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Background: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder associated with pregnancy and is usually diagnosed based on high serum bile acid. However, the pathogenesis of ICP is unclear. Ferroptosis has been reported as an iron-dependent mechanism of cell death. Although the role of Ferritin Heavy Chain 1 (FTH1) in ferroptosis has been extensively studied in various diseases, its mechanism in ICP through ferroptosis is yet to be analyzed. Methods: Placental tissues from patients with ICP and healthy controls were employed to verify the expression of FTH1. Taurocholic acid (TCA)-induced HTR-8/SVneo cells were established as an in vitro model for ICP, and ferroptosis-related experiments were performed. In particular, HTR-8/SVneo cells with or without overexpressing FTH1 and HTR-8/SVneo cells with or without TCA induction were investigated to explore the relationship between FTH1 and ferroptosis during ICP in vitro, respectively. Results: FTH1 was significantly downregulated in the ICP group compared with the control group. Furthermore, FTH1 and ferroptosis-related protein levels were downregulated, while the intracellular iron, reactive oxygen species, and lipid peroxidation levels were upregulated in the TCA-induced HTR-8/SVneo cells. In contrast, ferroptosis was inhibited by overexpression of FTH1 in TCA-induced HTR-8/SVneo cells. Conclusions: A high concentration of TCA in HTR-8/SVneo cells decreased the expression of FTH1. Overexpression of FTH1 could prevent cell death from ferroptosis induced by TCA. Thus, inhibiting the downregulation of FTH1 could be a potential therapeutic target for ICP treatment. [ABSTRACT FROM AUTHOR]

Muscle regeneration and functional restoration are crucial for patients with sarcopenia. Antarctic fish, which are well-adapted to extreme conditions, offer potential pharmacotherapeutic insights. Our study assessed muscle extracts from Trematomus bernacchii (TB) and T. newnesi (TN) in a BaCl2-muscle injury mouse model. TB and TN extracts notably enhanced myofiber formation during muscle regeneration, showing potent proregenerative properties. Grip strength restoration was significantly improved, accompanied by increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial content, which are vital for post-injury recovery. The activation of the mammalian target of rapamycin and insulin-like growth factor 2 muscle enhancer activity underpinned these effects. Ultra-performance liquid chromatography-mass spectrometry and Global Natural Product Social analysis annotated taurocholic acid and its derivatives, along with denatorium, as bioactive substances that contribute to muscle enhancement. These findings have implications for therapeutic development for muscle regeneration and functional recovery in patients with musculoskeletal injuries and sarcopenia.

BackgroundHepatocellular carcinoma (HCC) is rapidly increasing in the U.S. and is a leading cause of mortality for patients with cirrhosis. Discovering novel biomarkers for risk stratification of HCC is paramount. We examined biomarkers of the gut-liver axis in a prospective multicenter cohort.MethodsPatients with cirrhosis without a history of HCC were recruited between May 2015 and March 2020 and prospectively followed at 3 tertiary care hospitals in Los Angeles. Microbiome analysis was performed on duodenal biopsies and metabolomic analysis was performed on serum samples, collected at the time of enrollment. Optimal microbiome-based survival analysis and Cox proportional hazards regression analysis were used to determine microbiota and metabolite associations with HCC development, respectively.ResultsA total of 227 participants with liver cirrhosis contributed a total of 459.58 person-years of follow-up, with 14 incident HCC diagnoses. Male sex (HR = 7.06, 95% CI = 1.02-54.86) and baseline hepatic encephalopathy (HE, HR = 4.65, 95% CI = 1.60-13.52) were associated with developing HCC over follow-up. Adjusting for age, sex, baseline HE, and alkaline phosphatase, an increased risk of HCC were observed for participants with the highest versus lowest three quartiles for duodenal Alloprevotella (HR = 3.22, 95% CI = 1.06-9.73) and serum taurocholic acid (HR = 6.87, 95% CI = 2.32-20.27), methionine (HR = 9.97, 95% CI = 3.02-32.94), and methioninesulfoxide (HR = 5.60, 95% CI = 1.84-17.10). Being in the highest quartile for Alloprevotella or methionine had a sensitivity and specificity for developing HCC of 85.71% and 60.56%, respectively, with an odds ratio of 10.92 (95% CI = 2.23-53.48).ConclusionAlloprevotella and methionine, methioninesulfoxide, and taurocholic acid predicted future HCC development in a high-risk population of participants with liver cirrhosis.

Objective To investigate the effect of taurocholic acid (TLCA) regulating palmitic acid (PA)-induced macrophage polarization on hepatocyte lipid metabolism. Methods Mouse mononuclear macrophage (RAW264.7) cells, treated with TLCA and PA, were divided into control (CON), TLCA, PA and PA+TLCA groups. The conditioned medium (CM) was collected for culturing primary hepatocytes from C57 BL/6J and AML-12 liver cells. Triamterene was used to inhibit macrophage Takeda G-protein receptor 5(TGR5), which could investigate the role of TGR5 in regulating macrophage polarization and reducing lipid deposition in hepatocytes. BODIPY fluorescence staining was performed to detect lipid accumulation in hepatocytes; The mRNA levels of genes related to inflammatory factors and lipid metabolism were detected by RT-qPCR; Western blotting was performed to detect the level of protein expression of macrophage TGR5 and hepatic cell SREBP-1c. The expression of iNOS and CD206 were observed by immunofluorescence staining. Results BODIPY fluorescence staining showed that PA group displayed significantly increased lipid accumulation, compared with CON group, while TLCA treatment could reduce the PA-induced lipid accumulation(P < 0.05); Compared with the PA group, the PA+TLCA group had decreased mRNA levels of ACC1, FASN and SREBP-1c and protein expression of SREBP-1c (P < 0.05). However, there were no significant changes of expression of ACOX1 and CPT1A among these groups mentioned above. The outcome of RT-qPCR showed that PA stimulated RAW264.7 into M1-type polarization and significantly increased the levels of proinflammatory factors (iNOS, IL-6, IL-1β, TNF-α). PA combined with TLCA could reduce the levels of inflammatory factors and increased the mRNA expression levels of M2-type polarization-related genes, Arg1, IL-4 and IL-10 (P < 0.05). Compared with CON group, the PA group showed increased M1-type marker iNOS and decreased M2-type marker CD206, while TLCA could promote the protein expression of TGR5(P=0.0714). TGR5 inhibited by triamterene could suppress macrophage polarization regulated by TLCA and reduce hepatocyte lipid accumulation. Conclusion TLCA inhibits PA-induced M1-type polarization and promotes M2-type polarization via TGR5, which reduces proinflammatory factors, reduces hepatic lipogenesis and promotes hepatocyte lipid accumulation.

Type 2 diabetes mellitus (T2DM) therapy is facing the challenges of long-term medication and gradual destruction of pancreatic islet β-cells. Therefore, it is timely to develop oral prolonged action formulations to improve compliance, while restoring β-cells survival and function. Herein, we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property, which combined apical sodium-dependent bile acid transporter-mediated intestinal uptake and lymphatic transportation. In this system, taurocholic acid (TCA) modified poly(lactic-co-glycolic acid) (PLGA) was employed to achieve pancreas location, hydroxychloroquine (HCQ) was loaded to execute therapeutic efficacy, and 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) was introduced as stabilizer together with synergist (PLGA-TCA/DLPC/HCQ). In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction, thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day. In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress, remodeled the inflammatory pancreas microenvironment, and activated PI3K/AKT signaling pathway without obvious toxicity. This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment.

