Hepatic GDP-fucose transporter SLC35C1 attenuates cholestatic liver injury and inflammation by inducing CEACAM1 N153 fucosylation.

BACKGROUND AND AIMS: Inflammatory response is crucial for bile acid (BA)-induced cholestatic liver injury, but molecular mechanisms remain to be elucidated. Solute Carrier Family 35 Member C1 (SLC35C1) can transport Guanosine diphosphate-fucose into the Golgi to facilitate protein glycosylation. Its mutation leads to the deficiency of leukocyte adhesion and enhances inflammation in humans. However, little is known about its role in liver diseases. APPROACH AND RESULTS: Hepatic SLC35C1 mRNA transcripts and protein expression were significantly increased in patients with obstructive cholestasis and mouse models of cholestasis. Immunofluorescence revealed that the upregulated SLC35C1 expression mainly occurred in hepatocytes. Liver-specific ablation of Slc35c1 ( Slc35c1 cKO ) significantly aggravated liver injury in mouse models of cholestasis induced by bile duct ligation and 1% cholic acid-feeding, evidenced by increased liver necrosis, inflammation, fibrosis, and bile ductular proliferation. The Slc35c1 cKO increased hepatic chemokine Ccl2 and Cxcl2 expression and T cell, neutrophil, and F4/80 macrophage infiltration but did not affect the levels of serum and liver BA in mouse models of cholestasis. Liquid chromatography with tandem mass spectrometry analysis revealed that hepatic Slc35c1 deficiency substantially reduced the fucosylation of cell-cell adhesion protein CEACAM1 at N153. Mechanistically, cholestatic levels of conjugated BAs stimulated SLC35C1 expression by activating the STAT3 signaling to facilitate CEACAM1 fucosylation at N153, and deficiency in the fucosylation of CEACAM1 at N135 enhanced the BA-stimulated CCL2 and CXCL2 mRNA expression in primary mouse hepatocytes and Primary Liver Carcinoma/Poliomyelitis Research Foundation/5- ASBT cells. CONCLUSIONS: Elevated hepatic SLC35C1 expression attenuates cholestatic liver injury by enhancing CEACAM1 fucosylation to suppress CCL2 and CXCL2 expression and liver inflammation.

Runt-related transcription factor-1 ameliorates bile acid-induced hepatic inflammation in cholestasis through JAK/STAT3 signaling.

BACKGROUND AND AIMS: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. APPROACH AND RESULTS: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5- ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1 -P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2 , and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid-induced CCL2 and CXCL2 in hepatocytes. CONCLUSIONS: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.

Dimethyl fumarate attenuates cholestatic liver injury by activating the NRF2 and FXR pathways and suppressing NLRP3/GSDMD signaling in mice.

The progression of cholestasis is characterized by excessive accumulation of bile acids (BAs) in the liver, which leads to oxidative stress (OS), inflammation and liver injury. There are currently limited treatments for cholestasis. Therefore, appropriate drugs for cholestasis treatment need to be developed. Dimethyl fumarate (DMF) has been widely used in the treatment of various diseases and exerts antioxidant and anti-inflammatory effects, but its effect on cholestatic liver disease remains unclarified. We fed mice 3,5-diethoxycarbonyl-1,4-dihydrocollidine or cholic acid to induce cholestatic liver injury and treated these mice with DMF to evaluate its protective ability. Alanine aminotransferase, aspartate aminotransferase, and total liver BAs were assessed as indicators of liver function. The levels of OS, liver inflammation, transporters and metabolic enzymes were also measured. DMF markedly altered the relative ALT and AST levels and enhanced the liver antioxidant capacity. DMF regulated the MST/NRF2 signaling pathway to protect against OS and reduced liver inflammation through the NLRP3/GSDMD signaling pathway. DMF also regulated the levels of BA transporters by promoting FXR protein expression. These findings provide new strategies for the treatment of cholestatic liver disorders.

Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis.

