The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform

Carol A Podlasek - One of the best experts on this subject based on the ideXlab platform.

  • peptide amphiphile delivery of Sonic Hedgehog Protein promotes neurite formation in penile projecting neurons
    Nanomedicine: Nanotechnology Biology and Medicine, 2018
    Co-Authors: Ryan W Dobbs, Daniel A Harrington, Samuel I Stupp, Shawn Choe, Elizabeth Kalmanek, Kevin T Mcvary, Carol A Podlasek
    Abstract:

    Abstract Erectile dysfunction (ED) critically impacts quality of life in prostatectomy, diabetic and aging patients. The underlying mechanism involves cavernous nerve (CN) damage, resulting in ED in 80% of prostatectomy patients. Peptide amphiphile (PA) nanofiber hydrogel delivery of Sonic Hedgehog (SHH) Protein to the injured CN, improves erectile function by 60% at 6 weeks after injury, by an unknown mechanism. We hypothesize that SHH is a regulator of neurite formation. SHH treatment promoted extensive neurite formation in uninjured and crushed CNs, and SHH inhibition decreased neurites >80%. Most abundant neurites were observed with continuous SHH PA treatment of crushed CNs. Once induced with SHH, neurites continued to grow. SHH rescued neurite formation when not given immediately. SHH is a critical regulator of neurite formation in peripheral neurons under uninjured and regenerative conditions, and SHH PA treatment at the time of injury/prostatectomy provides an exploitable avenue for intervention to prevent ED.

  • peptide amphiphile nanofiber hydrogel delivery of Sonic Hedgehog Protein to the cavernous nerve to promote regeneration and prevent erectile dysfunction
    Nanomedicine: Nanotechnology Biology and Medicine, 2017
    Co-Authors: Shawn Choe, Christopher W Bond, Daniel A Harrington, Samuel I Stupp, Kevin T Mcvary, Carol A Podlasek
    Abstract:

    Erectile dysfunction (ED) has high impact on quality of life in prostatectomy, diabetic and aging patients. An underlying mechanism is cavernous nerve (CN) injury, which causes ED in up to 80% of prostatectomy patients. We examine how Sonic Hedgehog (SHH) treatment with innovative peptide amphiphile nanofiber hydrogels (PA), promotes CN regeneration after injury. SHH and its receptors patched (PTCH1) and smoothened (SMO) are localized in PG neurons and glia. SMO undergoes anterograde transport to signal to downstream targets. With crush injury, PG neurons degenerate and undergo apoptosis. SHH Protein decreases, SMO localization changes to the neuronal cell surface, and anterograde transport stops. With SHH treatment SHH is taken up at the injury site and undergoes retrograde transport to PG neurons, allowing SMO transport to occur, and neurons remain intact. SHH treatment prevents neuronal degeneration, maintains neuronal, glial and downstream target signaling, and is significant as a regenerative therapy.

  • Sonic Hedgehog Protein is decreased and penile morphology is altered in prostatectomy and diabetic patients
    PLOS ONE, 2013
    Co-Authors: Nicholas L Angeloni, Christopher W Bond, Kevin T Mcvary, Carol A Podlasek
    Abstract:

    Erectile dysfunction (ED) is a debilitating medical condition and current treatments are ineffective in patients with cavernous nerve (CN) injury, due to penile remodeling and apoptosis. A critical regulator of penile smooth muscle and apoptosis is the secreted Protein Sonic Hedgehog (SHH). SHH Protein is decreased in rat prostatectomy and diabetic ED models, SHH inhibition in the penis induces apoptosis and ED, and SHH treatment at the time of CN injury suppresses smooth muscle apoptosis and promotes regeneration of erectile function. Thus SHH treatment has significant translational potential as an ED therapy if similar mechanisms underlie ED development in patients. In this study we quantify SHH Protein and morphological changes in corpora cavernosal tissue of control, prostatectomy and diabetic patients and hypothesize that decreased SHH Protein is an underlying cause of ED development in prostatectomy and diabetic patients. Our results show significantly decreased SHH Protein in prostatectomy and diabetic penis. Morphological remodelling of the penis, including significantly increased apoptotic index and decreased smooth muscle/collagen ratio, accompanies declining SHH. SHH signaling is active in human penis and is altered in a parallel manner to previous observations in the rat. These results suggest that SHH has significant potential to be developed as an ED therapy in prostatectomy and diabetic patients. The increased apoptotic index long after initial injury is suggestive of ongoing remodeling that may be clinically manipulatable.