Background/Aims Disrupted bile acid regulation and accumulation in the liver can contribute to progressive liver damage and fibrosis. However, the effects of bile acids on the activation of hepatic stellate cells (HSCs) remain unclear. This study investigated the effects of bile acids on HSC activation during liver fibrosis, and examined the underlying mechanisms. Methods The immortalized HSCs, LX-2 and JS-1cells were used for the in vitro study. in vitro, the adeno-associated viruses adeno-associated virus-sh-S1PR2 and JTE-013 were used to pharmacologically inhibit the activity of S1PR2 in a murine model of fibrosis induced by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of S1PR2 in the regulation of fibrogenic factors as well as the activation properties of HSCs. Results S1PR2 was the predominant S1PR expressed in HSCs and was upregulated during taurocholic acid (TCA) stimulation and in cholestatic liver fibrosis mice. TCA-induced HSC proliferation, migration and contraction and extracellular matrix protein secretion were inhibited by JTE-013 and a specific shRNA targeting S1PR2 in LX-2 and JS-1 cells. Meanwhile, treatment with JTE-013 or S1PR2 deficiency significantly attenuated liver histopathological injury, collagen accumulation, and the expression of fibrogenesis-associated genes in mice fed a DDC diet. Furthermore, TCA-mediated activation of HSCs through S1PR2 was closely related to the yes-associated protein (YAP) signaling pathway via p38 mitogen-activated protein kinase (p38 MAPK). Conclusions TCA-induced activation of the S1PR2/p38 MAPK/YAP signaling pathways plays a vital role in regulating HSC activation, which might be therapeutically relevant for targeting cholestatic liver fibrosis.

Type 2 diabetes mellitus (T2DM) therapy is facing the challenges of long-term medication and gradual destruction of pancreatic islet β -cells. Therefore, it is timely to develop oral prolonged action formulations to improve compliance, while restoring β -cells survival and function. Herein, we designed a simple nanoparticle with enhanced oral absorption and pancreas accumulation property, which combined apical sodium-dependent bile acid transporter-mediated intestinal uptake and lymphatic transportation. In this system, taurocholic acid (TCA) modified poly(lactic-co-glycolic acid) (PLGA) was employed to achieve pancreas location, hydroxychloroquine (HCQ) was loaded to execute therapeutic efficacy, and 1,2-dilauroyl- sn -glycero-3-phosphocholine (DLPC) was introduced as stabilizer together with synergist (PLGA-TCA/DLPC/HCQ). In vitro and in vivo results have proven that PLGA-TCA/DLPC/HCQ reversed the pancreatic islets damage and dysfunction, thus impeding hyperglycemia progression and restoring systemic glucose homeostasis via only once administration every day. In terms of mechanism PLGA-TCA/DLPC/HCQ ameliorated oxidative stress, remodeled the inflammatory pancreas microenvironment, and activated PI3K/AKT signaling pathway without obvious toxicity. This strategy not only provides an oral delivery platform for increasing absorption and pancreas targetability but also opens a new avenue for thorough T2DM treatment. This oral nano-formulation provides a promising strategy for antidiabetic therapy. It can enhance pancreas accumulation, remodel the inflammatory pancreas microenvironment, regulate blood glucose level and enhance insulin sensitivity. [Display omitted] [ABSTRACT FROM AUTHOR]

A hyperactive immune response can be observed in patients with bacterial or viral infection, which may lead to the overproduction of proinflammatory cytokines, or "cytokine storm", and a poor clinical outcome. Extensive research efforts have been devoted to the discovery of effective immune modulators, yet the therapeutic options are still very limited. Here, we focused on the clinically indicated anti-inflammatory natural product Calculus bovis and its related patent drug Babaodan to investigate the major active molecules in the medicinal mixture. Combined with high-resolution mass spectrometry, transgenic zebrafish-based phenotypic screening, and mouse macrophage models, taurochiolic acid (TCA) and glycoholic acid (GCA) were identified as two naturally derived anti-inflammatory agents with high efficacy and safety. Both bile acids significantly inhibited the lipopolysaccharide-induced macrophage recruitment and the secretion of proinflammatory cytokines/chemokines in in vivo and in vitro models. Further studies identified strongly increased expression of the farnesoid X receptor at both the mRNA and protein levels upon the administration of TCA or GCA, which may be essential for mediating the anti-inflammatory effects of the two bile acids. In conclusion, we identified TCA and GCA as two major anti-inflammatory compounds in Calculus bovis and Babaodan, which could be important quality markers for the future development of Calculus bovis, as well as promising lead compounds in the treatment of overactive immune responses. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder specific to pregnancy. Taurocholic acid (TCA) has been implicated in the pathogenesis of ICP. This study aimed to investigate the association between serum TCA levels and adverse maternal and infant outcomes in women with ICP. Methods: Pregnant women diagnosed with ICP were categorized into normal or adverse groups based on their pregnancy outcomes. Baseline data, including age, pre-pregnancy body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting blood sample (5 mL), were collected at 28 weeks of gestation. Serum levels of total bile acid (TBA), alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), and TCA were measured using a fully automatic biochemical analyzer. The predictive value of serum TCA levels for adverse outcomes in ICP was analyzed using receiver operating characteristic (ROC) curve analysis. Subsequently, ICP patients were divided into high and low TCA expression groups, and the changes in baseline data and adverse outcomes were compared between the groups. The relationship between serum TCA levels and adverse outcomes was evaluated using adverse maternal and infant outcome curves. Logistic regression analysis was performed to identify independent risk factors for adverse outcomes in ICP patients. Results: The adverse outcome group showed significant differences in gestational age at delivery (median value of 37 years old, p = 0.0001), levels of TBA (mean ± standard deviation 47.05 ± 6.43 µmol/L, p < 0.0001), ICP severity (proportion of severe ICP patients was 85.14%, p < 0.0001), ALT (mean ± standard deviation 82.59 ± 6.29 U/L, p < 0.0001), AST (median value of 67.50 U/L, p < 0.0001), and TBIL (mean ± standard deviation 47.05 ± 6.99 µmol/L, p < 0.0001), compared to the normal outcome group. Serum TCA levels were higher in the adverse outcome group (mean ± standard deviation 17.79 ± 4.56 µmol/L) than in the normal outcome group (mean ± standard deviation 11.72 ± 3.68 µmol/L) (p < 0.001). Serum taurocholic acid (TCA) levels demonstrated predictive value for adverse outcomes in ICP patients, and the areas under the ROC curve/sensitivity/specificity/cutoff value were 0.8430, 66.22%, 91.03%, and 16.17, respectively. The high TCA expression group had higher levels of TBA (median value of 43.40 µmol/L, p < 0.0001), ALT (median value of 79.89 µmol/L, p < 0.0001), AST (median value of 63.87 µmol/L, p < 0.0001), and TBIL (median value of 43.79 µmol/L, p < 0.0001), a higher proportion of severe ICP cases (71.43%, p < 0.0001). There were a remarkably increased number of adverse pregnancy outcomes (postpartum hemorrhage, premature birth, neonatal asphyxia, fetal distress, amniotic fluid fecal staining, and low birth weight) in the high TCA expression group (n = 49) compared to the low TCA expression group (n = 25) (p < 0.0001). The Kaplan-Meier (KM) curve of patients with high TCA expression shifted to the left compared with patients with low TCA expression (p < 0.0001). The cumulative survival rate of patients with high serum TCA expression (22.22%) was prominently reduced compared to patients with low serum TCA expression (85.03%), indicating that high serum TCA levels increased the risk of maternal and infant adverse outcomes in ICP patients. TBAs, AST, and TCA were identified as independent risk factors for adverse maternal and fetal outcomes in ICP patients. Conclusion: Serum TCA is an independent risk factor for adverse outcomes in ICP patients. Serum TCA levels have predictive values for adverse maternal and infant outcomes in pregnant women with ICP, but there are still some false positives. In clinical diagnosis, it is essential to combine other clinical data to increase the diagnostic accuracy.

Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5+) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5+ cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5+ cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.

A specific liver disease during pregnancy is intrahepatic cholestasis of pregnancy (ICP). The current clinical diagnosis mainly depends on the level of serum total bile acid (TBA), which lacks sensitivity and specificity. Lactate dehydrogenase A (LDHA) is a new biomarker highly expressed in the serum of ICP patients, which was screened by data-independent acquisition (DIA) proteomic technology in our previous studies. There is currently a lack of a rapid, quantitative, and sensitive detection method to measure LDHA levels in serum. This study aimed to establish a time-resolved fluorescent nanomicrospheres immunochromatographic test strip to detect LDHA in serum and evaluate its value in clinical diagnosis and treatment of ICP. Subsequently, the mechanism of LDHA in mediating the inflammatory of ICP was explored in vitro. In vitro, taurocholic acid (TCA) at a concentration of 100 μM was used to simulate an ICP environment. The AKT/mTOR/HIF-1α signaling pathway was activated in TCA-treated HTR-8/SVeno cells, leading to an increase in LDHA levels. The lactic acid produced by LDHA-mediated glycolytic metabolism may be related to the regulation of inflammation in placental trophoblast cells. According to these findings, LDHA could be a new target that provide promising ideas for the diagnosis, prediction and treatment of ICP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Bile acids (BAs) are steroid detergents in bile that contribute to fat absorption, cell signaling, and microbiome interactions. The final step in their synthesis is amino acid conjugation with either glycine or taurine in the liver by the enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT). Here, we describe the microbial, chemical, and physiological consequences of Baat gene knockout. Baat-/- mice were underweight after weaning but quickly exhibited catch-up growth. At three weeks of age, KO animals had increased phospholipid excretion and decreased subcutaneous fat pad mass, liver mass, glycogen staining in hepatocytes, and hepatic vitamin A stores, but these were less marked in adulthood. Additionally, KO mice had an altered microbiome in early life. Their BA pool was highly enriched in cholic acid but not completely devoid of conjugated BAs. KO animals had 27-fold lower taurine-conjugated BAs than wild type in their liver but similar concentrations of glycine-conjugated BAs and higher microbially conjugated BAs. Furthermore, the BA pool in Baat-/- was enriched in a variety of unusual BAs that were putatively sourced from cysteamine conjugation with subsequent oxidation and methylation of the sulfur group mimicking taurine. Antibiotic treatment of KO mice indicated the microbiome was not the likely source of the unusual conjugations, instead, the unique BAs in KO animals were likely derived from the peroxisomal acyltransferases Acnat1 and Acnat2, which are duplications of Baat in the mouse genome that are inactivated in humans. This study demonstrates that BA conjugation is important for early life development of mice.

Bile acids, originally known to emulsify dietary lipids, are now established signalling molecules that regulate physiological processes. Signalling targets several proteins that include the ion channels involved in regulating intestinal motility and bile viscosity. Studies show that bile acids regulate the epithelial sodium channel (ENaC) in cultured cell models and heterologous expression systems. ENaC plays both local and systemic roles in regulating extracellular fluids. Here we investigated whether bile acids regulate ENaC expressed in native tissues. We found that taurocholic acid and taurohyodeoxycholic acid regulated ENaC in both the distal nephron and distal colon. We also tested the hypothesis that regulation occurs through direct binding. Using photoaffinity labelling, we found evidence for specific binding to both the β and γ subunits of the channel. In functional experiments, we found that the α subunit was sufficient for regulation. We also found that regulation by at least one bile acid was voltage‐sensitive, suggesting that one binding site may be closely associated with the pore‐forming helices of the channel. Our data provide evidence that bile acids regulate ENaC by binding to multiple sites to influence the open probability of the channel. Key points: Recent studies have shown that bile acids regulate the epithelial sodium channel (ENaC) in vitro. Here we investigated whether bile acids regulate ENaC in native tissues and whether bile acids directly bind the channel.We found that bile acids regulate ENaC expressed in the mouse cortical collecting duct and mouse colon by modulating open probability.Photoaffinity labelling experiments showed specific binding to the β and γ subunits of the channel, while channels comprising only α subunits were sensitive to taurocholic acid in functional experiments using Xenopus oocytes.Taurocholic acid regulation of ENaC was voltage‐dependent, providing evidence for binding to pore‐forming helices.Our data indicate that bile acids are ENaC regulatory effectors that may have a role in the physiology and pathophysiology of several systems. [ABSTRACT FROM AUTHOR]

Bile acids (BAs) usually display growth-promoting and lipid-lowering properties when supplemented to the diet. The effects of a high-lipid diet (HD) and BAs supplementation on growth performance and lipid deposition of hybrid grouper (Epinephelus fuscoguttatus♀ × E. lanceolatus♂) was evaluated in this study. Compared to the control diet (CD), the HD did not significantly affect the fish growth performance, but it promoted lipid deposition, as revealed by a significantly higher crude lipid content of the whole body, muscle, and liver. Among the HD supplemented with taurocholic acid (BD) groups, and compared to the HD, fish fed dietary supplementation of BAs at 900 mg kg−1 exhibited the best growth performance and lowest hepatic lipid deposition. In most BD groups, the content of total cholesterol, low-density lipoprotein cholesterol, and triglycerides in serum, as well as the content of total cholesterol in the liver, were decreased, whereas the content of high-density lipoprotein cholesterol in serum was increased. In addition, the most strongly influenced pathways between the control, HD, and B3D groups were fatty acid biosynthesis, insulin signaling pathway, and AMPK signaling pathway. The improvement of lipid metabolism induced by the supplementation of BAs may be attributed to decreased expression of lipogenesis genes and proteins (enzymes), and increased lipolysis. In conclusion, dietary supplementation of BAs at 900 mg kg−1 promoted growth performance and reduced lipid accumulation, whereas BAs supplementation improved the hepatic lipid metabolism by enhancing hepatic lipolysis, inhibiting lipogenesis, and regulating associated transcriptional factors in hybrid grouper.