Cholestasis is a common condition in which the flow of bile from the liver to the intestines is inhibited. It has been shown that organic anion-transporting polypeptide 3A1 (OATP3A1) is upregulated in cholestasis to promote bile acid efflux transport. We have previously shown that the growth factor fibroblast growth factor 19 and inflammatory mediator tumor necrosis factor α (TNFα) increased OATP3A1 mRNA levels in hepatoma peritoneal lavage cell/PRF/5 cell lines. However, the mechanism underlying TNFα-stimulated OATP3A1 expression in cholestasis is unknown. To address this, we collected plasma samples from control and obstructive cholestasis patients and used ELISA to detect TNFα levels. We found that the TNFα levels of plasma and hepatic mRNA transcripts were significantly increased in obstructive cholestatic patients relative to control patients. A significant positive correlation was also observed between plasma TNFα and liver OATP3A1 mRNA transcripts in patients with obstructive cholestasis. Further mechanism analysis revealed that recombinant TNFα induced OATP3A1 expression and activated NF-κB and extracellular signal-regulated kinase (ERK) signaling pathways as well as expression of related transcription factors p65 and specificity protein 1 (SP1). Dual-luciferase reporter and chromatin immunoprecipitation assays showed that recombinant TNFα upregulated the binding activities of NF-κB p65 and SP1 to the OATP3A1 promoter in peritoneal lavage cell/PRF/5 cells. These effects were diminished following the application of NF-κB and ERK inhibitors BAY11-7082 and PD98059. We conclude that TNFα stimulates hepatic OATP3A1 expression in human obstructive cholestasis by activating NF-κB p65 and ERK-SP1 signaling. These results suggest that TNFα-activated NF-κB p65 and ERK-SP1 signaling may be a potential target to ameliorate cholestasis-associated liver injury.

Semaphorin 7A interacts with nuclear factor NF-kappa-B p105 via integrin ß1 and mediates inflammation.

Semaphorin7a (SEMA7A), a membrane-anchored member of the semaphorin protein family, could be involved in a diverse range of immune responses via its receptor integrin ß1. Recently, we reported that the SEMA7AR148W mutation (a gain-of-function mutation, Sema7aR145W in mice) is a risk factor for progressive familial intrahepatic cholestasis and nonalcoholic fatty liver disease via upregulated membrane localization. In this study, we demonstrated that integrin ß1 is a membrane receptor for nuclear factor NF-kappa-B p105 (NF-κB p105) and a critical mediator of inflammation. Integrin ß1 could interact with the C-terminal domain of NF-κB p105 to promote p50 generation and stimulate the NF-κB p50/p65 signalling pathway, upregulate TNF-α and IL-1ß levels, and subsequently render hepatocytes more susceptible to inflammation. The induction of integrin ß1 depends on elevated Sema7a membrane localization. Moreover, we revealed elevated levels of Sema7aWT (SEMA7AWT) in hepatocellular carcinoma (HCC) patients and an HCC mouse model. In line with our findings, the NF-κB p50/p65 pathway could also be activated by high Sema7a expression and repressed by integrin ß1 silencing. In conclusion, our findings suggest that the Sema7aR145W (SEMA7AR148W) mutation and high Sema7aWT (SEMA7AWT) expression both activate the NF-κB p50/p65 pathway via integrin ß1 and play a crucial role in inflammatory responses. Video Abstract.

Melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response.

