Cholic Acid Research Articles

Combined effects of polyvinyl chloride or polypropylene microplastics with cadmium on the intestine of zebrafish at environmentally relevant concentrations

Cadmium (Cd) is a common additive in polyvinyl chloride (PVC) and polypropylene (PP) plastics. Aquatic organisms were inevitably co-exposed to PVC/PP microplastics (MPs) and Cd, but their combined toxicity is still unknown. In this study, adult zebrafish were exposed to 200 μg/L MPs (PVC or PP) and 10 μg/L Cd alone or in combination for 28 days to investigate their toxicity and mechanisms. Results showed that combined exposure with PVC/PP enhanced the Cd accumulation in the zebrafish intestine. Subsequently, toxicology analyses showed that both PVC and PP possessed synergistic toxicity with Cd, manifested by the exfoliation and necrosis of intestinal epithelial cells, and increased levels of interleukin-1β (IL-1β), superoxide dismutase (SOD) and malondialdehyde (MDA). PP exhibited a stronger synergistic effect than PVC. Integration of non-targeted metabolomics and 16S rRNA gene sequencing revealed that combined exposure to PVC and Cd induced intestine toxicity mainly through bile acid (BA) biosynthesis, fructose (Fru) and mannose (Man) metabolism, and pentose phosphate pathway (PPP). The combined exposure of PP and Cd induced toxicity through the arginine (Arg) and glutathione (GSH) metabolisms. Meanwhile, combined exposure of PVC/PP and Cd increased the abundance of intestinal Proteobacteria and pathogen Vibrio, and decreased the abundance of Gemmobacter. These changes indrectly promoted the synergistic toxicity of PVC/PP and Cd through metabolites, such as indole-3-pyruvate (IPyA), chenodeoxycholic acid (CDCA), and cholic acid (CA). These findings highlighted that more attention should be paid to the toxicity of chemicals at environmentally relevant concentrations, particularly those co-existing with MPs.

Mucoadhesive and drug release of cholic acid based thiomeric micelles and encapsulated silver and gold nanoparticles for anticancer studies

Among the various drug delivery system, mucoadhesive formulation is a promising approach to deliver drugs and vaccine through close contact with the absorption site and mucous membrane. Bile acids have received considerable interest in drug delivery (DD) applications owing to their advantages of biocompatibility, ability to act as both drug solubilizing and permeation-modifying agents. In this aspects, cholic acid (CA) based thiomeric micelles with improved mucoadhesive properties have been synthesized by functionalization of thiol groups and conjugation of PEG. The synthesized CA based thiomeric micelles (TCA-PEG) were characterized by 1HNMR, ATR-IR, GPC, Zeta potential and contact angle techniques. The critical micelle concentration (CMC) of TCA-PEG was measured by a fluorescence spectrometer using pyrene as a probe. The mucoadhesive properties of TCA-PEG polymeric micelles (PMs) were examined on the goat anterior tongue mucosa with an effectively higher adhesion of 40 % up to 3 h study period. Also, curcumin loaded TCA-PEG PMs showed only 13 % of the drug released up to the period of 3 h. The TCA-PEG PMs act as reducing and stabilizing agents for the preparation of gold and silver nanoparticle (Ag and Au NPs) and were characterized by UV–visible, DLS, Zeta potential, XPS, and HR-TEM techniques. The cytotoxicity and cellular apoptosis of TCA-PEG PMs encapsulated Ag and Au NPs were examined by MTT assay and AO/PI dual staining using MCF-7 breast cancer cells wherein AgNPs showed an effective cytotoxicity than AuNPs. The developed TCA-PEG PMs act as reservoir for soubilization of hydrophobic and hydrophilic drugs and ideal template for encapsulation of silver and gold nanoparticles for mucoadhesive DD system.

