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Background and Purpose: Non-alcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD) and no pharmacological treatment as yet been approved. Identification of novel therapeutic targets and their agents is critical to overcome the current inadequacy of drug treatment for NASH., Experimental Approach: The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were investigated by chromatin-immunoprecipitation sequencing. The effects and mechanisms of SYSU-3d in alleviating NASH were examined in relevant cell models and mouse models (the Ob/Ob mice, high-fat and high-cholesterol diet and the methionine-choline deficient diet-fed mice). The actions of SYSU-3d in vivo were evaluated., Key Results: HSF1 is progressively reduced with mitochondrial dysfunction in NASH pathogenesis and activation of this transcription factor by its newly identified activator SYSU-3d effectively inhibited all manifestations of NASH in mice. When activated, the phosphorylated HSF1 (Ser326) translocated to nucleus and bound to the promoter of PPARγ coactivator-1α (PGC-1α) to induce mitochondrial biogenesis. Thus, increasing mitochondrial adaptive oxidation and inhibiting oxidative stress. The deletion of HSF1 and PGC-1α or recovery of HSF1 in HSF1-deficiency cells showed the HSF1/PGC-1α pathway was mainly responsible for the anti-NASH effects of SYSU-3d independent of AMP-activated protein kinase (AMPK)., Conclusion and Implications: Activation of HSF1 is a practical therapeutic approach for NASH treatment via the HSF1/PGC-1α/mitochondrial pathway and SYSU-3d can be considered as a potential candidate for the treatment of NASH., (© 2021 The British Pharmacological Society.)

Aim: IQZ23, a novel β-indoloquinazoline derivative, is a potential therapeutic agent for obesity and related metabolic disorders. To assist pharmacokinetics evaluation, a quantitative method for IQZ23 in rat plasma is required. Methods & Results: An LC-MS/MS assay for the determination of IQZ23 in rat plasma was developed and validated for the first time. Chromatographic conditions were optimized to ameliorate matrix effect with direct monitoring of typical phospholipids, including phosphatidylcholine and lysophosphatidylcholine. The structural analog internal standard (SYSU-3d) was set at a proper concentration to avoid analyte sensitivity loss caused by internal standard interference. The well-validated method was employed in the pharmacokinetics study of IQZ23 in Sprague-Dawley rats. Conclusion: This study provided valuable references for the further preclinical study of IQZ23.

The indolyl-4(3 H )-quinazolinone core is an important structural motif in functional molecules. However, few methods exist for its direct modification, which limits its potential application. Reported herein is a palladium-mediated amination of halogen-containing indolyl-4(3 H )-quinazolinones with a variety of primary and secondary amines via the corresponding palladium oxidative addition complexes. The protocol allows the facile synthesis of indolyl-4(3 H )-quinazolinone derivatives with amino groups at all the positions of the benzene ring in moderate to good yields with mild reaction conditions and good functional group tolerance. Furthermore, the antitumor activity of these products was evaluated.

Coordinated development of neurons and glia is essential for the establishment of neuronal circuits during embryonic development. In the developing Drosophila visual system, photoreceptor (R cell) axons and wrapping glial (WG) membrane extend from the eye disc through the optic stalk into the optic lobe. Extensive studies have identified a number of genes that control the establishment of R-cell axonal projection pattern in the optic lobe. The molecular mechanisms directing the exit of R-cell axons and WG membrane from the eye disc, however, remain unknown. In this study, we show that integrins are required in R cells for the extension of R-cell axons and WG membrane from the eye disc into the optic stalk. Knockdown of integrins in R cells but not WG caused the stalling of both R-cell axons and WG membrane in the eye disc. Interfering with the function of Rhea (i.e. the Drosophila ortholog of vertebrate talin and a key player of integrin-mediated adhesion), caused an identical stalling phenotype. These results support a key role for integrins on R-cell axons in directing R-cell axons and WG membrane to exit the eye disc., (© 2021. The Author(s).)

