X-linked hypophosphatemia(XLH)represents the most common form of familial hypophosphatemia.Although significant advances have been made in the treatment of bone pathology,patients undergoing therapy continue to experi...X-linked hypophosphatemia(XLH)represents the most common form of familial hypophosphatemia.Although significant advances have been made in the treatment of bone pathology,patients undergoing therapy continue to experience significantly decreased oral health-related quality of life.The following study addresses this persistent oral disease by further investigating the effect of DMP1 expression on the differentiation of XLH dental pulp cells.Dental pulp cells were isolated from the third molars of XLH and healthy controls and stable transduction of full-length human DMP1 were achieved.RNA sequencing was performed to evaluate the genetic changes following the induction of odontogenic differentiation.RNAseq data shows the upregulation of inhibitors of the canonical Wnt pathway in XLH cells,while constitutive expression of full-length DMP1 in XLH cells reversed this effect during odontogenic differentiation.These results imply that inhibition of the canonical Wnt pathway may contribute to the pathophysiology of XLH and suggest a new therapeutic strategy for the management of oral disease.展开更多
Acute respiratory distress syndrome(ARDS)is a severe pulmonary disease characterized by acute,noncardiogenic pulmonary edema and hypoxemia leading to respiratory failure.It is induced by a diverse array of etiologies,...Acute respiratory distress syndrome(ARDS)is a severe pulmonary disease characterized by acute,noncardiogenic pulmonary edema and hypoxemia leading to respiratory failure.It is induced by a diverse array of etiologies,including recent SARS-CoV-2 infection.The current standard of care for ARDS remains predominantly supportive,underscoring the urgent need for targeted pharmacological interventions.To address this critical gap,we developed an inhibitor of the microtubule accessory factor endbinding protein 3(EB3),a key mediator of pathological calcium signaling in endothelial cells.During injury,EB3 facilitates inositol 1,4,5-trisphosphate receptor 3(IP3R3)clustering on the endoplasmic reticulum membrane,activating widespread calcium release from intracellular stores and leading to endothelial barrier disruption.Using nuclear magnetic resonance(NMR)-guided approaches,we designed and optimized a synthetic EB3 inhibitor,termed vascular therapeutics(VT)-109,with enhanced physicochemical properties.We evaluated the therapeutic potential of VT-109 across a wide range of preclinical models in which pathogenic insults target epithelial or endothelial barriers.Treatment with VT-109 promptly restored the tissue‒fluid balance in the injured lung by inducing the reannealing of VE-cadherin junctions and restoring the endothelial barrier.In addition to vascular protection,VT-109 improved lung architecture and function,normalized immune responses,and significantly reduced both morbidity and mortality in ARDS models.At the molecular level,VT-109 blocks inflammatory NFAT and NFκB signaling while concurrently activating FOXM1-dependent endothelial regeneration.These findings support EB3 inhibition as a promising therapeutic strategy for ARDS and highlight VT-109 as a versatile drug candidate capable of addressing the multifaceted pathophysiology of this disease.展开更多
基金our funding sources U.S.Department of Health&Human Services,NIH,NIDCR T32 DE018381[Multidisciplinary Oral Science Training Program]DE028193[E.G.]+1 种基金R01 DE031737 and DE 028531[A.G.]the Brodie Endowment Fund。
文摘X-linked hypophosphatemia(XLH)represents the most common form of familial hypophosphatemia.Although significant advances have been made in the treatment of bone pathology,patients undergoing therapy continue to experience significantly decreased oral health-related quality of life.The following study addresses this persistent oral disease by further investigating the effect of DMP1 expression on the differentiation of XLH dental pulp cells.Dental pulp cells were isolated from the third molars of XLH and healthy controls and stable transduction of full-length human DMP1 were achieved.RNA sequencing was performed to evaluate the genetic changes following the induction of odontogenic differentiation.RNAseq data shows the upregulation of inhibitors of the canonical Wnt pathway in XLH cells,while constitutive expression of full-length DMP1 in XLH cells reversed this effect during odontogenic differentiation.These results imply that inhibition of the canonical Wnt pathway may contribute to the pathophysiology of XLH and suggest a new therapeutic strategy for the management of oral disease.
基金supported in part by federal funds from the National Heart,Lung,and Blood Institute,National Institutes of Health,Department of Health and Human Services,under contract numbers HHSN268201700007C,R01HL045638,and T32HL007829Bioinformatics analysis in the project described was performed by the UIC Research Informatics Core,supported in part by NCATS through Grant UL1TR002003.
文摘Acute respiratory distress syndrome(ARDS)is a severe pulmonary disease characterized by acute,noncardiogenic pulmonary edema and hypoxemia leading to respiratory failure.It is induced by a diverse array of etiologies,including recent SARS-CoV-2 infection.The current standard of care for ARDS remains predominantly supportive,underscoring the urgent need for targeted pharmacological interventions.To address this critical gap,we developed an inhibitor of the microtubule accessory factor endbinding protein 3(EB3),a key mediator of pathological calcium signaling in endothelial cells.During injury,EB3 facilitates inositol 1,4,5-trisphosphate receptor 3(IP3R3)clustering on the endoplasmic reticulum membrane,activating widespread calcium release from intracellular stores and leading to endothelial barrier disruption.Using nuclear magnetic resonance(NMR)-guided approaches,we designed and optimized a synthetic EB3 inhibitor,termed vascular therapeutics(VT)-109,with enhanced physicochemical properties.We evaluated the therapeutic potential of VT-109 across a wide range of preclinical models in which pathogenic insults target epithelial or endothelial barriers.Treatment with VT-109 promptly restored the tissue‒fluid balance in the injured lung by inducing the reannealing of VE-cadherin junctions and restoring the endothelial barrier.In addition to vascular protection,VT-109 improved lung architecture and function,normalized immune responses,and significantly reduced both morbidity and mortality in ARDS models.At the molecular level,VT-109 blocks inflammatory NFAT and NFκB signaling while concurrently activating FOXM1-dependent endothelial regeneration.These findings support EB3 inhibition as a promising therapeutic strategy for ARDS and highlight VT-109 as a versatile drug candidate capable of addressing the multifaceted pathophysiology of this disease.
