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Hepatic fibrosis (HF) is a common pathological complication of liver cirrhosis which affects human health. It is well established that microRNAs (miRNAs) regulate the proliferation, activation and apoptosis of hepatic stellate cells (HSCs).To determine the function and molecular mechanism of miR-340-5p/secreted phosphoprotein 1 (SPP1) axis in HF and identify potential therapeutic targets.The HF model in cholestatic rats was induced by ligating the common bile duct. The histological sections of the liver tissues were stained with hematoxylin and eosin (HE), Masson's trichrome or Sirius Red. The differential expression of mRNAs in the liver tissues was examined using the microarray analysis. The expression levels of miR-340-5p, SPP1, alpha-smooth muscle actin (α-SMA), Collagen I, phosphorylated Smad2 (p-Smad2), and p-Smad3 were determined using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell proliferation was quantified using cell counting kit-8 (CCK-8) assays. The regulatory effect of miR-340-5p on SPP1 was determined with fluorescent reporter assay.The bile duct ligation (BDL) rat model was successfully induced, and SPP1 was upregulated in liver tissue from the BDL group compared to that of the sham group. The expression level of miR-340-5p was decreased in activated human primary normal fibroblasts (NFs) and activated LX-2 cells, and the mRNA and protein expression levels of SPP1 were increased in activated LX-2 cells. The SPP1 was the target of miR-340-5p, and the overexpression of SPP1 increased the proliferation of LX-2 cells, the expression of HF markers α-SMA and Collagen I, and key factors p-Smad2 and p-Smad3 (all p0.05). However, reverse results were obtained with the overexpression of miR-340-5p in LX-2 cells.Our findings provide evidence that SPP1 targeted by miR-340-5p promotes LX-2 cell proliferation and activation through the TGF-β1/Smads signaling pathway. Therefore, miR-340-5p and SPP1 may be possible therapeutic targets for HF.

The carbonyl-directed, mono C-H amination of arenes has been achieved using [Cp*Ir(III)Cl

Hepatic fibrosis (HF) is a worldwide health problem for which there is no medically effective drug treatment at present, and which is characterized by activation of hepatic stellate cells (HSCs) and excessive extracellular matrix (ECM) deposition. The HF model in cholestatic rats by ligating the common bile duct was induced and the differentially expressed miRNAs in the liver tissues were analyzed by microarray, which showed that miR-22-3p and miR-29a-3p were significantly downregulated in bile-duct ligation (BDL) rat liver compared with the sham control. The synergistic anti-HF activity and molecular mechanism of miR-22-3p and miR-29a-3p by targeting AKT serine/threonine kinase 3 (AKT3) in HSCs were explored. The expression levels of miR-22-3p and miR-29a-3p were downregulated in activated LX-2 and human primary normal hepatic fibroblasts (NFs), whereas AKT3 was found to be upregulated in BDL rat liver and activated LX-2 cells. The proliferation, colony-forming, and migration ability of LX-2 were inhibited synergistically by miR-22-3p and miR-29a-3p. In addition, cellular senescence was induced and the expressions of the LX-2 fibrosis markers COL1A1 and α-SMA were inhibited by miR-22-3p and miR-29a-3p synergistically. Subsequently, these two miRNAs binding to the 3’UTR of AKT3 mRNA was predicted and evidenced by the luciferase reporter assay. Furthermore, the proliferation, migration, colony-forming ability, and the expression levels of COL1A1 and α-SMA were promoted and cellular senescence was inhibited by AKT3 in LX-2 cells. Thus, miR-22-3p/miR-29a-3p/AKT3 regulates the activation of HSCs, providing a new avenue in the study and treatment of HF.

Pyruvate kinase M2 (PKM2), a glycolytic rate-limiting enzyme, reportedly plays an important role in tumorigenesis and the inflammatory response by regulating the metabolic reprogramming. However, its contribution to microglial activation during neuroinflammation is still unknown. In this study, we observed an enhanced glycolysis level in the lipopolysaccharide (LPS)-activated microglia. Utilizing the glycolysis inhibitor 2-DG, we proved that LPS requires glycolysis to induce microglial pyroptosis. Moreover, the protein expression, dimer/monomer formation, phosphorylation and nuclear translocation of PKM2 were all increased by LPS. Silencing PKM2 or preventing its nuclear translocation by TEPP-46 significantly alleviated the LPS-induced inflammatory response and pyroptosis in microglia. Employing biological mass spectrometry combined with immunoprecipitation technology, we identified for the first time that PKM2 interacts with activating transcription factor 2 (ATF2) in microglia. Inhibition of glycolysis or preventing PKM2 nuclear aggregation significantly reduced the phosphorylation and activation of ATF2. Furthermore, knocking down ATF2 reduced the LPS-induced pyroptosis of microglia. In vivo, we showed the LPS-induced pyroptosis in the cerebral cortex tissues of mice, and first found that an increased PKM2 expression was co-localized with ATF2 in the inflamed mice brain. Collectively, our data suggested for the first time that PKM2, a key rate-limiting enzyme of the Warburg effect, directly interacts with the pro-inflammatory transcription factor ATF2 to bridge glycolysis and pyroptosis in microglia, which might be a pivotal crosstalk between metabolic reprogramming and neuroinflammation in the CNS.

