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Generation of iPSC-derived limb progenitor-like cells for stimulating phalange regeneration in the adult mouse.

The capacity of digit tip regeneration observed both in rodents and humans establishes a foundation for promoting robust regeneration in mammals. However, stimulating regeneration at more proximal levels, such as the middle phalanges (P2) of the adult mouse, remains challenging. Having shown the effectiveness of transplantation of limb progenitor cells in stimulating limb regeneration in Xenopus, we are now applying the cell transplantation approach to the adult mouse. Here we report that both embryonic and induced pluripotent stem cell (iPSC)-derived limb progenitor-like cells can promote adult mouse P2 regeneration. We have established a simple and efficient protocol for deriving limb progenitor-like cells from mouse iPSCs. iPSCs are cultured as three-dimensional fibrin bodies, followed by treatment with combinations of Fgf8, CHIR99021, Purmorphamine and SB43542 during differentiation. These iPSC-derived limb progenitor-like cells resemble embryonic limb mesenchyme cells in their expression of limb-related genes. After transplantation, the limb progenitor-like cells can promote adult mouse P2 regeneration, as embryonic limb bud cells do. Our results provide a basis for further developing progenitor cell-based approaches for improving regeneration in the adult mouse limbs.

2320 related Products with: Generation of iPSC-derived limb progenitor-like cells for stimulating phalange regeneration in the adult mouse.

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WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome.

WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues. Wdr11-null mice also exhibit early-onset obesity. We find that WDR11 shuttles from the cilium to the nucleus in response to Hh signalling. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin-releasing hormone production. The CHH/KS-associated human mutations result in loss of function of WDR11. Treatment with the Hh agonist purmorphamine partially rescues the WDR11 haploinsufficiency phenotypes. Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum.

2476 related Products with: WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome.

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Wip1 regulates blood-brain barrier function and neuro-inflammation induced by lipopolysaccharide via the sonic hedgehog signaling signaling pathway.

The blood brain barrier (BBB) is a diffusion barrier that maintains the brain environment. Wip1 is a nuclear phosphatase induced by many factors and involved in various stresses, tumorigenesis, organismal aging, and neurogenesis. Wip1's role in BBB integrity has not been thoroughly investigated. The purpose of the present study was to investigate the effect and mechanism of Wip1 on lipopolysaccharide (LPS)-induced BBB dysfunction and inflammation in an in vitro BBB model. The in vitro BBB model was established by co-culturing human brain-microvascular endothelial cells and human astrocytes and then exposing them to 1μg/ml LPS for 6, 12, 18, 24, and 48h. Wip1 expression was significantly elevated by LPS treatment. Knockdown of Wip1 aggravated the increased permeability and decreased transepithelial electrical resistance, protein expression of ZO-1, and occludin induced by LPS. Wip1 silencing augmented the elevated inflammatory cytokines TNF-α, IL-1β, IL-12, and IL-6 of the BBB induced by LPS, whereas overexpression of Wip1 showed a contrary effect. Sonic hedgehog signaling (SHH) was activated by Wip1 overexpression and inhibited by Wip1 silencing. Additionally, activating or inhibiting the SHH pathway by purmorphamine or cyclopamine, respectively, abolished the Wip1-induced changes in transepithelial electrical resistance and permeability and inflammatory responses in the LPS-injured BBB model. Our results demonstrate that Wip1 may protect the BBB against LPS-induced integrity disruption and inflammatory response through the SHH signaling pathway.

1211 related Products with: Wip1 regulates blood-brain barrier function and neuro-inflammation induced by lipopolysaccharide via the sonic hedgehog signaling signaling pathway.

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Preconditioning potential of purmorphamine: a hedgehog activator against ischaemic reperfusion injury in ovariectomised rat heart.

The present study was been designed to investigate the role and pharmacological potential of hedgehog in oestrogen-deficient rat heart.

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[Mechanism of Ezhu-containing serum in inhibiting expression of Shh and Gli1 in hepatic stellate cells].

