Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

Distinct common signatures of gut microbiota associated with damp-heat syndrome in patients with different chronic liver diseases.

Background: Chronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD) are prevalent in China. According to traditional Chinese medicine (TCM) theory, damp-heat (DH) syndrome is common in chronic liver disease. However, the biological characteristics related to quantitative diagnosis remain to be determined. This study aimed to identify the consistent alterations in the gut microbiota associated with DH syndrome in patients with CHB or NAFLD. Methods: A total of 405 individuals were recruited, of which 146 were participants who met the consistent TCM diagnosis by three senior TCM physicians and were typical syndromes. All participants were required to provide fresh stool and serum samples. The gut microbiota was assessed by fecal 16S rRNA gene sequencing, and the serum metabolite profiles of participants were quantified by an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system. DH syndrome-related bacteria taxa were identified based on the 146 individuals with typical syndromes and validated in all 405 volunteers. Results: The results showed that CHB and NAFLD patients with typical TCM DH syndrome had consistently elevated serum total bile acid (TBA) levels. Significant alterations in microbial community were observed according to TCM syndromes identification. A total of 870 microbial operational taxonomic units and 21 serum metabolites showed the same variation trends in both the CHB and NAFLD DH syndrome groups. The functional analysis predicts consistent dysregulation of bile acid metabolism. Five genera (Agathobacter, Dorea, Lachnospiraceae_NC2004_group, Subdoligranulum, and unclassified_c__Clostridia) significantly decreased in abundance in patients with DH syndrome. We utilize these five genera combined with TBA to construct a random forest classifier model to predict TCM diagnosis. The diagnostic receiver-operator characteristic (ROC) areas for DH syndrome were 0.818 and 0.791 in internal tenfold cross-validation and the test set based on all 405 individuals, respectively. Conclusion: There are common signatures of gut microbiota associated with DH syndrome in patients with different chronic liver diseases. Serum TBA combined with DH-related genera provides a good diagnostic potential for DH syndrome in chronic liver disease.

QSHY Granules Promote White Adipose Tissue Browning and Correct BCAAs Metabolic Disorder in NAFLD Mice.

PURPOSE: White adipose tissue (WAT) has positive effects on peripheral metabolism parameters and liver energy metabolism. This study aimed to explain the pharmacological mechanism of Qushi Huayu (QSHY) granules in the treatment of nonalcoholic fatty liver disease (NALFD) mice based on branched-chain amino acid (BCAA) catabolism and WAT browning. PATIENTS AND METHODS: Thirty C57BL/6J mice were randomly divided into a (Ctrl) control group, fed with a control diet, a NAFLD model group, fed with a high-fat and high-sugar (HFHS) diet, and a QSHY granules treatment (HFHS+QSHY) group, administered with QSHY granules. After 14 weeks of feeding, HFHS+QSHY group mice were administered QSHY granules through oral gavage for 6 weeks. The metabolic parameters were assessed, the circular and fecal BCAA content was observed, and liver and epididymal WAT (eWAT) were collected for pathological, quantitative real-time polymerase chain reaction, and Western blotting analyses. RESULTS: Compared with the HFHS group, mice in the HFHS+QSHY group demonstrated restored liver histological changes, ameliorated hepatocyte steatosis, and alleviated inflammatory cell infiltration. Consistent with the pathological changes, QSHY granules significantly reduced the elevated levels of liver triglycerides, and serum alanine aminotransferase, and it relieved hypercholesterolemia and insulin resistance in mice with HFHS-induced NAFLD. Furthermore, it corrected BCAA metabolic disorders in serum and feces and promoted the expression of BCAA catabolic genes in the eWAT of HFHS mice. QSHY granules also increased the expression of phosphorylated AMP-activated protein kinase (AMPK) protein, up-regulating the protein expression of the AMPK/SIRT1/UCP-1 pathway in the eWAT. CONCLUSION: QSHY granules improved hepatic steatosis and corrected the BCAA disorder in NAFLD mice, and the related mechanisms regulated the AMPK/SIRT1/UCP-1 pathway and promoted WAT browning.

[Design of functional array electrode stimulation system with surface electromyography feedback].

In order to solve the problems of insufficient stimulation channels and lack of stimulation effect feedback in the current electrical stimulation system, a functional array electrode electrical stimulation system with surface electromyography (sEMG) feedback was designed in this paper. Firstly, the effectiveness of the system was verified through in vitro and human experiments. Then it was confirmed that there were differences in the number of amperage needed to achieve the same stimulation stage among individuals, and the number of amperage required by men was generally less than that of women. Finally, it was verified that the current required for square wave stimulation was smaller than that for differential wave stimulation if the same stimulation stage was reached. This system combined the array electrode and sEMG feedback to improve the accuracy of electrical stimulation and performed the whole process recording of feedback sEMG signal in the process of electrical stimulation, and the electrical stimulation parameters could change with the change of the sEMG signal. The electrical stimulation system and sEMG feedback worked together to form a closed-loop electrical stimulation working system, so as to improve the efficiency of electrical stimulation rehabilitation treatment. In conclusion, the functional array electrode electrical stimulation system with sEMG feedback developed in this paper has the advantages of simple operation, small size and low power consumption, which lays a foundation for the introduction of electrical stimulation rehabilitation treatment equipment into the family, and also provides certain reference for the development of similar products in the future.

