• Chronic inflammation
• Hepatocellular carcinoma
• Macrophages
• Microenvironment
• Tumorigenesis

• Humans
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/immunology
• Liver Neoplasms/therapy
• Macrophages/immunology
• Macrophages/pathology
• Macrophages/metabolism
• Tumor Microenvironment/immunology
• Animals
• Disease Progression
• Hepatitis/pathology
• Hepatitis/immunology
• Hepatitis/metabolism
• Macrophage Activation

• active targeting
• biomimetic nanoparticle
• hepatic stellate cell
• hepatic stellate cell membrane
• liver fibrosis

• Hepatic Stellate Cells/drug effects
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/pathology
• Animals
• Mice
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/pathology
• Nanoparticles/chemistry
• Antifibrotic Agents/pharmacology
• Antifibrotic Agents/chemistry
• Cell Membrane/drug effects
• Cell Membrane/metabolism
• Apoptosis/drug effects
• Humans
• Drug Delivery Systems
• Polylactic Acid-Polyglycolic Acid Copolymer/chemistry

• Liver Regeneration
• Humans
• Necrosis
• Liver/pathology
• Animals
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/pathology

• Intramural program of the NIAAA NIAAA NIH HHS

• antioxidants
• fibrosis
• inflammation
• oxidative stress

• Rats
• Animals
• NF-kappa B/metabolism
• Antioxidants/pharmacology
• Antioxidants/metabolism
• Carbon Tetrachloride/toxicity
• Actins/metabolism
• Actins/pharmacology
• Tumor Necrosis Factor-alpha/metabolism
• Cyclooxygenase 2/metabolism
• Liver/metabolism
• Signal Transduction
• Oxidative Stress
• Inflammation/metabolism
• Anti-Inflammatory Agents/pharmacology
• Chemical and Drug Induced Liver Injury/metabolism
• Aporphines

• Carbon tetrachloride
• cytochromes
• hepatotoxicity
• inflammation
• liver
• oxidative stress.

• Humans
• Carbon Tetrachloride/toxicity
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Animals
• Liver/metabolism
• Liver/pathology
• Liver/drug effects
• Cytokines/metabolism
• Apoptosis/drug effects

• 2019-1075 Ministry of Science and Higher Education of the Russian Federation

• Circulating miRNA
• Hepatic stellate cell
• Liver fibrosis
• Non-alcoholic fatty liver disease
• Non-invasive diagnosis

• Cell viability
• Cellular inhibitor of apoptosis-1/2 (cIAP1/2)
• Hepatic stellate cells
• Inhibitor of apoptosis (IAP)
• Macrophage subtype
• Tumor necrosis factor-α (TNFα)

• carbon tetrachloride
• hepatic stellate cells
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis
• transforming growth factor β1

• Male
• Mice
• Female
• Animals
• Transforming Growth Factor beta1/pharmacology
• Matrix Metalloproteinase 2/metabolism
• Estradiol/pharmacology
• Estradiol/metabolism
• Longevity
• Hepatic Stellate Cells/metabolism
• Hepatic Stellate Cells/pathology
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Liver/metabolism
• Collagen/metabolism

• R56 AG067754 NIA NIH HHS
• R01 AG070035 NIA NIH HHS
• R01 AG059430 NIA NIH HHS
• R01 DK131064 NIDDK NIH HHS
• R01 DK117965 NIDDK NIH HHS
• I01 BX003906 BLRD VA
• IK6 BX006033 BLRD VA
• HHS | NIH | National Institute on Aging (NIA)
• U.S. Department of Veterans Affairs (VA)

• NF-κB signaling
• acute liver injury
• apoptosis
• lncRNA
• oxidative stress

Liver fibrosis is a highly conserved wound healing response to liver injury, characterized by excessive deposition of extracellular matrix (ECM) in the liver which might lead to loss of normal functions. In most cases, many types of insult could damage hepatic parenchymal cells like hepatocytes and/or cholangiocytes, and persistent injury might lead to initiation of fibrosis. This process is accompanied by amplified inflammatory responses, with immune cells especially macrophages recruited to the site of injury and activated, in order to orchestrate the process of wound healing and tissue repair. In the liver, both resident macrophages and recruited macrophages could activate interstitial cells which are responsible for ECM synthesis by producing a variety of cytokines and chemokines, modulate local microenvironment, and participate in the regulation of fibrosis. In this review, we will focus on the main pathological characteristics of liver fibrosis, as well as the heterogeneity on origin, polarization and functions of hepatic macrophages in the setting of liver fibrosis and their underlying mechanisms, which opens new perspectives for the treatment of liver fibrosis.