  • peptide amphiphile nanofiber delivery of Sonic Hedgehog Protein to reduce smooth muscle apoptosis in the penis after cavernous nerve resection
    The Journal of Sexual Medicine, 2011
    Co-Authors: Christopher W Bond, Nicholas L Angeloni, Daniel A Harrington, Samuel I Stupp, Kevin E Mckenna, Carol A Podlasek
    Abstract:

    ABSTRACT Introduction Erectile dysfunction (ED) is a serious medical condition that affects 16–82% of prostate cancer patients treated by radical prostatectomy and current treatments are ineffective in 50–60% of prostatectomy patients. The reduced efficacy of treatments makes novel therapeutic approaches to treat ED essential. The secreted Protein Sonic Hedgehog (SHH) is a critical regulator of penile smooth muscle and apoptosis that is decreased in cavernous nerve (CN) injury and diabetic ED models. Past studies using Affi‐Gel beads have shown SHH Protein to be effective in suppressing apoptosis caused by CN injury. Aim We hypothesize that SHH Protein delivered via novel peptide amphiphile (PA) nanofibers will be effective in suppressing CN injury‐induced apoptosis. Methods Adult Sprague Dawley rats (n = 50) were used to optimize PA injection in vivo. PA with SHH Protein (n = 16) or bovine serum albumin (BSA) (control, n = 14) was injected into adult rats that underwent bilateral CN cut. Rats were sacrificed at 2, 4, and 7 days. Alexa Fluor‐labeled SHH Protein was used to determine the target of SHH signaling (n = 3). Main Outcome Measures Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and semiquantitative immunohistochemical analysis for SHH Protein and cluster differentiation Protein three (CD3) were performed. Results SHH‐PA caused a 25% and 16% reduction in apoptosis at 4 and 7 days after CN injury and a 9.3% and 19% increase in SHH Protein at 4 and 7 days after CN injury. CD3 Protein was not observed in SHH‐PA‐treated penis. In vitro, 73% of SHH Protein diffused from PA within 6 days. Labeled SHH was observed in smooth muscle. Conclusions PA technology is effective in delivering SHH Protein to the penis and SHH is effective in suppressing CN injury‐induced apoptosis. These results suggest substantial translational potential of this methodology and show that only a short duration of SHH treatment is required to impact the apoptotic index. Bond CW, Angeloni NL, Harrington DA, Stupp SI, McKenna KE, and Podlasek CA. Peptide amphiphile nanofiber delivery of Sonic Hedgehog Protein to reduce smooth muscle apoptosis in the penis after cavernous nerve resection. J Sex Med 2011;8:78–89.

Shengcai Chen - One of the best experts on this subject based on the ideXlab platform.

  • administration of Sonic Hedgehog Protein induces angiogenesis and has therapeutic effects after stroke in rats
    Neuroscience, 2017
    Co-Authors: Shengcai Chen, Ming Huang, Yan Zhang, Elvis Nana Opoku, Hang Yang, Huijuan Jin, Yuanpeng Xia
    Abstract:

