A Multiple Attention Convolutional Neural Networks for Diesel Engine Fault Diagnosis.

Fault diagnosis can improve the safety and reliability of diesel engines. An end-to-end method based on a multi-attention convolutional neural network (MACNN) is proposed for accurate and efficient diesel engine fault diagnosis. By optimizing the arrangement and kernel size of the channel and spatial attention modules, the feature extraction capability is improved, and an improved convolutional block attention module (ICBAM) is obtained. Vibration signal features are acquired using a feature extraction model alternating between the convolutional neural network (CNN) and ICBAM. The feature map is recombined to reconstruct the sequence order information. Next, the self-attention mechanism (SAM) is applied to learn the recombined sequence features directly. A Swish activation function is introduced to solve "Dead ReLU" and improve the accuracy. A dynamic learning rate curve is designed to improve the convergence ability of the model. The diesel engine fault simulation experiment is carried out to simulate three kinds of fault types (abnormal valve clearance, abnormal rail pressure, and insufficient fuel supply), and each kind of fault varies in different degrees. The comparison results show that the accuracy of MACNN on the eight-class fault dataset at different speeds is more than 97%. The testing time of the MACNN is much less than the machine running time (for one work cycle). Therefore, the proposed end-to-end fault diagnosis method has a good application prospect.

Effects of arsenic on gut microbiota and its bioaccumulation and biotransformation in freshwater invertebrate.

This study aimed to investigate the impact of arsenic stress on the gut microbiota of a freshwater invertebrate, specifically the apple snail (Pomacea canaliculata), and elucidate its potential role in arsenic bioaccumulation and biotransformation. Waterborne arsenic exposure experiments were conducted to characterize the snail's gut microbiomes. The results indicate that low concentration of arsenic increased the abundance of gut bacteria, while high concentration decreased it. The dominant bacterial phyla in the snail were Proteobacteria, Firmicutes, Bacteroidota, and Actinobacteriota. In vitro analyses confirmed the critical involvement of the gut microbiota in arsenic bioaccumulation and biotransformation. To further validate the functionality of the gut microbiota in vivo, antibiotic treatment was administered to eliminate the gut microbiota in the snails, followed by exposure to waterborne arsenic. The results demonstrated that antibiotic treatment reduced the total arsenic content and the proportion of arsenobetaine in the snail's body. Moreover, the utilization of physiologically based pharmacokinetic modeling provided a deeper understanding of the processes of bioaccumulation, metabolism, and distribution. In conclusion, our research highlights the adaptive response of gut microbiota to arsenic stress and provides valuable insights into their potential role in the bioaccumulation and biotransformation of arsenic in host organisms. ENVIRONMENTAL IMPLICATION: Arsenic, a widely distributed and carcinogenic metalloid, with significant implications for its toxicity to both humans and aquatic organisms. The present study aimed to investigate the effects of As on gut microbiota and its bioaccumulation and biotransformation in freshwater invertebrates. These results help us to understand the mechanism of gut microbiota in aquatic invertebrates responding to As stress and the role of gut microbiota in As bioaccumulation and biotransformation.

Insecticidal Activity and Molecular Target by Morphological Analysis, RNAseq, and Molecular Docking of the Aryltetralin Lignan Lactone Helioxanthin, Isolated from Taiwania flousiana Gaussen.

Botanical insecticides are considered an environmentally friendly approach to insect control because they are easily biodegraded and cause less environmental pollution compared to traditional chemical pesticides. In this study, we reported the insecticidal activities of the ingredients from Taiwania flousiana Gaussen (T. flousiana). Five compounds, namely helioxanthin (C1), taiwanin E (C2), taiwanin H (C3), 7,4'-dimethylamentoflavone (C4), and 7,7″-di-O-methylamentoflavone (C5), were isolated and tested against the second, third, and fourth instar larvae of Aedes aegypti. Our results indicated that all five compounds showed insecticidal activities, and helioxanthin, which is an aryltetralin lignan lactone, was the most effective with LC50 values of 0.60, 2.82, and 3.12 mg/L, respectively, 48 h after application, with its activity against the second instar larvae similar to that of pyrethrin and better than that of rotenone. Further studies found that helioxanthin accumulated in the gastric cecum and the midgut and caused swelling of mitochondria with shallow matrices and fewer or disappeared crista. Additionally, our molecular mechanisms studies indicated that the significantly differentially expressed genes (DEGs) were mainly associated with mitochondria and the cuticle, among which the voltage-dependent anion-selective channel (VDAC) gene was the most down-regulated by helioxanthin, and VDAC is the potential target of helioxanthin by binding to specific amino acid residues (His 122 and Glu 147) via hydrogen bonds. We conclude that aryltetralin lignan lactone is a potential class of novel insecticides by targeting VDAC.