• Fibrosis
• Humans
• Kupffer Cells
• Liver Cirrhosis
• Macrophages

Chronic liver disease is a worldwide health problem. Carbon tetra hydrochloride is an environmental toxin which is regarded as highly toxic and a potential human carcinogen. It can cause liver damage through the generation of metabolites and production of free radicals. Green tea contains catechins such as Epigallocatechin gallate which has been found to reduce the inflammation, oxidative stress, and fibrosis in experimental animal models. Hence, it represents a good source to prevent or ameliorate several chronic diseases. Silymarin is extracted from milk thistle seeds and has been found to be an effective agent to reduce the oxidative stress and free radical production and thereby exert protective effects in chronic liver conditions. The present study was planned to keep in view the above-mentioned facts. We included thirty rats in our study and divided them into five groups, each having six rats and the study continued for 8 weeks. Group I received normal saline; Group 2 received i.p. CCl4 injections; Group 3 received CCl4 i.p. injection and Epigallocatechin gallate (EGCG) oral gavage, Group 4 received CCl4 i.p. injection and silymarin by oral gavage; and Group 5 received CCl4 i.p. injection and combined EGCG + silymarin by oral gavage. The study found that in group 2, CCl4 induced significant elevation of ALT and MDA and reduced GSH thereby signifying increased oxidative stress. CCl4 also significantly increased inflammatory (TNFα, NFκB, IL1β, and TGFβ) as well as fibrotic markers (p-ERK and p-Smad1/2 protein expression). EGCG and silymarin significantly reversed the previously mentioned parameters either alone or in combination; however, the effect was more pronounced in case of EGCG. We conclude that EGCG and silymarin possess liver protective effects through their antioxidant, anti-inflammatory, and antifibrotic action.

• inflammation response
• lipid accumulation
• mesencephalic astrocyte-derived neurotrophic factor
• non-alcoholic steatohepatitis
• nuclear factor-κB
• sterol regulatory element binding protein 1

• Liver fibrosis
• herbal extract
• natural medicine
• “HSCs”

• Biological Products/pharmacology
• Biological Products/therapeutic use
• Fibrosis
• Hepatic Stellate Cells
• Humans
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/prevention & control
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use

Fibrosis is a worldwide public health problem, which typically results from chronic diseases and often leads to organ malfunction. Chronic inflammation has been suggested to be the major trigger for fibrogenesis, yet mechanisms by which inflammatory signals drive fibrogenesis have not been fully elucidated. Total C-21 steroidal glycosides (TCSG) from Baishouwu are the main active components of the root of Cynanchum auriculatum Royle ex Wight, which exert hepatoprotective and anti-inflammation properties. In this study, we established a mouse model with the coexistence of hepatic and renal fibrosis and aimed to investigate the effects of TCSG from Baishouwu on fibrosis and explored the potential mechanisms. The results of biochemical and pathological examinations showed that TCSG from Baishouwu improved liver and kidney function and alleviated hepatic and renal fibrosis by reducing collagen and extracellular matrix deposition in bile duct ligation and unilateral ureteral occlusion (BDL&UUO) mice. According to network pharmacology analysis, the mechanisms underlying the effects of TCSG from Baishouwu on hepatic and renal fibrosis were associated with inflammatory response pathways, including “Signaling by interleukins”, “MAP kinase activation”, “MyD88 cascade initiated on plasma membrane”, and “Interleukin-1 family signaling”. Regression analysis and western blot results revealed that IL-1β/MyD88 inflammation signaling played an essential role in the anti-fibrotic effects of TCSG from Baishouwu. Further data displayed that TCSG from Baishouwu affected inflammatory response and extracellular matrix deposition via suppressing the activation of p38 MAPK/JNK and NF-κB p65 signaling cascades both in the liver and kidney of BDL&UUO mice. Thus, our findings suggest TCSG from Baishouwu as a natural regimen against hepatic and renal fibrosis and provide direct evidence that IL-1β/MyD88 signaling crucially contributes to hepatic and renal fibrosis and modulates liver-kidney crosstalk by maintaining tight control over inflammatory responses.