Structural and functional analysis of a bile salt hydrolase from the bison microbiome

The bile salt hydrolases (BSHs) are significant constituents of animal microbiomes. An evolving appreciation of their roles in health and disease has established them as targets of pharmacological inhibition. These bacterial enzymes belong to the N-terminal nucleophile superfamily and are best known to catalyze the deconjugation of glycine or taurine from bile salts to release bile acid substrates for transformation and or metabolism in the gastrointestinal tract. Here, we identify and describe the BSH from a common member of the Plains bison microbiome, Arthrobacter citreus (BSHAc). Steady-state kinetic analyses demonstrated that BSHAc is a broad-spectrum hydrolase with a preference for glycine-conjugates and deoxycholic acid (DCA). Second-order rate constants (kcat/KM) for BSHAc-catalyzed reactions of relevant bile salts-glyco- and tauro-conjugates of cholic acid and DCA- varied by ∼30-fold and measured between 1.4× 105 and 4.3× 106M-1s-1. Interestingly, a pan-BSH inhibitor named AAA-10 acted as a slow irreversible inhibitor of BSHAc with a rate of inactivation (kinact)of ∼2h-1 and a second order rate constant (kinact/KI) of ∼24M-1s-1 for the process. Structural characterization of BSHAc reacted with AAA-10 showed covalent modification of the N-terminal cysteine nucleophile, providing molecular details for an enzyme-stabilized product formed from this mechanism-based inhibitor's α-fluoromethyl ketone warhead. Structural comparison of the BSHs and BSH:inhibitor complexes highlighted the plasticity of the steroid-binding site, including a flexible loop that is variable across well-studied BSHs.

Experimental Study of Hypolipidemic Effect of Manjal Noiku Kudineer

Hyperlipidemia, is a major stake for the development of serious diseases like atherosclerosis, Coronary Artery Diseases, Stroke. Siddha system of Medicine with the numerous combination of medicines has Manjal Noiku Kudineer(MNK), a Siddha poly herbal formulation indicated for Manjal Noi. This study deals with the Hypolipidemic activity of Manjal Noiku Kudineer on atherogenic diet induced hyperlipidemia in experimental Wistar Albino Rats Place of Study: The study was conducted at Arulmigu Kalasalingam College of Pharmacy, Virudhunagar. Methodology: The study protocol for MNK was reviewed and approved by Institutional Animal Ethics Committee (IAEC), Arulmigu Kalasalingam College of Pharmacy, Virudhunagar, with the IAEC number AKCP/IAEC/10/24-25. The experimental hyperlipidemic diet consists of well-pulverized 400 mg/kg cholesterol, 50 mg/kg cholic acid, and coconut oil. All groups other than the control group were fed the prepared atherogenic meal in lieu of the regular pellet diet. Group I served as normal control, Group II represented hyperlipidemic control rats given an atherogenic diet, Group III and IV represented test groups given MNK 200 mg/kg and MNK 400 mg/kg, respectively, and Group V represented standard-administered atorvastatin (10 mg/kg/day). All groups were compared, observations were noted and the observations were statistically evaluated. Results: The study shows the results of reduction in body weight, blood lipid profile, liver lipid profile of hyperlipidemic rats on treating with the study medicine, which possess hypolipidemic activity. Histopathologic images of rat liver also shown normal parenchyma and parenchyma with minimal necrosis and minimal inflammatory changes on treating with the study medicine MNK. Conclusion: The results stands as a support for MNK hypolipidemic activity, which in turn can be used as a antihyperlipidemic therapeutic agent from the Siddha System of Medicine.

Fluorinated boron nitride nanosheets for high thermal conductivity and low dielectric constant silicone rubber composites

AbstractIncreasing miniaturization and integration of microelectronic devices have led to an unprecedented attention on heat dissipation and signal transmission of electronic equipment. However, the mostly used method to enhance the thermal conductivity of polymers by adding thermally conductive fillers usually results in the increase of dielectric constant (Dk). It was still challenging to synergistically achieve low Dk and high thermal conductivity of polymer‐matrix composites. Herein, hydroxylated boron nitride nanosheet (BNNS‐OH) with a high yield of 35.67% was prepared by the liquid ultrasonic exfoliation under the assistance of sodium cholate (SC), and grafted with (1H,1H,2H,2H‐perfluorodecyl) trimethoxy silane to prepare fluorinated boron nitride nanosheets (F‐BNNS), which can uniformly disperse in liquid silicone rubber (LSR) and reduce the Dk of LSR composites. The thermal conductivity of LSR composites with 20 wt% F‐BNNS reached 0.489 W·m−1·K−1, showing an increase of 307.35% in comparison with pure LSR (0.12 W·m−1·K−1). Meantime, the Dk of as‐obtained LSR/F‐BNNS (20 wt%) composites is reduced from 3.4 to 2.6, and the dielectric loss (Df) is less than 0.012. The facile and rational design of fluorinated BNNS offers a new insight for the high‐end electronic packaging materials.Highlights A new method of exfoliation and fluorinated treatment of h‐BN was proposed. The LSR composites achieved an ultralow Dk of 2.63 via fluorinated BNNS. Thermal conductivity of LSR composites increased by 307.35% than pure LSR.

