Emodin promotes hepatic stellate cell senescence and alleviates liver fibrosis via a nuclear receptor (Nur77)-mediated epigenetic regulation of glutaminase 1.

BACKGROUND AND PURPOSE: Senescence in hepatic stellate cells (HSCs) limits liver fibrosis. Glutaminolysis promotes HSC activation. Here, we investigated how emodin affected HSC senescence involving glutaminolysis. EXPERIMENTAL APPROACH: Senescence, glutaminolysis metabolites, Nur77 nuclear translocation, glutaminase 1 (GLS1) promoter methylation and related signalling pathways were examined in human HSC-LX2 cells using multiple cellular and molecular approaches. Fibrotic mice with shRNA-mediated knockdown of Nur77 were treated with emodin-vitamin A liposome for investigating the mechanisms in vivo. Human fibrotic liver samples were examined to verify the clinical relevance. KEY RESULTS: Emodin upregulated several key markers of senescence and inhibited glutaminolysis cascade in HSCs. Emodin promoted Nur77 nuclear translocation, and knockdown of Nur77 abolished emodin blockade of glutaminolysis and induction of HSC senescence. Mechanistically, emodin facilitated Nur77/DNMT3b interaction and increased GLS1 promoter methylation, leading to inhibited GLS1 expression and blockade of glutaminolysis. Moreover, the glutaminolysis intermediate α-ketoglutarate promoted extracellular signal-regulated kinase (ERK) phosphorylation, which in turn phosphorylated Nur77 and reduced its interaction with DNMT3b. This led to decreased GLS1 promoter methylation and increased GLS1 expression, forming an ERK/Nur77/glutaminolysis positive feedback loop. However, emodin repressed ERK phosphorylation and interrupted the feedback cascade, stimulating senescence in HSCs. Studies in mice showed that emodin-vitamin A liposome inhibited glutaminolysis and induced senescence in HSCs, and consequently alleviated liver fibrosis; but knockdown of Nur77 abrogated these beneficial effects. Similar alterations were validated in human fibrotic liver tissues. CONCLUSIONS AND IMPLICATIONS: Emodin stimulated HSC senescence through interruption of glutaminolysis. HSC-targeted delivery of emodin represented a therapeutic option for liver fibrosis.

The roles of hepatokine and osteokine in liver-bone crosstalk: Advance in basic and clinical aspects.

Both the liver and bone are important secretory organs in the endocrine system. By secreting organ factors (hepatokines), the liver regulates the activity of other organs. Similarly, bone-derived factors, osteokines, are created during bone metabolism and act in an endocrine manner. Generally, the dysregulation of hepatokines is frequently accompanied by changes in bone mass, and osteokines can also disrupt liver metabolism. The crosstalk between the liver and bone, particularly the function and mechanism of hepatokines and osteokines, has increasingly gained notoriety as a topic of interest in recent years. Here, based on preclinical and clinical evidence, we summarize the potential roles of hepatokines and osteokines in liver-bone interaction, discuss the current shortcomings and contradictions, and make recommendations for future research.

Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway.

Background and Aims: Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin. Methods: The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro. Results: Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis. Conclusions: Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.

O-GlcNAcylation Coordinates Glutaminolysis by Regulating the Stability and Membrane Trafficking of ASCT2 in Hepatic Stellate Cells.

Background and Aims: Recognition of excessive activation of hepatic stellate cells (HSCs) in liver fibrosis prompted us to investigate the regulatory mechanisms of HSCs. We aimed to examine the role of O-GlcNAcylation modification of alanine, serine, cysteine transporter 2 (ASCT2) in HSCs and liver fibrosis. Methods: The expression of O-GlcNAcylation modification in fibrotic mice livers and activated HSCs was analyzed by western blotting. Immunoprecipitation was used to assess the interaction of ASCT2 and O-GlcNAc transferase (OGT). In addition, ASCT2 protein stability was assayed after cycloheximide (CHX) treatment. The O-GlcNAcylation site of ASCT2 was predicted and mutated by site-directed mutagenesis. Real-time PCR, immunofluorescence, kit determinations and Seahorse assays were used to clarify the effect of ASCT2 O-GlcNAcylation on HSC glutaminolysis and HSC activation. Western blotting, immunochemistry, and immunohistofluorescence were used to analyze the effect of ASCT2 O-GlcNAcylation in vivo. Results: We observed significantly increased O-GlcNAcylation modification of ASCT2. ASCT2 was found to interact with OGT to regulate ASCT2 stability. We predicted and confirmed that O-GlcNAcylation of ASCT2 at Thr122 site resulted in HSCs activation. We found Thr122 O-GlcNAcylation of ASCT2 mediated membrane trafficking of glutamine transport and attenuated HSC glutaminolysis. Finally, we validated the expression and function of ASCT2 O-GlcNAcylation after injection of AAV8-ASCT2 shRNA in CCl4-induced liver fibrosis mice in vivo. Conclusions: Thr122 O-GlcNAcylation regulation of ASCT2 resulted in stability and membrane trafficking-mediated glutaminolysis in HSCs and liver fibrosis. Further studies are required to assess its role as a putative therapeutic target.