Bile acid is the main component of bile, and the external secretion of bile acid into the intestine can help with the absorption of lipids and fat-soluble vitamins; in addition, bile acid acts as a signal molecule to regulate bile acid metabolism and help maintain intestinal homeostasis. The process of liver cirrhosis is accompanied by varying degrees of cholestasis, causing bile duct injury, and exposure of liver cells to a high concentration of bile acid will accelerate the progression of liver cirrhosis and form a vicious circle. Among these abnormally elevated bile acids, taurocholic acid (TCA) shows the greatest increase, suggesting that TCA may play an important role in the process of liver cirrhosis. At present, there are relatively few studies on the mechanism of TCA in liver cirrhosis, and current studies in China and globally have shown that TCA at a high concentration (≥50 μmol/L) can promote the progression of liver cirrhosis by acting on liver cells (hepatic stellate cells, hepatocytes, hepatic progenitor cells, and bile duct epithelial cells). This article discusses the detailed mechanism of TCA in promoting liver cirrhosis and points out that TCA has the clinical potential as a biomarker and therapeutic target for liver cirrhosis. [ABSTRACT FROM AUTHOR]

• Prebiotics alter the gut microbiome. • Prebiotics increase P. distasonis , Ruminiclostridium 5 , and C. leptum. • Prebiotics and circadian disruption (CDR) modulate bile acids. • Prebiotics facilitate realignment of core body temperature (CBT) and sleep to CDR. • Changes in Ruminiclostridium 5 and taurocholic acid relate to CBT and sleep changes. Chronic disruption of rhythms (CDR) impacts sleep and can result in circadian misalignment of physiological systems which, in turn, is associated with increased disease risk. Exposure to repeated or severe stressors also disturbs sleep and diurnal rhythms. Prebiotic nutrients produce favorable changes in gut microbial ecology, the gut metabolome, and reduce several negative impacts of acute severe stressor exposure, including disturbed sleep, core body temperature rhythmicity, and gut microbial dysbiosis. In light of previous compelling evidence that prebiotic diet broadly reduces negative impacts of acute, severe stressors, we hypothesize that prebiotic diet will also effectively mitigate the negative impacts of chronic disruption of circadian rhythms on physiology and sleep/wake behavior. Male, Sprague Dawley rats were fed diets enriched in prebiotic substrates or calorically matched control chow. After 5 weeks on diet, rats were exposed to CDR (12 h light/dark reversal, weekly for 8 weeks) or remained on undisturbed normal light/dark cycles (NLD). Sleep EEG, core body temperature, and locomotor activity were recorded via biotelemetry in freely moving rats. Fecal samples were collected on experimental days –33, 0 (day of onset of CDR), and 42. Taxonomic identification and relative abundances of gut microbes were measured in fecal samples using 16S rRNA gene sequencing and shotgun metagenomics. Fecal primary, bacterially modified secondary, and conjugated bile acids were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Prebiotic diet produced rapid and stable increases in the relative abundances of Parabacteroides distasonis and Ruminiclostridium 5. Shotgun metagenomics analyses confirmed reliable increases in relative abundances of Parabacteroides distasonis and Clostridium leptum , a member of the Ruminiclostridium genus. Prebiotic diet also modified fecal bile acid profiles; and based on correlational and step-wise regression analyses, Parabacteroides distasonis and Ruminiclostridium 5 were positively associated with each other and negatively associated with secondary and conjugated bile acids. Prebiotic diet, but not CDR, impacted beta diversity. Measures of alpha diversity evenness were decreased by CDR and prebiotic diet prevented that effect. Rats exposed to CDR while eating prebiotic, compared to control diet, more quickly realigned NREM sleep and core body temperature (ClockLab) diurnal rhythms to the altered light/dark cycle. Finally, both cholic acid and Ruminiclostridium 5 prior to CDR were associated with time to realign CBT rhythms to the new light/dark cycle after CDR; whereas both Ruminiclostridium 5 and taurocholic acid prior to CDR were associated with NREM sleep recovery after CDR. These results support our hypothesis and suggest that ingestion of prebiotic substrates is an effective strategy to increase the relative abundance of health promoting microbes, alter the fecal bile acid profile, and facilitate the recovery and realignment of sleep and diurnal rhythms after circadian disruption. [ABSTRACT FROM AUTHOR]

[Display omitted] • The muscle extracts of Antarctic fish species, Trematomus bernacchii and Trematomus newnesi , exhibit not only the ability to promote myofiber formation but also demonstrate effectiveness in restoring grip strength during muscle regeneration. • The extracts derived from Antarctic fish, Trematomus bernacchii and Trematomus newnesi , have been found to enhance mTOR activity. • Bioactive substances such as taurocholic acid and its potential derivatives, along with denatorium, have been identified and annotated through liquid chromatography-mass spectrometry and Global Natural Product Social (GNPS) molecular networking. Muscle regeneration and functional restoration are crucial for patients with sarcopenia. Antarctic fish, which are well-adapted to extreme conditions, offer potential pharmacotherapeutic insights. Our study assessed muscle extracts from Trematomus bernacchii (TB) and T. newnesi (TN) in a BaCl 2 -muscle injury mouse model. TB and TN extracts notably enhanced myofiber formation during muscle regeneration, showing potent proregenerative properties. Grip strength restoration was significantly improved, accompanied by increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial content, which are vital for post-injury recovery. The activation of the mammalian target of rapamycin and insulin-like growth factor 2 muscle enhancer activity underpinned these effects. Ultra-performance liquid chromatography-mass spectrometry and Global Natural Product Social analysis annotated taurocholic acid and its derivatives, along with denatorium, as bioactive substances that contribute to muscle enhancement. These findings have implications for therapeutic development for muscle regeneration and functional recovery in patients with musculoskeletal injuries and sarcopenia. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE), a neurological disease resulting from liver failure, is difficult to manage and its causes are unclear. Bile acids have been postulated to be involved in the provenance and progression of various diseases including HE. Hence, the characterization of bile acid profiles in the brains of subjects with and without liver failure can provide important clues for the potential treatment of HE. Nanoflow ultra‐performance liquid chromatography electrospray ionization ion mobility mass spectrometry (UPLC‐ESI‐IM‐MS) is a highly sensitive method for detection of specific molecules, such as bile acids in brain samples, at biologically relevant concentrations. We used UPLC‐ESI‐IM‐MS to characterize bile acid profiles in brain samples from seven "healthy" control rodents and 22 "diseased" rodents with liver failure (i.e., induced HE). An isomer of trihydroxycholanoyl‐taurine was detected in brain tissue samples from both rats and mice with induced HE; however, this isomer was not detected in the brains of healthy rats and mice. Our findings were confirmed by comparing IM arrival times (AT), exact mass measurements (m/z), and mass spectral fragmentation patterns of the experimentally observed suspected species to standards of trihydroxycholanoyl‐taurine isomers. Moreover, In Silico Fractionation was employed to provide an additional analytical dimension to verify bile acid identifications. [ABSTRACT FROM AUTHOR]