Studies on absorption mechanism and pharmacokinetic properties of albendazole-bile acid conjugate: In vivo and in vitro

PurposeTo improve the oral bioavailability of albendazole (ABZ), a series of albendazole-bile acid conjugates (ABCs) were synthesized. ABC's transmembrane transport mechanism and in vivo pharmacokinetic properties were preliminarily studied. MethodsThe transmembrane transport mechanism of ABCs was studied using the Caco-2 monolayer cell model and intestinal perfusion model. The concentration of ABCs and ABZ were evaluated using High-Performance Liquid Chromatography (HPLC) and HPLC-Mass Spectrometry (HPLC-MS/MS). ResultsCompared to ABZ, better permeability was observed for different types and concentrations of ABCs using the Caco-2 monolayer cell model, with ABC-C8 showing the highest permeability. The transmembrane transport of ABCs was affected by ASBT inhibitors, indicating an ASBT-mediated active transport mechanism. Additionally, introducing cholic acid resulted in ABZ no longer being a substrate for P-gp, MRP2, and BCRP, effectively reversing ABZ efflux. In vivo unidirectional intestinal perfusion results in rats showed that ABCs altered the absorption site of ABZ from the jejunum to the ileum. The absorption efficiency of ABCs in each intestinal segment was higher than that of ABZ, and the transmembrane transport efficiency decreased with increasing concentrations of ASBT inhibitors. This further confirmed the presence of both passive diffusion and ASBT-mediated active transport mechanisms in the transport of ABCs. The solubility of ABCs in gastric juice and pharmacokinetics in rats showed that ABZ-C4 exhibited enhanced solubility. Moreover, ABCs significantly increased oral bioavailability compared to ABZ, with ABC-C4 showing an approximately 31-fold increase in bioavailability. ConclusionThe transmembrane transport mechanism of ABCs involves a combination of ASBT-mediated active transport and passive diffusion. Moreover, the incorporation of BAs successfully reverses the efflux of ABZ by efflux proteins. Among the synthesized conjugates, ABC-C4 demonstrated superior dissolution behavior both in vitro and in vivo.

Pangenome analysis of Clostridium scindens : a collection of diverse bile acid and steroid metabolizing commensal gut bacterial strains.

Clostridium scindens is a commensal gut bacterium capable of forming the secondary bile acids deoxycholic acid and lithocholic acid from the primary bile acids cholic acid and chenodeoxycholic acid, respectively, as well as converting glucocorticoids to androgens. Historically, only two strains, C. scindens ATCC 35704 and C. scindens VPI 12708, have been characterized in vitro and in vivo to any significant extent. The formation of secondary bile acids is important in maintaining normal gastrointestinal function, in regulating the structure of the gut microbiome, in the etiology of such diseases such as cancers of the GI tract, and in the prevention of Clostridium difficile infection. We therefore wanted to determine the pangenome of 34 cultured strains of C. scindens and a set of 200 metagenome-assembled genomes (MAGs) to understand the variability among strains. The results indicate that the 34 strains of C. scindens have an open pangenome with 12,720 orthologous gene groups, and a core genome with 1,630 gene families, in addition to 7,051 and 4,039 gene families in the accessory and unique (i.e., strain-exclusive) genomes, respectively. The core genome contains 39% of the proteins with predicted metabolic function, and, in the unique genome, the function of storage and processing of information prevails, with 34% of the proteins being in that category. The pangenome profile including the MAGs also proved to be open. The presence of bile acid inducible ( bai ) and steroid-17,20-desmolase ( des ) genes was identified among groups of strains. The analysis reveals that C. scindens strains are distributed into two clades, indicating the possible onset of C. scindens separation into two species, confirmed by gene content, phylogenomic, and average nucleotide identity (ANI) analyses. This study provides insight into the structure and function of the C. scindens pangenome, offering a genetic foundation of significance for many aspects of research on the intestinal microbiota and bile acid metabolism.

