A Sonic Hedgehog-Gli-Bmi1 signaling pathway plays a critical role in p27 deficiency induced bone anabolism

Background: Intracerebral hemorrhage (ICH) is a fatal subtype of stroke that lacks effective therapy. Blood-brain barrier (BBB) damage is a hallmark of ICH-induced brain injury that leads to edema formation, leukocytes infiltration, influx of blood components into the perihematomal (PHE) region, and eventually brain injury. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted molecules that contribute to the association between these cells. Sonic hedgehog (SHH) derived from astrocytes promotes the maturity and integrity of the BBB by upregulating tight junctions (TJs) in brain capillary endothelial cells (ECs). However, the effect of SHH on BBB in ICH has not been investigated.Methods: Cyclopamine (CYC) is a potent, selective inhibitor that specifically blocks the SHH signaling pathway. Here, we used pharmacological inhibitions (CYC and its derivatives) to determine a critical role of the SHH signaling pathway in promoting BBB integrity after ICH by mechanisms of regulating the TJ proteins in vivo and in vitro.Results: The expression of astrocytic SHH was upregulated in mouse brains after ICH. Compared with the vehicle-treated group, inhibition of the SHH signaling pathway with CYC and its derivatives treatments aggravated neurological function deficits, brain edema, hematoma volume, and BBB impairment by downregulating TJs in ECs through the SHH-Gli-1 axis in vivo and in vitro.Conclusions: SHH signaling pathway at the level of the BBB provides a barrier-promoting effect, suggesting that the SHH signaling pathway may function as a potential therapeutic target for restoring BBB function in ICH.

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Faculty Opinions recommendation of A critical role for sonic hedgehog signaling in the early expansion of the developing brain.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1004354.50407 ◽

2002 ◽

Author(s):

Harukazu Nakamura

Keyword(s):

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Critical Role ◽

Developing Brain ◽

Sonic Hedgehog Signaling

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Sonic hedgehog signaling pathway in tumorigenesis of glioma

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2012.00553 ◽

2013 ◽

Vol 32 (5) ◽

pp. 553-557

Author(s):

Fang-miao JING ◽

Fei-fei TENG ◽

Meng-ye ZHANG

Keyword(s):

Signaling Pathway ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Hedgehog Signaling Pathway ◽

Sonic Hedgehog Signaling ◽

Sonic Hedgehog Signaling Pathway

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New Tricks for an Old (Hedge)Hog: Sonic Hedgehog Regulation of Astrocyte Function

Cells ◽

10.3390/cells10061353 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1353

Author(s):

A. Denise R. Garcia

Keyword(s):

Signaling Pathway ◽

Sonic Hedgehog ◽

Synapse Formation ◽

Inflammatory Responses ◽

Molecular Signaling ◽

Synaptic Organization ◽

Shh Signaling ◽

Broad Array ◽

And Function ◽

Molecular Signaling Pathway

The Sonic hedgehog (Shh) molecular signaling pathway is well established as a key regulator of neurodevelopment. It regulates diverse cellular behaviors, and its functions vary with respect to cell type, region, and developmental stage, reflecting the incredible pleiotropy of this molecular signaling pathway. Although it is best understood for its roles in development, Shh signaling persists into adulthood and is emerging as an important regulator of astrocyte function. Astrocytes play central roles in a broad array of nervous system functions, including synapse formation and function as well as coordination and orchestration of CNS inflammatory responses in pathological states. Neurons are the source of Shh in the adult, suggesting that Shh signaling mediates neuron–astrocyte communication, a novel role for this multifaceted pathway. Multiple roles for Shh signaling in astrocytes are increasingly being identified, including regulation of astrocyte identity, modulation of synaptic organization, and limitation of inflammation. This review discusses these novel roles for Shh signaling in regulating diverse astrocyte functions in the healthy brain and in pathology.

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Ginsenoside Rb1 Treatment Attenuates Pulmonary Inflammatory Cytokine Release and Tissue Injury following Intestinal Ischemia Reperfusion Injury in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/843721 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Ying Jiang ◽

Zhen Zhou ◽

Qing-tao Meng ◽

Qian Sun ◽

Wating Su ◽

...

Keyword(s):

Lung Injury ◽

Signaling Pathway ◽

Intestinal Ischemia ◽

Ischemia Reperfusion ◽

Critical Role ◽

Weight Ratio ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Ginsenoside Rb1 ◽

Intestinal Ischemia Reperfusion

Objective. Intestinal ischemia reperfusion (II/R) injury plays a critical role in remote organ dysfunction, such as lung injury, which is associated with nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. In the present study, we tested whether ginsenoside Rb1 attenuated II/R induced lung injury by Nrf2/HO-1 pathway.Methods. II/R injury was induced in male C57BL/6J mice by 45 min of superior mesenteric artery (SMA) occlusion followed by 2 hours of reperfusion. Ginsenoside Rb1 was administrated prior to reperfusion with or without ATRA (all-transretinoic acid, the inhibitor of Nrf2/ARE signaling pathway) administration before II/R.Results. II/R induced lung histological injury, which is accompanied with increased levels of malondialdehyde (MDA), interleukin- (IL-) 6, and tumor necrosis factor- (TNF-)αbut decreased levels of superoxide dismutase (SOD) and IL-10 in the lung tissues. Ginsenoside Rb1 reduced lung histological injury and the levels of TNF-αand MDA, as well as wet/dry weight ratio. Interestingly, the increased Nrf2 and HO-1 expression induced by II/R in the lung tissues was promoted by ginsenoside Rb1 treatment. All these changes could be inhibited or prevented by ATRA.Conclusion. Ginsenoside Rb1 is capable of ameliorating II/R induced lung injuries by activating Nrf2/HO-1 pathway.

