Natural Bile Acids Research Articles

The possibilities of using ursodeoxycholic acid in the practice of a gastroenterologist and therapist

Relevance. Ursodeoxycholic acid (UDCA) is a natural hydrophilic bile acid, which initially found its use in the treatment of a number of liver diseases as a first–line therapy. UDCA reduces the secretion of cholesterol into bile and is actively used in the treatment and prevention of gallstone disease; UDCA also has the ability to stimulate hepatobiliary secretion, which is important for patients with primary biliary cholangitis and primary sclerosing cholangitis. More recent studies have shown the pleiotropy of the effects of UDCA, in terms of effects on pathophysiological processes in the liver and the entire hepatobiliary complex, for example, anti-inflammatory and antifibrotic effects, immunomodulatory and anticarcinogenic effects. Even more interesting and important were the complex mechanisms of the effect of UDCA on the development and progression of non-alcoholic fatty liver disease (NAFLD) and, further, on the pathogenetic relationships of NAFLD and cardio-vascular pathology. The article examines the possibilities of using UDCA in diseases of the gastrointestinal tract and, more broadly, the possibilities of the drug in influencing NAFLD and the development and progression of cardiovascular and metabolic diseases.

Reduction of the risk of biliary lithiasis caused by various weight reduction options in obesity

At present obesity is a major public health challenge globally, which accounts for a significant portion of all healthcare costs. Obesity and its complications, insulin resistance and dyslipidemia, have been identified as independent risk factors for cholelithiasis. Cholelithiasis is mainly caused by four factors: bile cholesterol overload caused by excess cholesterol made in the liver due to genetic factors; systolic dysfunction of the gallbladder wall; bowel dysfunction with excess absorption of cholesterol or cholesterol overload caused by impaired hepatic bile circulation; and accelerated growth of cholesterol crystals and solid cholesterol crystals. Rapid weight loss (≥1.5 kg/week) due to low-calorie diets as the main treatment method, or after bariatric surgery is one of the risk factors for gallstone formation. Bariatric surgery is effective for the treatment of obesity and its complications, but bariatric surgery does not reduce the incidence of cholelithiasis. On the contrary, many studies showed that bariatric surgery may increase the incidence of cholelithiasis. The rapid weight loss causes fat mobilization and then increases serum cholesterol and triglyceride levels. On the other hand, bowel dysfunction due to bariatric surgery is accompanied by decreased cholecystokinin levels, causing impaired gallbladder contractility. Cholelithiasis requires close attention after bariatric surgery, with 10% of patients undergoing bariatric surgery having to undergo cholecystectomy postoperatively due to a high risk of cholelithiasis. UDCA is a natural bile acid that is prescribed to be taken orally (by mouth). UDCA inhibits the absorption of cholesterol in the bowel, enhances the biosynthesis of bile acids, and reduces biliary cholesterol secretion. UDCA is a choleretic agent, as all bile acids, but differs from other dihydroxy bile acids in being non-cytotoxic. The use of UDCA while following a low-calorie diet and after bariatric surgery significantly reduces the risk of gallstone formation and cholecystectomy with associated complications.

Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

Identification of bile acids in snake bile by hydrogen/deuterium exchange mass spectrometry and quantitative structure-retention relationship analysis

