CO2-Repurification Microemulsion Detergent for Oil-Based Slurry Cleaning.

In order to solve problems such as environmental pollution and pipeline blockage caused by oily wastewater after washing, N,N-dimethylcyclohexylamine (DMCHA) with CO2 response was selected as the oil phase, and an O/W microemulsion wellbore cleaning fluid with CO2 switching characteristics was successfully prepared with erucamide propyl betaine (EAB-40), sodium dodecyl benzene sulfonate (SDBS), n-butanol, silicone defoamer, and water. The water content of the microemulsion was 89.99%, and it had good stability at 40 and -5 °C. The emulsion was rapidly demulsified after being injected with CO2 in the CO2-repurification microemulsion detergent, and CO2 was removed with a N2 detergent. The emulsion was restored to its original state, which demonstrated the CO2/N2 switching properties of the emulsion. It is proven that the switching microemulsion has a good wetting transformation ability by cleaning the steel sheet and quartz sheet contaminated by oil-based slurry. The switching microemulsion system can clean the simulated wellbore contaminated by oil-based slurry, and the cleaning efficiency is above 99%. CO2 can be used at room temperature to separate oil and water from oily wastewater after cleaning.

SD2: spatially resolved transcriptomics deconvolution through integration of dropout and spatial information.

MOTIVATION: Unveiling the heterogeneity in the tissues is crucial to explore cell-cell interactions and cellular targets of human diseases. Spatial transcriptomics (ST) supplies spatial gene expression profile which has revolutionized our biological understanding, but variations in cell-type proportions of each spot with dozens of cells would confound downstream analysis. Therefore, deconvolution of ST has been an indispensable step and a technical challenge toward the higher-resolution panorama of tissues. RESULTS: Here, we propose a novel ST deconvolution method called SD2 integrating spatial information of ST data and embracing an important characteristic, dropout, which is traditionally considered as an obstruction in single-cell RNA sequencing data (scRNA-seq) analysis. First, we extract the dropout-based genes as informative features from ST and scRNA-seq data by fitting a Michaelis-Menten function. After synthesizing pseudo-ST spots by randomly composing cells from scRNA-seq data, auto-encoder is applied to discover low-dimensional and non-linear representation of the real- and pseudo-ST spots. Next, we create a graph containing embedded profiles as nodes, and edges determined by transcriptional similarity and spatial relationship. Given the graph, a graph convolutional neural network is used to predict the cell-type compositions for real-ST spots. We benchmark the performance of SD2 on the simulated seqFISH+ dataset with different resolutions and measurements which show superior performance compared with the state-of-the-art methods. SD2 is further validated on three real-world datasets with different ST technologies and demonstrates the capability to localize cell-type composition accurately with quantitative evidence. Finally, ablation study is conducted to verify the contribution of different modules proposed in SD2. AVAILABILITY AND IMPLEMENTATION: The SD2 is freely available in github (https://github.com/leihouyeung/SD2) and Zenodo (https://doi.org/10.5281/zenodo.7024684). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

pH-Induced reversible conversion between non-Pickering and Pickering high internal phase emulsion.

Solid-stabilized high internal phase emulsions have received extensive attention. Many previous studies have confirmed that solid emulsifiers in high internal phase Pickering emulsions (HIPPEs) provide a great interface mechanical barrier. With the development of research, novel solid-stabilized emulsions have emerged. These emulsions are stabilized by the electrostatic repulsion between the surfactants and hydrophilic solid particles. They are distinct from Pickering emulsions in that the solid particles do not exist at the oil-water interface, but are dispersed in the continuous phase, so it is called a non-Pickering emulsion. However, high internal phase non-Pickering emulsions (HIPNPEs) are rarely reported. Herein, HIPNPEs that are synergistically stabilized by anionic surfactants with dynamic covalent bonds and negatively charged nano-SiO2 particles were prepared. In the presence of dodecylamine, the acidity causes the dynamic covalent bonds to break and the surfactant to be inactivated. Additionally, the long-chain amine is protonated and adsorbed on nano-SiO2 particles to form a new surfactant for stabilizing HIPPEs. However, alkalinity causes the HIPNPEs to form again. In addition, rheological tests confirmed that the HIPNPEs and HIPPEs had similar rheological behaviors, which were typical gel-like fluids. The emulsion can quickly respond to realize the conversion between the different types of high internal phase emulsion by simple stimulation, which provides a new direction for stimulus-responsive high internal phase emulsions.