Comparative Analysis of Clinical and Medication Information between Chronic Hepatitis B Patients with Damp Heat Syndrome and Spleen Deficiency Syndrome.

Traditional Chinese medicine (TCM) has a long history in the treatment of chronic hepatitis B (CHB) based on the syndrome identification. Previous studies reported CHB patients with damp-heat (DH) syndrome accompanied with a severe liver function damage, but lacked the medication analysis. In this study, we analyzed 999 CHB patients with unidentified individual-level data from database to explore clinical features of two common syndromes of CHB patients based on the real world. Compared with the spleen deficiency (SD) syndrome, the CHB patients with DH syndrome had a significantly higher level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P < 0.05) but took more immunomodulators and hepatoprotective drugs (P < 0.1). Similarly, in the follow-up of 207 patients after 3 months, the improvement trend of ALT and AST of patients with sustained SD syndrome was significantly better than those whose TCM syndrome changed from SD to DH (P < 0.05). The logistic model indicated DH syndrome was a significant negative factor for reducing ALT level in CHB patients (OR = 4.854, P=0.032). This study suggests that CHB patients with DH syndrome have potentially more serious and sustained liver damage than the SD syndrome, which provides a reference for the personalized management of CHB patients from the perspective of TCM syndromes.

Altered oral microbiota in chronic hepatitis B patients with different tongue coatings.

AIM: To elucidate tongue coating microbiota and metabolic differences in chronic hepatitis B (CHB) patients with yellow or white tongue coatings. METHODS: Tongue coating samples were collected from 53 CHB patients (28 CHB yellow tongue coating patients and 25 CHB white tongue coating patients) and 22 healthy controls. Microbial DNA was extracted from the tongue samples, and the bacterial 16S ribosomal RNA gene V3 region was amplified from all samples and sequenced with the Ion Torrent PGM™ sequencing platform according to the standard protocols. The metabolites in the tongue coatings were evaluated using a liquid chromatography-mass spectrometry (LC-MS) platform. Statistical analyses were then performed. RESULTS: The relative compositions of the tongue coating microbiotas and metabolites in the CHB patients were significantly different from those of the healthy controls, but the tongue coating microbiota abundances and diversity levels were not significantly different. Compared with the CHB white tongue coating patients, the CHB yellow tongue coating patients had higher hepatitis B viral DNA (HBV-DNA) titers (median 21210 vs 500, respectively, P = 0.03) and a significantly lower level of Bacteroidetes (20.14% vs 27.93%, respectively, P = 0.013) and higher level of Proteobacteria (25.99% vs 18.17%, respectively, P = 0.045) in the microbial compositions at the phylum level. The inferred metagenomic pathways enriched in the CHB yellow tongue coating patients were mainly those involved in amino acid metabolism, which was consistent with the metabolic disorder. The abundances of bacteria from Bacteroidales at the order level were higher in the CHB white tongue coating patients (19.2% vs 27.22%, respectively, P = 0.011), whereas Neisseriales were enriched in the yellow tongue coating patients (21.85% vs 13.83%, respectively, P = 0.029). At the family level, the abundance of Neisseriaceae in the yellow tongue patients was positively correlated with the HBV-DNA level but negatively correlated with the S-adenosyl-L-methionine level. CONCLUSION: This research illustrates specific clinical features and bacterial structures in CHB patients with different tongue coatings, which facilitates understanding of the traditional tongue diagnosis.

Difference of proteomics vernalization-induced in bolting and flowering transitions of Beta vulgaris.

Sugar beet (Beta vulgaris) is a biennial crop that accounts for 30% sugar production of the world. Vernalization is an essential factor for sugar beet reproductative growth under long days. Although genes association with bolting and flowering were well explored, the difference of proteomics in the two growth stages were still poorly understood. To address the molecular mechanism at the level of proteins, an isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics approach was employed to the three different growth stages (germination, bolting, flowering) of vernalized samples and the corresponding stage germination (17W weeks), 19W and 20W of nonvernalized samples. A total of 1110 peptides, 842 unique peptides and 570 proteins were identified. Most of them were assigned to phenylpropanoid biosynthesis, hormone metabolism and protein processing pathway. IAA and Gibberellins (GA3) promoted growth and development in a threshold manner at growth stage germination after vernalization. A novel discovery was that IAA biosynthetic pathway of sugar beet was the Trp-dependent. In addition, two predominant pathways of protein processing association with vernalization were also identified in sugar beet at growth stage flowering. This study provided an in-depth understanding of the molecular mechanism of vernalization at the level of proteomics.

Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties.

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 µM) and hMAO-B (IC50 = 4.3 µM), significant antioxidant activity (41.33 µM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aß1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.

Rice protein improves adiposity, body weight and reduces lipids level in rats through modification of triglyceride metabolism.