Qingchang Wenzhong Decoction reduce ulcerative colitis in mice by inhibiting Th17 lymphocyte differentiation.

BACKGROUND: Qingchang Wenzhong Decoction (QCWZD), a chinese herbal prescription, is widely used for ulcerative colitis (UC). Nevertheless, the active ingredients and mechanism of QCWZD in UC have not yet been explained clearly. PURPOSE: This research focuses on the identification of the effective ingredients of QCWZD and the prediction and verification of their potential targets. METHODS: The UC mice were established by adding 3.0% dextran sulfate sodium (DSS) to sterile water for one week. Concurrently, mice in the treatment group were gavage QCWZD or mesalazine. LC-MS analyzed the main components absorbed after QCWZD treatment, and network pharmacology predicted their possible targets. ELISA, qPCR, immunohistochemistry and immunofluorescence experiments were used to evaluate the colonic inflammation level and the intestinal barrier completeness. The percentage of Th17 and Treg lymphocytes was detected by flow cytometry. RESULTS: After QCWZD treatment, twenty-seven compounds were identified from the serum. In addition, QCWZD treatment significantly reduced the increased myeloperoxidase (MPO) and inflammatory cell infiltration caused by DSS in the colonic. In addition, QCWZD can reduce the secretion of inflammatory factors in serum and promote the expression of mRNAs and proteins of occludin and ZO-1. Network pharmacology analysis indicated that inhibiting IL-6-STAT3 pathway may be necessary for QCWZD to treat UC. Flow cytometry analysis showed that QCWZD can restore the normal proportion of Th17 lymphocytes in UC mice. Mechanistically, QCWZD inhibited the phosphorylation of JAK2-STAT3 pathway, reducing the transcriptional activation of RORγT and IL-17A. CONCLUSIONS: Overall, for the first time, our work revealed the components of QCWZD absorbed into blood, indicated that the effective ingredients of QCWZD may inhibit IL-6-STAT3 pathway and inhibit the differentiation of Th17 lymphocytes to reduce colon inflammation.

Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis.

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). But little is known about how alanine-serine-cysteine transporter type-2 (ASCT2), a high affinity glutamine transporter, affects HSC senescence and SASP during liver fibrosis. Here, we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers. We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo. The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration. Mechanically, ASCT2 was a direct target of glutaminolysis-dependent proinflammatory SASP, interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82. From a translational perspective, atractylenolide III is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2. The presence of -OH group in atractylenolide III is suggested to be favorable for the inhibition of ASCT2. Importantly, atractylenolide III could be utilized to treat liver fibrosis mice. Taken together, ASCT2 controlled HSC senescence while modifying the proinflammatory SASP. Targeting ASCT2 by atractylenolide III could be a therapeutic candidate for liver fibrosis.

Investigating the Obsessive and Compulsive Features of Cyberchondria: A Holistic Review.

