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Emiliano Mori - One of the best experts on this subject based on the ideXlab platform.
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How the South was won: current and potential range expansion of the crested Porcupine in Southern Italy
Mammalian Biology, 2021Co-Authors: Emiliano Mori, Gentile Francesco Ficetola, Remo Bartolomei, Giovanni Capobianco, Paolo Varuzza, Mattia FalaschiAbstract:Since the 1970s, the crested Porcupine Hystrix cristata has expanded its range into Northern regions in Italy, where it was historically absent, helped by climatic change, legal protection, and forest re-expansion. In the past 10 years, a remarkable range expansion has also been observed in the southernmost Italian regions. The aim of our work was to summarize the distribution of this species in Southern Italy and assess potential range expansion under multiple future scenarios of global warming. We collected 1783 occurrence records of the crested Porcupine through ad-hoc web pages, online platforms, and some data directly collected by authors ( N = 976 occurrences between 1998 and 2008; N = 807 between 2008 and 2019). A remarkable increase in Porcupine records occurred in Lucania, Campania, and Apulia regions, in Southern Italy, mostly along the coastlines. Species distribution models showed that Porcupine presence is associated with warm temperatures and an intermediate level of precipitation. Although land-cover showed lower importance compared to climate, the species was positively associated with forests and negatively associated with agricultural, grasslands and shrublands, and urban landscapes. Model projections suggested that future global warming can improve suitability for Porcupines in the Apennine ridge, including the Southern Calabria and the Aspromonte National Park. However, increase in drought and urbanization may reduce the habitat suitability for the crested Porcupine in the Salento peninsula, limiting the success of the range expansion by this large rodent, and in Eastern Calabria, wih possible range contractions along the Tyrrhenian coast.
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suburban ecology of the crested Porcupine in a heavily poached area a global approach
European Journal of Wildlife Research, 2017Co-Authors: Sandro Lovari, Maria Teresa Corsini, Barbara Guazzini, Giorgia Romeo, Emiliano MoriAbstract:Urban areas not only provide wildlife with new ecological niches, in terms of food availability, human protection and den sites but also they increase the possibility of conflict with man. Despite being a protected species in Italy, the crested Porcupine is considered as an agricultural pest, with a tasty meat, thus widely poached. We studied food selection and other ecological factors shaping the ranging behaviour of crested Porcupines in a suburban area, where a high poaching pressure could be expected. We monitored radio-tagged adult, paired crested Porcupines throughout 1 year. Over 70% of individually marked Porcupines were poached. Despite the local absence of predators, but in presence of poaching pressure, Porcupines avoided clear moonlight nights and daylight activity, establishing dens in thorny thickets. Deciduous woodlands and shrubwood were positively selected for feeding throughout the year, while farmlands and fallows were underused. Although the crested Porcupine has been confirmed as a “generalist” species in terms of food selection, with adaptations to dig underground storage organs, a strong preference for fruits and epigeal parts of plants was detected in our study. Porcupines evolved in Asia and Africa with a number of competing grazing herbivores, as well as in presence of a heavy predation risk leading to development of quills. This might have confined them to exploit roots and rhizomes as food, as well as scrub habitats for protection. Our results suggest that Porcupines can revert to the use of optimal food resources, when local selective forces allow it.
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ectoparasite load in the crested Porcupine hystrix cristata linnaeus 1758 in central italy
Parasitology Research, 2015Co-Authors: Andrea Sforzi, Sandro Lovari, Emiliano Mori, Mattia Menchetti, Giuseppe Mazza, Benoit PisanuAbstract:The crested Porcupine Hystrix cristata is a large body-sized rodent, occurring in Europe only in the Italian Peninsula, where it may have been introduced in early Medieval times. Its parasite fauna is currently poorly known and limited to few anecdotal observations. We have analyzed the ectoparasite load of 165 crested Porcupines from Tuscany and Latium (Central Italy). Both captured and road-killed individuals were checked for fleas and ticks. Overall, only 39 Porcupines were infested by four species of ticks and five of fleas. Abundance of ectoparasites was higher in areas with higher habitat richness, with respect to densely wooded areas. The most frequent species was the flea Pulex irritans (25 %), whose prevalence peaked in winter probably because of optimal abiotic conditions in the Porcupine’s den. The remaining species of both hard ticks (Rhipicephalus bursa, Pholeoixodes hexagonus, and Ixodes ventalloi) and fleas (Paraceras melis, Ctenocephalides canis, Dasypsyllus gallinulae, and Hystrichopsylla talpae), all with prevalence lower than 5 %, could be due to den sharing with other vertebrates, mainly carnivores such as, e.g., red foxes and badgers. The second most prevalent species was the generalist tick Ixodes ricinus (21 %). An adult male-biased parasitism for ticks has been detected, suggesting a possible role of testosterone related immune-depressive effect. The low richness in dominant ectoparasite species, built up by locally acquired generalist taxa, provides support to the allochthonous origin of this rodent in Italy.