Melatonin, an indole neurohormone secreted mainly by the pineal gland, has been found to be involved in a variety of liver diseases. However, the underlying mechanism by which melatonin ameliorates cholestatic liver injury is not fully understood. In this study, we investigated the mechanism by which melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response. We measured the levels of serum melatonin in patients with obstructive cholestasis (n = 9), patients with primary biliary cholangitis (PBC) (n = 11), and control patients (n = 7). We performed experiments with C57BL/6 J mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and melatonin to verify the role of melatonin in the mouse model of cholestasis. Primary mouse hepatocytes were used for in vitro studies to study the mechanisms of action of melatonin in cholestasis. The levels of serum melatonin were markedly increased and negatively correlated with serum markers of liver injury in cholestatic patients. As expected, oral administration of melatonin significantly attenuated cholestasis-induced liver inflammation and fibrosis in 0.1% DDC diet-fed mice. Further mechanistic studies in cholestatic mice and primary hepatocytes revealed that melatonin reduced the conjugate BA-stimulated expression of cytokines (e.g. Ccl2, Tnfα, and Il6) through the ERK/Egr1 signalling pathway in these models. The levels of serum melatonin are significantly elevated in cholestatic patients. Melatonin treatment ameliorates cholestatic liver injury by suppressing the inflammatory response in vivo and in vitro. Therefore, melatonin is a promising novel therapeutic strategy for cholestasis.

Precise Immobilization Strategy Combined with Rational Design to Improve ß-Agarase Stability.

Recently, the orientational immobilization of enzymes has attracted extensive attention. In this study, we report the development of a strategy combined with rational design to achieve precise site-specific covalent immobilization of ß-agarase. We first rationally screened six surface sites that can be mutated to cysteine by combining molecular dynamics simulation and energy calculation. Site-specific immobilization was successfully achieved by Michael addition reaction of mutant enzymes and maleimide-modified magnetic nanoparticles (MAL-MNPs). The enzyme activity retention rate of R66C-MAL-MNPs and K588C-MAL-MNPs was greater than 96%. The thermal deactivation kinetics study revealed that the site-specific immobilization strategy significantly improved the thermal stability of Aga50D, resulting in a substantial increase in its antidenaturation activity at elevated temperatures, and the highest t1/2 of the immobilized mutant enzymes was increased by an impressive 21.25-fold at 40 °C. The immobilized mutant enzymes also showed significantly enhanced tolerance to metal ions and organic reagents. For instance, all of the immobilized enzymes maintained over 90% of their enzymatic activity in the 50% (v/v) acetone/water solution. The present work may pave the way for the design of precisely immobilized enzymes, which can help promote green manufacturing.

Study on the safety assessment and protection design of human exposure to low-frequency magnetic fields in electric vehicles.

As the power performance of electric vehicles continues to improve, the human body may be exposed to electromagnetic threats in the cabin. This study tested an electric vehicle to analyze the low-frequency magnetic field distribution in the cabin and to assess the safety of human low-frequency magnetic field exposure. A simulation analysis of human electromagnetic exposure was carried out to obtain the magnetic flux density, induced electric field strength and induced current density, and the test results were much lower than the limits specified in GB8702-2014 and the International Commission on Non-Ionizing Radiation Protection, and the relative error between the simulation results and the test results was <15%. This paper investigates the frequency, driving current, vehicle body material and cable layout to explore the law of human body induced electromagnetic field changing with power cable current, and provides theoretical reference for the design of human body low-frequency magnetic field protection.

Synthesis and characterisation of a novel poly(2-hydroxyethylmethacrylate)-chitosan hydrogels loaded cerium oxide nanocomposites dressing on cutaneous wound healing on nursing care of chronic wound.

This study was designed to establish the composition of wound dressing based on poly(2-hydroxyethylmethacrylate)-chitosan (PHEM-CS) hydrogels-loaded cerium oxide nanoparticle (CeONPs) composites for cutaneous wound healing on nursing care of the chronic wound. The as-synthesised PHEM-CS/CeONPs hydrogels nanocomposites were characterised by using UV-visible spectroscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and thermo gravimetric analysis. The influence of PHEM-CS/CeONPs hydrogels nanocomposites on the gelation time, swelling ratio, in vitro degradation, and mechanical properties was investigated. The as-prepared PHEM-CS/CeONPs hydrogels nanocomposites dressing shows high antimicrobial activity against Staphylococcus aureus and Escherichia coli. Similar trends were observed for the treatment of biofilms where PHEM-CS/CeONPs hydrogels nanocomposites displayed better efficiency. Furthermore, the biological properties of PHEM-CS/CeONPs hydrogels nanocomposites had non-toxic in cell viability and excellent cell adhesion behaviour. After 2 weeks, the wounds treated with the PHEM-CS/CeONPs hydrogels nanocomposite wound dressing achieved a significant closure to 98.5 ± 4.95% compared with the PHEM-CS hydrogels with nearly 71 ± 3.55% of wound closure. Hence, this study strongly supports the possibility of using this novel PHEM-CS/CeONPs hydrogels nanocomposites wound dressing for efficient cutaneous wound healing on chronic wound infection and nursing care.