Blockade of forkhead box protein O1 signaling alleviates primary sclerosing cholangitis-induced sarcopenia in mice model

AimsPrimary sclerosing cholangitis (PSC) is a cholestatic liver disease that affects the hepatic bile ducts, leading to hepatic inflammation and fibrosis. PSC can also impact skeletal muscle through the muscle-liver axis, resulting in sarcopenia, a complication characterized by a generalized loss of muscle mass and strength. The underlying mechanisms and therapy of PSC-induced sarcopenia are not well understood, but one potential regulator is the transcription factor forkhead box protein O1 (FOXO1), which is involved in the ubiquitin proteasome system. Thus, the aim of this study is to assess the pharmacological potential of FOXO1 inhibition for treating PSC-induced sarcopenia. Materials and methodsTo establish diet-induced PSC model, we provided mice with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 4 weeks. Mice were intramuscularly injected with AS1842856 (AS), a FOXO1 inhibitor, at a dose of 3.5 mg/kg twice a week for last two weeks. C2C12 myotubes with cholic acid (CA) or deoxycholic acid (DCA) were treated with AS. Key findingsWe observed a decrease in muscle size and performance in DDC-fed mice with upregulated expression of FOXO1 and E3 ligases such as ATROGIN1 and MuRF1. We found that myotube diameter and MyHC protein level were decreased by CA or DCA in C2C12 myotubes, but treatment of AS reversed these reductions. We observed that intramuscular injection of AS effectively mitigates DDC diet-induced sarcopenia in a rodent PSC model. SignificanceOur study suggests that a FOXO1 inhibitor could be a potential leading therapeutic drug for relieving PSC-induced sarcopenia.

Integrating sodium cholate-modified MOF hybrid lipase and solubilization of hydrophobic candidates into a step for liganding fishing lipase inhibitors from Nelumbinis Folium

Enzyme immobilization by metal organic frameworks (MOFs) is an efficient way for screening active constituents in natural products. However, the enzyme’s biocatalysis activity is usually decreased due to unfavorable conformational changes during the immobilization process. In this study, sodium cholate was firstly used as the modifier for zeolitic imidazolate framework-8 (ZIF-8) immobilized lipase to increase both the stability and activity. More importantly, with the help of solubilization of sodium cholate, a total of 3 flavonoids and 6 alkaloids candidate compounds were fished out. Their structures were identified and the enzyme inhibitory activities were verified. In addition, the binding information between the candidate compound and the enzyme was displayed by molecular docking. This study provides valuable information for the improvement of immobilized enzyme activity and functional active ingredients in complicated medicinal plant extracts.

Synthesis of N-acetylcysteine functionalized cholic acid based triarmed poly DL-Lactide and encapsulation of gold nanoparticles: Studies on the antimicrobial activity and biocompatibility for drug delivery applications

Cholic acid based biodegradable reverse polymeric micelles have been widely utilized as preclinically suitable drug delivery system for poorly water-soluble drugs. In this report, we developed N-acetylcysteine functionalized cholic acid based triarmed poly (Dl-lactide) (ACyCA-triarmed (DLL)n as reversed polymeric micelles for drug delivery studies. ACyCA was synthesized via thiol-yne click reaction and subsequently used as an initiator for the synthesis of ACyCA-triarmed (DLL)n through ring opening polymerization (ROP) using Sn (Oct)2 as a catalyst. The synthesized ACyCA-triarmed (DLL)n was characterized using GPC, FT-IR, 1H NMR, 13C NMR, spectrofluorometer, HR-TEM, DSC, TGA, XRD, DLS, and zeta potential techniques. The reverse critical micellar concentration of the polymer was determined to be 1.99 mg/mL using a spectrofluorometer. The synthesized reverse micelles (RMs) were utilized as a reducing and capping agent for the preparation of AuNPs under sunlight exposure. The formed AuNPs exhibited spherical in shape with an average size of ∼ 23.4 nm and Dh was found to be 86.8 ± 1.3 nm as evidenced by the TEM and DLS analysis. Furthermore, the antimicrobial activity, hemolytic activity, anti-oxidant activity, and in-vitro drug release studies were examined for the RMs-AuNPs and compared with RMs. The hydrophobic nature of RMs and RMs-AuNPs had better haemocompatibility at above the reversed CMC. The antioxidant activity RMs-AuNPs showed better inhibitory effect in a dose-dependent manner as compared to RMs. The RMs-AuNPs formulation act as reservoir for solubilization of hydrophobic doxorubicin (Dox.HCl) drugs and can be used as therapeutic platform for slow and sustained release of drugs in biological medium.

