Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder.

Tacrolimus, one of the macrolide calcineurin inhibitors, is the most frequently used immunosuppressant after transplantation. Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism. In this study, we investigated the mode of action and underlying mechanisms of this adverse reaction. Mice were administered tacrolimus (2.5 mg·kg-1·d-1, i.g.) for 10 weeks, then euthanized; the blood samples and liver tissues were collected for analyses. We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver. Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus. We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids, but markedly decreased fatty acid oxidation (FAO) in AML12 cells. Furthermore, we showed that tacrolimus dramatically decreased the expression of HMGCS2, the rate-limiting enzyme of ketogenesis, with decreased ketogenesis in AML12 cells, which was responsible for lipid deposition in normal hepatocytes. Moreover, we revealed that tacrolimus inhibited forkhead box protein O1 (FoxO1) nuclear translocation by promoting FKBP51-FoxO1 complex formation, thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells. The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation, which promoted mitochondrial protein acetylation, thereby resulting in FAO function inhibition. Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition, thus removing the lipid deposition in hepatocytes. Collectively, this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus, resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition, providing an alternative target for reversing tacrolimus-induced adverse reaction.

Spinel Nanostructures for the Hydrogenation of CO2 to Methanol and Hydrocarbon Chemicals.

Composite oxides have been widely applied in the hydrogenation of CO/CO2 to methanol or as the component of bifunctional oxide-zeolite for the synthesis of hydrocarbon chemicals. However, it is still challenging to disentangle the stepwise formation mechanism of CH3OH at working conditions and selectively convert CO2 to hydrocarbon chemicals with narrow distribution. Here, we investigate the reaction network of the hydrogenation of CO2 to methanol over a series of spinel oxides (AB2O4), among which the Zn-based nanostructures offer superior performance in methanol synthesis. Through a series of (quasi) in situ spectroscopic characterizations, we evidence that the dissociation of H2 tends to follow a heterolytic pathway and that hydrogenation ability can be regulated by the combination of Zn with Ga or Al. The coordinatively unsaturated metal sites over ZnAl2Ox and ZnGa2Ox originating from oxygen vacancies (OVs) are evidenced to be responsible for the dissociative adsorption and activation of CO2. The evolution of the reaction intermediates, including both carbonaceous and hydrogen species at high temperatures and pressures over the spinel oxides, has been experimentally elaborated at the atomic level. With the integration of a series of zeolites or zeotypes, high selectivities of hydrocarbon chemicals with narrow distributions can be directly produced from CO2 and H2, offering a promising route for CO2 utilization.

CARD9 deficiency promotes pancreatic cancer growth by blocking dendritic cell maturation via SLC6A8-mediated creatine transport.

Pancreatic cancer (PC) is featured with low survival rate and poor outcomes. Herein, we found that the expression of caspase-recruitment domain-containing protein 9 (CARD9), predominantly expressed in innate immune cells, was positively related to the prognosis of PC patients. CARD9-deficient PC mice exhibited rapider cancer progression and poorer survival rate. CARD9 knockout decreased dendritic cell (DC) maturation and impaired DC ability to activate T cells in vivo and in vitro. Adoptive DC transfer confirmed that the role of CARD9 deficiency in PC relied on DCs. Creatine was identified as the most significant differential metabolite between WT DCs and CARD9-/- DCs wherein it played an essential role in maintaining DC maturation and function. CARD9 deficiency led to decreased creatine levels in DCs by inhibiting the transcription of the creatine-specific transporter, solute carrier family 6 member 8 (SLC6A8). Furtherly, CARD9 deletion blocked p65 activation by abolishing the formation of CARD9-BCL10-MALT1 complex, which prevented the binding between p65 and SLC6A8 promoter. These events decreased the creatine transport into DCs, and led to DC immaturity and impairment in antitumor immunity, consequently promoting PC progression.

Tandem catalysis with double-shelled hollow spheres.

