Modulatory effects of bisphenol A on the hepatic immune response.

The liver is a primary line of defense for protection from external substances next to the intestinal barrier. As a result, the hepatic immune system plays a central role in liver pathophysiology. Bisphenol A (BPA) is one of the most common endocrine disrupting chemicals and is primarily metabolized in the liver. Due to its ability to bind to estrogen receptors, BPA is well known to possess estrogenic activity and disrupt reproductive functions. The phase I and Phase II metabolism reactions of BPA mainly occur in the liver with the help of enzymes including cytochrome P450 (CYP), uridine 5'-diphospho-glucuronosyltransferase-glucuronosyltransferases, sulfotransferases, and glutathione-S-transferases. Although the majority of BPA is excreted after conjugation by these enzymes, untransformed BPA induces the production of reactive oxygen species through disruption of the enzymatic complex CYP, lipid accumulation, mitochondrial dysfunction, endoplasmic reticulum stress and inflammatory injury in the liver. Moreover, it has been proposed to possess a potential immunomodulatory effect. Indeed, several in vivo and in vitro studies have reported that low doses of BPA increase the population of T cells with type 1 T helper (Th1), Th2, and Th17 cells. Although the current literature lacks clear evidence on the mechanisms by which BPA is involved in T cell mediated immune responses, recent multi-omics studies suggest that it may directly interact with the antigen processing and presentation pathways. In this review, we first discuss the metabolism of BPA in the liver, before exploring currently available data on its effects on liver injury. Finally, we review its modulatory effects on the hepatic immune response, as well as potential mechanisms. By conducting this review, we aim to improve understanding on the relationship between BPA exposure and immune-related liver injury, with a focus on the antigen processing and presentation pathway and T cell-mediated response in the liver.

The Identification and Quantitative Analysis of Unusual Keto-Carotenoids in Ripe Fruits of Maclura tricuspidate and Its Potential as a Valuable Source of Cryptocapsin.

Ripe fruits of Maclura tricuspidata (MT) are used as food material and a natural colorant in Korea. Although MT fruits have a deep red color due to carotenoid-like pigments, their chemical nature has not been explored in detail so far. The present study aimed at elucidating the chemical structures and composition of carotenoids in MT fruits and changes at different maturity stages. Two carotenoids from saponified MT fruit extract were isolated using repeated silica gel column chromatography. Based on interpretations of spectroscopic data, these compounds were determined as keto-carotenoids, i.e., capsanthin (3,3'-dihydroxy-ß,κ-caroten-6'-one) and cryptocapsin (3'-hydroxy-ß,κ-caroten-6'-one), and the contents of individual carotenoids were quantified with HPLC based on calibration curves obtained from authentic standards. The contents of capsanthin and cryptocapsin in the sample of saponified MT fruits were 57.65 ± 1.97 µg/g and 171.66 ± 4.85 µg/g as dry weight base (dw). The majority of these keto-carotenoids in the MT fruits were present in esterified forms with lauric, myristic or palmitic acid rather than in their free forms. The results also showed that esterification of these compounds occurred starting from early stage (yellow-brownish stage) of maturation. Considering the high cryptocapsin content, MT fruits can be applied as a potentially valuable source of cryptocapsin for food and medicinal application as well as a source of provitamin A.

Gut Microbiome in Non-Alcoholic Fatty Liver Disease: From Mechanisms to Therapeutic Role.

Non-alcoholic fatty liver disease (NAFLD) is considered to be a significant health threat globally, and has attracted growing concern in the research field of liver diseases. NAFLD comprises multifarious fatty degenerative disorders in the liver, including simple steatosis, steatohepatitis and fibrosis. The fundamental pathophysiology of NAFLD is complex and multifactor-driven. In addition to viruses, metabolic syndrome and alcohol, evidence has recently indicated that the microbiome is related to the development and progression of NAFLD. In this review, we summarize the possible microbiota-based therapeutic approaches and highlight the importance of establishing the diagnosis of NAFLD through the different spectra of the disease via the gut-liver axis.