Effects of Poria cocos extract and protein powder mixture on glucolipid metabolism and rhythm changes in obese mice.

Herein, we explored the effects of Poria cocos extract, protein powder mixture, and their combined intervention on weight loss in high-fat diet (HFD)-induced obese mice. Male C57BL/6J mice were selected and fed a HFD for 8 weeks; obese mice that were successfully modeled were divided into modeling and five intervention groups, and given the corresponding treatment for 10 weeks. Body weight, fat, and muscle tissue, blood glucose, lipids, inflammatory factors, and other glucose and lipid metabolism-related indicators were measured to evaluate the effect of P. cocos and protein powder intervention on weight loss in obese mice. The body weight of the intervention group was reduced compared with the HFD group. Fat content of mice in F3PM group decreased significantly (p < .05). Levels of blood glucose, lipids, adiponectin, leptin, and inflammatory factors, including interleukin-1 ß and tumor necrosis factor- α showed improvement. Lipoprotein lipase (lower about 2.97 pg/ml, vs. HFD mice 10.65 mmoL/ml) and sterol regulatory element-binding transcription factor (lower about 1413.63 pg/ml, vs. HFD mice 3915.33 pg/ml) levels in liver tissue were decreased. The respiratory exchange rate (RER) of mice in the HFD and subject intervention groups had no circadian rhythm and was maintained at approximately 0.80. The protein powder mixture (PM) group had the lowest RER (p < .05), the P. cocos extract (FL) and F1PM groups had similar RER to the HFD group (p < .05), and the F2PM group had a higher RER than the HFD group (p < .05). And food intake and energy metabolism returned to circadian rhythm, with an increase in the dose of P. cocos extract, the feeding rhythms of F1PM, F2PM, and F3PM were closer to that of the normal diet (ND) group. Feeding intervention with P. cocos and protein powder improved fat distribution, glucolipid metabolism, and energy metabolism, with the combination of F3PM showing more diverse benefits.

Hepatic Aquaporin 10 Expression Is Downregulated by Activated NFκB Signaling in Human Obstructive Cholestasis.

Background and Aims: Recent studies reported that the hepatic expression of AQP8 and AQP9 was downregulated in bile duct-ligated (BDL) rats and that overexpression of human AQP1 in the rat liver attenuated cholestasis. However, the hepatic expression of AQP10 and its regulatory mechanism in human cholestasis remain unclear. Methods: Serum and liver samples were collected from 34 patients with obstructive cholestasis and from 12 control patients. Eight-week-old male C57BL/6J mice were intravenously injected with an adeno-associated virus 8 (AAV8) encoding human AQP10 driven by a hepatocyte-specific Alb promotor (AAV8-Alb promotor-hAQP10) for functional studies. Constructs of the AQP10 promoter and PLC/PRF/5-ASBT cell lines were used for regulatory mechanism studies. Results: AQP10 was significantly downregulated in patients with obstructive cholestasis and negatively associated with the serum levels of total bile acid (TBA). The hepatocyte-specific overexpression of hAQP10 significantly attenuated the cholestatic liver injury and intrahepatic bile acids (BA) accumulation in BDL mice. Conjugated BAs, such as TCA and inflammatory factor TNFα, significantly repressed AQP10 expression. Furthermore, NFκB p65/p50 directly bound to the AQP10 promotor and decreased its activity in PLC/RPF/5-ASBT cells and in the livers of patients with obstructive cholestasis. However, these changes were diminished by BAY 11-7082 (a specific inhibitor of NFκB signaling). Conclusion: We are the first to report that AQP10 was significantly decreased in patients with obstructive cholestasis. AQP10 overexpression significantly attenuated cholestatic liver injury in BDL mice. Therefore, overexpression of hAQP10 in the liver may be a valuable strategy for cholestasis intervention.