• IL-1β/MyD88 signaling
• hepatic fibrosis
• inflammation
• renal fibrosis
• total C-21 steroidal glycosides

• chronic intermittent hypoxia
• fibrosis
• hypoxia-inducible factor (HIF)
• inflammation
• metabolism
• non-alcoholic fatty liver disease (NAFLD)
• non-alcoholic steatohepatitis (NASH)
• obstructive sleep apnea

• Wellcome Trust
• Research Councils UK

Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-β1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-β1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.

• ADSCs
• apoptosis
• cell-based therapy
• hepatoprotective pathways
• liver damage
• rapamycin

• hepatic stellate cells
• liver fibrosis
• long non-coding RNAs

• cirrhosis
• fibrosis
• hepatic progenitor cells
• hepatic stellate cells
• hepatocellular carcinoma
• immunosurveillance
• myofibroblasts
• regeneration
• regenerative nodules

• AMPK
• NAD+
• NAFLD
• NF-κB
• PPAR
• SIRT1
• STACs
• cathepsins
• inflammation
• liver

• Animals
• Anti-Inflammatory Agents/therapeutic use
• Humans
• Liver Diseases/drug therapy
• Liver Diseases/metabolism
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Signal Transduction
• Sirtuin 1/genetics
• Sirtuin 1/metabolism

• RTI2018-095572-B-I00 Ministerio de Ciencia e Innovación
• RTI2018-095672-B-I00 Ministerio de Ciencia e Innovación
• PI19/01410 Instituto de Salud Carlos III
• PI19/01410, RTI2018-095572-B-I00, RTI2018-095672-B-I00 European Regional Development Fund

• Cyp2c29
• NF-κB
• hepatocellular carcinoma
• proliferation
• time series gene expression

• Animals
• Carcinoma, Hepatocellular/chemically induced
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Proliferation/genetics
• Cytochrome P450 Family 2/genetics
• Cytokines/metabolism
• Diethylnitrosamine
• Down-Regulation
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Liver Neoplasms/chemically induced
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B/metabolism
• Signal Transduction
• Transcriptome/genetics

Chronic inflammatory cell death is a major risk factor for the development of diverse cancers including liver cancer. Herein, disruption of the hepatic microenvironment as well as the immune cell composition are major determinants of malignant transformation and progression in hepatocellular carcinomas (HCC). Considerable research efforts have focused on the identification of predisposing factors that promote induction of an oncogenic field effect within the inflammatory liver microenvironment. Among the most prominent factors involved in this so-called inflammation-fibrosis-cancer axis is the NF-κB pathway. The dominant role of this pathway for malignant transformation and progression in HCC is well documented. Pathway activation is significantly linked to poor prognostic traits as well as stemness characteristics, which places modulation of NF-κB signaling in the focus of therapeutic interventions. However, it is well recognized that the mechanistic importance of the pathway for HCC is highly context and cell type dependent. While constitutive pathway activation in an inflammatory etiological background can significantly promote HCC development and progression, absence of NF-κB signaling in differentiated liver cells also significantly enhances liver cancer development. Thus, therapeutic targeting of NF-κB as well as associated family members may not only exert beneficial effects but also negatively impact viability of healthy hepatocytes and/or cholangiocytes, respectively. The review presented here aims to decipher the complexity and paradoxical functions of NF-κB signaling in primary liver and non-parenchymal cells, as well as the induced molecular alterations that drive HCC development and progression with a particular focus on (immune-) therapeutic interventions.

• NF-κB signaling
• chronic inflammation
• hepatocarcinogenesis
• hepatocellular carcinoma

• Gentianella turkestanerum
• Hepatic L02 cell
• butanol
• carbon tetrachloride
• hydrogen peroxide
• liver injury.

Currently, there are no effective therapies for liver fibrosis; hence, the development of anti-liver fibrosis agents is urgently needed. Here, we attempted to investigate the therapeutic effect and mechanism of asiatic acid (AA) on liver fibrosis, mainly focusing on the impact of AA on nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor-kappa B (NF-κB)/IκBα, and JAK1/signal transducer and activator of transcription 3 (STAT3) signaling pathways.

Rats were induced liver fibrosis by carbon tetrachloride (CCl₄) for 6 weeks and concomitantly treated with AA (5 and 15 mg/kg) or vehicle by daily gavage. After AA treatment, the morphology of liver tissue was analyzed by H&E and Masson’s trichrome staining, and serum biochemical indicators were also assayed. Thereafter, the protein levels of Nrf2, HO-1, NQO-1, GCLC, NF-κB, IκBα, JAK1, p-JAK1, STAT3, and p-STAT3 were determined by Western blotting.

