Tauroursodeoxycholic Acid Decreases Keloid Formation by Reducing Endoplasmic Reticulum Stress as Implicated in the Pathogenesis of Keloid

Keloids are a common form of pathologic wound healing and are characterized by an excessive production of extracellular matrix. This study examined the major contributing mechanism of human keloid pathogenesis using transcriptomic analysis. We identified the upregulation of mitochondrial oxidative stress response, protein processing in the endoplasmic reticulum, and TGF-β signaling in human keloid tissue samples compared to controls, based on ingenuity pathway and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Electron microscopic examinations revealed an increased number of dysmorphic mitochondria and expanded endoplasmic reticulum (ER) in human keloid tissue samples than that in controls. Western blot analysis performed using human tissues suggested noticeably higher ER stress signaling in keloids than in normal tissues. Treatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, significantly decreased scar formation in rabbit models, compared to normal saline and steroid injections. In summary, our findings demonstrate the contributions of mitochondrial dysfunction and dysregulated ER stress signaling in human keloid formation and the potential of TUDCA in the treatment of keloids.

Tauroursodeoxycholic Acid Protects Retinal and Visual Function in a Mouse Model of Type 1 Diabetes

Purpose: Previous studies demonstrated that systemic treatment with tauroursodeoxycholic acid (TUDCA) is protective in in vivo mouse models of retinal degeneration and in culture models of hyperglycemia. This study tested the hypothesis that TUDCA will preserve visual and retinal function in a mouse model of early diabetic retinopathy (DR). Methods: Adult C57BL/6J mice were treated with streptozotocin (STZ) and made diabetic at 8–10 weeks of age. Control and diabetic mice were treated with vehicle or TUDCA starting 1 or 3 weeks after induction of diabetes, and were assessed bimonthly for visual function via an optomotor response and monthly for retinal function via scotopic electroretinograms. Results: Diabetic mice showed significantly reduced spatial frequency and contrast sensitivity thresholds compared to control mice, while diabetic mice treated early with TUDCA showed preservation at all timepoints. A-wave, b-wave, and oscillatory potential 2 (OP2) amplitudes decreased in diabetic mice. Diabetic mice also exhibited delays in a-wave and OP2-implicit times. Early TUDCA treatment ameliorated a-wave, b-wave, and OP2 deficits. Late TUDCA treatment showed reduced preservation effects compared to early treatment. Conclusions: Early TUDCA treatment preserved visual function in an STZ-mouse model of Type I diabetes. These data add to a growing body of preclinical research that may support testing whether TUDCA may be an effective early clinical intervention against declining visual function caused by diabetic retinopathy.

Combination of Plasma-Based Metabolomics and Machine Learning Algorithm Provides a Novel Diagnostic Strategy for Malignant Mesothelioma

Background: Malignant mesothelioma (MM) is an aggressive and incurable carcinoma that is primarily caused by asbestos exposure. However, the current diagnostic tool for MM is still under-developed. Therefore, the aim of this study is to explore the diagnostic significance of a strategy that combined plasma-based metabolomics with machine learning algorithms for MM. Methods: Plasma samples collected from 25 MM patients and 32 healthy controls (HCs) were randomly divided into train set and test set, after which analyzation was performed by liquid chromatography-mass spectrometry-based metabolomics. Differential metabolites were screened out from the samples of the train set. Subsequently, metabolite-based diagnostic models, including receiver operating characteristic (ROC) curves and Random Forest model (RF), were established, and their prediction accuracies were calculated for the test set samples. Results: Twenty differential plasma metabolites were annotated in the train set; 10 of these metabolites were validated in the test set. The seven most prevalent diagnostic metabolites were taurocholic acid), 0.7142 (uracil), 0.7142 (biliverdin), 0.8571 (histidine), 0.5000 (tauroursodeoxycholic acid), 0.8571 (pyrroline hydroxycarboxylic acid), and 0.7857 (phenylalanine). Furthermore, RF based on 20 annotated metabolites showed a prediction accuracy of 0.9286, and its optimized version achieved 1.0000 in the test set. Moreover, the comparison between the samples of peritoneal MM (n = 8) and pleural MM (n = 17) illustrated a significant increase in levels of taurocholic acid and tauroursodeoxycholic acid, as well as an evident decrease in biliverdin. Conclusions: Our results revealed the potential diagnostic value of plasma-based metabolomics combined with machine learning for MM. Further research with large sample size is worthy conducting. Moreover, our data demonstrated dysregulated metabolism pathways in MM, which aids in better understanding of molecular mechanisms related to the initiation and development of MM.

