Synthesis, Plant Growth Regulatory Activity, and Transcriptome Analysis of Novel Opabactin Analogs.

Abscisic acid (ABA), a phytohormone, and its analogs have been found to enhance plant resistance to various biotic and abiotic stresses, particularly drought, by activating the ABA signaling pathway. This study used a combination of structure-directed design and molecular docking screening methods to synthesize a novel series of opabactin (OP) analogs. Among them, compounds 4a-4d and 5a showed comparable or superior activity to OP in bioassays, including seed germination and seedling growth inhibition in A. thaliana and rice, stomatal closure, and drought resistance in wheat and soybean. Further transcriptome analysis revealed distinct mechanisms of action between compound 4c and iso-PhABA in enhancing drought tolerance in A. thaliana. These findings highlight the application prospect of 4c and its analogs in agricultural cultivation, particularly in drought resistance. Additionally, they provide new insights into the mechanisms by which different ABA receptor agonists enhance drought resistance.

Lentinan inhibits cell invasion via M2 polarization of tumor-associated macrophages and Wnt/ß-catenin signaling in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is an aggressive and devastating cancer due to its metastasis induced by increased invasion. Lentinan is a polysaccharide exerting antitumor roles in multiple cancers, including lung cancer. However, the influence of lentinan on cell invasion in NSCLC remains unclear. Cell invasion was detected by transwell analysis. Matrix metallopeptidase 9 (MMP9) levels were measured through immunofluorescence staining. The markers arginase-1 (Arg-1), CD206 and interleukin (IL)-10 (IL-10) of M2 macrophages, Wnt3a, and ß-catenin levels were measured by western blot or enzyme linked immunosorbent assay. Lentinan did not affect cell viability and proliferation in NSCLC cells. Lentinan suppressed cell invasion and reduced the expression and secretion of MMP9. Lentinan attenuated also M2 polarization of tumor-associated macrophages. Moreover, lentinan mitigated the M2 macrophage conditioned medium-mediated cell invasion and MMP9 alterations in NSCLC cells. Lentinan inhibited the activation of the Wnt/ß-catenin signaling in NSCLC cells. The activated Wnt/ß-catenin pathway reversed the suppressive effects of lentinan on cell invasion and MMP9 level in NSCLC cells. In conclusion, lentinan reduces cell invasion in NSCLC cells by inhibiting the M2 polarization of tumor-associated macrophages and the Wnt/ß-catenin signaling.

TSE-ARF: An adaptive prediction method of effectors across secretion system types.

Bacterial effector proteins are secreted by a variety of protein secretion systems and play an important role in the interaction between the host and pathogenic bacteria. Therefore, it is important to find a fast and inexpensive method to discover bacterial effectors. In this study, we propose a multi-type secretion effector adaptive random forest (TSE-ARF) to adaptively identify secretion effectors across T1SE-T4SE and T6SE based only on protein sequences. First, we proposed two new feature descriptors by considering some characteristic protein information and fused them with some universal features to form a 290-dimensional feature vector with good versatility. Then, the TSE-ARF model was used to make classification predictions by parameter adaptation of different secretion effectors integrating Shuffled Frog Leaping Algorithm and random forest. The perfect performance in TSE-ARF under different data sets and settings shows its considerable generalization ability, with which more candidate effectors were screened in the whole genome. Source code is available at https://github.com/AIMOVE/TSE-ARF.

Synthesis, Herbicidal Activity against Barnyard Grass, and Photolytic Behavior of Aryl 2,6-Dipyrimidinoxybenzoates.

