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Ammonia (NH 3 ) is essential for modern agriculture and industry and is a potential energy carrier. NH 3 is traditionally synthesized by the Haber–Bosch process at high temperature and pressure. The high-energy input of this process has motivated research into electrochemical NH 3 synthesis via nitrogen (N 2 )–water reactions under ambient conditions. However, the future of this low-cost process is compromised by the low yield rate and poor selectivity, ascribed to the inert N≡N bond and ultralow solubility of N 2 . Obtaining NH 3 directly from non-N 2 sources could circumvent these challenges. Here we report the eight-electron direct electroreduction of nitrate to NH 3 catalysed by copper-incorporated crystalline 3,4,9,10-perylenetetracarboxylic dianhydride. The catalyst exhibits an NH 3 production rate of 436 ± 85 μg h −1  cm −2 and a maximum Faradaic efficiency of 85.9% at −0.4 V versus a reversible hydrogen electrode. This notable performance is achieved by the catalyst regulating the transfer of protons and/or electrons to the copper centres and suppressing hydrogen production. Electrochemically reducing nitrogen-containing molecules could provide less energy-intense routes to produce ammonia than the traditional Haber–Bosh process. Here the authors use a catalyst comprising Cu embedded in an organic molecular solid to synthesize ammonia from nitrate ions.

Background Cholestatic liver fibrosis (CLF) is caused by inflammatory destruction of the intrahepatic bile duct and abnormal proliferation of the small bile duct after cholestasis. Activation of the Notch signaling pathway is required for hepatic stem cells to differentiate into cholangiocytes during the pathogenesis of CLF. Our previous research found that the expression of the Numb protein, a negative regulator of Notch signaling, was significantly reduced in the livers of patients with primary biliary cholangitis and CLF rats. However, the relationship between the Numb gene and CLF is largely unclear. In this study, we investigated the role of the Numb gene in the treatment of bile duct ligation (BDL)-induced CLF. Methods In vivo, bone marrow-derived mesenchymal stem cells (BM-MSCs) with Numb gene overexpression or knockdown obtained using lentivirus transfection were transplanted into the livers of rats with BDL-induced CLF. The effects of the Numb gene on stem cell differentiation and CLF were evaluated by performing histology, tests of liver function, and measurements of liver hydroxyproline, cytokine gene and protein levels. In vitro, the Numb gene was overexpressed or knocked down in the WB-F344 cell line by lentivirus transfection, Then, cells were subjected immunofluorescence staining and the detection of mRNA levels of related factors, which provided further evidence supporting the results from in vivo experiments. Results BM-MSCs overexpressing the Numb gene differentiated into hepatocytes, thereby inhibiting CLF progression. Conversely, BM-MSCs with Numb knockdown differentiated into biliary epithelial cells (BECs), thereby promoting the ductular reaction (DR) and the progression of CLF. In addition, we confirmed that knockdown of Numb in sodium butyrate-treated WB-F344 cells aggravated WB-F344 cell differentiation into BECs, while overexpression of Numb inhibited this process. Conclusions The transplantation of BM-MSCs overexpressing Numb may be a useful new treatment strategy for CLF.

Currently, active ingredients of herbal extracts that can suppress lipid accumulation in the liver have been considered a potential treatment option for non-alcoholic fatty liver disease. Steatosis rat model was created by high fat and high sucrose diet feeding and treated with oxymatrine (OMT). Serum biochemical parameters, liver histology and lipid profiles were examined. Hepatic differentially expressed proteins (DEPs) which were significantly changed by OMT treatment were identified by iTRAQ analysis. The expressions of representative DEPs, Sirt1 and AMPKα were evaluated by western blotting. OMT significantly reduced the body weight and liver weight of steatosis animals, decreased the serum levels of triglyceride and total cholesterol as well as the hepatic triglyceride and free fatty acid levels, and effectively alleviated fatty degeneration in the liver. A list of OMT-related DEPs have been screened and evaluated by bioinformatics analysis. OMT significantly decreased the expressions of L-FABP, Plin2, FASN and SCD1 and increased Sirt1 expression and AMPKα phosphorylation in the liver of rats with steatosis. The present study has confirmed the significant efficacy of OMT for improving steatosis and revealed hepatic proteomic changes and Sirt1/AMPK signaling activation by OMT treatment in rats with steatosis.