Background: Cyberchondria has been brought into sharp focus during the COVID-19 health emergency; it refers to individuals who obsessively and compulsively search for health information online, resulting in excessive health concerns. Recent scholarship focuses on its obsessive and compulsive aspect, following a biopsychosocial approach as opposed to a pathology of health anxiety. It lacks interpretation of the socio-psychological dynamics between the dimensions. Objective: This review aims to propose a holistic view toward understanding cyberchondria as an obsessive-compulsive syndrome and considers possible interventions. It specifically seeks to explain cyberchondria from diversified mediator variables and to pinpoint connections between each perspective. Methodology: Comprehensive searches of databases such as PubMed and Springer were conducted to identify English articles relating to cyberchondria from 2001 to 2022. Based on a systematic filtering process, 27 articles were finally reviewed. Findings: The authors compare and confirm three forecasts to predict cyberchondria, associating it with individual metacognition, uncertainty of unverified information, and algorithm-driven, biased information environments. Value: Theoretically, a holistic framework is proposed to explain the obsessive and compulsive features of cyberchondria. Clinically, the research calls for more professional psychoeducation and chain screening of cyberchondria and other psychological disorders. Socially, it promotes support for risk-sensitive, information-deficient groups during pandemics like COVID-19. It also stresses more careful use of algorithm-driven search engine technology for platforms delivering medical information. Future research may explore areas such as the association between cyberchondria and other social-related disorders, as well as correlations among cyberchondria, obsessive and compulsive disorders, medical trust, and algorithm-driven search results.

Crosstalk Between Autophagy and Innate Immunity: A Pivotal Role in Hepatic Fibrosis.

Liver fibrosis is a repair process of chronic liver injuries induced by toxic substances, pathogens, and inflammation, which exhibits a feature such as deposition of the extracellular matrix. The initiation and progression of liver fibrosis heavily relies on excessive activation of hepatic stellate cells (HSCs). The activated HSCs express different kinds of chemokine receptors to further promote matrix remodulation. The long-term progression of liver fibrosis will contribute to dysfunction of the liver and ultimately cause hepatocellular carcinoma. The liver also has abundant innate immune cells, including DCs, NK cells, NKT cells, neutrophils, and Kupffer cells, which conduct complicated functions to activation and expansion of HSCs and liver fibrosis. Autophagy is one specific type of cell death, by which the aberrantly expressed protein and damaged organelles are transferred to lysosomes for further degradation, playing a crucial role in cellular homeostasis. Autophagy is also important to innate immune cells in various aspects. The previous studies have shown that dysfunction of autophagy in hepatic immune cells can result in the initiation and progression of inflammation in the liver, directly or indirectly causing activation of HSCs, which ultimately accelerate liver fibrosis. Given the crosstalk between innate immune cells, autophagy, and fibrosis progression is complicated, and the therapeutic options for liver fibrosis are quite limited, the exploration is essential. Herein, we review the previous studies about the influence of autophagy and innate immunity on liver fibrosis and the molecular mechanism to provide novel insight into the prevention and treatment of liver fibrosis.

Curcumol alleviates liver fibrosis by inducing endoplasmic reticulum stress-mediated necroptosis of hepatic stellate cells through Sirt1/NICD pathway.

Liver fibrosis is a repair response process after chronic liver injury. During this process, activated hepatic stellate cells (HSCs) will migrate to the injury site and secrete extracellular matrix (ECM) to produce fibrous scars. Clearing activated HSCs may be a major strategy for the treatment of liver fibrosis. Curcumol isolated from plants of the genus Curcuma can effectively induce apoptosis of many cancer cells, but whether it can clear activated HSCs remains to be clarified. In the present study, we found that the effect of curcumol in treating liver fibrosis was to clear activated HSCs by inducing necroptosis of HSCs. Receptor-interacting protein kinase 3 (RIP3) silencing could impair necroptosis induced by curcumol. Interestingly, endoplasmic reticulum (ER) stress-induced cellular dysfunction was associated with curcumol-induced cell death. The ER stress inhibitor 4-PBA prevented curcumol-induced ER stress and necroptosis. We proved that ER stress regulated curcumol-induced necroptosis in HSCs via Sirtuin-1(Sirt1)/Notch signaling pathway. Sirt1-mediated deacetylation of the intracellular domain of Notch (NICD) led to degradation of NICD, thereby inhibiting Notch signalling pathway to alleviate liver fibrosis. Specific knockdown of Sirt1 by HSCs in male ICR mice further exacerbated CCl4-induced liver fibrosis. Overall, our study elucidates the anti-fibrotic effect of curcumol and reveals the underlying mechanism between ER stress and necroptosis.

Modification of lysine deacetylation regulates curcumol-induced necroptosis through autophagy in hepatic stellate cells.