The effects of Ascophyllum nodosum, Camellia sinensis-leaf extract, and their joint interventions on glycolipid and energy metabolism in obese mice.

Objectives: Obesity is often associated with glucolipid and/or energy metabolism disorders. Ascophyllum nodosum extract (seaweed extract, SE) and Camellia sinensis-leaf extract (tea extract, TE) have been reported to promote positive metabolic effects through different mechanisms. We investigated the effects of SE and TE on metabolic homeostasis in diet-induced obese mice and discussed their functional characteristics. Methods: Male C57BL/6J mice fed with high-fat diets for 8 weeks were established as obese models and subsequently divided into different intervention groups, followed by SE, TE, and their joint interventions for 10 weeks. Body weight and food intake were monitored. Fasting glucose and oral glucose tolerance tests were interspersed during the experiment. After the intervention, the effects on obesity control were assessed based on body composition, liver pathology section, blood lipids and glucose, respiratory exchange ratio (RER), energy expenditure (EE1, EE2, and EE3), inflammatory factors, lipid anabolism enzymes, and gut flora of the obese mice. Results: After continuous gavage intervention, the mice in the intervention groups exhibited lower body weight (lower ~4.93 g, vs. HFD 38.02 g), peri-testicular fat masses (lower ~0.61 g, vs. HFD 1.92 g), and perirenal fat masses (lower ~0.21 g, vs. HFD mice 0.70 g). All interventions prevented diet-induced increases in plasma levels of glucose, adiponectin, leptin, and the inflammatory factors IL-1ß and TNF-α. The RER was modified by the interventions, while the rhythm of the RER was not. Blood lipids (total cholesterol, triglycerides, and LDL) decreased and were associated with lower lipid anabolism enzymes. In addition, the SE and TE interventions altered the structure and abundance of specific flora. Different interventions inhibited the growth of different genera positively associated with obesity (Escherichia-Shigella, Helicobacter, etc.) and promoted the growth of Akkermansia and Bacteroides, thus affecting the chronic inflammatory state. Conclusion: SE and TE both have synergistic effects on weight control and glucolipid metabolism regulation by improving insulin sensitivity and reducing lipid synthesis-related enzyme expression, whereas the combination of SE and TE (3:1) has a better effect on regulating energy metabolism and inhibiting chronic inflammation.

Effects of Coix seed extract, Lactobacillus paracasei K56, and their combination on the glycolipid metabolism in obese mice.

Coix seed extract (CSE) and probiotics have been reported to regulate glycolipid metabolism through different modes of action. We tested the effects of CSE, Lactobacillus paracasei K56, and their combination to determine whether they have synergistic effects on glycolipid metabolism of obese mice. We fed male C57BL/6J mice with high-fat diet for 8 weeks to establish an obesity model. The obesity mice were selected and divided into five groups: the model control group and four intervention groups. After 10 weeks of continuous gavage intervention, the mice in the intervention groups exhibited lower body weight (lower about 2.31-4.41 g, vs. HFD 42.25 g, p < 0.01), and epididymal (lower about 0.58-0.92 g, vs. HFD 2.50 g, p < 0.01) and perirenal fat content (lower about 0.24-0.42 g, vs. HFD 0.88 g, p < 0.05); decreased fasting blood glucose, total cholesterol, triglycerides, and VLDL; and increased HLDL, respiratory exchange ratio, energy expenditure, and amount of exercise performed. K56 + CSE-combined intervention groups were more effective in lowering blood glucose, IL-1ß, and TNF-α levels than the CSE and K56 alone interventions. The content of fatty acid synthase and SREBP-1c protein in liver tissue was lower. The combination has synergistic effects on weight control, fat reduction, and blood glucose regulation by improving the chronic inflammatory state and reducing the content of lipid synthesis-related enzymes of obese mice, which can hinder chronic disease progression. PRACTICAL APPLICATION: Coix seed extract can be used in obese people to regulate abnormal glucose and lipid metabolism and delay the development of chronic diseases.

Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Application and Feasibility Study of Integrated Nursing Information Construction in Nephrology Nursing.

With the continuous deepening of medical reforms and the continuous attempts and explorations of various management models, the traditional health care model is undergoing tremendous changes, and patients' needs for medical institutions are becoming more and more comprehensive. Medical institutions are meeting the needs of providing medical services to patients at the same time. It is even more necessary to change our thinking and enhance the service concept. This article is based on case-based deep learning hospital nursing business process reengineering and the application and feasibility study of integrated nursing information construction in nephrology nursing. This article uses the literature analysis method, the social survey method, and other methods to discuss the construction of integrated nursing information. On the one hand, the content of this article uses the concept of process reengineering to analyze the current development status and existing problems of the hospital care industry and find countermeasures to solve problems. On the other hand, the main research content of this article is the construction of integrated nursing information and its analysis of the application and feasibility of nursing in the nephrology department. At the same time, under the background of the rapid development of the mobile Internet, we will carry out extended thinking on the continuous transformation of the construction of nursing information. According to the survey results, 87.5% of patients in the nephrology department are dissatisfied with the current hospital's work efficiency, and 85.7% of the nursing staff in the nephrology department are generally satisfied with the information management of the current department. After the implementation of the hospital information integration system, patient satisfaction is as high as 98.2%, and the satisfaction of medical staff reached 94.2%. The construction of integrated nursing information has played a great role in the application of nephrology nursing.

Concentration and distribution of sialic acid in human milk and its correlation with dietary intake.

Purpose: This study evaluates the content, distribution, and changing trend of sialic acid in human milk and the correlation between dietary intake of sialic acid and that in human milk. Methods: The study included 33 mothers of full-term and exclusively breastfed infants. At least 2 ml of milk was collected on the 3rd, 8th, 30th, and 90th day after delivery, and 24-h diet recalls of the lactating mothers were obtained each time. The correlation of human milk sialic acid concentration with lactating women's dietary sialic acid intake during lactation was analyzed by statistical analysis software SPSS. Results: The average concentration of sialic acid in colostrum, transition, and 1 and 3 months were 1,670.74 ± 94.53, 1,272.19 ± 128.74, 541.64 ± 55.2, and 297.65 ± 20.78 mg/L, respectively. The total sialic acid concentration in colostrum was about 5.6 times higher than that at 3 months (P < 0.001). The average dietary sialic acid intake of lactating mothers on the 2nd, 7th, 30th, and 90th day after delivery were 106.06 ± 7.51, 127.64 ± 8.61, 120.34 ± 10.21, and 95.40 ± 6.34 mg/day, respectively. The intake of sialic acid was relatively high on the 7th day, and there was no significant difference in dietary intake of sialic acid on different days (P < 0.05). In addition, there was no correlation between the intake of dietary sialic acid and the content of total sialic acid and various forms of sialic acid in milk (P < 0.05). Conclusion: During the lactation period, the distribution of sialic acid in breast milk is relatively stable and its content fluctuates greatly, which may not be affected by the mother's diet, but mainly depends on the self-regulation oft physiological needs.

Effects of Coix Seed Extract, Bifidobacterium BPL1, and Their Combination on the Glycolipid Metabolism in Obese Mice.

