Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2.

Background & Aims: Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods: The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results: FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions: Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications: Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element-binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.

Construction of BiOCl/Ti-MOFs type-II heterojunction photocatalyst for enhanced photocatalytic performance for multiple antibiotics removal.

The increased threats to environmental and human health caused by the widespread use of antibiotics have increased the need for efficient technologies for removing antibiotic remnants from wastewater after production. Photocatalysis, which is non-toxic, highly efficient, and low energy consumption, has played a vital role in wastewater treatment among the aforementioned technologies. Therefore, a MIL-125(Ti)/BiOCl type-II heterojunction photocatalyst was fabricated using solvothermal method. Investigations remarkably revealed that the enhanced photocatalytic performance of the photocatalyst for multiple antibiotics degradation (tetracycline and ofloxacin) was attributed to the construction of a heterojunction, which inhibits carrier recombination and enhances visible-light absorption. Furthermore, the radical trapping experiments and electron spin resonance determined superoxide radicals and holes to be the main species in the photocatalytic process. Finally, we presented a potential photocatalytic mechanism that could account for the observations. Overall, this study offered guidelines for developing more photocatalysts with visible-light responses and removing multiple antibiotics from water more efficiently.

The adsorption property of in-situ synthesis of MOF in alginate gel for ofloxacin in the wastewater.

Although metal-organic frameworks (MOFs) are advantageous to the removal of organic pollutants, the general MOFs in powder form is disadvantageous to their practical applications. In-situ MOF synthesis in alginate gel is a good way to fabricate an MOF composite for many applications, which is different from blending MOF particles with polymers. In-situ synthesis of Zeolitic Imidazolate Framework-8 (ZIF-8) in alginate gel is in the form of beads with rough wrinkles and has many pores inside. When used as an absorbent, in-situ synthesis of ZIF-8 in alginate gel could remove 97.7 ± 0.9% of ofloxacin from ofloxacin solution and the equilibrium adsorption capacity is up to 160.6 ± 1.3 mg/g. During the adsorption, ofloxacin is first brought into the gel by the solvent exchange and gel microchannel adsorption, and it can then be absorbed by in-situ ZIF-8. Moreover, the adsorption efficiency can reach 85.5% even after four cycles of adsorption. We believe that in-situ synthesis of ZIF-8 in alginate gel will be an appropriate material for the removal of ofloxacin in the wastewater.

Sustained activation of EGFR-ERK1/2 signaling limits the response to tigecycline-induced mitochondrial respiratory deficiency in liver cancer.

BACKGROUND: Identification of tumor dependencies is important for developing therapeutic strategies for liver cancer. METHODS: A genome-wide CRISPR screen was performed for finding critical vulnerabilities in liver cancer cells. Compounds screen, RNA sequencing, and human phospho-receptor tyrosine kinase arrays were applied to explore mechanisms and search for synergistic drugs. FINDINGS: We identified mitochondrial translation-related genes associated with proliferation for liver cancer cells. Tigecycline induced deficiency of respiratory chain by disturbing mitochondrial translation process and showed therapeutic potential in liver cancer. For liver cancer cells extremely insensitive to tigecycline, a compounds screen was applied to identify MEK inhibitors as synergistic drugs to tigecycline-insensitive liver cancer cells. Mechanistically, sustained activation of EGFR-ERK1/2-MYC cascade conferred the insensitivity to tigecycline, which was mediated by enhanced secretion of EREG and AREG. Moreover, glycolytic enzymes, such as HK2 and PKM2 were upregulated to stimulate glycolysisin a MYC-dependent manner. Tigecycline induced respiratory chain deficiency in combination with cutting off EGFR-ERK1/2-MYC cascade by MEK inhibitors or EGFR inhibitors, resulting in decrease of both oxidative phosphorylation and glycolysis in liver cancer cells. INTERPRETATION: Our study proved that blocking EGFR-ERK1/2-MYC cascade combined with tigecycline could be a potential therapeutic strategy for liver cancer. FUNDING: This work was funded by grants from the National Natural Science Foundation of China (82073039,82222047, 81920108025), Program of Shanghai Academic/Technology Research Leader (22XD1423100), Shanghai Municipal Science and Technology Project (20JC1411100), 111 Project (B21024), Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212700, SHSMU-ZDCX20210802) and Shanghai Jiao Tong University School of Medicine (YG2019GD01).