The excessive deposition of extracellular matrix (ECM) is the main characteristic of liver fibrosis, and hepatic stellate cells (HSCs) are the main source of ECM. The removal of activated HSCs has a reversal effect on liver fibrosis. Western blot and MTT analysis indicated that curcumol could relieve hepatic fibrosis by promoting HSCs receptor-interacting protein kinase 1/3 (RIP1/RIP3)-dependent necroptosis. Importantly, autophagy flow was monitored by constructing the mRFP-GFP-LC3 plasmid, and it was found that curcumol cleared activated HSCs in a necroptosis manner that was dependent on autophagy. Our study suggested that the activation of necrosome formed by RIP1 and RIP3 depended on Atg5, and that autophagosomes were also necessary for curcumol-induced necroptosis. Furthermore, microscale thermophoresis and co-immunoprecipitation assay results proved that curcumol could target Sirt1 to regulate autophagy by reducing the acetylation level of Atg5. The HSCs-specific silencing of Sirt1 exacerbated CCl4 -induced liver fibrosis in mice. The deacetylation of Atg5 not only accelerated the accumulation of autophagosomes but also enhanced the interaction between Atg5 and RIP1/RIP3 to induce necroptosis. Overall, our study indicated that curcumol could activate Sirt1 to promote Atg5 deacetylation and enhanced its protein-protein interaction function, thereby inducing autophagy and promoting the necroptosis of HSCs to reduce liver fibrosis.

Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15-LO.

Relevant researches have recognized the vital role of inducing ferroptosis in the treatment of tumor. The latest findings indicate that PEBP1/15-LO can play an essential role in the process of cell death. However, its role in regulating ferroptosis in hepatocellular carcinoma (simplified by HCC) remains unclear. The previous research of our team has proved that DHA can induce ferroptosis of hepatic stellate cells. In this study, we found that DHA could also induce ferroptosis in HCC cells. Interestingly, DHA induced ferroptosis by promoting the formation of PEBP1/15-LO and promoting cell membrane lipid peroxidation. In addition, we also found that DHA had no obvious regulatory effect on 15-LO, but it could promote PEBP1 protein expression. Importantly, we discovered the upregulation of PEBP1 induced by DHA was related to the inhibition of its ubiquitination degradation. In vivo experiments have also obtained consistent results that DHA can inhibit tumor growth and affect the expression of ferroptosis markers in tumor tissues, which would be partially offset by interference with PEBP1.

Influential Factors on Collective Anxiety of Online Topic-Based Communities.

Background: Under the uncertainty led by the decentralized information on social media, people seek homogeneity in either opinions or affection to establish group identity to better understand the information. This also means they are easily polarized, not only ideologically but also in their actions. Affective polarization is the emotional tendency for people to show animosity toward opposing partisans while seeking homogeneity from fellow partisans. Much research into online affective polarization has focused on quantifying anxiety at an individual level while neglecting that on a collective basis. Therefore, this paper examined the polarization of collective anxiety in topic-based communities on Weibo. Methods: We aim to interpret correlations between collective anxiety online and topic characteristics, user competence, as well as the proportion of influencers of Weibo topic-based communities. Our neural networks model and statistical analysis were based on 200 communities with 403,380 personal accounts and 1,012,830 messages. Results: Collective anxiety levels are correlated to (1) the extent to which a topic captures public interest, (2) how community members articulate topics on social network platforms, and (3) the ratio of influencers in the community. Specifically, people's conflicting perceptions and articulations of topics might increase collective anxiety, while the extent to which a topic is of the public interest and the number of influencers engaged in a topic account for any decline in its ranking. Furthermore, familiarity with a topic does not help predict collective anxiety levels. There are no significant links between community size or interactivity dynamics and the level of collective anxiety in the topic-based community. Our computational model has 85.00% precision and 87.00% recall. Conclusion: This study found the collective anxiety augment due to topic proximities to public interest and members' lack of declarative knowledge on topics, while to decline with an increasing portion of online influencers. These findings indicate that collective anxiety is induced due to a lack of credibility. Also, the amount of conflicting information shared by different people places them in a state of flux. Therefore, a community with more influencers may be more likely to experience anxiety polarization, bringing forth the issue of layered information and inequality.