Coix seed extract (CSE) and probiotics have been reported to regulate glycolipid metabolism via different modes of action. We tested the effects of CSE, Bifidobacterium BPL1, and their combination to determine their effects on glycolipid metabolism in obese mice. Male C57BL/6J mice were fed a high-fat diet for 8 weeks to establish an obesity model. Obese mice were selected and divided into four groups: the model control group and three intervention groups. After 10 weeks of continuous gavage intervention, the mice in the intervention groups exhibited lower body weight (lower about 2.31 g, vs. HFD mice 42.23 g) and epididymal (lower about 0.37 g, vs. HFD mice 2.5 g) and perirenal fat content (lower about 0.47 g, vs. HFD mice 0.884 g); decreased fasting blood glucose, total cholesterol, triglycerides, and VLDL; and increased HLDL, respiratory exchange ratio, energy expenditure, and amount of exercise performed. CSE, BPL1 and their combination can effectively control the weight gain in obese mice, reduce fat content, and regulate blood lipids and abnormal blood sugar. These results may be related to reduce the chronic inflammatory states, improve energy metabolism, exercise, relieve insulin sensitivity, and reduce lipid synthesis via the intervention of CSE, BPL1 and their combination. Compared with the single use of CSE alone, the combination of CSE + BPL1 can better exert the regulation function of intestinal flora, and change in the abundance of bacteria that could improve the level of inflammatory factors, such as increasing Bifidobacterium, reducing Lactococcus. Compared with the use of BPL1 alone, the combination of CSE and BPL1 can better regulate pancreatic islet and improve blood sugar. CSE may act directly on body tissues to exert anti-inflammatory effects. BPL1 and CSE + BPL1 may improve the structure and function of the intestinal flora, and reduce tissue inflammation.

SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface.

Genetic polymorphisms are associated with the development of nonalcoholic fatty liver disease (NAFLD). Semaphorin7a (Sema7a) deficiency in mouse peritoneal macrophages reduces fatty acid (FA) oxidation. Here, we identified 17 individuals with SEMA7A heterozygous mutations in 470 patients with biopsy-proven NAFLD. SEMA7A heterozygous mutations increased susceptibility to NAFLD, steatosis severity, and NAFLD activity scores in humans and mice. The Sema7aR145W mutation (equivalent to human SEMA7AR148W) significantly induced small lipid droplet accumulation in mouse livers compared with WT mouse livers. Mechanistically, the Sema7aR145W mutation increased N-glycosylated Sema7a and its receptor integrin ß1 proteins in the cell membranes of hepatocytes. Furthermore, Sema7aR145W mutation enhanced its protein interaction with integrin ß1 and PKC-α and increased PKC-α phosphorylation, which were both abrogated by integrin ß1 silencing. Induction of PKCα_WT, but not PKCα_dominant negative, overexpression induced transcriptional factors Srebp1, Chrebp, and Lxr expression and their downstream Acc1, Fasn, and Cd36 expression in primary mouse hepatocytes. Collectively, our findings demonstrate that the SEMA7AR148W mutation is a potentially new strong genetic determinant of NAFLD and promotes intrahepatic lipid accumulation and NAFLD in mice by enhancing PKC-α-stimulated FA and triglyceride synthesis and FA uptake. The inhibition of hepatic PKC-α signaling may lead to novel NAFLD therapies.

[Corrigendum] Effect of Yi Guan Jian decoction on differentiation of bone marrow mesenchymal stem cells into hepatocyte­like cells in dimethylnitrosamine­induced liver cirrhosis in mice.

Following the publication of the above article, an interested reader to the authors' attention that there appeared to be several duplications of data panels featured within Figs. 1­3. After having consulted their original data, the authors have realized that a number of the data panels were inadvertently assembled incorrectly in these figures. The corrected versions of Fig. 1A (showing the correct data for the NC­2W and NC­4W experiments), Fig. 1B (including the correct data for the C­4W, M­2W, NC­2W and NC­4W experiments), Fig. 2 (showing the correct data for the YGD­2W experiment), Fig. 3A (NC­3W data panel corrected), Fig. 3B (HGF­1W and NC­3W data panels corrected) and Fig. 3C (C­4W data panel corrected) are shown on the next four pages. All these corrections were approved by all authors. The authors regret that these errors were not resolved before the publication of the paper, thank the Editor of Molecular Medicine Reports for granting them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 15: 613­626, 2017; DOI: 10.3892/mmr.2016.6083].