Delivery of Sonic Hedgehog Gene Repressed Irradiation-induced Cellular Senescence in Salivary Glands by Promoting DNA Repair and Reducing Oxidative Stress

Bai, Hai; Zhao, Qingguo; Deveau, Michael A.; Liu, Fei

doi:10.7150/thno.23373

Cited by 36 publications

(42 citation statements)

References 43 publications

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“…IR induces persistent DNA damage and cellular senescence in mouse salivary glands, which is a major cause of hyposalivation following IR in mouse models 9 . We have revealed recently that Shh gene transfer in mouse salivary glands inhibited IR-induced cellular senescence by promoting DNA repair and reducing oxidative stress 25 . To determine whether IR induces cellular senescence in pig salivary glands, we performed staining for senescence-associated β-galactosidase (SA-β-gal) on sections of parotid glands collected 5 weeks after IR.…”

Section: Resultsmentioning

confidence: 99%

Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model

Hu¹,

Zhu²,

Bai³

et al. 2018

Theranostics

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Irreversible hypofunction of salivary glands is common in head and neck cancer survivors treated with radiotherapy and can only be temporarily relieved with current treatments. We found recently in mouse models that transient activation of Hedgehog pathway following irradiation rescued salivary gland function by preserving salivary stem/progenitor cells, parasympathetic innervation and microvessels. Due to huge differences between salivary glands of rodents and humans, to examine the translational potential of this approach, we evaluated effects of Shh gene transfer in a miniature pig model of irradiation-induced hyposalivation.Methods: The right parotid of each pig was irradiated with a single dose of 20 Gray. Shh and control GFP genes were delivered into irradiated parotid glands by noninvasive retrograde ductal instillation of corresponding adenoviral vectors 4 or 16 weeks after irradiation. Parotid saliva was collected every two weeks. Parotid glands were collected 5 or 20 weeks after irradiation for histology, Western blot and qRT-PCR assays.Results: Shh gene delivery 4 weeks after irradiation significantly improved stimulated saliva secretion and local blood supply up to 20 weeks, preserved saliva-producing acinar cells, parasympathetic innervation and microvessels as found in mouse models, and also activated autophagy and inhibited fibrogenesis in irradiated glands.Conclusion: These data indicate the translational potential of transient activation of Hedgehog pathway to preserve salivary function following irradiation.

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Section: Resultsmentioning

confidence: 99%

Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model

Hu¹,

Zhu²,

Bai³

et al. 2018

Theranostics

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“…In human endothelial cells, GDF-15 promotes radiation-induced senescence through the ROS-mediated p16 pathway, and contribute to the development of atherosclerosis [22]. GDF-15 levels are upregulated under the stress of ischemiareperfusion, and it is important for the generation of reactive oxygen species and the development of senescence [23]. Furthermore, Talia et al showed GDF-15 was associated with aging related impairment and changes, and predicted to be the potential biomarker of cognitive decline [24].…”

Section: Discussionmentioning

confidence: 99%

GDF-15 as a biomarker of aging

Liu

Huang

Lyu

et al. 2020

Preprint

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Background: The aging process is accompanied by the gradual development of chronic systemic inflammation (inflamm-aging). Growth differentiation factor-15 (GDF-15) is associated with inflammation and known to be a stress-induced factor. The present study aimed to explore the association of GDF-15 with aging.Methods: In this cross-sectional study, serum GDF-15, hematological parameters, and biomedical parameters were determined in 120 healthy individuals (23-83 years old, males). Three telomere related parameters, including telomere length, telomerase activity, and the expression of human telomerase reverse transcriptase (hTERT) mRNA were also quantified.Results: The older group has a higher levels of GDF-15 and lower expression of hTERT mRNA, and PBMC telomerase activity (p<0.001). In individuals with high GDF-15 levels, they were older, and presented with the lower level of hTERT mRNA and T/S ratio (p<0.01). Spearman correlation analysis shows that GDF-15 positively correlated with age (r=0.664, p<0.001), and negatively correlated with telomere length (r=-0.434, p<0.001), telomerase activity (r=-0.231, p=0.012), and hTERT mRNA (r=-0.206, p=0.024). Furthermore, in multivariate regression analysis, GDF-15 levels showed a statistically significant linear and negative relationship with PBMC telomerase activity (β-coefficient=-0.583, 95% CI -1.044 to -0.122, p=0.014), telomere length (β-coefficient=-0.200, 95% CI -0.305 to -0.094, p<0.001), and hTERT mRNA (β-coefficient=-0.207, 95% CI -0.312 to -0.102, p<0.001) after adjusting for confounders.Conclusions: In conclusion, our results show that circulating GDF-15 is the potential biomarkers of aging that may influence the risk and progression of multiple aging conditions.

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“…Despite the fact that hAQP1 gene therapy represents an attractive option for the treatment of radiation-induced salivary gland hypofunction, further studies will be necessary to prove its usefulness for the treatment of xerostomia in SS patients. Other gene therapies aiming at transferring sonic hedgehog [ 99 ] or heat shock protein 25 [ 100 ] were shown to both restore AQP5 expression and salivary secretion in irradiated mouse SG [ 101 ]. It still remains to be assessed whether other gene therapies correcting salivary hypofunction in SS mice models are capable of restoring AQP5 expression/localization with SG.…”

Section: Role Of Aqps In the Treatment Of Sjögren’s Syndromementioning

confidence: 99%

Involvement of Aquaporins in the Pathogenesis, Diagnosis and Treatment of Sjögren’s Syndrome

Soyfoo

Chivasso

Perret

et al. 2018

IJMS

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Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands resulting in diminished production of saliva and tears. The pathophysiology of SS has not yet been fully deciphered. Classically it has been postulated that sicca symptoms in SS patients are a double step process whereby lymphocytic infiltration of lacrimal and salivary glands (SG) is followed by epithelial cell destruction resulting in keratoconjunctivitis sicca and xerostomia. Recent advances in the field of the pathophysiology of SS have brought in new players, such as aquaporins (AQPs) and anti AQPs autoantibodies that could explain underlying mechanistic processes and unveil new pathophysiological pathways offering a deeper understanding of the disease. In this review, we delineate the link between the AQP and SS, focusing on salivary glands, and discuss the role of AQPs in the treatment of SS-induced xerostomia.

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Delivery of Sonic Hedgehog Gene Repressed Irradiation-induced Cellular Senescence in Salivary Glands by Promoting DNA Repair and Reducing Oxidative Stress

Cited by 36 publications

References 43 publications

Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model

Intragland Shh gene delivery mitigated irradiation-induced hyposalivation in a miniature pig model

GDF-15 as a biomarker of aging

Involvement of Aquaporins in the Pathogenesis, Diagnosis and Treatment of Sjögren’s Syndrome

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