Phenylephrine increases tear cathepsin S secretion in healthy murine lacrimal gland acinar cells through an alternative secretory pathway

Fu, Runzhong; Janga, Srikanth Reddy; Edman, Maria C.

doi:10.1016/j.exer.2021.108760

Cited by 4 publications

(3 citation statements)

References 67 publications

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“… 57 Cathepsin S exocytosis is also differentially modulated by sympathetic and parasympathetic autonomic stimuli. 58 Intriguingly, the increase in sympathetic activity that occurs with aging 59 is associated with increased cathepsin S secretion through an alternative pathway in lacrimal gland acinar cells. 58 Regarding its pathogenic action, cathepsin S disrupts intercellular tight junctions in cultured corneal epithelial cells, and topical ocular administration to Ctss −/− mice breaks down the corneal epithelial barrier, thus replicating the phenotype.…”

Section: Discussionmentioning

confidence: 99%

“… 58 Intriguingly, the increase in sympathetic activity that occurs with aging 59 is associated with increased cathepsin S secretion through an alternative pathway in lacrimal gland acinar cells. 58 Regarding its pathogenic action, cathepsin S disrupts intercellular tight junctions in cultured corneal epithelial cells, and topical ocular administration to Ctss −/− mice breaks down the corneal epithelial barrier, thus replicating the phenotype. 33 In addition, cathepsin S elicits extracellular matrix remodeling in other tissues 60 , 61 and can degrade the lubricating proteoglycans of the ocular surface.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Cathepsin S Inhibition in the Age-Related Dry Eye Phenotype

Galletti

Scholand

Trujillo-Vargas

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose Aged C57BL/6J (B6) mice have increased levels of cathepsin S, and aged cathepsin S ( Ctss − / − ) knockout mice are resistant to age-related dry eye. This study investigated the effects of cathepsin S inhibition on age-related dry eye disease. Methods Female B6 mice aged 15.5 to 17 months were randomized to receive a medicated diet formulated by mixing the RO5461111 cathepsin S inhibitor or a standard diet for at least 12 weeks. Cornea mechanosensitivity was measured with a Cochet–Bonnet esthesiometer. Ocular draining lymph nodes and lacrimal glands (LGs) were excised and prepared for histology or assayed by flow cytometry to quantify infiltrating immune cells. The inflammatory foci (>50 cells) were counted under a 10× microscope lens and quantified using the focus score. Goblet cell density was investigated in periodic acid–Schiff stained sections. Ctss − / − mice were compared to age-matched wild-type mice. Results Aged mice subjected to cathepsin S inhibition or Ctss − / − mice showed improved conjunctival goblet cell density and cornea mechanosensitivity. There was no change in total LG focus score in the diet or Ctss − / − mice, but there was a lower frequency of CD4 + IFN-γ + cell infiltration in the LGs. Furthermore, aged Ctss − / − LGs had an increase in T central memory, higher numbers of CD19 + B220 − , and fewer CD19 + B220 + cells than wild-type LGs. Conclusions Our results indicate that therapies aimed at decreasing cathepsin S can ameliorate age-related dry eye disease with a highly beneficial impact on the ocular surface. Further studies are needed to investigate the role of cathepsin S during aging.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Cathepsin S Inhibition in the Age-Related Dry Eye Phenotype

Galletti

Scholand

Trujillo-Vargas

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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“…Additionally, Lamp1 and Ctss were found in the same co-expression module, which was strongly associated with TMAO therapy. They play roles in both phagosome and lysosome pathways [ 58 ]. The potential mechanism of TMAO regulating phagosome and lysosome pathways might be associated with its effect of reducing the endoplasmic reticulum-stress response [ 36 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

The effect of trimethylamine N-oxide on the metabolism of visceral white adipose tissue in spontaneously hypertensive rat

Liu

Hou

et al. 2022

Adipocyte

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Strong links have been reported among trimethylamine N-oxide (TMAO), visceral white adipose tissue (vWAT), and cardiometabolic diseases. However, the effects of TMAO on vWAT in hypertension remained incompletely explored. The impact of a chronic 22-week-long treatment with 1 g/L TMAO on vWAT, and its transcriptional and metabolic changes in spontaneously hypertensive rats (SHRs) were evaluated by serum cytokine measurements, histological analysis, fatty acid determinations, and co-expression network analyses. TMAO increased the serum interleukin-6 levels and insulin secretion in SHRs. The adipocyte size was diminished in the SHR 1 g/L TMAO group. In addition, one kind of monounsaturated fatty acids (cis-15-tetracosenoate) and four kinds of polyunsaturated fatty acids (cis-11,14,17-eicosatrienoic acid, docosatetraenoate, docosapentaenoate n-3, and docosapentaenoate n-6) were elevated by TMAO treatment. Three co-expression modules significantly related to TMAO treatment were identified and pathway enrichment analyses indicated that phagosome, lysosome, fatty acid metabolism, valine, leucine, and isoleucine degradation and metabolic pathways were the most significantly altered biological pathways. This study shed new light on the metabolic roles of TMAO on the vWAT of SHRs. TMAO regulated the metabolic status of vWAT, including reduced lipogenesis and an improved specific fatty acid composition. The mechanisms underlying these effects likely involve phagosome and lysosome pathways.

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Cathepsin S is a novel target for age-related dry eye

Govindarajan

et al. 2022

Experimental Eye Research

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Phenylephrine increases tear cathepsin S secretion in healthy murine lacrimal gland acinar cells through an alternative secretory pathway

Cited by 4 publications

References 67 publications

Effects of Cathepsin S Inhibition in the Age-Related Dry Eye Phenotype

Effects of Cathepsin S Inhibition in the Age-Related Dry Eye Phenotype

The effect of trimethylamine N-oxide on the metabolism of visceral white adipose tissue in spontaneously hypertensive rat

Cathepsin S is a novel target for age-related dry eye

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