Effective Halogen- and Phosphorus-Free Polyphenylene Ether Resin-Based Flame-Retardant Foam.

A novel halogen- and phosphorus-free intrinsic flame-retardant foam is fabricated from curable phenol-terminated polyphenylene ether resin with a high molecular weight using phenol, formaldehyde, and diphenyl ether as starting materials. The limiting oxygen index (LOI) of the pure foam is 24.90% ± 0.28. When 0.5 wt % silica sol is added, the LOI of the foam (SPF-0.5) is up to 28.5% ± 0.15 and both the combustion heat release rate and total combustion heat are low. Moreover, the SPF-0.5 foam exhibits high carbon residue, high compressive strength, and low pulverization rate and is superior to some previously reported phenolic foam. The flame-retardant mechanism includes the condensed-phase flame retardation and the gas-phase flame retardation, with the former being the main step, which is based on the high cross-linking density, the higher strength and smaller size of foam cells, and the formation of a carbon-silicon compound in the foam. This halogen- and phosphorous-free flame-retardant foam is also environmentally benign.

Minocycline inhibition of microglial rescues nigrostriatal dopaminergic neurodegeneration caused by mutant alpha-synuclein overexpression.

Studies indicate that mutant α-synuclein (mαSyn) is involved in the pathogenesis of Parkinson's disease (PD). The mαSyn expression leads to the loss of dopaminergic neurons in the substantia nigra (SN) and consequent motor dysfunctions. Additionally, studies found that PD was accompanied by extensive neuroinflammation of SN. However, it remains unclear as to whether microglia participate in the mαSyn pathology. This issue is addressed by using AAV-mα-Syn (A30P-A53T) to overexpress the human mαSyn in the SN in view of establishing the PD model. Subsequently, minocycline (Mino) was used to inhibit microglia activity, and an interleukin-1 receptor (IL-1R1) antagonist was used to hinder the IL-1R1 function. Finally, immunohistochemistry was used to analyze phosphorylated αSyn (Ser129) and TH-positive cells in the SN. Dopamine levels were analyzed by high performance liquid chromatography. mαSyn overexpression in the SN induced motor dysfunction, decreased striatal dopamine levels, and increased pathological αSyn 12 weeks after AAV injection. The data demonstrated that inhibiting microglial activation or hindering IL-1R1 reversed the persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system, and development of Lewy body pathology caused by human mαSyn overexpression in the SN. Additionally, these findings indicate that neuroinflammation promotes the loss of neuronal cells.

Effect of ultrasonic separation on the structure and properties of diallyl phthalate prepolymer.

The bulk polymerization of diallyl phthalate (DAP) was carried out at high temperature (190 degrees C) without using any initiator, and the reaction was stopped before the gelation point in order to get the prepolymer of DAP. The mixture for the prepolymer and the monomer was successfully separated by a novel ultrasonic method for the first time, and the separation efficiency for the new method was obviously higher than that for the traditional reprecipitation. The product obtained by ultrasonic separation was characterized by infrared spectroscopy (IR), gel permeation chromatography (GPC) and iodine number measurement. It was shown that the average molecular weight of the prepolymer got by the ultrasonic method was lower than that of the prepolymer got by the multi-precipitation, moreover, the molecular weight distribution of the prepolymer got by the ultrasonic separation was broader. Besides, the residual unsaturation degree of the prepolymer separated by ultrasonic was slightly higher than that of prepolymer separated by reprecipitation.