Transcriptomic and metabolomic analysis of the mechanisms underlying stress responses of the freshwater snail, Pomacea canaliculata, exposed to different levels of arsenic.

Arsenic (As) pollution poses an important problem, but limited information is available about the physiological effects of As on freshwater invertebrates. Here, we investigated the physiological effects of chronic As exposure on Pomacea canaliculata, a freshwater invertebrate. High level of As (Ⅲ, 5 mg/L) inhibited the growth of P. canaliculata, whereas low level of As (Ⅲ, 2 mg/L) promoted growth. Pathological changes in shell and cellular ultrastructure due to As accumulation likely explain the growth inhibition at high As level. Low level of As simulated the expression of genes related to DNA replication and chitosan biosynthesis, potentially accounting for the growth promotion observed. High level of As enrichment pathways primarily involved cytochrome P450, glutathione, and arachidonic acid-mediated metabolism of xenobiotics. ATP-binding cassette (ABC) transporters, specifically the ABCB and ABCC subfamilies, were involved in As transport. Differential metabolites were mainly associated with the metabolism and biosynthesis of amino acids. These findings elucidate the dose-dependent effects of As stress on P. canaliculata growth, with low levels promoting and high levels inhibiting. Additionally, our findings also provide insights into As metabolism and transport in P. canaliculata.

Survival strategies in arsenic-contaminated environments: Comparative insights from native and exotic aquatic species.

The aim of this work was to study the sublethal effects, biokinetics, subcellular partitioning and detoxification of arsenic in two native Chinses species, Bellamya quadrata and Cipangopaludina cathayensis, as well as an exotic South American species, Pomacea canaliculata. The exotic species exhibited higher tolerance than native species. Physiologically based pharmacokinetic model results showed that the exotic species P. canaliculata exhibited a lower bioaccumulation rate and a greater metabolism capacity of As. Subcellular partitioning of As revealed that P. canaliculata exhibits superior As tolerance compared to the native species B. quadrata and C. cathayensis. This is attributed to P. canaliculata effective management of the metal sensitive fraction and enhanced accumulation of As in the biologically detoxified metal fraction. Under As stress, the biochemical parameters (superoxide dismutase, malondialdehyde, glutathione and glutathione S-transferase) of the exotic species P. canaliculata changed less in the native species, and they returned to normal levels at the end of depuration period. Our study provides evidence of the superior survival capability of the exotic species P. canaliculata compared to the native species B. quadrata and C. cathayensis under environmentally relevant levels of As contamination.

Acoustic emission-based intelligent identification of piston aero-engine ignition advance angle anomalies.

Ignition advance angle is one of the important factors affecting the performance of the engine, when it occurs abnormally will make the engine power and economy worse, and even cause serious damage to the engine. Therefore, it is very necessary to recognize the abnormal ignition advance angle of the engine. However, the engine system is closed and has a complex structure, which makes traditional diagnostic methods difficult. This paper proposes an intelligent identification method based on acoustic emission (AE) signals, which collects the AE signals from the engine surface and divides their spectra into equal parts, and selects the frequency bands with high contribution to the classification based on the minimum distance method to construct feature maps, which is used as the input to the convolutional neural network (CNN). The extracted frequency band features of this method can better characterize the AE signals, and the constructed feature maps make the fault information more obvious. Experiments show that the accuracy of this method for abnormal ignition advance angle under normal operating conditions of piston aero-engine is 100%, which is better than the traditional methods. In addition, the recognition accuracies under the other two operating conditions are 99.75% and 98.5%, respectively, indicating that the method has a certain universality.