Paste slurry exhibits significant thixotropy, which has a significant influence on the slurry pipeline transportation resistance. This paper proposes a novel test method for the thixotropy of paste slurry, which can ensure that the slurry reaches flow equilibrium during the test. Accordingly, the influences of the solid mass concentration, cement-to-tailings ratio, and temperature on thixotropy were studied by employing a control variable method, and the influences of the above three factors on the stress overshoot and rheological parameters were evaluated. The results revealed that the solid mass concentration and temperature have significant influence on the thixotropy. Moreover, with an increase in the solid mass concentration, the time required for the slurry to reach flow equilibrium decreases. The cement content and temperature are proportional to the significance of the stress overshoot, and the change in dynamic yield stress can be considered an indicator for the effective quantification of thixotropy. In the continuous shearing cycles, the maximum apparent viscosity at the start of shearing significantly decreases on the time axis. The solid mass concentration has a significant influence on the minimum apparent viscosity in the slurry flow process, whereas the cement-to-tailings ratio and temperature have no significant influences.

In the present work, thermal exposure was performed on the 7B50-T7451 aluminium alloy friction stir welding (FSW) joints at different temperatures (150 °C, 175 °C and 220 °C) for 200h. The results show that the microstructure and mechanical properties of as-welded joints along the thickness direction of the plate are heterogeneous. The hardness and strength of FSW joints decrease while the elongation continuously increases with increasing thermal exposure temperature. Compared with the base material, the joints present much higher hardening capacity which is further increased with increasing temperature. The precipitates in the heat-affected zone (HAZ) exhibit continuous coarsening and the precipitate distribution becomes broader as the temperature rises. The transformation from η' phase to η phase is obvious at 220 °C. The weld nugget zone (WNZ) re-precipitates a large number of nano-scale η particles subjected to 200h thermal exposure at 150 °C and re-precipitated η phase in WNZ of the double-sided joint has reached micron-sized at 175 °C and 220 °C. When exposed at different temperatures, all FSW joints show typical ductile fracture features. Fracture positions at different thermal exposure temperatures are inconsistent and this variation is closely related to different microstructural characteristics.

Sulfinic acids and their salts are a useful source of sulfur-containing structures. Photocatalysis of these compounds with visible light enables to achieve various transformations under mild conditions. This review summarizes visible-light-induced reactions of sulfinic acids and their salts. It is organized by reaction type and brief discussions on plausible reaction mechanisms for typical transformations are presented.1 Introduction2 Sulfonylation Reactions2.1 Sulfonylation of Alkenes2.2 Sulfonylation of Alkynes2.3 Sulfonylation of Arenes2.4 sp3 C–H Functionalization3 Desulfonylation Reactions4 Sulfenylation Reactions4.1 Sulfenylation of Heteroarenes4.2 Sulfenylation of Carbonyl Chlorides5 Conclusions

Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It is of great significance to identify their shared key regulatory molecules and thus explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model in mice, we reported an elevated expression of PDCD4 both in injured neurons and activated microglia of the inflamed brain. A similar change in PDCD4 expression was observed in vitro in the microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear translocation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPK/NF-κB signaling activation to boost PDCD4 expression in microglia, indicating the presence of a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic proteins BAX and Cleaved-PARP, suggesting the proapoptotic activity of PDCD4 in neurons. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4–MAPK–NF-κB positive feedback loop may act as pivotal signaling for neuroinflammation which subsequently exaggerates neuronal injury, and thus may become a potential therapeutic target for neuroinflammatory diseases.

Alkyl constitutes one of the most widely used groups in organic synthesis. Here, the development of a series of thianthrenium salts, which act as reliable alkylation reagents, are ready to engage in copper-catalyzed Sonogashira reaction to build C(sp 3 )-C(sp) bonds under mild photoinduced conditions. Diverse alkyl thianthrenium salts, methyl and disubstituted thianthrenium salts are employed with great functional breadth, since sensitive Cl, Br and I are compatible and challenging to achieve by conventional approaches. The generality of the developed alkyl reagents has also been demonstrated in copper-catalyzed Kumada reactions.