Our results showed that AA treatment dramatically ameliorated CCl₄-induced oxidative stress, inflammation, and fibrosis in rats. The expression of nuclear Nrf2 was increased after AA treatment, whereas cytoplasm Nrf2 levels were decreased. The protein expression of Nrf2 target proteins including HO-1, NQO-1, and GCLC was significantly increased by AA treatment. Furthermore, AA treatment decreased the levels of nuclear NF-κB to inhibit NF-κB/IκBα signaling pathway. In addition, we also found that AA treatment regulated JAK1/STAT3 signaling by decreasing the phosphorylation levels of JAK1 and STAT3.

These results demonstrate that AA ameliorates CCl₄-induced liver fibrosis in rats by regulating Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways, which suggests that AA might be a new antifibrosis agent that improves liver fibrosis.

• JAK1/STAT3
• NF-κB/IκBα
• Nrf2-ARE
• asiatic acid
• liver fibrosis

• Carbon tetrachloride
• Liver fibrosis
• Mitogen-activated protein kinase
• Nuclear factor kappa B
• Sasa veitchii

• Hydroxyproline
• Nitric oxide
• Nuclear factor-kappaB
• Schistosoma mansoni
• Vinpocetine
• isosorbide-5-mononitrate

Hepatic fibrosis is the wound-healing process of chronic hepatic disease that leads to the end-stage of hepatocellular carcinoma and demolition of hepatic structures. Epithelial–mesenchymal transition (EMT) has been identified to phenotypic conversion of the epithelium to mesenchymal phenotype that occurred during fibrosis. Smad decoy oligodeoxynucleotide (ODN) is a synthetic DNA fragment containing a complementary sequence of Smad transcription factor. Thus, this study evaluated the antifibrotic effects of Smad decoy ODN on carbon tetrachloride (CCl₄)-induced hepatic fibrosis in mice. As shown in histological results, CCl₄ treatment triggered hepatic fibrosis and increased Smad expression. On the contrary, Smad decoy ODN administration suppressed fibrogenesis and EMT process. The expression of Smad signaling and EMT-associated protein was markedly decreased in Smad decoy ODN-treated mice compared with CCl₄-injured mice. In conclusion, these data indicate the practicability of Smad decoy ODN administration for preventing hepatic fibrosis and EMT processes.

• CCl4
• Smad
• decoy
• liver fibrosis
• oligodeoxynucleotide

Heme oxygenase-1 (HO-1) is an antioxidant and cytoprotective protein, which has been proven to alleviate the proliferation of hepatic stellate cells (HSCs) and the development of liver fibrosis. However, the role of HO-1 in HSC apoptosis remains unclear. The aim of the present study was to investigate the effect of HO-1 on HSC apoptosis and its possible underlying mechanisms. HSCs-T6 were incubated with different concentrations of hemin (HO-1 chemical inducer) and Znpp-IX (HO-1 chemical inhibitor) for 12, 24 and 48 h. Cell viability was determined using an MTT assay. HSCs were classified into 4 groups as follows: Control, hemin, Znpp-IX and hemin+Znpp-IX co-treatment groups. Apoptosis was quantitatively measured by Annexin V/propidium iodide double staining and a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The mRNA and protein expression of HO-1, α-smooth muscle actin, B-cell lymphoma (Bcl)-2, caspase-3 and nuclear factor (NF)-κB p65 were measured using quantitative polymerase chain reaction and western blotting. The levels of tumor growth factor (TGF)-β and interleukin (IL)-6 in HSC supernatants were examined by ELISA. The results demonstrated that HO-1 exerted antiproliferative effects on HSCs in a time- and concentration-dependent manner. Increasing HO-1 expression induced HSC apoptosis in vitro as demonstrated by a significant decrease in Bcl-2 and an increase in caspase-3 expression. Additionally, the expression of NF-κB p65 and its downstream inflammatory factors TGF-β and IL-6 in the HO-1 overexpression group was significantly decreased compared with the control group. Therefore, the present study provided evidence that HO-1 serves an anti-fibrosis role in the liver by enhancing HSC apoptosis, which was partially associated with the regulation of NF-κB and its downstream effectors.