Validation and update of a multivariable prediction model for the identification and management of patients at risk for hepatocellular carcinoma.

BACKGROUND: A hepatocellular carcinoma (HCC) prediction model (ASAP), including age, sex, and the biomarkers alpha-fetoprotein and prothrombin induced by vitamin K absence-II, showed potential clinical value in the early detection of HCC. We validated and updated the model in a real-world cohort and promoted its transferability to daily clinical practice. METHODS: This retrospective cohort analysis included 1012 of the 2479 eligible patients aged 35 years or older undergoing surveillance for HCC. The data were extracted from the electronic medical records. Biomarker values within the test-to-diagnosis interval were used to validate the ASAP model. Due to its unsatisfactory calibration, three logistic regression models were constructed to recalibrate and update the model. Their discrimination, calibration, and clinical utility were compared. The performance statistics of the final updated model at several risk thresholds are presented. The outcomes of 855 non-HCC patients were further assessed during a median of 10.2 months of follow-up. Statistical analyses were performed using packages in R software. RESULTS: The ASAP model had superior discriminative performance in the validation cohort [C-statistic = 0.982, (95% confidence interval 0.972-0.992)] but significantly overestimated the risk of HCC (intercept - 3.243 and slope 1.192 in the calibration plot), reducing its clinical usefulness. Recalibration-in-the-large, which exhibited performance comparable to that of the refitted model revision, led to the retention of the excellent discrimination and substantial improvements in the calibration and clinical utility, achieving a sensitivity of 100% at the median prediction probability of the absence of HCC (1.3%). The probability threshold of 1.3% and the incidence of HCC in the cohort (15.5%) were used to stratify the patients into low-, medium-, and high-risk groups. The cumulative HCC incidences in the non-HCC patients significantly differed among the risk groups (log-rank test, p-value < 0.001). The 3-month, 6-month and 18-month cumulative incidences in the low-risk group were 0.6%, 0.9% and 0.9%, respectively. CONCLUSIONS: The ASAP model is an accurate tool for HCC risk estimation that requires recalibration before use in a new region because calibration varies with clinical environments. Additionally, rational risk stratification and risk-based management decision-making, e.g., 3-month follow-up recommendations for targeted individuals, helped improve HCC surveillance, which warrants assessment in larger cohorts.

The "Traditional Chinese medicine regulating liver regeneration" treatment plan for reducing mortality of patients with hepatitis B-related liver failure based on real-world clinical data.

On the basis of real-world clinical data, the study aimed to explore the effect and mechanisms of the treatment plan of "traditional Chinese medicine (TCM) regulating liver regeneration." A total of 457 patients with HBV-related liver failure were retrospectively collected. The patients were divided into three groups: the modern medicine control group (MMC group), patients treated with routine medical treatment; the control group combining traditional Chinese and Western medicine (CTW), patients treated with routine medical treatment plus the common TCM formula; and the treatment group of "TCM regulating liver regeneration" (RLR), patients treated with both routine medical treatment and the special TCM formula of RLR. After 8 weeks of treatment, the mortality of patients in the RLR group (12.31%) was significantly lower than those in the MMC (50%) and CTW (29.11%) groups. Total bilirubin level significantly decreased and albumin increased in the RLR group when compared with the MMC and CTW groups (P < 0.05). In addition, there were significant differences in the expression of several cytokines related to liver regeneration in the RLR group compared with the MMC group. RLR treatment can decrease jaundice, improve liver function, and significantly reduce the mortality in patients with HBV-related liver failure. The mechanism may be related to the role of RLR treatment in influencing cytokines related to liver regeneration.

Ingredients, Anti-Liver Cancer Effects and the Possible Mechanism of DWYG Formula Based on Network Prediction.

