Bile acids regulation of cellular stress responses in liver physiology and diseases.

Bile acids are physiological detergents and signalling molecules that are critically implicated in liver health and diseases. Dysregulation of bile acid homeostasis alters cell function and causes cell injury in chronic liver diseases. Therapeutic agents targeting bile acid synthesis, transport and signalling hold great potential for treatment of chronic liver diseases. The broad cellular and physiological impacts of pharmacological manipulations of bile acid metabolism are still incompletely understood. Recent research has discovered new links of bile acid signalling to the regulation of autophagy and lysosome biology, redox homeostasis and endoplasmic reticulum stress. These are well-conserved mechanisms that allow cells to adapt to nutrient and organelle stresses and play critical roles in maintaining cellular integrity and promoting survival. However, dysregulation of these cellular pathways is often observed in chronic liver diseases, which exacerbates cellular dysfunction to contribute to disease pathogenesis. Therefore, identification of these novel links has significantly advanced our knowledge of bile acid biology and physiology, which is needed to understand the contributions of bile acid dysregulation in disease pathogenesis, establish bile acids as diagnostic markers and develop bile acid-based pharmacological interventions. In this review, we will first discuss the roles of bile acid dysregulation in the pathogenesis of chronic liver diseases, and then discuss the recent findings on the crosstalk of bile acid signalling and cellular stress responses. Future investigations are needed to better define the roles of these crosstalks in regulating cellular function and disease processes.

Bile acid signaling in metabolic and inflammatory diseases and drug development.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity, and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), type-2 diabetes, and inflammatory bowel diseases (IBD). Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. Significance Statement Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling hold promise for treating metabolic and inflammatory diseases.

Sodium Tanshinone IIA Sulfonate Protects Primary Cardiomyocytes Against Radiation-Induced Myocardial Injury via the p38 Pathway.

Sodium tanshinone IIA sulfonate (STS), which is extracted from a Chinese medicinal herb, possesses many pharmacologic functions, such as coronary dilation, anti-inflammatory properties, and antiapoptotic and antioxidant effects. It remains unknown whether STS can protect cardiomyocytes injured after radiation therapy. An in vitro Sprague-Dawley (SD) rat neonatal cardiomyocyte system was established. Primary cardiomyocytes (PCMs) from neonatal SD rats were isolated under sterile conditions. PCM cells were divided into a control group (0 Gy/hour) and 5 experimental radiation therapy groups (0.25 Gy/hour, 0.5 Gy/hour, 1 Gy/hour, 2 Gy/hour, and 4 Gy/hour). Cell viability, the content of malondialdehyde (MDA), the lactate dehydrogenase (LDH) leakage rate, and superoxide dismutase (SOD) and glutathione (GSH) activities were recorded separately in each group after 7 days of culture. Western blot was used to detect the levels of p38, caspase-3 protein, and X protein (BAX) associated with B-cell lymphoma 2 (Bcl-2) in PCMs. X-rays inhibited cell growth, decreased cell viability, and induced an oxidative stress response in PCMs. STS and SB203580 (the inhibitor of P38 mitogen-activated protein kinase pathway) alleviated X-ray-induced damage to PCMs. An enzyme-linked immunosorbent assay showed that X-rays increased the cTnT level. STS and SB203580 ameliorated the X-ray-induced increase in cTnT leakage. X-rays enhanced the expression of p38/p-p38 and caspase-3 while reducing the expression of Bcl-2/BAX in PCMs, as demonstrated by western blotting. STS and SB203580 mitigated the changes in protein expression triggered by X-ray radiation. In conclusions, STS was shown to exert significant cardioprotective, anti-inflammatory, and antioxidant effects in PCMs by inhibiting the p38 mitogen-activated protein kinase pathway.

Adherence to the dietary approaches to stop hypertension diet reduces the risk of diabetes mellitus: a systematic review and dose-response meta-analysis.