• apoptosis
• heme oxygenase-1
• hepatic stellate cells
• nuclear factor-κB
• proliferation
• α-smooth muscle actin

Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1β in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -β1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.

• Dangguiliuhuang decoction
• NF-κB
• PPAR-γ
• hepatic fibrosis
• network pharmacology

• CCL4
• D-Limonene
• antifibrotic
• fibrosis and liver

• Animals
• Anti-Inflammatory Agents/therapeutic use
• Antioxidants/therapeutic use
• Carbon Tetrachloride
• Cyclohexenes/therapeutic use
• Glutathione/metabolism
• Limonene
• Liver/drug effects
• Liver/metabolism
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/metabolism
• Male
• NF-kappa B/metabolism
• Oxidative Stress/drug effects
• Rats, Wistar
• Terpenes/therapeutic use
• Transforming Growth Factor beta/metabolism
• Tumor Necrosis Factor-alpha/metabolism

• Animals
• Glucose Metabolism Disorders/etiology
• Glucose Metabolism Disorders/immunology
• Glucose Metabolism Disorders/metabolism
• Humans
• Immunity, Innate
• Inflammation/immunology
• Inflammation/metabolism
• Systems Integration

• P01 DK074868 NIDDK NIH HHS
• P30 DK063491 NIDDK NIH HHS
• R01 DK101395 NIDDK NIH HHS

As a prototypical pro-inflammatory transcription factor, constitutive activation of NF-κB signaling pathway has been reported in several chronic inflammatory disorders including inflammatory bowel disease, cystic fibrosis, rheumatoid arthritis and cancer. Application of decoy oligodeoxynucleotides (ODNs) against NF-κB, as an effective molecular therapy approach, has brought about several promising outcomes in treatment of chronic inflammatory disorders. However, systematic administration of these genetic constructs is mostly hampered due to their instability, rapid degradation by nucleases and poor cellular uptake. Both chemical modification and application of delivery systems have shown to effectively overcome some of these limitations. Among different administered delivery systems, nanomaterials have gained much attention for delivering NF-κB decoy ODNs owing to their high loading capacity, targeted delivery and ease of synthesis. In this review, we highlight some of the most recently developed nanomaterial-based delivery systems for overcoming limitations associated with clinical application of these genetic constructs.

• NF-κB
• decoy oligodeoxynucleotides
• inflammation
• nanomaterials

• Antifibrotic food components
• Hepatic stellate cells
• Liver disease
• Liver fibrosis
• NAFLD

Angiotensin II (Ang II) promotes hepatic fibrosis by increasing extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF) plays a crucial role in the pathogenesis of hepatic fibrosis and emerges as downstream of the profibrogenic cytokine transforming growth factor-β (TGF-β). We aimed to investigate the molecular events that lead from the Ang II receptor to CTGF upregulation in human hepatic stellate cells, a principal fibrogenic cell type. Ang II produced an early, AT₁ receptor-dependent stimulation of CTGF expression and induced a rapid activation of PKC and its downstream p38 MAPK, thereby activating a nuclear factor-κB (NF-κB) and Smad2/3 cross-talk pathway. Chemical blockade of NF-κB and Smad2/3 signaling synergistically diminished Ang II-mediated CTGF induction and exhibited an additive effect in abrogating the ECM accumulation caused by Ang II. Furthermore, we demonstrated that CTGF expression was essential for Ang II-mediated ECM synthesis. Interestingly, the ability of dephosphorylated, but not phosphorylated JNK to activate Smad2/3 signaling revealed a novel role of JNK in Ang II-mediated CTGF overexpression. These results suggest that Ang II induces CTGF expression and ECM accumulation through a special TGF-β-independent interaction between the NF-κB and Smad2/3 signals elicited by the AT₁/PKCα/p38 MAPK pathway.

Liver injury is a common pathological basis of various liver diseases, and long-term liver injury is often an important initiation factor leading to liver fibrosis and even liver cirrhosis and hepatocellular carcinoma (HCC). It has been reported that deproteinized extract of calf blood (DECB) can inhibit the replication of hepatitis B virus and confers a protective effect on the liver after traumatic liver injury. However, few studies on the regulatory factors and mechanisms of DECB have been reported. In this current study, an acute mouse liver injury model was established with carbon tetrachloride (CCl₄). The differentially expressed genes and related cell signal transduction pathways were screened using mRNA expression microarray. STEM software V1.3.6 was used for clustering gene functions, and the DAVID and KEGG databases were applied for the analysis. A total of 1355 differentially expressed genes were selected, among which nine were validated by RT-qPCR. The results showed that the Fas, IL1b, Pik3r1, Pik3r5, Traf2, Traf2, Csf2rb2, Map3k14, Pik3cd and Ppp3cc genes were involved in the regulation of DECB in an acute mouse liver injury model. Targets of the protective effects of DECB and its related mechanisms were found in mice with acute liver injury induced by carbon tetrachloride, which may provide an important theoretical basis for further DECB research.

