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Abstract Introduction Severe acute pancreatitis (SAP) is a crucial gastrointestinal disease characterized by systemic inflammatory responses and persistent multiple organ failure. The role of bile acids (BAs) in diverse inflammatory diseases is increasingly recognized as crucial, but the underlying role of BA conjugation remains elusive. Objectives Our study aim to investigate the potential role of conjugated bile acids in SAP and reveal the molecular mechanisms underlying its regulatory effects. We hypothesized that taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) could protect SAP through inhibiting the activation of NLRP3 inflammasomes via the TGR5 pathway in macrophages. Methods To test our hypothesis, we used BA-CoA: amino acid N-acyltransferase knockout (Baat −/− ) mice and established SAP mouse models using caerulein- and sodium taurocholate- induced. We utilized a range of methods, including pathology sections, qRT-PCR, immunofluorescence, Western blotting, and ELISA, to identify the mechanisms of regulation. Results BA-CoA: Amino acid N-acyltransferase knockout (Baat −/− ) mice significantly exacerbated pancreatitis by increasing pancreatic and systemic inflammatory responses and pancreatic damage in SAP mouse models. Moreover, the serum TCDCA levels in Baat −/− mice were lower than those in wild-type (WT) mice with or without SAP, and GCDCA and TCDCA showed stronger anti-inflammatory effects than chenodeoxycholic acid (CDCA) in vitro. TCDCA treatment alleviated SAP in a Takeda G protein-coupled receptor 5 and NOD-like receptor family, pyrin domain containing 3—dependent manner in vivo. Reinforcing our conclusions from the mouse study, clinical SAP patients exhibited decreased serum content of conjugated BAs, especially GCDCA, which was inversely correlated with the severity of systemic inflammatory responses. Conclusion Conjugated bile acids significantly inhibit NLRP3 inflammasome activation by activating TGR5 pathway, thereby alleviating pancreatic immunopathology. The results provide new insights into the variability of clinical outcomes and paves the way for developing more effective therapeutic interventions for AP.

Bear bile powder is a precious medicinal material. It is characterized by high content of tauroursodeoxycholic acid (TUDCA) at a ratio of 1.0-1.5 to taurochenodeoxycholic acid (TCDCA). Here, we reported the biotransformation of tauroursodeoxycholic acid (TUDCA) through Escherichia coli engineered with a two-step mimic biosynthetic pathway of TUDCA from taurochenodeoxycholic acid (TCDCA). Two 7α-hydroxysteroid dehydrogenase (7α-HSDH) and two 7β-hydroxysteroid dehydrogenase (7β-HSDH) genes (named as α, α, β, and β) were selected and synthesized to create four pathway variants using ePathBrick. All could convert TCDCA to TUDCA and the one harboring α and β (pαβ) showed the strongest capability. Utilizing the oxidative and reductive properties of 7α- and 7β-HSDH, an ideal balance between TUDCA and TCDCA was established by optimizing the fermentation conditions. By applying the optimal condition, E. coli containing pαβ (BL-pαβ) produced up to 1.61 ± 0.13 g/L of TUDCA from 3.23 g/L of TCDCA at a ratio of 1.3 to TCDCA. This study provides a potential approach for bear bile substitute production from cheap and readily available chicken bile. [ABSTRACT FROM AUTHOR]

Our former studies have suggested that taurochenodeoxycholic acid (TCDCA) as a signaling molecule shows obvious anti-inflammatory and immune regulation properties. In this research, we tentatively explored the potential effects and the possible mechanism that involve in the apoptotic process in NR8383 cells induced by TCDCA. Using flow cytometry analysis, we evaluated the apoptosis rate. Gene expression levels were determined by qPCR. The expressions of protein kinase C (PKC), Jun N-terminal kinase (JNK) and their phosphorylation were measured by Western Blot. We observed the activities of caspase-3 and caspase-8 with Caspase-Glo® regent. The results demonstrated that TCDCA dramatically improved the apoptosis rate of NR8383 cells in a concentration-dependent manner. In the meantime, PKC mRNA levels and activities were significantly augmented by TCDCA treatments. In addition, JNK, caspase-3 and caspase-8 mRNA expression levels and activities were increased by TCDCA, while they were markedly decreased by specific inhibitors. We conclude that TCDCA contributes to the apoptosis through the activation of the caspase cascade in NR8383 cells, and the PKC/JNK signaling pathway may be involved in this process. These results indicate that TCDCA may be a latent effective pharmaceutical product for apoptosis-related diseases. [ABSTRACT FROM AUTHOR]