    The Sonic Hedgehog (Shh) signaling pathway is recapitulated in response to ischemic injury. Here, we investigated the clinical implications of Shh Protein in the ischemic stroke and explored the underlying mechanism. Intracerebroventricular injection of Shh, Cyclopamine, or anti-vascular endothelial growth factor (VEGF) was performed immediately after permanent middle cerebral artery occlusion (pMCAO) surgery and lasted for 7days (d). Phosphate-buffered saline (PBS) was used as control. Neurological deficits and infarct volume were examined 7d after pMCAO. Microvascular density with fluorescein-iso-thiocyanate (FITC) assay and double staining with CD31 and Ki-67 was measured at 7d. To observe in vitro angiogenesis, rat brain microvascular endothelial cells (RBMECs) were incubated under oxygen glucose deprivation (OGD) for 6h (h) and treated with Shh/anti-VEGF. We found that (1) Shh improved neurological scores and reduced infarct volume, which was blocked by Cyclopamine, (2) Shh improved the microvascular density and promoted angiogenesis and neuron survival in the ischemic boundary zone, (3) Shh enhanced VEGF expression and VEGF antibody could reverse angiogenic and protective effect of Shh in vivo and in vitro. These data demonstrate that the administration of Shh Protein could protect brain from ischemic injury, in part by promoting angiogenic repair.

  • recombinant human Sonic Hedgehog Protein regulates the expression of zo 1 and occludin by activating angiopoietin 1 in stroke damage
    PLOS ONE, 2013
    Co-Authors: Yuanpeng Xia, Shengcai Chen, Ming Huang, Yong Wang, Yuan Gao, Yan Huang, Mengdie Wang, Ling Mao
    Abstract:

    This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 Protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage.

  • recombinant human Sonic Hedgehog Protein regulates the expression of zo 1 and occludin by activating angiopoietin 1 in stroke damage
    PLOS ONE, 2013
    Co-Authors: Quanwei He, Shengcai Chen, Ming Huang, Yong Wang, Yan Huang, Mengdie Wang, Yanan Li, Bo Hu
    Abstract:

    This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 Protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage.

Yuanpeng Xia - One of the best experts on this subject based on the ideXlab platform.

  • administration of Sonic Hedgehog Protein induces angiogenesis and has therapeutic effects after stroke in rats
    Neuroscience, 2017
    Co-Authors: Shengcai Chen, Ming Huang, Yan Zhang, Elvis Nana Opoku, Hang Yang, Huijuan Jin, Yuanpeng Xia
    Abstract:

    The Sonic Hedgehog (Shh) signaling pathway is recapitulated in response to ischemic injury. Here, we investigated the clinical implications of Shh Protein in the ischemic stroke and explored the underlying mechanism. Intracerebroventricular injection of Shh, Cyclopamine, or anti-vascular endothelial growth factor (VEGF) was performed immediately after permanent middle cerebral artery occlusion (pMCAO) surgery and lasted for 7days (d). Phosphate-buffered saline (PBS) was used as control. Neurological deficits and infarct volume were examined 7d after pMCAO. Microvascular density with fluorescein-iso-thiocyanate (FITC) assay and double staining with CD31 and Ki-67 was measured at 7d. To observe in vitro angiogenesis, rat brain microvascular endothelial cells (RBMECs) were incubated under oxygen glucose deprivation (OGD) for 6h (h) and treated with Shh/anti-VEGF. We found that (1) Shh improved neurological scores and reduced infarct volume, which was blocked by Cyclopamine, (2) Shh improved the microvascular density and promoted angiogenesis and neuron survival in the ischemic boundary zone, (3) Shh enhanced VEGF expression and VEGF antibody could reverse angiogenic and protective effect of Shh in vivo and in vitro. These data demonstrate that the administration of Shh Protein could protect brain from ischemic injury, in part by promoting angiogenic repair.

  • recombinant human Sonic Hedgehog Protein regulates the expression of zo 1 and occludin by activating angiopoietin 1 in stroke damage
    PLOS ONE, 2013
    Co-Authors: Yuanpeng Xia, Shengcai Chen, Ming Huang, Yong Wang, Yuan Gao, Yan Huang, Mengdie Wang, Ling Mao
    Abstract:

    This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 Protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage.