• Actihaemyl
• Animals
• Apoptosis/drug effects
• Blood Proteins/metabolism
• Blotting, Western
• Carbon Tetrachloride/toxicity
• Disease Models, Animal
• Liver/injuries
• Liver/metabolism
• Male
• Mice
• Mice, Inbred ICR
• Oxidative Stress/drug effects
• Real-Time Polymerase Chain Reaction
• Signal Transduction/drug effects
• Software

• the Healthe Department of Jilin Province
• Sci-tech Department of Jilin Province

UBC9, the only known E2-conjugating enzyme involved in SUMOylation, is a key regulator in fibrosis. However, the roles of UBC9 in liver fibrosis remain unclear. Therefore, in this study, we investigated the roles of UBC9 in HSC apoptosis and liver fibrogenesis. Our results showed that the UBC9 levels in activated LX-2 cells, HepG2 and SMMC-7721 were increased compared with LO2, and the expression of UBC9 in activated LX-2 cells, HepG2 and SMMC-7721 were no significant differences. The expression of UBC9 was effectively down-regulated by the UBC9-shRNA plasmid, and this effect was accompanied by the attenuated expression of the myofibroblast markers smooth muscle actin (α-SMA) and Collagen I. Downregulation of UBC9 also promotes activated HSCs apoptosis by up-regulating cell apoptosis-related proteins. Further, knockdown of UBC9 in activated HSCs inhibited cell viability and caused cell cycle arrest in the G2 phase. Moreover, knockdown of UBC9 suppressed the activation of NF-κB signaling pathways. In conclusion, these results demonstrated that down-regulation of UBC9 expression induced activated LX-2 cell apoptosis and promoted cells to return to a quiescent state by inhibiting the NF-κB signaling pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of UBC9.

• Actins/genetics
• Actins/metabolism
• Apoptosis
• Blotting, Western
• Cell Line, Tumor
• Collagen Type I/genetics
• Collagen Type I/metabolism
• Flow Cytometry
• Fluorescent Antibody Technique
• Hep G2 Cells
• Hepatic Stellate Cells/metabolism
• Humans
• NF-kappa B/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction/genetics
• Signal Transduction/physiology
• Ubiquitin-Conjugating Enzymes/genetics
• Ubiquitin-Conjugating Enzymes/metabolism

• Animals
• Dendritic Cells/immunology
• Dendritic Cells/pathology
• Hepatic Stellate Cells/immunology
• Hepatic Stellate Cells/pathology
• Hepatitis/immunology
• Hepatitis/pathology
• Humans
• Inflammation/immunology
• Inflammation/pathology
• Kupffer Cells/immunology
• Kupffer Cells/pathology
• Liver/immunology
• Liver/pathology
• Liver Cirrhosis/immunology
• Liver Cirrhosis/pathology
• Myofibroblasts/immunology
• Myofibroblasts/pathology
• Neutrophils/immunology
• Neutrophils/pathology
• T-Lymphocytes/immunology
• T-Lymphocytes/pathology

• P42 ES010337 NIEHS NIH HHS
• P50 AA011999 NIAAA NIH HHS
• U01 AA021856 NIAAA NIH HHS

• 8-hydroxy deoxyguanosine
• Cycloxygenase-2
• Date Fruits
• Liver fibrosis
• Matrix metalloproteinase
• Nuclear factor-kappa B

• Animals
• Carbon Tetrachloride/toxicity
• Cyclooxygenase 2/metabolism
• DNA Damage/drug effects
• Fruit/chemistry
• Heme Oxygenase-1/metabolism
• Liver/drug effects
• Liver/pathology
• Liver Cirrhosis/chemically induced
• Liver Cirrhosis/metabolism
• Male
• NF-kappa B/metabolism
• Phoeniceae/chemistry
• Plant Extracts/chemistry
• Plant Extracts/pharmacology
• Protective Agents/chemistry
• Protective Agents/pharmacology
• Rats
• Rats, Wistar
• Tissue Inhibitor of Metalloproteinases/metabolism

