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Eleftherios P Diamandis - One of the best experts on this subject based on the ideXlab platform.
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biochemical and functional characterization of the Human Tissue kallikrein 9
Biochemical Journal, 2017Co-Authors: Sofia Farkona, Panagiota Filippou, Davor Brinc, Ioannis Prassas, Eleftherios P DiamandisAbstract:Human Tissue kallikrein 9 (KLK9) is a member of the kallikrein-related family of proteases. Despite its known expression profile, much less is known about the functional roles of this protease and its implications in normal physiology and disease. We present here the first data on the biochemical characterization of KLK9, investigate parameters that affect its enzymatic activity (such as inhibitors) and provide preliminary insights into its putative substrates. We show that mature KLK9 (mat-KLK9) is a glycosylated chymotrypsin-like enzyme with strong preference for tyrosine over phenylalanine at the P1 cleavage position. The enzyme activity is enhanced by Mg 2+ and Ca 2+ , but is reversibly attenuated by Zn 2+ . KLK9 is inhibited in vitro by many naturally occurring or synthetic protease inhibitors. Using a combination of degradomic and substrate specificity assays, we identified candidate KLK9 substrates in two different epithelial cell lines (the non-tumorigenic Human keratinocyte cells (HaCaT) and the tumorigenic tongue squamous carcinoma cells (SCC9)). Two potential KLK9 substrates (KLK10 and midkine) were subjected to further validation. Taken together, our data delineate some functional and biochemical properties of KLK9 for future elucidation of the role of this enzyme in health and disease.
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Human Tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions
Biological Chemistry, 2008Co-Authors: Azza Eissa, Eleftherios P DiamandisAbstract:Human Tissue kallikreins (KLKs) are the largest family of secreted serine protease endopeptidases encoded by 15 genes clustered on chromosome 19q13.4. Multiple KLK enzymes are co-localized in the upper stratum granulosum and stratum corneum of Human epidermis, and in associated appendages such as hair follicle epithelia and sweat glands. Until recently, kallikrein proteolytic activity in the skin was exclusively attributed to KLK5 and KLK7. However, wider cutaneous roles of kallikreins became evident in recent years as the proposal of KLK proteolytic activation cascades emerged. We postulate that these proteolytic enzymes may serve as promiscuous mediators of different skin barrier functions, since they are capable of proteolysing different substrates that govern skin desquamation, antimicrobial defense, and lipid permeability. Growing evidence now attests to potential kallikrein involvement in skin inflammation, pigmentation, and tumor suppression via their ability to target proteinase-activated receptor signaling pathways. Current knowledge on kallikrein roles in skin physiology and pathobiology is described in this review.
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a consolidated catalogue and graphical annotation of dbsnp polymorphisms in the Human Tissue kallikrein klk locus
Molecular Oncology, 2007Co-Authors: Carolyn A Goard, Marc B. Elliott, Eleftherios P Diamandis, Irvin L BrombergAbstract:Abstract The Human Tissue kallikreins, 15 secreted serine proteases, may play diverse roles in pathophysiology. The National Center for Biotechnology Information's dbSNP was mined for polymorphisms located within the kallikrein ( KLK ) locus using custom-designed “ParSNPs” and “LocusAnnotator” software tools. Using “ParSNPs”, a filterable catalogue of 1856 KLK polymorphisms (1023 validated) was generated. “LocusAnnotator” was used to annotate the KLK locus sequence with gene and polymorphism features. A second locus was examined to validate the use of both programs on a non-kallikrein locus. This report may assist in the informed selection of KLK polymorphisms for future association and biochemical studies in relation to disease. Furthermore, “ParSNPs” and “LocusAnnotator” are available at no cost from our website ( www.acdcLab.org/annotations ) to examine other loci.