For decarbonization of ammonia production in industry, alternative methods by exploiting renewable energy sources have recently been explored. Nonetheless, they still lack yield and efficiency to be industrially relevant. Here, we demonstrate an advanced approach of nitrogen fixation to synthesize ammonia at ambient conditions via laser–induced multiphoton dissociation of lithium oxide. Lithium oxide is dissociated under non–equilibrium multiphoton absorption and high temperatures under focused infrared light, and the generated zero–valent metal spontaneously fixes nitrogen and forms a lithium nitride, which upon subsequent hydrolysis generates ammonia. The highest ammonia yield rate of 30.9 micromoles per second per square centimeter is achieved at 25 °C and 1.0 bar nitrogen. This is two orders of magnitude higher than state–of–the–art ammonia synthesis at ambient conditions. The focused infrared light here is produced by a commercial simple CO 2 laser, serving as a demonstration of potentially solar pumped lasers for nitrogen fixation and other high excitation chemistry. We anticipate such laser-involved technology will bring unprecedented opportunities to realize not only local ammonia production but also other new chemistries . Emerged sustainable techniques for nitrogen fixation still lack ammonia yield rate to be practically relevant. Here, the authors demonstrate a laser–induced method to deliver a yield rate of 30.9 µmol s-1 cm−2 at ambient conditions, which is two orders of magnitude higher than other methods.

Liver fibrosis is a common pathological process of all chronic liver diseases. Hepatic stellate cells (HSCs) play a central role in the development of liver fibrosis. Cyclin-dependent kinase 9 (CDK9) is a cell cycle kinase that regulates mRNA transcription and elongation. A CDK9 inhibitor SNS-032 has been reported to have good effects in anti-tumor. However, the role of SNS-032 in the development of liver fibrosis is unclear. In this study, SNS-032 was found to alleviate hepatic fibrosis by inhibiting the activation and inducing the apoptosis of active HSCs in carbon tetrachloride-induced model mice. In vitro , SNS-032 inhibited the activation and proliferation of active HSCs and induced the apoptosis of active HSCs by downregulating the expression of CDK9 and its downstream signal transductors, such phosphorylated RNA polymerase II and Bcl-2. CDK9 short hairpin RNA was transfected into active HSCs to further elucidate the mechanism of the above effects. Similar results were observed in active HSCs after CDK9 knockdown. In active HSCs with CDK9 knockdown, the expression levels of CDK9, phosphorylated RNA polymerase II, XIAP, Bcl-2, Mcl-1, and ɑ-SMA significantly decreased, whereas those of cleaved-PARP1 and Bax decreased prominently. These results indicated that SNS-032 is a potential drug and CDK9 might be a new prospective target for the treatment of liver fibrosis.

Cholestasis can occur in various acute and chronic liver diseases, with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) being the most common clinical manifestations. Without appropriate treatment, these conditions may ultimately progress to liver cirrhosis and hepatic failure. Therefore, identifying novel therapeutic targets is of great importance. Our previous research had found a gene target named Numb which is a determinant of stem cell fate can increase the anti-cholestatic liver fibrosis (CLF) effect of bone marrow mesenchymal stem cells (BM-MSCs). However, whether the Numb gene or its exon has direct anti-CLF activity is unclear. In this study, an adeno-associated virus (AAV) was used as a gene delivery vector to overexpress the full-length Numb gene directly in the rat liver. In addition, Exon3 was overexpressed to clarify the effective site of Numb gene for comparison. AAV. Numb can alleviate CLF and suppressed the activation of Notch signaling and the differentiation of hepatic progenitor cells (HPCs) into biliary epithelial cells (BECs), and the anti-CLF effect of Numb -Exon3 was similar to that of full-length Numb . The findings revealed that Numb gene may be a new therapeutic target for PBC and that Exon3 may be an effective site.

