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Journal articles on the topic 'Novel Bile Acid Conjugates'

Author: Grafiati

Published: 4 June 2021

Last updated: 6 September 2023

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1

Mishra, Satyendra, and Sejal Patel. "Design, Synthesis, and Anti-bacterial Activity of Novel Deoxycholic Acid- Amino Alcohol Conjugates." Medicinal Chemistry 16, no. 3 (April 17, 2020): 385–91. http://dx.doi.org/10.2174/1573406415666190206231002.

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Background: Numerous synthetic bile acid derivatives have been recognized for their various biological activities. Among these, bile acid amides have emerged as an attractive antibacterial agent. We herein illustrate the synthesis and antibacterial evaluation of deoxycholic acidamino alcohols conjugates. Objective: Design and Synthesis of novel deoxycholic acid-amino alcohol conjugates to investigate their antibacterial activity against E. coli and S. aureus. Methods: Novel deoxycholic acid-amino alcohol conjugates were synthesized, from conjugation of deoxycholic acid-NHS ester with amino alcohols. Various amino alcohols moieties were appended to the C24 position of deoxycholic acid to yield deoxycholic acid-amino alcohol conjugates. All the synthesized compounds were characterized by 1H NMR, 13C NMR, IR and massspectroscopy. The entire synthesized deoxycholic acid-amino alcohol conjugates were evaluated for their antibacterial activity against E. coli and S. aureus using the broth dilution method. Results: The outcome illustrated that some of the novel deoxycholic acid-amino alcohol conjugates exhibited enhanced anti-bacterial activities. Amongst them, deoxycholic acid-amino alcohol conjugate containing (-R)-2-aminocyclohexanol (1) demonstrated promising efficacy against both strains S. aureus ATCC 25923 (MIC 15 μg/mL) and E. coli ATCC 25922 (MIC 45 μg/mL) and was identified as a lead molecule. Conclusion: Numbers of novel deoxycholic acid-amino alcohol conjugates were synthesized and their antimicrobial activities provided useful information that the potency was strongly depending on the structures of deoxycholic acid-amino alcohol conjugates.

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2

Ahonen, Kari V., Manu K. Lahtinen, Miika S. Löfman, Anniina M. Kiesilä, Arto M. Valkonen, Elina I. Sievänen, Nonappa, and Erkki T. Kolehmainen. "Structural studies of five novel bile acid-4-aminopyridine conjugates." Steroids 77, no. 11 (September 2012): 1141–51. http://dx.doi.org/10.1016/j.steroids.2012.06.003.

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3

Chong, Hyun-Soon, Yunwei Chen, Chi Soo Kang, Xiang Sun, and Ningjie Wu. "Novel 64Cu-radiolabeled bile acid conjugates for targeted PET imaging." Bioorganic & Medicinal Chemistry Letters 25, no. 5 (March 2015): 1082–85. http://dx.doi.org/10.1016/j.bmcl.2015.01.008.

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4

Li, Yan, Weijun Chu, and Yong Ju. "Novel bile acid derivedH-phosphonate conjugates: Synthesis and spectroscopic characterization." Heteroatom Chemistry 19, no. 4 (2008): 402–7. http://dx.doi.org/10.1002/hc.20447.

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5

Jin, Xue-Yuan, Chuan-Bao Zhu, Shi-Yong Fan, Jia-Lin Sun, Yu-Cong Shi, Chu-Han Wang, Hui-Fen Wang, Bo-Hua Zhong, Yi-Shan Yao, and Wei-Guo Shi. "Novel hypolipidemic conjugates of fatty acid and bile acid with lysine for linkage." Drug Development and Industrial Pharmacy 45, no. 6 (March 20, 2019): 995–98. http://dx.doi.org/10.1080/03639045.2019.1590393.

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6

Koivukorpi, Juha, and Erkki Kolehmainen. "Novel bile acid conjugates with aryl/alkenyl linker: Synthesis and characterization." Journal of Molecular Structure 889, no. 1-3 (October 2008): 211–16. http://dx.doi.org/10.1016/j.molstruc.2008.01.050.

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7

Noponen, Virpi, Shreedhar Bhat, Elina Sievänen, and Erkki Kolehmainen. "Novel two-step synthesis of gold nanoparticles capped with bile acid conjugates." Materials Science and Engineering: C 28, no. 7 (August 2008): 1144–48. http://dx.doi.org/10.1016/j.msec.2007.10.001.

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8

Blagbrough, I. S., A. J. Geall, and A. P. Neal. "Polyamines and novel polyamine conjugates interact with DNA in ways that can be exploited in non-viral gene therapy." Biochemical Society Transactions 31, no. 2 (April 1, 2003): 397–406. http://dx.doi.org/10.1042/bst0310397.

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As a part of our continuing studies on ‘Polyamines and their role in human disease’ we are investigating how polyamines, and especially how novel polyamine conjugates, interact with DNA. We are studying how these conjugates interact with circular plasmids in order to produce nanometre-sized particles suitable for transfecting cells. Our considerations of structure--activity relationships (SAR) within naturally occurring and synthetic polyamines have shown the significance of the inter-atomic distances between the basic nitrogen atoms. As these atoms are typically fully protonated under physiological conditions, they exist in equilibrium as polyammonium ions. The covalent addition of a lipid moiety, typically one or two alkyl or alkenyl chains, or a steroid, allows much greater efficiency in DNA condensation and in the cellular transfection achieved. Thus efficient DNA condensation and subsequently drug delivery (i.e. with DNA as the drug) can be brought about using novel polyamine conjugates. Taking further advantage of the functionalization of specific steroids (e.g. cholesterol and certain bile acids), we have designed and prepared novel fluorescent molecular probes as tools to throw light on the problematic steps in non-viral gene delivery which still impede efficient gene therapy. Thus, the current aims of our research are to understand, design and prepare small-molecule lipopolyamines for non-viral gene therapy (NVGT). The rational design and practical preparation of non-symmetrical polyamine carbamates and amides, based on steroid templates of cholesterol and the bile acid lithocholic acid as the lipid moiety, provides fluorescent molecular probes that condense DNA. These novel lipopolyamine conjugates mimic the positive charge distribution found in the triamine spermidine and the tetra-amine spermine alkaloids. After optimizing their SAR, these fluorescent probes will be useful in monitoring gene delivery in NVGT.

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9

Yang, Min, Yu Gu, Lingfeng Li, Tianyu Liu, Xueli Song, Yue Sun, Xiaocang Cao, Bangmao Wang, Kui Jiang, and Hailong Cao. "Bile Acid–Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside." Nutrients 13, no. 9 (September 9, 2021): 3143. http://dx.doi.org/10.3390/nu13093143.

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Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract, with increasing prevalence, and its pathogenesis remains unclear. Accumulating evidence suggested that gut microbiota and bile acids play pivotal roles in intestinal homeostasis and inflammation. Patients with IBD exhibit decreased microbial diversity and abnormal microbial composition marked by the depletion of phylum Firmicutes (including bacteria involved in bile acid metabolism) and the enrichment of phylum Proteobacteria. Dysbiosis leads to blocked bile acid transformation. Thus, the concentration of primary and conjugated bile acids is elevated at the expense of secondary bile acids in IBD. In turn, bile acids could modulate the microbial community. Gut dysbiosis and disturbed bile acids impair the gut barrier and immunity. Several therapies, such as diets, probiotics, prebiotics, engineered bacteria, fecal microbiota transplantation and ursodeoxycholic acid, may alleviate IBD by restoring gut microbiota and bile acids. Thus, the bile acid–gut microbiota axis is closely connected with IBD pathogenesis. Regulation of this axis may be a novel option for treating IBD.

