Regioselective synthesis of isoquinolinonediones through remote unactivated C(sp3)-H bonds.

Herein, a general strategy for the remote-site-selective cascade addition/cyclization of unactivated C(sp3)-H bonds in free alcohols and sulfonamides to build isoquinolinonedione skeletons is developed. The site selectivity occurs predominantly via a 1,5-hydrogen atom transfer (HAT) process, triggered by heteroatom-centred radicals generated directly under silver catalysis. A broad substrate scope and excellent regio-/chemo-selective control are demonstrated in this method.

Recent Progress on Conversion of Lignocellulosic Biomass by MOF-Immobilized Enzyme.

The enzyme catalysis conversion of lignocellulosic biomass into valuable chemicals and fuels showed a bright outlook for replacing fossil resources. However, the high cost and easy deactivation of free enzymes restrict the conversion process. Immobilization of enzymes in metal-organic frameworks (MOFs) is one of the most promising strategies due to MOF materials' tunable building units, multiple pore structures, and excellent biocompatibility. Also, MOFs are ideal support materials and could enhance the stability and reusability of enzymes. In this paper, recent progress on the conversion of cellulose, hemicellulose, and lignin by MOF-immobilized enzymes is extensively reviewed. This paper focuses on the immobilized enzyme performances and enzymatic mechanism. Finally, the challenges of the conversion of lignocellulosic biomass by MOF-immobilized enzyme are discussed.

PKCiota Inhibits the Ferroptosis of Esophageal Cancer Cells via Suppressing USP14-Mediated Autophagic Degradation of GPX4.

Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant tumors, and the mechanisms underlying the anti-ferroptosis of esophageal cancer cells are still largely unclear. This study aims to explore the roles of amplified protein kinase C iota (PKCiota) in the ferroptosis of ESCC cells. Cell viability, colony formation, MDA assay, Western blotting, co-IP, PLA, and RNA-seq technologies are used to reveal the roles and mechanisms underlying the PKCiota-induced resistance of ESCC cells to ferroptosis. We showed here that PKCiota was amplified and overexpressed in ESCC and decreased during RSL3-induced ferroptosis of ESCC cells. PKCiota interacted with GPX4 and the deubiquitinase USP14 and improved the protein stability of GPX4 by suppressing the USP14-mediated autophagy-lysosomal degradation pathway. PKCiota was negatively regulated by miR-145-5p, which decreased in esophageal cancer, and also regulated by USP14 and GPX4 by a positive feedback loop. PKCiota silencing and miR-145-5p overexpression suppressed tumor growth of ESCC cells in vivo, respectively; even a combination of silencing PKCiota and RSL3 treatment showed more vital suppressive roles on tumor growth than silencing PKCiota alone. Both PKCiota silencing and miR-145-5p overexpression sensitized ESCC cells to RSL3-induced ferroptosis. These results unveiled that amplified and overexpressed PKCiota induced the resistance of ESCC cells to ferroptosis by suppressing the USP14-mediated autophagic degradation of GPX4. Patients with PKCiota/USP14/GPX4 pathway activation might be sensitive to GPX4-targeted ferroptosis-based therapy.

Dihydroorotate dehydrogenase promotes cell proliferation and suppresses cell death in esophageal squamous cell carcinoma and colorectal carcinoma.

Background: Ferroptosis is defined as an iron-dependent non-apoptotic form of programmed cell death. Dihydroorotate dehydrogenase (DHODH) is a newly discovered anti-ferroptosis molecule independent from the well-known GPX4 and AIFM2. However, the expression pattern and especially the functional roles of DHODH during cancer cell death are generally unknown. Methods: The databases of Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, and Tumor Immune Estimation Resource (TIMER), and methods of colony formation, Cell Counting Kit-8 (CCK-8), adenosine triphosphate (ATP) detection, RNA-seq, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to analyze the expression level, prognostic role, and oncogenic roles of DHODH in cancers. Results: DHODH overexpression was identified in many types of cancers including esophageal carcinoma (ESCA), colon adenocarcinoma (COAD), rectum adenocarcinoma (READ), and so on. Silence and inactivation of DHODH decreased the abilities of cell proliferation, colony formation, and cellular ATP levels both in esophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC) cells. Z-VAD-FMK (an apoptosis inhibitor) partially rescued blockade of DHODH-induced death of ESCC cells, and ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) together with the necroptosis inhibitor (necrostatin-1) partially rescued inhibition of DHODH-induced death of CRC cells, respectively. Pathways including rheumatoid arthritis, salmonella infection, cytokine-cytokine receptor interaction, pertussis, and nuclear factor-κB (NF-κB) were enriched in DHODH-silenced ESCC cells. Conclusions: Overexpression of DHODH augments cell proliferation and suppresses cell death in ESCC and CRC, and DHODH might be developed as a potential anticancer target.