BACKGROUND: Despite several epidemiological studies reporting a significant association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and the risk of diabetes mellitus, the results remain controversial. In this systematic review and meta-analysis, we aimed to summarize the existing evidence from published observational studies and evaluate the dose-response relationship between adherence to the DASH diet and diabetes mellitus risk. METHODS: We performed a systematic search for relevant articles published up to September 2023 using electronic databases of PubMed, Embase, Scopus, and China National Knowledge Infrastructure (CNKI). A random-effects model was applied to calculate the combined relative risks (RR) with 95% confidence intervals (CIs) for the highest compared to the lowest categories of DASH score in relation to diabetes mellitus risk. Heterogeneity among the included studies was assessed using the Cochran's Q test and I-squared (I2) statistic. Literature search, study selection, data extraction, and quality assessment were performed by two independent reviewers. RESULTS: Fifteen studies involving 557,475 participants and 57,064 diabetes mellitus cases were eligible for our analyses. Pooled analyses from included studies showed that high adherence to the DASH diet was significantly associated with a reduced risk of diabetes mellitus (RR: 0.82; 95% CI: 0.76-0.90, P < 0.001). Moreover, the dose-response meta-analysis revealed a linear trend between adherence to the DASH diet and diabetes mellitus (RR:0.99; 95%CI: 0.97-1.02, Pdose-response = 0.546, Pnonlinearity = 0.701). Subgroup analyses further revealed a significant inverse association between adherence to the DASH diet and diabetes mellitus risk in case-control studies (RR: 0.65; 95%CI: 0.29-1.43, P < 0.001), with a marginal inverse association in cohort studies (RR:0.83; 95%CI: 0.76-0.91, P < 0.001). Additionally, we conducted analyses separately by comparison and found a significant inverse association between DASH diet and diabetes mellitus risk in T3 vs T1 comparison studies (RR = 0.74; 95%CI: 0.64-0.86, P = 0.012). CONCLUSION: The findings of this study demonstrate a protective association between adherence to the DASH diet and risk of diabetes mellitus. However, further prospective cohort studies and randomized controlled trials are needed to validate these findings.

Prenatal diagnosis of interrupted aortic arch using high-definition flow render mode and spatiotemporal image correlation.

OBJECTIVES: To evaluate the clinical utility of two dimensional (2D) ultrasound combined with spatiotemporal image correlation (STIC) in diagnosing interrupted aortic arch (IAA) in fetal life. METHODS: A total of 53 cases of fetal IAA were diagnosed using 2D ultrasound combined with STIC, and 53 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to assess the utility of employing 2D ultrasound combined with STIC in the diagnosis of IAA. RESULTS: 2D ultrasound combined with STIC detected 22 cases of type A IAA, 24 cases of type B IAA, and seven cases of type C IAA. Furthermore, combining 2D ultrasound with STIC enabled dynamic visualization of the IAA, aiding in prenatal diagnosis. The diagnostic coincidence rate of IAA was found to be higher in the HD-flow combined with STIC than that in the 2D combined with HD-flow. CONCLUSION: HD-flow combined with STIC can assist in diagnosing fetal IAA, and this technique has important clinical value.

Cullin 3 RING E3 ligase inactivation causes NRF2-dependent NADH reductive stress, hepatic lipodystrophy, and systemic insulin resistance.

Cullin RING E3 ligases (CRL) have emerged as key regulators of disease-modifying pathways and therapeutic targets. Cullin3 (Cul3)-containing CRL (CRL3) has been implicated in regulating hepatic insulin and oxidative stress signaling. However, CRL3 function in liver pathophysiology is poorly defined. Here, we report that hepatocyte Cul3 knockout results in rapid resolution of steatosis in obese mice. However, the remarkable resistance of hepatocyte Cul3 knockout mice to developing steatosis does not lead to overall metabolic improvement but causes systemic metabolic disturbances. Liver transcriptomics analysis identifies that CRL3 inactivation causes persistent activation of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant defense pathway, which also reprograms the lipid transcriptional network to prevent TG storage. Furthermore, global metabolomics reveals that NRF2 activation induces numerous NAD+-consuming aldehyde dehydrogenases to increase the cellular NADH/NAD+ ratio, a redox imbalance termed NADH reductive stress that inhibits the glycolysis-citrate-lipogenesis axis in Cul3 knockout livers. As a result, this NRF2-induced cellular lipid storage defect promotes hepatic ceramide accumulation, elevates circulating fatty acids, and worsens systemic insulin resistance in a vicious cycle. Hepatic lipid accumulation is restored, and liver injury and hyperglycemia are attenuated when NRF2 activation and NADH reductive stress are abolished in hepatocyte Cul3/Nrf2 double-knockout mice. The resistance to hepatic steatosis, hyperglycemia, and NADH reductive stress are observed in hepatocyte Keap1 knockout mice with NRF2 activation. In summary, our study defines a critical role of CRL3 in hepatic metabolic regulation and demonstrates that the CRL3 downstream NRF2 overactivation causes hepatic metabolic maladaptation to obesity and insulin resistance.