The Lactobacillus as a Probiotic: Focusing on Liver Diseases.

Over the past decade, scientific evidence for the properties, functions, and beneficial effects of probiotics for humans has continued to accumulate. Interest in the use of probiotics for humans has increased tremendously. Among various microorganisms, probiotics using bacteria have been widely studied and commercialized, and, among them, Lactobacillus is representative. This genus contains about 300 species of bacteria (recently differentiated into 23 genera) and countless strains have been reported. They improved a wide range of diseases including liver disease, gastrointestinal diseases, respiratory diseases, and autoimmune diseases. Here, we intend to discuss in depth the genus Lactobacillus as a representative probiotic for chronic liver diseases.

Identification of Novel Parishin Compounds from the Twig of Maclura tricuspidata and Comparative Analysis of Parishin Derivatives in Different Parts.

Parishin compounds are rare polyphenolic glucosides mainly found in the rhizome of the traditional Chinese medicinal plant, Gastrodia elata. These constituents are reported to have several biological and pharmacological activities. In the present study, two novel parishin derivatives not previously reported as plant-based phytochemicals were identified from a twig of Maclura tricuspidata (MT) and two new compounds were elucidated as 1-(4-(ß-d-glucopyranosyloxy)benzyl)-3-hydroxy-3-methylpentane-1,5-dioate (named macluraparishin E) and 1,3-bis(4-(ß-d-glucopyranosyloxy)benzyl)-3-hydroxy-3-methylpentane- 1,5-dioate (macluraparishin C), based on the experimental data obtained by UV-Visible (UV-Vis) spectroscopy, high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) and nuclear magnetic resonance (NMR) spectroscopy. Additionally, gastrodin, parishin A and parishin B were positively identified by spectroscopic evidence and the comparison of HPLC retention time with the corresponding authentic standards. Gastrodin, parishin A and parishin B, macluraparishin E and macluraparishin C were found to be the most abundant constituents in the MT twig. The compositions and contents of these constituents were found to vary depending on the different parts of the MT plant. In particular, the contents of parishin A, parishin B, macluraparishin C and macluraparishin E were higher in the twig, bark and root than in the leaves, xylem and fruit.

T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.

Gut Microbiota-Related Cellular and Molecular Mechanisms in the Progression of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common and increasing liver diseases worldwide. NAFLD is a term that involves a variety of conditions such as fatty liver, steatohepatitis, or fibrosis. Gut microbiota and its products have been extensively studied because of a close relation between NAFLD and microbiota in pathogenesis. In the progression of NAFLD, various microbiota-related molecular and cellular mechanisms, including dysbiosis, leaky bowel, endotoxin, bile acids enterohepatic circulation, metabolites, or alcohol-producing microbiota, are involved. Currently, diagnosis and treatment techniques using these mechanisms are being developed. In this review, we will introduce the microbiota-related mechanisms in the progression of NAFLD and future directions will be discussed.

The Gut Microbiota-Derived Immune Response in Chronic Liver Disease.

In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut-liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.

Production of Minor Ginsenosides C-K and C-Y from Naturally Occurring Major Ginsenosides Using Crude ß-Glucosidase Preparation from Submerged Culture of Fomitella fraxinea.