The Numerical and Experimental Investigation of Piezoresistive Performance of Carbon Nanotube/Carbon Black/Polyvinylidene Fluoride Composite.

The composites with multiple types of nano-carbon fillers have better electrical conductivity and piezoresistive properties as compared with composites with a single type of nano-carbon fillers. As previously reported, the nano-carbon fillers with various aspect ratios, such as carbon nanotube (CNT) and carbon black (CB), have synergistic enhanced effects on the piezoresistive performance of composite sensors. However, most of the works that have been reported are experimental investigations. The efficient and usable numerical simulation investigation needs to be further developed. In this study, based on an integrated 3D statistical resistor network model, a numerical simulation model was created to calculate the piezoresistive behavior of the CNT/CB/ Polyvinylidene Fluoride (PVDF) composite. This model also takes into account the tunneling effect between nearby nano-fillers. It is found from numerical simulation results that the piezoresistive sensitivity of composite simulation cells can be influenced by the fraction of CNT and CB. In the case that the CNT content is 0.073 wt.%, the best force-electrical piezoresistive sensitivity can be achieved when the CB loading is up to 0.2 wt.%. To verify the validity of the simulation model, the previous experimental investigation results are also compared. The experimental results confirm the validity of the model. The investigation is valuable and can be utilized to design a strain sensor for this nano-composite with increased sensitivity.

Heteroatom Introduction to Reconstruct Interfacial Chemical Structures for High-Reliability CFRTP/A6061-T6 Hybrid Structures.

The application of carbon-fiber-reinforced thermoplastic (CFRTP)/metal hybrid structures is a vital step for realizing the lightweight design concepts in aerospace. However, the CFRTP/metal hybrid structures are usually not reliable enough in practical applications due to the high differences in chemical and physical properties between these two materials. The current work provides a bottom-up strategy of introducing heteroatoms into CFRTP/metal interfaces to reconstruct the interfacial chemical structures and thus manufacture high-reliability hybrid structures. Based on the principle of utmost using reaction sites at metal surfaces, the heteroatoms of oxygen and hydrogen are specially designed and introduced to the CFRTP/A6061-T6 (6061) interfaces by simple and green plasma polymerization. The introduced oxygen and hydrogen heteroatoms react with the aluminum and oxygen of the oxidation film at 6061 surfaces to produce great interfacial Al-O covalencies and hydrogen bonds. The reconstructing interfacial chemical structures strengthen the joint strength of CFRTP/6061 hybrid structures from 8.82 to 23.97 MPa. Our heteroatom introduction strategy is expected to get a fresh insight into the interfacial design concept and has several important implications for the future application of high-reliability CFRTP/metal hybrid structures.

Single-Sensor Engine Multi-Type Fault Detection.

Engine fault detection is conducive to improving equipment reliability and reducing maintenance costs. In practical scenarios, high-quality data is difficult to obtain. Usually, only single-sensor data is available. This paper proposes a fault detection method combining Variational Mode Decomposition (VMD) and Random Forest (RF). At first, the spectral energy distribution is obtained by decomposing and statistic the engine data of multiple working conditions. Based on the spectral energy distribution, the overall optimal mode number was identified, and the quadratic penalty term was optimized using SNR. The improved VMD (IVMD) improves mode aliasing and iterative efficiency and unifies feature dimensions. Decomposition of real signals demonstrates the effectiveness. The paper designs a feature vector composed of seven types of attributes, including unit bandwidth energy, center frequency, maximum singular value and so on. The feature vector is then fed to RF for classification. Features are selected in order of importance to classification to improve the training efficiency. By comparing with various algorithms, the proposed method has higher accuracy and faster training efficiency in single-speed, multi-speed and cross-speed single-sensor data diagnosis. The results show that the method has application prospects with little training data and low hardware requirements.

A Conceptual Strategy toward High-Reliability Metal-Thermoplastic Hybrid Structures Based on a Covalent-Bonding Mechanism.

