The mechanism of submandibular gland dysfunction after menopause may be associated with the ferroptosis

Kwon, Hyun-Keun; Kim, Ji Min; Shin, Sung‐Chan; Sung, Eui‐Suk; Kim, Hyung–Sik; Park, Gi Cheol; Cheon, Yong-Il; Lee, Jin‐Choon; Lee, Byung‐Joo

doi:10.18632/aging.103882

Cited by 20 publications

(25 citation statements)

References 39 publications

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“…Several mechanisms such as oxidative stress, apoptosis and ferroptosis have been reported as the mechanisms of degeneration and dysfunction of salivary glands in ovariectomized rodents and postmenopausal women [3,5]. However, few studies have been performed to elucidate the mechanisms of degeneration and dysfunction of salivary glands in males after deprivation of sex hormones.…”

Section: Discussionmentioning

confidence: 99%

“…While, enhanced oxidative phosphorylation usually leads to generation of much reactive oxgen species, thus causing oxidative stress [24]. Both cell apoptosis and oxidative stress have already been demonstrated to be the main causes of degeneration and dysfunction of SMG in postmenopausal women [3,5]. Therefore, ER stress and oxidative stress secondary to hyperfunction of ribosome and mitochondrion may exacerbate cell death and tissue degeneration of SMG in ORC rats.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have reported degeneration of the submaxillary gland tubules after hypophysectomy and recovery after administration of testosterone in male rats [4]. Similarly, ovariectimized rodents and menopausal women also shown salivary gland degeneration and dysfunction, characterized by a reduction in the quantity of salivary acini and ducts [5][6][7]. It is clear that dysfunction of salivary glands secondary to de ciency of sex steroids, like menopause in women usually causes a signi cant decrease in salivary ow, resulting in hypo-salivation and xerostomia [8].…”

Section: Introductionmentioning

confidence: 90%

“…However, the mechanisms by which de ciency of sex steroids cause degeneration and dysfunction of salivary glands still remain largely unknown. Additionally, to date, studies on the relationship between sex steroids and the functionality of salivary glands are mainly focused on females, especially on menopausal women [5][6][7], few studies have been carried out on males.…”

Section: Introductionmentioning

confidence: 99%

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RNA-Seq Coupling Two Different Methods of Castration Reveals New Insights Into Androgen Deficiency-caused Degereration of Submaxillary Gland in Male Sprague Dawley Rats

Han

Xia

Zhuo

et al. 2022

Preprint

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Backgroud: Salivary gland degeneration and dysfunction are common symptoms that occur after sex hormone deprivation, but the underlying mechanisms remain largely unknown. Additionally, immunocastration, which causes drop of sex hormones, has been developed as an alternative to surgical castration, however whether it exerts similar effects as surgical castration on the salivary glands is unknown. Through histological and RNA-seq analysis, we assessed changes in morphology and transcriptome of submaxillary gland (SMG) in response to immunocastration (IM) versus surgical castration (bilateral orchiectomy, ORC). Results: Compared to intact males (EM), ORC caused a dramatical degeneration of SMG in rats, as evidenced by both decreased (P < 0.01) SMG weight and organ index, and by decreased (P < 0.01) quantity of SMG acini and ducts. IM had minimal effects (P > 0.05) on SMG weight and organ index, but it still caused degeneration (P < 0.05) of the acini and ducts. Even though, the quantity of both SMG acini and ducts was much higher (P < 0.001) in IM than in ORC. Functional enrichment analysis of the common regulated genes by ORC/IM revealed disrupted epithelial cell development, angiogenesis, anatomical structure morphogenesis and enhanced cell death are associated with SMG degeneration in deprivation of androgens. Integrated data analysis shown that there existed a selective hyperfunction of SMG ribosome and mitochondrion in ORC but not in IM, which might be associated with more severe degeneration of SMG in ORC than in IM. Conclusions: Our findings suggested that both surgical castration and immunocastration caused SMG degeneration by disrupting epithelial cell development, angiogenesis, anatomical structure morphogenesis and enhancing cell death. But, surgical castration selectively induced hyperfunction of SMG ribosome and mitochondrion, thus causing more severe degeneration of SMG than immunocastration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

RNA-Seq Coupling Two Different Methods of Castration Reveals New Insights Into Androgen Deficiency-caused Degereration of Submaxillary Gland in Male Sprague Dawley Rats