Minor ginsenosides, such as compounds (C)-K and C-Y, possess relatively better bioactivity than those of naturally occurring major ginsenosides. Therefore, this study focused on the biotransformation of major ginsenosides into minor ginsenosides using crude ß-glucosidase preparation isolated from submerged liquid culture of Fomitella fraxinea (FFEP). FFEP was prepared by ammonium sulfate (30-80%) precipitation from submerged culture of F. fraxinea. FFEP was used to prepare minor ginsenosides from protopanaxadiol (PPD)-type ginsenoside (PPDG-F) or total ginsenoside fraction (TG-F). In addition, biotransformation of major ginsenosides into minor ginsenosides as affected by reaction time and pH were investigated by TLC and HPLC analyses, and the metabolites were also identified by UPLC/negative-ESI-Q-TOF-MS analysis. FFEP biotransformed ginsenosides Rb1 and Rc into C-K via the following pathways: Rd → F2 → C-K for Rb1 and both Rd → F2→ C-K and C-Mc1 → C-Mc → C-K for Rc, respectively, while C-Y is formed from Rb2 via C-O. FFEP can be applied to produce minor ginsenosides C-K and C-Y from PPDG-F or TG-F. To the best of our knowledge, this study is the first to report the production of C-K and C-Y from major ginsenosides by basidiomycete F. fraxinea.

Pathophysiological Roles of Mucosal-Associated Invariant T Cells in the Context of Gut Microbiota-Liver Axis.

Mucosal-associated invariant T (MAIT) cells are a subset of T lymphocytes expressing a semi-invariant T-cell receptor (TCR) present as TCR Vα7.2-Jα33 in humans and TCR Vα19-Jα33 in mice. They are activated by ligands produced during microbial biosynthesis of riboflavin that is presented by major histocompatibility complex class I-related (MR1) molecules on antigen-presenting cells. MAIT cells also possess interleukin (IL)-12 and IL-18 receptors and can be activated by the respective cytokines released from microbially stimulated antigen-presenting cells. Therefore, MAIT cells can be involved in bacterial and viral defenses and are a significant part of the human immune system. They are particularly abundant in the liver, an organ serving as the second firewall of gut microbes next to the intestinal barrier. Therefore, the immune functions of MAIT cells are greatly impacted by changes in the gut-microbiota and play important roles in the gut-liver pathogenesis axis. In this review, we discuss the nature and mechanisms of MAIT cell activation and their dynamics during different types of liver pathogenesis conditions. We also share our perspectives on important aspects that should be explored further to reveal the exact roles that MAIT cells play in liver pathogenesis in the context of the gut microbiota.

Recent Advances of Microbiome-Associated Metabolomics Profiling in Liver Disease: Principles, Mechanisms, and Applications.

Advances in high-throughput screening of metabolic stability in liver and gut microbiota are able to identify and quantify small-molecule metabolites (metabolome) in different cellular microenvironments that are closest to their phenotypes. Metagenomics and metabolomics are largely recognized to be the "-omics" disciplines for clinical therapeutic screening. Here, metabolomics activity screening in liver disease (LD) and gut microbiomes has significantly delivered the integration of metabolomics data (i.e., a set of endogenous metabolites) with metabolic pathways in cellular environments that can be tested for biological functions (i.e., phenotypes). A growing literature in LD and gut microbiomes reports the use of metabolites as therapeutic targets or biomarkers. Although growing evidence connects liver fibrosis, cirrhosis, and hepatocellular carcinoma, the genetic and metabolic factors are still mainly unknown. Herein, we reviewed proof-of-concept mechanisms for metabolomics-based LD and gut microbiotas' role from several studies (nuclear magnetic resonance, gas/lipid chromatography, spectroscopy coupled with mass spectrometry, and capillary electrophoresis). A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to improve liver health.

Nutritional Status and Diet Style Affect Cognitive Function in Alcoholic Liver Disease.

