Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition

Kang, Min‐Kyung; Park, Sin‐Hye; Choi, Yong‐Kook; Shin, Dong‐Bin; Kang, Young‐Hee

doi:10.1007/s00109-015-1301-3

Cited by 56 publications

(53 citation statements)

References 41 publications

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“…Urinary albumin was measured using the Albuwell M ELISA kit (Exocell, Philadelphia, PA, USA) according to a manufacturer's instructions. The 24-h urine volume in the db/db mice was 20-fold higher than that of db/m controls, whereas in chrysin-treated mice, the volume declined by ≈50% [22] . Fasting blood glucose and blood glycated hemoglobin HbA1C levels in mouse tail veins were measured every other week.…”

Section: In Vivo Animal Experimentsmentioning

confidence: 74%

“…However, whether chrysin restores optimal structure and function to the glomerular epithelial podocytes in diabetic kidney remains unknown. Our previous study showed that chrysin attenuated renal tubulointerstitial fibrosis via blocking the induction of the epithelial to mesenchymal transition in renal tubular epithelial cells and in db/db mice [22] . The epithelial to mesenchymal transition and tubulointerstitial fibrosis could be considered as novel routes and potential drug targets for the future therapeutic interventions using chrysin.…”

Section: Introductionmentioning

confidence: 97%

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Chrysin ameliorates podocyte injury and slit diaphragm protein loss via inhibition of the PERK-eIF2α-ATF-CHOP pathway in diabetic mice

et al. 2017

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Glomerular epithelial podocytes are highly specialized cells that play a crucial role in maintaining normal function of the glomerular filtration barrier via their foot processes. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid found in propolis and mushrooms that has anti-inflammatory, antioxidant and anticancer properties. This study aimed to evaluate the renoprotective effects of chrysin on podocyte apoptotic loss and slit diaphragm protein deficiency in high glucose-exposed podocytes and in db/db mouse kidneys. Exposure to high glucose (33 mmol/L) caused glomerular podocyte apoptosis in vitro, which was dose-dependently attenuated by nontoxic chrysin (1-20 μmol/L) through reduction of DNA fragmentation. Chrysin treatment dose-dependently restored the increased Bax/Bcl-2 ratio, and suppressed Apaf-1 induction and the elevated cytochrome c release in high glucose-exposed renal podocytes. In diabetic db/db mice, oral administration of chrysin (10 mg·kg·d, for 10 weeks) significantly attenuated proteinuria, and alleviated the abnormal alterations in glomerular ultrastructure, characterized by apoptotic podocytes and foot process effacement. In addition, this compound improved the induction of slit diaphragm proteins podocin/nephrin in the diabetic glomeruli. Exposure to high glucose elevated the unfolded protein response (UPR) to ER stress in renal podocytes, evidenced by up-regulation of PERK-eIF2α-ATF4-CHOP. Chrysin treatment blocked such ER stress responses pertinent to podocyte apoptosis and reduced synthesis of slit diaphragm proteins in vitro and in vivo. These observations demonstrate that targeting ER stress is an underlying mechanism of chrysin-mediated amelioration of diabetes-associated podocyte injury and dysfunction.

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Section: In Vivo Animal Experimentsmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 97%

Chrysin ameliorates podocyte injury and slit diaphragm protein loss via inhibition of the PERK-eIF2α-ATF-CHOP pathway in diabetic mice

et al. 2017

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“…Chrysin (Figure 1A) is a flavone-type flavonoid found in honey and herbs and possesses diverse pharmacological activities and multiple biological effects in the central nervous and immune systems [29,30]. Our previous study showed that the multifunctional chrysin exhibited the renoprotection by inhibiting diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition [31]. However, whether chrysin maintains eye health in diabetes remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Dietary Compound Chrysin Inhibits Retinal Neovascularization with Abnormal Capillaries in db/db Mice

