Comparative transcriptome analysis of Fusarium graminearum challenged with distinct fungicides and functional analysis of FgICL gene.

Fusarium graminearum is an economically important phytopathogenic fungus. Chemical control remains the dominant approach to managing this plant pathogen. In the present study, we performed a comparative transcriptome analysis to understand the effects of four commercially used fungicides on F. graminearum. The results revealed a significant number of differentially expressed genes related to carbohydrate, amino acid, and lipid metabolism, particularly in the carbendazim and phenamacril groups. Central carbon pathways, including the TCA and glyoxylate cycles, were found to play crucial roles across all treatments except tebuconazole. Weighted gene co-expression network analysis reinforced the pivotal role of central carbon pathways based on identified hub genes. Additionally, critical candidates associated with ATP-binding cassette transporters, heat shock proteins, and chitin synthases were identified. The crucial functions of the isocitrate lyase in F. graminearum were also validated. Overall, the study provided comprehensive insights into the mechanisms of how F. graminearum responds to fungicide stress.

Bronchial thermoplasty decreases airway remodeling by inhibiting autophagy via the AMPK/mTOR signaling pathway.

Bronchial thermoplasty (BT), an effective treatment for severe asthma, requires heat to reach the airway to reduce the mass of airway smooth muscle cells (ASMCs). Autophagy is involved in the pathological process of airway remodeling in patients with asthma. However, it remains unclear whether autophagy participates in controlling airway remodeling induced by BT. In this study, we aim to elucidate the autophagy-mediated molecular mechanisms in BT. Our study reveal that the number of autophagosomes and the level of alpha-smooth muscle actin (α-SMA) fluorescence are significantly decreased in airway biopsy tissues after BT. As the temperature increased, BT causes a decrease in cell proliferation and a concomitant increase in the apoptosis of human airway smooth muscle cells (HASMCs). Furthermore, increase in temperature significantly downregulates cellular autophagy, autophagosome accumulation, the LC3II/LC3I ratio, and Beclin-1 expression, upregulates p62 expression, and inhibits the AMPK/mTOR pathway. Furthermore, cotreatment with AICAR (an AMPK agonist) or RAPA (an mTOR antagonist) abolishes the inhibition of autophagy and attenuates the increase in the apoptosis rate of HASMCs induced by the thermal effect. Therefore, we conclude that BT decreases airway remodeling by blocking autophagy induced by the AMPK/mTOR signaling pathway in HASMCs.

Related Factors of CRKP Infection in Neurosurgery and Comparison of Therapeutic Effects of Tigecycline Versus Polymyxin B for CRKP Infection.

Objective: This paper aimed to identify the factors related to Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection in neurosurgical patients, and to compare the therapeutic effects of tigecycline versus polymyxin B against CRKP infection, so as to provide a reliable reference for neurosurgery in future prevention and treatment of CRKP infection. Methods: One hundred and fifty cases of KPN treated in the neurosurgery department of our hospital from January 1, 2019 to December 31, 2021 were selected, 50 of which were found to be infected with CRKP and the other 100 were detected with carbapenem-sensitive Klebsiella pneumoniae (CSKP) by culture, analysis of factors associated with infection with CRKP. Subsequently, CRKP-infected patients were randomized into a group treated with Ti (group Ti) and a group treated with PB (group PB). The clinical efficacy, bacterial clearance, adverse reactions, and pre- and post-treatment hepatorenal function were comparatively analyzed. Results: Based on the Logistic regression analysis, tracheal intubation (or mechanical ventilation), combination of multiple underlying diseases, presence of impaired consciousness, and use of carbapenem antibiotics are independent risk factors for CRKP infection (P < .05). Ti and PB groups had no evident differences in clinical efficacy and bacterial clearance (P > .05); however, Ti group presented a worse hepatorenal function and a higher incidence of adverse reactions than PB group (P < .05). Conclusions: Tracheal intubation (or mechanical ventilation), multiple underlying diseases, consciousness disturbance, and use of carbapenem antibiotics are related factors affecting CRKP infection in neurosurgical patients. Both Ti and PB have excellent therapeutic efficacy, but the former has more obvious toxicity and side effects.

Effects of penthiopyrad on the hypothalamic-pituitary-thyroid (HPT) axis in zebrafish.