In this study, we investigated the characteristics and herbicidal potential of bispyribac phenolic esters, which belong to the 2-(pyrimidin-2-yloxy)benzoic acid (PYB) class of acetohydroxyacid synthase (AHAS-)-inhibiting herbicides. These herbicides are primarily used for controlling Poaceae and broadleaf weeds. Among them, bispyribac-sodium stands out as a representative in this class. Surprisingly, other bispyribac esters, including alkanol and phenol esters exhibit considerably reduced herbicidal activity compared to bispyribac-sodium. In contrast, oxime esters (e.g., pyribenzoxim) demonstrate high activity. To further understand and develop novel PYB herbicides, we synthesized and screened a series of bispyribac phenolic esters while investigating their photochemical behaviors. Several compounds displayed excellent herbicidal activity, with compounds Ia-19 and Ic showing impressive 90% effective dosages for fresh weight inhibition of barnyard grass, measuring 0.55 and 0.60 g a.i./hm2, respectively. These values were approximately half of bispyribac-sodium or pyribenzoxim. The results indicate that the herbicidal activity of phenolic esters is influenced by both their binding ability to the AHAS enzyme and their decomposition into bispyribac acid. For instance, bispyribac phenol ester exhibited considerably reduced receptor affinity compared to bispyribac-sodium, and faced challenges in transforming into bispyribac acid, explaining its diminished herbicidal activity. However, introducing a photosensitive nitro group led to a complete transformation. This modification improved its affinity with AHAS and accelerated its decomposition into bispyribac acid, further accelerated by photocatalysis. Consequently, nitro-containing compounds displayed heightened herbicidal activity. The findings from this study open possibilities for structural optimization of phenolic esters through quantitative structure-activity relationship analysis, potentially regulating their activity-releasing period. Furthermore, the high activity of aromatic heterocyclic esters offers new insights into developing novel PYB herbicides.

Construction of a Two-Dimensional GO/Ti3C2TX Composite Membrane and Investigation of Mg2+/Li+ Separation Performance.

Graphene oxide (GO) two-dimensional (2D) membranes with unique layer structures and tunable layer spacing have special advantages and great potential in the field of water treatment. However, GO membranes face the issues of weak anti-swelling ability as well as poor permeability. We prepared GO/Ti3C2TX 2D composite membranes with 2D/2D structures by intercalating Ti3C2TX nanosheets with slightly smaller sizes into GO membranes. Ti3C2TX intercalation can effectively expand the layer spacing of GO, thereby substantially enhancing the flux of the composite membrane (2.82 to 6.35 L·m-2·h-1). Moreover, the GO/Ti3C2TX composite membrane exhibited a good Mg2+/Li+ separation capability. For the simulated brine, the separation factor of M2 was 3.81, and the salt solution flux was as high as 5.26 L·m-2·h-1. Meanwhile, the incorporation of Ti3C2TX nanosheets significantly improved the stability of GO/Ti3C2TX membranes in different pH environments. This study provides a unique insight into the preparation of highly permeable and ion-selective GO membranes.

Capsule Endoscopy-Based Diagnosis of Lung Squamous Cell Carcinoma Associated with Abdominal Pain and Metastasis to Small Intestine: A Case Report.

Gastrointestinal metastases of lung cancer are relatively uncommon, yet occur at a higher frequency than would be expected among patients that exhibit a longer survival interval. Metastases that arise in the small intestines are often associated with no or few symptoms such that their early diagnosis can be challenging. In this report, we describe an extremely rare case of a lung squamous cell carcinoma that had metastasized to the small intestine and was associated with symptoms of abdominal pain. The patient underwent capsule endoscopy which detected an irregular mass in the distal ileum that was hemorrhagic, after which laparoscopic ileal resection and anastomosis in parallel with partial bladder resection were performed. Subsequent pathological biopsy confirmed that the intestinal mass was consistent with metastatic squamous cell carcinoma. With surgery and subsequent maintenance therapy with targeted drugs, the survival of the patient was more than 6 months. As a noninvasive testing strategy, capsule endoscopy can be easily performed to support etiological diagnostic efforts in cases where other diagnostic options are lacking. Early diagnosis and therapeutic intervention can contribute to better prognostic outcomes for GMLC patients.

Unveiling the dynamics of antibiotic resistome, bacterial communities, and metals from the feces of patients in a typical hospital wastewater treatment system.

