A germline-to-soma signal triggers an age-related decline of mitochondrial stress response
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The abilities of an organism to cope with extrinsic stresses and activate cellular stress responses decline during aging. The signals that modulate stress responses in aged animals remain to be elucidated. Here, we discover that feeding Caenorhabditis elegans (C. elegans) embryo lysates to adult worms enabled the animals to activate the mitochondrial unfolded protein response (UPRKeywords:
Piwi-interacting RNA
The hedgehog (Hh) signaling pathway regulates many processes of development and tissue homeostasis. Activation of hedgehog signaling has been reported in about 30% of human cancer including ovarian cancer. Inhibition of hedgehog signaling has been pursued as an effective strategy for cancer treatment including an ongoing phase II clinical trial in ovarian cancer. However, the rate of hedgehog signaling activation in ovarian cancer was reported differently by different groups. To predict the successful for future clinical trials of hedgehog signaling inhibitors in ovarian cancer, we assessed hedgehog pathway activation in 34 ovarian epithelial tumor specimens through analyses of target gene expression by in-situ hybridization, immunohistochemistry, RT-PCR and real-time PCR. In contrast to previous reports, we only detected a small proportion of ovarian cancers with hedgehog target gene expression, suggesting that identification of the tumors with activated hedgehog signaling activation will facilitate chemotherapy with hedgehog signaling inhibitors.
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Indian hedgehog
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Indian hedgehog
Cyclopamine
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The Hedgehog signaling pathway is important for human development and carcinogenesis in various malignancies.One tissue microarray with triplets of 28 samples from 25 patients with Merkel cell carcinoma (MCC) was constructed. Six samples of normal skin and 5 samples of normal oral mucosa served as controls. All samples were analyzed immunohistochemically with antibodies directed against Sonic hedgehog, Indian hedgehog, Patched, Smoothened, Gli-1, Gli-2, and Gli-3.All investigated proteins were frequently and intensely overexpressed in MCCs (Sonic hedgehog, 93%; Indian hedgehog, 84%; Patched, 86%; Smoothened, 79%; Gli-1, 79%; Gli-2, 79%; Gli-3, 86%) compared with control samples. High levels of Patched and Indian hedgehog were significantly associated with an increase in patients overall (p = .015) and recurrence-free survival (p = .011), respectively.Our results indicate that the Hedgehog signaling pathway is strongly activated in MCC and thus may play a role in carcinogenesis.
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The hedgehog (Hh) signaling pathway regulates many processes of development and tissue homeostasis. Activation of hedgehog signaling has been reported in about 30% of human cancer including ovarian cancer. Inhibition of hedgehog signaling has been pursued as an effective strategy for cancer treatment including an ongoing phase II clinical trial in ovarian cancer. However, the rate of hedgehog signaling activation in ovarian cancer was reported differently by different groups. To predict the successful for future clinical trials of hedgehog signaling inhibitors in ovarian cancer, we assessed hedgehog pathway activation in 34 ovarian epithelial tumor specimens through analyses of target gene expression by in-situ hybridization, immunohistochemistry, RT-PCR and real-time PCR. In contrast to previous reports, we only detected a small proportion of ovarian cancers with hedgehog target gene expression, suggesting that identification of the tumors with activated hedgehog signaling activation will facilitate chemotherapy with hedgehog signaling inhibitors.
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Signaling pathways direct organogenesis, often through concentration-dependent effects on cells. The hedgehog pathway enables cells to sense and respond to hedgehog ligands, of which the best studied is sonic hedgehog. Hedgehog signaling is essential for development, proliferation, and stem cell maintenance, and it is a driver of certain cancers. Lipid metabolism has a profound influence on both hedgehog signal transduction and the properties of the ligands themselves, leading to changes in the strength of hedgehog signaling and cellular functions. Here we review the evolving understanding of the relationship between lipids and hedgehog signaling.
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Abstract Recently, it has become clear that the developmental hedgehog pathway is activated in ischaemic adult tissue where it aids in salvaging damaged tissue. The exact driving force for the initial hedgehog response is unclear and as most physiological and cellular processes are disturbed in ischaemic tissue, hedgehog‐activating signals are hard to dissect. Here, we demonstrate that hypoxia per se is able to induce a rapid systemic hedgehog response in adult mice, as evident from expression of the pathway ligand, Sonic hedgehog, as well as the pathway activity marker Patched1 in various organs. Using in vitro models of hypoxia, we showed that the hedgehog response was transient and preceded by the accumulation of HIF‐1α, which we hypothesized to communicate between hypoxia and hedgehog expression. Indeed, pharmacological inhibition, knockdown or genetic ablation of HIF‐1α abolished hedgehog pathway activation. In conclusion, we have established that hypoxia is translated into a hedgehog response through HIF‐1α and this mechanism is likely to be responsible for the hedgehog response observed in various ischaemia models.
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Objectives Tissue fi brosis is a leading cause of death
in patients with systemic sclerosis (SSc). Effective
antifi brotic treatments are not available. Here, the
authors investigated inhibition of hedgehog signalling
by targeting Smoothened (Smo) as a novel antifi brotic
approach.
Methods The activation status of the hedgehog
pathway was assessed by immunohistochemistry for Gli
transcription factors and by quantifi cation of hedgehog
target genes. Hedgehog signalling was inhibited by the
selective inhibitor LDE223 and by small interfering RNA
against Smo in the models of bleomycin-induced dermal
fi brosis and in tight-skin-1 mice.
Results Hedgehog signalling is activated in SSc and in
murine models of SSc. Inhibition of Smo either by LDE223
or by small interfering RNA prevented dermal thickening,
myofi broblast differentiation and accumulation of collagen
upon challenge with bleomycin. Targeting Smo also
exerted potent antifi brotic effects in tight-skin-1 mice and
did prevent progression of fi brosis and induced regression
of pre-established fi brosis.
Conclusions Inhibition of hedgehog signalling exerted
potent antifi brotic effects in preclinical models of SSc in
both preventive and therapeutic settings. These fi ndings
might have direct translational implications because
inhibitors of Smo are already available and yielded
promising results in initial clinical trials.
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