The Upregulation of Leucine-Rich Repeat Containing 1 Expression Activates Hepatic Stellate Cells and Promotes Liver Fibrosis by Stabilizing Phosphorylated Smad2/3.

Liver fibrosis poses a significant global health risk due to its association with hepatocellular carcinoma (HCC) and the lack of effective treatments. Thus, the need to discover additional novel therapeutic targets to attenuate liver diseases is urgent. Leucine-rich repeat containing 1 (LRRC1) reportedly promotes HCC development. Previously, we found that LRRC1 was significantly upregulated in rat fibrotic liver according to the transcriptome sequencing data. Herein, in the current work, we aimed to explore the role of LRRC1 in liver fibrosis and the underlying mechanisms involved. LRRC1 expression was positively correlated with liver fibrosis severity and significantly elevated in both human and murine fibrotic liver tissues. LRRC1 knockdown or overexpression inhibited or enhanced the proliferation, migration, and expression of fibrogenic genes in the human hepatic stellate cell line LX-2. More importantly, LRRC1 inhibition in vivo significantly alleviated CCl4-induced liver fibrosis by reducing collagen accumulation and hepatic stellate cells' (HSCs) activation in mice. Mechanistically, LRRC1 promoted HSC activation and liver fibrogenesis by preventing the ubiquitin-mediated degradation of phosphorylated mothers against decapentaplegic homolog (Smad) 2/3 (p-Smad2/3), thereby activating the TGF-ß1/Smad pathway. Collectively, these results clarify a novel role for LRRC1 as a regulator of liver fibrosis and indicate that LRRC1 is a promising target for antifibrotic therapies.

Dysfunction of CCT3-associated network signals for the critical state during progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is a serious threat to human health; thus, early diagnosis and adequate treatment are essential. However, there are still great challenges in identifying the tipping point and detecting early warning signals of early HCC. In this study, we aimed to identify the tipping point (critical state) of and key molecules involved in hepatocarcinogenesis based on time series transcriptome expression data of HCC patients. The phase from veHCC (very early HCC) to eHCC (early HCC) was identified as the critical state in HCC progression, with 143 genes identified as key candidate molecules by combining the DDRTree (dimensionality reduction via graph structure learning) and DNB (dynamic network biomarker) methods. Then, we ranked the candidate genes to verify their mRNA levels using the diethylnitrosamine (DEN)-induced HCC mouse model and identified five early warning signals, namely, CCT3, DSTYK, EIF3E, IARS2 and TXNRD1; these signals can be regarded as the potential early warning signals for the critical state of HCC. We identified CCT3 as an independent prognostic factor for HCC, and functions of CCT3 involving in the "MYCtargets_V1" and "E2F-Targets" are closely related to the progression of HCC. The predictive method combining the DDRTree and DNB methods can not only identify the key critical state before cancer but also determine candidate molecules of critical state, thus providing new insight into the early diagnosis and preemptive treatment of HCC.

Construction of Z scheme S-g-C3N4/Bi5O7I photocatalysts for enhanced photocatalytic removal of Hg0 and carrier separation.

Photocatalysis has demonstrated the potential to solve challenges in various practical application fields such as energy and environmental science due to its environmental friendliness. However, the photocatalytic activity is mainly affected by the weak absorption of visible light and the low separation efficiency of photogenerated carriers. Herein, an S-doped g-C3N4/Bi5O7I heterojunction was designed by the calcination method. It was found that S doping not only reduces the band gap of g-C3N4, which raises the optical absorption boundary of g-C3N4 from 465 nm to 550 nm. At the same time, the introduction of S elements leads to new doping energy levels, which can act as photogenerated electron trapping centers and thus inhibit the complexation of photogenerated carriers. Second, the construction of the heterojunction greatly facilitates the transport of carriers and the separation of electrons and holes driven by the built-in electric field. Finally, the abundant oxygen vacancies in the system result in defective energy levels that not only promote the activation of molecular oxygen, but also act as photogenerated electron traps, which further boost the separation of electron-hole pairs. Benefiting from the optimized performance, the photocatalytic reaction rates of S-doped g-C3N4/Bi5O7I are 5.2 and 2.1 times higher than those of g-C3N4 and Bi5O7I, respectively. This work provides a viable idea for the potential development of non-metal doping combined with heterojunction photocatalytic systems.

Isoandrographolide from Andrographis paniculata ameliorates tubulointerstitial fibrosis in ureteral obstruction-induced mice, associated with negatively regulating AKT/GSK-3ß/ß-cat signaling pathway.

