Protein S Exacerbates Chronic Liver Injury and Fibrosis

Totoki, Toshiaki; Alessandro-Gabazza, Corina N. D'; Toda, Masaaki; Tonto, Prince Baffour; Takeshita, Atsuro; Yasuma, Taro; Nishihama, Kota; Iwasa, Motoh; Horiki, Noriyuki; Takei, Yoshiyuki; Gabazza, Esteban C.

doi:10.1016/j.ajpath.2018.01.007

Cited by 8 publications

(9 citation statements)

References 29 publications

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“…On the contraly, there were several reports about unfavorable effects of PS. PS exacerbates acute liver injury by prolonging the natural killer T cells survival and worsens liver fibrosis by inhibiting apoptosis of extracellular matrix-producing fibroblasts 28 , 29 . The expression of PS may also be disease stage-related.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of Protein S in eyes with diabetic retinopathy and diabetic macular edema

Sugimoto

Kondo

Yasuma

et al. 2021

Sci Rep

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Protein S (PS) is a multifunctional glycoprotein that ameliorates the detrimental effects of diabetes mellitus (DM). The aim of this study was to evaluate the distribution of PS in diabetic retinopathy (DR) and diabetic macular edema (DME). This was a study of 50 eyes with DM (37 with DME, 6 with proliferative DR, and 7 with no DR) and 19 eyes without DM. The level of PS was measured by enzyme immunoassay and was compared between eyes with or without DM, with or without DME, and with severe DME (≥ 350 μm) or mild DME (< 350 μm). We also performed immunohistopathologic evaluations of post-mortem eyes and the cystoid lesions excised during surgery. The aqueous free PS was significantly higher with DM (7.9 ± 1.2 ng/ml, P < 0.01) than without DM (6.1 ± 0.7). The aqueous free PS was significantly elevated with DME (8.2 ± 1.2, P < 0.05) compared to proliferative DR (7.0 ± 1.0) and no DR (7.0 ± 0.7). Eyes with severe DME had significantly higher aqueous free PS than mild DME (8.5 ± 1.3 vs. 7.7 ± 1.0, P < 0.05). Immunohistochemistry showed PS in the outer plexiform layer of the retina and cystoid lesion. The higher expression of PS with DR and DME suggests that PS is involved in their pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Increased expression of Protein S in eyes with diabetic retinopathy and diabetic macular edema

Sugimoto

Kondo

Yasuma

et al. 2021

Sci Rep

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“…Interaction of PS with TAM receptors activates the signaling pathways of phosphoinosotide 3-kinase(PI3k)/Akt and the mitogen-activated protein kinase/extracellular signal-regulated kinase(MAPK/Erk) that promote cell growth and inhibit cell apoptosis [25,26,27,28]. In addition, we previously demonstrated that hPS inhibits apoptosis by activating the PI3K/Akt pathway in a variety of cells including lung epithelial cells [17,18,19,20]. However, to date whether hPS also suppresses apoptosis of lung cells in ALI remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…It is worth noting here that inhibition of apoptosis by hPS may be detrimental in some acute or chronic diseases in which its target cells play a pathological role. For example, there is evidence showing that hPS may worsen acute alcoholic liver injury by inhibiting apoptosis of activated natural killer T cells, enhance liver fibrosis by prolonging the survival of fibrogenic stellate cells or promote cancer progression and metastasis by providing a survival advantage to cancer cells [19,20,29]. However, beneficial effects of hPS have been reported in animal models of acute and chronic disorders of the lungs including ALI and pulmonary fibrosis [16,17].…”

Section: Discussionmentioning

confidence: 99%

“…PS reduces bleomycin-induced pulmonary fibrosis by inhibiting apoptosis of lung epithelial cells and ameliorates streptozotocin-induced diabetes by suppressing apoptosis of pancreatic β-cells [17,18]. However, the strong anti-apoptotic activity of PS can be also detrimental; for example, previous studies have shown that administration of PS worsens acute liver injury induced by alcohol and chronic liver injury and liver fibrosis caused by carbon tetrachloride [19,20].…”

Section: Introductionmentioning

confidence: 99%

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Protein S is Protective in Acute Lung Injury by Inhibiting Cell Apoptosis

