scholarly journals Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Cheng Wei ◽  
Yibin Pan ◽  
Yinli Zhang ◽  
Yongdong Dai ◽  
Lingling Jiang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Sonic Hedgehog Signaling ◽  
Endometrial Stromal Cells ◽  
Shh Pathway ◽  
Intrauterine Adhesion ◽  
Stromal Cell Line ◽  
Pathway Inhibition ◽  
The Impact

Abstract Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2cre/+R26-SmoM2+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.

scholarly journals Correction: Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Cheng Wei ◽  
Yibin Pan ◽  
Yinli Zhang ◽  
Yongdong Dai ◽  
Lingling Jiang ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Stromal Cells ◽  
Hedgehog Signaling ◽  
Sonic Hedgehog Signaling ◽  
Endometrial Stromal Cells ◽  
Intrauterine Adhesion

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Sonic hedgehog signaling in epithelial tissue development

2019 ◽  
Vol 7 ◽  
pp. 3
Author(s):  
Lu Zheng ◽  
Chen Rui ◽  
Hao Zhang ◽  
Jing Chen ◽  
Xiuzhi Jia ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Gastric Epithelium ◽  
Epithelial Tissue ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Tissue Repair And Regeneration ◽  
New Treatment

The Sonic hedgehog (SHH) signaling pathway is essential for embryonic development and tissue regeneration. The dysfunction of SHH pathway is involved in a variety of diseases, including cancer, birth defects, and other diseases. Here we reviewed recent studies on main molecules involved in the SHH signaling pathway, specifically focused on their function in epithelial tissue and appendages development, including epidermis, touch dome, hair, sebaceous gland, mammary gland, tooth, nail, gastric epithelium, and intestinal epithelium. The advance in understanding the SHH signaling pathway will give us more clues to the mechanisms of tissue repair and regeneration, as well as the development of new treatment for diseases related to dysregulation of SHH signaling pathway.

scholarly journals Native V. Californicum Alkaloid Combinations Induce Differential Inhibition of Sonic Hedgehog Signaling

2018 ◽  
Author(s):  
Matthew W. Turner ◽  
Roberto Cruz ◽  
Jordan Elwell ◽  
John French ◽  
Jared Mattos ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Plant Part ◽  
Differential Inhibition ◽  
Sonic Hedgehog Signaling ◽  
Alkaloid Composition ◽  
Hh Signaling ◽  
Inhibitory Potential ◽  
Pathway Inhibition

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine if additional alkaloids in the extracts contribute to Hh signaling inhibition, we replicated the concentrations of these alkaloids observed in extracts using commercially available standards and compared the inhibitory potential of the extracts to alkaloid standard mixtures using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts contribute to Hh signaling inhibition.

Abstract WMP36: The Sonic Hedgehog Signaling Pathway Mediates Cerebrolysin-Improved Neurological Functions after Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Li Zhang ◽  
Michael Chopp ◽  
Zheng Gang Zhang
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Functional Recovery ◽  
Hedgehog Signaling ◽  
Artery Occlusion ◽  
Vehicle Group ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Stroke Treatment ◽  
Shh Pathway