Bacterial pathogens and antibiotic resistance genes (ARGs) are extensively disseminated into the environment via hospital wastewater (HWW), as it contains large quantities of feces from resident patients. However, studies on the antibiotic resistome and pathogenic bacteria from the gut of resident patients within the hospital wastewater treatment plant (hWWTP) are limited. Here, we examined and compared the occurrence and abundance of ARGs, mobile genetic elements (MGEs), metals, and bacterial communities from the feces of patients in a typical hWWTP system and determined the pathogenic hosts responsible for transferring ARGs. There were 176 ARGs and 43 MGEs detected in the feces of hospitalized patients, 129 genes were persistent, and 88 genes were enriched after HWW treatment, particularly for the blaVEB, blaNDM, and class 1 integron (intI1), with an average of 659-fold, 202-fold, and seven-fold enrichment, respectively. MGEs, especially Is613, in the feces of hospitalized patients were exceptionally abundant and even surpassed the abundance of total ARGs, which explained the persistence of ARGs in hWWTPs due to possible gene mobilization events. Bacteroidetes and Firmicutes were the most abundant phyla in these feces, accounting for 81 % of the total gut microbiota, while Epsilonbacteraeota and Proteobacteria dominated the hWWTPs. Additionally, 54 possible bacterial pathogens were found in the hospital environment, including four "ESKAPE" pathogens and 14 cancer-related pathogens. Many of them were strongly associated with different types of ARGs. Notably, Bacteroides was the major potential ARG-harboring pathogenic genus, as determined by the network analysis, and was highly abundant after the treatment. The altered microbial community was the major contributing factor shaping antibiotic resistome. This study might provide a comprehensive insight into the distribution profiles of ARGs and pathogens from the gut of inpatients throughout the HWW treatment system, which could be used as a reference for optimizing HWW treatment and monitoring public risk.

Natural Antisense Long Noncoding RNA HHIP-AS1 Suppresses Non-Small-Cell Lung Cancer Progression by Increasing HHIP Stability via Interaction with CELF2.

Non-small-cell lung cancer (NSCLC) is a major category of lung cancer, with high incidence and high mortality. Natural antisense long noncoding RNAs (lncRNAs) are involved in the development of NSCLC via their regulation of biological processes. However, the function of the lncRNA Hedgehog-interacting protein antisense RNA 1 (HHIP-AS1) in NSCLC is mostly unknown. In the study discussed here, HHIP-AS1 and HHIP levels were predicted based on the TCGA database, and detected via qRT-PCR or western blotting assays. Cell proliferation, migration, and invasion were measured via CCK-8 and trans-well assays. Related protein levels were measured using western blotting analysis. The results showed that HHIP-AS1 and HHIP levels are downregulated in NSCLC, and that low HHIP-AS1 and HHIP expression is associated with poor outcomes. HHIP-AS1 overexpression represses cell proliferation, migration, and invasion in NSCLC. HHIP-AS1 enhances HHIP expression and stability, and this effect is mediated by CELF2. HHIP silencing attenuates the suppressive roles of HHIP-AS1 in proliferation, migration, and invasion. As a result of these findings, it is concluded that HHIP-AS1 overexpression restrains proliferation, migration, and invasion of NSCLC cells by increasing HHIP stability via its targeting of CELF2.

Design, synthesis, and insecticidal activity of a novel series of flupyrimin analogs bearing 1-aryl-1H-pyrazol-4-yl subunits.

To discover new potential insecticides to protect agricultural crops from damage, a series of novel flupyrimin derivatives containing an arylpyrazole core were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Bioassays indicated that the 31 compounds synthesized possessed excellent insecticidal activity against Plutella xylostella. Among these target compounds, the lethality of A3, B1-B6, D4, and D6 reached 100% at 400 µg/ml. Moreover, when the concentration dropped to 25 µg/ml, the insecticidal activities against the Plutella xylostella for compounds B2, B3, and B4 still reached more than 70%. The structure-activity relationship of the Plutella xylostella was discussed. The density functional theory analysis of flupyrimin and B4 was carried out to support the abovementioned structure-activity relationship. The possible binding modes between receptor and active groups in title compounds were also verified by docking simulation. These results provided new ideas for the development of these novel candidate insecticides in the future.

Synthesis and insecticidal activity of novel 1,2,4-triazole derivatives containing trifluoroacetyl moieties.

A series of compounds containing trifluoroacetyl groups were synthesized, and their insecticidal activity against Nilaparvata lugens and Aphis craccivora was evaluated. The compound structure was identified by NMR, HRMS, and single-crystal diffraction. The bioassay results indicated that compound 4-1 (R1 is chloropyridine, R2 is H), 4-2 (R1 is chlorothiazole, R2 is H) and 4-19 (R1 is benzyl, R2 is isopropyl) had the best activity against Nilaparvata lugens (93.5%, 94.1% and 95.5%) at 100 mg/L concentration. The effect of different substituents of R1 or R2 on the activity was studied through the structure-activity relationship. Molecular docking of compounds 4-1 and 4-2 was discussed.