BACKGROUND: Hepatitis virus infection plays a critical role in liver cancer initiation and development; so the purpose of this study was to investigate the anti-liver cancer effects of DiWuYangGan (DWYG) which was effective for hepatitis. METHODS: Network predictions were performed. Next, several tests, including HPLC, Caco-2 absorption models, MMT, protein chip, Western blotting and H22-tumor-bearing mouse, were carried out to investigate the effects and possible mechanism of DWYG. RESULTS: Network results showed DWYG might be involved in some processes such as STAT cascade. Some target genes may correspondingly participate in these procedures, such as IL-6, CASP3, AKT1, PPAR, and TP53. Diseases associated with DWYG formula may be liver cancer and hepatitis. Potential active compounds might be CUR and ISO. Chemical analysis results showed that ingredients in the formula, including DEO, SCHB, SOLA, SOLB, SCHA, LIQ, ISO, POT, and CHL, could be determined, indicating that DWYG samples for the following experiments were controllable and consistent. Caco-2 absorption of ingredients in DWYG, including DEO, SCHB, SOLA, SOLB, and LIQ, worked very well. In vitro experiment results showed that DWYG could inhibit the growth of cell lines and its effective ingredients might be SCHB, SOLB, SINA, SINB, SOLB, CUR, DEM, BIS, and GER. Further protein results showed that DWYG could upregulate the expressions of some proteins, including ERK1/2, AKT Ser473, BAD Ser112, PRAS40, Thr246, P38, Gsk-3ß, and Ser9. In vivo experiment results showed that DWYG could shrink tumor size, recover ALT and AST, and decrease IL-6 levels. Their possible mechanism might be through the JAK/STAT3 pathway. CONCLUSION: Besides the known pharmacological function of anti-hepatitis, DWYG extract expressed anti-liver cancer effects and the results were consistent partly with network predictions.

Antitumor Effects of Curcumin and Glycyrrhetinic Acid-Modified Curcumin-Loaded Cationic Liposome by Intratumoral Administration.

Curcumin is a hydrophobic polyphenolic compound extracted from the rhizome of Curcuma longa and shows a line of active biological functions, but its application has been limited and questioned because of its low solubility, low bioavailability, and rapid metabolism. In terms of antitumor effect, these disadvantages can be overcome by intratumoral injection. In this study, we present the intratumoral injection of curcumin and glycyrrhetinic acid-modified curcumin-loaded cationic liposome (GAMCLCL) in H22 tumor-bearing mice. The experimental results demonstrated that curcumin exhibited positive antitumor activities in vitro and in vivo by intratumoral injection, but its activities were much weaker than GAMCLCL and adriamycin. Compared with free curcumin, GAMCLCL showed much better effects in improving the blood parameters (WBC, RBC, PLT, ALT, CRE, and LDH), inhibiting tumor growth, reducing tumor microvascular density, downregulating the expression of VEGF-protein and mRNA, and upregulating the expression of caspase-3 protein and mRNA in H22 tumor tissues. Under the experimental conditions of this study, the antitumor effect of high-dose GAMCLCL was similar to adriamycin. In conclusion, the experimental results demonstrated that free curcumin possessed definite antitumor efficacy, but its antitumor activities were weaker, and some strategies should be adopted to overcome its disadvantages, improve, and ensure its clinical efficacy.

Hepatoprotective effects of Di Wu Yang Gan: A medicinal food against CCl4-induced hepatotoxicity in vivo and in vitro.

The development of functional foods based on medicinal food ingredients has become a hot topic in China. Di Wu Yang Gan (DWYG) is a Chinese medicinal food that contains five dietary plants. Various health benefits, including anti-inflammation, liver regeneration regulation, have been reported, though the mechanism is not clear. This study aimed to investigate the protective effect of DWYG on carbon tetrachloride-induced acute liver injury (ALI) in embryonic liver L-02 cells and mice model. DWYG-medicated serum protected L-02 cells from carbon tetrachloride-induced damage, reduced the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the culture medium, decreased the expression of Bax and increased the expression of Bcl-2. Mice study suggested that DWYG decreased the levels of malondialdehyde, ALT and AST. Together, these results suggest the hepatoprotective effects of DWYG against ALI and provide an experimental basis for the utilization of DWYG to treat liver damage.

Research Progress in Liver-Regenerating Microenvironment and DNA Methylation in Hepatocellular Carcinoma: The Role of Traditional Chinese Medicine.