Han

Xia

Zhuo

et al. 2022

Preprint

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“…Thin sections were examined with a transmission electron microscope (JEM-1200 EXII, JEOL Ltd., Tokyo, Japan). We referred to the previous research method 13 .…”

Section: Transmission Electron Microscopy (Tem)mentioning

confidence: 99%

Differentiation of Human Adipose-Derived Stem Cells into Parathyroid Hormone-Secreting Cells

Eh¹,

Ss²,

Ji³

et al. 2020

Preprint

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IntroductionComplications arising from neck surgery are the most common causes of acquired hypoparathyroidism. Parathyroid hormone (PTH) regulates serum calcium and vitamin D levels. The current treatments for hypoparathyroidism, including PTH supplements and high doses of calcium and vitamin D, are a life-long burden and may cause side effects. Recent studies have shown that parathyroid gland differentiation occurs from embryonic stem cells, thymic epithelial cells, and tonsil-derived stem cells. Because adipose-derived stem cells (ADSCs) do not face ethical concerns raised for studies with human embryonic stem cells, in the present study, we attempted to induce differentiation of ADSCs into parathyroid cells.MethodsADSCs were isolated from abdominal subcutaneous adipose tissues obtained by plastic surgery from three male donors (mean age, 40 years). For differentiation into parathyroid-like cells, ADSCs were incubated in minimum essential medium-alpha supplemented with activin A and soluble Sonic hedgehog for 7–21 d. The parathyroid differentiation markers PTH, glial cells missing homolog 2 (GCM2), and chemokine (C-C motif) ligand 21 (CCL21) were detected using real-time quantitative polymerase chain reaction to confirm differentiation.ResultsThe ADSCs exhibited flat and vacuolated morphology, which changed into secretory parathyroid gland–like nodules on day 21 after differentiation. The mRNA expression of PTH, GCM2, and CCL21 increased in the differentiated cells. Furthermore, a significant amount of PTH protein was detected in differentiated cells on day 7 post-differentiation.ConclusionHuman ADSCs isolated from adipose tissues successfully differentiated into PTH-secreting cells. ADSC-secreted PTH may be a promising therapeutic for hypoparathyroidism patients.

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TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions

Oh,

Shin,

Ahn

et al. 2024

Advanced Science

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Despite the high incidence of dry mouth in postmenopausal women, its underlying mechanisms and therapeutic interventions remain underexplored. Using ovariectomized (OVX) mouse models, here this study identifies ferroptosis, an iron‐dependent regulated cell death, as a central mechanism driving postmenopausal salivary gland (SG) dysfunction. In the OVX‐SGs, TGFβ signaling pathway is enhanced with the aberrant TGFβ2 expression in SG mesenchymal cells. Intriguingly, TGFβ2 treatment reduces iron‐storing ferritin levels, leading to lipid peroxidation and ferroptotic death in SG epithelial organoids (SGOs). Mechanistically, TGFβ2 promotes the autophagy‐mediated ferritin degradation, so‐called ferritinophagy. A notable overexpression of the type III TGFβ receptor (TβRIII) is found in the OVX‐SGs and TGFβ2‐treated SGOs, while the silencing of TβRIII mitigates the ferroptosis‐mediated deleterious effects of TGFβ2 on SGOs. Finally, administration of ferroptosis inhibitor, Liproxstatin‐1 (Lip‐1), improves saliva secretion in OVX mice. Present findings collectively suggest a link between TGFβ signaling, ferroptosis, and SG injury, offering new therapeutic avenues for postmenopausal xerostomia.

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The mechanism of submandibular gland dysfunction after menopause may be associated with the ferroptosis

Cited by 20 publications

References 39 publications

RNA-Seq Coupling Two Different Methods of Castration Reveals New Insights Into Androgen Deficiency-caused Degereration of Submaxillary Gland in Male Sprague Dawley Rats

RNA-Seq Coupling Two Different Methods of Castration Reveals New Insights Into Androgen Deficiency-caused Degereration of Submaxillary Gland in Male Sprague Dawley Rats

Differentiation of Human Adipose-Derived Stem Cells into Parathyroid Hormone-Secreting Cells

TGFβ2‐Driven Ferritin Degradation and Subsequent Ferroptosis Underlie Salivary Gland Dysfunction in Postmenopausal Conditions

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