Gene prediction of aging-related diseases based on DNN and Mashup.

BACKGROUND: At present, the bioinformatics research on the relationship between aging-related diseases and genes is mainly through the establishment of a machine learning multi-label model to classify each gene. Most of the existing methods for predicting pathogenic genes mainly rely on specific types of gene features, or directly encode multiple features with different dimensions, use the same encoder to concatenate and predict the final results, which will be subject to many limitations in the applicability of the algorithm. Possible shortcomings of the above include: incomplete coverage of gene features by a single type of biomics data, overfitting of small dimensional datasets by a single encoder, or underfitting of larger dimensional datasets. METHODS: We use the known gene disease association data and gene descriptors, such as gene ontology terms (GO), protein interaction data (PPI), PathDIP, Kyoto Encyclopedia of genes and genomes Genes (KEGG), etc, as input for deep learning to predict the association between genes and diseases. Our innovation is to use Mashup algorithm to reduce the dimensionality of PPI, GO and other large biological networks, and add new pathway data in KEGG database, and then combine a variety of biological information sources through modular Deep Neural Network (DNN) to predict the genes related to aging diseases. RESULT AND CONCLUSION: The results show that our algorithm is more effective than the standard neural network algorithm (the Area Under the ROC curve from 0.8795 to 0.9153), gradient enhanced tree classifier and logistic regression classifier. In this paper, we firstly use DNN to learn the similar genes associated with the known diseases from the complex multi-dimensional feature space, and then provide the evidence that the assumed genes are associated with a certain disease.

miR-10b promoted melanoma progression through Wnt/ß-catenin pathway by repressing ITCH expression.

Dysregulation of microRNAs (miRNAs) have been reported to contribute to malignant progression in melanoma. However, the roles and mechanisms of several miRNAs in melanoma remain poorly understood. In our study, we showed that miR-10b was significantly up-regulated in melanoma tissues and cell lines, and was associated with overall survival of melanoma patients. Inhibition of miR-10b dramatically suppressed melanoma cell proliferation, migration and invasion in vitro and inhibited tumor growth in vivo. Moreover, we defined ITCH as a direct and functional downstream target of miR-10b, and showed that there was an inverse correlation between the expression of ITCH and miR-10b on melanoma tissues. Down-regulation of ITCH partially attenuated the inhibitory effects of miR-10b inhibition on melanoma cell proliferation, migration and invasion. Furthermore，we found that miR-10b exerted its effects on melanoma by regulating the Wnt/ß-catenin pathway. Taken together, our results demonstrated that miR-10b was an important epigenetic modifier, promoting melanoma progression through regulating ITCH/Wnt/ß-catenin pathway. These results offer a new strategy for epigenetic cancer therapy.

Agomelatine versus fluoxetine in glycemic control and treating depressive and anxiety symptoms in type 2 diabetes mellitus subjects: a single-blind randomized controlled trial.

BACKGROUND: Depressive and anxiety symptoms could seriously affect the quality of life of type 2 diabetes mellitus (T2DM) subjects. Currently, little is known about the efficacy and acceptability of agomelatine versus fluoxetine in treating these symptoms in T2DM subjects. Therefore, this study was performed to find out which one was better in treating these symptoms in T2DM subjects. MATERIALS AND METHODS: T2DM subjects with depressive and anxiety symptoms were randomly assigned to receive either fluoxetine (30-40 mg/day) or agomelatine (25-50 mg/day). The treatment was continued for 12 weeks. The data of the Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were collected (at baseline and also at weeks 4, 8 and 12) to assess the depressive and anxiety symptoms, respectively. The metabolic parameters, including body mass index (BMI), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c), were assessed at baseline and after 12 weeks of treatment. The treatment-related adverse events during the scheduled treatment period were recorded to compare the acceptability of these two drugs. RESULTS: After 12 weeks of treatment, the average HDRS and HARS scores were significantly decreased in both groups. The average HDRS scores were not significantly different between the two groups, although the agomelatine group had a lower average HDRS score. The response and remission rates were similar between the two groups, and these two drugs had no significant effects on BMI and FPG. However, compared with the fluoxetine group, the agomelatine group had the significantly lower average HARS score (p=0.0017) and lower average HbA1c level (p<0.00001). Moreover, the incidence of adverse events was significantly lower in the agomelatine group than in the fluoxetine group (p=0.032). CONCLUSION: Both fluoxetine and agomelatine could effectively reduce depressive and anxiety symptoms in T2DM subjects, but agomelatine might be more effective and acceptable. Future studies with more subjects are needed to support and validate our conclusion.