Exposure to specific pesticides has been demonstrated to alter normal thyroid function of aquatic vertebrates. This study aimed to investigate the impact of penthiopyrad (PO) on the thyroid function of zebrafish, further elucidating its toxic mechanisms on the early developmental stages of zebrafish. Exposure to sublethal doses of PO (0.3-1.2 mg/L) for 8 days from 2 h after fertilization resulted in a significant reduction in larval swim bladder size and body weight, accompanied by developmental abnormalities such as pigment deposition and abnormal abdominal development. Perturbations in the hypothalamic-pituitary-thyroid (HPT) axis in larvae manifested as a marked upregulation of crh, tg, ttr, and ugt1ab expression, alongside downregulation of trß expression, culminating in elevated thyroxine (T4) and triiodothyronine (T3) levels. Additionally, molecular docking results suggest that PO and its metabolites may disrupt the binding of thyroid hormones to thyroid hormone receptor beta (TRß), compromising the normal physiological function of TRß. These findings highlight the PO-induced adverse effects on the HPT axis of larvae under sublethal doses, eventually leading to abnormal development and growth inhibition.

Inhibitory activities of five fungicides on Alternaria suffruticosae and their field control efficacy against tree peony black spot.

Tree peony black spot (TPBS), mainly caused by Alternaria suffruticosae, is a common leaf disease on the ornamental peony, which posed a great threat on the flower buds in the current year and the flowering quality in the next year. However, there was only one fungicide registered for the control of the disease, difenoconazole. In order to avoid the severe problem of pathogen resistance caused by long-term use of difenoconazole, it is necessary to screen more chemical fungicides for the prevention and control of TPBS. In the paper, the biological activities of flutolanil, phenamacril, pyraclostrobin, and boscalid on mycelial growth, conidial germination, germ tube elongation and sporulation quantity of A. suffruticosae were determined, and field control efficacy were conducted to evaluate the preventive and therapeutic activities. Difenoconazole, was used as a control simultaneously. The results showed that pyraclostrobin had the strongest inhibitory effects on the conidial germination, mycelium growth, germ tube elongation and sporulation quantity, with the average EC50 of 0.0517, 0.5343, 0.0008 and 0.8068 µg/mL respectively. The inhibitory activity of flutolanil on the four developmental stages of A. suffruticosae was weaker than the other three fungicides. Compared with flutolanil, boscalid, the other succinate dehydrogenase inhibitors, had more srtong inhibitory effects on the mycelial growth and sporulation quantity, with the average EC50 of 3.8603 and 1.4760 µg/mL respectively. Phenamacril had a moderate inhibitory level, which had more inhibitory activity on conidial germination and germ tube elongation, with the average EC50 of 31.5349 and 5.2597 µg/mL. All of the four fungicides had no significant effects on the shape of spores and germ tubes. The control fungicide difenoconazole had the strongest inhibitory activity on mycelial growth, and the average EC50 was only 0.3297 µg/ml. However, its inhibitory activity on the other three growth stages was not high. In the field trials, pyraclostrobin had high control efficacy on TPBS even at low concentrations, reaching a minimum of 62.6293%, which was higher than that of difenoconazole. The other three fungicides had higher control efficacy at high concentrations, but decreased significantly at low concentrations. Considering the dosage and control efficacy, pyraclostrobin was the first choice for the control of TPBS. Pyraclostrobin is the preferred alternative fungicide of difenoconazole for the prevention and control of TPBS in production.

Design, synthesis, and anti-oomycete activity of 3-acyloxymaltol/ethyl maltol derivatives.

Twenty 3-acyloxymaltol/ethyl maltol derivatives (7a-j and 8a-j) were synthesized and evaluated in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of twenty derivatives, more than half of the compounds 7f, 7h, 8a-h and 8j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 22.23 mg/L), and the EC50 values of 18.66, 20.32, 12.80, 16.18, 10.59, 14.98, 16.80, 10.36, 15.32, 12.64, and 13.59 mg/L, respectively. Especially, compounds 8c and 8f exhibited the best anti-oomycete activity against P. capsici with EC50 values of 10.59 and 10.36 mg/L, respectively. Overall, hydroxyl group of maltol/ethyl maltol is important active modification site.