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t:The present study investigated the influence of taurochenodeoxycholic acid (TCDCA) on EP2 receptors on synovial fibroblast (FLS) from adjuvant arthritis (AA) rat. The FLS from AA rat were cultured in vitro and used Elisa method to measure the quantity of second messenger cAMP, in order to determine the best drug concentration of TCDCA. And then, with the treatment of TCDCA in vitro, using real time RT-PCR measured EP2 receptors expression on FLS. The resule of Elisa method indicated that after TCDCA treatment, the concentration of cAMP had asignificantly change in FLS when existence of PGE2 (10–6mol/L), with dose-dependent. In addition, real-time RT-PCR results showed that PGE2 could promote EP2 mRNA expression in the FLS, while TCDCA(10–5-10–7mol/L) could significantly reduce the mRNA expression of EP2 receptors (P < 0.01). These results indicated that TCDCA may have an impact on PGE2 pathway, which may be one of a new breakthrough point for further research TCDCA biological effects. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the anti-inflammatory action of taurochenodeoxycholic acid (TCDCA). Researchers perform an intragastric administration of TCDCA into adjuvant arthritis rats, and measure the contents of nitric oxide (NO) and lymphotoxin-beta (LTB4) of peripheral blood by fluorospectrophotometry and enzyme-linked immunosorbent assay (ELISA). Results show the relationship between the anti-inflammatory action of TCDCA and production of LTB4 and NO .

Excessive intrahepatic accumulation of bile acids (BAs) is a key mechanism underlying cholestasis. The aim of this study was to quantitatively explore the relationship between cytotoxicity of BAs and their intracellular accumulation in sandwich-cultured rat hepatocytes (SCRH). Following exposure of SCRH (on day-1 after seeding) to various BAs for 24h, glycine-conjugated BAs were most potent in exerting toxicity. Moreover, unconjugated BAs showed significantly higher toxicity in day-1 compared to day-3 SCRH. When day-1/-3 SCRH were exposed (0.5-4h) to 5-100μM (C)DCA, intracellular levels of unconjugated (C)DCA were similar, while intracellular levels of glycine conjugates were up to 4-fold lower in day-3 compared to day-1 SCRH. Sinusoidal efflux was by far the predominant efflux pathway of conjugated BAs both in day-1 and day-3 SCRH, while canalicular BA efflux showed substantial interbatch variability. After 4h exposure to (C)DCA, intracellular glycine conjugate levels were at least 10-fold higher than taurine conjugate levels. Taken together, reduced BA conjugate formation in day-3 SCRH results in lower intracellular glycine conjugate concentrations, explaining decreased toxicity of (C)DCA in day-3 versus day-1 SCRH. Our data provide for the first time a direct link between BA toxicity and glycine conjugate exposure in SCRH., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The farnesoid X receptor (FXR) is a key sensor in bile acid homeostasis. Although four human FXR isoforms have been identified, the physiological role of this diversity is poorly understood. Here we investigated their subcellular localization, agonist sensitivity and response of target genes. Measurement of mRNA revealed that liver predominantly expressed FXRα1(+/-), whereas FXRα2(+/-) were the most abundant isoforms in kidney and intestine. In all cases, the proportion of FXRα(1/2)(+) and FXRα(1/2)(-) isoforms, i.e., with and without a 12bp insert, respectively, was approximately 50%. When FXR was expressed in liver and intestinal cells the magnitude of the response to GW4064 and bile acids differs among FXR isoforms. In both cell types the strongest response was that of FXRα1(-). Different efficacy of bile acids species to activate FXR was found. The four FXR isoforms shared the order of sensitivity to bile acids species. When in FXR-deficient cells FXR was transfected, unconjugated, but not taurine- and glycine-amidated bile acids, were able to activate FXR. In contrast, human hepatocytes and cell lines showing an endogenous expression of FXR were sensitive to both unconjugated and conjugated bile acids. This suggests that to activate FXR conjugated, but not unconjugated, bile acids require additional component(s) of the intracellular machinery not related with uptake processes, which are missing in some tumor cells. In conclusion, cell-specific pattern of FXR isoforms determine the overall tissue sensitivity to FXR agonists and may be involved in the differential response of FXR target genes to FXR activation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The cell-toxic bile salt glycochenodeoxycholic acid (GCDCA) and taurochenodeoxycholic acid (TCDCA) are responsible for hepatocyte demise in cholestatic liver diseases, while tauroursodeoxycholic acid (TUDCA) is regarded hepatoprotective. We demonstrate the direct mitochondrio-toxicity of bile salts which deplete the mitochondrial membrane potential and induce the mitochondrial permeability transition (MPT). The bile salt mediated mechanistic mode of destruction significantly differs from that of calcium, the prototype MPT inducer. Cell-toxic bile salts initially bind to the mitochondrial outer membrane. Subsequently, the structure of the inner boundary membrane disintegrates. And it is only thereafter that the MPT is induced. This progressive destruction occurs in a dose- and time-dependent way. We demonstrate that GCDCA and TCDCA, but not TUDCA, preferentially permeabilize liposomes containing the mitochondrial membrane protein ANT, a process resembling the MPT induction in whole mitochondria. This suggests that ANT is one decisive target for toxic bile salts. To our knowledge this is the first report unraveling the consecutive steps leading to mitochondrial destruction by cell-toxic bile salts., (Copyright © 2013 Elsevier B.V. All rights reserved.)