Ultrasonic Diagnosis of Congenital Enterocolitis Fistula: A Case Report.

Background: Congenital enterocolic fistula, an abnormal connection between the small intestine and the colon, is a rare condition with the potential for significant complications affecting the patient's quality of life. Case Report: A 2 year and 7 months old girl presented with abdominal pain and diarrhea lasting more than 10 days. The formation of the intestinal fistula was first detected by ultrasound, and the blood flow in the intestinal wall was preliminally analyzed. Surgical exploration revealed a colonic fistula formed by the attachment of the jejunum to the descending colon. Postoperatively, symptoms improved; no secondary infection occurred and the fistula healed well. Conclusion: Congenital colon fistula is rarely reported, and ultrasound is becoming more and more important in its diagnosis. Here, we report a case of congenital colonic fistula diagnosed by ultrasound. Ultrasound can dynamically and in real-time observe the intestinal condition, which is conducive to the early diagnosis and staging of congenital intestinal diseases and the determination of diagnosis and treatment schemes.

Deletion of hepatocyte cysteine dioxygenase type 1, a bile acid repressed gene, enhances glutathione synthesis and ameliorates acetaminophen hepatotoxicity.

Liver is a major organ that metabolizes sulfur amino acids cysteine, which is the substrate for the synthesis of many essential cellular molecules including GSH, taurine, and coenzyme A. Bile acid-activated farnesoid x receptor (FXR) inhibits cysteine dioxygenase type 1 (CDO1), which mediates hepatic cysteine catabolism and taurine synthesis. To define the impact of bile acid inhibition of CDO1 on hepatic sulfur amino acid metabolism and antioxidant capacity, we developed hepatocyte-specific CDO1 knockout mice (Hep-CDO1 KO) and hepatocyte specific CDO1 transgenic mice (Hep-CDO1 Tg). Liver metabolomics revealed that genetic deletion of hepatic CDO1 reduced de novo taurine synthesis but had no impact on hepatic taurine abundance or bile acid conjugation. Consistent with reduced cysteine catabolism, Hep-CDO1 KO mice showed increased hepatic cysteine abundance but unaltered methionine cycle intermediates and coenzyme A synthesis. Upon acetaminophen overdose, Hep-CDO1 KO mice showed increased GSH synthesis capacity and alleviated liver injury. In contrast, hepatic CDO1 overexpression in Hep-CDO1 Tg mice stimulated hepatic cysteine to taurine conversion, resulting in reduced hepatic cysteine abundance. However, Hep-CDO1 Tg mice and WT showed similar susceptibility to acetaminophen-induced liver injury. Hep-CDO1 Tg mice showed similar hepatic taurine and coenzyme A compared to WT mice. In summary, these findings suggest that bile acid and FXR signaling inhibition of CDO1-mediated hepatic cysteine catabolism preferentially modulates hepatic GSH synthesis capacity and antioxidant defense, but has minimal effect on hepatic taurine and coenzyme A abundance. Repression of hepatic CDO1 may contribute to the hepatoprotective effects of FXR activation under certain pathologic conditions.

Targeting iron-metabolism:a potential therapeutic strategy for pulmonary fibrosis.