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10

Thorpe, Cheleste M., Xi Qian, Karin Yanagi, Anne Kane, Nicholas Alden, David R. Snydman, and Kyongbum Lee. "2567. Effect of Broad vs. Narrow-Spectrum Clostridioides difficile Treatment on Human Stool Bile Acid Composition Over Time." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S891. http://dx.doi.org/10.1093/ofid/ofz360.2245.

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Abstract Background Secondary bile acid production by a diverse commensal flora may be a critical factor in preventing recurrence of Clostridioides difficile infection (CDI). Key enzymes involved are bacterial-encoded bile salt hydrolases (BSHs), felt to be “gatekeepers” to secondary bile acid synthesis. Ridinilazole, a novel narrow-spectrum drug for CDI, demonstrated superior sustained clinical response compared with vancomycin in Phase 2. Longitudinal sampling during this trial allowed for assessment of metabolites differentially present in stools during/after therapy with either broad or narrow-spectrum anti-CDI agent. Previous work characterizing subject’s fecal microbiota in this trial showed that unlike vancomycin, ridinilazole has little effect on commensal flora during and after therapy. We hypothesized that ridinilazole’s microbiota-preserving effect is associated with lack of accumulation of conjugated primary bile acids and/or reaccumulation/persistence of secondary bile acids over the course of CDI treatment, when compared with vancomycin-treated subjects. Furthermore, we hypothesized that we would observe correlations between bile acid profiles and predicted BSH gene abundances. Methods Sequential stool samples were obtained from 44 subjects treated with either ridinilazole or vancomycin (22 in each arm), ranging from time of CDI diagnosis, at end-of-therapy, and up to 40 days after diagnosis. Bile acids were quantitated by liquid chromatography-mass spectrometry. Using the PICRUSt algorithm, metagenomic predictions of BSH gene abundances were performed. Results Stool bile acid compositions differed between ridinilazole-treated and vancomycin-treated subjects at end-of-therapy. In vancomycin-treated subjects, stool composition became dominated by conjugated primary bile acids and decreased levels of secondary bile acids compared with baseline; the ratio of stool conjugated bile acids to secondary bile acids significantly predicted treatment arm. This ratio was also associated with predicted BSH gene abundance in ridinilazole-treated subjects. Conclusion Microbiota-preserving CDI treatment with ridinilazole preserves bile acid composition, which may decrease likelihood of recurrence. Disclosures All authors: No reported disclosures.

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11

Yu, Lei, Yan-Fang Jiang, Lei Sun, Bo-Hua Zhong, and Jun-Qi Niu. "EBHU18, a novel derivative of fatty acid bile acid conjugates, prevents cholesterol gallstone formation in experimental mice." Medicinal Chemistry Research 21, no. 11 (November 19, 2011): 3382–89. http://dx.doi.org/10.1007/s00044-011-9828-5.

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12

Li, Yan, Yong Ju, and Yufen Zhao. "Synthesis and Characterization of Novel Bile Acids Derived H-Phosphonates Conjugates." Phosphorus, Sulfur, and Silicon and the Related Elements 183, no. 2-3 (January 14, 2008): 706–11. http://dx.doi.org/10.1080/10426500701807533.

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13

Trauner, Michael, Emina Halilbasic, Thierry Claudel, Daniel Steinacher, Claudia Fuchs, Tarek Moustafa, Marion Pollheimer, et al. "Potential of nor-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders." Digestive Diseases 33, no. 3 (2015): 433–39. http://dx.doi.org/10.1159/000371904.

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24-nor-ursodeoxycholic acid (norUDCA) is a side-chain shortened derivate of ursodeoxycholic acid (UDCA). Since norUDCA is only ineffectively conjugated with glycine or taurine, it has specific physicochemical and therapeutic properties distinct from UDCA. Nonamidated norUDCA undergoes cholehepatic shunting enabling ‘ductular targeting' and inducing a bicarbonate-rich hypercholeresis, with cholangioprotective effects. At the same time it has direct anti-inflammatory, antilipotoxic, anti fibrotic, and antiproliferative properties targeting various liver cell populations. norUDCA appears to be one of the most promising novel treatment approaches targeting the liver and the bile duct system at multifactorial and multicellular levels. This review article is a summary of a lecture given at the XXIII International Bile Acid Meeting (Falk Symposium 194) on ‘Bile Acids as Signal Integrators and Metabolic Modulators' held in Freiburg, October 8-9, 2014, and summarizes the recent progress with norUDCA as a novel therapeutic approach in cholestatic and metabolic (liver) disorders.

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14

Zhu, Quan-Fei, Yan-Zhen Wang, Na An, Jun-Di Hao, Peng-Cheng Mei, Ya-Li Bai, Yu-Ning Hu, Pei-Rong Bai, and Yu-Qi Feng. "Alternating Dual-Collision Energy Scanning Mass Spectrometry Approach: Discovery of Novel Microbial Bile-Acid Conjugates." Analytical Chemistry 94, no. 5 (January 27, 2022): 2655–64. http://dx.doi.org/10.1021/acs.analchem.1c05272.

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15

Koivukorpi, Juha, Arto Valkonen, Manu Lahtinen, and Erkki Kolehmainen. "Synthesis and characterization of novel bile-acid – heteroaryl conjugates with N-(2-aminoethyl)amido linker." Journal of Molecular Structure 892, no. 1-3 (December 2008): 53–57. http://dx.doi.org/10.1016/j.molstruc.2008.04.057.

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16

Koivukorpi, Juha, and Erkki Kolehmainen. "Design, synthesis and spectral studies of novel bile acid-arene conjugates: Trans to cis isomerization of azobenzene core controlled by bile acid hydrophobicity." Journal of Molecular Structure 875, no. 1-3 (March 2008): 63–67. http://dx.doi.org/10.1016/j.molstruc.2007.03.058.

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17

Déjean, Guillaume, Héloïse Tudela, Lisa Bruno, Déborah Kissi, Georges Rawadi, and Sandrine P. Claus. "Identifying a Novel Bile Salt Hydrolase from the Keystone Gut Bacterium Christensenella minuta." Microorganisms 9, no. 6 (June 9, 2021): 1252. http://dx.doi.org/10.3390/microorganisms9061252.

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Christensenella minuta are human gut dwelling bacteria that have been proposed as key members of the gut microbiome, regulating energy balance and adiposity of their host. We formerly identified that a novel strain of C. minuta (strain DSM33407) boosted microbiota diversity and stimulated deconjugation of the primary bile acid taurocholic acid in human samples. However, there is no description of a bile salt hydrolase (BSH) protein carried in the genome of C. minuta. Here, we identified and cloned a protein from C. minuta’s genome that carries a potent BSH activity, which preferentially deconjugates glycine-conjugated bile acids. We then retrieved 14,319 putative BSH sequences from the NCBI database and filtered them using the UHGP database to collect a total of 6701 sequences that were used to build the most comprehensive phylogenetic tree of BSH-related enzymes identified in the human microbiome so far. This phylogenetic tree revealed that C. minuta’s BSH amino acid sequence clusters away from others with a threshold of 70% identity. This is therefore the first description of C. minuta’s BSH protein, which may be involved in its unique role within the human gut microbial ecosystem.

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18

Ray, Abhijit, Antara Banerjee, Cheng Chang, Chandra M. Khantwal, and Peter W. Swaan. "Design of novel synthetic MTS conjugates of bile acids for site-directed sulfhydryl labeling of cysteine residues in bile acid binding and transporting proteins." Bioorganic & Medicinal Chemistry Letters 16, no. 6 (March 2006): 1473–76. http://dx.doi.org/10.1016/j.bmcl.2005.12.050.

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19

Peters, D., L. Norris, L. Tenora, I. Snajdr, X. Zhu, S. Sakamoto, V. Veeravalli, et al. "P068 Discovery of IBD3540: A Novel Gut-Restricted Glutamate Carboxypeptidase II Inhibitor with Preclinical Anti-Colitis Activity." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i174—i175. http://dx.doi.org/10.1093/ecco-jcc/jjab232.197.