Polarization of hepatocytes is manifested by bile canalicular network formation and activation of LKB1 and AMPK, which control cellular energy metabolism. The bile acid, taurocholate, also regulates development of the canalicular network through activation of AMPK. In the present study, we used collagen sandwich hepatocyte cultures from control and liver-specific LKB1 knockout mice to examine the role of LKB1 in trafficking of ABCB11, the canalicular bile acid transporter. In polarized hepatocytes, ABCB11 traffics from Golgi to the apical plasma membrane and endogenously cycles through the rab 11a-myosin Vb recycling endosomal system. LKB1 knockout mice were jaundiced, lost weight and manifested impaired bile canalicular formation and intracellular trafficking of ABCB11, and died within three weeks. Using live cell imaging, fluorescence recovery after photobleaching (FRAP), particle tracking, and biochemistry, we found that LKB1 activity is required for microtubule-dependent trafficking of ABCB11 to the canalicular membrane. In control hepatocytes, ABCB11 trafficking was accelerated by taurocholate and cAMP; however, in LKB1 knockout hepatocytes, ABCB11 trafficking to the apical membrane was greatly reduced and restored only by cAMP, but not taurocholate. cAMP acted through a PKA-mediated pathway which did not activate AMPK. Our studies establish a regulatory role for LKB1 in ABCB11 trafficking to the canalicular membrane, hepatocyte polarization, and canalicular network formation.

Inflammation, apoptosis and oxidative stress play crucial roles in the deterioration of severe acute pancreatitis-associated acute respiratory distress syndrome (SAP-ARDS). Unfortunately, despite a high mortality rate of 45 %[1], there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies[2]. This study investigated the potential therapeutic role and mechanisms of AQP9 inhibitor RG100204 in two animal models of severe acute pancreatitis, inducing acute respiratory distress syndrome: 1) a sodium-taurocholate induced rat model, and 2) and Cerulein and lipopolysaccharide induced mouse model. RG100204 treatment led to a profound reduction in inflammatory cytokine expression in pancreatic, and lung tissue, in both models. In addition, infiltration of CD68 + and CD11b + cells into these tissues were reduced in RG100204 treated SAP animals, and edema and SAP associated tissue damage were improved. Moreover, we demonstrate that RG100204 reduced apoptosis in the lungs of rat SAP animals, and reduces NF-κB signaling, NLRP3, expression, while profoundly increasing the Nrf2-dependent anti oxidative stress response. We conclude that AQP9 inhibition is a promising strategy for the treatment of pancreatitis and its systemic complications, such as ARDS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated., Methods: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy., Results: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP., Conclusions: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP., (© 2024. The Author(s).)

The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(−/−), but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(−/−) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.

Abstract Background Previous studies have indicated that bile acid is associated with progression of liver cirrhosis. However, the particular role of specific bile acid in the development of liver cirrhosis is not definite. The present study aims to identify the specific bile acid and explore its possible mechanisms in promoting liver cirrhosis. Methods Thirty two cirrhotic patients and 27 healthy volunteers were enrolled. Age, gender, Child-Pugh classification and serum of patients and volunteers were collected. Liquid chromatography tandem mass spectrometry (LC-MS) was utilized to determine concentrations of 12 bile acids in serum. Principal component analysis, fold change analysis and heatmap analysis were used to identify the most changed bile acid. And pathway analysis was used to identify the most affected pathway in bile acid metabolism. Spearman rank correlation analysis was employed to assess correlation between concentrations of bile acids and Child-Pugh classification. Hepatic stellate cells (LX-2) were cultured in DMEM. LX-2 cells were also co-cultured with HepG2 cells in the transwell chambers. LX-2 cells were treated with Na+/taurocholate in different concentrations. Western blot was used to evaluate the expression of alpha smooth muscle actin (α-SMA), type I collagen, and Toll-like receptor 4 (TLR4) in LX-2 cells. Results Concentrations of 12 bile acids in serum of patients and healthy volunteers were determined with LC-MS successively. Principal component analysis, fold change analysis and heatmap analysis identified taurocholic acid (TCA) to be the most changed bile acid. Pathway analysis showed that TCA biosynthesis increased significantly. Spearman rank correlation analysis showed that concentration of TCA in serum of cirrhotic patients was positively associated with Child-Pugh classification. TCA increased the expression of α-SMA, type I collagen, and TLR4 in LX-2 cells. Moreover, the above effect was strengthened when LX-2 cells were co-cultured with HepG2 cells. Conclusions Increased TCA concentration in serum of liver cirrhotic patients is mainly due to increased bile acid biosynthesis. TCA is an active promoter of the progression of liver cirrhosis. TCA promoting liver cirrhosis is likely through activating hepatic stellate cells via upregulating TLR4 expression. TCA is a potential therapeutic target for the prevention and treatment of liver cirrhosis.

Taurocholic acid (TCA), a conjugation of cholic acid with taurine, is one of the main bile acids that is elevated in liver disease. Considering the epidemiologic linkage of periodontal disease to liver disease, the question arises about the possible effect of elevated TCA levels on periodontal cells. To answer this question, gingival fibroblasts and human oral squamous cell carcinoma cell line (HSC-2) were pretreated with interleukine1β (IL1β) and tumor necrosis factorα (TNFα) in the presence and absence of TCA. Also, mouse macrophages (RAW 264.7) were incubated with sterile-filtered human saliva with and without TCA. Inflammatory cytokines were measured by real time polynucleotide chain reaction (RT-PCR) and an immunoassay. The nuclear translocation of the p65 subunit was visualized by immunostaining. In pretreated gingival fibroblasts and HSC-2 cells, TCA considerably reduced the expression of IL1β, IL6, and IL8. In support of these observations, TCA lowered the saliva-induced expression of IL1α, IL1β and IL6 in RAW 264.7 cells. An immunoassay confirmed the capacity of TCA to diminish inflammation-induced expression of IL6 in gingival fibroblasts, HSC-2 and RAW 264.7 cells. Consistently, TCA blocked the nuclear translocation of p65 in fibroblasts. These findings suggest that TCA has anti-inflammatory activity in gingival fibroblasts, human oral squamous cell carcinoma cells and macrophages in vitro. [ABSTRACT FROM AUTHOR]

A recent study showed an association between diabetes development and the bile acid lithocholic acid (LCA), while another study demonstrated positive biological effects of the conjugated bile acid, taurocholic acid (TCA), on pancreatic cells. Thus, this study aimed to encapsulate TCA with primary islets (graft) and study the biological effects of the graft, post-transplantation, in diabetic mice, including effects on LCA concentrations. Sixteen mature adult mice were made diabetic and randomly divided into two equal groups, control and test (transplanted encapsulated islets without or with TCA). Graft pharmaceutical features pre-transplantation, and biological effects including on LCA concentrations post-transplantation, were measured. TCA-microcapsules had an oval shape and similar size compared with the control. The treatment group survived longer, showed improved glucose and interleukin-6 concentrations, and lower LCA concentrations in plasma, large intestine, faeces, liver and spleen, compared with control. Results suggest that TCA incorporation with islets encapsulated graft exerted beneficial effects, but there was no direct and significant dependency between concentrations of interleukin-6 and LCA.