The development, progression, recurrence, and metastasis of hepatocellular carcinoma (HCC) are closely associated with an abnormal liver-regenerating microenvironment (LRM). Therefore, preventing and reversing an abnormal LRM is a potential therapeutic strategy against HCC. Studies are increasingly focusing on the impact of regeneration, fibrosis, angiogenesis, inflammation, immunomodulation, and hepatic stem cells on HCC development and progression. As a key epigenetic mechanism, DNA methylation is extensively involved in regulating physiological and pathological pathways. In this review, we summarize recent findings on the role of DNA methylation in the fibrotic, angiogenic, inflammatory/immune, and stem cell microenvironments of HCC, and discuss new advances in Traditional Chinese Medicine (TCM) on influencing the abnormal LRM, so as to gain new insights into alleviating the abnormal LRM via regulating DNA methylation by TCM.

Diwu Yanggan Modulates the Wnt/ß-catenin Pathway and Inhibits Liver Carcinogenesis Signaling in 2-AAF/PH Model Rats.

The activation of the Wnt/ß-catenin signaling pathway in oval cells after liver injury is implicated in hepatocarcinogenesis. Diwu Yanggan capsule is a Chinese herbal medicine that has been used for treating liver disorder. The present study aimed to examine the mechanism by which Diwu Yanggan inhibits liver carcinogenesis, and the involvement of the Wnt/ß-catenin signaling pathway. Diwu Yanggan capsule was administered to 2-acetaminofluorene/partial hepatectomy (2-AAF/PH) rats, a murine model of liver injury. The biomarkers of oval cells and key proteins in the Wnt/ß-catenin signaling pathway were assessed on postoperative day 8, 10, 14, 17, 19 and 22. The results showed that treatment with Diwu Yanggan was associated with reduced expression of oval cell and stem cell biomarkers in the 2-AAF/PH animals. The expression pattern of key proteins in the Wnt/ß-catenin pathway was altered in Diwu Yanggan-treated animals, indicating that the Diwu Yanggan treatment accelerated the activation of the Wnt/ß-catenin pathway in the initial stage and contributed to its deactivation in the later stage. Histological findings indicated that hepatocyte proliferation was suppressed in Diwu Yanggan-treated animals, compared with untreated 2-AAF/PH animals. Taken together, Diwu Yanggan capsule may reduce the risk of hepatocarcinogenesis by modulating the Wnt/ß-catenin signaling pathway.

Chinese Medicine Jiedu Huayu Granules Reduce Liver Injury in Rats by Regulating T-Cell Immunity.

Liver injury, one of the causes of liver failure, is mainly due to T-cell-mediated immunity. Traditional Chinese medicine Jiedu Huayu granules are often used to suppress liver damage and improve liver function. The specific regulatory mechanism of Jiedu Huayu granules has not been fully studied, and its function in the immune system remains unclear. Therefore, in this study, the mechanism of Jiedu Huayu granules in the prevention of hepatic injury was studied in a rat model of hepatic injury induced by D-galactoside and lipopolysaccharide. The cytotoxic T lymphocytes (CTLs) in the peripheral blood were examined. Perforin, granule B, and PD1 expression in CTL increased after the induction of hepatic injury and could be reduced by Jiedu Huayu granules. Hepatic apoptotic factors OX62, FAS, and TNFR1 associated with CTL function were also reduced by Jiedu Huayu granules. These results suggested that Jiedu Huayu granules could inhibit the inflammatory response to relieve liver damage by mediating the T-cell immunity. Therefore, the discovery of the mechanism of action of Jiedu Huayu granules in the immune system could allow their use more effectively in clinical practice.

Preventive Effects of Escitalopram Against Anxiety-Like Depressive Behaviors in Monosodium Glutamate-Teated Rats Subjected to Partial Hepatectomy.