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Abstract Background Glutamate carboxypeptidase II (GCPII) is robustly overexpressed in both Crohn’s disease and ulcerative colitis and is a promising therapeutic target for IBD. We have previously published that systemically or enema administered small molecule GCPII inhibitors have efficacy in multiple mouse colitis models. While this is a highly encouraging activity profile for a candidate IBD drug, an oral dose route would be strongly preferred. Thus, here we develop and characterize a new class of GCPII inhibitors designed to be gut-restricted for oral administration, with the intention of selecting a lead inhibitor for further clinical development. Methods Anti-inflammatory secondary bile acids lithocholic acid, deoxycholic acid and ursodeoxycholic acid were conjugated to GCPII inhibitor, 2-PMPA, yielding three novel constructs. These conjugates were screened for oral activity in murine dextran sulfate sodium (DSS) colitis, followed by detailed characterization of the most active inhibitor to: measure GCPII inhibition (IC50), confirm colon target engagement, evaluate plasma and colon pharmacokinetic profiles, compare efficacy versus standard-of-care agents, evaluate mechanisms of anti-inflammatory activity in vivo, confirm efficacy in a second colitis model (IL10-/-), and assess safety in standard preclinical assays. Results The deoxycholic acid 2-PMPA conjugate, IBD3540, was identified as the lead inhibitor (IC50 = 4nM). Oral IBD3540 was robustly efficacious in acute DSS colitis, where it dose-dependently inhibited colon GCPII, attenuated both gross disease activity index and blinded colon histopathology scores, and had improved efficacy relative to both sulfasalazine and tofacitinib when compared head-to-head. Mechanistically, we determined that IBD3540 attenuated pathogenic monocytic inflammation in the colon, as measured by flow cytometry, and also decreased colon pro-inflammatory cytokine content. We confirmed efficacy of IBD3540 in spontaneously occurring, chronic, IL10-/- colitis, where treatment initiated 4 weeks after the onset of colon inflammation improved multiple disease endpoints. Further, in preclinical safety screens, inclusive of CYP inhibition/induction assays, Eurofins SafetyScreen44TM, and AMES/hERG mutagenicity testing, no concerns were identified. Conclusion IBD3540 is a novel, gut-restricted, GCPII inhibitor with potent oral anti-colitis efficacy in both acute (DSS) and chronic (IL10-/-) mouse colitis models and a promising preclinical safety profile. Further development of this mechanistically unique candidate IBD drug is warranted.

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Peters, Diane, Lauren Norris, Lukas Tenora, Ivan Snajdr, Xiaolei Zhu, Shinji Sakamoto, Ajit Thomas, Pavel Majer, Rana Rais, and Barbara Slusher. "DISCOVERY OF IBD3540: A NOVEL GUT-RESTRICTED GLUTAMATE CARBOXYPEPTIDASE II INHIBITOR WITH ORAL ACTIVITY IN MOUSE COLITIS MODELS." Inflammatory Bowel Diseases 28, Supplement_1 (January 22, 2022): S4. http://dx.doi.org/10.1093/ibd/izac015.007.

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Abstract BACKGROUND & AIMS Glutamate carboxypeptidase II (GCPII) is robustly overexpressed in both Crohn’s disease and ulcerative colitis and is a promising therapeutic target for IBD. We have previously published that systemically or enema administered small molecule GCPII inhibitors have efficacy in multiple mouse colitis models. While this is a highly encouraging activity profile for a candidate IBD drug, an oral dose route would be strongly preferred. Thus, here we develop and characterize a new class of GCPII inhibitors designed to be gut-restricted for oral administration, with the intention of selecting a lead inhibitor for further clinical development. METHODS Anti-inflammatory secondary bile acids lithocholic acid, deoxycholic acid and ursodeoxycholic acid were conjugated to GCPII inhibitor, 2-PMPA, yielding three novel constructs. These conjugates were screened for oral activity in murine dextran sulfate sodium (DSS) colitis, followed by detailed characterization of the most active inhibitor to: measure GCPII inhibition (IC50), confirm colon target engagement, evaluate plasma and colon pharmacokinetic profiles, compare efficacy versus standard-of-care agents, evaluate mechanisms of anti-inflammatory activity in vivo, confirm efficacy in a second colitis model (IL10-/-), and assess safety in standard preclinical assays. RESULTS The deoxycholic acid 2-PMPA conjugate, IBD3540, was identified as the lead inhibitor (IC50 = 4nM). Oral IBD3540 was robustly efficacious in acute DSS colitis, where it dose-dependently inhibited colon GCPII, attenuated both gross disease activity index and blinded colon histopathology scores, and exhibited improved efficacy relative to both sulfasalazine and tofacitinib when compared head-to-head. Mechanistically, we determined that IBD3540 attenuated pathogenic monocytic inflammation in the colon, as measured by flow cytometry, and also decreased colon pro-inflammatory cytokine content. We confirmed efficacy of IBD3540 in spontaneously occurring, chronic, IL10-/- colitis, where treatment initiated 4 weeks after the onset of colon inflammation improved multiple disease endpoints. Further, in preclinical safety screens, inclusive of CYP inhibition/induction assays, Eurofins SafetyScreen44, and AMES/hERG mutagenicity testing, no concerns were identified. CONCLUSION IBD3540 is a novel, gut-restricted, GCPII inhibitor with potent oral anti-colitis efficacy in both acute (DSS) and chronic (IL10-/-) mouse colitis models and a promising preclinical safety profile. Further development of this mechanistically unique candidate IBD drug is warranted.

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21

Call, Lee, Tiffany Molina, Barbara Stoll, Greg Guthrie, Shaji Chacko, Jogchum Plat, Jason Robinson, et al. "Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs." Journal of Lipid Research 61, no. 7 (April 29, 2020): 1038–51. http://dx.doi.org/10.1194/jlr.ra120000652.

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Multi-component lipid emulsions, rather than soy-oil emulsions, prevent cholestasis by an unknown mechanism. Here, we quantified liver function, bile acid pools, and gut microbial and metabolite profiles in premature parenterally fed pigs given a soy-oil lipid emulsion, Intralipid (IL), a multi component lipid emulsion, SMOFlipid (SMOF), a novel emulsion with a modified fatty-acid composition [experimental emulsion (EXP)], or a control enteral diet (ENT) for 22 days. We assayed serum cholestasis markers, measured total bile acid levels in plasma, liver, and gut contents, and analyzed colonic bacterial 16S rRNA gene sequences and metabolomic profiles. Serum cholestasis markers (i.e., bilirubin, bile acids, and γ-glutamyl transferase) were highest in IL-fed pigs and normalized in those given SMOF, EXP, or ENT. Gut bile acid pools were lowest in the IL treatment and were increased in the SMOF and EXP treatments and comparable to ENT. Multiple bile acids, especially their conjugated forms, were higher in the colon contents of SMOF and EXP than in IL pigs. The colonic microbial communities of SMOF and EXP pigs had lower relative abundance of several gram-positive anaerobes, including Clostridrium XIVa, and higher abundance of Enterobacteriaceae than those of IL and ENT pigs. Differences in lipid and microbial-derived compounds were also observed in colon metabolite profiles. These results indicate that multi-component lipid emulsions prevent cholestasis and restore enterohepatic bile flow in association with gut microbial and metabolomic changes. We conclude that sustained bile flow induced by multi-component lipid emulsions likely exerts a dominant effect in reducing bile acid-sensitive gram-positive bacteria.

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22

Parikh, Kalpesh, Dhaval Savaliya, and Deepkumar Joshi. "Antibacterial and Antifungal Screening of Novel α-amino Acid Conjugated Bile Acid Derivatives." Current Bioactive Compounds 10, no. 4 (February 6, 2015): 260–70. http://dx.doi.org/10.2174/1573407210666140909201409.