To explore the mechanism of Ezhu-containing serum in inhibiting the expression of sonic hedgehog(Shh) and glioma-associated oncogene homolog-1(Gli1) in hepatic stellate cells(HSCs) induced by leptin. Twenty sprague-dawley (SD) rats were randomly divided into 2 groups (n=10), and given Ezhu-decoction and physiological saline by gavage for 10 days to prepare drug-containing serums. The HSCs during the exponential growth phase were divided into 7 groups: blank control group, model group, hedgehog pathway inhibitor(cyclopamine) group, Ezhu group, Ezhu and cyclopamine group, hedgehog pathway agonost(pumorphamine) group, Ezhu and purmorphamine group. HSCs were cultured in vitro and induced with 100 μg•L ⁻¹ leptin(except for the blank control group), then treated separately with the corresponding drugs for 24 hours. After the cells were collected, HSCs proliferation was detected using MTT colorimetric assay; the expressions of Shh and Gli1 were determined by PT-PCR, Western blot and immunofluorescence, respectively. The expressions of Shh and Gli1 were significantly increased after the HSCs of rats were induced by leptin (compared with the blank control group, P<0.01). After being interfered with Hh pathway inhibitor (cyclopamine) and Ezhu-containing serum, the expressions of Shh and Gli1 were decreased significantly(compared with the model group, P<0.01). After Ezhu-containing serum was used to interfere the Hh pathway inhibitor group, the mRNA and protein expressions of Shh and Gli1 were decreased significantly(compared with the model group, P<0.01). After Ezhu-containing serum was used to interfere the purmorphamine group, the mRNA and protein expressions of Shh and Gli1 decreased significantly(compared with the purmorphamine group, P<0.01). Ezhu-containing serum plays an important role in inhibiting HSCs activation by taking part in hedgehog signaling pathway, so as to regulate the expression of Shh and Gli1 in leptin-induced HSCs and then inhibit liver fibrosis.

1488 related Products with: [Mechanism of Ezhu-containing serum in inhibiting expression of Shh and Gli1 in hepatic stellate cells].

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Directed transdifferentiation of Müller glial cells to photoreceptors using the sonic hedgehog signaling pathway agonist purmorphamine.

Specification of distinct cell types from Müller glial cells is key to the potential application of endogenous repair in retinal regeneration. Sonic hedgehog (SHH) has been established as a potent mitogen for rat Müller glial cells, which also induces Müller glial cells to dedifferentiate and adopt the phenotype of rod photoreceptors. The present study investigated the effects of purmorphamine, a small molecule that activates the SHH‑pathway, in the proliferation, dedifferentiation and transdifferentiation of Müller glial cells, as determined by several methods including immunofluorescence, polymerase chain reaction and western blotting. It was demonstrated that it may be able to replace SHH for the regeneration of retinal neurons. Purmorphamine was revealed to stimulate the proliferation of Müller glial cells by increasing the expression of cyclin D1 and cyclin D3. In addition, purmorphamine‑treated Müller glial cells were induced to dedifferentiate by inducing the expression of progenitor‑specific markers; subsequently differentiating into rod‑like photoreceptors. Intraocular injection of purmorphamine promoted the activation of Müller glial cells, and in turn, the production of rod‑like photoreceptors in acute damaged retina. These results suggested that the endogenous neurogenic capacity of retinal Müller glial cells may be enhanced by this small molecular agonist of the SHH signaling pathway.

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A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies.

Joubert syndrome (JBTS) is the archetypal ciliopathy caused by mutation of genes encoding ciliary proteins leading to multi-system phenotypes, including a cerebello-retinal-renal syndrome. JBTS is genetically heterogeneous, however mutations in CEP290 are a common underlying cause. The renal manifestation of JBTS is a juvenile-onset cystic kidney disease, known as nephronophthisis, typically progressing to end-stage renal failure within the first two decades of life, thus providing a potential window for therapeutic intervention. In order to increase understanding of JBTS and its associated kidney disease and to explore potential treatments, we conducted a comprehensive analysis of primary renal epithelial cells directly isolated from patient urine (human urine-derived renal epithelial cells, hURECs). We demonstrate that hURECs from a JBTS patient with renal disease have elongated and disorganized primary cilia and that this ciliary phenotype is specifically associated with an absence of CEP290 protein. Treatment with the Sonic hedgehog (Shh) pathway agonist purmorphamine or cyclin-dependent kinase inhibition (using roscovitine and siRNA directed towards cyclin-dependent kinase 5) ameliorated the cilia phenotype. In addition, purmorphamine treatment was shown to reduce cyclin-dependent kinase 5 in patient cells, suggesting a convergence of these signalling pathways. To our knowledge, this is the most extensive analysis of primary renal epithelial cells from JBTS patients to date. It demonstrates the feasibility and power of this approach to directly assess the consequences of patient-specific mutations in a physiologically relevant context and a previously unrecognized convergence of Shh agonism and cyclin-dependent kinase inhibition as potential therapeutic targets.

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Curcumin inhibits bladder cancer stem cells by suppressing Sonic Hedgehog pathway.