Objective To observe the effect of amygdalin on liver fibrosis in a liver fibrosis mouse model, and the underlying mechanisms were partly dissected in vivo and in vitro . Methods Thirty-two male mice were randomly divided into 4 groups, including control, model, low- and high-dose amygdalin-treated groups, 8 mice in each group. Except the control group, mice in the other groups were injected intraperitoneally with 10% carbon tetrachloride (CCl 4 )-olive oil solution 3 times a week for 6 weeks to induce liver fibrosis. At the first 3 weeks, amygdalin (1.35 and 2.7 mg/kg body weight) were administered by gavage once a day. Mice in the control group received equal quantities of subcutaneous olive oil and intragastric water from the fourth week. At the end of 6 weeks, liver tissue samples were harvested to detect the content of hydroxyproline (Hyp). Hematoxylin and eosin and Sirius red staining were used to observe the inflammation and fibrosis of liver tissue. The expressions of collagen I (Col-I), alpha-smooth muscle actin (α-SMA), CD31 and transforming growth factor β (TGF-β)/Smad signaling pathway were observed by immunohistochemistry, quantitative real-time polymerase chain reaction and Western blot, respectively. The activation models of hepatic stellate cells, JS-1 and LX-2 cells induced by TGF-β1 were used in vitro with or without different concentrations of amygdalin (0.1, 1, 10 µmol/L). LSECs. The effect of different concentrations of amygdalin on the expressions of liver sinusoidal endothelial cells (LSECs) dedifferentiation markers CD31 and CD44 were observed. Results High-dose of amygdalin significantly reduced the Hyp content and percentage of collagen positive area, and decreased the mRNA and protein expressions of Col-I, α-SMA, CD31 and p-Smad2/3 in liver tissues of mice compared to the model group ( P <0.01). Amygdalin down-regulated the expressions of Col-I and α-SMA in JS-1 and LX-2 cells, and TGFβ R1, TGFβ R2 and p-Smad2/3 in LX-2 cells compared to the model group ( P <0.05 or P <0.01). Moreover, 1 and 10 µmol/L amygdalin inhibited the mRNA and protein expressions of CD31 in LSECs and increased CD44 expression compared to the model group ( P <0.05 or P <0.01). Conclusions Amygdalin can dramatically alleviate liver fibrosis induced by CCl 4 in mice and inhibit TGF-β/Smad signaling pathway, consequently suppressing HSCs activation and LSECs dedifferentiation to improve angiogenesis.

Background Fuzheng Huayu formula (FZHY) has been extensively applied in clinical for liver fibrosis treatment in China, its therapeutic potential in cholestatic liver injury remains underexplored. Objective To evaluate the protective effects and underlying mechanisms of FZHY against chronic cholestatic liver injury. Methods The therapeutic effect of FZHY was initially validated in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced murine model of chronic cholestasis. Subsequent mechanistic investigations were conducted through comparative analyses in peroxisome proliferator-activated receptor α gene knockout ( Pparα −/− ) mice subjected to DDC challenge. Results FZHY significantly ameliorated chronic cholestatic liver injury phenotypes in DDC-induced mice, as evidenced by bile acids (BAs) accumulation, inflammation, ductular reaction and biliary fibrosis was remarkably reduced after treatment with FZHY. Transcriptome sequencing analysis revealed that the effect of FZHY on chronic cholestatic liver injury was closely associated with activating PPAR signaling pathway and suppressing nuclear factor kappa-B (NF-κB) signaling. Further research found FZHY did not only enhance the total hepatic content of PPARα protein, but also increased its nuclear to cytoplasmic ratio that was reduced by DDC inducing. Additionally, FZHY suppressed hepatic phosphorylation of IκBα and NF-κB. The therapeutic effect of FZHY in treating DDC-induced mice with chronic cholestatic liver injury is similar to that of fenofibrate, a PPARα agonist. Crucially, genetic ablation of Pparα substantially abrogated the hepatoprotective and anti-fibrotic effects of FZHY in DDC-induced mice. Conclusions The present study underscores FZHY regulated BAs metabolism and alleviated hepatic inflammation and fibrosis by upregulating PPARa in DDC-induced mice. Our study provides novel insights that FZHY might be a promising drug for chronic cholestatic liver injury. Graphical Abstract