Chiral Ruthenium Nanozymes with Self-Cascade Reaction Driven the NO Generation Induced Macrophage M1 Polarization Realizing the Lung Cancer "Cocktail Therapy".

Macrophages as the main cause of cancer immunosuppression, how to effectively induce macrophage M1 polarization remain the major challenge in lung cancer therapy. Herein, inspired by endogenous reactions, a strategy is proposed to coactivate macrophage M1 polarization by reactive oxygen species (ROS) and nitric oxide (NO) with self-autocatalytic cascade reaction. To enhance the generation of NO and ROS, NO Precursor-Arginine as capping agents for inducing synthesis two kinds of chiral ruthenium nanozyme (D/L-Arginine@Ru). Under the properties of Ru nanozymes through synchronously mimicking the activity of oxidase and nitric oxide synthase (NOS), chiral Ru nanozyme can rapidly generate 1 O2 and O2 at first stage, and then catalyze Arginine to produce sufficient NO, thus enhance macrophage M1 polarization to reverse tumor immunosuppression. Moreover, combination the antitumor activity of 1 O2 , NO, the chiral Ru nanozymes realize the "cocktail therapy" by inducing tumor cell apoptosis as well as ferroptosis. In addition, the chirality influences the bioactivity of Ru nanozymes that L-Arginine@Ru shows the better therapeutic effect with stronger catalytic activity and natural homology. It is hoped the high performance of chiral Ru nanozyme with "cocktail therapy" is an effective therapeutic reagent and can provide a feasible treatment strategy for tumor catalytic therapy.

Zn(II) Coordination Polymer: Luminescence Sensing for Fe3+ Ion and Used as Metal Gel Particles Against Lung Cancer.

Presented here is a new Zn(II) coordination polymer, namely [Zn2(L)2(bpe)]n (1, H2L = 4-({2-[(4-carboxyphenoxy)methyl]phenyl}methoxy)benzoic acid, bpe = 1,2-bis(4-pyridinyl)ethane), which has been hydrothermally synthesized via the mixed-ligand strategy. Moreover, compound 1 emits intense luminescence at room temperature, and can be used as a luminescent sensor for the detection of Fe3+ in water solution with high selectivity and sensitivity. As representatives of natural polysaccharides, hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) have good biocompatibility. A new type of HA/CMCS gel particles loaded with Paclitaxel drug metal-organic framework was prepared by chemical synthesis method and its micromorphology was studied. Finally, biological experiments were conducted to evaluate the new system's effect on the activity of human lung cancer cells.

L-shaped association of serum α-Klotho and frailty among the middle-aged and older adults: results from NHANES 2007-2016.

BACKGROUND: Frailty is common and not limited to older age group. Serum α-Klotho works as a biomarker of anti-aging effect. However, there is limited research about the relationship between them in middle-aged and older people and controversy still exists. METHODS: Based on data from National Health and Nutrition Examination Survey (NHANES) 2007-2016, we constructed weighted logistic regression models and conducted sensitivity tests to investigate the correlation between frailty and α-Klotho among people aged 40 to 79. And then their relationship was visualized by Restricted Cubic Spline (RCS). Finally, the stratified analyses and interaction tests of covariables was presented in the forest plot. RESULTS: A total of 7052 individuals were involved in this study, with mean age of 62.76 ± 0.18 years and females accounting for 51.05%. 2554 of them were in "frailty". After adjustment for relevant covariables, weighted logistic regression models showed that the odds ratio and 95% confidence interval [ORs (95%CI)] of correlation between frailty and Natural Logarithm(ln)-transformed α- Klotho[ln(α-Klotho)] was 0.63 (0.50, 0.79); we then performed a sensitivity analysis and found that the results remained stable. In model 3, individuals in quartiles 2, 3, and 4 showed statistical differences compared with the lowest ln(α-Klotho) quartiles, ORs (95% CI) were 0.74 (0.59, 0.93), 0.72 (0.57, 0.91), 0.71 (0.57, 0.87), respectively. Subsequently, non-linear associations were exhibited by RCS (p<0.001). The turning point for α-Klotho and ln(α-Klotho) were 785.7(pg/ml) and 6.67, respectively. Finally, analysis of the relationship between different levels of ln(α-Klotho) and frailty in different populations revealed differences between groups. The results of the interaction test showed that no other covariables had significant interaction with serum α-Klotho in our study. CONCLUSION: The L-shaped and negative correlation was found between α-Klotho and frailty among people aged 40 to 79 in the NHANES from 2007 to 2016.