Metal-zeolite composites with metal (oxide) and acid sites are promising catalysts for integrating multiple reactions in tandem to produce a wide variety of wanted products without separating or purifying the intermediates. However, the conventional design of such materials often leads to uncontrolled and non-ideal spatial distributions of the metal inside/on the zeolites, limiting their catalytic performance. Here we demonstrate a simple strategy for synthesizing double-shelled, contiguous metal oxide@zeolite hollow spheres (denoted as MO@ZEO DSHSs) with controllable structural parameters and chemical compositions. This involves the self-assembly of zeolite nanocrystals onto the surface of metal ion-containing carbon spheres followed by calcination and zeolite growth steps. The step-by-step formation mechanism of the material is revealed using mainly in situ Raman spectroscopy and X-ray diffraction and ex situ electron microscopy. We demonstrate that it is due to this structure that an Fe2O3@H-ZSM-5 DSHSs-showcase catalyst exhibits superior performance compared with various conventionally structured Fe2O3-H-ZSM-5 catalysts in gasoline production by the Fischer-Tropsch synthesis. This work is expected to advance the rational synthesis and research of hierarchically hollow, core-shell, multifunctional catalyst materials.

MicroRNAs in Body Fluids: A More Promising Biomarker for Clear Cell Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the second most common cancer of the urinary system, accounting for approximately 10-15% of kidney cancers in the world. Clear cell renal cell carcinoma (ccRCC) is the most common RCC subtype with the highest mortality. Surgical resection or puncture of tumor tissue is still an important clinical treatment and diagnosis of ccRCC, but its high recurrence rate and poor prognosis often lead to the short survival period of patients. Hence, the development of novel molecular biomarkers is of great clinical importance. miRNAs are endogenous non-coding small RNAs with a length of 19-24 nt. A growing number of studies have reported that miRNAs, as proto-oncogenes or tumor suppressor genes, play a key role in the development of ccRCC and might be effective diagnostic and prognostic biomarkers. In addition, miRNAs can also predict the efficacy of treatment drug, thus improving the accuracy of clinical medication. Furthermore, non-invasive detection of miRNAs or extracellular vesicles (EV) in body fluids has better convenience and repeatability, which shows remarkable advantages compared with tissue detection. In this review, we summarized the typical miRNAs reported in recent years and place emphasis on evaluating miRNAs in different body fluids to provide reference for the clinical diagnosis and prognosis of ccRCC in the future.

Huganbuzure Granule Attenuates Concanavalin-A-Induced Immune Liver Injury in Mice via Regulating the Balance of Th1/Th2/Th17/Treg Cells and Inhibiting Apoptosis.

In Uygur medicine, Huganbuzure granule (HBG) is one of the classical prescriptions for liver protection. However, its role in immune liver injury remains unknown. This study evaluates the effect of HBG on concanavalin-A- (ConA-) induced immune liver injury and investigates its protective underlying mechanism. BALB/c mice were randomly divided into five groups (n = 24 mice per group): control, ConA, 1.6 g/kg HBG + ConA, 3.2 g/kg HBG + ConA, and 6 mg/kg prednisolone + ConA. HBG was intragastrically administrated once daily for ten consecutive days, prior to ConA (20 mg/kg) injection. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), superoxide dismutase (SOD), and malondialdehyde (MDA) in mouse serum were measured after ConA injection. Moreover, liver-related mRNA levels were evaluated by qPCR. The detection of liver-related proteins was assessed by immunohistochemistry and western blot analysis. Compared with the ConA group, HBG reduced the mRNA expression of IL-17A and IFN-γ and the protein expression of T-bet and ROR-γt. In addition, HBG increased the mRNA expression of IL-4 and TGF-ß and protein expression of GATA3 and Foxp3, indicating that HBG regulated the balance of Th1/Th2 and Th17/Treg. Furthermore, HBG alleviated immune liver injury by reducing oxidative stress, inhibiting apoptosis, and decreasing the expression of p-JNK, p-ERK, p-p38, p-JAK1, p-STAT1, p-STAT3, and IRF1. Our data suggested that HBG attenuated ConA-induced immune liver injury by regulating the immune balance and inhibiting JAK1/STATs/IRF1 signaling, thereby reducing apoptosis induced by JNK activation. The findings indicate that HBG may be a promising drug for immune liver injury.

Functionalized Carbon Materials in Syngas Conversion.