• National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia

• Hepatic stellate cells
• High-mobility group box 1
• Liver fibrosis
• Nuclear factor kappa-B
• Quercetin
• Toll like receptors

Fibrogenesis is induced by repeated injury to the liver and reactive regeneration and leads eventually to liver cirrhosis. Pigment epithelium derived factor (PEDF) has been shown to prevent liver fibrosis induced by carbon tetrachloride (CCl₄). A 44 amino acid domain of PEDF (44-mer) was found to have a protective effect against various insults to several cell types. In this study, we investigated the capability of synthetic 44-mer to protect against liver injury in mice and in primary cultured hepatocytes. Acute liver injury, induced by CCl₄, was evident from histological changes, such as cell necrosis, inflammation and apoptosis, and a concomitant reduction of glutathione (GSH) and GSH redox enzyme activities in the liver. Intraperitoneal injection of the 44-mer into CCl₄-treated mice abolished the induction of AST and ALT and markedly reduced histological signs of liver injury. The 44-mer treatment can reduce hepatic oxidative stress as evident from lower levels of lipid hydroperoxide, and higher levels of GSH. CCl₄ caused a reduction of Bcl-xL, PEDF and PPARγ, which was markedly restored by the 44-mer treatment. Consequently, the 44-mer suppressed liver fibrosis induced by repeated CCl₄ injury. Furthermore, our observations in primary culture of rat hepatocytes showed that PEDF and the 44-mer protected primary rat hepatocytes against apoptosis induced by serum deprivation and TGF-β1. PEDF/44-mer induced cell protective STAT3 phosphorylation. Pharmacological STAT3 inhibition prevented the antiapoptotic action of PEDF/44-mer. Among several PEDF receptor candidates that may be responsible for hepatocyte protection, we demonstrated that PNPLA2 was essential for PEDF/44-mer-mediated STAT3 phosphorylation and antiapoptotic activity by using siRNA to selectively knockdown PNPLA2. In conclusion, the PEDF 44-mer protects hepatocytes from single and repeated CCl₄ injury. This protective effect may stem from strengthening the counter oxidative stress capacity and induction of hepatoprotective factors.

• Animals
• Apoptosis
• Carbon Tetrachloride
• Cell Line
• Cricetinae
• Eye Proteins/chemistry
• Eye Proteins/metabolism
• Female
• Glutathione/metabolism
• Hep G2 Cells
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Injections, Intraperitoneal
• Lipid Peroxides/chemistry
• Liver/metabolism
• Mice
• Mice, Inbred C57BL
• Nerve Growth Factors/chemistry
• Nerve Growth Factors/metabolism
• Oxidation-Reduction
• Oxidative Stress/drug effects
• Rats
• Recombinant Proteins/chemistry
• Serpins/chemistry
• Serpins/metabolism

• Mackay Medical College
• Ministry of Science and Technology, Taiwan

• Liver fibrosis
• TNFα
• hepatic stellate cell
• hepatocyte
• macrophage

• P42 ES010337 NIEHS NIH HHS
• R01 AA020172 NIAAA NIH HHS
• R01 DK085252 NIDDK NIH HHS

AIM: To investigate the hepatoprotective effects and mechanisms of an extract of Salvia miltiorrhiza and Carthamus tinctorius in vivo.

METHODS: C57BL/6J mice were randomly assigned to five groups and intraperitoneally administered 0.9% saline, Salvia miltiorrhiza and Carthamus tinctorius extract [Danhong injection (DHI), 0.75 and 3 g/kg mixed extract] or reduced glutathione for injection (RGI, 300 mg/kg) for 30 min before exposure to lipopolysaccharide (LPS, 16 mg/kg). After intraperitoneal LPS stimulation for 90 min or 6 h, the mice were sacrificed by ether anaesthesia, and serum and liver samples were collected. Histological analysis (H&E) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining were performed. Alanine transferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), glutathione-S-transferase (GST), malondialdehyde (MDA), tumour necrosis factor (TNF)-α, interleukin (IL)-6, and caspase-3 levels were measured. Bax, Bcl-2, P-IκBα, IκBα, P-NF-κB p65, and NF-κB p65 protein levels were determined by Western blot. TNF-α, IL-6, caspase-3, Bax and Bcl-2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR).