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patterns of spatial overlap in a monogamous large rodent the crested Porcupine
Behavioural Processes, 2014Co-Authors: Emiliano Mori, Andrea Sforzi, Sandro Lovari, Alessandro Massolo, Giorgia Romeo, Caterina Pisani, Lorenzo FattoriniAbstract:Abstract The crested Porcupine Hystrix cristata is a large rodent which pairs for life. We studied the space use of 17 female and 9 male radio-tracked Porcupines in an evergreen coastal woodland (“macchia”, EW) and in an agricultural estate (AE), with special reference to the use of cultivations. Home range sizes of male Porcupines (4.72–323.40) ranged around 114 ha (median) during the warm period (April–September) and 162 ha during the cold one (October–March). Home ranges of females (2.48–323.40) were c. 91 ha during the warm period and c. 143 ha during the cold one. Habitat composition and selection changed from the cold to the warm months, with Porcupines being present in agricultural areas especially in the latter. Home range overlap between members of the same pair varied from 57% to 97% (median, 75%). Habitat selection was analyzed at the second (within study area) and at the third (within home range) order of selection. Within study areas, Porcupines avoided cultivations and selected habitats with dense vegetation, providing cover and food. Within home ranges, in the warm period, Porcupines selected agricultural areas in EW, where this habitat represented a minor portion of the study site. In that season, the Mediterranean “macchia” is a poor source of food, forcing Porcupines to travel long distances to reach feeding sites. No significant difference of habitat selection within home ranges was detected between members of the same pair. Cultivations may play a key-role for Porcupine survival, especially in poor habitats, as they provide abundant food resources in the warm period.
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Interspecific den sharing: a study on European badger setts using camera traps
acta ethologica, 2014Co-Authors: Emiliano Mori, Mattia Menchetti, Alessandro BalestrieriAbstract:Many mammals, both potential competitors and preys, have been reported to use the complex burrow system of European badger Meles meles setts as shelter, mainly in northern Europe and during winter, when badgers are lethargic. Nonetheless, until recent times observations of den sharing have been largely restricted to anecdotal information, because of the mainly nocturnal activity of most sett occupants. Using camera-trapping, we investigated both the mammal fauna associated with 24 badger setts located in northern and central Italy, and seasonal variation in the composition of specific assemblages, without interfering with the occupants’ activity. Trapping effort was 1,605 camera trap-days from December 2010 to December 2013. Badgers (two to six individuals per sett) shared their setts with a total of eight mammal species: crested Porcupine Hystrix cristata, Eastern cottontail Sylvilagus floridanus, red fox Vulpes vulpes, pine marten Martes martes, stone marten Martes foina, wood mouse Apodemus sp., brown rat Rattus norvegicus and coypu Myocastor coypus. Den sharing was observed throughout the year, with a significant reduction of sharing during winter, when badgers were probably induced to move to alternative setts to avoid breeding Porcupines. Eastern cottontails used badger burrows permanently and, at least in one occasion, reared their pups inside, although they can be easily preyed upon by badgers. Badger sett sharing may have favoured both the recent northward expansion of crested Porcupines and settling of introduced cottontails in agricultural habitats.
David M Virshup - One of the best experts on this subject based on the ideXlab platform.