Local administration with tauroursodeoxycholic acid could improve osseointegration of hydroxyapatite-coated titanium implants in ovariectomized rats

Despite advances in the pathogenesis of Tauroursodeoxycholic acid (TUDCA) on bone, the understanding of the effects and mechanisms of bone osseointegration in TUDCA-associated Hydroxyapatite (HA)-coated titanium implants remains poor. Therefore, the present work was aimed to evaluate the effect of local administration with TUDCA on HA-coated titanium implants osseointegration in ovariectomized(OVX) rats and further investigation of the possible mechanism. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into three groups: sham operation(Sham) group, OVX group and TUDCA group, and all the rats from Sham group and OVX group received HA implants and animals belonging to group TUDCA received TUDCA-HA implants until death at 12 weeks. The bilateral femurs of rats were harvested for evaluation. TUDCA increased new bone formation around the surface of titanium rods and push-out force other than group OVX. Histology, Micro-CT and biochemical analysis results showed systemic TUDCA showed positive effects than OVX group on bone formation in osteopenic rats, with beneficial effect on via activation OPG/RANKL pathway and BMP-2/Smad1 pathway and microarchitecture as well as by reducing protein expression of TNF-α and IFN-γ. The present study suggests that local use of TUDCA may bring benefits to the osseointegration of HA-coated titanium implants in patients with osteoporosis, and this effect may be related to the inhibition of inflammatory reaction and promotion of osteogenesis.

Study on the Determination of Tauroursodeoxycholic Acid in Bear Bile Powder by HPLC-MS/MS

Objective — To establish a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the rapid determination of tauroursodeoxycholic acid (TUDCA) in bear bile powder. Method — The chromatographic conditions were optimized. A Hypersil GOLD chromatographic column (Thermo Fisher, 100 mm×2.1 mm) was used with the mobile phase of methanol:water (0.1mmol/l ammonium acetate + 0.1% formic acid) = 75:25 for isocratic elution; the column temperature is 30.0℃; the flow rate is 0.2mL/min; the injection volume is 5uL; the negative ion scanning mode and the select reaction monitoring are used. Through the compound optimization function of the instrument, the two characteristic ion pairs of TUDCA are m/z: 498.5/124.0 and m/z: 498.5/79.8 (quantitative ion pair). Results — The detection limit of this method was 5ng/mL, and the linear range was 20~1000ng/mL (r=0.9993). The same sample was measured in parallel with the high performance liquid chromatography (HPLC/UV) method, and the analysis results were basically the same. Conclusion — Compared with HPLC/UV, HPLC-MS/MS is simple, more sensitive and accurate for the determination of TUDCA in bear bile powder. The method can be used in the quality assessment and process control of bear bile powder.

Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice

Background Burkholderia pseudomallei, a facultative intracellular bacterium, is the aetiological agent of melioidosis that is responsible for up to 40% sepsis-related mortality in epidemic areas. However, no effective vaccine is available currently, and the drug resistance is also a major problem in the treatment of melioidosis. Therefore, finding new clinical treatment strategies in melioidosis is extremely urgent. Results We demonstrated that tauroursodeoxycholic acid (TUDCA), a clinically available endoplasmic reticulum (ER) stress inhibitor, can promote B. pseudomallei clearance both in vivo and in vitro. In this study, we investigated the effects of TUDCA on the survival of melioidosis mice, and found that treatment with TUDCA significantly decreased intracellular survival of B. pseudomallei. Mechanistically, we found that B. pseudomallei induced apoptosis and activated IRE1 and PERK signaling ways of ER stress in RAW264.7 macrophages. TUDCA treatment could reduce B. pseudomallei-induced ER stress in vitro, and TUDCA is protective in vivo. Conclusion Taken together, our study has demonstrated that B. pseudomallei infection results in ER stress-induced apoptosis, and TUDCA enhances the clearance of B. pseudomallei by inhibiting ER stress-induced apoptosis both in vivo and in vitro, suggesting that TUDCA could be used as a potentially alternative treatment for melioidosis.