Natural bile acids, a class of steroids with a valeric acid side chain at the C-17 position, present significant challenges in separation and analysis due to structural similarities, isomerism, and large polarity differences. Therefore, advanced analytical methods are essential for the accurate identification and quantification of bile acids. This study conducted a comprehensive qualitative analysis of bile acids by integrating liquid chromatography-tandem mass spectrometry (LC-MS/MS), hydrogen-deuterium exchange tandem mass spectrometry (HDX-MS/MS), and quantitative structure-retention relationship (QSRR) methods. Firstly, LC-MS/MS conditions were optimized to enhance chromatographic separation and improve the reliability of characteristic fragment ions. MS/MS fragmentation rules for bile acids were derived from the mass spectral data of bile acid standards and validated through HDX-MS/MS experiments. Secondly, potential bile acids in snake bile were identified based on these validated fragmentation rules, and a QSRR model was established to predict the retention times of the proposed structures. Thirdly, HDX-MS/MS was applied to assist in identifying bile acid isomers. Finally, a total of 150 bile acids, including 11 free bile acids (free BA), 5 glyco-bile acids (GBA) and 134 tauro-bile acids (TBA), were detected in snake bile. Thirteen bile acids were accurately characterized by comparing their retention time and MS/MS spectra with standards. Forty-nine bile acids were reasonably annotated using the QSRR model and HDX-MS/MS. This study is notable for being the first to utilize the QSRR and HDX-MS/MS techniques for the annotation of bile acids in snake bile, providing a robust framework for the structural elucidation of these compounds.

"Seasoning" antimalarial drugs' action: chloroquine bile salts as novel triple-stage antiplasmodial hits.

Malaria is one of the "big three" global infectious diseases, having caused above two hundred million cases and over half a million deaths in 2020. The continuous demand for new treatment options prioritizes the cost-effective development of new chemical entities with multi-stage antiplasmodial activity, for higher efficacy and lower propensity to elicit drug-resistant parasite strains. Following up on our long-term research towards the rescue of classical antimalarial aminoquinolines like chloroquine and primaquine, we have developed new organic salts by acid-base pairing of those drugs with natural bile acids. These antimalarial drug-derived bile salts were screened in vitro against the hepatic, blood and gametocyte stages of Plasmodium parasites, unveiling chloroquine bile salts as unprecedented triple-stage antiplasmodial hits. These findings pave a new pathway for drug rescuing, even beyond anti-malarial and other anti-infective drugs.

Ursodeoxycholic acid alleviates sepsis-induced lung injury by blocking PANoptosis via STING pathway

Acute lung injury (ALI), a progressive lung disease mostly caused by sepsis, is characterized by uncontrolled inflammatory responses, increased oxidative stress, pulmonary barrier dysfunction, and pulmonary edema. Ursodeoxycholic acid (UDCA) is a natural bile acid with various pharmacological properties and is extensively utilized in clinical settings for the management of hepatobiliary ailments. Nonetheless, the potential protective effects and mechanism of UDCA on sepsis-induced lung injuries remain unknown. In this study, we reported that UDCA effectively inhibited pulmonary edema, inflammatory cell infiltration, pro-inflammatory cytokines production, and oxidative stress. Furthermore, UDCA treatment significantly alleviated the damage of pulmonary barrier and enhanced alveolar fluid clearance. Importantly, UDCA treatment potently suppressed PANoptosis-like cell death which is demonstrated by the block of apoptosis, pyroptosis, and necroptosis. Mechanistically, UDCA treatment prominently inhibited STING pathway. And the consequential loss of STING substantially impaired the beneficial effects of UDCA treatment on the inflammatory response, pulmonary barrier, and PANoptosis. These results indicate that STING plays a pivotal role in the UDCA treatment against sepsis-induced lung injury. Collectively, our findings show that UDCA treatment can ameliorate sepsis-induced lung injury and verified a previously unrecognized mechanism by which UDCA alleviated sepsis-induced lung injury through blocking PANoptosis-like cell death via STING pathway.