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opposing actions of renal tubular and myeloid derived Porcupine in obstruction induced kidney fibrosis
Kidney International, 2019Co-Authors: Nathan P Rudemiller, Jiafa Ren, Yi Wen, Bo Yang, Robert Griffiths, Jamie R Privratsky, Babita Madan, David M Virshup, Steven D CrowleyAbstract:Wnt/β-catenin signaling is essential in the pathogenesis of renal fibrosis. We previously reported inhibition of the Wnt O-acyl transferase Porcupine, required for Wnt secretion, dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Here, we investigated the tissue-specific contributions of Porcupine to renal fibrosis and inflammation in ureteral obstruction using mice with Porcupine deletion restricted to the kidney tubular epithelium or infiltrating myeloid cells. Obstruction of the ureter induced the renal mRNA expression of Porcupine and downstream targets, β-catenin, T-cell factor, and lymphoid enhancer factor in wild type mice. Renal tubular specific deficiency of Porcupine reduced the expression of collagen I and other fibrosis markers in the obstructed kidney. Moreover, kidneys from obstructed mice with tubule-specific Porcupine deficiency had reduced macrophage accumulation with attenuated expression of myeloid cytokine and chemokine mRNA. In co-culture with activated macrophages, renal tubular cells from tubular-specific Porcupine knockout mice had blunted induction of fibrosis mediators compared with wild type renal tubular cells. In contrast, macrophages from macrophage-specific Porcupine deficient mice in co-culture with wild type renal tubular cells had markedly enhanced expression of pro-fibrotic cytokines compared to wild type macrophages. Consequently, Porcupine deletion specifically within macrophages augmented renal scar formation following ureteral obstruction. Thus, our experiments suggest a benefit of interrupting Wnt secretion specifically within the kidney epithelium while preserving Wnt O-acylation in infiltrating myeloid cells during renal fibrogenesis.
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scaffold hopping and optimization of maleimide based Porcupine inhibitors
Journal of Medicinal Chemistry, 2017Co-Authors: Jenefer Alam, Weiling Wang, Duraiswamy Athisayamani Jeyaraj, Shi Hua Ang, Eldwin Sum Wai Tan, Grace Ruiting Lin, May Ann Lee, Babita Madan, David M Virshup, Li Jun DingAbstract:Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting Porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently Porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against Porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.
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abstract 1172 in vivopharmacokinetic properties and antitumor efficacy of Porcupine lead inhibitors in the orthotopic murine mmtv wnt1 breast tumor model and the human hpaf ii pancreatic xenograft mouse model
Cancer Research, 2017Co-Authors: Vishal Pendharkar, Weiling Wang, Babita Madan, David M Virshup, Yun Shan Chew, Vithya Manoharan, Choon Bing Low, Hongqian Esther Ong, Jeyaraj Duraiswamy Athisayamani, Thomas H KellerAbstract:Porcupine (PORCN), a muti-pass integral membrane-bound-O-Acyl acyltransferase (MBOAT), resides in the in the endoplasmic reticulum (ER) and is required for biogenesis of Wnt ligands. The secreted mature Wnt ligands bind to their cognate receptors (Frizzled, LRP5/6 and transmembrane receptor ROR) to form the ligand - receptor complex which is capable to activate the Wnt-β-catenin signalling cascade and downstream signalling pathways such as mTOR, GSK3, Akt, and PKC. The deregulation of and aberrant activation of the various components of Wnt-β-catenin signalling pathway have been implicated in tumorigenesis, cell proliferation, survival and differentiation. Hyperactivity of PORCN is found to be associated with cancerous cell growth. Knockdown of Porcn mRNA significantly reduced the proliferation of breast cancer cells and resulted in the delay of MDA-MB-231 tumor formation in mouse xenograft models (Covey et al 2012). Loss of function mutations of RNF43, a negative regulation of Wnt-signalling via Frizzled receptor, is recently reported to be involved with pancreatic ductal adenocarcinoma. Inhibition of the PDAC cell lines bearing RNF43 mutations enhanced Wnt-β-catenin signalling and resulted in suppression of proliferation and differentiation of PDAC tumor cells (Jiang et al 2013). Taken together