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23

Domingue, Jada C., Mei Ao, Jayashree Sarathy, and Mrinalini C. Rao. "Chenodeoxycholic acid requires activation of EGFR, EPAC, and Ca2+ to stimulate CFTR-dependent Cl− secretion in human colonic T84 cells." American Journal of Physiology-Cell Physiology 311, no. 5 (November 1, 2016): C777—C792. http://dx.doi.org/10.1152/ajpcell.00168.2016.

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Bile acids are known to initiate intricate signaling events in a variety of tissues, primarily in the liver and gastrointestinal tract. Of the known bile acids, only the 7α-dihydroxy species, deoxycholic acid and chenodeoxycholic acid (CDCA), and their conjugates, activate processes that stimulate epithelial Cl− secretion. We have previously published that CDCA acts in a rapid manner to stimulate colonic ion secretion via protein kinase A (PKA)-mediated activation of the dominant Cl− channel, the cystic fibrosis transmembrane conductance regulator (CFTR) (Ao M, Sarathy J, Domingue J, Alrefai WA, and Rao MC. Am J Physiol Cell Physiol 305: C447–C456, 2013); however, PKA signaling did not account for the entire CDCA response. Here we show that in human colonic T84 cells, CDCA's induction of CFTR activity, measured as changes in short-circuit current ( Isc), is dependent on epidermal growth factor receptor (EGFR) activation and does not involve the bile acid receptors TGR5 or farnesoid X receptor. CDCA activation of Cl− secretion does not require Src, mitogen-activated protein kinases, or phosphoinositide 3-kinase downstream of EGFR but does require an increase in cytosolic Ca2+. In addition to PKA signaling, we found that the CDCA response requires the novel involvement of the exchange protein directly activated by cAMP (EPAC). EPAC is a known hub for cAMP and Ca2+ cross talk. Downstream of EPAC, CDCA activates Rap2, and changes in free cytosolic Ca2+ were dependent on both EPAC and EGFR activation. This study establishes the complexity of CDCA signaling in the colonic epithelium and shows the contribution of EGFR, EPAC, and Ca2+ in CDCA-induced activation of CFTR-dependent Cl− secretion.

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24

Richards, Steven J., Thomas W. von Geldern, Peer Jacobson, Denise Wilcox, Phong Nguyen, Lars Öhman, Marie Österlund, et al. "Synthesis and activity of novel bile-acid conjugated glucocorticoid receptor antagonists." Bioorganic & Medicinal Chemistry Letters 16, no. 23 (December 2006): 6086–90. http://dx.doi.org/10.1016/j.bmcl.2006.08.133.

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25

Vicens, Marta, Manuel Medarde, Rocio I. R. Macias, Monica G. Larena, Antonio Villafaina, Maria A. Serrano, and Jose J. G. Marin. "Novel cationic and neutral glycocholic acid and polyamine conjugates able to inhibit transporters involved in hepatic and intestinal bile acid uptake." Bioorganic & Medicinal Chemistry 15, no. 6 (March 2007): 2359–67. http://dx.doi.org/10.1016/j.bmc.2007.01.027.

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26

GOTO, T., A. SHIBATA, D. SASAKI, N. SUZUKI, T. HISHINUMA, G. KAKIYAMA, T. IIDA, N. MANO, and J. GOTO. "Identification of a novel conjugate in human urine: bile acid acyl galactosides." Steroids 70, no. 3 (March 2005): 185–92. http://dx.doi.org/10.1016/j.steroids.2004.12.006.

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Mohammed, Ahmed Dawood, Ioulia Chatzistamou, Mary Roland, Amy Jolly, Lillian Schoettmer, Mitzi Nagarkatti, Prakash Nagarkatti, and Jason L. Kubinak. "Does Dysbiosis Drive CVID Enteropathy by Enhancing Bile Acid Cytotoxicity?" Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 83.15. http://dx.doi.org/10.4049/jimmunol.204.supp.83.15.

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Abstract Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by defects in the humoral immune response. CVID patients commonly present with a gastrointestinal enteropathy characterized by intestinal malabsorption. CVID is linked with abnormal gut microbiota composition (i.e. dysbiosis), which may be a contributing factor to CVID enteropathy. Recently, we demonstrated that CD19−/− mice represent a spontaneous animal model of CVID enteropathy that develop an associated dysbiosis. We now expand upon this work to identify how microbial dysbiosis may contribute to CVID enteropathy. We first demonstrate a significant association between dysbiosis in CD19−/− mice with defects in bile acid (BA) homeostasis (increased luminal BA titers and decreased abundance of conjugated BA species). Enteropathy in CD19−/− mice is associated with enhanced apoptosis of intestinal epithelial cells (IECs). Adoptive transfer of WT B cells (but not CD19−/− B cells) reduces luminal BA concentrations, protects IECs from apoptosis, and resolves enteropathy, indicating that functional B cells are important regulators of BA homeostasis and gastrointestinal health. Additionally, dietary supplementation with a taurine conjugated BA also protects animals from disease demonstrating that enhanced BA deconjugation enhances disease severity. Finally, direct ablation of the ability of a model commensal microbe to deconjugate BAs also rescues animals from disease. Collectively, these data suggest that enhanced bacterial deconjugation of BAs in the gut contributes to CVID enteropathy by enhancing BA cytotoxicity to IECs. Thus, microbial BA deconjugation may represent a novel therapeutic target for the treat of CVID enteropathy.

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Danese, Elisa, Patricia M. J. Lievens, Andrea Padoan, Denise Peserico, Roberta Galavotti, Davide Negrini, Matteo Gelati, et al. "Plasma Bile Acid Profiling and Modulation of Secreted Mucin 5AC in Cholangiocarcinoma." International Journal of Molecular Sciences 24, no. 16 (August 14, 2023): 12794. http://dx.doi.org/10.3390/ijms241612794.

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Studies investigating the potential role of circulating bile acids (BAs) as diagnostic biomarkers for cholangiocarcinoma (CCA) are sparse and existing data do not adjust for confounding variables. Furthermore, the mechanism by which BAs affect the expression of the oncogenic mucin 5AC (MUC5AC) has never been investigated. We performed a case–control study to characterise the profile of circulating BAs in patients with CCA (n = 68) and benign biliary disease (BBD, n = 48) with a validated liquid chromatography–tandem mass spectrometry technique. Odd ratios (OR) for CCA associations were calculated with multivariable logistic regression models based on a directed acyclic graph structure learning algorithm. The most promising BAs were then tested in an in vitro study to investigate their interplay in modulating MUC5AC expression. The total concentration of BAs was markedly higher in patients with CCA compared with BBD controls and accompanied by a shift in BAs profile toward a higher proportion of primary conjugated BAs (OR = 1.50, CI: 1.14 to 1.96, p = 0.003), especially taurochenodeoxycholic acid (TCDCA, OR = 42.29, CI: 3.54 to 504.63, p = 0.003) after multiple adjustments. Western blot analysis of secreted MUC5AC in human primary cholangiocytes treated with primary conjugated BAs or with TCDCA alone allowed us to identify a novel 230 kDa isoform, possibly representing a post-translationally modified MUC5AC specie.

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Kim, Dongmyong, Jongseong Yoon, Seoju Kim, Hosoon Choi, and Insuk Han. "A Novel Transdermal Delivery System based on a Bile Acid- Conjugated Nanoparticle Model for Cosmetics." Asian Journal of Beauty and Cosmetology 17, no. 1 (March 18, 2019): 81–91. http://dx.doi.org/10.20402/ajbc.2018.0265.