Hepatic Gα13 ablation shifts region-specific colonic inflammatory status by modulating the bile acid synthetic pathway in mice

Inflammatory bowel disease is defined by inflammation and immune dysregulation. This study investigated the effects of Gα13 liver-specific knockout (LKO) on proximal and distal colons of dextran sodium sulfate (DSS)-induced mice in conjunction with a high-fat diet (HFD). HFD improved body weight gain and disease activity index scores. Gα13LKO exerted no improvement. In the proximal colon, HFD augmented the DSS effect on Il6, which was not observed in Gα13LKO mice. In the distal colon, HFD plus DSS oppositely fortified an increase in Tnfa and Cxcl10 mRNA in Gα13LKO but not WT. Il6 levels remained unchanged. Bioinformatic approaches using Gα13LKO livers displayed bile acid and cholesterol metabolism-related gene sets. Cholic acid and chenodeoxycholic acid levels were increased in the liver of mice treated with DSS, which was reversed by Gα13LKO. Notably, mice treated with DSS showed a reduction in hepatic ABCB11, CYP7B1, CYP7A1, and CYP8B1, which was reversed by Gα13LKO. Overall, feeding HFD augments the effect of DSS on Il6 in the proximal colon of WT, but not Gα13LKO mice, and enhances DSS effect on Tnfa and Cxcl10 in the distal colon of Gα13LKO mice, suggesting site-specific changes in the inflammatory cytokines, potentially resulting from changes in BA synthesis and excretion.

Hawthorn-leaf flavonoid alleviate intestinal health and microbial dysbiosis problems induced by glyphosate

Glyphosate is the active ingredient in the herbicide (i.e., Roundup, Touchdown and Erasure), the safety of which has become a social concern. Hawthorn-leaf flavonoid (HF) possesses various biological functions, including antioxidant, regulating lipid metabolism and intestinal microbiota. Whether HF could reduce the health risk of pure glyphosate to birds remain unknown. The experiment aimed to evaluate the effects of pure glyphosate (25 mg/kg added to water) on the intestinal health and microbiota of chicks and the protective roles of HF (60 mg/kg added to the diet). Exposure to glyphosate decreased growth performance, ileal morphology structure, and antioxidant capacity, and increased the serum level of lipid and pro-inflammatory factors. 16S rRNA sequencing indicated that glyphosate decreased bacterial richness and the abundance of Lactobacillus, and increased proportions of pathogens in the ileum. Metabolomic results revealed that glyphosate increased the level of the cholic acid and fatty acids in the ileac digesta. Meanwhile, glyphosate down-regulated the protein expression associated with lipid transport, antioxidant and tight junction in the ileal mucosal tissue, and up-regulated the pro-inflammatory, oxidative stress proteins. However, dietary HF supplementation effectively mitigated the adverse effects of glyphosate and improved intestinal health of chicks. Therefore, dietary HF can ameliorate the harmful effects of glyphosate on birds, which highlights the potential application of HF in reducing the health risks.

Unresolved alterations in bile acid composition and dyslipidemia in maternal and cord blood after ursodeoxycholic acid treatment for intrahepatic cholestasis of pregnancy.

This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.

A Validated LC-MS/MS Assay for the Quantification of Cholate Isotopes in Human Serum.