Functionalized carbon materials are widely used in heterogeneous catalysis due to their unique properties such as adjustable surface properties, excellent thermal conductivity, high surface areas, tunable porosity, and moderate interactions with guest metals. The transformation of syngas into hydrocarbons (known as the Fischer-Tropsch synthesis) or oxygenates is an exothermic reaction and is typically catalyzed by transition metals dispersed on functionalized supports. Various carbon materials have been employed in syngas conversions not only for improving the performance or decreasing the dosage of expensive active metals but also for building model catalysts for fundamental research. This article provides a critical review on recent advances in the utilization of carbon materials, in particular the recently developed functionalized nanocarbon materials, for syngas conversions to either hydrocarbons or oxygenates. The unique features of carbon materials in dispersing metal nanoparticles, heteroatom doping, surface modification, and building special nanoarchitectures are highlighted. The key factors that control the reaction course and the reaction mechanism are discussed to gain insights for the rational design of efficient carbon-supported catalysts for syngas conversions. The challenges and future opportunities in developing functionalized carbon materials for syngas conversions are briefly analyzed.

Network pharmacology and molecular docking reveal the mechanism of Scopoletin against non-small cell lung cancer.

AIMS: Scopoletin is a natural anticarcinogenic and antiviral coumarin component. Many studies have proved its anti-cancer effect, and after the preliminary screening of this study, Scopoletin had the best inhibitory effect on Non-small cell lung cancer (NSCLC). But its mechanism for treating NSCLC is still unclear. Therefore, network pharmacology and molecular docking technology were used to explore the potential anti-NSCLC targets and pathways of Scopoletin. The results were verified in vitro. MAIN METHODS: First, Scopoletin was isolated from Fennel and screened to conduct cell proliferation assay on Human lung cancer cell line A549, Human colon cancer cell line HCT-116 and Human hepatoma cell line HepG2 respectively, through the MTT test. Then, the key targets and related pathways were screened through Protein-protein Interaction (PPI) network and "component-target-pathway" (C-TP) network constructed by network pharmacology. And the key targets were selected to dock with Scopoletin via molecular docking. A549 and Human normal lung epithelial cell BEAS-2B were used to verify the results, finally. KEY FINDINGS: Through MTT, A549 was chosen as the test cancer cell. From network pharmacology, 16 targets, 27 signaling pathways and 16 GO items were obtained (P < 0.05). The results of PPI network and molecular docking showed that EGFR, BRAF and AKT1 were the key targets of Scopoletin against NSCLC, which were consistent with the western-blot results. SIGNIFICANCE: Through network pharmacology, molecular docking and experiments in vitro, Scopoletin was verified to against NSCLC through RAS-RAF-MEK-ERK pathway and PI3K/AKT pathway.

Yu Gan Long Ameliorates Hepatic Fibrosis by Inhibiting PI3K/AKT, Ras/ERK and JAK1/STAT3 Signaling Pathways in CCl4-induced Liver Fibrosis Rats.

Yu Gan Long (YGL) is a Chinese traditional herbal formula which has been reported to attenuate liver fibrosis for many years and we have explored its anti-fibrotic mechanism through blocking transforming growth factor (TGF-ß) in the previous study. But the mechanisms associated with platelet-derived growth factor (PDGF)-BB remain obscure. In this study, we further investigated the mechanism of YGL reducing carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Our results showed that YGL suppressed CCl4-induced upregulation of collagen IV (Col IV), type HI precollagen (PCHI), hyaluronuc acid (HA) and laminin (LN), which are implicated in liver fibrosis. Also, YGL reduced the α-smooth muscle actin (α-SMA) expression, which acts as the indicator of liver fibrosis. Furthermore, YGL decreased the serum levels of hepatic stellate cell (HSC) mitogen PDGF-BB and inflammation cytokines, including TNF-α, IL-1ß, IL-6. Markers involved in liver fibrosis, such as Ras, p-Raf-1, p-ERK1/2, p-JNK, p-P38, p-PI3K, p-AKT, p-JAKl, p-STAT3 were downregulated significantly after treatment with YGL. Our results indicated that YGL ameliorated CCl4-induced liver fibrosis by reducing inflammation cytokines production, and suppressing Ras/ERK, PI3K/AKT, and JAK1/STAT3 signaling pathways, which provided further evidence towards elucidation of the anti-fibrotic mechanism of YGL.

Selective transformation of carbon dioxide into lower olefins with a bifunctional catalyst composed of ZnGa2O4 and SAPO-34.

A bifunctional catalyst composed of ZnGa2O4 with a spinel structure and molecular sieve SAPO-34 catalyses the direct conversion of CO2 to C2-C4 olefins with a selectivity of 86% and a CO2 conversion of 13% at 370 °C. The oxygen vacancies on ZnGa2O4 surfaces are responsible for CO2 activation, forming a methanol intermediate, which is then converted into C2-C4 olefins in SAPO-34.