Porcupine could be an attractive therapeutic approach for a particular Wnt-driven cancer population. We have identified the Porcupine lead compounds (ETC-159, ETC-535, ETC-611 and ETC-539) from different novel chemical scaffolds. The aim of this study was to evaluate their pharmacokinetic properties and antitumor efficacy in different cancer mouse models, the murine MMTV-Wnt1 breast cancer and the human pancreatic HPAF-II cancer. All Porcupine lead compounds had good oral pharmacokinetic properties with the absolute oral bioavailability greater than 42%. They had the maximum tolerated dose (MTD-7d) up to 200 mg/kg. They produced antitumor efficacy ranging from 24% to 79% at 1 mg/kg, 38% to 89% at 3 mg/kg, and 58 to 97% at 10 mg/kg in MMTV-Wnt1 tumor mouse model. In vivo inhibition of PORCN led to reduce the expression level of Axin2 in MMTV-Wnt tumors upto 8h. At 100 mg/kg, they produced antitumor efficacy ranging from 34% to 91% in human HPAF-II pancreatic xenograft mouse model. Of 4 Porcupine lead compounds, ETC-159 demonstrated great oral pharmacokinetic properties and produced significantly antitumor efficacy (p value Citation Format: Vishal Pendharkar, Yun Shan Chew, Vithya Manoharan, Choon Bing Low, Hongqian Esther Ong, Soo Yei Ho, Wei Ling Wang, Jeyaraj Duraiswamy Athisayamani, Babita Madan, David Virshup, Thomas Hugo Keller, May Ann Lee, Alex Matter, Jeffrey Hill, Kanda Sangthongpitag. In vivo pharmacokinetic properties and antitumor efficacy of Porcupine lead inhibitors in the orthotopic murine MMTV-Wnt1 breast tumor model and the human HPAF-II pancreatic xenograft mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1172. doi:10.1158/1538-7445.AM2017-1172
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experimental inhibition of Porcupine mediated wnt o acylation attenuates kidney fibrosis
Kidney International, 2016Co-Authors: Babita Madan, Nathan P Rudemiller, Robert Griffiths, David M Virshup, Mehul B Patel, Jiandong Zhang, Ralph M Bunte, Steven D CrowleyAbstract:Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase Porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting Porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, Porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of Porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.
Babita Madan - One of the best experts on this subject based on the ideXlab platform.
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opposing actions of renal tubular and myeloid derived Porcupine in obstruction induced kidney fibrosis
Kidney International, 2019Co-Authors: Nathan P Rudemiller, Jiafa Ren, Yi Wen, Bo Yang, Robert Griffiths, Jamie R Privratsky, Babita Madan, David M Virshup, Steven D CrowleyAbstract:Wnt/β-catenin signaling is essential in the pathogenesis of renal fibrosis. We previously reported inhibition of the Wnt O-acyl transferase Porcupine, required for Wnt secretion, dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Here, we investigated the tissue-specific contributions of Porcupine to renal fibrosis and inflammation in ureteral obstruction using mice with Porcupine deletion restricted to the kidney tubular epithelium or infiltrating myeloid cells. Obstruction of the ureter induced the renal mRNA expression of Porcupine and downstream targets, β-catenin, T-cell factor, and lymphoid enhancer factor in wild type mice. Renal tubular specific deficiency of Porcupine reduced the expression of collagen I and other fibrosis markers in the obstructed kidney. Moreover, kidneys from obstructed mice with tubule-specific Porcupine deficiency had reduced macrophage accumulation with attenuated expression of myeloid cytokine and chemokine mRNA. In co-culture with activated macrophages, renal tubular cells from tubular-specific Porcupine knockout mice had blunted induction of fibrosis mediators compared with wild type renal tubular cells. In contrast, macrophages from macrophage-specific Porcupine deficient mice in co-culture with wild type renal tubular cells had markedly enhanced expression of pro-fibrotic cytokines compared to wild type macrophages. Consequently, Porcupine deletion specifically within macrophages augmented renal scar formation following ureteral obstruction. Thus, our experiments suggest a benefit of interrupting Wnt secretion specifically within the kidney epithelium while preserving Wnt O-acylation in infiltrating myeloid cells during renal fibrogenesis.