Excising the nitrogen in secondary amines, and coupling the two residual fragments is a skeletal editing strategy that can be used to construct molecules with new skeletons, but which has been largely unexplored. Here we report a versatile method of N-atom excision from N-heterocycles. The process uses readily available N-heterocycles as substrates, and proceeds by N-sulfonylazidonation followed by the rearrangement of sulfamoyl azide intermediates, providing various cyclic products. Examples are provided of deletion of nitrogen from natural products, synthesis of chiral O-heterocycles from commercially available chiral β-amino alcohols, formal inert C-H functionalization through a sequence of N-directed C-H functionalization and N-atom deletion reactions in which the N-atom can serve as a traceless directing group.

An aryl radical in situ SO2-capture reaction is reported for the first time. Using aryl diazonium salts as arylradical precursors, and vinyl triflates and allyl(alkynyl) trifluoromethylsulfones as radical acceptors and in situ SO2 donors, this protocol produces various β-keto, allyl and alkynyl arylsulfone derivatives, which are recognized as useful synthons. The reaction can be performed under mild visible-light photoredox-catalytic conditions without any external SO2 sources.

C-H amination of arenes directed by weakly coordinating Weinreb amides has been achieved with an iridium catalyst and 2,2,2-trichloroethoxycarbonyl (Troc) azide as an aminating agent, providing a robust method of producing synthetic useful

Methyl group is not only an important building block of biologically active molecules and drug molecules, but also the important structural unit of complex molecules. Methylation of complex molecules is generally achieved through methylating reactions, which mainly include nucleophilic attack, electrophilic attack, and radical pathways. This review summarized the literatures of the past few decades and covered commonly used methylating agents used in methylation. In this review, the recently developed new methylating agents and methylation reactions are highlighted, and the reaction mechanisms are also detailed discussed. We expect that this review will inspire others to devote their research in the field of methylation.

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays critical roles in the pathogenesis of aortic aneurysm (AA). The function of nuclear receptor corepressor1 (NCOR1) in regulation of VSMC phenotype and AA is unclear. Herein, using smooth muscle NCOR1 knockout mice, we demonstrated that smooth muscle NCOR1 deficiency decreased both mRNA and protein levels of contractile genes, impaired stress fibers formation and RhoA pathway activation, reduced synthesis of elastin and collagens, and induced the expression and activity of MMPs, manifesting a switch from contractile to degradative phenotype of VSMCs. NCOR1 modulated VSMC phenotype through 3 different mechanisms. First, NCOR1 deficiency increased acetylated FOXO3a to inhibit the expression of Myocd, which downregulated contractile genes. Second, deletion of NCOR1 derepressed NFAT5 to induce the expression of Rgs1, thus impeding RhoA activation. Third, NCOR1 deficiency increased the expression of Mmp12 and Mmp13 by derepressing ATF3. Finally, a mouse model combined apoE knockout mice with angiotensin II was used to study the role of smooth muscle NCOR1 in the development of AA. The results showed that smooth muscle NCOR1 deficiency increased the incidence of aortic aneurysms and exacerbated medial degeneration in angiotensin II-induced AA mouse model. Collectively, our data illustrated that NCOR1 interacts with FOXO3a, NFAT5, and ATF3 to maintain contractile phenotype of VSMCs and suppress AA development. Manipulation of smooth muscle NCOR1 may be a potential approach for AA treatment.

Overnutrition-induced hypothalamic inflammation greatly disturbs feeding behavior and energy homeostasis as well as the pathogenesis of obesity. Butyrate, a short-chain fatty acid, reportedly participates in the regulation of the immune response and energy metabolism in the body. However, the role of butyrate in overnutrition-induced microglial activation and hypothalamic inflammation remains unclear. In the present study, we established a high-fat diet (HFD)-induced hypothalamic inflammation model in mice. Oral supplementation with sodium butyrate (NaB) significantly reduced HFD-induced microgliosis, inflammatory cytokine expression, endoplasmic reticulum (ER) stress, neuronal apoptosis, and neuropeptide Y (NPY) expression in the mouse hypothalamus. Utilizing a high-glucose (HG)-stimulated microglial activation model in vitro, we found that NaB inhibited the HG-induced expression of the inflammatory factor IL-1β. Moreover, NaB exerted an antioxidant effect by balancing HO-1 and NOX4 expression, thus preventing reactive oxygen species (ROS) production in HG-treated microglia. Interestingly, NaB treatment promoted microglial process formation and extension via the Akt/Cdc42 pathway under both normal and HG-stimulated conditions, indicating a resting morphology of microglia. Taken together, our study revealed for the first time the anti-inflammatory and antioxidant effects of NaB in overnutrition-induced microglial activation and hypothalamic inflammation, which might become a potential therapeutic option for obesity prevention and treatment.

