The ability to repair damaged or lost tissues varies significantly among vertebrates.The regenerative ability of the heart is clinically very relevant,because adult teleost fish and amphibians can regenerate heart tis...The ability to repair damaged or lost tissues varies significantly among vertebrates.The regenerative ability of the heart is clinically very relevant,because adult teleost fish and amphibians can regenerate heart tissue,but we mammals cannot.Interestingly,heart regeneration is possible in neonatal mice,but this ability is lost within 7 days after birth.In zebrafish and neonatal mice,lost cardiomyocytes are regenerated via proliferation of spared,differentiated cardiomyocytes.While some cardiomyocyte turnover occurs in adult mammals,the cardiomyocyte production rate is too low in response to injury to regenerate the heart.Instead,mammalian hearts respond to injury by remodeling of spared tissue,which includes cardiomyocyte hypertrophy.Wnt/β-catenin signaling plays important roles during vertebrate heart development,and it is re-activated in response to cardiac injury.In this review,we discuss the known functions of this signaling pathway in injured hearts,its involvement in cardiac fibrosis and hypertrophy,and potential therapeutic approaches that might promote cardiac repair after injury by modifying Wnt/β-catenin signaling.Regulation of cardiac remodeling by this signaling pathway appears to vary depending on the injury model and the exact stages that have been studied.Thus,conflicting data have been published regarding a potential role of Wnt/β-catenin pathway in promotion of fibrosis and cardiomyocyte hypertrophy.In addition,the Wnt inhibitory secreted Frizzled-related proteins(sFrps)appear to have Wnt-dependent and Wnt-independent roles in the injured heart.Thus,while the exact functions of Wnt/β-catenin pathway activity in response to injury still need to be elucidated in the non-regenerating mammalian heart,but also in regenerating lower vertebrates,manipulation of the pathway is essential for creation of therapeutically useful cardiomyocytes from stem cells in culture.Hopefully,a detailed understanding of the in vivo role of Wnt/β-catenin signaling in injured mammalian and non-mammalian hearts will also contribute to the success of current efforts towards developing regenerative therapies.展开更多
Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous p...Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.展开更多
文摘The ability to repair damaged or lost tissues varies significantly among vertebrates.The regenerative ability of the heart is clinically very relevant,because adult teleost fish and amphibians can regenerate heart tissue,but we mammals cannot.Interestingly,heart regeneration is possible in neonatal mice,but this ability is lost within 7 days after birth.In zebrafish and neonatal mice,lost cardiomyocytes are regenerated via proliferation of spared,differentiated cardiomyocytes.While some cardiomyocyte turnover occurs in adult mammals,the cardiomyocyte production rate is too low in response to injury to regenerate the heart.Instead,mammalian hearts respond to injury by remodeling of spared tissue,which includes cardiomyocyte hypertrophy.Wnt/β-catenin signaling plays important roles during vertebrate heart development,and it is re-activated in response to cardiac injury.In this review,we discuss the known functions of this signaling pathway in injured hearts,its involvement in cardiac fibrosis and hypertrophy,and potential therapeutic approaches that might promote cardiac repair after injury by modifying Wnt/β-catenin signaling.Regulation of cardiac remodeling by this signaling pathway appears to vary depending on the injury model and the exact stages that have been studied.Thus,conflicting data have been published regarding a potential role of Wnt/β-catenin pathway in promotion of fibrosis and cardiomyocyte hypertrophy.In addition,the Wnt inhibitory secreted Frizzled-related proteins(sFrps)appear to have Wnt-dependent and Wnt-independent roles in the injured heart.Thus,while the exact functions of Wnt/β-catenin pathway activity in response to injury still need to be elucidated in the non-regenerating mammalian heart,but also in regenerating lower vertebrates,manipulation of the pathway is essential for creation of therapeutically useful cardiomyocytes from stem cells in culture.Hopefully,a detailed understanding of the in vivo role of Wnt/β-catenin signaling in injured mammalian and non-mammalian hearts will also contribute to the success of current efforts towards developing regenerative therapies.
基金supported by the German Research Foundation(DFG)through the CRC1279supported by the DFG under Germany’s Excellence Strategy-EXC 2033-390677874-RESOLVby the Boehringer Ingelheim Foundation(Plus-3 Program)
文摘Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.