Ursodeoxycholic acid: unique properties and clinical applications

Ursodeoxycholic acid (UDCA) is a natural hydrophilic bile acid, which is present in humans as a small fraction of the total amount of bile acids (5%). Its unique properties underlie its use in a number of liver diseases as a first-line therapy. The ability of UDCA to reduce the secretion of cholesterol into bile, form mixed micelles (liquid crystals) with cholesterol molecules and interact with multifunctional nuclear receptors, are actively used in the treatment and prevention of cholelithiasis. UDCA has the ability to stimulate hepatobiliary secretion, promotes the secretion of bicarbonate by cholangiocytes, which is relevant for patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). UDCA activates transporter proteins such as bile acid export pump (BSEP), multiresistance protein 2 (MRP2) – conjugates transporter, type 2 anion exchanger (AE2), and promotes their movement to the canalicular membrane of cells. UDCA acts as a pleiotropic agent that plays a unique role in modulating the classical mitochondrial pathway of apoptosis in various cell types. Double molecular bonds of UDCA serve as a trap for free radicals, which suppresses the processes of lipid peroxidation. The ability of UDCA to penetrate into mitochondrial membranes leads to suppression of the activity of mitochondrial oxidase enzymes responsible for the production of superoxide anion. UDCA activates autophagy and promotes the elimination of toxic fatty acids from hepatocytes, reducing liver steatosis, UDCA has anti-inflammatory, antifibrotic, immunomodulatory and anticarcinogenic effects. UDCA is included in international and Russian clinical guidelines for the treatment of patients with various liver diseases (PBC, PSC, intrahepatic cholestasis of pregnancy, drug-induced cholestasis, alcoholic liver disease with cholestatic component), cholelithiasis, cystic fibrosis. In the pharmacotherapy of non-alcoholic fatty liver disease, UDCA is the only drug that has a bi-directional effect on the liver and cardiovascular system.

Taurohyodeoxycholic acid alleviates trinitrobenzene sulfonic acid induced ulcerative colitis via regulating Th1/Th2 and Th17/Treg cells balance

AimsTaurohyodeoxycholic acid (THDCA), a natural 6α-hydroxylated bile acid, exhibits intestinal anti-inflammatory effects. This study aimed to explore the efficacy of THDCA on ulcerative colitis and to reveal its mechanisms of action. Main methodsColitis was induced by intrarectal administration of trinitrobenzene sulfonic acid (TNBS) to mice. Mice in the treatment group were gavage THDCA (20, 40, and 80 mg/kg/day) or sulfasalazine (500 mg/kg/day) or azathioprine (10 mg/kg/day). The pathologic markers of colitis were comprehensively assessed. The levels of Th1-/Th2-/Th17-/Treg-related inflammatory cytokines and transcription factors were detected by ELISA, RT-PCR, and Western blotting. The balance of Th1/Th2 and Th17/Treg cells was analyzed by Flow cytometry. Key findingsTHDCA significantly alleviated colitis by improving the body weight, colon length, spleen weight, histological characteristics, and MPO activity of colitis mice. THDCA reduced the secretion of Th1-/Th17-related cytokines (IFN-γ, IL-12p70, IL-6, IL-17A, IL-21, IL-22, and TNF-α) and the expressions of transcription factors (T-bet, STAT4, RORγt, and STAT3), but increase the production of Th2-/Treg-related cytokines (IL-4, IL-10, and TGF-β1) and the expressions of transcription factors (GATA3, STAT6, Foxp3, and Smad3) in the colon. Meanwhile, THDCA inhibited the expressions of IFN-γ, IL-17A, T-bet, and RORγt, but improved the expression of IL-4, IL-10, GATA3, and Foxp3 in the spleen. Furthermore, THDCA restored the proportion of Th1, Th2, Th17, and Treg cells, and balanced the Th1/Th2 and Th17/Treg immune response of colitis mice. SignificanceTHDCA can alleviate TNBS-induced colitis via regulating Th1/Th2 and Th17/Treg balance, which may represent a promising treatment for patients with colitis.

Structure-based virtual screening and molecular dynamics of potential inhibitors targeting sodium-bile acid co-transporter of carcinogenic liver fluke Clonorchis sinensis.