Analysis of clinical characteristics and prognosis of 68 patients with primary pulmonary choriocarcinoma.

BACKGROUND: Primary pulmonary choriocarcinoma (PPC) is a highly malignant intrapulmonary tumor with a notorious prognosis. Few clinical studies have been undertaken to investigate the clinical characteristics and prognosis of PPC. MATERIAL AND METHODS: We systematically conducted a retrospective analysis of patients with PPC in the literature published in PubMed and CNKI databases until March 31, 2022. The primary outcome was all-cause mortality. Survival curves were depicted using the Kaplan‒Meier method and compared using the stratified log-rank test. A Cox proportional hazards model was used to estimate the prognostic factors. RESULTS: A total of 68 patients were included, which consisted of 32 females and 36 males, with an average age of (44.5 ± 16.8) years old, ranging from 19 to 77 years. The clinical characteristics were mostly cough (49.2%), dyspnea (22.2%), hemoptysis (39.7%) and chest pain (39.7%). Kaplan‒Meier analysis showed that sex, age, hemoptysis, metastasis and treatment combining surgery with chemotherapy had a significant effect on survival. There were no effects on other outcomes. Furthermore, univariate and multivariable Cox regression analyses showed that the impact of the treatment combining surgery with chemotherapy on OS showed independent prognostic significance. CONCLUSION: PPC is a rare disease that lacks specific clinical features. Early diagnosis with optimal management is a significant goal. Surgery followed by adjuvant chemotherapy may be the best treatment for PPC.

Circulating inflammatory cytokines and risk of idiopathic pulmonary fibrosis: a Mendelian randomization study.

BACKGROUND: The previous epidemiological and experimental evidence has implied the linkage between chronic inflammation to idiopathic pulmonary fibrosis (IPF). However, it was still unclear whether there were casual associations between circulating inflammatory cytokines and IPF development. The objective of present study was to examine whether altered genetically predicted concentration of circulating cytokines were associated with IPF development using a two-sample Mendelian randomization (MR) analysis. MATERIALS AND METHODS: The causal effects of 23 circulating inflammatory cytokines were evaluated on IPF using MR analysis. The primary approach of MR analysis was the inverse variance-weighted (IVW) method. The sensitivity analyses were conducted by simple median, weighted median, penalized weighted median and MR-Egger regression methods. RESULTS: The present MR study found suggestive evidence that a higher circulating IL-14 level was associated with an increased risk of IPF (random effects IVW method: odds ratio: 1.001, 95% confidence interval: 1.000-1.001, P = 0.026). The sensitivity analysis yielded directionally similar results for IL-14. There was no significant association found between other circulating inflammatory cytokines and IPF. CONCLUSION: The high level of IL14 predicted by genes had a casual relationship with the increased risk of IPF. This finding provided epidemiological evidence for drug therapy targeting inflammatory factors in the prevention and treatment of IPF. It's warranted further exploration to validate the clinical significance of IL14 associated with developmental risk of IPF.

Assessment of reproductive toxicity in adult zebrafish (Danio rerio) following sublethal exposure to penthiopyrad.