Objective: To investigate whether small conductance Ca 2+  activated K+  channels; Trigeminal ganglion; Trigeminal neuralgia. (SK3) exists in normal rats' trigeminal ganglions (TG) and its effect on their pain thresholds. Methods: In total, 110 healthy adult male Sprague-Dawley (SD) rats were involved in this study. Ten rats were dissected to collect their liver tissues, TG and DRG. The rest of the rats were randomly assigned to either the experimental group or the control group. The animal model of trigeminal neuralgia (TN) was established by infraorbital nerve ligation. The expression of SK3 channels in their livers, TG and dorsal root ganglions (DRG) were detected. And different doses of SK3 channel activator and inhibitor were administered to the rats in both groups 15 days after the operation; meanwhile, their pain thresholds were also measured. Results: The expression of SK3 channel was found in TG. In the experimental group, the pain threshold was significantly decreased and there was a decreased level of SK3 than that in the control group at 15 days after operation. The administration of SK3 channel agonist (CyPPA) could significantly improve the pain threshold, while, the pain threshold decreased after administration of SK3 channel antagonist (Apamin). Conclusion: The SK3 channel may play a pivotal role in the pathogenesis of trigeminal neuralgia, and it may be one of the potential targets for the treatment of trigeminal neuralgia.

Despite early domestication around 3000 BC, the evolutionary history of the ancient allotetraploid species Brassica juncea (L.) Czern & Coss remains uncertain. Here, we report a chromosome-scale de novo assembly of a yellow-seeded B. juncea genome by integrating long-read and short-read sequencing, optical mapping and Hi-C technologies. Nuclear and organelle phylogenies of 480 accessions worldwide supported that B. juncea is most likely a single origin in West Asia, 8,000-14,000 years ago, via natural interspecific hybridization. Subsequently, new crop types evolved through spontaneous gene mutations and introgressions along three independent routes of eastward expansion. Selective sweeps, genome-wide trait associations and tissue-specific RNA-sequencing analysis shed light on the domestication history of flowering time and seed weight, and on human selection for morphological diversification in this versatile species. Our data provide a comprehensive insight into the origin and domestication and a foundation for genomics-based breeding of B. juncea., (© 2021. The Author(s).)

Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novel β-indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound 23 (named as IQZ23) was selected for further studies. IQZ23 exerted a high efficacy in decreasing the triglyceride level (EC 50  = 0.033 μM) in 3T3-L1 adipocytes. Mechanistic studies revealed the lipid-lowering activity of IQZ23 was dependent on the AMPK pathway by modulating ATP synthase activity. This activation was accompanied by mitochondrial biogenesis and oxidation capacity increased, and insulin sensitivity enhanced in pertinent cell models by various interventions. Correspondingly, IQZ23 (20 mg/kg, i.p.) treatment significantly reversed high fat and cholesterol diet (HFC)- induced body weight increases and accompanying clinical symptoms of obesity in mice but without indicative toxicity. These results indicate that IQZ23 could be a useful candidate for the treatment of obesity and related metabolic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The establishment of the functional nervous system requires coordinated development of neurons and glia in the embryo. Our understanding of underlying molecular and cellular mechanisms, however, remains limited. The developing Drosophila visual system is an excellent model for understanding the developmental control of the nervous system. By performing a systematic transgenic RNAi screen, we investigated the requirements of secreted proteins and cell-surface receptors for the development of photoreceptor neurons (R cells) and wrapping glia (WG) in the Drosophila visual system. From the screen, we identified seven genes whose knockdown disrupted the development of R cells and/or WG, including amalgam (ama), domeless (dome), epidermal growth factor receptor (EGFR), kuzbanian (kuz), N-Cadherin (CadN), neuroglian (nrg), and shotgun (shg). Cell-type-specific analysis revealed that ama is required in the developing eye disc for promoting cell proliferation and differentiation, which is essential for the migration of glia in the optic stalk. Our results also suggest that nrg functions in both eye disc and WG for coordinating R-cell and WG development.