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Sundrud, Mark S., Wei Cao, Hisako Kayama, Mei Lan Chen, Amber Delmas, Amy Sun, Sang Yong Kim, et al. "The xenobiotic transporter Mdr1 permits T cell adaptation to mucosa-associated bile acids in the ileum." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 65.14. http://dx.doi.org/10.4049/jimmunol.198.supp.65.14.

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Abstract Intestinal CD4+ T helper (TH) cells are subject to extensive regulation by microbiota. By contrast, it is not known whether or how TH cells interface with other, host-derived intestinal metabolites. Here we show that bile acids directly regulate mucosal TH cell function in the distal small intestine (i.e., ileum) via the xenobiotic transporter, Mdr1. Using both Mdr1-dependent dye efflux and a novel CRISPR-generated Mdr1 reporter mouse, we show that wild type RORγt+IL-17A+ (Th17) and RORγt-IFNγ+ (Th1) cells upregulate Mdr1 expression upon migration into the ileum. By contrast, germline ablation or shRNAmir-mediated knockdown of Mdr1 in Th17 and Th1 cells results in local dysfunction in the ileum, and these cells transfer Crohn’s disease-like ileitis in Rag1−/− hosts. Mdr1 enforces Th17 and Th1 cell survival and limits pro-inflammatory cytokine (TNFα, IFNγ) expression in the presence of conjugated bile acids (CBAs), which are actively reabsorbed through the ileal mucosa as a function of enterohepatic bile acid circulation. Accordingly, genetic or pharmacologic blockade of ileal CBA reabsorption restores Mdr1-deficient Th17 and Th1 cell homeostasis in ilea of transferred Rag1−/− hosts and rescues ileitis. In addition, MDR1 loss-of-function is evident in both ileitis-prone (SAMP1/YitFc) mice, and a subset of ileal Crohn’s disease patients. These data indicate that coordinated, local and druggable interactions between mucosal TH cells and mucosa-associated bile acids in the ileum contribute to intestinal immune homeostasis.

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Huang, Yueh-Hsiang, Yi-Hong Wu, Hsiang-Yu Tang, Szu-Tah Chen, Chih-Ching Wang, Wan-Jing Ho, Yi-Hsuan Lin, et al. "Gut Microbiota and Bile Acids Mediate the Clinical Benefits of YH1 in Male Patients with Type 2 Diabetes Mellitus: A Pilot Observational Study." Pharmaceutics 14, no. 9 (September 2, 2022): 1857. http://dx.doi.org/10.3390/pharmaceutics14091857.

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Our previous clinical trial showed that a novel concentrated herbal extract formula, YH1 (Rhizoma coptidis and Shen-Ling-Bai-Zhu-San), improved blood glucose and lipid control. This pilot observational study investigated whether YH1 affects microbiota, plasma, and fecal bile acid (BA) compositions in ten untreated male patients with type 2 diabetes (T2D), hyperlipidemia, and a body mass index ≥ 23 kg/m2. Stool and plasma samples were collected for microbiome, BA, and biochemical analyses before and after 4 weeks of YH1 therapy. As previous studies found, the glycated albumin, 2-h postprandial glucose, triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were significantly improved after YH1 treatment. Gut microbiota revealed an increased abundance of the short-chain fatty acid-producing bacteria Anaerostipes and Escherichia/Shigella. Furthermore, YH1 inhibited specific phylotypes of bile salt hydrolase-expressing bacteria, including Parabacteroides, Bifidobacterium, and Bacteroides caccae. Stool tauro-conjugated BA levels increased after YH1 treatment. Plasma total BAs and 7α-hydroxy-4-cholesten-3-one (C4), a BA synthesis indicator, were elevated. The reduced deconjugation of BAs and increased plasma conjugated BAs, especially tauro-conjugated BAs, led to a decreased glyco- to tauro-conjugated BA ratio and reduced unconjugated secondary BAs. These results suggest that YH1 ameliorates T2D and hyperlipidemia by modulating microbiota constituents that alter fecal and plasma BA compositions and promote liver cholesterol-to-BA conversion and glucose homeostasis.

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Thakare, Rhishikesh, Hongying Gao, Rachel E. Kosa, Yi-An Bi, Manthena V. S. Varma, Matthew A. Cerny, Raman Sharma, et al. "Leveraging of Rifampicin-Dosed Cynomolgus Monkeys to Identify Bile Acid 3-O-Sulfate Conjugates as Potential Novel Biomarkers for Organic Anion-Transporting Polypeptides." Drug Metabolism and Disposition 45, no. 7 (April 10, 2017): 721–33. http://dx.doi.org/10.1124/dmd.117.075275.

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Stravitz, R. T., Y. P. Rao, Z. R. Vlahcevic, E. C. Gurley, W. D. Jarvis, and P. B. Hylemon. "Hepatocellular protein kinase C activation by bile acids: implications for regulation of cholesterol 7 alpha-hydroxylase." American Journal of Physiology-Gastrointestinal and Liver Physiology 271, no. 2 (August 1, 1996): G293—G303. http://dx.doi.org/10.1152/ajpgi.1996.271.2.g293.

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We have recently shown that taurocholate (TCA) represses the transcriptional activity of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme of the bile acid biosynthetic pathway, through a protein kinase C (PKC)-dependent mechanism in primary cultures of rat hepatocytes. The present studies sought to determine the mechanisms by which bile acids activate hepatic PKC activity and the consequences of this activation on isoform distribution and cholesterol 7 alpha-hydroxylase mRNA levels. TCA (12.5-100 microM for 15 min) increased membrane-associated "classic" isoenzyme cPKC-alpha and "novel" isoenzymes nPKC-delta, and nPKC by two- to sixfold. Membrane-associated PKC progressively increased, and cytosolic PKC decreased, for 1 h after the addition of TCA (50 microM); after 24 h whole cell cPKC-alpha, nPKC-delta, and nPKC were downregulated by 35-55% compared with untreated controls. In a reconstituted assay system, TCA or taurodeoxycholate (10-100 microM) increased calcium-dependent and -independent PKC activity by three- and fourfold, respectively. Taurine-conjugated bile acids stimulated PKC activity in proportion to their hydrophobicity index (r = 0.99). Finally, cholesterol 7 alpha-hydroxylase mRNA was repressed > 75% by phorbol 12-myristate 13-acetate (100 nM for 3 h), a nonselective activator of PKC isoforms. In contrast, selective cPKC-alpha activation with thymeleatoxin (100 nM for 3 h) had no significant effect on cholesterol 7 alpha-hydroxylase mRNA levels. We conclude that bile acids activate hepatocellular PKC, resulting in sequential redistribution and down-regulation of calcium-dependent and -independent isoforms. The calcium-independent PKC isoforms may mediate the repression of cholesterol 7 alpha-hydroxylase mRNA by TCA.

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Sigurdsson, Valgardur, Hajime Takei, Svetlana Soboleva, Takashi Iida, Hiroshi Nittono, and Kenichi Miharada. "Taurine-Conjugated Bile Acids Protect Expanding Hematopoietic Stem/Progenitor Cells from Unfolded Protein Stress As Natural Chaperones." Blood 124, no. 21 (December 6, 2014): 4318. http://dx.doi.org/10.1182/blood.v124.21.4318.4318.