The mechanism research on the anti-liver fibrosis of emodin based on network pharmacology.

AIMS: This study was designated to illustrate the underlying mechanisms of emodin anti-liver fibrosis via network pharmacology and experiment. METHODS: The TSMCP and Genecards database were applied to screen the relevant targets of emodin or liver fibrosis. The essential target was selected by using Cytoscape to analyze the topological network of potential targets. Furthermore, we constructed a preliminary molecule docking study to explore the binding site by Surflex-Dock suite SYBYL X 2.0. The DAVID database was selected for gene functional annotations and KEGG enrichment analysis. Moreover, we demonstrated the ameliorating effect of emodin on carbon tetrachloride (CCl4 )-induced liver injury in mice. We also verified the network predictions in vitro via various techniques. RESULTS: The collected results showed that 35 targets were related to emodin, and 6,198 targets were associated with liver fibrosis. The Venn analysis revealed that 17 intersection targets were correlated with emodin anti-liver fibrosis. The topological network analysis suggested that the p53 was the remarkable crucial target. Besides, the molecule docking results showed that emodin could directly interact with p53 by binding the active site residues ASN345, GLN331, and TYR347. Finally, KEGG pathway enrichment results indicated that essential genes were mainly enriched in mitogen-activated protein kinase (MAPK) signaling pathways. Moreover, our study confirmed that emodin alleviated CCl4 -induced liver injury in mice, inducing hepatic stellate cells (HSCs) apoptosis via regulating the p53/ERK/p38 axis. CONCLUSIONS: This study partially verified the network pharmacological prediction of emodin inducing HSCs cell apoptosis through the p53/ERK/p38 axis.

Yi-Qi-Jian-Pi Formula Suppresses RIPK1/RIPK3-Complex-Dependent Necroptosis of Hepatocytes Through ROS Signaling and Attenuates Liver Injury in Vivo and in Vitro.

Acute-on-chronic liver failure (ACLF) is described as a characteristic of acute jaundice and coagulation dysfunction. Effective treatments for ACLF are unavailable and hence are urgently required. We aimed to define the effect of Yi-Qi-Jian-Pi Formula (YQJPF) on liver injury and further examine the molecular mechanisms. In this study, we established CCl4-, LPS-, and d-galactosamine (D-Gal)-induced ACLF rat models in vivo and LPS- and D-Gal-induced hepatocyte injury models in vitro. We found that YQJPF significantly ameliorates liver injury in vivo and in vitro that is associated with the regulation of hepatocyte necroptosis. Specifically, YQJPF decreased expression of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and pseudokinase mixed lineage kinase domain-like (MLKL) to inhibit the migration of RIPK1 and RIPK3 into necrosome. YQJPF also reduces the expression of inflammatory cytokines IL-6, IL-8, IL-1ß, and TNF-α, which were regulated by RIPK3 mediates cell death. RIPK1 depletion was found to enhance the protective effect of YQJPF. Furthermore, we showed that YQJPF significantly downregulates the mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization, with ROS scavenger, 4-hydroxy-TEMPO treatment recovering impaired RIPK1-mediated necroptosis and reducing the expression of IL-6, IL-8, IL-1ß, and TNF-α. In summary, our study revealed the molecular mechanism of protective effect of YQJPF on hepatocyte necroptosis, targeting RIPK1/RIPK3-complex-dependent necroptosis via ROS signaling. Overall, our results provided a novel perspective to indicate the positive role of YQJPF in ACLF.

Methionine metabolism in chronic liver diseases: an update on molecular mechanism and therapeutic implication.

As one of the bicyclic metabolic pathways of one-carbon metabolism, methionine metabolism is the pivot linking the folate cycle to the transsulfuration pathway. In addition to being a precursor for glutathione synthesis, and the principal methyl donor for nucleic acid, phospholipid, histone, biogenic amine, and protein methylation, methionine metabolites can participate in polyamine synthesis. Methionine metabolism disorder can aggravate the damage in the pathological state of a disease. In the occurrence and development of chronic liver diseases (CLDs), changes in various components involved in methionine metabolism can affect the pathological state through various mechanisms. A methionine-deficient diet is commonly used for building CLD models. The conversion of key enzymes of methionine metabolism methionine adenosyltransferase (MAT) 1 A and MAT2A/MAT2B is closely related to fibrosis and hepatocellular carcinoma. In vivo and in vitro experiments have shown that by intervening related enzymes or downstream metabolites to interfere with methionine metabolism, the liver injuries could be reduced. Recently, methionine supplementation has gradually attracted the attention of many clinical researchers. Most researchers agree that adequate methionine supplementation can help reduce liver damage. Retrospective analysis of recently conducted relevant studies is of profound significance. This paper reviews the latest achievements related to methionine metabolism and CLD, from molecular mechanisms to clinical research, and provides some insights into the future direction of basic and clinical research.