Bioassay-guided fractionation of an ethanolic extract of Ochrosia borbonica led to the isolation of two known pyridocarbazole alkaloids, ellipticine (1) and 9-methoxyellipticine (2), and six known monoterpenoid indole alkaloids (3-8). Lipid-lowering assay in 3T3-L1 cell model revealed that 1 and 2 could significantly inhibit the lipid droplet formation (EC 50 = 0.41 and 0.92 μmol·L -1 , respectively) and lower triglyceride levels by 50%-60% at the concentration of 1 μmol·L -1 , being more potent than the positive drug luteolin (EC 50 = 2.63 μmol·L -1 ). A mechanistic study indicated that 1 and 2 could intercalate into supercoiled DNA, which consequently inhibited the mitotic clonal expansion of 3T3-L1 cells at the early differentiation phase, leading to the retardance of following adipogenesis and lipogenesis. These findings suggest that 1 and 2 may serve as promising leads for further development of anti-obesity drugs., (Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Based on first-principles calculations, we study the hydrogen evolution reaction (HER) on metal-free C2N and make efforts to improve its catalytic performance. At H* coverages (θ) of 3/6 and 4/6, the free energy of hydrogen adsorption (ΔGH*) is 0.10 eV and 0.07 eV, respectively, which is competitive with the precious catalyst Pt. Moreover, ΔGH* can be modulated to zero under a tensile strain, and the strength of the strain depends on the H concentration. Experimentally, it is possible to achieve a strain of around 2% through coupling C2N with graphene, and the HER performance of the hybrids would be generally enhanced. Moreover, the catalytic activity of the hybrids is tunable via electron and hole doping of graphene. In the strong H binding cases (θ = 1/6), anchoring Mn atoms into C2N exhibits a perfect catalytic property with ΔGH* of -0.04 eV. Therefore, C2N-based catalysts are expected to be easily synthesized and highly active catalysts for the HER. These findings may shed light on replacing Pt by metal-free or/and non-precious metal counterparts.

Inhibition of the differentiation of adipocytes and reduced lipid synthesis are efficacious approaches for treating obesity-related metabolic disorders. Bouchardatine (Bou) is a natural alkaloid that has been reported to moderately inhibit the differentiation of 3T3-L1 cells without inducing toxicity. To explore the importance of aldehyde group at 8a-position of Bou and optimize the activity, we synthesized 35 (31 novel) compounds by discarding or replacing aldehyde group with halogen and introducing different amine chains at 5-position of Bou. The lipid-lowering activity was evaluated using a cell-based screening system. The substitution of the group at the 8a-position of compounds was important for its lipid-lowering activity, and the SAR was discussed. The selective compound 6e showed a 93-fold increase in its lipid-lowering effect (EC 50  = 0.24 μM) compared with Bou (EC 50  ≈ 25 μM). Further mechanistic studies revealed that compound 6e activated AMP-activated protein kinase (AMPK) pathway and inhibited MCE activity to block cell proliferation and induce cell cycle arrest at the early stage of differentiation, thus decreasing the expression of adipogenic factors and fatty acid synthesis-related proteins., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objective: To summarize the effectiveness of bone cement combined with screws for repairing tibial plateau defect in total knee arthroplasty (TKA)., Methods: Between March 2013 and March 2016, 30 patients were treated with TKA and bone cement combined with screws for repairing tibial plateau defect. Of the 30 patients, 8 were male and 22 were female, with an average age of 64.7 years (range, 55-71 years). And 17 cases were involved in left knees and 13 cases in right knees; 22 cases were osteoarthritis and 8 cases were rheumatoid arthritis. The disease duration ranged from 9 to 27 months (mean, 14 months). Knee Society Score (KSS) was 41.63±6.76. Hospital for Special Surgery Knee Score (HSS) was 38.10±7.00. The varus deformity of knee were involved in 19 cases and valgus deformity in 11 cases. According to the Rand classification criteria, tibial plateau defect were rated as type Ⅱb., Results: All incisions healed by first intention, without infection or deep vein thrombosis. All the patients were followed up 27.5 months on average (range, 10-42 months). At last follow-up, HSS score was 90.70±4.18 and KSS score was 93.20±3.75, showing significant differences when compared with preoperative values ( t =-58.014， P =0.000; t =-60.629， P =0.000)., Conclusion: It is a simple and safe method to repair tibial plateau defect complicated with varus and valgus deformities with bone cement and srews in TKA.

Hybrid structures have attracted a great deal of attention because of their excellent properties, which can open up a way we could not foresee in materials science and device physics. Here, we investigate the electrical and optical behaviors of SiC(GeC)/MoS 2 heterostructures, using first principles calculations based on density functional theory. Non-covalent bonding exists between the junctions due to the weak orbital coupling. Both junctions have optically active band gaps, smaller than that of the SiC or GeC and MoS 2 layers, which result in enhanced optical adsorption under visible-light irradiation. A small number of electrons transfer from SiC/GeC to MoS 2 causing its n-doping. Furthermore, the charge density states of the valence band maximum and the conduction band minimum are localized at different sides, and thus the electron-hole pairs are spatially separated. Our results provide a potential scheme for photovoltaic materials.

