Rapamycin delays salivary gland atrophy following ductal ligation

Bozorgi, Sophie; Proctor, Gordon; Carpenter, Guy

doi:10.1038/cddis.2014.108

Cited by 21 publications

(26 citation statements)

References 30 publications

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“…Histologic findings showed submandibular gland atrophy, disappearance of the acinar portion and an increase in duct-like structures and fibrous connective tissue after 2 months of ligation. These findings were similar to those of short-term ligation studies [1, 2, 31, 32, 35]. Gene expression analysis showed low levels of the acinar cell marker AQP5 [11, 13, 16, 25] and the functional marker α-amylase [11, 36], which is consistent with previous results [17].…”

Section: Discussionsupporting

confidence: 91%

Expression of c-kit and Cytokeratin 5 in the Submandibular Gland after Release of Long-Term Ligation of the Main Excretory Duct in Mice

Watanabe

Takahashi

Hata-Kawakami

et al. 2017

Acta Histochem. Cytochem

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Long-term submandibular duct obstruction is thought to cause irreversible atrophy and dysfunction of the submandibular gland. As an atrophic gland may be induced clinically by chronic or recurrent infection, it is generally removed surgically. However, the regenerative capacity of atrophic submandibular glands after long-term obstruction is not completely understood. We studied the regenerative capacity of the mouse submandibular duct using an aneurysm clip ligation model. We documented changes in the size, histologic structure and gene expression of the submandibular gland after 2 months of ligation, and 1 week, 1 month and 2 months after clip removal. Two months of ligation caused atrophy, particularly in the acinar portion. In the 2 months after clip removal, we observed a steady and significant increase in the expression of the acinar cell precursor gene cytokeratin 5 (CK5), and a significant decrease in the expression of the stem cell marker c-kit. These findings suggest that the submandibular gland retains some capacity for regeneration even after long-term obstruction, and that CK5 could serve as a marker of this regenerative process.

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Section: Discussionsupporting

confidence: 91%

Expression of c-kit and Cytokeratin 5 in the Submandibular Gland after Release of Long-Term Ligation of the Main Excretory Duct in Mice

Watanabe

Takahashi

Hata-Kawakami

et al. 2017

Acta Histochem. Cytochem

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“…Lupus and Sjogren's syndrome occur when mTOR is activated, and its blockade with rapamycin is therapeutically effective [70]. Recent investigations have demonstrated that both mTOR and rapamycin have pivotal roles of antiaging, development, various diseases such as cancer, diabetes, obesity and also tissue injury [71][72][73][74][75][76]. Aging is a continuation of developmental growth [75], and rapamycin slows aging by inhibitory effects on mTOR driving conversion from quiescence to senescence (geroconversion) [76,77].…”

Section: Discussionmentioning

confidence: 99%

Role of the mTOR signalling pathway in salivary gland development

et al. 2019

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Development of the salivary gland is characterized by extensive branching morphogenesis. Although various molecules have been implicated in salivary gland development, the role of the mammalian target of rapamycin (mTOR) signalling pathway, including both mTOR complexes 1 and 2 (mTORC1 and 2), in salivary gland development is unknown. Here, we examined protein expression levels related to the mTOR signalling pathway using an ex vivo submandibular salivary gland (SMG) organ culture. We showed that branching buds in the salivary glands were substantially decreased and phosphorylation of mTORC1 signalling pathway related proteins (mTOR, p70 ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E‐binding protein 1) was inhibited by rapamycin (an mTOR inhibitor). In addition, AKT, which is an upstream protein kinase of mTORC1 and is downstream of mTORC2, is inhibited by LY294002 (a phosphatidylinositol 3‐kinase inhibitor), but not by rapamycin. Moreover, rapamycin‐treated ICR neonatal mice exhibited a reduction in both body weight and salivary glands compared with vehicle‐treated neonatal mice. The present data indicate that the mTOR signalling pathway, including both mTORC1 and mTORC2, plays a critical role in salivary gland development both in ex vivo SMG organ culture and ICR neonatal mice in vivo.

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“…Our previous data showed activation of mTOR occurs in submandibular glands undergoing atrophy. 20 However this study underlines the complexity of the in vivo regulation of mTOR in salivary glands as other tissues such as adipose do become activated by HFD.…”

Section: Discussionmentioning

confidence: 99%

“…18,19 In most normal healthy tissues such as liver and muscle, mTOR is active and drives protein synthesis. In salivary glands it is normally inactive but becomes activated with atrophy 20,21 However the effect of diet on salivary glands regarding mTOR pathway has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Altered autophagy and sympathetic innervation in salivary glands from high-fat diet mice

Carvalho

Gavião

Carpenter

2017

Archives of Oral Biology

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2 Highlights: Adiponectin levels decreased in the High Fat Diet group after three months  Autophagy increased after three months of High Fat Diet  mTOR showed no activation regarding the time point studied  Tyrosine hydroxylase decreased after two and three month of High Fat Diet Abstract Objective: to investigate the effects of a high fat diet (HFD) on salivary glands in vivo, in a mouse model. In particular, whether it will induce the appearance of fat cells in salivary glands, alterations related to autophagy, mTOR pathway and sympathetic innervation.Design: 27 adult female ICR mice were separated in six groups. Three groups fed with (HFD) containing 55% fat, for one, two and three month and another three groups fed with normal diet (2.7% of fat), for the same time periods. The submandibular glands and liver were dissected and part homogenized for protein analyses and part fixed in formalin for histological analyses Results: After three months the HFD fed mice total body weight fold change increased compared to controls. The Oil Red O staining showed no fat cells deposit in salivary gland however a large increase was observed in liver after three months of HFD.Adiponectin levels were significantly decreased in the HFD group after three months. The group fed with HFD for three months showed increased conversion of the LC3 autophagy marker in salivary gland. mTOR showed no activation regarding the time point studied.Tyrosine hydroxylase significantly decreased after two and three month of HFD. Conclusion:HFD caused several changes after three months however the earliest change was noticed after two months regarding sympathetic innervation. This suggests neural alteration may drive other diet induced changes in salivary glands. These early changes may be the starting point for longer term alterations of salivary glands with alterations in diet.3

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Rapamycin delays salivary gland atrophy following ductal ligation

Cited by 21 publications

References 30 publications

Expression of c-kit and Cytokeratin 5 in the Submandibular Gland after Release of Long-Term Ligation of the Main Excretory Duct in Mice

Expression of c-kit and Cytokeratin 5 in the Submandibular Gland after Release of Long-Term Ligation of the Main Excretory Duct in Mice

Role of the mTOR signalling pathway in salivary gland development

Altered autophagy and sympathetic innervation in salivary glands from high-fat diet mice

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