Cytokine-induced killer cells combined with dendritic cells inhibited liver cancer cells.

OBJECTIVES: To investigate the prognosis of advanced liver cancer patients treated with CIK-DCs and the mechanism of apoptosis of HEPG 2 cells. METHODS: 67 patients were enrolled in the study. Peripheral blood mononuclear cells (PBMCs) were separated, of which adherent PBMCs used granulocyte 2 macrophage colony2 stimulating factor (GM2CSF), tumor necrosis factor 2α (TNF2α), and interleukin 24 (IL24) to induce DCs, which were sensitized with antigen of autologous or exogenous cancer cells to obtain Ag-DCs; suspended PBMCs used interferon 2γ (IFN2γ), IL-2, and CD 3 monoclonal antibody (CD3mAb) respectively, to induce CIK cells. DCs and CIK cells were cultured together. Flow cytometry was used to detect the phenotypes of DCs and CIK cells, and the blood retransfused into patients. Western blot and flow cytometer were used to analyze the growth cycle of HepG 2 cells and the expression of BAX and PCNA. RESULTS: No patients underwent complete remission, 5 obtained partial remission and 29 had stable disease. Of the 31 patients whose lesions could not be evaluated, 17 received effective treatment, showing that the immune response was enhanced. In vitro laboratory experiments revealed that DC-CIK cells markedly affected the growth cycle of HepG 2 cells. Analysis showed that DC-CIK cells enhanced the gene expression of BAX and inhibited the activity of PCNA. CONCLUSIONS: Co-cultured DCs and CIK cells inhibit the proliferation and migration of liver cancer cells by down-regulating PCNA and up-regulating BAX. This approach may be an effective method to treat advanced liver cancer.

Preparation and antitumor effect of a toxin-linked conjugate targeting vascular endothelial growth factor receptor and urokinase plasminogen activator.

The aberrant signaling activation of vascular endothelial growth factor receptor (VEGFR) and urokinase plasminogen activator (uPA) is a common characteristic of many tumors, including lung cancer. Accordingly, VEGFR and uPA have emerged as attractive targets for tumor. KDR (Flk-1/VEGFR-2), a member of the VEGFR family, has been recognized as an important target for antiangiogenesis in tumor. In this study, a recombinant immunotoxin was produced to specifically target KDR-expressing tumor vascular endothelial cells and uPA-expressing tumor cells and mediate antitumor angiogenesis and antitumor effect. Based on its potent inhibitory effect on protein synthesis, Luffin-beta (Lß) ribosome-inactivating protein was selected as part of a recombinant fusion protein, a single-chain variable fragment against KDR (KDRscFv)-uPA cleavage site (uPAcs)-Lß-KDEL (named as KPLK). The KDRscFv-uPAcs-Lß-KDEL (KPLK) contained a single-chain variable fragment (scFv) against KDR, uPAcs, Lß, and the retention signal for endoplasmic reticulum proteins KDEL (Lys-Asp-Glu-Leu). The KPLK-expressing vector was expressed in Escherichia coli, and the KPLK protein was isolated with nickel affinity chromatography and gel filtration chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis test demonstrated KPLK was effectively expressed. Result of in vitro cell viability assay on non-small cell lung cancer (NSCLC) H460 cell line (uPA-positive cell) revealed that KPLK significantly inhibited cell proliferation, induced apoptosis, and accumulated cells in S and G2/M phases, but the normal cell line (human submandibular gland cell) was unaffected. These effects were enhanced when uPA was added to digest KPLK to release Lß. For in vivo assay of KPLK, subcutaneous xenograft tumor model of nude mice were established with H460 cells. Growth of solid tumors was significantly inhibited in animals treated with KPLK up to 21 days, tumor weights were decreased, and the expression of angiogenesis marker CD31 was downregulated; meanwhile, the apoptosis-related protein casspase-3 was upregulated. These results suggested that the recombinant KPLK may have therapeutic applications on tumors, especially uPA-overexpressing ones.