Effect of Desiccating Stress on Mouse Meibomian Gland Function

Suhalim, Jeffrey L.; Parfitt, Geraint J.; Xie, Yong; Paiva, Cintia S. de; Pflugfelder, Stephen C.; Shah, Tejas N.; Potma, Eric O.; Brown, Donald J.; Jester, James V.

doi:10.1016/j.jtos.2013.08.002

Cited by 59 publications

(58 citation statements)

References 42 publications

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“…1,14 Specifically, desiccating stress delivered by low humidity in a mouse model resulted in several meibocyte associated abnormalities including a 3-fold increase in basal acinar cell proliferation, altered meibum protein/lipid ratio, irregular meibocyte differentiation and meibocyte stem cell depletion. 6 These are likely interconnected; in normal conditions, protein to lipid ratios decrease as meibum travels from the acini to the central duct.…”

Section: Pathophysiology Of Mgdmentioning

confidence: 99%

Meibomian Gland Disease

Chhadva

Goldhardt²,

Galor³

2017

Ophthalmology

262

135

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Meibomian gland dysfunction (MGD) is an umbrella term that encompasses several meibomian gland disorders, ranging from congenital to acquired. Disruption of meibomian gland function negatively impacts both the quality and quantity of meibum secreted, which in turn affects ocular surface health through changes in tear film composition. Increased tear evaporation, hyperosmolarity, inflammation, and ocular surface damage can subsequently occur. This may cause discomfort, visual disruption, and sensation of dry eye. This review article discusses the pathology, causes, and ocular surface impact of MGD, as well as its relationship to dry eye.

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Section: Pathophysiology Of Mgdmentioning

confidence: 99%

Meibomian Gland Disease

Chhadva

Goldhardt²,

Galor³

2017

Ophthalmology

262

135

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“…CARS microscopy detects the C-H bond in FAs, allowing quantification of the LD abundance (36). TPEF microscopy detects fluorescence from reduced NADH and oxidized flavin adenine dinucleotide (FAD).…”

Section: Significancementioning

confidence: 99%

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Wright

Hou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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143

102

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Triple-negative breast cancer (TNBC) is notoriously aggressive with high metastatic potential, which has recently been linked to high rates of fatty acid oxidation (FAO). Here we report the mechanism of lipid metabolism dysregulation in TNBC through the prometastatic protein, CUB-domain containing protein 1 (CDCP1). We show that a "low-lipid" phenotype is characteristic of breast cancer cells compared with normal breast epithelial cells and negatively correlates with invasiveness in 3D culture. Using coherent anti-Stokes Raman scattering and two-photon excited fluorescence microscopy, we show that CDCP1 depletes lipids from cytoplasmic lipid droplets (LDs) through reduced acyl-CoA production and increased lipid utilization in the mitochondria through FAO, fueling oxidative phosphorylation. These findings are supported by CDCP1's interaction with and inhibition of acyl CoA-synthetase ligase (ACSL) activity. Importantly, CDCP1 knockdown increases LD abundance and reduces TNBC 2D migration in vitro, which can be partially rescued by the ACSL inhibitor, Triacsin C. Furthermore, CDCP1 knockdown reduced 3D invasion, which can be rescued by ACSL3 co-knockdown. In vivo, inhibiting CDCP1 activity with an engineered blocking fragment (extracellular portion of cleaved CDCP1) lead to increased LD abundance in primary tumors, decreased metastasis, and increased ACSL activity in two animal models of TNBC. Finally, TNBC lung metastases have lower LD abundance than their corresponding primary tumors, indicating that LD abundance in primary tumor might serve as a prognostic marker for metastatic potential. Our studies have important implications for the development of TNBC therapeutics to specifically block CDCP1-driven FAO and oxidative phosphorylation, which contribute to TNBC migration and metastasis.he transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), is a driver of migration and invasion in multiple forms of carcinoma, including renal (1, 2), ovarian (3, 4), prostate (5), pancreatic (6, 7), colon (8-12), and triple-negative breast (TNBC) (13, 14) carcinomas, among others. Furthermore, CDCP1's role in tumor metastasis was confirmed in vivo in lung (15, 16), ovarian (17), prostate (5), and colon (9) cancers. Although CDCP1's role in TNBC metastasis has not been established to date, high CDCP1 expression has been validated as a prognostic marker of poor survival in TNBC when combined with positive node status (18).Our understanding of CDCP1's upstream regulators, its mechanism of activation, and downstream signaling continues to expand (recently reviewed in ref. 19). Studies by others (5) and our group (14) have demonstrated that CDCP1 cleavage is necessary for its activation, and recently, we have further shown that cleavage stimulates CDCP1 homodimerization (14). Homodimeric CDCP1 stimulates phosphorylation of protein kinase C δ (PKCδ) by Src kinase, leading to migration and invasion of TNBC cells in vitro (14). Adding to our knowledge of CDCP1's downstream signaling, we report that CDCP1 regulates lipid m...

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“…There is strong evidence from IR studies (Borchman et al, 2012a(Borchman et al, , 2010a and Raman scattering micrsoscopy (Suhalim et al, 2014) that proteins are a component of meibum and so would be secreted with meibum. Attempts to investigate the nature of proteins in meibum have been limited.…”

Section: The Role Of Proteins In the Tfllmentioning

confidence: 99%