Tauroursodeoxycholic Acid, a Bile Acid, Promotes Blood Vessel Repair by Recruiting Vasculogenic Progenitor Cells

Cho, Jin Gu; Lee, Jun Hee; Hong, Shin Hee; Lee, Han Na; Kim, Chul Min; Kim, Seo Yoon; Yoon, Kang Jun; Oh, Bong Ryoul; Kim, Jae Hyun; Jung, Seok Yoon; Asahara, Takayuki; Kwon, Sang‐Mo; Park, Sang Gyu

doi:10.1002/stem.1901

Cited by 56 publications

(37 citation statements)

References 58 publications

(70 reference statements)

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“…However, this hydrophilic BA can cross the blood-brain barrier and likely can cross the blood-retinal barrier. In support of the ability of circulating TUDCA to reach the retina and act on retinal cells are the observations that TUDCA can inhibit photoreceptor apoptosis (47,48,51), improve retinal pigment epithelial function (49), inhibit proliferation of human retinal endothelial cells (53), promote the recruitment of endothelial progenitor cells (54), and protect against DR (53). At the molecular level, TUDCA has been shown to inhibit apoptosis through reduction of endoplasmic reticulum stress (55) and modulation of the unfolded protein response (56).…”

Section: Discussionmentioning

confidence: 98%

Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice

et al. 2018

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Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with mice on ad libitum feeding, changes in the microbiome of the mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in on IF but not in on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.

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Section: Discussionmentioning

confidence: 98%

Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice

et al. 2018

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“…In regard to the beneficial effects of these bile acids on endothelial cells, little is known. Nevertheless, it was shown that TUDCA is able to protect against amyloid-β-induced apoptosis (Viana et al, 2009 ) and leukocyte rolling and adhesion to the endothelium induced by lipid peroxidation products (Vladykovskaya et al, 2012 ), as well as to promote vessel repair (Cho et al, 2015 ). Interestingly, UDCA was shown to inhibit endothelin-1 production (Ma et al, 2004 ) and to have an anti-angiogenic capacity (Suh et al, 1997 ; Woo et al, 2010 ), suggesting an influence on endothelial cells in a much more complex manner.…”

Section: Introductionmentioning

confidence: 99%

Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: an in vitro study

et al. 2015

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Ursodeoxycholic acid and its main conjugate glycoursodeoxycholic acid are bile acids with neuroprotective properties. Our previous studies demonstrated their anti-apoptotic, anti-inflammatory, and antioxidant properties in neural cells exposed to elevated levels of unconjugated bilirubin (UCB) as in severe jaundice. In a simplified model of the blood-brain barrier, formed by confluent monolayers of a cell line of human brain microvascular endothelial cells, UCB has shown to induce caspase-3 activation and cell death, as well as interleukin-6 release and a loss of blood-brain barrier integrity. Here, we tested the preventive and restorative effects of these bile acids regarding the disruption of blood-brain barrier properties by UCB in in vitro conditions mimicking severe neonatal hyperbilirubinemia and using the same experimental blood-brain barrier model. Both bile acids reduced the apoptotic cell death induced by UCB, but only glycoursodeoxycholic acid significantly counteracted caspase-3 activation. Bile acids also prevented the upregulation of interleukin-6 mRNA, whereas only ursodeoxycholic acid abrogated cytokine release. Regarding barrier integrity, only ursodeoxycholic acid abrogated UCB-induced barrier permeability. Better protective effects were obtained by bile acid pre-treatment, but a strong efficacy was still observed by their addition after UCB treatment. Finally, both bile acids showed ability to cross confluent monolayers of human brain microvascular endothelial cells in a time-dependent manner. Collectively, data disclose a therapeutic time-window for preventive and restorative effects of ursodeoxycholic acid and glycoursodeoxycholic acid against UCB-induced blood-brain barrier disruption and damage to human brain microvascular endothelial cells.

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“…TUDCA is approved by the U.S. Food and Drug Administration for use in biliary cirrhosis, and it is used effectively for cholestatic liver diseases11. Recent studies have revealed that TUDCA has an ameliorating effect on several diseases, including neurodegenerative diseases, osteoarthritis, vascular diseases, and diabetes12131415. In addition, TUDCA regulates stem cell differentiation into various lineages such as adipogenic and osteogenic lineages1617.…”

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confidence: 99%

Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein

Yoon

Lee

Yun

et al. 2016

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Although mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine, ischemia-induced endoplasmic reticulum (ER) stress induces low MSC engraftment and limits their therapeutic efficacy. To overcome this, we investigated the protective effect of tauroursodeoxycholic acid (TUDCA), a bile acid, on ER stress in MSCs in vitro and in vivo. In ER stress conditions, TUDCA treatment of MSCs reduced the activation of ER stress-associated proteins, including GRP78, PERK, eIF2α, ATF4, IRE1α, JNK, p38, and CHOP. In particular, TUDCA inhibited the dissociation between GRP78 and PERK, resulting in reduced ER stress-mediated cell death. Next, to explore the ER stress protective mechanism induced by TUDCA treatment, TUDCA-mediated cellular prion protein (PrPC) activation was assessed. TUDCA treatment increased PrPC expression, which was regulated by Akt phosphorylation. Manganese-dependent superoxide dismutase (MnSOD) expression also increased significantly in response to signaling through the TUDCA-Akt axis. In a murine hindlimb ischemia model, TUDCA-treated MSC transplantation augmented the blood perfusion ratio, vessel formation, and transplanted cell survival more than untreated MSC transplantation did. Augmented functional recovery following MSC transplantation was blocked by PrPC downregulation. This study is the first to demonstrate that TUDCA protects MSCs against ER stress via Akt-dependent PrPC and Akt-MnSOD pathway.

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Tauroursodeoxycholic Acid, a Bile Acid, Promotes Blood Vessel Repair by Recruiting Vasculogenic Progenitor Cells

Cited by 56 publications

References 58 publications

Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice

Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice

Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: an in vitro study

Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein

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