Cihui Tian,1 Sajid Asghar,2 Yifan Wu,1 Zhipeng Chen,3 Xin Jin,1 Lining Yin,1 Lin Huang,1 Qineng Ping,1 Yanyu Xiao1 1Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; 2Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan; 3Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China Abstract: The expression of multiple receptors on intestinal epithelial cells enables an actively targeted carrier to significantly enhance the oral delivery of payloads. Conjugating the receptors’ ligands on the surfaces of a particulate-delivery system allows site-specific targeting. Here, we used taurocholic acid (TCA) as a ligand for uptake of nanostructured lipid carriers (NLCs) mediated by a bile-acid transporter to improve oral bioavailability of curcumin (Cur). First, synthesis of TCA–polyethylene glycol 100–monostearate (S100-TCA) was carried out. Then, the physical and chemical properties of S100-TCA-modified Cur-loaded NLCs (Cur-TCA NLCs) with varying levels of S100-TCA modifications were investigated. Small particle size (90%), drug loading (about 3%), negative ζ-potential (–7 to –3 mV), and sustained release were obtained. In situ intestinal perfusion studies demonstrated improved absorption rate and permeability coefficient of Cur-TCA NLCs. Depending on the degree of modification, Cur-TCA NLCs displayed about a five- to 15-fold higher area under the curve in rats after oral administration than unmodified Cur NLCs, which established that the addition of S100-TCA to the NLCs boosted absorption of Cur. Further investigations of TCA NLCs might reveal a bright future for effective oral delivery of poorly bioavailable drugs. Keywords: curcumin, nanostructured lipid carriers, taurocholic acid, oral administration, pharmacokinetics, bioavailability

Diets rich in taurine can increase the production of taurine-conjugated bile acids, which are known to exert antihypertensive effects. Despite their benefits to the heart, kidney and arteries, their role in the central nervous system during the antihypertensive process remains unclear. Since hypothalamic paraventricular nucleus (PVN) plays a key role in blood pressure regulation, we aimed to investigate the function of bile acids in the PVN. The concentration of bile acids in the PVN of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKY) fed with normal chow was measured using LC-MS/MS, which identified taurocholic acid (TCA) as the most down-regulated bile acid. To fully understand the mechanism of TCA's functions in the PVN, bi-lateral PVN micro-infusion of TCA was carried out. TCA treatment in the PVN led to a significant reduction in the blood pressure of SHRs, with decreased plasma levels of norepinephrine and improved morphology of cardiomyocytes. It also decreased the number of c-fos+ neurons, reduced the inflammatory response, and suppressed oxidative stress in the PVN of the SHRs. Most importantly, the TGR5 receptors in neurons and microglia were activated. PVN infusion of SBI-115, a TGR5 specific antagonist, was able to counteract with TCA in the blood pressure regulation of SHRs. In conclusion, TCA supplementation in the PVN of SHRs can activate TGR5 in neurons and microglia, reduce the inflammatory response and oxidative stress, suppress activated neurons, and attenuate hypertension.

Background: Acute pancreatitis (AP) is a prevalent exocrine inflammatory disorder of the pancreas characterized by pancreatic inflammation and injury to acinar cells. Vitamin B6 (VB6) is a vital nutrient that plays a significant role in preserving human health and has anti-inflammatory and anti-apoptotic effects., Methods: This study aimed to explore the potential pancreatic protective effects of VB6 in mitigating pancreatic inflammation and apoptosis induced by taurocholate sodium (TLCS) in an AP model and to assess the underlying mechanism of action. AP was induced in Sprague‒Dawley (SD) rats through TLCS administration and lipopolysaccharide (LPS)-treated AR42J cells, followed by treatment with VB6., Results: Various parameters associated with AP were assessed in both plasma and pancreatic tissues. VB6 has been shown to ameliorate the severity of AP through various mechanisms. It effectively reduces the levels of serum amylase, lipase, and inflammatory factors, thereby mitigating histological injury to the pancreas. Moreover, VB6 inhibited pancreatic apoptosis by downregulating bax expression and up-regulating Bcl2 expression in TLCS-treated rats. Additionally, VB6 suppressed the expression of caspase3. The anti-inflammatory and anti-apoptotic effects of VB6 observed in LPS-treated AR42J cells are consistent with those observed in a rat model of AP., Conclusions: These results suggest that VB6 exerts anti-inflammatory and anti-apoptotic effects through inhibition of the caspase3 signaling pathway and has a protective effect against AP., (© 2024. The Author(s).)