Current methods for evaluating liver health rely on nonspecific blood tests, elastography surrogates for fibrosis, and invasive procedures, none of which directly measure liver function and physiology. Herein we present the analytical validation of a unique, highly sensitive LC-MS/MS assay and dual-sample oral (DuO) cholate challenge test to reliably quantify serial serum concentrations of cholate isotopes administered to patients with liver diseases. The clearance of administered cholate isotopes measured by the assay provides information about liver function and physiology. Analytical method validation of the cholate assay analytes (endogenous unlabeled cholic acid, 24-13C-cholic acid, and 2,2,4,4-D4-cholic acid) in terms of accuracy, precision, analytical sensitivity, analytical specificity, and range of reliable response was completed in human serum samples spiked with quality controls and calibrators in accordance with applicable guidelines. DuO test parameters were validated using samples from 48 subjects representing various liver disease etiologies. Accuracy (mean biases) for all analytes ranged from 0.1% to 3.7%. Using a nested components-of-variance design (20 days, 2 runs per day, 2 replicates per sample), total imprecision for all analytes ranged from 2.3% to 8.4%. Lower and upper limits of quantitation were established and validated at 0.1 to 10.0 µM. Matrix effects and potential interferents did not affect assay performance. DuO test validation met all prespecified acceptance criteria. The method validation studies described herein established the performance characteristics in terms of accuracy, precision, analytical sensitivity, analytical specificity, reportable ranges, and reference intervals of the LC-MS/MS cholate assay and DuO test.

Cholic Acid/Glutathione-Assembled Nanofibrils for Stabilizing Pickering Emulsion Biogels.

Achieving the delicate balance required for both emulsion and gel characteristics, while also imparting biological functionality in gelled emulsions, poses a significant challenge. Herein, Pickering emulsion biogels stabilized is reported by novel biological nanofibrils assembled from natural glutathione (GSH) and a tripod cholic acid derivative (TCA) via electrostatic interactions. GSH, composed of tripeptides with carboxyl groups, facilitates the protonation and dissolution of TCA compounds in water and the electrostatic interactions between GSH and TCA trigger nanofibrillar assembly. Fibrous nuclei initially emerge, and the formed mature nanofibrils can generate a stable hydrogel at a low solid concentration. These nanofibrils exhibit efficient emulsifying capability, enabling the preparation of stable Pickering oil-in-water (O/W) emulsion gels with adjustable phase volume ratios. The entangled nanofibrils adsorbed at the oil-water interface restrict droplet movement, imparting viscoelasticity and injectability to the emulsions. Remarkably, the biocompatible nanofibrils and stabilized emulsion gels demonstrate promising scavenging properties against reactive oxygen species (ROS). This strategy may open new scenarios for the design of advanced emulsion gel materials using natural precursors and affordable building blocks for biomedical applications.

Establishment of 3D cell culture systems with decellularized lung-derived extracellular matrix hydrogel scaffold

Decellularized tissue hydrogels, especially that mimic the native tissue, have a high potential for tissue engineering, three-dimensional (3D) cell culture, bioprinting, and therapeutic agent encapsulation due to their excellent biocompatibility and ability to facilitate the growth of cells. It is important to note that the decellularization process significantly affects the structural integrity and properties of the extracellular matrix, which in turn shapes the characteristics of the resulting hydrogels at the macromolecular level. Therefore, our study aims to identify an effective chemical decellularization method for sheep lung tissue, using a mixing/agitation technique with a range of detergents, including commonly [Sodium dodecyl sulfate (SDS), Triton X-100, and 3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate] (CHAPS), and rarely used (sodium cholate hydrate, NP-40, and 3-[N,N-Dimethyl(3-myristoylaminopropyl)ammonio]propanesulfonate) (ASB-14). After the effectiveness of the used detergents on decellularization was determined by histological and biochemical methods, lung derived decellularized extracellular matrix was converted into hydrogel. We investigated the interactions between lung cells and decellularized extracellular matrix using proliferation assay, scanning electron microscopy, and immunofluorescence microscopy methods on BEAS-2B cells in air-liquid interface. Notably, this study emphasizes the effectiveness of ASB-14 in the decellularization process, showcasing its crucial role in removing cellular components while preserving vital extracellular matrix biological macromolecules, including glycosaminoglycans, collagen, and elastin. The resulting hydrogels demonstrated favorable mechanical properties and are compatible with both cell-cell and cell-extracellular matrix interactions.