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scaffold hopping and optimization of maleimide based Porcupine inhibitors
Journal of Medicinal Chemistry, 2017Co-Authors: Jenefer Alam, Weiling Wang, Duraiswamy Athisayamani Jeyaraj, Shi Hua Ang, Eldwin Sum Wai Tan, Grace Ruiting Lin, May Ann Lee, Babita Madan, David M Virshup, Li Jun DingAbstract:Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting Porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently Porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against Porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.
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abstract 1172 in vivopharmacokinetic properties and antitumor efficacy of Porcupine lead inhibitors in the orthotopic murine mmtv wnt1 breast tumor model and the human hpaf ii pancreatic xenograft mouse model
Cancer Research, 2017Co-Authors: Vishal Pendharkar, Weiling Wang, Babita Madan, David M Virshup, Yun Shan Chew, Vithya Manoharan, Choon Bing Low, Hongqian Esther Ong, Jeyaraj Duraiswamy Athisayamani, Thomas H KellerAbstract:Porcupine (PORCN), a muti-pass integral membrane-bound-O-Acyl acyltransferase (MBOAT), resides in the in the endoplasmic reticulum (ER) and is required for biogenesis of Wnt ligands. The secreted mature Wnt ligands bind to their cognate receptors (Frizzled, LRP5/6 and transmembrane receptor ROR) to form the ligand - receptor complex which is capable to activate the Wnt-β-catenin signalling cascade and downstream signalling pathways such as mTOR, GSK3, Akt, and PKC. The deregulation of and aberrant activation of the various components of Wnt-β-catenin signalling pathway have been implicated in tumorigenesis, cell proliferation, survival and differentiation. Hyperactivity of PORCN is found to be associated with cancerous cell growth. Knockdown of Porcn mRNA significantly reduced the proliferation of breast cancer cells and resulted in the delay of MDA-MB-231 tumor formation in mouse xenograft models (Covey et al 2012). Loss of function mutations of RNF43, a negative regulation of Wnt-signalling via Frizzled receptor, is recently reported to be involved with pancreatic ductal adenocarcinoma. Inhibition of the PDAC cell lines bearing RNF43 mutations enhanced Wnt-β-catenin signalling and resulted in suppression of proliferation and differentiation of PDAC tumor cells (Jiang et al 2013). Taken together Porcupine could be an attractive therapeutic approach for a particular Wnt-driven cancer population. We have identified the Porcupine lead compounds (ETC-159, ETC-535, ETC-611 and ETC-539) from different novel chemical scaffolds. The aim of this study was to evaluate their pharmacokinetic properties and antitumor efficacy in different cancer mouse models, the murine MMTV-Wnt1 breast cancer and the human pancreatic HPAF-II cancer. All Porcupine lead compounds had good oral pharmacokinetic properties with the absolute oral bioavailability greater than 42%. They had the maximum tolerated dose (MTD-7d) up to 200 mg/kg. They produced antitumor efficacy ranging from 24% to 79% at 1 mg/kg, 38% to 89% at 3 mg/kg, and 58 to 97% at 10 mg/kg in MMTV-Wnt1 tumor mouse model. In vivo inhibition of PORCN led to reduce the expression level of Axin2 in MMTV-Wnt tumors upto 8h. At 100 mg/kg, they produced antitumor efficacy ranging from 34% to 91% in human HPAF-II pancreatic xenograft mouse model. Of 4 Porcupine lead compounds, ETC-159 demonstrated great oral pharmacokinetic properties and produced significantly antitumor efficacy (p value Citation Format: Vishal Pendharkar, Yun Shan Chew, Vithya Manoharan, Choon Bing Low, Hongqian Esther Ong, Soo Yei Ho, Wei Ling Wang, Jeyaraj Duraiswamy Athisayamani, Babita Madan, David Virshup, Thomas Hugo Keller, May Ann Lee, Alex Matter, Jeffrey Hill, Kanda Sangthongpitag. In vivo pharmacokinetic properties and antitumor efficacy of Porcupine lead inhibitors in the orthotopic murine MMTV-Wnt1 breast tumor model and the human HPAF-II pancreatic xenograft mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1172. doi:10.1158/1538-7445.AM2017-1172
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experimental inhibition of Porcupine mediated wnt o acylation attenuates kidney fibrosis
Kidney International, 2016Co-Authors: Babita Madan, Nathan P Rudemiller, Robert Griffiths, David M Virshup, Mehul B Patel, Jiandong Zhang, Ralph M Bunte, Steven D CrowleyAbstract:Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase Porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting Porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, Porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of Porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.