The reasons for the relationship between depression and chronic liver disease (CLD) are complex and multifactorial. Further research is needed to decipher the etiology and establish an optimal management approach for depression in patients, including the potential role of non-pharmacological treatments. monosodium glutamate (MSG)-treated rats are more likely to develop anxiogenic- and depressive-like behaviors, which could be related to the dysfunction of serotonergic system. In this study, partial hepatectomy (PH) was performed in MSG-treated rats and the histopathological changes were observed in orbitofrontal cortex (OFC) and liver. The effect of escitalopram, a widely used antidepressant, on neural and liver injury in this model was also examined. The MSG + PH-treated rats displayed decreased distances traveled in total, in center arena, and in the left side of arena in inner open field test (OFT), as compared to saline, saline + PH, and MSG-treated animals. The present study established that PH aggravated anxiety-like depressive behaviors in MSG-treated rats, concordant with damaged Nissl bodies (and neurites), decreased IBA-1 and Sox-2 expression in OFC and neurotransmitter disorder. Escitalopram treatment could alleviate these pathological changes as well as reduce hepatic steatosis and lipid metabolism.

Antitumor activities of novel glycyrrhetinic acid-modified curcumin-loaded cationic liposomes in vitro and in H22 tumor-bearing mice.

At present, the chemotherapy of advanced inoperable liver cancer is limited with serious side effects. Curcumin possesses multiple cancer preventive activities and low safety concerns. However, its poor solubility and instability in water pose significant pharmacological barriers to its clinical application. In this study, we presented a novel delivery system - the glycyrrhetinic acid modified curcumin-loaded cationic liposomes (GAMCLCL) and investigated its antitumor activities on HepG2 cells in vitro and in H22 tumor-bearing mice. The experimental results demonstrated that GAMCLCL was a cationic liposome and could be Intravenous administration. Compared to free curcumin, GAMCLCL exhibited stronger antitumor activities in vitro and in vivo. The antitumor results of GAMCLCL after intravenous administration were very similar to those after intratumoral administration. The main activities of GAMCLCL and curcumin included inhibition of HepG2 cell proliferation, inhibition of tumor growth, reduction of tumor microvascular density, down-regulation of the expression of VEGF protein, and up-regulation of the expression of Caspases3 protein in H22 tumor tissues. Furthermore, GAMCLCL improved the parameters of WBC, RBC, ALT, CRE, LDH of H22 tumor-bearing mice. Curcumin is a nontoxic natural compound with definite antitumor activities, its antitumor effects can be enhanced by preparation of GAMCLCL.

Protective Effects of Liu Wei Di Huang Wan on the Liver, Orbitofrontal Cortex Nissl Bodies, and Neurites in MSG+PH-Induced Liver Regeneration Rat Model.

Introduction. To examine the protective effects of Liu Wei Di Huang Wan formula (LWDH) on liver and orbitofrontal cortex (OFC) injuries in monosodium glutamate (MSG) and partial hepatectomy (PH) rat model. Methods. Neonatal Wistar rats were given MSG or saline on postnatal days 2, 4, 6, 8, and 10. The rats were caged into five groups and treated accordingly at six weeks old as follows: Saline group, Saline+PH group, MSG group, MSG+PH group, and LWDH group (MSG+PH+LWDH). The PH was performed during week 8 by excision of the left and median hepatic lobes (occupying about 68% of whole liver).On day 8 after the PH, the rats were subjected to an inner OFT before being sacrificed. The liver and OFC were stained using H&E, ORO, or Nissl staining. The expression of neurotrophic factors (ß-NGF, BDNF) was examined in the OFC lysates by ELISA. Serum levels of cytokines (IL-1ß, VEGF) were examined using the Bio-Plex suspension array. Results. LWDH increased the total distance traveled by the animals (p<0.05), and LWDH improved the integrity of the Nissl bodies in the OFC (mean area of the Nissl bodies, p<0.01; mean diameter, p<0.05; mean density, p<0.05; and IOD, p<0.01). There were less white area in the liver (p>0.05) and decreased hepatic steatosis (p<0.01) in LWDH group. LWDH administration decreased the expression of serum levels of IL-1ß (p>0.05), while it increased VEGF (p>0.05) expression. LWDH administration increased the expression of BDNF (p>0.05) and ß-NGF (p>0.05) in the OFC, all as compared to the MSG+PH group. Conclusion. LWDH partly protected the animals from depressive-like behaviors in the MSG+PH-induced liver regeneration neonatal rat model. LWDH alleviated hepatic injury and steatosis and, furthermore, protected the Nissl body integrity and the growth of neurites.