Background: Severe acute pancreatitis (SAP) is associated with tremendous systemic inflammation, T-helper 17 (Th17) cells, and regulatory T (Treg) cells play an essential role in the inflammatory responses. Meanwhile, soluble fibrinogen-like protein 2 (Sfgl2) is a critical immunosuppressive effector cytokine of Treg cells and modulates immune responses. However, the impact of SAP induction on Sfgl2 expression and the role of Sfgl2 in immunomodulation under SAP conditions are largely unknown., Methods: A taurocholate-induced mouse SAP model was established. The ratios of CD4 + CD25 + Foxp3 + Treg cells or CD4 + IL-17 + Th17 cells in blood and pancreatic tissues as well as surface expression of CD80, CD86, and major histocompatibility complex class II (MHC-II) were determined by flow cytometry. Gene mRNA expression was determined by qPCR. Serum amylase and soluble factors were quantitated by commercial kits. Bone marrow-derived dendritic cells (DCs) were generated, and NF-κB/p65 translocation was measured by immunofluorescence staining., Results: SAP induction in mice decreased the Th17/Treg ratio in the pancreatic tissue and increased the Th17/Treg ratio in the peripheral blood. In addition, SAP was associated with a reduced level of Sfgl2 in the pancreatic tissue and blood: higher levels of serum IL-17, IL-2, IFN-α, and TNF-α, and lower levels of serum IL-4 and IL-10. Furthermore, the SAP-induced reduction in Sfgl2 expression was accompanied by dysregulated maturation of bone marrow-derived DCs., Conclusions: SAP causes reduced Sfgl2 expression and Th17/Treg imbalance, thus providing critical insights for the development of Sfgl2- and Th17/Treg balance-targeted immunotherapies for patients with SAP., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Telomere length refers to the protective cap at the end of chromosomes, and it plays a crucial role in many diseases. The objective of this study is to explore the relationship between blood metabolites and telomere length, aiming to identify novel biological factors that influence telomere length., Methods: In this study, we extracted genome-wide association study (GWAS) data for blood metabolites from a sample of 7824 Europeans. Additionally, GWAS data for telomere length were obtained from the Open GWAS database (GWAS ID: ieu-b-4879). The primary analysis of this study utilized the random inverse variance weighted (IVW) method. Complementary analyses were also conducted using the MR-Egger and weighted median approaches. Sensitivity analyses were performed to assess the robustness of the findings. These included the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. To investigate the possibility of reverse causation, reverse MR analysis was conducted. Additionally, multivariable MR was utilized to evaluate the direct effect of metabolites on telomere length., Results: The results suggested a potential association between 15-methylpalmitate, taurocholate, levulinate, and X-12712 and telomere length. MVMR analysis further showed that 15-methylpalmitate, taurocholate, and levulinate can directly influence telomere length, regardless of other metabolites., Conclusions: This study suggests that 15-methylpalmitate, taurocholate, and levulinate are likely factors correlated with telomere length. These findings will contribute to the development of strategies for protecting telomeres, preventing related diseases, and establishing a new biological foundation for achieving healthy aging., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen Gao. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Amaranth is a dicotyledonous plant, now considered a health-promoting food. It has been rediscovered by the worldwide food industry, which is increasingly becoming aware of the many uses and benefits provided by amaranth in various food preparations. Amaranth dietary fibers, soluble and insoluble fractions, obtained from flour, protein isolate, and beverage were physicochemically characterized and their potential bile acid binding capacity was evaluated. Primary bile acids binding to fiber might contribute to a hypocholesterolemic effect, while the binding of secondary bile acids could minimize the cytotoxic effect that these metabolites exert on the colon. Amaranth fiber fractions were capable of sequestering cholate, taurocholate, deoxycholate, and bovine bile, with a percentage depending not only on the origin and the type of amaranth fiber evaluated but also on the bile acid studied. Flour fiber and the protein isolate insoluble fractions were the most efficient for binding bile and bile acids with uptake values between 29 and 100% relative to cholestyramine. Moreover, deoxycholate, a hydrophobic secondary bile acid, was the most captured by all the fractions, reaching 100% uptake with total and insoluble fibers of the three amaranth products. These results would suggest that the main effect through which amaranth fiber binds bile acids corresponds to an adsorptive effect mediated by hydrophobic interactions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Accumulation of bile acids (BAs) in hepatocytes has a role in liver disease and also in drug-induced liver injury. The constitutive androstane receptor (CAR) has been shown to protect against BA-induced liver injury. The polymorphism of CAR has recently been shown to modify the pharmacokinetics and pharmacodynamics of various drugs. Thus, it was hypothesized that polymorphism of CAR may also influence BA homeostasis. Using CAR-null and WT mice, this study modeled the potential consequences of CAR polymorphism on BA homeostasis. Our previous study showed that chemical activation of CAR decreases the total BA concentrations in livers of mice. Surprisingly the absence of CAR also decreased the BA concentrations in livers of mice, but to a lesser extent than in CAR-activated mice. Neither CAR activation nor elimination of CAR altered the biliary excretion of total BAs, but CAR activation increased the proportion of 6-OH BAs (TMCA), whereas the lack of CAR increased the excretion of taurocholic acid, TCDCA, and TDCA. Serum BA concentrations did not parallel the decrease in BA concentrations in the liver in either the mice after CAR activation or mice lacking CAR. Gene expression of BA synthesis, transporter and regulator genes were mainly similar in livers of CAR-null and WT mice. In summary, CAR activation decreases primarily the 12-OH BA concentrations in liver, whereas lack of CAR decreases the concentrations of 6-OH BAs in liver. In bile, CAR activation increases the biliary excretion of 6-OH BAs, whereas absence of CAR increases the biliary excretion of 12-OH BAs and TCDCA. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) and its hepadnavirus relatives infect a wide range of vertebrates, from fish to human. Hepadnaviruses and their hosts have a long history of acquiring adaptive mutations. However, there are no reports providing direct molecular evidence for such a coevolutionary "arms race" between hepadnaviruses and their hosts. Here, we present evidence suggesting that the adaptive evolution of the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, has been influenced by virus infection. Evolutionary analysis of the NTCPencoding genes from 20 mammals showed that most NTCP residues are highly conserved among species, exhibiting evolution under negative selection (dN/dS ratio [ratio of nonsynonymous to synonymous evolutionary changes] of <1); this observation implies that the evolution of NTCP is restricted by maintaining its original protein function. However, 0.7% of NTCP amino acid residues exhibit rapid evolution under positive selection (dN/dS ratio of >1). Notably, a substitution at amino acid (aa) 158, a positively selected residue, converting the human NTCP to a monkeytype sequence abrogated the capacity to support HBV infection; conversely, a substitution at this residue converting the monkey Ntcp to the human sequence was sufficient to confer HBV susceptibility. Together, these observations suggested a close association of the aa 158 positive selection with the pressure by virus infection. Moreover, the aa 158 sequence determined attachment of the HBV envelope protein to the host cell, demonstrating the mechanism whereby HBV infection would create positive selection at this NTCP residue. In summary, we provide the first evidence in agreement with the function of hepadnavirus as a driver for inducing adaptive mutation in host receptor. [ABSTRACT FROM AUTHOR]

A routine multiresidue method developed for the detection and quantification of veterinary drug residues in animal-based food was used to analyze sheep (ovine) liver. Unlike when working with previously validated matrices (e.g., bovine liver), some of the analytes of interest chromatographed in the form of split- or even fully baseline separated peaks. In other cases a significantly longer retention times (tR) was observed. A detailed investigation led to the elucidation of taurocholic acid as the causative agent. This compound is present in sheep liver at significantly higher concentrations than in most other animal tissues. Taurocholic acid is a zwitterionic compound and likely acts as an ion pairing agent, which modifies the selectivity of the stationary phase in a highly spatial and dynamic way. Injecting smaller volumes of matrix extract or the use of a significantly higher formic acid concentration in the mobile phase reduced or even completely eliminated the peak splitting. A more detailed examination led to the observation that the problem is not restricted to this particular matrix and extraction procedure or the used stationary phase. In fact, a higher formic acid concentration (e.g., 1.0 % versus 0.1 %) significantly improves the peak shape of many analytes present in fortified matrix samples as well as in pure standard solutions. In addition, analytical column aging was observed as being slower with a higher formic acid concentration. Finally the peak shape of analytes interacting with the metallic parts along the flow path of the liquid chromatograph was also significantly improved. Use of 0.1 % acid in mobile phases is often taken for granted in LC-MS. Regardless of the stationary phase, a higher ionic strength better stabilizes the pH and reduces unwanted interactions, which ultimately improves the method robustness. Flow injection experiments often show that 0.1 % acid concentrations produce the highest analyte signals. Yet, the use of 1 % acid in the mobile phase often leads to narrower and therefore taller chromatographic peaks, which may lead to lower detection limits for many analytes and to an improved separation efficiency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The evolutionary origins of sexual preferences for chemical signals remain poorly understood, due, in part, to scant information on the molecules involved. In the current study, we identified a male pheromone in lake char (Salvelinus namaycush) to evaluate the hypothesis that it exploits a non-sexual preference for juvenile odour. In anadromous char species, the odour of stream-resident juveniles guides migratory adults into spawning streams. Lake char are also attracted to juvenile odour but have lost the anadromous phenotype and spawn on nearshore reefs, where juvenile odour does not persist long enough to act as a cue for spawning site selection by adults. Previous behavioural data raised the possibility that males release a pheromone that includes components of juvenile odour. Using metabolomics, we found that the most abundant molecule released by males was also released by juveniles but not females. Tandem mass spectrometry and nuclear magnetic resonance were used to identify the molecule as taurocholic acid (TCA), which was previously implicated as a component of juvenile odour. Additional chemical analyses revealed that males release TCA at high rates via their urine during the spawning season. Finally, picomolar concentrations of TCA attracted pre-spawning and spawning females but not males. Taken together, our results indicate that male lake char release TCA as a mating pheromone and support the hypothesis that the pheromone is a partial match of juvenile odour., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Bile acid diarrhoea is often missed because gold standard nuclear medicine tauroselcholic [75-Se] acid (SeHCAT) testing has limited availability. Empirical treatment effect has unknown diagnostic performance, whereas plasma 7α-hydroxy-4-cholesten-3-one (C4) is inexpensive but lacks sensitivity., Aims: To determine diagnostic characteristics of empirical treatment and explore improvements in diagnostics with potential better availability than SeHCAT., Methods: This diagnostic accuracy study was part of a randomised, placebo-controlled trial of colesevelam. Consecutive patients with chronic diarrhoea attending SeHCAT had blood and stool sampled. Key thresholds were C4 > 46 ng/mL and SeHCAT retention ≤10%. A questionnaire recorded patient-reported empirical treatment effect. We analysed receiver operating characteristics and explored machine learning applied logistic regression and decision tree modelling with internal validation., Results: Ninety-six (38%) of 251 patients had SeHCAT retention ≤10%. The effect of empirical treatment assessed with test results for bile acid studies blinded had 63% (95% confidence interval 44%-79%) sensitivity and 65% (47%-80%) specificity; C4 > 46 ng/mL had 47% (37%-57%) and 92% (87%-96%), respectively. A decision tree combining C4 ≥ 31 ng/mL with ≥1.1 daily watery stools (Bristol type 6 and 7) had 70% (51%-85%) sensitivity and 95% (83%-99%) specificity. The logistic regression model, including C4, the sum of measured stool bile acids and daily watery stools, had 77% (58%-90%) sensitivity and 93% (80%-98%) specificity., Conclusions: Diagnosis of bile acid diarrhoea using empirical treatment was inadequate. Exploration suggested considerable improvements in the sensitivity of C4-based testing, offering potential widely available diagnostics. Further validation is warranted., Clinicaltrials: gov: NCT03876717., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