Steven D Crowley - One of the best experts on this subject based on the ideXlab platform.
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opposing actions of renal tubular and myeloid derived Porcupine in obstruction induced kidney fibrosis
Kidney International, 2019Co-Authors: Nathan P Rudemiller, Jiafa Ren, Yi Wen, Bo Yang, Robert Griffiths, Jamie R Privratsky, Babita Madan, David M Virshup, Steven D CrowleyAbstract:Wnt/β-catenin signaling is essential in the pathogenesis of renal fibrosis. We previously reported inhibition of the Wnt O-acyl transferase Porcupine, required for Wnt secretion, dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Here, we investigated the tissue-specific contributions of Porcupine to renal fibrosis and inflammation in ureteral obstruction using mice with Porcupine deletion restricted to the kidney tubular epithelium or infiltrating myeloid cells. Obstruction of the ureter induced the renal mRNA expression of Porcupine and downstream targets, β-catenin, T-cell factor, and lymphoid enhancer factor in wild type mice. Renal tubular specific deficiency of Porcupine reduced the expression of collagen I and other fibrosis markers in the obstructed kidney. Moreover, kidneys from obstructed mice with tubule-specific Porcupine deficiency had reduced macrophage accumulation with attenuated expression of myeloid cytokine and chemokine mRNA. In co-culture with activated macrophages, renal tubular cells from tubular-specific Porcupine knockout mice had blunted induction of fibrosis mediators compared with wild type renal tubular cells. In contrast, macrophages from macrophage-specific Porcupine deficient mice in co-culture with wild type renal tubular cells had markedly enhanced expression of pro-fibrotic cytokines compared to wild type macrophages. Consequently, Porcupine deletion specifically within macrophages augmented renal scar formation following ureteral obstruction. Thus, our experiments suggest a benefit of interrupting Wnt secretion specifically within the kidney epithelium while preserving Wnt O-acylation in infiltrating myeloid cells during renal fibrogenesis.
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experimental inhibition of Porcupine mediated wnt o acylation attenuates kidney fibrosis
Kidney International, 2016Co-Authors: Babita Madan, Nathan P Rudemiller, Robert Griffiths, David M Virshup, Mehul B Patel, Jiandong Zhang, Ralph M Bunte, Steven D CrowleyAbstract:Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase Porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting Porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, Porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of Porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.
Andrea Sforzi - One of the best experts on this subject based on the ideXlab platform.
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ectoparasite load in the crested Porcupine hystrix cristata linnaeus 1758 in central italy
Parasitology Research, 2015Co-Authors: Andrea Sforzi, Sandro Lovari, Emiliano Mori, Mattia Menchetti, Giuseppe Mazza, Benoit PisanuAbstract:The crested Porcupine Hystrix cristata is a large body-sized rodent, occurring in Europe only in the Italian Peninsula, where it may have been introduced in early Medieval times. Its parasite fauna is currently poorly known and limited to few anecdotal observations. We have analyzed the ectoparasite load of 165 crested Porcupines from Tuscany and Latium (Central Italy). Both captured and road-killed individuals were checked for fleas and ticks. Overall, only 39 Porcupines were infested by four species of ticks and five of fleas. Abundance of ectoparasites was higher in areas with higher habitat richness, with respect to densely wooded areas. The most frequent species was the flea Pulex irritans (25 %), whose prevalence peaked in winter probably because of optimal abiotic conditions in the Porcupine’s den. The remaining species of both hard ticks (Rhipicephalus bursa, Pholeoixodes hexagonus, and Ixodes ventalloi) and fleas (Paraceras melis, Ctenocephalides canis, Dasypsyllus gallinulae, and Hystrichopsylla talpae), all with prevalence lower than 5 %, could be due to den sharing with other vertebrates, mainly carnivores such as, e.g., red foxes and badgers. The second most prevalent species was the generalist tick Ixodes ricinus (21 %). An adult male-biased parasitism for ticks has been detected, suggesting a possible role of testosterone related immune-depressive effect. The low richness in dominant ectoparasite species, built up by locally acquired generalist taxa, provides support to the allochthonous origin of this rodent in Italy.