BACKGROUND: To elucidate whether rice protein can possess a vital function in improving lipids level and adiposity, the effects of rice proteins extracted by alkaline (RP-A) and α-amylase (RP-E) on triglyceride metabolism were investigated in 7-week-old male Wistar rats fed cholesterol-enriched diets for 2 weeks, as compared with casein (CAS). RESULTS: Compared with CAS, plasma concentrations of glucose and lipids were significantly reduced by RP-feeding (P < 0.05), as well as hepatic accumulation of lipids (P < 0.05). RP-A and RP-E significantly depressed the hepatic activities of fatty acid synthase (FAS), glucose 6-phosphate dehydrogenase (G6PD) and malate dehydrogenase (MDH) (P < 0.05), whereas the activities of lipoprotein lipase (PL) and hepatic lipase (HL) were significantly stimulated (P < 0.05), as compared to CAS. Neither lipids level nor activities of enzymes were different between RP-A and RP-E (P > 0.05). There was a significant positive correlation between protein digestibility and deposit fat (r = 0.8567, P < 0.05), as well as the plasma TG concentration (r = 0.8627, P < 0.05). CONCLUSIONS: The present study demonstrates that rice protein can modify triglyceride metabolism, leading to an improvement of body weight and adiposity. Results suggest that the triglyceride-lowering action as well as the potential of anti-adiposity induced by rice protein is attributed to upregulation of lipolysis and downregulation of lipogenesis, and the lower digestibility of rice protein may be the main modulator responsible for the lipid-lowering action.

Chemoprotective effects of Curcuma aromatica on esophageal carcinogenesis.

Previous studies have demonstrated a decrease in manganese superoxide dismutase (MnSOD) in both Barrett's epithelium of patients and columnar esophageal epithelium of rats after esophagoduodenal anastomosis (EDA). Curcuma aromatica, an herbal medicine, has been shown to display anti-carcinogenic properties in a wide variety of cell lines and animals. This study was designed to investigate the ability of Curcuma aromatica oil for the prevention of BE and EAC, possibly through its ability to preserve MnSOD function. EDA was performed on rats and Curcuma aromatica oil was administered by i.p. injection. Histological changes and oxidative damage were determined after EDA of 1, 3, and 6 months. MnSOD protein level and MnSOD enzymatic activity were evaluated. Lipid peroxidation was determined by TBARs assay and 8-hydroxy-deoxyguanosine for DNA oxidative damage was measured by immunohistochemical staining. In addition, the indexes of both apoptosis and proliferation were determined by PCNA staining and TUNEL assay, respectively. Severe esophagitis were seen in EDA rats, and morphological transformation within the esophageal epithelium was observed with intestinal metaplasia and EAC identified after 3 months. The EDA rats treated with Curcuma aromatica oil showed that both MnSOD enzymatic activity and protein level were similar to sham controls. Decreased incidences of intestinal metaplasia and EAC also were observed in the EDA rats with Curcuma aromatica oil treatment. Curcuma aromatica oil prevented loss of MnSOD in EDA rat esophageal epithelium, and this preservation of MnSOD is associated with the potential protective mechanism against transformation of esophageal epithelial to BE to EAC.

Chemoprevention of carcinogenic progression to esophageal adenocarcinoma by the manganese superoxide dismutase supplementation.

PURPOSE: Oxidative stress is related to the carcinogenic pathway of reflux esophagitis to Barrett's metaplasia to esophageal adenocarcinoma (EAC). Recent studies have shown that a decreased manganese superoxide dismutase (MnSOD) level is associated with the increased incidences of Barrett's esophagus (BE) and EAC. The aim of this study was to investigate MnSOD supplementation as a chemopreventive agent to prevent oxidative injury and subsequent BE and EAC formation. EXPERIMENTAL DESIGN: Our esophagoduodenal anastomotic (EDA) model was done on rats according to our established procedure and treated with Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP; 10 mg/kg, i.p. every 3 days). Histologic changes were determined after the EDA model at 1, 3, and 6 months. Lipid peroxidation and 8-hydroxy-deoxyguanosine for DNA oxidative damage were determined by thiobarbituric acid-reactive substance assay and immunohistochemical staining. Enzymatic activities of MnSOD and Cu/ZnSOD were evaluated, and the rate of proliferation was determined by proliferating cell nuclear antigen staining. RESULTS: Severe esophagitis was seen in 100% of the EDA rats, and morphologic transformation within the esophageal epithelium was observed with intestinal metaplasia (40% of animals) and cancer (40% of animals) identified after 3 months. Decreased oxidative damage, along with the decreased degree of esophagitis and incidence of BE (20%) and EAC (0%), was found in MnTBAP-treated EDA rats comparing with the saline-treated EDA control. Decreased proliferation (46%) and increased SOD enzymatic activities (25%) were also found in the EDA rats treated with MnTBAP. CONCLUSION: MnTBAP protected rat esophageal epithelium from oxidative injury induced by EDA, and it could prevent the transformation of esophageal epithelial cell to BE to EAC by preservation of antioxidants.