Tubulointerstitial fibrosis (TIF) is a prominent pathological manifestation for the progression of almost all chronic kidney diseases (CKDs) to end-stage renal failure. However, there exist few efficient therapies to cure TIF. Our recent results showed that (8R, 12S)-isoandrographolide (ISA), a diterpenoid lactone ingredient of traditional Chinese herbal Andrographis paniculata (Burm.f.) Nees, exhibited anti-pulmonary fibrosis in silica-induced mice. Herein, we investigated the therapeutic effect of ISA on TIF, using mice subjected to unilateral ureteral obstruction (UUO) and human kidney proximal tubular epithelial (HK-2) cells treated with transforming growth factor-ß1 (TGF-ß1) or tumor necrosis factor-α (TNF-α). The pathological changes and collagen deposition results displayed that ISA administration significantly attenuated inflammatory response, ameliorated TIF, and protected the kidney injury. Interestingly, ISA revealed much lower cytotoxicity on HK-2 cells, but exhibited stronger inhibitory effect on tubular epithelial mesenchymal transformation (EMT) and inflammation, as compared to andrographolide (AD), the major ingredient of A. paniculata extract that has been reported to ameliorate TIF in diabetic nephropathy mice. It was further clarified that the amelioration of TIF by ISA was associated with suppressing the aberrant activation of AKT/GSK-3ß/ß-catenin pathway through network pharmacology analysis and experimental validation. Taken together, these findings indicate that ISA is a promising lead compound for development of anti-TIF, and even broad-spectrum anti-fibrotic drugs.

Isoandrographolide inhibits NLRP3 inflammasome activation and attenuates silicosis in mice.

Silicosis is an irreversible occupational disease caused by silica particle exposure. Abundant evidences suggest that NLRP3-mediated inflammation acts an essential role in fibrogenesis and the pathogenesis of silicosis. In the current work, we firstly reported that (8R-12S)-isoandrographolide (ISA), a diterpenoid lactone ingredient of Chinese traditional medicinal plant Andrographis paniculata (Burm.f.) Nees, could reduce pulmonary inflammation and fibrosis by inhibiting NLRP3, and thereby ameliorate silicosis. ISA administration significantly alleviated lung injury, and attenuated inflammatory response, EMT, as well as collagen deposition in the lung of silica-induced mice. Further studies verified that ISA inhibited the expressions of NLRP3 inflammasome-related proteins NLRP3, ASC and caspase-1 in vivo and in vitro, leading to the attenuation of inflammation and EMT. Additionally, the molecular docking assay indicated that ISA possibly interacted with the residues of LYS26 and GLU47 of NLRP3, implying that ISA might directly bond to protein NLRP3. Of note, ISA revealed a lower cytotoxicity but more potent therapeutic effect than andrographolide (AD), the major active extract of A. paniculata, which has been traditionally used to treat inflammation-related diseases. Taken together, our study clarified a novel role of ISA in attenuating inflammation and fibrosis in silicosis, and indicated a bright future of ISA as a lead compound for developing therapeutic drug for silicosis.

In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis.

It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.

Cu Nanoparticles Inlaid Mesoporous Carbon Aerogels as a High Performance Desulfurizer.

In the present study, to insert the Cu nanoparticles (NPs) into mesoporous carbon aerogels and first applied it to remove H2S efficiently. This desulfurizer was made based on the dimensional policy by inserting the Cu NPs on mesoporous carbon aerogels to overcome the sintering problem and improve the activity, which has potential performance at high-temperature catalysis. The obtained desulfurizer was employed for H2S removal at middle temperature conditions (optimal H2S adsorption at 550 °C). We explored the optimum doping amount of CuOx, optimum temperature conditions, and the influence of textural parameters of carbon aerogels. The desulfurizers were characterized by means of field-emission scanning electron microscopy (FESEM), N2-adsorption, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), H2 temperature-programmed reduction (H2-TPR), and Raman spectra techniques. The results confirmed that the presence of H2 was unfavorable for sulfidation and obviously shortened the breakthrough time. However, the existence of CO had little impact on the desulfurization and sulfur capacity. In a nutshell, this work could provide a new synthetic route to prepare Cu NPs deep into the lattice of carbon aerogels structure of desulfurizers and understand the desulfurization mechanism.

Influences of ammonia contamination on leaching from air-pollution-control residues.