Ming Huang - One of the best experts on this subject based on the ideXlab platform.

  • administration of Sonic Hedgehog Protein induces angiogenesis and has therapeutic effects after stroke in rats
    Neuroscience, 2017
    Co-Authors: Shengcai Chen, Ming Huang, Yan Zhang, Elvis Nana Opoku, Hang Yang, Huijuan Jin, Yuanpeng Xia
    Abstract:

    The Sonic Hedgehog (Shh) signaling pathway is recapitulated in response to ischemic injury. Here, we investigated the clinical implications of Shh Protein in the ischemic stroke and explored the underlying mechanism. Intracerebroventricular injection of Shh, Cyclopamine, or anti-vascular endothelial growth factor (VEGF) was performed immediately after permanent middle cerebral artery occlusion (pMCAO) surgery and lasted for 7days (d). Phosphate-buffered saline (PBS) was used as control. Neurological deficits and infarct volume were examined 7d after pMCAO. Microvascular density with fluorescein-iso-thiocyanate (FITC) assay and double staining with CD31 and Ki-67 was measured at 7d. To observe in vitro angiogenesis, rat brain microvascular endothelial cells (RBMECs) were incubated under oxygen glucose deprivation (OGD) for 6h (h) and treated with Shh/anti-VEGF. We found that (1) Shh improved neurological scores and reduced infarct volume, which was blocked by Cyclopamine, (2) Shh improved the microvascular density and promoted angiogenesis and neuron survival in the ischemic boundary zone, (3) Shh enhanced VEGF expression and VEGF antibody could reverse angiogenic and protective effect of Shh in vivo and in vitro. These data demonstrate that the administration of Shh Protein could protect brain from ischemic injury, in part by promoting angiogenic repair.

  • recombinant human Sonic Hedgehog Protein regulates the expression of zo 1 and occludin by activating angiopoietin 1 in stroke damage
    PLOS ONE, 2013
    Co-Authors: Yuanpeng Xia, Shengcai Chen, Ming Huang, Yong Wang, Yuan Gao, Yan Huang, Mengdie Wang, Ling Mao
    Abstract:

    This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 Protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage.

  • recombinant human Sonic Hedgehog Protein regulates the expression of zo 1 and occludin by activating angiopoietin 1 in stroke damage
    PLOS ONE, 2013
    Co-Authors: Quanwei He, Shengcai Chen, Ming Huang, Yong Wang, Yan Huang, Mengdie Wang, Yanan Li, Bo Hu
    Abstract:

    This study examines the regulating effect of Sonic Hedgehog (Shh) on the permeability of the blood-brain barrier (BBB) in cerebral ischemia. By employing permanent middle cerebral artery occlusion (pMCAO) model, we find that Shh significantly decreases brain edema and preserves BBB permeability. Moreover, Shh increases zonula occludens-1 (ZO-1), occludin and angiopiotetin-1 (Ang-1) expression in the ischemic penumbra. Blockage of Shh with cyclopamine abolishes the effects of Shh on brain edema, BBB permeability and ZO-1, occludin, Ang-1 expression. Primary brain microvessel endothelial cells (BMECs) and astrocytes were pre-treated with Shh, cyclopamine, Ang-1-neutralizing antibody, and subjected to oxygen-glucose deprivation (OGD). Results show that the Ang-1 Protein level in the culture medium of Shh-treated astrocytes is significantly higher. Shh also increased ZO-1, occludin and Ang-1 expression in BMECs, while cyclopamine and Ang-1-neutralizing antibody inhibited the effects of Shh on the ZO-1 and occludin expression, respectively. This study suggests that, under ischemic insults, Shh triggers Ang-1 production predominantly in astrocytes, and the secreted Ang-1 acts on BMECs, thereby upregulating ZO-1 and occludin to repair the tight junction and ameliorate the brain edema and BBB leakage.