Malnutrition and cognitive dysfunction are typical features of alcoholic liver disease (ALD) and are correlated with the development of complications. The aim of this study is to explore the effect of nutritional state and diet on cognitive function in ALD. A total of 43 patients with compensated alcoholic cirrhosis were enrolled, and a neuropsychological test was assessed according to body mass index (BMI, <22 and ≥22). In the ALD animal study, mice were divided into five groups (n = 9/group; normal liquid, 5% EtOH + regular liquid, 5% EtOH + high-carbohydrate liquid, 5% EtOH + high-fat liquid, and 5% EtOH + high-protein liquid diet) and fed the same calories for eight weeks. To assess cognitive function, we performed T-maze studies weekly before/after alcohol binging. In cognitive function (BMI < 22/≥22), language score of Korea mini-mental state (7.4 ± 1.4/7.9 ± 0.4), Boston naming (11.7 ± 2.7/13.0 ± 1.8), forward digit span (6.7 ± 1.8/7.5 ± 1.6), Korean color word stroop (24.2 ± 26.5/43.6 ± 32.4), and interference score (33.9 ± 31.9/52.3 ± 33.9) revealed significant differences. In the T-maze test, alcohol significantly delayed the time to reach food, and binge drinking provided a temporary recovery in cognition. The alcohol-induced delay was significantly reduced in the high-carbohydrate and high-fat diet groups. Synaptic function exhibited no changes in all groups. Cognitive dysfunction is affected by nutritional status and diet in ALD.

Isolation and Characterization of Probiotic LAB from Kimchi and Spontaneously Fermented Teff (Eragrostis tef (Zucc.) Trotter) Batter: Their Effects on Phenolic Content of Teff during Fermentation.

Microbial fermentation is proven to induce molecular transformations and produce bioactive compounds thereby enhancing sensory and nutritional quality of flour-based fermented foods. In this study, lactic acid bacteria (LAB) were isolated from Korean kimchi and Ethiopian fermented teff (Eragrostis tef (Zucc.) Trotter) flour batter. Isolates were identified using 16S rRNA gene sequencing and characterized for various probiotic properties. Few trains were selected for further teff flour batter fermentation and evaluating their effects on phenolic contents and compositions. Out of 200 bacterial isolates, 44 of them showed considerable acid and bile tolerance and 22 were tested positive for protease activity. A large number of the isolates showed antimicrobial activities against Salmonella gallinarium indicator strains. Majority of these probiotic strains belonged to Lactobacillus plantarum and Lactobacillus brevis species. All the strains used for fermentation of teff were able to significantly increase total phenolic contents (TPC). An increase in TPC of up to 7-fold was observed in some strains.

Chemical Composition and Antioxidant Activity of Steam-Distilled Essential Oil and Glycosidically Bound Volatiles from Maclura Tricuspidata Fruit.

Essential oil obtained from Maclura triscuspidata fruit has been reported to have functional properties. This study aimed at determining chemical compositions and antioxidant activities of steam-distilled essential oil (SDEO) and glycosidically bound aglycone fraction (GBAF) isolated from fully ripe M. triscuspidata fruit. SDEO was isolated by simultaneous steam distillation and extraction (SDE). GBAF was prepared by Amberlite XAD-2 adsorption of methanol extract, followed by methanol elution and enzymatic hydrolysis. Both fractions were analyzed by gas chromatography-mass spectrometry (GC-MS). A total of 76 constituents were identified from both oils. Apart from fatty acids and their esters, the SDEO contained p-cresol in the highest concentration (383.5 ± 17.7), followed by δ-cadinene (147.7 ± 7.7), ß-caryophyllene (145.7 ± 10.5), ß-ionone (141.0 ± 4.5), n-nonanal (140.3 ± 20.5), theaspirane A (121.3 ± 4.5) and theaspirane B (99.67 ± 9.05 µg/g). Thirteen carotenoid-derived compounds identified in the SDEO are being isolated from M. triscuspidata fruit for the first time. Out of the 22 components identified in GBAF, 14 were present only in the glycosidically bound volatiles. Antioxidant activity of the GBAF was higher than that of SDEO. These results suggest that glycosidically bound volatiles of M. triscuspidata fruit have a good potential as natural antioxidants.

Variations in Amino Acid and Protein Profiles in White versus Brown Teff (Eragrostis Tef) Seeds, and Effect of Extraction Methods on Protein Yields.