Two series of compounds (chalcones and bis-chalcones) were designed, synthesized, and evaluated as α-glucosidase inhibitors (AGIs) with 1-deoxynojirimycin as positive control in vitro. Most of the compounds with two or four hydroxyl groups showed better inhibitory activities than 1-deoxynojirimycin towards α-glucosidase with noncompetitive mechanism. Moreover, most of the hydroxy bis-chalcones exhibit good α-glucosidase inhibitory activities in enzyme test. Inspiringly, bis-chalcones 2g (at 1 μM concentration) has stronger effect than 1-deoxynojirimycin on reducing the glucose level in HepG-2 cells (human liver cancer cell line)., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Bouchardatine (1), a naturally occurring β-indoloquinazoline alkaloid, was synthesized. For the first time, the lipid-lowering effect and mechanism of 1 was investigated in 3T3-L1 adipocytes. Our study showed that 1 could significantly reduce lipid accumulation without cytotoxicity and mainly inhibited early differentiation of adipocyte through proliferation inhibition and cell cycle arrested in dose-dependent manner. Furthermore, the inhibition of early differentiation was reflected by down-regulation of key regulators of adipogenesis/lipogenesis, including CCAAT enhancer binding proteins (C/EBPβ, C/EBPδ, C/EBPα), peroxisome proliferator-activated receptors γ (PPARγ) and sterol-regulatory element binding protein-1c (SREBP-1c), in both of mRNA and protein levels. Subsequently decreasing the protein levels of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and stearyl coenzyme A desaturated enzyme 1 (SCD-1), the rate-limited metabolic enzymes of fatty acid synthesis, were also observed. Further studies revealed that 1 persistently activated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) during differentiation, suggesting that the AMPK may be an upstream mechanism for the effect of 1 on adipogenesis and lipogenesis. Our data suggest that 1 can be a candidate for the development of new therapeutic drugs against obesity and related metabolic disorders., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Semaphorin family proteins are well-known axon guidance ligands. Recent studies indicate that certain transmembrane Semaphorins can also function as guidance receptors to mediate axon-axon attraction or repulsion. The mechanisms by which Semaphorin reverse signaling modulates axon-surface affinity, however, remain unknown. In this study, we reveal a novel mechanism underlying upregulation of axon-axon attraction by Semaphorin-1a (Sema1a) reverse signaling in the developing Drosophila visual system. Sema1a promotes the phosphorylation and activation of Moesin (Moe), a member of the ezrin/radixin/moesin family of proteins, and downregulates the level of active Rho1 in photoreceptor axons. We propose that Sema1a reverse signaling activates Moe, which in turn upregulates Fas2-mediated axon-axon attraction by inhibiting Rho1.

While it is well established that Semaphorin family proteins function as axon guidance ligands in invertebrates and vertebrates, several recent studies indicate that the Drosophila Semaphorin-1a (Sema1a), a transmembrane Semaphorin, can also function as a receptor during neural development. The regulator of Sema1a reverse signaling, however, remains unknown. In this study, we show that like Sema1a, the well known Semaphorin receptor Plexin A (PlexA), is required for the proper guidance of photoreceptor (R cell) axons in the Drosophila visual system. Loss of PlexA, like loss of semala, disrupted the association of R-cell growth cones in the optic lobe. Conversely, overexpression of PlexA, like overexpression of sema1a, induced the hyperfasciculation of R-cell axons. Unlike Sema1a, however, the cytoplasmic domain of PlexA is dispensable. Epistasis analysis suggests that PlexA functions upstream of semala. And PlexA and sema1a interact genetically with Rho1. We propose that PlexA regulates Semala reverse signaling in the Drosophila visual system.

The evolutionarily conserved Semaphorin family proteins are well known axon guidance ligands that mediate both attractive and repulsive responses in invertebrates and vertebrates. In this study, we show that the Drosophila Semaphorin-1a (Sema1a), a transmembrane Semaphorin, is required cell autonomously in adult photoreceptor (R-cell) axons for the establishment of an appropriate topographic termination pattern in the optic lobe. Loss of sema1a disrupts the association of neighboring R-cell growth cones leading to defects in local termination pattern, whereas overexpression of sema1a induces the hyper-fasciculation of R-cell axons. The function of Sema1a in R-cell axon guidance absolutely requires its cytoplasmic domain. We propose that Sema1a functions as a receptor in regulating R-cell axon guidance in the Drosophila visual system.