfonamides/administration & dosage ; Sulfonamides/chemistry ; Sulfonamides/pharmacokinetics ; Sulfonamides/pharmacology ; TRPV Cation Channels/antagonists & inhibitors
    Chemical Substances Pyrrolidines ; Sulfonamides ; TRPV Cation Channels ; pyrrolidine (LJU5627FYV)
    Language English
    Publishing date 2018-10-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.8b01317
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  5. Article: Discovery of GSK2798745: A Clinical Candidate for Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4).

    Brooks, Carl A / Barton, Linda S / Behm, David J / Eidam, Hilary S / Fox, Ryan M / Hammond, Marlys / Hoang, Tram H / Holt, Dennis A / Hilfiker, Mark A / Lawhorn, Brian G / Patterson, Jaclyn R / Stoy, Patrick / Roethke, Theresa J / Ye, Guosen / Zhao, Steve / Thorneloe, Kevin S / Goodman, Krista B / Cheung, Mui

    ACS medicinal chemistry letters

    2019  Volume 10, Issue 8, Page(s) 1228–1233

    Abstract: GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this ... ...

    Abstract GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable
    Language English
    Publishing date 2019-07-15
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.9b00274
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  6. Article: Discovery of GSK2193874: An Orally Active, Potent, and Selective Blocker of Transient Receptor Potential Vanilloid 4.

    Cheung, Mui / Bao, Weike / Behm, David J / Brooks, Carl A / Bury, Michael J / Dowdell, Sarah E / Eidam, Hilary S / Fox, Ryan M / Goodman, Krista B / Holt, Dennis A / Lee, Dennis / Roethke, Theresa J / Willette, Robert N / Xu, Xiaoping / Ye, Guosen / Thorneloe, Kevin S

    ACS medicinal chemistry letters

    2017  Volume 8, Issue 5, Page(s) 549–554

    Abstract: Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. ... ...

    Abstract Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4'-bipiperidin-1'-ylmethyl)-7-bromo-
    Language English
    Publishing date 2017-03-20
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.7b00094
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  7. Article: Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.

    Kallander, Lara S / Washburn, David / Hilfiker, Mark A / Eidam, Hilary Schenck / Lawhorn, Brian G / Prendergast, Joanne / Fox, Ryan / Dowdell, Sarah / Manns, Sharada / Hoang, Tram / Zhao, Steve / Ye, Guosen / Hammond, Marlys / Holt, Dennis A / Roethke, Theresa / Hong, Xuan / Reid, Robert A / Gampe, Robert / Zhang, Hong /
    Diaz, Elsie / Rendina, Alan R / Quinn, Amy M / Willette, Bob

    ACS medicinal chemistry letters

    2018  Volume 9, Issue 7, Page(s) 736–740

    Abstract: Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors ... ...

    Abstract Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral
    Language English
    Publishing date 2018-07-02
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.8b00173
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  8. Article ; Online: TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury.

    Balakrishna, Shrilatha / Song, Weifeng / Achanta, Satyanarayana / Doran, Stephen F / Liu, Boyi / Kaelberer, Melanie M / Yu, Zhihong / Sui, Aiwei / Cheung, Mui / Leishman, Emma / Eidam, Hilary S / Ye, Guosen / Willette, Robert N / Thorneloe, Kevin S / Bradshaw, Heather B / Matalon, Sadis / Jordt, Sven-Eric

    American journal of physiology. Lung cellular and molecular physiology

    2014  Volume 307, Issue 2, Page(s) L158–72

    Abstract: The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel ...