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Abstract Hematopoietic stem cells (HSCs) give rise to all lineages of hematopoietic cells in the body for entire life span and are thus protected from risk factors by multiple defense systems. We have recently discovered that HSCs are highly susceptible to stress caused by accumulation of mis-/un-folded proteins, so called endoplasmic reticulum (ER) stress upon enhanced growth conditions, and addition of a specific type of bile acid (BA), Tauroursodeoxycholic acid (TUDCA), known as a chemical chaperone can maintain functional murine HSCs for 2 weeks in vitro, by reducing ER stress (Miharada et al., Cell Rep. 2014). This work depicts the importance of proper protein quality control in HSC maintenance, particularly during the expansion. HSCs are kept in dormant state in the adult body, but actively expanding in the fetal liver. BAs are synthesized from cholesterol in the liver. Interestingly, bile acid synthesis is highly up-regulated in the fetal liver during embryogenesis and the composition of fetal BAs gradually reduces after birth. In addition, composition of bile acids in the fetus is different from adult liver, with the vast majority of fetal BAs are of Taurine-conjugated form that is more stable and non-toxic. Of note, hematopoietic cells and hepatocytes producing BAs are in close contact in the fetal liver and HSCs are therefore exposed to BAs, whereas the adult liver has anatomically isolated bile duct structures that separate blood flow and bile flow. However the role for these fetal BAs has been unknown. Here we report that bile acids support expansion of hematopoietic stem and progenitor cells (HSPCs) in the fetal liver and ex vivo. Since TUDCA is a rare component in human and mouse BAs, even in the fetal liver, we sought analogue(s) that similarly function as ER stress inhibitors. We identified that Taurocholic acid (TCA), one of the main components of fetal BA, and Tauro-alpha-muricholic acid (TαMCA) that is a rodent specific BA have a potential to reduce ER stress, similar to TUDCA. Mouse HSCs cultured with TCA or TαMCA in vitro for 2 weeks showed a robust increase in the reconstitution level compared to non-treated cells (14-fold, n=14, p<0.001 and 13-fold, n=9, p<0.05, respectively), which has comparable or even better potential to support HSC function than TUDCA. To study physiological roles of BA in ER stress reduction and HSC expansion in the fetal liver, an inhibitor of BA synthesis, GW4064 (an agonist of a nuclear receptor FxR that negatively regulates key enzymes in the BA biosynthesis, CYP7A1 and CYP8B1), was intraperitoneally injected into pregnant mice. E16.5 fetuses derived from GW4064-injected pregnant mice showed severe decrease in the number of HSPCs (0.40-fold, n=28-33, p<0.001) in the fetal liver, due to increased apoptosis triggered by elevated ER stress levels. Importantly, co-injection of TCA or Salubrinal (inhibitor of the ER stress-induced apoptosis signal) rescued the effects of GW4064 on cellularity of the fetal liver and levels of ER stress, confirming that the phenotype seen here is due to increased ER stress resulting from lowered levels of BA. Analyses of CYP27A1 knockout (KO) mice that have reduced BA synthesis observed decreased HSC number and increased ER stress in the fetal liver, whereas CYP8B1 KO mice that have increased Tα/βMCA synthesis instead of lack of TCA didn’t show any difference. These findings strongly suggest that fetal BA, particularly TCA and TαMCA, supports the expansion of HSPCs in the fetal liver and the ex vivo culture as chemical chaperones by lowering ER stress levels. Our findings propose a new role of bile acids in hematopoiesis as natural chaperones and provide a novel connection between hematopoiesis and fetal liver. Disclosures No relevant conflicts of interest to declare.

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Pheiffer, Fazlin, Yannik K. H. Schneider, Espen Holst Hansen, Jeanette Hammer Andersen, Johan Isaksson, Tobias Busche, Christian Rückert, Jörn Kalinowski, Leonardo van Zyl, and Marla Trindade. "Bioassay-Guided Fractionation Leads to the Detection of Cholic Acid Generated by the Rare Thalassomonas sp." Marine Drugs 21, no. 1 (December 20, 2022): 2. http://dx.doi.org/10.3390/md21010002.

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Bacterial symbionts of marine invertebrates are rich sources of novel, pharmaceutically relevant natural products that could become leads in combatting multidrug-resistant pathogens and treating disease. In this study, the bioactive potential of the marine invertebrate symbiont Thalassomonas actiniarum was investigated. Bioactivity screening of the strain revealed Gram-positive specific antibacterial activity as well as cytotoxic activity against a human melanoma cell line (A2058). The dereplication of the active fraction using HPLC-MS led to the isolation and structural elucidation of cholic acid and 3-oxo cholic acid. T. actiniarum is one of three type species belonging to the genus Thalassomonas. The ability to generate cholic acid was assessed for all three species using thin-layer chromatography and was confirmed by LC-MS. The re-sequencing of all three Thalassomonas type species using long-read Oxford Nanopore Technology (ONT) and Illumina data produced complete genomes, enabling the bioinformatic assessment of the ability of the strains to produce cholic acid. Although a complete biosynthetic pathway for cholic acid synthesis in this genus could not be determined based on sequence-based homology searches, the identification of putative penicillin or homoserine lactone acylases in all three species suggests a mechanism for the hydrolysis of conjugated bile acids present in the growth medium, resulting in the generation of cholic acid and 3-oxo cholic acid. With little known currently about the bioactivities of this genus, this study serves as the foundation for future investigations into their bioactive potential as well as the potential ecological role of bile acid transformation, sterol modification and quorum quenching by Thalassomonas sp. in the marine environment.

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Pashankar, Dinesh, and Richard A. Schreiber. "Neonatal Cholestasis: A Red Alert for the Jaundiced Newborn." Canadian Journal of Gastroenterology 14, suppl d (2000): 67D—72D. http://dx.doi.org/10.1155/2000/657368.

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Neonatal jaundice may indicate cholestasis rather than a benign, physiological condition. Any four-week-old newborn with persistent jaundice should have a fractionated bilirubin screen to determine whether the hyperbilirubinemia is unconjugated. Conjugated hyperbilirubinemia, a hallmark of neonatal cholestasis, is pathological and requires further investigation. These infants need prompt diagnosis, early intervention and careful follow-up to ensure continued growth and development. Recent progress in the physiology of bile flow is reviewed, and the evaluation and management of neonatal cholestasis are summarized. Further advances in delineating the cellular and molecular processes that regulate bile acid metabolism in both health and disease will lead to a greater understanding of the conditions causing neonatal cholestasis. Unravelling the etiopathogenesis of these neonatal cholestatic disorders will allow the development of novel diagnostic and therapeutic interventions that ultimately will effectuate the prognosis for these young patients.

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Keizman, D., N. Maimon, M. Ish-Shalom, D. Buchbut, M. Inbar, B. Klein, J. Bernheim, et al. "An animal model for chemotherapy-associated steatohepatitis (CASH) and its prevention by the oral administration of fatty acid bile acid conjugate (FABAC)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 4098. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4098.

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4098 Background: Preoperative chemotherapy (irinotecan and oxaliplatin), used in patients undergoing hepatic resection of colorectal liver metastases, is associated with the development of CASH. This hepatic injury increases the risk of perioperative morbidity and mortality. An animal model for CASH has not yet been described. Fatty acid bile acid conjugates (FABACs) are novel synthetic lipid molecules that were shown to prevent the formation of diet induced fatty liver. The present study was designed to establish an animal model of CASH and to use it to study the effect of FABAC on its occurrence. Methods: C57B1/6 mice were given different doses of intraperitoneally injected oxaliplatin and irinotecan. Once weekly administered oxaliplatin at a dose of 6mg/m2 for a total dose of 24mg/ m2, was best tolerated and most consistently associated with CASH in comparison to higher doses of oxaliplatin or different irinotecan regimens. Thus it was chosen as the induction model for CASH. Subsequently, 32 mice were divided into a control group (no treatment, n=6), oxaliplatin group (n=14), and a CASH prevention group (n=12) treated by oxaliplatin and C20-FABAC (arachidyl-amido-cholanoic acid) at a dose of 150 mg/kg/day administered by gavage. The animals were sacrificed after 28 days. Their livers were homogenized and analyzed for fat content (measured as mg lipid/g liver tissue). Results: There were no significant differences in animal or liver weights between the groups. Liver fat content, was significantly lower (P<0.0001) among the control (51.63 mg/g) and prevention (62.13 mg/g) groups versus the oxaliplatin group (95.35 mg/g). The difference between the control and prevention groups was not significant. To the best of our knowledge this is the first description of a model and a potential preventive treatment for CASH. Conclusions: C57B1/6 mice treated by intraperitoneal injection of weekly oxaliplatin at a dose of 6mg/m2 for a total of 24mg/m2, can be used as a model for CASH. Oral FABAC therapy reduces the development of chemotherapy associated steatohepatitis in animals treated with oxaliplatin. No significant financial relationships to disclose.

