Tauroursodeoxycholic Acid Reduces Arterial Stiffness and Improves Endothelial Dysfunction in Type 2 Diabetic Mice

Battson, Micah L.; Lee, Dustin M.; Jarrell, Dillon K.; Hou, Shoufei; Ecton, Kayl E.; Phan, Anna; Gentile, Christopher L.

doi:10.1159/000479967

Cited by 22 publications

(19 citation statements)

References 28 publications

(31 reference statements)

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“…TUDCA also decreased tunicamycin-induced expression of protein tyrosine phosphatase 1B (PTP1B) in cultured myotubes [110] and reduced arterial stiffness in aortic and perivascular adipose tissue of type 2 diabetic mice [111]. All these effects were demonstrated to occur as a result of the alleviation of ER stress as demonstrated by decreased expressions of GRP78, ATF4, p-eIF2α, XBP-1 and CHOP, and reduced activation of caspases-12 and -3 [109][110][111].…”

Section: Tudca In Diabetes and Obesitymentioning

confidence: 93%

“…TUDCA has been demonstrated to prevent palmitate-induced apoptosis in rat pancreatic β-cell line INS-1 and to evoke beneficial effects on acinar cells in the experimental model of acute pancreatitis mostly by reducing ER stress [108,109]. TUDCA also decreased tunicamycin-induced expression of protein tyrosine phosphatase 1B (PTP1B) in cultured myotubes [110] and reduced arterial stiffness in aortic and perivascular adipose tissue of type 2 diabetic mice [111]. All these effects were demonstrated to occur as a result of the alleviation of ER stress as demonstrated by decreased expressions of GRP78, ATF4, p-eIF2α, XBP-1 and CHOP, and reduced activation of caspases-12 and -3 [109][110][111].…”

Section: Tudca In Diabetes and Obesitymentioning

confidence: 99%

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Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Kusaczuk

2019

Cells

128

118

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Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed.

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Section: Tudca In Diabetes and Obesitymentioning

confidence: 93%

Section: Tudca In Diabetes and Obesitymentioning

confidence: 99%

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Kusaczuk

2019

Cells

128

118

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“…30 Oleanolic acid and TUDCA are selective agonists of TGR5 with demonstrable efficacy against vascular injury. 31,32 In a rat model of subarachnoid hemorrhage, oleanolic acid significantly reduced blood-brain barrier permeability and relieved brain edema by increasing protein expression of tight junctions and adherent junctions. 33 Oleanolic acid inhibits angiogenesis during the development of retinopathy of prematurity model in the mouse retina.…”

Section: Tgr5-mediated Endothelial Permeability Under Tnf-α Stimulationmentioning

confidence: 99%

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

et al. 2020

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Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Abnormal energy metabolism in microvascular endothelium is involved in the progression of diabetic retinopathy. Bile Acid G‐Protein‐Coupled Membrane Receptor (TGR5) has emerged as a novel regulator of metabolic disorders. However, the role of TGR5 in diabetes mellitus‐induced microvascular dysfunction in retinas is largely unknown. Herein, enzyme‐linked immunosorbent assay was used for analyzing bile acid (BA) profiles in diabetic rat retinas and retinal microvascular endothelial cells (RMECs) cultured in high glucose medium. The effects of TGR5 agonist on streptozotocin (STZ)‐induced diabetic retinopathy were evaluated by HE staining, TUNEL staining, retinal trypsin digestion, and vascular permeability assay. A pharmacological inhibitor of RhoA was used to study the role of TGR5 on the regulation of Rho/Rho‐associated coiled‐coil containing protein kinase (ROCK) and western blot, immunofluorescence and siRNA silencing were performed to study the related signaling pathways. Here we show that bile acids were downregulated during DR progression in the diabetic rat retinas and RMECs cultured in high glucose medium. The TGR5 agonist obviously ameliorated diabetes‐induced retinal microvascular dysfunction in vivo, and inhibited the effect of TNF‐α on endothelial cell proliferation, migration, and permeability in vitro. In contrast, knockdown of TGR5 by siRNA aggravated TNF‐α‐induced actin polymerization and endothelial permeability. Mechanistically, the effects of TGR5 on the improvement of endothelial function was due to its regulatory role on the ROCK signaling pathway. An inhibitor of RhoA significantly reversed the loss of tight junction protein under TNF‐α stimulation. Taken together, our findings suggest that insufficient BA signaling plays an important pathogenic role in the development of DR. Upregulation or activation of TGR5 may inhibit RhoA/ROCK‐dependent actin remodeling and represent an important therapeutic intervention for DR.

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“…More recently, Cheang et al (2017) have reported that oral administration of TUDCA to diabetic mice was found to decrease ER stress and to protect against endothelial dysfunction. In addition, another study by Battson et al (2017) has reported that acute incubation and chronic administration of TUDCA improved endothelium-dependent dilation in mesenteric arteries of type 2 diabetic mice. Chronic TUDCA administration also reduced arterial stiffness and was associated with reductions in ER stress markers in aortic and perivascular adipose tissue.…”

Section: Discussionmentioning

confidence: 96%

Potential prophylactic effect of chemical chaperones for alleviation of endoplasmic reticulum stress in experimental diabetic cataract

et al. 2019

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Background: Imbalance between protein synthesis and endoplasmic reticulum (ER) capacity to modify and fold proteins lead to the accumulation of unfolded proteins resulting in ER stress and apoptosis. Chaperones are major defense molecules assisting in protein folding, transport, and cellular signaling. ER stress plays a major role in the pathogenesis of diabetes mellitus (DM) and its complications, e.g., diabetic cataract. In the present investigation, the chemical chaperones 4-phenylbutyric acid (4-PBA), tauroursodeoxycholic acid (TUDCA), and trimethylamine N-oxide (TMAO) are used as potential therapeutic agents for alleviation of DM-induced ER stress and diabetic cataract in rats. Animals are subjected to biochemical analysis of blood and lenses for ER stress and apoptosis markers. Moreover, ophthalmologic examination and histopathologic examination of the lenses were done to confirm the results. Results: Both ophthalmic and lens histopathologic examination revealed that treatment with 4-PBA and TUDCA retarded the occurrence of cataract markedly. Whereas, treatment with TMAO caused a partial improvement of cataract. Moreover, biochemical tests showed that both 4-PBA and TUDCA produced a remarkable improvement in the ER marker levels (VEGF and caspase-12), GSH, MDA, TAC levels in lens tissues. On the other hand, TMAO had no significant effect on these parameters. However, Western blot analysis of lens homogenates showed a suppressed expression of GRP78 and CHOP after treatment with 4-PBA, TUDCA, and TMAO. Moreover, all treated groups showed a significant improvement of lens soluble proteins and their UV spectra absorption. A significant improvement in fasting blood sugar, GSH, serum MDA, and TAC were noted in all treated groups. 4-PBA produced a significant decrease in insulin resistance, whereas TUDCA and TMAO showed insignificant change. Conclusion: The present research found that the tested chaperones could be used as a therapeutic approach for clinically relevant disorders featuring ER dysfunction such as DM and for reducing its complications in the eye mainly cataract. However, TUDCA and 4-PBA were found to have a more potential efficacy in reducing most of the tested parameters as compared to TMAO.

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Tauroursodeoxycholic Acid Reduces Arterial Stiffness and Improves Endothelial Dysfunction in Type 2 Diabetic Mice

Cited by 22 publications

References 28 publications

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

Potential prophylactic effect of chemical chaperones for alleviation of endoplasmic reticulum stress in experimental diabetic cataract

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