The O2-Mediated Cross-Dehydrogenative Coupling: Rose Bengal-Catalyzed Direct Oxidative α-Acyloxylation of Ketones.

A general and facile approach for the direct oxidative α-acyloxylation of ketones using molecular oxygen as the oxidant is developed. This method avoids the use of excessive peroxides and expensive metal catalysts, affording a variety of α-acyloxylated ketones in satisfactory yields. Experimental studies indicate that the reaction proceeds via a radical pathway. Additionally, α-hydroxy ketones could be obtained by changing the solvent.

Exploring the growing forest musk deer (Moschus berezovskii) dietary protein requirement based on gut microbiome.

It is necessary to assess the appropriate dietary protein level of the forest musk deer (FMD), as nutritional needs are unclear. The microbiome in gastrointestinal tracts plays an important role in regulating nutrient utilization, absorption and host growth or development. Thus, we aimed to evaluate growth performance, nutrient digestibility and fecal microbiome of growing FMD supplied with different protein levels of diets. Eighteen 6-month-old male FMD with an initial weight 5.0 ± 0.2 kg were used in a 62-day trial. The animals were randomly distributed to three groups, the dietary crude protein (CP) level was 11.51% (L), 13.37% (M), and 15.48% (H). The results showed that the CP digestibility decreased as dietary CP level increased (p < 0.01). Compared with group L and H, FMD in M group has higher average daily gain, feed efficiency and neutral detergent fiber digestibility. For the fecal bacterial community, the percentage of Firmicutes was increased, Bacteroidetes was decreased and the diversity of microbiota significantly reduced (p < 0.05) with the increasing of dietary protein. The proportion of Ruminococcaceae_005, Ruminococcaceae_UCG-014 and uncultured_bacterium_f_Lachnospiraceae were significantly increased wtih rising CP, the proportions of Bacteroides and Rikenellaceae_RC9_gut_group were significantly decrease nevertheless at the genus level. The higher abundance of f_Prevotellaceae and g_Prevotellaceae_UCG_004 were found at M group by LEfSe analysis. The relative abundance of uncultured_bacterium_f_Ruminococcaceae was positively correlated with the average daily gain and feed conversion ratio (p < 0.05), whereas Family_XIII_AD3011_group was negatively correlated with feed conversion ratio (p < 0.05). The UPGMA tree showed L and M groups were closer in clustering relationship, while H group was clustered separately into a branch, which indicated that the bacterial structure had changed greatly with protein level increased from 13.37 to 15.48%. Overall, our results indicated that the optimum dietary CP for the growing FMD was 13.37%.

Phototriggered Self-Catalyzed Three-Component Minisci Reaction: A Route to ß-C(sp3) Heteroarylated Alcohols/Ethers.

Herein, a visible-light-triggered photocatalyst-free radical cascade Minisci reaction of heteroarenes, alkenes, and water/alcohols to obtain diverse ß-C(sp3) heteroarylated alcohols/ethers has been developed. Achieved under mild and simple conditions, this protocol is scalable and features broad substrate scope and functional group tolerance. Mechanistic studies demonstrate that the heteroarene can be served as a photocatalyst to engage single-electron transfer with persulfate.

Electrochemical Oxidative C-H Arylation of Quinoxalin(on)es with Arylhydrazine Hydrochlorides under Mild Conditions.

A practical and scalable protocol for electrochemical arylation of quinoxalin(on)es with arylhydrazine hydrochlorides under mild conditions has been developed. This method exhibits high efficiency, easy scalability, and broad functional group tolerance. Various quinoxalin(on)es and arylhydrazines underwent this transformation smoothly in an undivided cell, providing the corresponding aryl-substituted quinoxalin(on)es in moderate to good yields. A radical mechanism is involved in this arylation reaction.

Prognostic and Immunological Role of Key Genes of Ferroptosis in Pan-Cancer.

Solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and apoptosis inducing factor mitochondria associated 2 (AIFM2) are the key regulators in ferroptosis. However, the expression patterns and prognostic roles of these genes in pan-cancer are still largely unclear. The expression patterns and prognostic roles of SLC7A11, GPX4, and AIFM2 and the relationships between the expression levels of these genes and immune infiltration levels in pan-cancer were analyzed by using TIMER, gene expression profiling interactive analysis (GEPIA), Oncomine, and Kaplan-Meier databases. Our results showed that both SLC7A11 and GPX4 were overexpressed in colorectal cancer, and SLC7A11 was overexpressed in lung cancer. High levels of SLC7A11 and AIFM2 were significantly linked with the shortened disease-free survival and overall survival (OS) in adrenocortical carcinoma (ACC), respectively. And high expression of SLC7A11, GPX4, and AIFM2 were significantly correlated with the shortened OS of acute myeloid leukemia patients. In esophageal carcinoma (ESCA), GPX4 expression was significantly associated with the infiltration of macrophage and myeloid dendritic cell, and AIFM2 expression was significantly associated with the infiltration of CD4+ T cell. Importantly, GPX4 expression was positively correlated with the expression levels of monocyte markers (CD14 and CD115) and M2 macrophage markers (VSIG4 and MS4A4A) both in ESCA and in head and neck squamous cell carcinoma (HNSC). In summary, SLC7A11, GPX4, and AIFM2 are dysregulated in many types of cancers, and are candidate prognostic biomarkers for many types of cancers, and can be used to evaluate the infiltration of immune cells in tumor tissues.

Improved in vitro and in vivo properties of telmisartan in the co-amorphous system with hydrochlorothiazide: A potential drug-drug interaction mechanism prediction.

The aim of this study is to improve in vitro and in vivo properties of an antihypertensive poorly soluble drug Telmisartan (TEL) by co-amorphization with a pharmacologically relevant drug Hydrochlorothiazide (HCT), and to improve the stability of single amorphous drugs. Herein, TEL-HCT co-amorphous systems (CAMs) (1:1, 2:3, 1:2, 1:3) were prepared by solvent evaporation. The apparent solubility and the dissolution of TEL in the TEL-HCT CAM (1:3) were increased by 79 times and 10 times compared to crystalline TEL, which showed the optimal properties. Cmax and AUC0-48h value of TEL-HCT CAM (1:3) were 10-fold and 3-fold as the crystalline state. Moreover, TEL-HCT CAM (1:3) remained stable in 60 °C, 0 % RH (30 days), 40 °C, 75 % RH (90 days) and 25 °C, 0 % RH (180 days). Positive ΔTgs were observed in all CAMs, suggesting the existence of potential intermolecular force. Fourier Transform-Infrared and Raman spectra were used to further prove the drug-drug interaction and predict potential mechanisms. Therefore, in the strategy of combined medication, CAM provides a promising way to transfer drugs with poor properties into systems with enhanced dissolution, greater bioavailability, and stabilized amorphous state, which has been proven in this study.

Improving the Solubility, Dissolution, and Bioavailability of Ibrutinib by Preparing It in a Coamorphous State With Saccharin.

At present, coamorphous systems have attracted increasing interest in the pharmaceutical field owing to their enhanced stabilities, increased solubilities, and improved bioavailabilities compared with those of their pure amorphous and crystalline counterparts. In this study, a novel coamorphous solid form of ibrutinib (IBT) and saccharin (SAC) (1:1 molar ratio) was prepared through rotary vacuum evaporation and then characterized. Differential scanning calorimetry and X-ray powder diffraction indicated the formation of the coamorphous IBT-SAC after rotary vacuum evaporation. Compared with amorphous IBT, coamorphous IBT-SAC exhibited enhanced stability owing to the intermolecular interaction between IBT and SAC. Moreover, the solubility and dissolution of the coamorphous IBT-SAC were increased up to 4.0-7.7 times and 4.3 times, respectively, compared with those of its crystalline Form A. In addition to the superior behaviors of coamorphous IBT-SAC in vitro, the in vivo bioavailability study revealed notable increases in the Cmax and area under the curve0-t of the coamorphous form compared with those of its crystalline Form A. The current study demonstrates that the coamorphization of IBT and SAC presents a promising technology to overcome the limitations of solubility and stability that arise from IBT and can therefore contribute to a major improvement in the bioavailability of IBT.