et al. 2016

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Diabetic retinopathy (DR) develops in a significant proportion of patients with chronic diabetes, characterized by retinal macular edema and abnormal retinal vessel outgrowth leading to vision loss. Chrysin, a naturally-occurring flavonoid found in herb and honeycomb, has anti-inflammatory, antioxidant, and anti-cancer properties. This study sought to determine the protective effects of chrysin on retinal neovascularization with abnormal vessels and blood-retinal barrier (BRB) breakdown in 33 mM glucose-exposed human retinal endothelial cells and in db/db mouse eyes. High glucose caused retinal endothelial apoptotic injury, which was inhibited by submicromolar chrysin. This compound diminished the enhanced induction of HIF-1α, vascular endothelial growth factor (VEGF), and VEGF receptor-2 (VEGFR2) in high glucose-exposed retinal endothelial cells. Consistently, oral administration of 10 mg/kg chrysin reduced the induction of these proteins in db/db mouse eye tissues. In addition, chrysin restored the decrement of VE-cadherin and ZO-1 junction proteins and PECAM-1 in hyperglycemia-stimulated retinal endothelial cells and diabetic mouse retina, possibly maintaining tight cell-cell interactions of endothelial cells and pericytes. Anti-apoptotic chrysin reduced the up-regulation of Ang-1, Ang-2, and Tie-2 crucial to retinal capillary occlusion and BRB permeability. Furthermore, orally treating chrysin inhibited acellular capillary formation, neovascularization, and vascular leakage observed in diabetic retinas. These observations demonstrate, for the first time, that chrysin had a capability to encumber diabetes-associated retinal neovascularization with microvascular abnormalities and BRB breakdown.

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“…However, the mechanistic intracellular signaling and functional effects on human endometriotic cells remain unknown. Chrysin (5,7-dihydroxyflavone) is a flavone found in natural materials, such as chamomile, passion flowers, oyster mushrooms (Pleurotus ostreatus), and honeycombs (Kang, Park, Choi, Shin, & Kang, 2015;Lim, Ryu, Bazer, Kim, & Song, 2018). Chrysin has various biological functions, including anticancer (Khoo, Chua, & Balaram, 2010), antiinflammatory (Ha, Moon, & Kim, 2010), and antiangiogenic effects (F. Yang et al, 2015).…”

Section: O R I G I N a L R E S E A R C H A R T I C L Ementioning

confidence: 99%

Chrysin leads to cell death in endometriosis by regulation of endoplasmic reticulum stress and cytosolic calcium level

Ryu

Bazer

Lim

et al. 2018

Journal Cellular Physiology

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Chrysin is a natural compound derived from honey, propolis, or passion flowers and has many functional roles, such as antiinflammatory and antiangiogenesis effects. Although endometriosis is a benign gynecological disease, there is a need to identify the pathology and develop a therapy for endometriosis. Elucidating the biological mechanism of chrysin on endometriosis will improve the understanding of endometriosis. In this study, we confirmed the apoptotic effects of chrysin in human endometriotic cells using End1/E6E7 (endocervix‐derived endometriotic cells) and VK2/E6E7 (vaginal mucosa‐derived epithelial endometriotic cells). The results showed that chrysin suppressed the proliferation of endometriosis and induced programmed cell death through changing the cell cycle proportion and increasing the cytosolic calcium level and generation of reactive oxygen species. In addition, chrysin activated endoplasmic reticulum (ER) stress by stimulating the unfolded protein response proteins, especially the 78‐kDa glucose‐regulated protein–PRKR‐like ER kinase (PERK)–eukaryotic translation initiation factor 2α (eIF2α) pathway in both endometriotic cell lines. Furthermore, chrysin inactivated the intracellular phosphoinositide 3‐kinase (PI3K)/protein kinase B (PKB, also known as AKT) signaling pathway in a dose‐dependent manner. Collectively, the results of this study indicated that chrysin induced programmed cell death by activating the ER stress response and inactivating the PI3K signaling pathways in human endometriotic cells.

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Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition

Cited by 56 publications

References 41 publications

Chrysin ameliorates podocyte injury and slit diaphragm protein loss via inhibition of the PERK-eIF2α-ATF-CHOP pathway in diabetic mice

Chrysin ameliorates podocyte injury and slit diaphragm protein loss via inhibition of the PERK-eIF2α-ATF-CHOP pathway in diabetic mice

Dietary Compound Chrysin Inhibits Retinal Neovascularization with Abnormal Capillaries in db/db Mice

Chrysin leads to cell death in endometriosis by regulation of endoplasmic reticulum stress and cytosolic calcium level

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