Data on variations in amino acid compositions and protein profiles among white and brown teff, a grain of growing interest, is either limited or contradicting at the moment. In this study, three white (Addis-W, Mekel-W and Debre-W) and three brown (Addis-B, Mekel-B and Debre-B) teff seed samples were used for whole flour amino acid analysis and protein fractionation with three different methods. White and brown seed types showed different physical changes during protein extraction. Brown teff displayed higher essential amino acid content than white with lysine present in high concentration in both seed types. Extraction with tert-butanol increased prolamin yields in teff compared to ethanol. The major protein fraction in teff was glutelin with white teff containing higher glutelin proportion than brown. Sodium Dodecyl Sulfate Gel Electrophoresis (SDS-PAGE) analysis revealed clear genetic variability between white and brown teff seed types.

Changes of Phytochemical Components (Urushiols, Polyphenols, Gallotannins) and Antioxidant Capacity during Fomitella fraxinea⁻Mediated Fermentation of Toxicodendron vernicifluum Bark.

The stem bark of Toxicodendron vernicifluum (TVSB) has been widely used as a traditional herbal medicine and food ingredients in Korea. However, its application has been restricted due to its potential to cause allergies. Moreover, there is limited data available on the qualitative and quantitative changes in the composition of its phytochemicals during fermentation. Although the Formitella fraxinea-mediated fermentation method has been reported as an effective detoxification tool, changes to its bioactive components and the antioxidant activity that takes place during its fermentation process have not yet been fully elucidated. This study aimed to investigate the dynamic changes of urushiols, bioactive compounds, and antioxidant properties during the fermentation of TVSB by mushroom F. fraxinea. The contents of urushiols, total polyphenols, and individual flavonoids (fisetin, fustin, sulfuretin, and butein) and 1,2,3,4,6-penta-O-galloyl-ß-D-glucose (PGG) significantly decreased during the first 10 days of fermentation, with only a slight decrease thereafter until 22 days. Free radical scavenging activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6- sulfonic acid) (ABTS), and ferric reducing/antioxidant power (FRAP) as an antioxidant function also decreased significantly during the first six to nine days of fermentation followed by a gentle decrease up until 22 days. These findings can be helpful in optimizing the F. fraxinea⁻mediated fermentation process of TVSB and developing functional foods with reduced allergy using fermented TVSB.

Early molecular responses of bone to obstructive nephropathy induced by unilateral ureteral obstruction in mice.

AIM: This study was performed to address the bone injury and the early molecular responses of bone to obstructive nephropathy induced by unilateral ureteral obstruction in mice. METHODS: The male mice were subjected to unilateral ureteral obstruction (UUO, n = 10) or sham operation (n = 10). All mice were killed on day 7 after the surgical operation. Hematoxylin and eosin and tartate-resistant acid phosphatase staining were performed on paraffin-embedded bone sections. Expression of genes and proteins was analyzed by reverse transcription-polymerase chain reaction, and Western blotting and immunohistochemistry staining, respectively. RESULTS: The serum calcium level was significantly reduced in UUO mice compared with that of Sham mice. The proximal tibia of UUO mice exhibited the increased expansion of chondrocytes zone, the reduction of osteoid content, and the increased separation and disconnection of woven bones. Reverse transcription-polymerase chain reaction results showed the downregulation of Cbfa1 and Col mRNA expression and the upregulation of Tgf-ß, CtsK, CaII, Opg and Rankl mRNA expression in tibia of UUO mice compared to those of Sham mice. The ratio of Opg and Rankl was unchanged between Sham and the UUO group. Local protein expression of angiotensin II and its type 2 receptor was dramatically upregulated in tibia of UUO mice. CONCLUSION: Together, it is concluded that the obstructive nephropathy has defective effects on bone, and the underlying mechanisms are the reduction of bone formation and the increase of bone resorption, which is mediated, at least partially through local angiotensin II signalling.