Clonorchis sinensis requires bile acid transporters as this fluke inhabits bile juice-filled biliary ducts, which provide an extreme environment. Clonorchis sinensis sodium-bile acid co-transporter (CsSBAT) is indispensable for the fluke's survival in the final host, as it circulates taurocholate and prevents bile toxicity in the fluke; hence, it is recognized as a useful drug target. In the present study, using structure-based virtual screening approach, we presented inhibitor candidates targeting a bile acid-binding pocket of CsSBAT. CsSBAT models were built using tertiary structure modeling based on a bile acid transporter template (PDB ID: 3zuy and 4n7x) and were applied into AutoDock Vina for competitive docking simulation. First, potential compounds were identified from PubChem (holding more than 100,000 compounds) by applying three criteria: i) interacting more favorably with CsSBAT than with a human homolog, ii) intimate interaction to the inward- and outward-facing conformational states, iii) binding with CsSBAT preferably to natural bile acids. Second, two compounds were identified following the Lipinski's rule of five. Third, other two compounds of molecular weight higher than 500 Da (Mr > 500 Da) were presumed to efficiently block the transporter via a feasible rational screening strategy. Of these candidates, compound 9806452 exhibited the least hepatotoxicity that may enhance drug-likeness properties. It is proposed that compound 9806452 act as a potential inhibitor toward CsSBAT and further studies are warranted for drug development process against clonorchiasis.

Hyodeoxycholic acid inhibits lipopolysaccharide-induced microglia inflammatory responses through regulating TGR5/AKT/NF-κB signaling pathway.

Hyodeoxycholic acid (HDCA) is a natural secondary bile acid with enormous pharmacological effects, such as modulating inflammation in neuron. However, whether HDCA could suppress microglial inflammation has not been elucidated yet. To determine the anti-microglial inflammatory effect of HDCA in lipopolysaccharide (LPS) models and its mechanisms. The effect of HDCA was evaluated in LPS-stimulated BV2 microglial cells in vitro and the cortex of LPS-treated mice in vivo. Immunohistochemistry and immunofluorescence were used to visualize the localization of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and ionized calcium-binding adaptor protein-1 (Iba-1), respectively. The mRNA expression of inflammatory cytokines was measured by RT-qPCR. The protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), takeda G-coupled protein receptor 5 (TGR5), and the phosphorylation of protein kinase B (AKT), NF-κB, and inhibitor of NF-κB protein α (IκBα) was examined by Western blot. HDCA inhibited the inflammatory responses in LPS-treated BV2 cells and in the cortex of LPS-treated mice, evidenced by decreased production of inflammatory mediators such as iNOS, COX-2, tumor necrosis factor (TNF-α), interleukin (IL)-6, and IL-1β. Further study demonstrated that HDCA repressed the phosphorylation, nuclear translocation, and transcriptional activity of NF-κB and inhibited the activation of AKT in BV-2 cells induced by LPS. Meanwhile, addition of TGR5 inhibitor, triamterene, abolished the effects of HDCA on TGR5, AKT, and NF-κB. The present study demonstrated that HDCA prevents LPS-induced microglial inflammation in vitro and in vivo, the action of which is via regulating TGR5/AKT/NF-κB signaling pathway.

High-confidence structural annotation of metabolites absent from spectral libraries

Untargeted metabolomics experiments rely on spectral libraries for structure annotation, but, typically, only a small fraction of spectra can be matched. Previous in silico methods search in structure databases but cannot distinguish between correct and incorrect annotations. Here we introduce the COSMIC workflow that combines in silico structure database generation and annotation with a confidence score consisting of kernel density P value estimation and a support vector machine with enforced directionality of features. On diverse datasets, COSMIC annotates a substantial number of hits at low false discovery rates and outperforms spectral library search. To demonstrate that COSMIC can annotate structures never reported before, we annotated 12 natural bile acids. The annotation of nine structures was confirmed by manual evaluation and two structures using synthetic standards. In human samples, we annotated and manually validated 315 molecular structures currently absent from the Human Metabolome Database. Application of COSMIC to data from 17,400 metabolomics experiments led to 1,715 high-confidence structural annotations that were absent from spectral libraries.

