Tumor necrosis factor-inducible gene 6 protein and its derived peptide ameliorate liver fibrosis by repressing CD44 activation in mice with alcohol-related liver disease.

BACKGROUND: Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood. METHODS: To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks. RESULTS: Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice. CONCLUSIONS: These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.

Identifying Novel Subtypes of Functional Gastrointestinal Disorder by Analyzing Nonlinear Structure in Integrative Biopsychosocial Questionnaire Data.

Background/Objectives: Given the limited success in treating functional gastrointestinal disorders (FGIDs) through conventional methods, there is a pressing need for tailored treatments that account for the heterogeneity and biopsychosocial factors associated with FGIDs. Here, we considered the potential of novel subtypes of FGIDs based on biopsychosocial information. Methods: We collected data from 198 FGID patients utilizing an integrative approach that included the traditional Korean medicine diagnosis questionnaire for digestive symptoms (KM), as well as the 36-item Short Form Health Survey (SF-36), alongside the conventional Rome-criteria-based Korean Bowel Disease Questionnaire (K-BDQ). Multivariate analyses were conducted to assess whether KM or SF-36 provided additional information beyond the K-BDQ and its statistical relevance to symptom severity. Questions related to symptom severity were selected using an extremely randomized trees (ERT) regressor to develop an integrative questionnaire. For the identification of novel subtypes, Uniform Manifold Approximation and Projection and spectral clustering were used for nonlinear dimensionality reduction and clustering, respectively. The validity of the clusters was assessed using certain metrics, such as trustworthiness, silhouette coefficient, and accordance rate. An ERT classifier was employed to further validate the clustered result. Results: The multivariate analyses revealed that SF-36 and KM supplemented the psychosocial aspects lacking in K-BDQ. Through the application of nonlinear clustering using the integrative questionnaire data, four subtypes of FGID were identified: mild, severe, mind-symptom predominance, and body-symptom predominance. Conclusions: The identification of these subtypes offers a framework for personalized treatment strategies, thus potentially enhancing therapeutic outcomes by tailoring interventions to the unique biopsychosocial profiles of FGID patients.

Therapeutic strategies to improve liver regeneration after hepatectomy.

Chronic liver disease is one of the most common diseases worldwide, and its prevalence is particularly high among adults aged 40-60 years; it takes a toll on productivity and causes significant economic burden. However, there are still no effective treatments that can fundamentally treat chronic liver disease. Although liver transplantation is considered the only effective treatment for chronic liver disease, it has limitations in that the pool of available donors is vastly insufficient for the number of potential recipients. Even if a patient undergoes liver transplantation, side effects such as immune rejection or bile duct complications could occur. In addition, impaired liver regeneration due to various causes, such as aging and metabolic disorders, may cause liver failure after liver resection, even leading to death. Therefore, further research on the liver regeneration process and therapeutic strategies to improve liver regeneration are needed. In this review, we describe the process of liver regeneration after hepatectomy, focusing on various cytokines and signaling pathways. In addition, we review treatment strategies that have been studied to date to improve liver regeneration, such as promotion of hepatocyte proliferation and metabolism and transplantation of mesenchymal stem cells. This review helps to understand the physiological processes involved in liver regeneration and provides basic knowledge for developing treatments for successful liver regeneration.

Targeted Deletion of Thymosin Beta 4 in Hepatic Stellate Cells Ameliorates Liver Fibrosis in a Transgenic Mouse Model.

Liver fibrosis is the most common feature of liver disease, and activated hepatic stellate cells (HSCs) are the main contributors to liver fibrosis. Thus, finding key targets that modulate HSC activation is important to prevent liver fibrosis. Previously, we showed that thymosin ß4 (Tß4) influenced HSC activation by interacting with the Hedgehog pathway in vitro. Herein, we generated Tß4 conditional knockout (Tß4-flox) mice to investigate in vivo functions of Tß4 in liver fibrosis. To selectively delete Tß4 in activated HSCs, double-transgenic (DTG) mice were generated by mating Tß4-flox mice with α-smooth muscle actin (α-Sma)-Cre-ERT2 mice, and these mice were administered carbon tetrachloride (CCl4) or underwent bile duct ligation to induce liver fibrosis. Tß4 was selectively suppressed in the activated HSCs of DTG mouse liver, and this reduction attenuated liver injury, including fibrosis, in both fibrotic models by repressing Hedgehog (Hh) signaling. In addition, the re-expression of Tß4 by an adeno-associated virus reversed the effect of HSC-specific Tß4 deletion and led to liver fibrosis with Hh activation in CCl4-exposed mice treated with tamoxifen. In conclusion, our results demonstrate that Tß4 is a crucial regulator of HSC activation, suggesting it as a novel therapeutic target for curing liver fibrosis.

Formyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is an important health concern worldwide and progresses into nonalcoholic steatohepatitis (NASH). Although prevalence and severity of NAFLD/NASH are higher in men than premenopausal women, it remains unclear how sex affects NAFLD/NASH pathophysiology. Formyl peptide receptor 2 (FPR2) modulates inflammatory responses in several organs; however, its role in the liver is unknown. Here we show that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH. NASH-like liver injury was induced in both sexes during choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) feeding, but compared with females, male mice had more severe hepatic damage. Fpr2 was more highly expressed in hepatocytes and healthy livers from females than males, and FPR2 deletion exacerbated liver damage in CDAHFD-fed female mice. Estradiol induced Fpr2 expression, which protected hepatocytes and the liver from damage. In conclusion, our results demonstrate that FPR2 mediates sex-specific responses to diet-induced NAFLD/NASH, suggesting a novel therapeutic target for NAFLD/NASH.

A System-Level Mechanism of Anmyungambi Decoction for Obesity: A Network Pharmacological Approach.

Obesity is a low-grade systemic inflammatory disease involving adipocytokines. As though Anmyungambi decoction (AMGB) showed significant improvement on obesity in a clinical trial, the molecular mechanism of AMGB in obesity remains unknown. Therefore, we explored the potential mechanisms of action of AMGB on obesity through network pharmacological approaches. We revealed that targets of AMGB are significantly associated with obesity-related and adipocyte-elevated genes. Evodiamine, berberine, genipin, palmitic acid, genistein, and quercetin were shown to regulate adipocytokine signaling pathway proteins which mainly involved tumor necrosis factor receptor 1, leptin receptor. In terms of the regulatory pathway of lipolysis in adipocytes, norephedrine, pseudoephedrine, quercetin, and limonin were shown to affect adrenergic receptor-beta, protein kinase A, etc. We also found that AMGB has the potentials to enhance the insulin signaling pathway thereby preventing type II diabetes mellitus. Additionally, AMGB was discovered to be able to control not only insulin-related proteins but also inflammatory mediators and apoptotic regulators and caspases, hence reducing hepatocyte injury in nonalcoholic fatty liver disease. Our findings help develop a better understanding of how AMGB controls obesity.

Effect of Roasting Time and Cryogenic Milling on the Physicochemical Characteristics of Dried Ginseng Powder.

This study aimed to evaluate the effect of reduced particle size of ginseng by roasting and cryogenic milling on increasing its water solubility and physiological activity. The samples were roasted for different times (9-21 min) and generated in different sizes (10-50, and >50 µm). All roasted samples revealed significantly smaller particle sizes than did non-roasted samples, based on Sauter mean diameter (D [3,2], p < 0.05). Furthermore, the particle sizes of roasted samples decreased until roasting up to 15 min. In terms of the water solubility index (WSI), antioxidant activity, total polyphenol content (TPC), and total polysaccharides according to particle size, 10-20 µm-sized samples showed the highest values when compared with >50 µm-sized samples. Based on roasting time, WSI values of all samples roasted for up to 15 min were higher than those of the control (not roasted) (p < 0.05). Antioxidant activity and TPC also increased with increasing roasting time. Total polysaccharide content was the highest upon roasting for 15 min, except for the 10-20 µm sample. Ginsenoside content of roasted samples >20 µm size was higher than that of the control (not roasted) except after 15 min of roasting. Therefore, roasting and cryogenic milling are effective in producing ginseng root powder.