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Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer

Biomedicines ◽

10.3390/biomedicines9070821 ◽

2021 ◽

Vol 9 (7) ◽

pp. 821

Author(s):

Wanglong Qiu ◽

Chia-Yu Kuo ◽

Yu Tian ◽

Gloria H. Su

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Critical Role ◽

Genetic Mutations ◽

Cancer Genetic ◽

Dual Roles ◽

Activin Signaling ◽

Physiological Processes ◽

Cancer Types ◽

Related Proteins

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.

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RTEF-1 Inhibits Vascular Smooth Muscle Cell Calcification through Regulating Wnt/β-Catenin Signaling Pathway

Calcified Tissue International ◽

10.1007/s00223-021-00833-4 ◽

2021 ◽

Author(s):

Jingjing Cong ◽

Bei Cheng ◽

Jinyu Liu ◽

Ping He

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Osteogenic Differentiation ◽

Signaling Pathway ◽

Glycogen Synthase ◽

Critical Role ◽

Transcriptional Enhancer ◽

Alizarin Red ◽

Gsk 3Β ◽

Enhancer Factor

AbstractVascular calcification (VC) is highly prevailing in cardiovascular disease, diabetes mellitus, and chronic kidney disease and, when present, is associated with cardiovascular events and mortality. The osteogenic differentiation of vascular smooth muscle cells (VSMCs) is regarded as the foundation for mediating VC. Related transcriptional enhancer factor (RTEF-1), also named as transcriptional enhanced associate domain (TEAD) 4 or transcriptional enhancer factor-3 (TEF-3), is a nuclear transcriptional factor with a potent effect on cardiovascular diseases, apart from its oncogenic role in the canonical Hippo pathway. However, the role and mechanism of RTEF-1 in VC, particularly in calcification of VSMCs, are poorly understood. Our results showed that RTEF-1 was reduced in calcified VSMCs. RTEF-1 significantly ameliorated β-glycerophosphate (β-GP)-induced VSMCs calcification, as detected by alizarin red staining and calcium content assay. Also, RTEF-1 reduced alkaline phosphatase (ALP) activity and decreased expressions of osteoblast markers such as Osteocalcin and Runt-related transcription factor-2 (Runx2), but increased expression of contractile protein, including SM α-actin (α-SMA). Additionally, RTEF-1 inhibited β-GP-activated Wnt/β-catenin pathway which plays a critical role in calcification and osteogenic differentiation of VSMCs. Specifically, RTEF-1 reduced the levels of Wnt3a, p-β-catenin (Ser675), glycogen synthase kinase-3β (GSK-3β), and p-GSK-3β (Ser9), but increased the levels of p-β-catenin (Ser33/37). Also, RTEF-1 increased the ratio of p-β-catenin (Ser33/37) to β-catenin proteins and decreased the ratio of p-GSK-3β (Ser9) to GSK-3β protein. LiCl, a Wnt/β-catenin signaling activator, was observed to reverse the protective effect of RTEF-1 overexpression on VSMCs calcification induced by β-GP. Accordingly, Dickkopf-1 (Dkk1), a Wnt antagonist, attenuated the role of RTEF-1 deficiency in β-GP-induced VSMCs calcification. Taken together, we concluded that RTEF-1 ameliorated β-GP-induced calcification and osteoblastic differentiation of VSMCs by inhibiting Wnt/β-catenin signaling pathway.

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Ibrutinib in B-cell lymphoma: single fighter might be enough?

Cancer Cell International ◽

10.1186/s12935-020-01518-y ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Chao Xue ◽

Xin Wang ◽

Lingyan Zhang ◽

Qingyuan Qu ◽

Qian Zhang ◽

...

Keyword(s):

B Cell ◽

Signaling Pathway ◽

Cell Lymphoma ◽

Critical Role ◽

B Cell Lymphoma ◽

Cell Receptor ◽

High Response Rate ◽

Main Body ◽

Combination Strategies ◽

Bcr Signaling

Abstract Background In recent years, the B cell receptor (BCR) signaling pathway has become a “hot point” because it plays a critical role in B-cell proliferation and function. Bruton’s tyrosine kinase (BTK) is overexpressed in many subtypes of B-cell lymphoma as a downstream kinase in the BCR signaling pathway. Ibrutinib, the first generation of BTK inhibitor, has shown excellent antitumor activity in both indolent and aggressive B-cell lymphoma. Main body Ibrutinib monotherapy has been confirmed to be effective with a high response rate (RR) and well-tolerated in many B-cell lymphoma subgroups. To achieve much deeper and faster remission, combination strategies contained ibrutinib were conducted to evaluate their synergistic anti-tumor effect. Conclusions For patients with indolent B-cell lymphoma, most of them respond well with ibrutinib monotherapy. Combination strategies contained ibrutinib might be a better choice to achieve deeper and faster remission in the treatment of aggressive subtypes of B-cell lymphoma. Further investigations on the long-term efficacy and safety of the ibrutinib will provide novel strategies for individualized treatment of B-cell lymphoma.

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The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia

Endocrinology ◽

10.1210/en.2011-0263 ◽

2011 ◽

Vol 152 (7) ◽

pp. 2894-2903 ◽

Cited By ~ 42

Author(s):

Shinichi Miyagawa ◽

Daisuke Matsumaru ◽

Aki Murashima ◽

Akiko Omori ◽

Yoshihiko Satoh ◽

...

Keyword(s):

Signaling Pathway ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

External Genitalia ◽

Sexually Dimorphic ◽

Hedgehog Signaling Pathway ◽

Initial Development ◽

Urethral Plate ◽

Male External Genitalia

During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling.

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