Metal-thermoplastic hybrid structures have proven their effectiveness to achieve lightweight design concepts in both primary and secondary structural components of advanced aircraft. However, the drastic differences in physical and chemical properties between metal and thermoplastic make it challenging to fabricate high-reliability hybrid structures. Here, a simple and universal strategy to obtain strong hybrid structures thermoplastics is reported by regulating the bonding behavior at metal/thermoplastic interfaces. To achieve such, we first researched and uncovered the bonding mechanism at metal/thermoplastic interfaces by experimental methods and density functional theory (DFT) calculations. The results suggest that the interfacial covalency, which is formed due to the interfacial reaction between high-electronegativity elements of thermoplastics and metallic elements at metal surfaces, dominates the interfacial bonding interaction of metal-thermoplastic hybrid structures. The differences in electronegativity and atomic size between bonding atoms influence the covalent-bond strength and finally control the interfacial reliability of hybrid structures. Based on our covalent-bonding mechanism, the carboxyl functional group (COOH) is specifically grafted on polyetheretherketone (PEEK) by plasma polymerization to increase the density and strength of interfacial covalency and thus fabricate high-reliability hybrid structures between PEEK and A6061-T6 aluminum alloy. Current work provides an in-depth understanding of the bonding mechanism at metal-thermoplastics interfaces, which opens a fascinating direction toward high-reliability metal-thermoplastic hybrid structures.

Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrotic disease with high mortality. Currently, pirfenidone and nintedanib are the only approved drugs for IPF by the U.S. Food and Drug Administration (FDA), but their efficacy is limited. The activation of multiple phosphotyrosine (pY) mediated signaling pathways underlying the pathological mechanism of IPF has been explored. A Src homology-2 (SH2) superbinder, which contains mutations of three amino acids (AAs) of natural SH2 domain has been shown to be able to block phosphotyrosine (pY) pathway. Therefore, we aimed to introduce SH2 superbinder into the treatment of IPF. Methods: We analyzed the database of IPF patients and examined pY levels in lung tissues from IPF patients. In primary lung fibroblasts obtained from IPF patient as well as bleomycin (BLM) treated mice, the cell proliferation, migration and differentiation associated with pY were investigated and the anti-fibrotic effect of SH2 superbinder was also tested. In vivo, we further verified the safety and effectiveness of SH2 superbinder in multiple BLM mice models. We also compared the anti-fibrotic effect and side-effect of SH2 superbinder and nintedanib in vivo. Results: The data showed that the cytokines and growth factors pathways which directly correlated to pY levels were significantly enriched in IPF. High pY levels were found to induce abnormal proliferation, migration and differentiation of lung fibroblasts. SH2 superbinder blocked pY-mediated signaling pathways and suppress pulmonary fibrosis by targeting high pY levels in fibroblasts. SH2 superbinder had better therapeutic effect and less side-effect compare to nintedanib in vivo. Conclusions: SH2 superbinder had significant anti-fibrotic effects both in vitro and in vivo, which could be used as a promising therapy for IPF.

The Insulin Receptor: An Important Target for the Development of Novel Medicines and Pesticides.

The insulin receptor (IR) is a transmembrane protein that is activated by ligands in insulin signaling pathways. The IR has been considered as a novel therapeutic target for clinical intervention, considering the overexpression of its protein and A-isoform in multiple cancers, Alzheimer's disease, and Type 2 diabetes mellitus in humans. Meanwhile, it may also serve as a potential target in pest management due to its multiple physiological influences in insects. In this review, we provide an overview of the structural and molecular biology of the IR, functions of IRs in humans and insects, physiological and nonpeptide small molecule modulators of the IR, and the regulating mechanisms of the IR. Xenobiotic compounds and the corresponding insecticidal chemicals functioning on the IR are also discussed. This review is expected to provide useful information for a better understanding of human IR-related diseases, as well as to facilitate the development of novel small-molecule activators and inhibitors of the IR for use as medicines or pesticides.

Insecticidal Triterpenes in Meliaceae: Plant Species, Molecules, and Activities: Part II (Cipadessa, Melia).

Plant-originated triterpenes are important insecticidal molecules. Research on the insecticidal activity of molecules from Meliaceae plants has always been a hotspot due to the molecules from this family showing a variety of insecticidal activities with diverse mechanisms of action. In this paper, we discussed 116 triterpenoid molecules with insecticidal activity from 22 plant species of five genera (Cipadessa, Entandrophragma, Guarea, Khaya, and Melia) in Meliaceae. In these genera, the insecticidal activities of plants from Entandrophragma and Melia have attracted substantial research attention in recent years. Specifically, the insecticidal activities of plants from Melia have been systemically studied for several decades. In total, the 116 insecticidal chemicals consisted of 34 ring-intact limonoids, 31 ring-seco limonoids, 48 rearranged limonoids, and 3 tetracyclic triterpenes. Furthermore, the 34 ring-intact limonoids included 29 trichilin-class chemicals, 3 azadirone-class chemicals, and 1 cedrelone-class and 1 havanensin-class limonoid. The 31 ring-seco limonoids consisted of 16 C-seco group chemicals, 8 B,D-seco group chemicals, 4 A,B-seco group chemicals, and 3 D-seco group chemicals. Furthermore, among the 48 rearranged limonoids, 46 were 2,30-linkage group chemicals and 2 were 10,11-linkage group chemicals. Specifically, the 46 chemicals belonging to the 2,30-linkage group could be subdivided into 24 mexicanolide-class chemicals and 22 phragmalin-class chemicals. Additionally, the three tetracyclic triterpenes were three protolimonoids. To sum up, 80 chemicals isolated from 19 plant species exhibited antifeedant activity toward 14 insect species; 18 chemicals isolated from 17 plant species exhibited poisonous activity toward 10 insect species; 16 chemicals isolated from 11 plant species possessed growth-regulatory activity toward 8 insect species. In particular, toosendanin was the most effective antifeedant and insect growth-regulatory agent. The antifeedant activity of toosendanin was significant. Owing to its high effect, toosendanin has been commercially applied. Three other molecules, 1,3-dicinnamoyl-11-hydroxymeliacarpin, 1-cinnamoyl-3-methacryl-11-hydroxymeliacarpin, and 1-cinnamoyl-3-acetyl-11-hydroxymeliacarpin, isolated from Meliaazedarach, exhibited a highly poisonous effect on Spodoptera littoralis; thus, they deserve further attention.

Natural herbicidal alkaloid berberine regulates the expression of thalianol and marneral gene clusters in Arabidopsis thaliana.

BACKGROUND: Berberine is a plant-derived herbicidal alkaloid. The herbicidal mechanism of berberine is still not clear. In this study, our aim is to clarify the mechanism of berberine inhibiting the root growth of Arabidopsis thaliana, aiming at providing new insight into identifying the molecular targets of berberine. RESULTS: The whole-genome RNA sequencing had revealed that 403 genes were down-regulated, and 422 genes were up-regulated in Arabidopsis roots with berberine treatment. According to KEGG and GO analysis, the expression of two genes AT5G48010 (Thas) and AT5G42600 (MRN1) which are in the sesquiterpenoid and triterpenoid biosynthesis pathway were affected most. These two genes belong to thalianol and marneral gene clusters. RT-PCR showed that Arabidopsis responds to berberine by inhibiting root growth through repressing the expression of thalianol and marneral gene clusters, which was independent of the upstream effectors ARP6 and HTA9-1. GC-MS analysis showed that berberine could inhibit THAH in the biosynthetic network of triterpenoid gene cluster in Arabidopsis and thus cause the accumulation of thalianol. CONCLUSION: Our study indicated the repression of the thalianol and marneral gene clusters as the primary mechanism of action of berberine in Arabidopsis, which may result in plant growth defects by interrupting the thalianol metabolic pathway. This provides novel clues as to the possible molecular herbicidal mechanism of berberine. © 2022 Society of Chemical Industry.

Src acts as the target of matrine to inhibit the proliferation of cancer cells by regulating phosphorylation signaling pathways.

Studies have shown that matrine has antitumor activity against many types of cancers. However, the direct target in cancer cells of its anticancer effect has not been identified. The purpose of this study was to find the molecular target of matrine to inhibit the proliferation of cancer cells and explore its mechanism of action. Herein we showed that matrine inhibited the proliferation of cancer in vitro and in vivo. Pull-down assay with matrine-amino coupling resins and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) identified Src as the target of matrine. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) provided solid evidences that matrine directly bound to Src. Bioinformatics prediction and pull-down experiment demonstrated that Src kinase domain was required for its interaction with matrine and Ala392 in the kinase domain participated in matrine-Src interaction. Intriguingly, matrine was proven to inhibit Src kinase activity in a non-ATP-competitive manner by blocking the autophosphorylation of Tyr419 in Src kinase domain. Matrine down-regulated the phosphorylation levels of MAPK/ERK, JAK2/STAT3, and PI3K/Akt signaling pathways via targeting Src. Collectively, matrine targeted Src, inhibited its kinase activity, and down-regulated its downstream MAPK/ERK, JAK2/STAT3, and PI3K/Akt phosphorylation signaling pathways to inhibit the proliferation of cancer cells.

Enhancing Interfacial Reliability of Metal-Thermoplastic Hybrid Joints via Adding Carbon Fiber and Adjusting Welding Heat Input.

Interfacial structures govern the reliability of metal-thermoplastic hybrid joints used in the aerospace industry. The current work demonstrated by experimental methods and density functional theory (DFT) calculations that introduction of carbon fibers (CFs) enhanced the mechanical properties and weakened the corrosion resistance of polyamide 6 (PA6)/A6061-T6 (6061) joints. The bonding strength of typical PA6/6061 joints was increased by 33.70% with the introduction of CF. However, the differences in intrinsic work functions of the CF and various phases within 6061 led to the formation of serious cracks at CFRPA6/6061 interfaces and heavy corrosion on 6061 surfaces, corresponding to the decreased corrosion resistance of PA6/6061 joints. Herein, we present a potential solution to adjust the welding heat input to enhance metal/thermoplastic interfacial reliability. With a rotation speed of 400 mm/min during friction lap joining (FLJ), the fabricated CFRPA6/6061 joint could achieve a strong interface with high strength (bonding strength = 1.730 kN) and relative corrosion resistance (corrosion rate < 0.1 mm/a). The results provide a reliable explanation for the effect of CF on mechanical properties and corrosion resistance of CFRPA6/6061 joints. Furthermore, the knowledge gained in this work will benefit future research in the optimization of processes to improve the reliability of metal-thermoplastic hybrid structures.

Experimental and Numerical Investigation of the Micro-Crack Damage in Elastic Solids by Two-Way Collinear Mixing Method.

This study experimentally and numerically investigated the nonlinear behavior of the resonant bulk waves generated by the two-way collinear mixing method in 5052 aluminum alloy with micro-crack damage. When the primary longitudinal and transverse waves mixed in the micro-crack damage region, numerical and experimental results both verified the generation of resonant waves if the resonant condition ωL/ωT=2κ/(κ-1) was satisfied. Meanwhile, we found that the acoustic nonlinearity parameter (ANP) increases monotonously with increases in micro-crack density, the size of the micro-crack region, the frequency of resonant waves and friction coefficient of micro-crack surfaces. Furthermore, the micro-crack damage in a specimen generated by low-temperature fatigue experiment was employed. It was found that the micro-crack damage region can be located by scanning the specimen based on the two-way collinear mixing method.