Identification of key pathways and biomarkers in sorafenib-resistant hepatocellular carcinoma using bioinformatics analysis.

Hepatocellular carcinoma (HCC) is one of the most common malignant types of cancer, with a high mortality rate. Sorafenib is the sole approved oral clinical therapy against advanced HCC. However, individual patients exhibit varying responses to sorafenib and the development of sorafenib resistance has been a new challenge for its clinical efficacy. The current study identified gene biomarkers and key pathways in sorafenib-resistant HCC using bioinformatics analysis. Gene dataset GSE73571 was obtained from the Gene Expression Omnibus (GEO) database, including four sorafenib-acquired resistant and three sorafenib-sensitive HCC phenotypes. Differentially expressed genes (DEGs) were identified using the web tool GEO2R. Functional and pathway enrichment of DEGs were analyzed using the Database for Annotation, Visualization and Integrated Discovery and the protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape. A total of 1,319 DEGs were selected, which included 593 upregulated and 726 downregulated genes. Functional and pathway enrichment analysis revealed DEGs enriched in negative regulation of endopeptidase activity, cholesterol homeostasis, DNA replication and repair, coagulation cascades, insulin resistance, RNA transport, cell cycle and others. Eight hub genes, including kininogen 1, vascular cell adhesion molecule 1, apolipoprotein C3, alpha 2-HS glycoprotein, erb-b2 receptor tyrosine kinase 2, secreted protein acidic and cysteine rich, vitronectin and vimentin were identified from the PPI network. In conclusion, the present study identified DEGs and key genes in sorafenib-resistant HCC, which further the knowledge of potential mechanisms in the development of sorafenib resistance and may provide potential targets for early diagnosis and new treatments for sorafenib-resistant HCC.

Diwu Yanggan capsule improving liver histological response for patients with HBeAg-negative chronic hepatitis B: a randomized controlled clinical trial.

The number of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) has shown a significant upward trend in recent years. However, antiviral drugs are not very effective. Regulation of liver regeneration by traditional Chinese medicine is an important way to improve clinical efficacy. This randomized controlled trial assessed the efficacy and safety of DWYG in patients with HBeAg-negative CHB. Overall, 130 subjects were randomized to (A) DWYG 1.2 g three times daily (n = 44), (B) entecavir 0.5 mg/day (n = 43) in combination with DWYG or (C) entecavir 0.5 mg/day (n = 43). The liver histological response rate was assessed as the primary efficacy endpoint. The results showed that the liver histological response rate in the combination treatment group was significantly higher than that in the group with entecavir (71.43% versus 22.22%; P = 0.036) after 48 weeks of treatment. And the pathological progression rate of liver in the group with DWYG was significantly lower than that of the entecavir group during 228 weeks of follow-up (0% versus 60.00%; P = 0.019). No significant adverse events occurred during the study. In conclusion, treating HBeAg-negative CHB with DWYG is safe and effective to improve liver histological response.

Developmental Toxicity of Diethylnitrosamine in Zebrafish Embryos/Juveniles Related to Excessive Oxidative Stress.

Diethylnitrosamine (DEN) is present in food, water, and daily supplies and is regarded as a toxicant of carcinogenicity. The developmental toxicity of DEN has been rarely reported as yet. In this study, zebrafish were exposed to different concentrations of DEN at 6 h post-fertilization (hpf) to access embryonic toxicity of the compound. The results show that DEN resulted in negative effects of hatching rate, heartbeat, body length, and spontaneous movement. Deformities, including notochord malformation, pericardium edema, embryonic membrane turbidity, tail hypoplasia, yolk sac deformity, and growth retardation, happened during exposure period. Moreover, production of reactive oxygen species (ROS) significantly increased after DEN treatment. Then, alterations of the expression level of oxidative stress-related genes were observed in our results. To our knowledge, this is the first study concerning the effect of DEN on zebrafish. And from the information of our research, we speculated that development toxicity of DEN should be related to the excessive oxidative stress.

Diwu Yanggan capsule inhibits the occurrence and development of liver cancer in the Solt-Farber rat model by regulating the Ras/Raf/Mek/Erk signaling pathway.