Hyodeoxycholic acid rescues lipopolysaccharide-induced neuroinflammation via regulating TGR5/AKT/NF-κB pathway

Hyodeoxycholic acid (HDCA) is a natural secondary bile acid with enormous pharmacological effects. It can act as a takeda G-coupled protein receptor 5 (TGR5) agonist, activation of TGR5 is found to alleviate neuroinflammation by suppressing serine/threonine kinase (AKT)/ nuclear factor-κB (NF-κB) signaling pathway. In this study, the anti-microglial inflammatory effect of HDCA was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells and mice (n=12/group). One-way ANOVA followed by Tukey’s post hoc analysis was conducted. p <.05 is statistically significant. HDCA was shown to inhibit the over-activation of microglia both in vitro and in vivo , evidenced by down-regulated mRNA expression of inflammatory cytokines such as interleukin 1β, decreased protein expression of inducible nitric oxide synthase and cyclooxygenase 2. Moreover, in LPS-induced microglial cells, HDCA was found to counteract the suppression of TGR5 and the increased phosphorylation of AKT, NF-κB and NF-κB inhibitor factor, as well as the nuclear translocation of NF-κB, however, the effect of HDCA onTGR5, AKT and NF-κB was abolished by the TGR5 inhibitor - triamterene. HDCA suppresses LPS-induced neuroinflammation through regulating TGR5/AKT/NF-κB signaling pathway. The novel findings suggest the therapeutic potential of HDCA in central nervous system disorders with prominent neuroinflammation.

Tauroursodeoxycholic acid/TGR5 signaling promotes survival and early development of glucose-stressed porcine embryos†.

Conditions of impaired energy and nutrient homeostasis, such as diabetes and obesity, are associated with infertility. Hyperglycemia increases endoplasmic reticulum stress as well as oxidative stress and reduces embryo development and quality. Oxidative stress also causes deoxyribonucleic acid damage, which impairs embryo quality and development. The natural bile acid tauroursodeoxycholic acid reduces endoplasmic reticulum stress and rescues developmentally incompetent late-cleaving embryos, as well as embryos subjected to nuclear stress, suggesting the endoplasmic reticulum stress response, or unfolded protein response, and the genome damage response are linked. Tauroursodeoxycholic acid acts via the Takeda-G-protein-receptor-5 to alleviate nuclear stress in embryos. To evaluate the role of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling in embryo unfolded protein response, we used a model of glucose-induced endoplasmic reticulum stress. Embryo development was impaired by direct injection of tauroursodeoxycholic acid into parthenogenetically activated oocytes, whereas it was improved when tauroursodeoxycholic acid was added to the culture medium. Attenuation of the Takeda-G-protein-receptor-5 precluded the positive effect of tauroursodeoxycholic acid supplementation on development of parthenogenetically activated and fertilized embryos cultured under standard conditions and parthenogenetically activated embryos cultured with excess glucose. Moreover, attenuation of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling induced endoplasmic reticulum stress, oxidative stress and cell survival genes, but decreased expression of pluripotency genes in parthenogenetically activated embryos cultured under excess glucose conditions. These data suggest that Takeda-G-protein-receptor-5 signaling pathways link the unfolded protein response and genome damage response. Furthermore, this study identifies Takeda-G-protein-receptor-5 signaling as a potential target for mitigating fertility issues caused by nutrient excess-associated blastomere stress and embryo death.

Hexagonal Microparticles from Hierarchical Self-Organization of Chiral Trigonal Pd3L6 Macrotetracycles