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Fu, Zhenzhen, Qinyi Wu, Wen Guo, Jingyu Gu, Xuqin Zheng, Yingyun Gong, Chenyan Lu, et al. "Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles." Diabetes Care 45, no. 2 (December 8, 2021): 425–35. http://dx.doi.org/10.2337/dc21-1023.

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OBJECTIVE To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs). RESEARCH DESIGN AND METHODS In cohort 1, insulin secretion, sensitivity, and endogenous insulin clearance were evaluated with an oral glucose tolerance test in 460 recruited participants. In cohort 2, 81 participants underwent an intravenous glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, obese participants without diabetes were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance. RESULTS All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in obese subjects without diabetes. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum-conjugated BAs, especially glycodeoxycholic acid (GDCA; β = −0.335, P = 0.004) and taurodeoxycholic acid (TDCA; β = −0.333, P = 0.003), were negatively correlated with insulin clearance. The ratio of unconjugated to conjugated BAs (β = 0.335, P = 0.002) was positively correlated with insulin clearance. CONCLUSIONS Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.

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Park, So-Hyeon, Jun-Hyuck Lee, Seong-Bin Yang, Dong-Nyeong Lee, Tae-Bong Kang, and Jooho Park. "Development of a Peptide-Based Nano-Sized Cathepsin B Inhibitor for Anticancer Therapy." Pharmaceutics 15, no. 4 (April 3, 2023): 1131. http://dx.doi.org/10.3390/pharmaceutics15041131.

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Numerous cathepsin B inhibitors have been developed and are under investigation as potential cancer treatments. They have been evaluated for their ability to inhibit cathepsin B activity and reduce tumor growth. However, they have shown critical limitations, including low anticancer efficacy and high toxicity, due to their low selectivity and delivery problems. In this study, we developed a novel peptide and drug conjugate (PDC)-based cathepsin B inhibitor using cathepsin-B-specific peptide (RR) and bile acid (BA). Interestingly, this RR and BA conjugate (RR–BA) was able to self-assemble in an aqueous solution, and as a result, it formed stable nanoparticles. The nano-sized RR–BA conjugate showed significant cathepsin B inhibitory effects and anticancer effects against mouse colorectal cancer (CT26) cells. Its therapeutic effect and low toxicity were also confirmed in CT26 tumor-bearing mice after intravenous injection. Therefore, based on these results, the RR–BA conjugate could be developed as an effective anticancer drug candidate for inhibiting cathepsin B in anticancer therapy.

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Barbara, Cecilia, Paola Orlandi, Guido Bocci, Anna Fioravanti, Antonello Di Paolo, Gianfranco Natale, Mario Del Tacca, and Romano Danesi. "In vitro and in vivo antitumour effects of novel, orally active bile acid-conjugated platinum complexes on rat hepatoma." European Journal of Pharmacology 549, no. 1-3 (November 2006): 27–34. http://dx.doi.org/10.1016/j.ejphar.2006.08.015.

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Suarez, Gabriel, Bo Liu, Jeremy Herzog, and Ryan Sartor. "PRO-INFLAMMATORY MOLECULAR AND INFLAMMATORY MECHANISMS OF SULFUR METABOLISM IN IBD-RELEVANT CLOSTRIDIA SPECIES." Inflammatory Bowel Diseases 27, Supplement_1 (January 1, 2021): S30—S31. http://dx.doi.org/10.1093/ibd/izaa347.072.

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Abstract Sulfur metabolism is emerging as a signature of IBD gut microbiota. Overrepresentation of sulfur-reducing bacteria (SRB) in IBD results in SRB-derived epithelial toxic H2S production that can overwhelm the body’s detoxification capacity, leading to impaired cellular respiration by inhibiting oxygen binding to mitochondrial cytochrome-c-oxidase. Butyrate potently inhibits SRBs and H2S, yet IBD patients have reduced short chain fatty acid (SCFA) production. More critically, H2S blocks butyrate oxidation, the primary energy source of colonocytes; butyrate oxidation deficiency is a defining characteristic of IBD. Since cysteine is the preferred substrate for H2S production by SRBs, a cysteine-rich environment provided by either a high protein diet or local intestinal mucus degradation promotes ideal conditions for SRB establishment and proliferation. SRBs can catabolize other sulfur-containing compounds critical for immune homeostasis and cellular health, such as taurine-conjugated bile acids and the “master antioxidant” glutathione, leading to further toxic H2S production. However, the molecular underpinnings of sulfur metabolism by specific bacterial genera is understudied in IBD. Results: Using a combination of in-vivo and in-vitro screening to detect the relative induction of interleukin 10 (IL-10) and interferon g (IFNg) by 19 resident bacterial strains isolated from a healthy human donor, we identified 4 bacterial strains that induce a low IL-10/IFNg ratio. These 4 strains (low group), but not 3 bacterial strains that induce a high IL-10/IFNg ratio, induce colitis in selectively colonized gnotobiotic Il10-/- mice (Fig.1A). Two of these 4 disease-inducing strains, Clostridium perfringens (A12) and Clostridium bolteae (B6), produce high concentrations of H2S in monoassociated mice (Fig.1B). In-vitro H2S production by these strains is dependent on cysteine (Fig.1C). C. perfringens and C. bolteae each induce colitis in monoassociated Il10-/- mice (Fig.1D). We are dissecting the sulfur metabolic pathways in C. perfringens and C. bolteae and their contribution to inflammatory processes by interrupting key genes predicted to contribute to H2S production, cysteine catabolism and bile acid metabolism. We will use these mutants in both in-vitro and in-vivo Il10 -/- gnotobiotic mice models to characterize their metabolic and inflammatory profiles. We have created several mutants using Targetron gene editing, including the dissimilatory sulfate reductase (Δdsr), a putative sulfonate membrane transporter (ΔssuA), anaerobic sulfite reductase (ΔasrA) and bile salt hydrolase (Δbsh). Conclusions: H2S producing bacterial strains can induce experimental colitis. Our planned mechanistic studies will determine the metabolic routes for H2S production by specific aggressive bacteria to guide novel therapeutic or dietary interventions to improve IBD prognosis.

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Sigurdsson, Valgardur, Hajime Takei, Svetlana Soboleva, Visnja Radulovic, Roman Galeev, Kavitha Siva, L. M. Fredrik Leeb-Lundberg, Takashi Iida, Hiroshi Nittono, and Kenichi Miharada. "Bile Acids Protect Expanding Hematopoietic Stem Cells from Unfolded Protein Stress in Fetal Liver." Blood 126, no. 23 (December 3, 2015): 897. http://dx.doi.org/10.1182/blood.v126.23.897.897.