Dietary bile acids supplementation decreases hepatic fat deposition with the involvement of altered gut microbiota and liver bile acids profile in broiler chickens

BackgroundHigh-fat diets (HFD) are known to enhance feed conversion ratio in broiler chickens, yet they can also result in hepatic fat accumulation. Bile acids (BAs) and gut microbiota also play key roles in the formation of fatty liver. In this study, our objective was to elucidate the mechanisms through which BA supplementation reduces hepatic fat deposition in broiler chickens, with a focus on the involvement of gut microbiota and liver BA composition.ResultsNewly hatched broiler chickens were allocated to either a low-fat diet (LFD) or HFD, supplemented with or without BAs, and subsequently assessed their impacts on gut microbiota, hepatic lipid metabolism, and hepatic BA composition. Our findings showed that BA supplementation significantly reduced plasma and liver tissue triglyceride (TG) levels in 42-day-old broiler chickens (P < 0.05), concurrently with a significant decrease in the expression levels of fatty acid synthase (FAS) in liver tissue (P < 0.05). These results suggest that BA supplementation effectively diminishes hepatic fat deposition. Under the LFD, BAs supplementation increased the BA content and ratio of Non 12-OH BAs/12-OH BAs in the liver and increased the Akkermansia abundance in cecum. Under the HFD, BA supplementation decreased the BAs and increased the relative abundances of chenodeoxycholic acid (CDCA) and cholic acid (CA) in hepatic tissue, while the relative abundances of Bacteroides were dramatically reduced and the Bifidobacterium, Escherichia, and Lactobacillus were increased in cecum. Correlation analyses showed a significant positive correlation between the Akkermansia abundance and Non 12-OH BA content under the LFD, and presented a significant negative correlation between the Bacteroides abundance and CA or CDCA content under the HFD.ConclusionsThe results indicate that supplementation of BAs in both LFD and HFD may ameliorate hepatic fat deposition in broiler chickens with the involvement of differentiated microbiota–bile acid profile pathways.Graphical

Core biomarkers analysis benefit for diagnosis on human intrahepatic cholestasis of pregnancy

BackgroundThe pregnant women with intrahepatic cholestasis were at high risk of fetal distress, preterm birth and unexpected stillbirth. Intrahepatic cholestasis of pregnancy (ICP) was mainly caused by disorder of bile acid metabolism, whereas the specific mechanism was obscure.MethodsWe performed proteomics analysis of 10 ICP specimens and 10 placenta specimens from patients without ICP through data-independent acquisition (DIA) technique to disclose differentially expressed proteins. We executed metabolomic analysis of 30 ICP specimens and 30 placenta specimens from patients without ICP through UPLC-MS/MS to identify differentially expressed metabolites. Enrichment and correlation analysis was used to obtain the direct molecular insights of ICP development. The ICP rat models were constructed to validate pathological features.ResultsThe heatmap of proteomics analysis showed the top 30 up-regulated and 30 down-regulated proteins. The metabolomic analysis revealed 20 richer and 4 less abundant metabolites in ICP samples compared with placenta specimens from patients without ICP, and enrichment pathways by these metabolites included primary bile acid biosynthesis, cholesterol metabolism, bile secretion, nicotinate and nicotinamide metabolism, purine metabolism and metabolic pathways. Combined analysis of multiple omics results demonstrated that bile acids such as Glycohyocholic acid, Glycine deoxycholic acid, beta-Muricholic acid, Noncholic acid, cholic acid, Gamma-Mercholic Acid, alpha-Muricholic acid and Glycochenodeoxycholic Aicd were significantly associated with the expression of GLRX3, MYL1, MYH7, PGGT1B, ACTG1, SP3, LACTB2, C2CD5, APBB2, IPO9, MYH2, PPP3CC, PIN1, BLOC1S1, DNAJC7, RASAL2 and ATCN3 etc. The core protein ACAT2 was involved in lipid metabolic process and animal model showed that ACAT2 was up-regulated in placenta and liver of pregnant rats and fetal rats. The neonates had low birth weight and Safranin O-Fast green FCF staining of animal models showed that poor osteogenic and chondrogenic differentiation of fetal rats.ConclusionMultiple metabolites-alpha-Muricholic acid, beta-Muricholic acid, Glycine deoxycholic acid and Glycochenodeoxycholic Acid etc. were perfect biomarkers to predict occurrence of ICP. Bile acids were significantly associated with varieties of protein expression and these proteins were differentially expressed in ICP samples. Our study provided several biomarkers for ICP detection and potential therapeutic targets for ICP development.