Cancer stem cells (CSCs) is responsible for the recurrence of human cancers. Thus, targeting CSCs is considered to be a valid way for human cancer treatment. Curcumin is a major component of phytochemicals that exerts potent anticancer activities. However, the effect of curcumin on bladder cancer stem cells (BCSCs) remains to be elucidated. In this study, we investigated the mechanism of curcumin suppressing bladder cancer stem cells. In this study, UM-UC-3 and EJ cells were cultured in serum-free medium (SFM) to form cell spheres that was characterized as BCSCs. Then cell spheres were separately treated with different concentrations of curcumin and purmorphamine. Cell cycle analysis were used to determine the percentage of cells in different phases. Western blot and quantitative real-time PCR analysis were used to detect the expression of relative molecules. Immunofluorescence staining analysis were also utilized to measure the protein level of CD44. We found that CSC markers, including CD44, CD133, ALDH1-A1, OCT-4 and Nanog, were obviously highly expressed in cell spheres. Moreover, we observed that curcumin reduced the cell spheres formation, decreased the expression of CSC markers, suppressed cell proliferation and induced cell apoptosis. We also found that curcumin inhibited the activation of Shh pathway, while the inhibitory effects of curcumin on BCSCs could be weakened by upregulation of Sonic Hedgehog (Shh) pathway. Altogether, these data suggested that curcumin inhibited the activities of BCSCs through suppressing Shh pathway, which might be an effective chemopreventive agent for bladder cancer intervention.

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Knockdown of PRMT1 suppresses IL-1β-induced cartilage degradation and inflammatory responses in human chondrocytes through Gli1-mediated Hedgehog signaling pathway.

Osteoarthritis (OA) is characterized by articular cartilage degradation and joint inflammation. The purpose of the present study is to elucidate the role of the specific function of PRMT1 in chondrocytes and its association with the pathophysiology of OA. We observed that the expression of PRMT1 was apparently upregulated in OA cartilage, as well as in chondrocytes stimulated with IL-1β. Additionally, knockdown of PRMT1 suppressed interleukin 1 beta (IL-1β)-induced extracellular matrix (ECM) metabolic imbalance by regulating the expression of MMP-13, ADAMTS-5, COL2A1, and ACAN. Furthermore, silencing of PRMT1 dramatically declined the production of prostaglandin E2 (PGE2) and nitric oxide as well as the level of pro-inflammatory cytokine IL-6 and TNF-α. Mechanistic analyses further revealed that IL-1β-induced activation of the Hedgehog/Gli-1 signaling is suppressed upon PRMT1 knockdown. However, the effects of inhibition of PRMT1-mediated IL-1β-induced cartilage matrix degradation and inflammatory response in OA chondrocytes were obviously abolished by Hedgehog agonist Purmorphamine (Pur). Our data collectively suggest that silencing of PRMT1 exerts anti-catabolic and anti-inflammatory effects on IL-1β-induced chondrocytes via suppressing the Gli-1 mediated Hedgehog signaling pathway, indicating that PRMT1 plays a critical role in OA development and serves as a promising therapeutic target for OA.

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Activation of Sonic hedgehog signal by Purmorphamine, in a mouse model of Parkinson's disease, protects dopaminergic neurons and attenuates inflammatory response by mediating PI3K/AKt signaling pathway.

In Parkinson's disease (PD), microglial activation-mediated neuroinflammation is associated with dopaminergic neurons degeneration in the substantia nigra pars compacta. Previous studies that have investigated this neurodegenerative disease have reported that the Sonic hedgehog (SHH) signaling pathway, through inhibiting the inflammatory processes, exerts a beneficial neuroprotective effect. However, the mechanisms underlying the anti‑inflammatory and neuroprotective effects of this signaling pathway remain poorly understood. The present study aimed to further investigate these mechanisms in vitro and in vivo. At first, BV2 microglial cells treated with lipopolysaccharide (LPS) were used to induce an inflammatory response. It was observed that the activation of SHH signaling by Purmorphamine attenuated the LPS‑induced inflammatory response, increased the expression of transforming growth factor‑β1 through the phosphatidylinositol 3‑kinase (PI3K)/AKT serine/threonine kinase (Akt) intracellular signaling pathway and inhibited nuclear receptor subfamily 4 group A member 2, independently of the PI3K/Akt signaling pathway. Furthermore, the blockade of the PI3K/Akt signaling pathway by intranasal administration of LY294002, significantly reduced the SHH‑associated neuroprotective effects on dopaminergic neurons, improved motor functions, and increased the microglial activation and inflammatory response in a mouse model of PD induced using 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine. In conclusion, the data of the present study reported that anti‑inflammatory and neuroprotective effects can be obtained in BV2 microglial cells and in a mouse model of PD by successive activation of the SHH and PI3K/Akt signaling pathways.

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