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Abstract Hematopoietic stem cells (HSCs) are effectively expanded in fetal liver (FL), while they are maintained in a dormant state in adult bone marrow (BM). However, developmental mechanisms allowing this have not been fully explained. BM-HSCs have the lowest protein synthesis rate within the blood hierarchy, even under forced self-renewal divisions. In addition, HSCs are vulnerable to and quickly activate endoplasmic reticulum (ER) stress responses fueled by accumulation of unfolded / misfolded proteins (Miharada et al., Cell Rep. 2014). Of note, we have seen that FL-HSCs have low levels of ER stress related genes despite their high proliferation status without an increase in heat shock protein levels, strongly indicating that other factor(s) block ER stress elevation. This raises the question how HSCs deal with the higher protein-folding requirement during expansion in the FL. Here we demonstrate that bile acids (BAs) are required to eliminate ER stress in the FL and are essential for proper expansion of FL-HSCs. Measurement of protein synthesis rate using OP-puro incorporation revealed that protein synthesis was enhanced in FL-HSCs, whereas BM-HSCs have half the rate of other populations in BM. Mass spectrometry analyses showed that BAs in the FL were all taurine conjugated while 30% of BA in the adult liver was taurine-conjugated, and the main proportion was taurocholic acid (TCA) that is known for its low toxicity. In the FL we also detected secondary BAs (e.g. TDCA), requiring intestinal bacteria in the production process, suggesting that FL BAs are a mixture of fetal and maternal BAs. Reduction of BA levels using GW4064, a chemical inhibitor of BA synthesis, significantly decreased the number of HSCs (6.6 fold decrease compared to vehicle treatment). This decrease was due to increased apoptosis caused by elevated ER stress levels. Similarly, dual deletion of Cyp27a1, a key BA synthetic enzyme, in both mother and fetus severely decreased total cellularity (2.0 fold decrease compared to littermate heterozygotes) and number of HSCs (6.8 fold decrease) in FL due to increased ER stress and subsequent apoptosis. Interestingly, FL of homozygotes grown in heterozygous mothers did not show any significant differences compared to littermate heterozygotes, suggesting that the contribution of maternal BA in FL is critical for HSCs. In both models, ER stress-oriented apoptosis and reduction in cellularity were most pronounced within the HSC population, indicating that stem cells are particularly sensitive to BA levels during development in FL. Importantly, injection of TCA or Salubrinal, an ER stress inhibitor, rescued the effects of BA reduction in both models. These data strongly suggest that BAs are required to block ER stress elevation in expanding FL-HSCs. ER stress and protein aggregation are closely linked together in number of pathological diseases like AlzheimerÕs- and HuntingtonÕs disease. Quantification of aggregated proteins (aggresomes) revealed that Cyp27a1 KO FL-HSCs from homozygote mothers contained significantly higher amount of aggresomes (2.0 fold), while KO FL-HSCs from heterozygote mothers showed no increase. Higher levels of aggregated proteins were most pronounced within the HSC population and BA suppressed formation of aggresomes during in vitro culture. This leads to reduction of ER stress and the maintenance of functional HSCs. Finally, transplantation assay showed that TCA can support functional HSCs ex vivo for up to 14 days. These findings propose a novel role for BA as a critical part of fetal hematopoiesis supporting expansion of HSC. Maternal and fetal BA coordinately contribute to this natural chaperone regulation. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Petzinger, Ernst, Annette Wickboldt, Peter Pagels, Dieter Starke, and Werner Kramer. "Hepatobiliary transport of bile acid amino acid, bile acid peptide, and bile acid oligonucleotide conjugates in rats." Hepatology 30, no. 5 (November 1999): 1257–68. http://dx.doi.org/10.1002/hep.510300529.

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Salunke, Deepak B., Braja G. Hazra, and Vandana S. Pore. "Bile acid-polyamine conjugates as synthetic ionophores." Arkivoc 2003, no. 9 (March 12, 2004): 115–25. http://dx.doi.org/10.3998/ark.5550190.0004.914.

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Gilat, Tuvia, Giora Somjen, Yehuda Mazur, Alicia Leikin-Frenkel, Ruth Rosenberg, Zamir Halpern, and Fred M. Konikoff. "The prevention of cholesterol crystallization in bile using fatty acid bile acid conjugates." Gastroenterology 118, no. 4 (April 2000): A714. http://dx.doi.org/10.1016/s0016-5085(00)84985-9.

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Lillienau, J., and B. Borgstrom. "Bacterial deconjugation and enterohepatic circulation of norursocholic acid conjugates in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 261, no. 6 (December 1, 1991): G1065—G1071. http://dx.doi.org/10.1152/ajpgi.1991.261.6.g1065.

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Experiments were performed to define the metabolism of norusocholic acid (nUC) conjugates and to quantify to what extent the bile acid pool can be enriched in these bile acids. In vitro incubations of norusocholylglycine (nUCG) and -taurine (nUCT) with small intestinal or cecal content showed deconjugation with only cecal content. Cholylglycine (CG) was deconjugated by small intestinal and cecal content. Infusion of nUCG and CG showed that only a small proportion of nUCG was deconjugated after 24 h of enterohepatic circulation, whereas all CG was deconjugated. When nUCT was administered orally, deconjugation was shown to take place mainly in the cecum. Chronic feeding of nUCT enriched the bile acid pool with only 20% nUCT. We conclude that nUC conjugates are deconjugated primarily by bacteria in the cecum and colon, in contrast to CG, which, in addition to cecum and colon, is deconjugated in the distal small intestine. nUCT and its metabolites do not enrich in the circulating bile acid pool mainly for the following reasons: 1) nUC conjugates have a low affinity for the ileal transport system; 2) nUC, even if formed by deconjugation, is not passively absorbed at a sufficient rate; 3) the small amount of norursodeoxycholic acid formed from nUC is glucuronidated in the liver and glucuronide conjugates do not undergo enterohepatic circulation; and 4) nUC conjugates do not suppress bile acid biosynthesis.

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Dayal, B., K. R. Rapole, G. Salen, S. Shefer, G. S. Tint, and S. R. Wilson. "Microwave-induced Rapid Synthesis of Bile acid Conjugates." Synlett 1995, no. 08 (August 1995): 861–62. http://dx.doi.org/10.1055/s-1995-5101.

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Jin, Xue-Yuan, and Hui-Fen Wang. "Research progress in liver targeted fatty acid bile acid conjugates." World Chinese Journal of Digestology 16, no. 33 (2008): 3769. http://dx.doi.org/10.11569/wcjd.v16.i33.3769.

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Konikoff, Fred M., Alicia Leikin-Frenkel, Ilana Goldiner, Moshe Michowitz, Eli Brezowski, Dror Harats, and Tuvia Gilat. "Biliary and systemic effects of fatty acid bile acid conjugates." European Journal of Gastroenterology & Hepatology 15, no. 6 (June 2003): 649–55. http://dx.doi.org/10.1097/00042737-200306000-00012.

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Mireault, Myriam, Vivaldy Prinville, Leanne Ohlund, and Lekha Sleno. "Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury." International Journal of Molecular Sciences 24, no. 3 (January 27, 2023): 2489. http://dx.doi.org/10.3390/ijms24032489.

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Abstract:

Using a semi-targeted approach, we have investigated the effect of acetaminophen on circulating bile acid profiles in rats, including many known bile acids and potential isomeric structures, as well as glucuronide and sulfate conjugates. The chromatographic separation was based on an optimized reverse-phase method exhibiting excellent resolution for a complex mix of bile acids using a solid-core C18 column, coupled to a high-resolution quadrupole time-of-flight system. The semi-targeted workflow consisted of first assigning all peaks detectable in samples from 46 known bile acids contained in a standard mix, as well as additional peaks for other bile acid isomers. The presence of glucuronide and sulfate conjugates was also examined based on their elemental formulae and detectable peaks with matching exact masses were added to the list of features for statistical analysis. In this study, rats were administered acetaminophen at four different doses, from 75 to 600 mg/kg, with the highest dose being a good model of drug-induced liver injury. Statistically significant changes were found by comparing bile acid profiles between dosing levels. Some tentatively assigned conjugates were further elucidated using in vitro metabolism incubations with rat liver fractions and standard bile acids. Overall, 13 identified bile acids, 23 tentatively assigned bile acid isomers, and 9 sulfate conjugates were found to increase significantly at the highest acetaminophen dose, and thus could be linked to drug-induced liver injury.

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