Tonto

Yasuma

Kobayashi

et al. 2019

IJMS

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Acute lung injury is a fatal disease characterized by inflammatory cell infiltration, alveolar-capillary barrier disruption, protein-rich edema, and impairment of gas exchange. Protein S is a vitamin K-dependent glycoprotein that exerts anticoagulant, immunomodulatory, anti-inflammatory, anti-apoptotic, and neuroprotective effects. The aim of this study was to evaluate whether human protein S inhibits cell apoptosis in acute lung injury. Acute lung injury in human protein S transgenic and wild-type mice was induced by intratracheal instillation of lipopolysaccharide. The effect of human protein S on apoptosis of lung tissue cells was evaluated by Western blotting. Inflammatory cell infiltration, alveolar wall thickening, myeloperoxidase activity, and the expression of inflammatory cytokines were reduced in human protein S transgenic mice compared to the wild-type mice after lipopolysaccharide instillation. Apoptotic cells and caspase-3 activity were reduced while phosphorylation of extracellular signal-regulated kinase was enhanced in the lung tissue from human protein S transgenic mice compared to wild-type mice after lipopolysaccharide instillation. The results of this study suggest that human protein S is protective in lipopolysaccharide-induced acute lung injury by inhibiting apoptosis of lung cells.

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“…4D). Notably, functional markers of the heart (such as PDZ and LIM domain 3 [PDLIM3], microtubule-associated protein RP/EB family member 3 [MAPRE3], Egl-9 family hypoxia inducible factor 1 [EGLN1]) [34][35][36], the brain (leucine-rich repeat neuronal 3 [LRRN3], glutamate ionotropic receptor NMDA type subunit 2A [GRIN2A], SH2 domain containing 5 [SH2D5], neuroendocrine convertase 1 [NPC1], secretogranin V [SCG5]) [37][38][39][40], and the liver (aldo-keto reductase family 1 member C1 [AKR1C1], AKR1C2, serpin family A member 3 [SERPINA3], protein S [PROS1], AFP) [41][42][43][44], were detected in Phago-cardio-Muse, Phago-neuro-Muse, and Phago-hepa-Muse cells, respectively (Fig. 4D).…”

Section: Single-cell Rna Sequence Analysis (Scrna-seq)mentioning

confidence: 99%

Phagocytosing differentiated cell-fragments is a novel mechanism for controlling somatic stem cell differentiation within a short time frame

Wakao

Oguma

Kushida

et al. 2022

Cell. Mol. Life Sci.

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Stem cells undergo cytokine-driven differentiation, but this process often takes longer than several weeks to complete. A novel mechanism for somatic stem cell differentiation via phagocytosing ‘model cells’ (apoptotic differentiated cells) was found to require only a short time frame. Pluripotent-like Muse cells, multipotent mesenchymal stem cells (MSCs), and neural stem cells (NSCs) phagocytosed apoptotic differentiated cells via different phagocytic receptor subsets than macrophages. The phagocytosed-differentiated cell-derived contents (e.g., transcription factors) were quickly released into the cytoplasm, translocated into the nucleus, and bound to promoter regions of the stem cell genomes. Within 24 ~ 36 h, the cells expressed lineage-specific markers corresponding to the phagocytosed-differentiated cells, both in vitro and in vivo. At 1 week, the gene expression profiles were similar to those of the authentic differentiated cells and expressed functional markers. Differentiation was limited to the inherent potential of each cell line: triploblastic-, adipogenic-/chondrogenic-, and neural-lineages in Muse cells, MSCs, and NSCs, respectively. Disruption of phagocytosis, either by phagocytic receptor inhibition via small interfering RNA or annexin V treatment, impeded differentiation in vitro and in vivo. Together, our findings uncovered a simple mechanism by which differentiation-directing factors are directly transferred to somatic stem cells by phagocytosing apoptotic differentiated cells to trigger their rapid differentiation into the target cell lineage.

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Protein S Exacerbates Chronic Liver Injury and Fibrosis

Cited by 8 publications

References 29 publications

Increased expression of Protein S in eyes with diabetic retinopathy and diabetic macular edema

Increased expression of Protein S in eyes with diabetic retinopathy and diabetic macular edema

Protein S is Protective in Acute Lung Injury by Inhibiting Cell Apoptosis

Phagocytosing differentiated cell-fragments is a novel mechanism for controlling somatic stem cell differentiation within a short time frame

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