Application of selective non-catalytic reduction systems at municipal solid waste incinerators (MSWIs) often involves over-stoichiometric injection of ammonia into flue gases. Un-reacted ammonia may be deposited on fly ash particles and can ultimately influence the leaching behaviour of air-pollution-control (APC) residues. Batch tests were conducted to investigate the impacts of ammonia levels on leaching of a range of metals (sodium, potassium, calcium, aluminium, chromium, iron, lead, cadmium, copper, nickel and zinc), as well as chloride and dissolved organic carbon (DOC). Specific conductivity was also identified to reflect the soluble components. The results showed that with ammonia concentrations rising from a background level of 4 to 26,400 mg l(-1), the specific conductivity increased by 2-7 times as pH varied from alkaline to acidic values. DOC release was also significantly enhanced with high ammonia levels of 1400 mg l(-1) or higher at pH > 9; however at these high ammonia concentrations, the role of DOC in cadmium, copper, nickel and zinc leaching was negligible. Based on the experimental data, chloride, sodium and potassium were leached at high concentrations regardless of pH and ammonia concentrations. For aluminium, chromium, iron and lead, ammonia had little impact on their leaching behaviour. With respect to cadmium, copper, nickel and zinc, high ammonia concentrations significantly increased leaching in the pH range of 8-12 due to the formation of metal-ammonia complexes, which was also proved in the speciation calculations. However, the overall results suggest that typical levels of ammonia injection in MSWIs are not likely to affect metal leaching from APC residues.

[Influence of ammonia on leaching behaviors of incineration fly ash and its geochemical modeling].

Incineration fly ash could be contaminated with NH3 that was slipped from the ammonia-based selective non-catalytic reduction(SNCR) process and from evaporation of municipal solid wastes' leachate involved in the wastes. This research was conducted to investigate the impacts of ammonia on leaching of dissolved organic carbon (DOC) and metals from incineration fly ash in the pH range of 3.66-12.44 with an active ammonia spike. A geochemical modeling software Visual MINTEQ was adopted to calculate the chemical speciation of metals under the leaching conditions to reveal the mechanism behind the impacts. It was proved that at pH > 9, the leaching of DOC increased significantly in the presence of high concentrations of ammonia (> or = 1 357 mg x L(-1)), but there was little effect when the ammonia level in eluates was not higher than 537 mg x L(-1). At pH < 6, metals in fly ash were released mainly in the form of free metal ions and chloride complexes, which were little influenced by ammonia; while at pH 8-12, higher concentrations of ammonia (> or = 3 253 mg x L(-1)) mobilized Cd, Cu, Ni and Zn significantly due to the formation of soluble metal-ammonia complexes, and the leaching rates reached their peaks at pH around 9; however, ammonia had little impacts on Al and Pb leaching within this pH range. At pH > 12, for Cd, Cu, Ni and Zn, their leaching species were predominantly in the form of hydroxide complexes. Under the ammonia concentration of 3253 mg x L(-1), the Visual MINTEQ modeling results were compared with the experimental data, and it was proved that the leaching of Al, Pb and Zn was mainly controlled by precipitation/dissolution modeling, while Cd, Cu and Ni were controlled by precipitation/dissolution and surface complexation/precipitation processes; Visual MINTEQ modeling could well describe the leaching behaviors of Al, Cu, Pb and Zn from incineration fly ash.

[Study on inhibition of NO(x) and dioxin emissions by carbohydrazide under moderate to high temperatures].

Experimental researches were carried out on the inhibition effects of carbohydrazide (CHZ) on NO(x) and dioxin emissions under moderate to high temperatures, namely De-NO(x) effect of CHZ was investigated in the temperature range of 450-1 050 degrees C with the O2 concentration between 10.1% and 16.7%; and its suppression effect on dioxin emissions was studied both by spraying CHZ solution into incineration flue gases and by mixing CHZ in iron ore in the sintering pot. It was proved that CHZ could reduce NO(x) with dual temperature-linked peaks, i. e. the De-NO(x) efficiency peaks appeared both around 600 degrees C and 967 degrees C, with a vale around 850 degrees C. The results also indicated that CHZ had good suppression effect on dioxin synthesis in the fly ash precipitated in the temperature range of 250-450 degrees C when CHZ solution was sprayed into flue gases at proper temperatures; comparably, for dioxin emissions from the iron ore sintering pot, the more CHZ mixed into iron ore, the less dioxin emissions took place; when the mixture proportion of CHZ (mass fraction) was up to 0.1%, the concentration of PCDD/Fs in TEQ in sintering flue gases was decreased by 78.8% compared to the scenario without CHZ mixing, showing that CHZ is an effective inhibitors for reducing dioxin emissions in the iron ore sintering furnace. All of these results showed that CHZ is a potential inhibitor for dioxin emissions from incinerators and iron ore sintering furnaces as well as a reduction agent for NO(x).