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Human Tissue kallikreins a road under construction
Clinica Chimica Acta, 2007Co-Authors: Nashmil Emami, Eleftherios P DiamandisAbstract:Abstract Background The Human Tissue kallikrein gene family, located at chromosome 19q13.4, is the largest contiguous family of proteases in the Human genome. The locus encodes all 15 members of the family, 13 of which have been reported as potential biomarkers for several carcinomas and other non-neoplastic diseases. Kallikreins are expressed by a wide range of Tissues and implicated in a number of physiological functions, including skin desquamation, semen liquefaction, neural plasticity and the regulation of blood pressure. Kallikrein function is regulated at various levels, including transcription, translation and post-translation. The proteolytic activity of kallikreins is believed to be cascade mediated and may cross-talk with other proteases. These cascades are highly regulated through a series of feedback loops, inhibitors, (auto) degradation and internal cleavage. Uncontrolled proteolytic activity of kallikreins is implicated in a large number of neoplastic and non-neoplastic pathological conditions. Conclusions As our understanding of their regulatory and functional mechanisms continues to expand, kallikreins are expected to become novel targets for the design of new therapeutics.
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Human Tissue kallikreins the cancer biomarker family
Cancer Letters, 2007Co-Authors: Miltiadis Paliouras, Eleftherios P Diamandis, Carla A. BorgoñoAbstract:Human Tissue kallikreins (KLKs) are attracting increased attention due to their role as biomarkers for the screening, diagnosis, prognosis, and monitoring of various cancers including those of the prostate, ovarian, breast, testicular, and lung. Human Tissue kallikrein genes represent the largest contiguous group of proteases within the Human genome. Originally thought to consist of three genes, the identification of the Human kallikrein locus has expanded this number to fifteen. These genes, and their encoded proteins, share a high degree of homology and are expressed in different Tissues. Prostate-specific antigen (PSA), the most commonly known kallikrein, is a useful biomarker for prostate cancer. Several other kallikreins, including kallikreins 2 (KLK2) and 11 (KLK11) are emerging as complementary prostate cancer biomarkers. Along with these kallikreins, several others have been implicated in the other cancers. For example, KLK5, 6, 7, 10, 11, and 14 are emerging biomarkers for ovarian cancer. The identification of kallikrein substrates and the development of proteolytic cascade models implicate kallikrein proteins in cancer progression. This review describes the current status of kallikreins as cancer biomarkers.
Julie Chao - One of the best experts on this subject based on the ideXlab platform.
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Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Induces Angiogenesis in Normoperfused Skeletal Muscle
2016Co-Authors: Costanza Emanueli, Julie Chao, Antonella Zacheo, Maria Bonaria Salis, Tiziana Stacca, Stefania Straino, Maurizio C Capogrossi, Ra Minasi, Lee Chao, Paolo MadedduAbstract:Abstract—We investigated whether local delivery of the Tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the Human Tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant Human Tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascular-ization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B1 or B2 receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) Human Tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the Tissue kallikrein-kinin system in vascular biology. (Arterioscler Thromb Vasc Biol. 2000;20:2379-2385.) Key Words: gene delivery n angiogenesis n kallikrein n kinins n nitric oxid
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gene therapy with Human Tissue kallikrein reduces hypertension and hyperinsulinemia in fructose induced hypertensive rats
Hypertension, 2003Co-Authors: Chunxia Zhao, Julie Chao, Peihua Wang, Xiao Xiao, Dao Wen Wang, Darryl C ZeldinAbstract:This study investigates gene therapy with Human Tissue kallikrein as a treatment for fructose-induced hypertension in rats. Hypertension was induced by addition of 10% fructose to drinking water. Fructose-fed rats also had increased serum insulin and triglycerides, decreased urine osmolarity, increased urine volume and endothelin-1, and increased aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels. Fructose-induced hypertensive and control rats were injected intravenously with a construct containing the Human Tissue kallikrein cDNA. Two weeks after injection of hypertensive rats, systolic blood pressure and serum insulin levels normalized, urine osmolarity increased, urine endothelin-1 levels decreased, and aortic endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 mRNA levels decreased. In contrast, injection of the Human Tissue kallikrein cDNA had minimal effect on blood pressure or insulin levels in control rats. These results suggest that gene therapy with Human Tissue kallikrein may have potential as a treatment for hypertension and associated insulin resistance. Moreover, our data suggest that the beneficial effects of Human Tissue kallikrein on these parameters are associated with changes in endothelin-1, endothelin-A receptor, and angiotensin II receptor type 1 expression.