Phytogenic effects of Marrubium vulgare on the growth performance of weaned piglets: biochemical parameters and liquid chromatographic-electrospray ionization-mass spectrometric profile of plant and animal serum.

Multidrug-resistant bacteria in humans have prompted the search for alternative solutions derived from herbal medicines that can substitute antibiotics in livestock production. Thus, the goal of this study was to evaluate the phytogenic properties of Marrubium vulgare infusion (MVI) on weaned pigs. Thirty animals were randomly divided into five groups of six animals, each receiving a physiological solution, clenbuterol and the infusion extract at doses of 0.01 (MVI 1%), 0.1 (MVI 10%) and 0.2 (MVI 20%) mg kg-1 for 28 days. Biochemical parameters and the liquid chromatographic-electrospray ionization-mass spectrometric (LC-ESI-MS) chemical profiles of the infusion extract and animal serum were studied. The doses MVI 1 and 10% led to weight gain higher than the controls. No significant changes were noted in the biochemical parameters including erythrocytes, hemoglobin, hematocrit, mean corpuscular volume and others. Evaluation of enzymatic levels in blood revealed no significant changes. LC-ESI-MS data of MVI showed the presence of 34 secondary metabolites, and successive chromatographic purification of MVI yielded marrubiin and apigenin as major components. LC-ESI-MS data of animal serum showed the presence of a diterpene, a flavonoid and diverse cholic acid derivatives. Results indicated the doses MVI 1 and 10% promote weight gain with no significant alterations in blood biochemicals, and liver and kidney function. © 2024 Society of Chemical Industry.

Analysis of the prognostic value of mitochondria-related genes in patients with acute myocardial infarction

BackgroundAcute myocardial infarction (AMI) is a leading cause of death worldwide. Mitochondrial dysfunction is a key determinant of cell death post-AMI. Preventing mitochondrial dysfunction is thus a key therapeutic strategy. This study aimed to explore key genes and target compounds related to mitochondrial dysfunction in AMI patients and their association with major adverse cardiovascular events (MACE).MethodsDifferentially expressed genes in AMI were identified from the Gene Expression Omnibus (GEO) datasets (GSE166780 and GSE24519), and mitochondria-related genes were obtained from MitoCarta3.0 database. By intersection of the two gene groups, mitochondria-related genes in AMI were identified. Next, the identified genes related to mitochondria were subject to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Protein-protein interaction (PPI) network was constructed, and key genes were screened. Then, targeted drug screening and molecular docking were performed. Blood samples from AMI patients and healthy volunteers were analyzed for the key genes expressions using quantitative real time polymerase chain reaction (qRT-PCR). Later, receiver operating characteristic (ROC) curves assessed the diagnostic value of key genes, and univariate and multivariate COX analyses identified risk factors and protective factors for MACE in AMI patients.ResultsAfter screening and identification, 138 mitochondria-related genes were identified, mainly enriched in the processes and pathways of cellular respiration, redox, mitochondrial metabolism, apoptosis, amino acid and fatty acid metabolism. According to the PPI network, 5 key mitochondria-related genes in AMI were obtained: translational activator of cytochrome c oxidase I (TACO1), cytochrome c oxidase subunit Va (COX5A), PTEN-induced putative kinase 1 (PINK1), SURF1, and NDUFA11. Molecular docking showed that Cholic Acid, N-Formylmethionine interacted with COX5A, nicotinamide adenine dinucleotide + hydrogen (NADH) and NDUFA11. Subsequent basic experiments revealed that COX5A and NDUFA11 expressions were significantly lower in the blood of patients with AMI than those in the corresponding healthy volunteers; also, AMI patients with MACE had lower COX5A and NDUFA11 expressions in the blood than those without MACE (P < 0.01). ROC analysis also showed high diagnostic value for COX5A and NDUFA11 [area under the curve (AUC) > 0.85]. In terms of COX results, COX5A, NDUFA11 and left ventricular ejection fraction (LVEF) were protective factors for MACE in AMI, while C-reactive protein (CRP) was a risk factor.ConclusionCOX5A and NDUFA11, key mitochondria-related genes in AMI, may be used as biomarkers to diagnose AMI and predict MACE.