Iron homeostasisis is integral to normal physiological and biochemical processes of lungs. The maintenance of iron homeostasis involves the process of intake, storage and output, dependening on iron-regulated protein/iron response element system to operate tightly metabolism-related genes, including TFR1, DMT1, Fth, and FPN. Dysregulation of iron can lead to iron overload, which increases the virulence of microbial colonisers and the occurrence of oxidative stress, causing alveolar epithelial cells to undergo necrosis and apoptosis, and form extracellular matrix. Accumulated iron drive iron-dependent ferroptosis to exacerbated pulmonary fibrosis. Notably, the iron chelator deferoxamine and the lipophilic antioxidant ferritin-1 have been shown to attenuate ferroptosis and inhibit lipid peroxidation in pulmonary fibrosis. The paper summarises the regulatory mechanisms of dysregulated iron metabolism and ferroptosis in the development of pulmonary fibrosis. Targeting iron metabolism may be a potential therapeutic strategy for the prevention and treatment of pulmonary fibrosis.

Prenatal Ultrasound Diagnosis of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome with Persistent Hyperplastic Primary Vitreous: A Case Report.

INTRODUCTION: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare autosomal dominant disorder characterized by megalencephaly (i.e., overgrowth of the brain), polymicrogyria, focal hypoplasia of the cerebral cortex, and polydactyly. Persistent hyperplastic primary vitreous (PHPV) involves a spectrum of congenital ocular abnormalities that are characterized by the presence of a vascular membrane behind the lens. CASE PRESENTATION: Here, we present a case of foetal MPPH with PHPV that was diagnosed using prenatal ultrasound. Ultrasound revealed the presence of megalencephaly, multiple cerebellar gyri, and hydrocephalus. Whole-exome sequencing confirmed the mutation of the AKT3 gene, which led to the consideration of MPPH syndrome. Moreover, an echogenic band with an irregular surface was observed between the lens and the posterior wall of the left eye; therefore, MPPH with PHPV was suspected. CONCLUSION: MPPH syndrome with PHPV can be diagnosed prenatally.

Astragalus polysaccharide protects experimental colitis through an aryl hydrocarbon receptor-dependent autophagy mechanism.

BACKGROUND AND PURPOSE: Disruption of intestinal barriers plays a vital role in the pathogenesis of colitis. The aryl hydrocarbon receptor (AhR) is a recognition sensor that mediates intestinal immune homeostasis and minimizes intestinal inflammation. Astragalus polysaccharide (APS) exerts pharmacological actions in colitis; however, the mechanism has not been elucidated. We investigated whether APS protects through AhR-dependent autophagy. EXPERIMENTAL APPROACH: The symptoms of dextran sulfate sodium (DSS)-induced colitis in mice involving intestinal barrier function and inflammatory injury were evaluated after APS administration. Intestinal-specific Becn1 conditional knockout (Becn1 cKO) mice were constructed and compared with wild-type mice. Autophagy and the effects of APS were investigated after the deactivation of AhRs. The relationship between APS-induced AhRs and autophagic Becn1 was investigated using a dual-luciferase reporter system and chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction assay. Caco-2 cells were used to investigate inflammatory responses and AhR-dependent autophagy. KEY RESULTS: APS improved intestinal barrier function in inflammatory injury in colitis mice. APS triggered autophagic flow; however, knockout of Becn1 in the gut increased susceptibility to colitis, leading to diminished epithelial barrier function and severe intestinal inflammation, impairing the protective effects of APS. Mechanistically, APS-triggered autophagy depends on AhR expression. Activated AhR binds to the promoter Becn1 to operate transcription of genes involved in anti-inflammation and intestinal barrier repair, while deactivation of AhR correlated with intestinal inflammation and the therapeutic function of APS. CONCLUSIONS AND IMPLICATIONS: APS protects colitis mice by targeting autophagy, especially as the AhR stimulates the repair of damaged intestinal barrier functions.

Molecular mechanism of Xiaohuoluo wan for rheumatoid arthritis by integrating in vitro and in vivo chemomics and network pharmacology.

The cause of rheumatoid arthritis (RA) is unclear. Xiaohuoluo wan (XHLW) is a classical Chinese medicine that is particularly effective in the treatment of RA. Given the chemical composition of XHLW at the overall level has been little studied and the molecular mechanism for the treatment of RA is not clear, we searched for the potential active compounds of XHLW and explored their anti-inflammatory mechanism in the treatment of RA by flexibly integrating the high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based in vitro and in vivo chemomics, network pharmacology, and other means. The results of the study identified that the active compounds of XHLW, such as alkaloids, nucleosides, and fatty acids, may play an anti-inflammatory role by regulating key targets such as IL-2, STAT1, JAK3, and MAPK8, inducing immune response through IL-17 signaling pathway, T-cell receptor, FoxO, tumor necrosis factor (TNF), and so forth, inhibiting the release of inflammatory factors and resisting oxidative stress and other pathways to treat RA. The results of this study provide referable data for the screening of active compounds and the exploration of molecular mechanisms of XHLW in the treatment of RA.