Endoplasmic reticulum stress and protein degradation in chronic liver disease.

Endoplasmic reticulum (ER) stress is easily observed in chronic liver disease, which often causes accumulation of unfolded or misfolded proteins in the ER, leading to unfolded protein response (UPR). Regulating protein degradation is an integral part of UPR to relieve ER stress. The major protein degradation system includes the ubiquitin-proteasome system (UPS) and autophagy. All three arms of UPR triggered in response to ER stress can regulate UPS and autophagy. Accumulated misfolded proteins could activate these arms, and then generate various transcription factors to regulate the expression of UPS-related and autophagy-related genes. The protein degradation process regulated by UPR has great significance in many chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, liver fibrosis, and hepatocellular carcinoma(HCC). In most instances, the degradation of excessive proteins protects cells with ER stress survival from apoptosis. According to the specific functions of protein degradation in chronic liver disease, choosing to promote or inhibit this process is promising as a potential method for treating chronic liver disease.

Liver regeneration in traditional Chinese medicine: advances and challenges.

Liver diseases pose a serious problem for national health care system all over the world. Liver regeneration has profound impacts on the occurrence and development of various liver diseases, and it remains an extensively studied topic. Although current knowledge has suggested two major mechanisms for liver regeneration, including compensatory hyperplasia of hepatocytes and stem or progenitor cell-mediated regeneration, the complexity of this physiopathological process determines that its effective regulation cannot be achieved by single-target or single-component approaches. Alternatively, using traditional Chinese medicine (TCM) to regulate liver regeneration is an important strategy for prevention and treatment of liver disorder and the related diseases. From the perspectives of TCM, liver regeneration can be caused by the disrupted balance between hepatic damage and regenerative capacity, and the "marrow"-based approaches have important therapeutic implications for liver regeneration. These two points have been massively supported by a number of basic studies and clinical observations during recent decades. TCM has the advantages of overall dynamic fine-tuning and early adjustment, and has exhibited enormous therapeutic benefits for various liver diseases. Here, we review the recent advances in the understanding of liver regeneration in TCM system in the hope of facilitating the application of TCM for liver diseases via regulation of liver regeneration.

Astaxanthin ameliorates experimental diabetes-induced renal oxidative stress and fibronectin by upregulating connexin43 in glomerular mesangial cells and diabetic mice.

Oxidative stress is the major cause of renal fibrosis in the progression of DN. Connexin43 (Cx43) exerts an anti-fibrosis effect on diabetic kidneys. The current study aimed to investigate whether astaxanthin (AST) could ameliorate the pathological progression of DN by upregulating Cx43 and activating the Nrf2/ARE signaling, which is a pivotal anti-oxidative stress system, to strengthen the cellular anti-oxidative capacity and diminish fibronectin (FN) accumulation in HG-induced glomerular mesangial cells (GMCs). Our hypothesis was verified in GMCs and the kidneys from db/db mice by western blot, immunofluorescence, immunohistochemistry, immunoprecipitation, dual luciferase reporter assay and reactive oxygen related detection kits. Results showed that AST simultaneously upregulated the Cx43 protein level and promoted the Nrf2/ARE signaling activity in the kidney of db/db mice and HG-treated GMCs. However, Cx43 depletion abrogated the Nrf2/ARE signaling activation induced by AST. AST reduced the interaction between c-Src and Nrf2 in the nuclei of GMCs cultured with HG, thereby enhancing the Nrf2 accumulation in the nuclei of GMCs. Our data suggested that AST promoted the Nrf2/ARE signaling by upregulating the Cx43 protein level to prevent renal fibrosis triggered by HG in GMCs and db/db mice. c-Src acted as a mediator in these processes.