Construction of structurally complex architectures using inherently chiral, asymmetric, or multi-heterotopic ligands is a major challenge in metallosupramolecular chemistry. Moreover, the hierarchical self-organization of such complexes is unique. Here, we introduce a water-soluble, facially amphiphilic, amphoteric, chiral, asymmetric, and hetero-tritopic ligand derived from natural bile acid, ursodeoxycholic acid. We show that via the supramolecular transmetalation reaction, using nitrates of Cu(II) or Fe(III), and subsequently Pd(II), a superchiral Pd 3 L 6 complex can be obtained. Even though several possible constitutional isomers of Pd 3 L 6 could be formed, because of the ligand asymmetry and relative flexibility of carbamate-pyridyl moieties attached to the steroid scaffold, only a single product with C 3 rotational symmetry was obtained. Finally, we demonstrate that these amphiphilic complexes can self-organize into hexagonal microparticles in aqueous media. This finding may lead to the development of novel self-assembled metal-organic functional materials made of natural, abundant, and relatively inexpensive steroidal compounds. Asymmetric, amphiphilic, chiral, and hetero-tritopic ligand from bile acid Supramolecular transmetalation self-assembly leads to symmetric superchiral complex Complexes self-organize in aqueous environment into hexagonal microparticles Materials with high density of chiral centers and optical activity are prepared Jurček et al. report an amphiphilic bile-acid-based ligand (L) used for the preparation of large hollow metallosupramolecular complex Pd 3 L 6 , accomplished via a supramolecular transmetalation process. The complexes prepared can self-organize into hexagonal microparticles upon contact with water.

Physicochemical characterization of novel 3-carboxymethyl-bile salts, as permeability and solubility enhancers

New bile acid derivatives are synthesized: 3-(carboxymethyl)-5β-chol-3-ene-7α,12α,24-triol (ND-1) and 3α-(carboxymethyl)-5β-cholan-7α,12α,24-triol (ND-2). The derivative ND-1 has more hydrophobic convex surface than deoxycholic acid (D), but its partition coefficient in 1-octanol-aqueous phase is lower than one of ursodeoxycholic acid (UD), which means that ND-1 has smaller total hydrophobic surface in comparison to UD. The anion D shows greater increase in DPPC monolayer surface pressure than it can be derived from the size of its hydrophobic surface at the β side of steroid skeleton. Membrane toxicity of ND-1 and ND-2 is lower than the one of D. The derivative ND-1 has lower value of the critical micellar concentration (cmc) than the anion D. At cmc ND-1 and ND-2 build Small primary micelles, while at the concentrations several times higher than cmc they form secondary micelles. The equilibrium constant of nitrazepane incorporation into the ND-1 and the ND-2 micelles implies that these micelles have larger hydrophobic nuclei than the micelles of natural dihydroxy bile acid derivative anions.

The inhibitory effects of bile acids on catalytic and non-catalytic functions of acetylcholinesterase as a therapeutic target in Alzheimer’s disease

Acetylcholine is a fast-acting neurotransmitter in synapses and neuromuscular junctions that is decreased in Alzheimer's disease (AD) by hyper‑activation of acetylcholinesterase (AChE), which leads to progressive loss of memory and neurobehavioral abnormalities. Therefore, AChE inhibitors have therapeutic potential in AD that could include natural compounds such as bile acids. Bile acids, as potent molecules, could improve some types of neurodegenerative diseases via antioxidant effects and other unknown mechanisms. The aim of this study was to investigate beneficial effects of bile acids on AChE catalytic and non‑catalytic functions, amyloid plaque deposit and memory in a rat model of AD. The effects of sodium deoxycholate and cholic acid on AChE activity were assessed by in vitro assay. Then, the bile acids' potential therapeutic effects were investigated on nucleus basalis of Meynert lesioned rats using behavioral evaluation, biochemical tests and histological methods. Molecular docking simulation was also implemented to investigate the possible interaction between bile acids and AChE. According to the in vitro and in vivo results, sodium deoxycholate could efficiently inhibit the catalytic function of the enzyme by interacting with the catalytic site, while cholic acid interacted with the peripheral anionic site and inhibited chaperone activity of the enzyme that led to the reduced amyloid plaque deposition. The co‑administration of cholic acid and sodium deoxycholate showed these compounds are able to simultaneously inhibit the catalytic and non‑catalytic functions of the enzyme. This study clarifies the roles of natural bile acids in the nervous system and in AChE function through multiple experimental and simulation methods.