Alkyl groups are one of the most widely used groups in organic synthesis. Here, a a series of thianthrenium salts have been synthesized that act as reliable alkylation reagents and readily engage in copper-catalyzed Sonogashira reactions to build C(sp3 )-C(sp) bonds under mild photochemical conditions. Diverse alkyl thianthrenium salts, including methyl and disubstituted thianthrenium salts, are employed with great functional breadth, since sensitive Cl, Br, and I atoms, which are poorly tolerated in conventional approaches, are compatible. The generality of the developed alkyl reagents has also been demonstrated in copper-catalyzed Kumada reactions.

An efficient synthesis of 4-methyleneproline derivatives has been developed through an Rh-catalyzed [4 + 1] cycloaddition strategy using 3-methyleneazetidines and diazo compounds. The reaction proceeds under very mild conditions with a high degree of chemoselectivity, and competing experiments revealed that it is the preferred reaction, dominant over the C-H insertion, O-H insertion, and olefin cyclopropanation reactions which are commonly observed in Rh carbene chemistry. This method can incorporate the proline ester scaffold in pharmaceuticals and natural products. The intramolecular version of the reaction effectively provides proline-fused small to medium-sized tricyclic heterocycles. Gram-scale reactions, one-time addition of diazo compounds, and a minimum catalyst loading of 0.1 mol %, proceeded smoothly, implying their practicality.

The first report of the in situ capture of the SO2 fragment of the trifluoromethylsulfonyl radical is described here. With cyclobutanone oximes as representative alkyl radical precursors, vinyl triflates and allyl trifluoromethylsulfones were employed as radical acceptors and SO2 sources to provide various β-ketosulfones and allylsulfones, known to be significant building blocks. Without the use of any additives including external SO2 gas, the reaction was performed under mild photoredox- or metal-catalytic conditions while tolerating various functional groups.

A synthetic strategy with the visible-light photo-catalytic synergistic combination of electron and energy transfer processes has been developed. The mild reaction conditions allow the radical-radical cross-coupling phenomenon for the multicomponent synthesis of β-arylsulfonyl(diarylphosphinoyl)-α,α-diarylethyl-amines from readily available arylsulfinic acids (diarylphosphine oxides), 1,1-diarylethylenes and arylazides.

The dehydrogenative cross-coupling (CDC) reaction of diversely substituted azoles, synergistically catalyzed by copper and cobalt, is reported. This protocol represents the first example of the use of air as an oxidant to carry out this chemical reaction. The process provides a convenient and economical method for the construction of valuable unsymmetrical bis-heteroaryl compounds, including bis-benzoazole compounds that were not obtained in previous catalytic CDC reactions.

A new catalytic radical system involving CoII -based metalloradical catalysis is effective in activating sulfamoyl azides for enantioselective radical 1,6-amination of C(sp3 )-H bonds, affording six-membered chiral heterocyclic sulfamides in high yields with excellent enantioselectivities. The CoII -catalyzed C-H amination features an unusual degree of functional-group tolerance and chemoselectivity. The unique reactivity and stereoselectivity is attributed to the underlying stepwise radical pathway. The resulting optically active cyclic sulfamides can be readily converted into synthetically useful chiral 1,3-diamine derivatives without loss in enantiopurity.

Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It will be of great significance to identify their shared regulatory mechanisms and explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model on mice, we first reported an elevated expression of PDCD4 in both injured neurons and activated microglia of the inflamed mice brain. A similar change of PDCD4 expression was observed in the in vitro microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear transportation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPKs/NF-κB signaling activation to boost PDCD4 expression in microglia, and thus form a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic protein BAX, suggesting the pro-apoptotic activity of PDCD4 in the neuron. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes both the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4/MAPKs/NF-κB positive feedback loop may exaggerate the vicious cycle of neuroinflammation and neuronal injury, and thus may become potential therapeutic targets for neuroinflammatory diseases.