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local delivery of Human Tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia
Circulation, 2001Co-Authors: Costanza Emanueli, Julie Chao, Antonella Zacheo, Alessandra Minasi, Maria Bonaria Salis, Stefania Straino, Lee Chao, Maria Grazia Tozzi, Robert S Smith, Leonardo GaspaAbstract:Background —Human Tissue kallikrein (HK) releases kinins from kininogen. We investigated whether adenovirus-mediated HK gene delivery is angiogenic in the context of ischemia. Methods and Results —Hindlimb ischemia, caused by femoral artery excision, increased muscular capillary density ( P 1 receptor gene ( P 1 receptors blunted ischemia-induced angiogenesis ( P 2 receptor antagonism was ineffective. Intramuscular delivery of adenovirus containing the HK gene (Ad.CMV-cHK) enhanced the increase in capillary density caused by ischemia (969±32 versus 541±18 capillaries/mm 2 for control, P P P 1 or B 2 receptors prevented HK-induced angiogenesis. Conclusions —HK gene delivery enhances the native angiogenic response to ischemia. Angiogenesis gene therapy with HK might be applicable to peripheral occlusive vascular disease.
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adenovirus mediated Human Tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle
Arteriosclerosis Thrombosis and Vascular Biology, 2000Co-Authors: Costanza Emanueli, Julie Chao, Antonella Zacheo, Alessandra Minasi, Maria Bonaria Salis, Tiziana Stacca, Stefania Straino, Maurizio C Capogrossi, Paolo MadedduAbstract:Abstract—We investigated whether local delivery of the Tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the Human Tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant Human Tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascularization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B 1 or B 2 receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) Human Tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the Tissue kallikrein-kinin system in vascular biology.
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DNA polymorphisms in the 5'-flanking region of the Human Tissue kallikrein gene
Human genetics, 1997Co-Authors: Qing Song, Julie ChaoAbstract:Human Tissue kallikrein gene polymorphisms were identified in the promoter region by polymerase chain reaction (PCR) and DNA sequencing. One polymorphic region was identified between nucleotides -121 and -133 with respect to the transcription initiation site of the Tissue kallikrein gene. Ten alleles with length and nucleotide sequence variations were detected among 108 unrelated Caucasians, African-Americans, and Asians. The polymorphisms show Hardy-Weinberg equilibrium. Allele-specific amplification and PCR analyses were used to detect the various forms of polymorphism. The promoter activity was analyzed in Human embryonic kidney 293 cells by transient transfection assays. Sequential 5'-deletion analysis of the Tissue kallikrein gene promoter revealed that the region from -144 to -98 is crucial for its promotor activity, while alleles D and H had significantly lower promoter activities than the other alleles in the -940/+10 deletion constructs. The high variability and the proximity to the Tissue kallikrein gene render it suitable for application as a new tool in genetic studies for evaluation of the Tissue kallikrein gene in the pathogenesis of Human essential hypertension.
Steven Fagien - One of the best experts on this subject based on the ideXlab platform.
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Facial soft-Tissue augmentation with allogeneic Human Tissue collagen matrix (Dermalogen and Dermaplant).
Clinics in plastic surgery, 2001Co-Authors: Steven Fagien, Melvin L. ElsonAbstract:Soft-Tissue augmentation has been established as a viable means of facial rejuvenation where age-related or postsurgical changes manifest as contour or structural defects, and is available for those who desire volume enhancement for various areas. A growing number of agents and techniques are currently available that when used appropriately, can improve or correct facial rhytides, regional volume depletion, and iatrogenic structural soft-Tissue malposition. Failures of some agents are caused by either reduced biocompatibility, inadequate technique of administration, or failure to match the actual underlying pathology with the most appropriate solution. Soft-Tissue augmentation with allogenic Human Tissue collagen matrix by intradermal injection and surgically implantable forms, is physiologic, seems to be ultimately safe and effective, and heralds many qualities consistent with an ideal agent. Several allogenic (cadaver-derived), heterologous, and alloplastic agents are discussed with regard to rationale, patient selection, optimum technique of administration, and persistence.
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Facial soft-Tissue augmentation with injectable autologous and allogeneic Human Tissue collagen matrix (autologen and dermalogen).