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patterns of spatial overlap in a monogamous large rodent the crested Porcupine
Behavioural Processes, 2014Co-Authors: Emiliano Mori, Andrea Sforzi, Sandro Lovari, Alessandro Massolo, Giorgia Romeo, Caterina Pisani, Lorenzo FattoriniAbstract:Abstract The crested Porcupine Hystrix cristata is a large rodent which pairs for life. We studied the space use of 17 female and 9 male radio-tracked Porcupines in an evergreen coastal woodland (“macchia”, EW) and in an agricultural estate (AE), with special reference to the use of cultivations. Home range sizes of male Porcupines (4.72–323.40) ranged around 114 ha (median) during the warm period (April–September) and 162 ha during the cold one (October–March). Home ranges of females (2.48–323.40) were c. 91 ha during the warm period and c. 143 ha during the cold one. Habitat composition and selection changed from the cold to the warm months, with Porcupines being present in agricultural areas especially in the latter. Home range overlap between members of the same pair varied from 57% to 97% (median, 75%). Habitat selection was analyzed at the second (within study area) and at the third (within home range) order of selection. Within study areas, Porcupines avoided cultivations and selected habitats with dense vegetation, providing cover and food. Within home ranges, in the warm period, Porcupines selected agricultural areas in EW, where this habitat represented a minor portion of the study site. In that season, the Mediterranean “macchia” is a poor source of food, forcing Porcupines to travel long distances to reach feeding sites. No significant difference of habitat selection within home ranges was detected between members of the same pair. Cultivations may play a key-role for Porcupine survival, especially in poor habitats, as they provide abundant food resources in the warm period.
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from the apennines to the alps recent range expansion of the crested Porcupine hystrix cristata l 1758 mammalia rodentia hystricidae in italy
Italian Journal of Zoology, 2013Co-Authors: Emiliano Mori, Andrea Sforzi, M Di FebbraroAbstract:AbstractIn the last few decades, the crested Porcupine (Hystrix cristata L., 1758) showed a marked range expansion in Italy. Published and unpublished material was collected to reconstruct this phenomenon. Data were gathered by means of: (i) specific papers on crested Porcupine distribution and more generic books and articles, (ii) expert collaboration in various Italian regions and (iii) information from the national Vertebrates mailing list. Until the 1970s, H. cristata was only present in Central and Southern Italy, mostly in the western part. Since 1978, the Porcupine has been protected by Italian national law. The species first crossed the Apennines from the Tyrrhenian coast to the Marche, where the expansion to the north may have begun, and then reached the northernmost regions. An analysis of the potential distribution of the species was performed in a species distribution modeling framework (Maxent). The model suggested a high suitability of most of the Central and Southern Italian Peninsula for H...
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chemical immobilization of crested Porcupines with tiletamine hcl and zolazepam hcl zoletil under field conditions
Journal of Wildlife Diseases, 2003Co-Authors: Alessandro Massolo, Andrea Sforzi, Sandro LovariAbstract:The combination of tiletamine HCl and zolazepam HCl has been used on many species of wild mammals. Short induction time, low dosage, satisfactory safety margins, relatively constant immobilization time, and smooth recovery are benefits reported. This combination (Zoletil® 100) was used during a study on behavioural ecology of the crested Porcupine (Hystrix cristata) in a Mediterranean coastal area (Maremma Regional Park, Tuscany, Italy). We used this mixture 42 times on 31 individuals. Mean adult dose was (±SE) 7.24±0.37 mg/kg (74.0±3.0 mg/individual). Average adult induction time was 5.3 min (±1.1) and average adult immobilization time was 22.6 min (±6.0). One adult male Porcupine died after chemical restraints. The use of tiletamine-zolazepam seems adequate for chemical immobilization of crested Porcupines under field conditions, mainly because of its short induction time, small volume to be injected and wide safety margin.