To investigate the mechanism of pancreatic alveolar cell autophagy in rats with severe acute pancreatitis (SAP) by phillygenin (PHI) based on the PI3K/Akt/mToR pathway. Rats were randomly divided into control group (CON group), SAP model group (SAP group) and PHI treatment group (SAP+PHI group), with 10 rats in each group. 5% sodium taurocholate was injected retrogradely into the biliopancreatic duct to establish a SAP rat model, and PHI was injected intraperitoneally into the pancreas after successful establishment of the model. The colorimetric assay was used to determine serum amylase and lipase activity levels. Pancreatic morphology and histological changes were assessed by H&E staining. Autophagy-related indices were determined by immunohistochemistry: LC3-II, P62, LAMP. Autophagy pathway-related indices were determined by western blotting assay: p-PI3K, PI3K, p-Akt, Akt, p-mToR, mToR. Autophagy vesicle alteration. Compared with the SAP group, the SAP+PHI group showed a decrease in amylase, lipase and pathological score, an increase in the expression of LAMP-2, and a decrease in the expression of p62, p-PI3K, p-Akt and p-mToR, with a statistically significant difference ( p  < 0.05). Electron microscopy showed that autophagic flux was restored and accumulated autophagic vehicles were relatively reduced by PHI intervention. PHI can rescue the impaired autophagic flux by inhibiting the PI3K/Akt/mToR pathway, allowing abnormal autophagic vesicles to complete autophagy to protect the rat., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Graphical abstract Abstract Oral siRNA delivery is an ideal way to translate siRNA therapeutic effects in the clinic due to its ability to be administered in convenient and multiple dosages. However, an effective oral delivery system requires overcoming both a hostile gastrointestinal (GI) environment and non-specific targeting. Here, an HTsRP-NC system is a new oral siRNA delivery system consisting of a siRNA/protamine (sRP) nano-complex protected by a multi-functional hyaluronic acid-taurocholic acid (HA-TCA) conjugate. The HTsRP-NC promotes cell penetration and enhances endosomal escape in cancer cells. Moreover, protection of the sRP by HA-TCA from the hostile GI environment helps the AKT siRNA complex to reach the liver through the utilization of a TCA-mediated enterohepatic bile acid recycling system. AKT siRNA was released by 90% in presence of hyaluronidase in the tumor cells which indicate the potential use of HTsRP-NCs for siRNA delivery to treat tumor. After HA receptor (CD44)-mediated cellular uptake of the HTsRP-NC by the liver cancer cells, functional expression of AKT siRNA leads to the suppression of metastatic liver cancer growth in a colorectal liver metastasis (CLM) murine model. Tumor nodules were reduced by more than 1 mm size compared to control group and tumor cells were suppressed by 50% after HTsRP-NCs treatment with AKT siRNA. Overall, oral administration of the HTsRP-NC supports its potential in therapeutic applications for the effective treatment of CLM. [ABSTRACT FROM AUTHOR]

Graphical abstract The mechanism of SRT1720. In sodium taurocholate-induced acute pancreatitis, SRT1720 reduces inflammatory reaction by suppressing NF-κB signalling. SIRT1 was over-expressed after SRT1720 injection. Then followed by the down-regulation of p65 and up-regulation of IκBα, in addition, p-P65 decreased the expression. The suppression of NF-κB signalling leads to a decrease in proinflammatory cytokines such as IL-6 and TNF-α released by inflammatory cells, resulting in a reduction in inflammation. Highlights • SRT1720 is a SIRT1 activator that exerts multiple pharmacological activities. • SIRT1 expression level is impaired in rats with severe acute pancreatitis (SAP). • SRT1720 protects rats from sodium taurocholate-induced SAP. • SRT1720 suppresses the NF-κB signalling pathway in rat model of SAP. • SIRT1 activators may represent a new class of therapeutics for SAP. Abstract Severe acute pancreatitis (SAP) is a medical emergency that is often associated with multiple organ failure and high mortality. Although an SAP diagnosis requires prompt treatment, therapeutic options remain limited. SRT1720 is a newly formulatedSIRT1 activator that exerts multiple pharmacological activities with beneficial health effects. However, its potential as an SAP treatment has not been explored. The current study assessed the effect of SRT1720 on a rat model of sodium taurocholate-induced SAP and explored the underlying mechanism. SAP was induced in rats by retrograde injection of a 3.5% sodium taurocholate solution (1 ml/kg) in the biliopancreatic duct. SRT1720 (5 mg/kg) was administered intraperitoneally after sodium taurocholate exposure. Serum samples were analysed for inflammatory cytokine levels and select enzymatic activities using the enzyme-linked immunosorbent assay and commercial enzyme activity assay kits, respectively; protein expression levels were evaluated by western blotting; mRNA levels of biomarkers were determined by quantitative real-time PCR; histopathological changes were analysed by haematoxylin and eosin staining and immunohistochemistry.SRT1720 treatment significantly reduced serum amylase, lipase, pancreatic histological scores, proinflammatory cytokine (TNF-α and IL-6) levels, and expression of NF-κB and p65 in sodium taurocholate-induced SAP rats. Importantly, the treatment stimulated SIRT1 and IκBα levels in pancreatic tissue. Our data suggest that SRT1720 protects rats from sodium taurocholate-induced SAP by suppressing the NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]