    Abstract The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function.
    MeSH term(s) Acute Lung Injury/chemically induced ; Acute Lung Injury/drug therapy ; Animals ; Anti-Inflammatory Agents/pharmacology ; Bronchoalveolar Lavage Fluid/chemistry ; Chlorine/toxicity ; HEK293 Cells ; Humans ; Hydrochloric Acid/toxicity ; Male ; Mice ; Pneumonia/drug therapy ; Rats ; TRPV Cation Channels/agonists ; TRPV Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/deficiency
    Chemical Substances Anti-Inflammatory Agents ; TRPV Cation Channels ; Trpv4 protein, mouse ; Chlorine (4R7X1O2820) ; Hydrochloric Acid (QTT17582CB)
    Language English
    Publishing date 2014-05-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00065.2014
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  9. Article ; Online: Author Correction: Design of amidobenzimidazole STING receptor agonists with systemic activity.

    Ramanjulu, Joshi M / Pesiridis, G Scott / Yang, Jingsong / Concha, Nestor / Singhaus, Robert / Zhang, Shu-Yun / Tran, Jean-Luc / Moore, Patrick / Lehmann, Stephanie / Eberl, H Christian / Muelbaier, Marcel / Schneck, Jessica L / Clemens, Jim / Adam, Michael / Mehlmann, John / Romano, Joseph / Morales, Angel / Kang, James / Leister, Lara /
    Graybill, Todd L / Charnley, Adam K / Ye, Guosen / Nevins, Neysa / Behnia, Kamelia / Wolf, Amaya I / Kasparcova, Viera / Nurse, Kelvin / Wang, Liping / Puhl, Ana C / Li, Yue / Klein, Michael / Hopson, Christopher B / Guss, Jeffrey / Bantscheff, Marcus / Bergamini, Giovanna / Reilly, Michael A / Lian, Yiqian / Duffy, Kevin J / Adams, Jerry / Foley, Kevin P / Gough, Peter J / Marquis, Robert W / Smothers, James / Hoos, Axel / Bertin, John

    Nature

    2019  Volume 570, Issue 7761, Page(s) E53

    Abstract: Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    Abstract Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    Language English
    Publishing date 2019-05-29
    Publishing country England
    Document type Published Erratum
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-019-1265-5
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  10. Article ; Online: Design of amidobenzimidazole STING receptor agonists with systemic activity.

    Ramanjulu, Joshi M / Pesiridis, G Scott / Yang, Jingsong / Concha, Nestor / Singhaus, Robert / Zhang, Shu-Yun / Tran, Jean-Luc / Moore, Patrick / Lehmann, Stephanie / Eberl, H Christian / Muelbaier, Marcel / Schneck, Jessica L / Clemens, Jim / Adam, Michael / Mehlmann, John / Romano, Joseph / Morales, Angel / Kang, James / Leister, Lara /
    Graybill, Todd L / Charnley, Adam K / Ye, Guosen / Nevins, Neysa / Behnia, Kamelia / Wolf, Amaya I / Kasparcova, Viera / Nurse, Kelvin / Wang, Liping / Puhl, Ana C / Li, Yue / Klein, Michael / Hopson, Christopher B / Guss, Jeffrey / Bantscheff, Marcus / Bergamini, Giovanna / Reilly, Michael A / Lian, Yiqian / Duffy, Kevin J / Adams, Jerry / Foley, Kevin P / Gough, Peter J / Marquis, Robert W / Smothers, James / Hoos, Axel / Bertin, John

    Nature

    2018  Volume 564, Issue 7736, Page(s) 439–443

    Abstract: Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self ... ...

    Abstract Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA
    MeSH term(s) Animals ; Benzimidazoles/administration & dosage ; Benzimidazoles/chemistry ; Benzimidazoles/pharmacology ; Benzimidazoles/therapeutic use ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/immunology ; Drug Design ; Humans ; Ligands ; Membrane Proteins/agonists ; Membrane Proteins/immunology ; Mice ; Models, Molecular ; Nucleotides, Cyclic/metabolism
    Chemical Substances Benzimidazoles ; Ligands ; Membrane Proteins ; Nucleotides, Cyclic ; STING1 protein, human ; Sting1 protein, mouse ; cyclic guanosine monophosphate-adenosine monophosphate
    Language English
    Publishing date 2018-11-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-018-0705-y
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