Plastic and reconstructive surgery, 2000Co-Authors: Steven FagienAbstract:Facial soft-Tissue augmentation has become increasingly popular as an option for those patients in whom age-related changes manifest as contour defects or who desire volume enhancement for various areas of the face. A variety of agents and techniques are currently available that, when used appropriately, can improve or correct facial rhytids and regional volume depletion. Failures of some agents are due to reduced biocompatibility, inadequate administration technique, or failure to match the actual underlying defeat with the most appropriate solution. Dermal soft-Tissue augmentation with Human Tissue collagen matrix (Autologen and Dermalogen) is physiologic, appears to be ultimately safe and effective, and has many qualities consistent with an ideal dermal filler. Several autologous, allogeneic (cadaver-derived), heterologous, and alloplastic agents will be discussed in this article with regard to rationale, patient selection, optimum administration technique, and persistence.
Costanza Emanueli - One of the best experts on this subject based on the ideXlab platform.
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Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Induces Angiogenesis in Normoperfused Skeletal Muscle
2016Co-Authors: Costanza Emanueli, Julie Chao, Antonella Zacheo, Maria Bonaria Salis, Tiziana Stacca, Stefania Straino, Maurizio C Capogrossi, Ra Minasi, Lee Chao, Paolo MadedduAbstract:Abstract—We investigated whether local delivery of the Tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the Human Tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant Human Tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascular-ization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B1 or B2 receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) Human Tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the Tissue kallikrein-kinin system in vascular biology. (Arterioscler Thromb Vasc Biol. 2000;20:2379-2385.) Key Words: gene delivery n angiogenesis n kallikrein n kinins n nitric oxid
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local delivery of Human Tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia
Circulation, 2001Co-Authors: Costanza Emanueli, Julie Chao, Antonella Zacheo, Alessandra Minasi, Maria Bonaria Salis, Stefania Straino, Lee Chao, Maria Grazia Tozzi, Robert S Smith, Leonardo GaspaAbstract:Background —Human Tissue kallikrein (HK) releases kinins from kininogen. We investigated whether adenovirus-mediated HK gene delivery is angiogenic in the context of ischemia. Methods and Results —Hindlimb ischemia, caused by femoral artery excision, increased muscular capillary density ( P 1 receptor gene ( P 1 receptors blunted ischemia-induced angiogenesis ( P 2 receptor antagonism was ineffective. Intramuscular delivery of adenovirus containing the HK gene (Ad.CMV-cHK) enhanced the increase in capillary density caused by ischemia (969±32 versus 541±18 capillaries/mm 2 for control, P P P 1 or B 2 receptors prevented HK-induced angiogenesis. Conclusions —HK gene delivery enhances the native angiogenic response to ischemia. Angiogenesis gene therapy with HK might be applicable to peripheral occlusive vascular disease.
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adenovirus mediated Human Tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle
Arteriosclerosis Thrombosis and Vascular Biology, 2000Co-Authors: Costanza Emanueli, Julie Chao, Antonella Zacheo, Alessandra Minasi, Maria Bonaria Salis, Tiziana Stacca, Stefania Straino, Maurizio C Capogrossi, Paolo MadedduAbstract:Abstract—We investigated whether local delivery of the Tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the Human Tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant Human Tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascularization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B 1 or B 2 receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) Human Tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the Tissue kallikrein-kinin system in vascular biology.
Paolo Madeddu - One of the best experts on this subject based on the ideXlab platform.
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Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Induces Angiogenesis in Normoperfused Skeletal Muscle
2016Co-Authors: Costanza Emanueli, Julie Chao, Antonella Zacheo, Maria Bonaria Salis, Tiziana Stacca, Stefania Straino, Maurizio C Capogrossi, Ra Minasi, Lee Chao, Paolo MadedduAbstract:Abstract—We investigated whether local delivery of the Tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the Human Tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant Human Tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascular-ization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B1 or B2 receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) Human Tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the Tissue kallikrein-kinin system in vascular biology. (Arterioscler Thromb Vasc Biol. 2000;20:2379-2385.) Key Words: gene delivery n angiogenesis n kallikrein n kinins n nitric oxid
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adenovirus mediated Human Tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle
Arteriosclerosis Thrombosis and Vascular Biology, 2000Co-Authors: Costanza Emanueli, Julie Chao, Antonella Zacheo, Alessandra Minasi, Maria Bonaria Salis, Tiziana Stacca, Stefania Straino, Maurizio C Capogrossi, Paolo MadedduAbstract:Abstract—We investigated whether local delivery of the Tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the Human Tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant Human Tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascularization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B 1 or B 2 receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) Human Tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the Tissue kallikrein-kinin system in vascular biology.