Philip A Beachy - One of the best experts on this subject based on the ideXlab platform.

  • scube you activity mediates release of dually lipid modified Hedgehog signal in soluble form
    Genes & Development, 2012
    Co-Authors: Adrian Creanga, Thomas D Glenn, Randall K Mann, Adam M Saunders, William S Talbot, Philip A Beachy
    Abstract:

    Owing to their covalent modification by cholesterol and palmitate, Hedgehog (Hh) signaling Proteins are localized predominantly to the plasma membrane of expressing cells. Yet Hh Proteins are also capable of mobilizing to and eliciting direct responses from distant cells. The zebrafish you gene, identified genetically >15 years ago, was more recently shown to encode a secreted glycoProtein that acts cell-nonautonomously in the Hh signaling pathway by an unknown mechanism. We investigated the function of the Protein encoded by murine Scube2, an ortholog of you, and found that it mediates release in soluble form of the mature, cholesterol- and palmitate-modified Sonic Hedgehog Protein signal (ShhNp) when added to cultured cells or purified detergent-resistant membrane microdomains containing ShhNp. The efficiency of Scube2-mediated release of ShhNp is enhanced by the palmitate adduct of ShhNp and by coexpression in ShhNp-producing cells of mDispatchedA (mDispA), a transporter-like Protein with a previously defined role in the release of lipid-modified Hh signals. The structural determinants of Scube2 required for its activity in cultured cell assays match those required for rescue of you mutant zebrafish embryos, and we thus conclude that the role of Scube/You Proteins in Hh signaling in vivo is to facilitate the release and mobilization of Hh Proteins for distant action.

  • molecular mechanisms of Sonic Hedgehog mutant effects in holoprosencephaly
    Proceedings of the National Academy of Sciences of the United States of America, 2005
    Co-Authors: Tapan K Maity, Naoyuki Fuse, Philip A Beachy
    Abstract:

    Holoprosencephaly (HPE), a human developmental brain defect, usually is also associated with varying degrees of midline facial dysmorphism. Heterozygous mutations in the Sonic Hedgehog (SHH) gene are the most common genetic lesions associated with HPE, and loss of Shh function in the mouse produces cyclopia and alobar forebrain development. The N-terminal domain (ShhNp) of Sonic Hedgehog Protein, generated by cholesterol-dependent autoprocessing and modification at the C terminus and by palmitate addition at the N terminus, is the active ligand in the Shh signal transduction pathway. Here, we analyze seven reported missense mutations (G31R, D88V, Q100H, N115K, W117G, W117R, and E188Q) that alter the N-terminal signaling domain of Shh Protein, and show that two of these mutations (Q100H and E188Q), which are questionably linked to HPE, produce no detectable effects on function. The remaining five alterations affect normal processing, Ptc binding, and signaling to varying degrees. These effects include introduction of a recognition site for furin-like proteases by the G31R alteration, resulting in cleavage of 11 amino acid residues from the N terminus of ShhNp and consequent reduced signaling potency. Two other alterations, W117G and W117R, cause temperature-dependent misfolding and retention in the sterol-poor endoplasmic reticulum, thus disrupting cholesterol-dependent autoprocessing.

  • Hedgehog regulated processing of gli3 produces an anterior posterior repressor gradient in the developing vertebrate limb
    Cell, 2000
    Co-Authors: Baolin Wang, John F Fallon, Philip A Beachy
    Abstract:

    Ci/Gli zinc finger Proteins mediate the transcriptional effects of Hedgehog Protein signals. In Drosophila, Ci action as transcriptional repressor or activator is contingent upon Hedgehog-regulated, PKA-dependent proteolytic processing. We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic Hedgehog Protein. The resulting anterior/posterior Gli3 repressor gradient can be perturbed by mutations of Gli3 in human genetic syndromes or by misregulation of Gli3 processing in the chicken mutant talpid2, producing a range of limb patterning malformations. The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation.