Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

Discovery of 4-methoxy-N-(1-naphthyl)benzenesulfonamide derivatives as small molecule dual-target inhibitors of tubulin and signal transducer and activator of transcription 3 (STAT3) based on ABT-751.

Overexpressed tubulin and continuously activated STAT3 play important roles in the development of many cancers and are potential therapeutic targets. A series of 4-methoxy-N -(1-naphthalene) benzenesulfonamide derivatives were designed and optimized based on ß-tubulin inhibitor ABT-751 to verify whether STAT3 and tubulin dual target inhibitors have better antitumor effects. Compound DL14 showed strong inhibitory activity against A549, MDA-MB-231 and HCT-116 cells in vitro with IC50 values of 1.35 µM, 2.85 µM and 3.04 µM, respectively. Further experiments showed that DL14 not only competitively bound to colchicine binding site to inhibit tubulin polymerization with IC50 values 0.83 µM, but also directly bound to STAT3 protein to inhibit STAT3 phosphorylation with IC50 value of 6.84 µM. Three other compounds (TG03, DL15, and DL16) also inhibit this phosphorylation. In terms of single target inhibition, DL14 is slightly inferior to positive drugs, but it shows a good anti-tumor effect in vivo, and can inhibit >80% of xenograft tumor growth. This study describes a novel 4-methoxy-N-(1-naphthyl) benzenesulfonamide skeleton as an effective double-targeted anticancer agent targeting STAT3 and tubulin.

No subchronic toxicity of multiple herbicide-resistant soybean FG72 in Sprague-Dawley rats by 90-days feeding study.

The genetically modified (GM) soybean FG72 contains two exogenous genes: p-hydroxyphenylpyruvate dioxygenase (hppd) and double mutant 5-enol pyruvylshikimate-3-phosphate synthase (2mepsps), endowing the FG72 with the glyphosate and isoxaflutole herbicides resistant abilities for presence of the 2mEPSPS and HPPD W336 proteins. A food safety assessment of GM soybean FG72 was evaluated by a 90-days feeding study using three different dietary concentrations (7.5%, 15%, or 30% w/w) of the GM soybean or its corresponding non-GM cultivar Jack fed to Sprague-Dawley rats. In our study, no biologically significant differences on animal daily clinical signs, body weights, clinical observations, hematology, clinical chemistry, histopathology on selected organs were observed within the GM soybean groups and among the GM soybean groups, the non-GM soybean groups and the control group. The results of the 90-days subchronic feeding study demonstrated that the GM soybean FG72 is as safe as the conventional non-GM soybean Jack.

Design, synthesis and biological evaluation of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives as novel FGFR1 inhibitors for treatment of non-small cell lung cancer.

A series of 4-bromo-N-(3,5-dimethoxyphenyl)benzamide derivatives were designed and synthesised as novel fibroblast growth factor receptor-1 (FGFR1) inhibitors. We found that one of the most promising compounds, C9, inhibited five non-small cell lung cancer (NSCLC) cell lines with FGFR1 amplification, including NCI-H520, NCI-H1581, NCI-H226, NCI-H460 and NCI-H1703. Moreover, the IC50 values for the compound C9 were 1.36 ± 0.27 µM, 1.25 ± 0. 23 µM, 2.31 ± 0.41 µM, 2.14 ± 0.36 µM and 1.85 ± 0.32 µM, respectively. The compound C9 arrested the cell cycle at the G2 phase in NSCLC cell lines. The compound C9 also induced cellular apoptosis and inhibited the phosphorylation of FGFR1, PLCγ1 and ERK in a dose-dependent manner. In addition, molecular docking experiments showed that compound C9 binds to FGFR1 to form six hydrogen bonds. Taken together, our data suggested that the compound C9 represented a promising lead compound-targeting FGFR1.

Manganese disrupts the maturation and degradation of axonal autophagosome leading to hippocampal synaptic toxicity in mice via the activation of LRRK2 on phosphorylation of Rab10.

Manganese (Mn) overexposure induces hippocampal synaptotoxicity by the accumulation of dysfunctional synaptic vesicles (SVs). Leucine-rich repeat kinase 2 (LRRK2) kinase activity is involved in regulating axonal transport (autophagosomal maturation) and lysosomal function. Nevertheless, it remains unclear whether Mn-induced synaptotoxicity is associated with the LRRK2-mediated disruption of autophagosomal maturation in axonal transport and the impairment of lysosomes in hippocampal neurons. Here, we established models of manganism in C57BL/6 mice and hippocampal neuronal HT22 cells to verify the role of LRRK2-mediated Rab10 phosphorylation in the Mn-induced dysfunction of autophagy- lysosomal fusion. Our results proved that Mn-induced the disorder of axonal transport and that lysosome impairments were associated with the increased recruitment of phospho-Rab10 at the axon and lysosomes. Next, we established Lrrk2-KD and LRRK2 kinase- specific inhibitor (GNE-0877, GNE) pre-treated HT22 cells to inhibit Lrrk2 gene expression and kinase activity, respectively. In Mn-treated Lrrk2-KD or GNE-pretreated normal neurons, our results indicated that lysosomal pH and integrity and autophagic flow were restored, indicating by decreased levels of phospho-Rab10 on lysosomes and JNK-interacting proteins (JIP4). In addition, GNE pretreatment could provide protection against Mn-induced synaptotoxicity in vivo, which was evidenced by the partial recovery in synaptic plasticity and synaptic damage. Thus, the Mn-induced abnormal activation of LRRK2 affected lysosomes and the recruitment of phospho-Rab10 by JIP4, which disrupted autophagosomal maturation in proximal axons and resulted in the hippocampal synaptic toxicity of mice.

Comparative analysis of physical traits, mineral compositions, antioxidant contents, and metabolite profiles in five cherry tomato cultivars.

Cherry tomatoes (Solanum lycopersicum var. cerasiforme) are cultivated and consumed worldwide. While numerous cultivars have been bred to enhance fruit quality, few studies have comprehensively evaluated the fruit quality of cherry tomato cultivars. In this study, we assessed fruits of five cherry tomato cultivars (Qianxi, Fengjingling, Fushan88, Yanyu, and Qiyu) at the red ripe stage through detailed analysis of their physical traits, mineral compositions, antioxidant contents, and metabolite profiles. Significant variations were observed among the cultivars in terms of fruit size, shape, firmness, weight, glossiness, and sepal length, with each cultivar displaying unique attributes. Mineral analysis revealed distinct patterns of essential and trace element accumulation, with notable differences in calcium, sodium, manganese, and selenium concentrations. Fenjingling was identified as a selenium enriched cultivar. Analysis of antioxidant contents highlighted Yanyu as particularly rich in vitamin C and Fenjingling as having elevated antioxidant enzyme activities. Metabolomics analysis identified a total number of 3,396 annotated metabolites, and the five cultivars showed distinct metabolomics profiles. Amino acid analysis showed Fushan88 to possess a superior profile, while sweetness and tartness assessments indicated that Yanyu exhibited higher total soluble solids (TSS) and acidity. Notably, red cherry tomato cultivars (Fushan88, Yanyu, and Qiyu) accumulated significantly higher levels of eugenol and α-tomatine, compounds associated with undesirable flavors, compared to pink cultivars (Qianxi and Fengjingling). Taken together, our results provide novel insights into the physical traits, nutritional value, and flavor-associated metabolites of cherry tomatoes, offering knowledge that could be implemented for the breeding, cultivation, and marketing of cherry tomato cultivars.

Inhibition of DDR1 promotes ferroptosis and overcomes gefitinib resistance in non-small cell lung cancer.

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which serves the critical pillar for the treatment of non-small cell lung cancer (NSCLC). However, the acquired resistance remains a challenge for its clinical application, for which, practical strategies to reverse gefitinib resistance in NSCLC are necessary. Ferroptosis, a programmed cell death driven by ferritin-dependent lipid peroxidation, involves in NSCLC progression and related chemoresistance. In our previous work, the self-synthesised EGFR inhibitor Yfq07 (N4, N6-disubstituted pyrimidine-4,6-diamine derivatives) displayed a considerable inhibitory effect on NSCLC both in vitro and in vivo. Herein, we observed that Yfq07 suppressed the proliferation of PC-9GR and HCC827GR cells, two gefitinib resistance NSCLC cell lines. Mechanically, Yfq07 inhibited the phosphorylation of the Discoidin Domain Receptor 1 (DDR1), a receptor tyrosine kinase (RTK) highly expressed in multiple cancers, accompanied by downregulated miR-3648 and upregulated SOCS2. Inhibition or knockdown of DDR1 suppressed the proliferation, migration, and invasion of gefitinib-resistant NSCLC cells, and on the other hand, also downregulated miR-3648 and promoted SOCS2 expression. More specifically, miR-3648 targeted the 3'UTR segment of SOCS2 mRNA and thus affecting the P-ERK signalling pathway to regulate the malignant behaviors of gefitinib-resistant NSCLC cells. Furthermore, Yfq07 also indirectly induced the ferroptosis of gefitinib-resistant NSCLC cells via SOCS2 triggered inhibition of xCT-GPX4 pathway. In conclusion, our study indicates that DDR1 inhibitor Yfq07 promotes ferroptosis and reverses gefitinib-resistance of NSCLC through DDR1-miR-3648-SOCS2 signalling pathway, which provides insights for targeted therapy of gefitinib-resistant NSCLC and drug developments targeting ferroptosis.

Identification and verification of atrial fibrillation hub genes caused by primary mitral regurgitation.

In the clinic, atrial fibrillation (AF) is a common arrhythmia. Despite constant innovation in treatments for AF, they remain limited by a lack of knowledge of the underlying mechanism responsible for AF. In this study, we examined the molecular mechanisms associated with primary mitral regurgitation (MR) in AF using several bioinformatics techniques. Limma was used to identify differentially expressed genes (DEGs) associated with AF using microarray data from the GSE115574 dataset. WGCNA was used to identify significant module genes. A functional enrichment analysis for overlapping genes between the DEGs and module genes was done and several AF hub genes were identified from a protein-protein interaction (PPI) network. Receiver operating characteristic (ROC) curves were generated to evaluate the validity of the hub genes. We examined 306 DEGs and 147 were upregulated and 159 were downregulated. WGCNA analysis revealed black and ivory modules that contained genes associated with AF. Functional enrichment analysis revealed various biological process terms related to AF. The AUCs for the 8 hub genes screened by the PPI network analysis were > 0.7, indicating satisfactory diagnostic accuracy. The 8 AF-related hub genes included SYT13, VSNL1, GNAO1, RGS4, RALYL, CPLX1, CHGB, and CPLX3. Our findings provide novel insight into the molecular mechanisms of AF and may lead to the development of new treatments.

Electric Resistance of Elastic Strain Sensors-Fundamental Mechanisms and Experimental Validation.

Elastic strain sensor nanocomposites are emerging materials of high scientific and commercial interest. This study analyzes the major factors influencing the electrical behavior of elastic strain sensor nanocomposites. The sensor mechanisms were described for nanocomposites with conductive nanofillers, either dispersed inside the polymer matrix or coated onto the polymer surface. The purely geometrical contributions to the change in resistance were also assessed. The theoretical predictions indicated that maximum Gauge values are achieved for mixture composites with filler fractions slightly above the electrical percolation threshold, especially for nanocomposites with a very rapid conductivity increase around the threshold. PDMS/CB and PDMS/CNT mixture nanocomposites with 0-5.5 vol.% fillers were therefore manufactured and analyzed with resistivity measurements. In agreement with the predictions, the PDMS/CB with 2.0 vol.% CB gave very high Gauge values of around 20,000. The findings in this study will thus facilitate the development of highly optimized conductive polymer composites for strain sensor applications.

Spatial and Temporal Characteristics of Phytoplankton Communities in Drinking Water Source Reservoirs in Shenzhen, China.

Phytoplankton diversity and community characteristics are closely associated with aquatic environmental factors. Understanding these dynamics can provide insights into the ecological health of water bodies. We investigate the spatial and temporal characteristics of phytoplankton communities in 27 drinking water source reservoirs in Shenzhen, China. As a method, we collected samples during the dry season in 2021 and the wet season in 2022, analyzed the alpha and beta diversities of phytoplankton communities, and correlated these with the environmental factors. The results reveal that Cyanobacteria dominate the phytoplankton communities in the Shenzhen reservoirs. Phytoplankton diversity is greater during the dry season. The algal composition varies spatially, and the phytoplankton diversity tends to decrease with increasing eutrophication. A co-occurrence network analysis indicates denser and stronger correlations among phytoplankton nodes during the wet season than dry season. Reservoirs with moderate eutrophication levels exhibit denser nodes and stronger correlations compared to those with low or high eutrophication levels. The chemical oxygen demand, water temperature, pH, and total nitrogen are identified as key influencers of the phytoplankton community structure. Our results contribute to the enhanced understanding of the spatial and temporal dynamics of phytoplankton communities in reservoirs in South China and provides insights into the management and conservation of these drinking water reservoirs.