Sulfonium salts bearing a positively charged sulfur atom with three organic substituents have intrigued chemists for more than a century for their unusual structures and high chemical reactivity. These compounds are known to undergo facile single-electron reduction to emerge as a valuable and alternative source of aryl radicals for organic synthesis. However, the generation of non-stabilized alkyl radicals from sulfonium salts has been a challenge for several decades. Here we report the treatment of S-(alkyl) thianthrenium salts to generate non-stabilized alkyl radicals as key intermediates granting the controlled and selective outcome of the ensuing reactions under mild photoredox conditions. The value of these reagents has been demonstrated through the efficient construction of alkylboronates and other transformations, including heteroarylation, alkylation, alkenylation, and alkynylation. The developed method is practical, and provides the opportunity to convert C–OH bond to C–B and C–C bonds., The generation of non-stabilized alkyl radicals from sulfonium salts has been a challenge for several decades. Here, the authors show the treatment of S-(alkyl) thianthrenium salts, which can generate non-stabilized alkyl radicals as key intermediates that enable controlled and selective reactions under mild photoredox conditions.

Objective. To explore the postoperative complications of distal radius fractures and analyze the related factors that affect its prognosis. Methods. The clinical data of 50 patients with distal radius fractures admitted to our hospital from October 2016 to September 2019 were retrospectively analyzed. All patients were followed up for 6–12 months, and their postoperative complications were recorded. Collect general patient information and related clinical data. During the follow-up process, Gartland and Werley wrist function scoring system was used to evaluate the prognosis of patients’ joint function. Univariate analysis and multiple logistic regression models were used to analyze the related factors that affected the prognosis of patients. Results. 15 patients with postoperative complications were found during the follow-up period, with an incidence rate of 30.00%. Univariate analysis showed that the patient’s age, cause of injury, AO classification, shortened deformity, whether it was osteoporosis, surgical method, whether it was combined with other fractures on the same side, whether it was comminuted fracture, and the time to start postoperative exercise were all related to the distal radius. The prognosis of fractures is related ( P < 0.05 ). Multivariate logistic analysis showed that age, AO classification, surgical method, whether it was combined with other fractures on the same side, whether it was comminuted fracture, and the time to start postoperative exercise were the independent factors affecting the prognosis of distal radius fractures ( P < 0.05 ). Conclusion. The postoperative complications of distal radius fractures are higher. The prognosis is related to the patient’s age, AO classification, surgical method, whether it is combined with other fractures on the same side, whether it is comminuted fracture, and the time to start postoperative exercise. Therefore, choosing an appropriate surgical method and starting exercise in time can effectively improve the recovery of the patient’s wrist function and reduce the occurrence of complications.

Transition-metal-catalyzed sp2 C-N bond formation is a reliable method for the synthesis of aryl amines. Catalytic sp3 C-N formation reactions have been reported occasionally, and methods that can realize both sp2 and sp3 C-N formation are relatively unexplored. Herein, we address this challenge with a method of catalytic decarboxylative C-N formation that proceeds through a cascade carboxylic acid activation, acyl azide formation, Curtius rearrangement and nucleophilic addition reaction. The reaction uses naturally abundant organic carboxylic acids as carbon sources, readily prepared azidoformates as the nitrogen sources, and 4-dimethylaminopyridine (DMAP) and Cu(OAc)2 as catalysts with as low as 0.1 mol % loading, providing protected alkyl, alkenyl and aryl amines in high yields with gaseous N2 and CO2 as the only byproducts. Examples are demonstrated of the late-stage functionalization of natural products and drug molecules, stereospecific synthesis of useful α-chiral alkyl amines, and rapid construction of different ureas and primary amines.

We report a redox-neutral P(O)-N coupling reaction of P(O)-H compounds with azides via photoredox and copper catalysis, providing new access to useful phosphinamides, phosphonamides, and phosphoramides. This transformation tolerates a wide range of nucleophilic functionalities including alcohol and amine nucleophiles, which makes up for the deficiency of classical nitrogen nucleophilic substitution reactions. As a demonstration of the broad potential applications of this new methodology, late-stage functionalization of a diverse array of azido-bearing natural products and drug molecules, a preliminary asymmetric reaction, and a continuous visible-light photoflow process have been developed.

An efficient fluorocyclization of α,β-unsaturated amides through a formal halocyclization process is developed. The reaction proceeds under transition-metal-free conditions and leads to the formation of fluorinated oxazolidine-2,4-diones with excellent regio- and diastereoselectivity. The evaluation of the reaction mechanism based on preliminary experiments and density functional theory calculations suggests that a synergetic syn-oxo-fluorination occurs and is followed by an anti-oxo substitution reaction. The reaction opens a new window in the field of stereospecific fluorofunctionalization.