Confusion from prenatal diagnosis: Type C persistent fifth aortic arch or right-side ductus arteriosus.

We described a case of a double aortic arch (DAA) with a subaortic left brachiocephalic vein (LBCV) and right-side ductus arteriosus using high-definition (HD) flow render mode and spatiotemporal image correlation (STIC). We experienced uncertainty regarding this interesting case despite the diagnosis of right-sided ductus arteriosus. The ductus arteriosus originates from the right pulmonary artery (PA) and converges into the descending aorta (DAO), whereas the vessel originated from the PA and converged into the ascending aorta (AAO). Therefore, we assumed that the vessel connecting the PA to AAO may be a type-C persistent fifth aortic arch (PFAA).

Clinical value of prenatal ultrasound in diagnosis and classification of common arterial trunk.

OBJECTIVES: To investigate the clinical value of prenatal ultrasound in the diagnosis of the common arterial trunk (CAT) classification and associated malformations. MATERIALS AND METHODS: The 2D ultrasound images, spatiotemporal image correlations (STICs) and clinical data of 88 fetuses diagnosed with CAT malformations by prenatal ultrasound were retrospectively analyzed and classified. The correlation between different types, fetal malformation and pregnancy outcomes were analyzed. RESULTS: Among the 88 fetuses, there were 39 cases (44.32%) of type A1, 40 cases (45.45%) of type A2, 8 cases (9.09%) of type A3, and 1 case of type A4 (1.14%). There were 16 cases (18.18%) with isolated CAT, 48 cases (54.55%) with complex intra-cardiac structural abnormalities, and 24 cases (27.27%) with intra-cardiac and extra-cardiac structural abnormalities. In extra-cardiac structural malformations, 14 cases were associated with 1 other system abnormality, 4 cases with 2 other system abnormalities, 3 cases with 3 other system abnormalities, while 3 cases were combined with 4 other system abnormalities, among which the facial and physical abnormalities had the highest incidence (39.13%). The STIC images were completely displayed in all 88 cases. There was a statistical difference between isolated CAT and CAT combined with other abnormalities in fetal pregnancy outcomes. CONCLUSIONS: Prenatal ultrasound had a high clinical application value in CAT classification. Pregnancy outcomes were highly correlated with the classification and associated intra-cardiac and extra-cardiac structural malformations. The early evaluation of fetal prognosis before birth has important value for clinical intervention.

Glycine-ß-Muricholic Acid Improves Liver Fibrosis and Gut Barrier Function by Reducing Bile Acid Pool Size and Hydrophobicity in Male Cyp2c70 Knockout Mice.

Cyp2c70 knockout mice lack the enzyme that produces muricholic acids and show a "human-like" hydrophobic bile acid pool-induced hepatobiliary injury. In this study, we investigated the potential anti-cholestasis effect of glycine-conjugated ß muricholic acid (G-ß-MCA) in male Cyp2c70 KO mice based on its hydrophilic physiochemical property and signaling property as an farnesoid X receptor (FXR) antagonist. Our results showed that G-ß-MCA treatment for 5 weeks alleviated ductular reaction and liver fibrosis and improved gut barrier function. Analysis of bile acid metabolism suggested that exogenously administered G-ß-MCA was poorly absorbed in the small intestine and mostly deconjugated in the large intestine and converted to taurine-conjugated MCA (T-MCA) in the liver, leading to T-MCA enrichment in the bile and small intestine. These changes decreased the biliary and intestine bile acid hydrophobicity index. Furthermore, G-ß-MCA treatment decreased intestine bile acid absorption via unknown mechanisms, resulting in increased fecal bile acid excretion and a reduction in total bile acid pool size. In conclusion, G-ß-MCA treatment reduces the bile acid pool size and hydrophobicity and improves liver fibrosis and gut barrier function in Cyp2c70 KO mice.