Aptamer-SH2 superbinder-based targeted therapy for pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors with a 5-year survival rate of less than 10% and a median survival of 6 months after diagnosis. Numerous targeted agents have been developed and evaluated to improve the survival benefit in patients with PDAC. Unfortunately, most agents have been proven futile mainly owing to the dense stroma and the sophisticated signaling pathways of PDAC. Here, we show the potent effectiveness of Aptamer-SH2 superbinder-(Arg)9 conjugate on the treatment of PDAC. In this conjugate, DNA aptamer selected against PDAC cell line confers the function of specifically recognizing and binding to the PDAC cells and activated pancreatic stellate cells (PSCs) in stroma; cell penetrating peptide (Arg)9 facilitates the intracellular delivery of fused proteins; SH2 superbinder conducts the drastic blockade of multiple phosphotyrosines (pY)-based signaling pathways in tumor cells. METHODS: PDAC-associated pY were reanalyzed by bioinformatics screen. XQ-2d and SH2 superbinder-(Arg)9 were crosslinked with BMH to form XQ-2d-SH2 CM-(Arg)9 conjugate. Immunofluorescence was utilized to assess the potency of the conjugate entering cells. MTT and wound healing assays were performed to evaluate the proliferation or migration of PANC-1 and BxPC-3 cells, respectively. Western blot and Pulldown assays revealed that conjugate influenced several pY-based signaling pathways. Tumor-bearing mice were used to validate XQ-2d-SH2 CM-(Arg)9, which restrained the growth and metastasis of cancer cells. RESULTS: XQ-2d-His-SH2 CM-(Arg)9 conjugate restrained proliferation, invasion, and metastasis of PDAC cells with potent efficacy via blocking the activity of several pY-related signaling cascades. XQ-2d-His-SH2 CM-(Arg)9 could eliminate the dense stroma of PDAC and then arrive at tumor tissues. CONCLUSIONS: XQ-2d-SH2 CM-(Arg)9 conjugate may efficiently destroy the pancreatic stroma and show potent antitumor efficacy with minimal toxic effect by regulating tumor cell proliferation and metastasis in vitro and in vivo, which makes it to be a promising targeted therapy of PDAC.

Laboratory bioassay, greenhouse experiment and 3D-QSAR studies on berberine analogues: a search for new herbicides based on natural products.

BACKGROUND: Berberine is a herbicidal chemical that we isolated from Coptis chinensis. In continuation of our program aimed at discovering and developing natural botanical herbicides, we evaluated the herbicidal activities of 39 berberine analogues and developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model. RESULTS: Among these 39 analogs, the most active compounds were determined to be worenine chloride and coptisine chloride, with median inhibitory concentration (IC50 ) values on all eight tested weed species of < 10 mg L-1 . As a reference, the IC50 values of berberine on six weed species were < 10 mg L-1 . Furthermore, the results of a greenhouse experiment showed that at 10 mg L-1 , and 7 days after treatment, the effects of worenine chloride and coptisine chloride on Lemna minor and Ageratum conyzoides were significantly higher than those of glyphosate and sulcotrione. In the 3D-QSAR analysis, the electrostatic field contour map indicated that introducing an electropositive group in the N-7, C-9 and C-10 positions would potentially improve the inhibition rate. A positively charged nitrogen atom at the N-7 position was important for activity. Replacement of -OCH3 by -OH at the C-9 and C-10 positions could decrease the inhibitory activity, while the hydrophobic field contour map revealed that the hydrophobicity of the C-10 position was associated with high activity. Moreover, the hydrogen bond acceptor field contour map suggested that the existence of a hydrogen bond acceptor at the C-3 and C-9 positions might affect the inhibition rate. CONCLUSIONS: 3D-QSAR provided meaningful clues to the structural features of berberine analogues that will assist the design of more potent herbicidal compounds in the future. © 2020 Society of Chemical Industry.

Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors.

CBP bromodomain could recognize acetylated lysine and function as transcription coactivator to regulate transcription and downstream gene expression. Furthermore, CBP has been shown to be related to many human malignancies including acute myeloid leukemia. Herein, we identified DC-CPin734 as a potent CBP bromodomain inhibitor with a TR-FRET IC50 value of 19.5 ± 1.1 nM and over 400-fold of selectivity against BRD4 bromodomains through structure based rational drug design guided iterative chemical modification endeavoring to discover optimal tail-substituted tetrahydroquinolin derivatives. Moreover, DC-CPin734 showed potent inhibitory activity to AML cell line MV4-11 with an IC50 value of 0.55 ± 0.04 µM, and its cellular on-target effects were further evidenced by c-Myc downregulation results. In summary, DC-CPin734 showing good potency, selectivity and anti AML activity could serve as a potent and selective in vitro and in vivo probe of CBP bromodomain and a promising lead compound for future drug development.