Background Bone marrow-derived macrophages (BMDMs) regulate hepatic progenitor cells (HPCs) differentiation, potentially via the Wnt signaling pathway. While M1-polarized BMDMs (M1-BMDMs) exert anti-fibrotic effects in the liver, Wnt5a is implicated in fibrosis progression. The specific influence of Wnt5a levels within M1-BMDMs on HPCs fate and cirrhosis development remains unclear. This study aimed to elucidate the relationship between M1-BMDM-derived Wnt5a and HPCs differentiation during cirrhosis progression. Methods First, Wnt5a protein expression was assessed in liver biopsy tissues from patients with hepatitis B-associated liver fibrosis. Second, cirrhosis was induced in rats using CCl 4 /2-AAF. In week 9, rats received intravenous injections of M1-BMDMs with Wnt5a knockdown (M1-BMDM Wnt5a −KD ) or overexpression (M1-BMDM Wnt5a −OE ); peripheral BMDMs recruitment was blocked using a CCR2 inhibitor. Fibrosis progression, ductular reaction (DR), and HPC differentiation were evaluated. In vitro, WB-F344 cells subjected to frizzled 2 ( Fzd 2) knockdown (WB-F344 Fzd2 −KD ) or overexpression (WB-F344 Fzd2 −OE ) were cultured with conditioned medium from M1-BMDM Wnt5a −KD (CM Wnt5a−KD ) or M1-BMDM Wnt5a −OE (CM Wnt5a −OE ). Results In patients with hepatitis B-related fibrosis, hepatic Wnt5a expression increased progressively with METAVIR fibrosis grade. In the rat cirrhosis model, M1-BMDMs Wnt5a −KD attenuated fibrosis, whereas M1-BMDMs Wnt5a −OE exacerbated it. Mechanistically, in vivo injection of M1-BMDMs Wnt5a −KD significantly inhibited HPCs differentiation into biliary epithelial cells (BECs), while M1-BMDM Wnt5a −OE promoted this differentiation. In vitro, CM Wnt5a −KD inhibited the differentiation of WB-F344 cells into BECs; this inhibition was potentiated by Fzd2 knockdown in WB-F344 cells but abrogated by Fzd2 overexpression. Conversely, under CM Wnt5a −OE conditions, WB-F344 Fzd2 −OE cells exhibited increased cholangiocytic differentiation, an effect largely negated by Fzd2 knockdown. Conclusions M1-BMDMs Wnt5a −KD demonstrated superior therapeutic efficacy against cirrhosis compared to unmodified M1-BMDMs. Wnt5a/Fzd2 signaling mediated the crosstalk between M1-BMDMs Wnt5a −KD and HPCs, revealing a novel therapeutic target for cirrhosis treatment.

Acoustic emission has a direct correspondence to the internal damage of a material. To determine the effects of the loading rate on the mechanical properties of rock, the initial damage was characterized using the acoustic emission technique when a uniaxial preloading was imposed on a cylindrical rock sample. On this basis, the uniaxial compression test was conducted on sandstone that contains initial damage induced under a range of loading rates. The effects of the initial damage and loading rate on the mechanical properties of rock were analyzed. The uniaxial preloading generated randomly distributed microcracks in the natural rock. The results showed that the acoustic emission and positioning technique can characterize accurately the damage and its position due to preloading. The development of microcracks was found to be strongly dependent on the loading rate. Moreover, the loading rate accelerated the degradation of the rock strength. The effects of the loading rate and initial damage on the mechanical properties of rock are a complicated coupled process. From the experimental test result, a constitutive equation was constructed based on the damage mechanics.