RESULTS: Hematoxylin-eosin staining and TUNEL results suggested that DHI (3 g/kg) treatment alleviated inflammatory and apoptotic (P < 0.01) injury in the liver of mice. DHI treatment dose-dependently blunted the abnormal changes in biochemical parameters such as ALT (72.53 ± 2.83 for 3 g/kg, P < 0.01), AST (76.97 ± 5.00 for 3 g/kg, P < 0.01), TBil (1.17 ± 0.10 for 3 g/kg, P < 0.01), MDA (0.81 ± 0.36 for 3 g/kg, P < 0.01), and GST (358.86 ± 12.09 for 3 g/kg, P < 0.01). Moreover, DHI (3 g/kg) remarkably decreased LPS-induced protein expression of TNF-α (340.55 ± 10.18 for 3 g/kg, P < 0.01), IL-6 (261.34 ± 10.18 for 3 g/kg, P < 0.01), and enzyme activity of caspase-3 (0.93 ± 0.029 for 3 g/kg, P < 0.01). The LPS-induced mRNA expression of TNF-α, IL-6 and caspase-3 was also decreased by DHI. Western blot analysis revealed that DHI antagonised LPS-stimulated decrease of Bcl-2 and increase of Bax protein expression. Furthermore, DHI inhibited LPS-induced IκBα and NF-κB p65 phosphorylation.

CONCLUSION: DHI may be a multi-function protectant against acute hepatic injury in mice through its anti-inflammatory, anti-oxidative and anti-apoptotic activities.

• Salvia miltiorrhiza
• Carthamus tinctorius
• Apoptosis
• Anti-inflammatory
• Antioxidant
• Acute liver injury

• Animals
• Anti-Inflammatory Agents/isolation & purification
• Anti-Inflammatory Agents/pharmacology
• Antioxidants/isolation & purification
• Antioxidants/pharmacology
• Apoptosis/drug effects
• Apoptosis Regulatory Proteins/genetics
• Apoptosis Regulatory Proteins/metabolism
• Biomarkers/blood
• Camphanes
• Carthamus tinctorius/chemistry
• Chemical and Drug Induced Liver Injury/blood
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/genetics
• Chemical and Drug Induced Liver Injury/pathology
• Chemical and Drug Induced Liver Injury/prevention & control
• Cytoprotection
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drugs, Chinese Herbal/isolation & purification
• Drugs, Chinese Herbal/pharmacology
• Gene Expression Regulation
• Inflammation Mediators/blood
• Lipopolysaccharides
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Male
• Mice, Inbred C57BL
• Oxidative Stress/drug effects
• Panax notoginseng
• Phytotherapy
• Plants, Medicinal
• RNA, Messenger/metabolism
• Salvia miltiorrhiza/chemistry
• Time Factors

• damps
• pamps
• gut liver axis
• innate lymphoid
• cirrhosis

• Dendrobium huoshanense
• anti-inflammation
• hepatoprotection
• polysaccharide

Chronic liver diseases with different aetiologies rely on the chronic activation of liver injuries which result in a fibrogenesis progression to the end stage of cirrhosis and liver failure. Based on the underlying cellular and molecular mechanisms of a liver fibrosis, there has been proposed several kinds of approaches for the treatment of liver fibrosis. Recently, liver gene therapy has been developed as an alternative way to liver transplantation, which is the only effective therapy for chronic liver diseases. The activation of hepatic stellate cells, a subsequent release of inflammatory cytokines and an accumulation of extracellular matrix during the liver fibrogenesis are the major obstacles to the treatment of liver fibrosis. Several targeted strategies have been developed, such as antisense oligodeoxynucleotides, RNA interference and decoy oligodeoxynucleotides to overcome this barriers. With this report an overview will be provided of targeted strategies for the treatment of liver cirrhosis, and particularly, of the targeted gene therapy using short RNA and DNA segments.

• Liver cirrhosis
• Gene therapy
• Oligodeoxynucleotides
• Antisense
• Small interfering RNA
• Micro RNA
• Decoy

• Animals
• Gene Expression Regulation
• Genetic Therapy/methods
• Humans
• Liver Cirrhosis/genetics
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/therapy
• MicroRNAs/therapeutic use
• Oligonucleotides, Antisense/therapeutic use
• RNA Interference
• RNA, Small Interfering/therapeutic use
• Treatment Outcome