Cerebrolysin, a mixture of neurotrophic peptides, enhances neurogenesis in experimental neurodegenerative diseases and stroke. Sonic hedgehog (Shh) signaling pathway stimulates neurogenesis after stroke. In the present study, we tested the hypothesis that the Shh signaling pathway mediates Cerebrolysin enhanced neurogenesis and functional recovery after stroke. Rats were subjected to embolic middle cerebral artery occlusion (MCAo). To examine whether blockage of the Shh signaling pathway abolishes the Cerebrolysin induced neurogenesis and functional recovery, Cyclopamine (0.2mg/kg), a Shh receptor inhbitor, or vehicle (45% 2-hydroxypropyl-cyclodextrin) was intraventricularly infused using an osmotic pump for 28 days starting 24h after MCAo with or without intraperitoneally (IP) administration of Cerebrolysin (2.5ml/kg, daily for 28d). For mitotic labeling, Bromodeoxyuridine (BrdU, 100mg/kg, IP) was administered daily for 7 days starting 24h after MCAo. Neurological functional tests including, adhesive removal test, foot-fault test, and modified neurological severity score (mNSS) were performed weekly for 5 weeks after stroke. Treatment with Cerebrolysin significantly (p<0.05) increased the number of BrdU positive cells (148±24/mm 2 vs 90±9/mm 2 in the vehicle group, n=10/group) in the ipsilateral subventricular zone (SVZ), which was associated with significant improvement of functional recovery from week 3 thought week 5 after MCAo compared with vehicle treated rats. However, inhibition of the Shh pathway with Cyclopamine significantly reduced BrdU positive cells (51±10/mm 2 ) in the SVZ, and cyclopamine treated animals failed to improve neurological function compared with vehicle treated rats. Furthermore, Cyclopamine completely reversed the effects of Cerebrolysin on SVZ cell proliferation (90±10/mm 2 ) and functional recovery. These results demonstrate that the Shh pathway mediates Cerebrolysin-enhanced neural progenitor proliferation and improves functional recovery in rats after stroke.

scholarly journals Lhx2 is a progenitor-intrinsic modulator of Sonic Hedgehog signaling during early retinal neurogenesis

2021 ◽  
Author(s):  
Xiaodong Li ◽  
Patrick J Gordon ◽  
John A Gaynes ◽  
Alexandra W Fuller ◽  
Randy Ringuette ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Sonic Hedgehog Signaling ◽  
Shh Signaling ◽  
Downstream Targets ◽  
Shh Pathway ◽  
Pathway Activation ◽  
Retinal Neurogenesis

An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.

scholarly journals Sonic Hedgehog signaling impairs ionizing radiation–induced checkpoint activation and induces genomic instability

2008 ◽  
Vol 183 (3) ◽  
pp. 385-391 ◽  
Author(s):  
Jennifer M. Leonard ◽  
Hong Ye ◽  
Cynthia Wetmore ◽  
Larry M. Karnitz
Keyword(s):  
Ionizing Radiation ◽  
Signaling Pathway ◽  
Genomic Instability ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Adaptor Protein ◽  
Sonic Hedgehog Signaling ◽  
Checkpoint Signaling ◽  
Downstream Target ◽  
Shh Pathway

The Sonic Hedgehog (Shh) pathway plays important roles in embryogenesis, stem cell maintenance, tissue repair, and tumorigenesis. Haploinsufficiency of Patched-1, a gene that encodes a repressor of the Shh pathway, dysregulates the Shh pathway and increases genomic instability and the development of spontaneous and ionizing radiation (IR)–induced tumors by an unknown mechanism. Here we show that Ptc1+/− mice have a defect in the IR-induced activation of the ATR–Chk1 checkpoint signaling pathway. Likewise, transient expression of Gli1, a downstream target of Shh signaling, disrupts Chk1 activation in human cells by preventing the interaction of Chk1 with Claspin, a Chk1 adaptor protein that is required for Chk1 activation. These results suggest that inappropriate Shh pathway activation promotes tumorigenesis by disabling a key signaling pathway that helps maintain genomic stability and inhibits tumorigenesis.

scholarly journals Native V. californicum Alkaloid Combinations Induce Differential Inhibition of Sonic Hedgehog Signaling

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2222 ◽  
Author(s):  
Matthew Turner ◽  
Roberto Cruz ◽  
Jordan Elwell ◽  
John French ◽  
Jared Mattos ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Plant Part ◽  
Differential Inhibition ◽  
Sonic Hedgehog Signaling ◽  
Alkaloid Composition ◽  
Hh Signaling ◽  
Pathway Inhibition

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine whether additional alkaloids in the extracts contribute to Hh signaling inhibition, the concentrations of these four alkaloids present in extracts were replicated using commercially available standards, followed by comparison of extracts to alkaloid standard mixtures for inhibition of Hh signaling using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts are capable of inhibiting Hh signaling.

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