Antifouling activity of peracetylated cholic acid, a natural bile acid derivative

The antifouling activity of peracetylated cholic acid (1), a bile acid derivative which was isolated in a previous work as a natural product from the Patagonian sponge Siphonochalina fortis, was evaluated in laboratory and field trials. Toxicity and settlement assays were performed with the mussel Mytilus edulis platensis, while the field trials were carried out by addition of the compound to experimental soluble-matrix paints, which were then tested in the sea. The results obtained in this work show that 1 has a good antifouling activity and low toxicity, and the paints aditivated with 0,6% Wt showed promissory performances in the field trials at the sea. These results confirm the previous hypothesis that the few acetylated and lipophilic bile acid derivatives isolated from marine invertebrates may act as natural antifoulants. Compound 1 is a natural, biodegradable product that can be easily prepared from cholic acid, which in turn can be isolated in industrial scale from cattle bile. All these facts make cholic acid a good scaffold for the preparation of derivatives, which can be natural product-like, effective and sustainable antifouling additives for marine paints and other applications.

Generation of the Thymine Triplet State by Through-Bond Energy Transfer.

Benzophenone (BP) and drugs containing the BP chromophore, such as the non-steroidal anti-inflammatory drug ketoprofen, have been widely reported as DNA photosensitizers through triplet-triplet energy transfer (TTET). In the present work, a direct spectroscopic fingerprint for the formation of the thymine triplet (3 Thy*) by through-bond (TB) TTET from 3 BP* has been uncovered. This has been achieved in two new systems that have been designed and synthesized with one BP and one thymine (Thy) covalently linked to the two ends of the rigid skeleton of the natural bile acids cholic and lithocholic acid. The results shown here prove that it is possible to achieve triplet energy transfer to a Thy unit even when the photosensitizer is at a long (nonbonding) distance.

Glycopolymers Made from Polyrotaxanes Terminated with Bile Acids: Preparation, Self-Assembly, and Targeting Delivery.

The use of natural compounds to construct biomaterials, including delivery system, is an attractive strategy. In the present study, through threading functional α-cyclodextrins onto the conjugated macromolecules of poly(ethylene glycol) (PEG) and natural compound bile acid, glycopolymers of polyrotaxanes with the active targeting ability are obtained. These glycopolymers self-assemble into micelles as evidenced by dynamic light scattering and transmission electron microscopy, in which glucosamine, as an example of targeting groups, is introduced. These micelles after loading doxorubicin (DOX) exhibit the selective recognition with cancer cells 4T1. Meanwhile, the maximal half inhibitory concentration is determined to be ≈2.5mg L-1 for the DOX-loaded micelles, close to the value of free DOX·HCl (1.9mg L-1 ). The cumulative release of DOX at pH 5.5 is faster than at pH 7.4, which may be used as the controlled release system. This drug delivery system assembled by glycopolymers features high drug loading of DOX, superior biocompatibility. The strategy not only utilizes the micellization induced by bile acids, but also overcomes the major limitation of PEG such as the lack of targeting groups. In particular, this drug delivery platform can extend to grafting the other targeting groups, rendering this system more versatile.

A New Drug Delivery System Based on Tauroursodeoxycholic Acid and PEDOT.

Localized drug delivery represents one of the most challenging uses of systems based on conductive polymer films. Typically, anionic drugs are incorporated within conductive polymers through electrostatic interaction with the positively charged polymer. Following this approach, the synthetic glucocorticoid dexamethasone phosphate is often delivered from neural probes to reduce the inflammation of the surrounding tissue. In light of the recent literature on the neuroprotective and anti-inflammatory properties of tauroursodeoxycholic acid (TUDCA), for the first time, this natural bile acid was incorporated within poly(3,4-ethylenedioxythiophene) (PEDOT). The new material, PEDOT-TUDCA, efficiently promoted an electrochemically controlled delivery of the drug, while preserving optimal electrochemical properties. Moreover, the low cytotoxicity observed with viability assays, makes PEDOT-TUDCA a good candidate for prolonging the time span of chronic neural recording brain implants.