This study sought to determine the effect and explore the mechanism of the Chinese medicinal compound preparation Diwu Yanggan (DWYG) capsule on the occurrence and development of liver cancer using the Solt-Farber rat model. Sprague-Dawley rats were randomly distributed into a normal group, sham group, DWYG group, sorafenib group, and model group. The DWYG group and sorafenib group were given DWYG capsule and sorafenib tablet, respectively, with induction of the model. Hematoxylin-eosin (HE) staining was used to detect liver pathological changes. The content of nuclear DNA in the liver was detected by Feulgen staining, and the expression of PCNA was detected by immunohistochemical staining. Molecular biology methods were used to detect the expression of liver regeneration-related factors and Ras/Raf/Mek/Erk signaling pathway-related proteins and mRNAs. HE staining showed that compared with those in the model group, the liver pathological changes in the DWYG group were significantly reduced (P < 0.05). The nuclear DNA content in the liver based on Feulgen staining and the expression of PCNA in the DWYG group was lower than that in the model group (P < 0.05). The expression of regeneration-related factors and Ras/Raf/Mek/Erk signaling pathway-related proteins and mRNAs was significantly lower in the DWYG group than in the model group (P < 0.05). In conclusion, DWYG capsules to some degree inhibit the occurrence and development of liver cancer in the Solt-Farber rat model, and the effect is not inferior to that of sorafenib. DWYG capsules likely delay the occurrence and development of liver cancer and improve the liver regeneration microenvironment by regulating the Ras/Raf/Mek/Erk signaling pathway and regeneration-related factors.

Wisp2 disruption represses Cxcr4 expression and inhibits BMSCs homing to injured liver.

Liver regeneration/repair is a compensatory regrowth following acute liver failure, and bone marrow-derived mesenchyme stem cell (BMSC) transplantation is an effective therapy that promotes liver regeneration/repair. Wnt1 inducible signaling pathway protein 2 (Wisp2) is highly expressed in BMSCs, however, its function remains unclear. In this work, we used clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein -9 nuclease (CRISPR/Cas9) genome editing technology to knockdown Wisp2 in BMSCs, and these modified cells were then transplanted into rats which were induced by the 2-AAF/PH. By linking the expression of Cas9 to green fluorescent protein (GFP), we tracked BMSCs in the rats. Disruption of Wisp2 inhibited the homing of BMSCs to injured liver and aggravated liver damage as indicated by remarkably high levels of ALT and AST. Moreover, the key factor in BMSC transplantation, C-X-C chemokine receptor type 4 (Cxcr4), was down-regulated in the Wisp2 depleted BMSCs and had a lower expression in the livers of the corresponding rats. By tracing the GFP marker, more BMSCs were observed to differentiate into CD31 positive endothelial cells in the functional Wisp2 cells but less in the Wisp2 gene disrupted cells. In summary, Wisp2 promotes the homing of BMSCs through Cxcr4 related signaling during liver repair in rats.

The Injury-Related Activation of Hedgehog Signaling Pathway Modulates the Repair-Associated Inflammation in Liver Fibrosis.

Liver fibrosis is a wound healing response initiated by inflammation responding for different iterative parenchymal damages caused by diverse etiologies. Immune cells, which exert their ability of either inducing injury or promoting repair, have been regarded as crucial participants in the fibrogenic response. A characteristic feature of the fibrotic microenvironment associated with chronic liver injury is aberrant activation of hedgehog (Hh) signaling pathway. Growing evidence from a number of different studies in vivo and in vitro has indicated that immune-mediated events involved in liver fibrogenesis are regulated by Hh signaling pathway. In this review, we emphasize the impacts of injury-activated Hh signaling on liver fibrogenesis through modulating repair-related inflammation and focus on the regulatory action of aberrant Hh signaling on repair-related inflammatory responses mediated by hepatic classical and non-classical immune cell populations in the progression of liver fibrosis. Moreover, we also assess the potentiality of Hh pathway inhibitors as good candidates for anti-fibrotic therapeutic agents because of their immune regulation actions for fibrogenic liver repair. The identification of immune-modulatory mechanisms of Hh signaling pathway underlying the fibrotic process of chronic liver diseases might provide a basis for Hh-centered therapeutic strategies for liver fibrosis.