Penthiopyrad (PO), a succinate dehydrogenase inhibitor (SDHI) fungicide, poses a potential risk to fish. Here, we investigated the adverse effects of PO on endocrine regulation and reproductive capacity in zebrafish during a 21-d sublethal exposure to PO concentrations ranging from 0.02 to 2.00 mg/L. Following exposure to PO (0.20 and 2.00 mg/L), female-specific effects including follicle necrosis, structural disturbance of the yolk follicle, fusion of cortical follicles appeared in ovarian tissue of adult females, which led to a significant reduction in fertility. Correspondingly, 0.20 and 2.00 mg/L PO led to a marked reduction in the GSI values of females, and 2.00 mg/L PO caused a 31% decline in the proportion of perinucleolar oocytes (PCO) in oocytes. In addition, testosterone (T) level was obviously suppressed and 17ß-estradiol (E2) level was increased in females after exposure to 2.00 mg/L PO. Male zebrafish treated with 0.20 and 2.00 mg/L of PO exhibited significant interstitial enlargement, edema in the testes, and reduced diameter of seminiferous tubules, along with a thinner basement membrane. The effects of PO on males were associated with significant increase in E2 level, suggesting that PO has an estrogenic effect on male fish. Greater E2 levels in serum were further supported by increased transcription levels of genes linked to the hypothalamic-pituitary-gonad-liver (HPGL) axis. Notably, transcription levels of cyp19a, er2b, era, and cyp19b was remarkably increased, exhibiting a clear link with variations in E2 levels. Overall, the present study demonstrates that PO induces reproductive impairment in zebrafish by promoting steroidogenesis.

Resistance risk assessment of Fusarium pseudograminearum from wheat to prothioconazole.

Fusarium crown rot (FCR), primarily caused by Fusarium pseudograminearum, poses significant threats to cereal crops worldwide. Prothioconazole is a demethylation inhibitor (DMI) fungicide used to control FCR. However, the risk of resistance in F. pseudograminearum to prothioconazole has not yet been evaluated. In this study, the sensitivity of a total of 255 F. pseudograminearum strains obtained from Henan Province, China to prothioconazole were determined by the mycelial growth inhibition. The results showed that the effective concentration to 50% growth inhibition (EC50) of these strains ranged from 0.4228 µg/mL to 2.5284 µg/mL, with a mean EC50 value of 1.0692 ± 0.4527 µg/mL (mean ± SD). Thirty prothioconazole-resistant mutants were obtained out of six selected sensitive parental strains by means of fungicide taming. The resistant mutants exhibited defects in vegetative growth, conidia production, and pathogenicity on wheat seedlings compared to their parental strains. Under ion, cell wall, and temperature stress conditions but not osmotic stress, all the mutants exhibited decreased growth rates compared with their parental strains, which was consistent with the control treatment. Cross-resistance test showed that there was a cross-resistance relationship between prothioconazole and four DMI fungicides, including prochloraz, metconazole, tebuconazole and hexaconazole, but no cross-resistance was observed between prothioconazole and carbendazim, phenamacril, fludioxonil, or azoxystrobin. Although no site mutation occurred on Cyp51a and Cyp51b genes, the constitutive expression level of the Cyp51a gene was significantly increased in all mutants. After being treated with prothioconazole, the Cyp51a and Cyp51b genes were significantly increased in both the resistant mutants and their parents. These results suggested that the resistance to prothioconazole of the mutants may be attributed to the changes of the relative expression level of Cyp51a and Cyp51b genes. Taken together, these results could provide a theoretical basis for the scientific use of prothioconazole in the field and fungicide resistance management strategies.

Synthesis, Anti-Oomycete and Anti-fungal Activities of Novel Cinchona Alkaloid Derivatives Containing Sulfonate Moiety.

Using cinchona alkaloid as the lead compound, twenty-four cinchona alkaloid sulfonate derivatives (1 a-l, 2 a-c, 3 a-c, 4 a-c, and 5 a-c) were designed and prepared by modifying their C9 position, and structurally confirmed by 1 H-NMR, 13 C-NMR, HR-MS and melting points. Moreover, the stereochemical configurations of compounds 1 f and 1 l were unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we determined the anti-oomycete and anti-fungal activities of these target compounds against Phytophthora capsici and Fusarium graminearum in vitro. The results showed that two compounds 4 b and 4 c exhibited prominent anti-oomycete activity, and the median effective concentration (EC50 ) values of 4 b and 4 c against P. capsici were 22.55 and 16.32 mg/L, respectively. This study suggested that when the C9 position of cinchona alkaloid sulfonate derivatives is in the S configuration and the 6'-position methoxy group is not present, the anti-oomycete activity is superior. In addition, five compounds 1 e, 1 f, 1 k, 3 c and 4 c displayed significant anti-fungal activity, with EC50 values of 43.64, 45.07, 80.18, 48.58 and 41.88 mg/L against F. graminearum, respectively. This result indicates that only when a specific substituent is introduced into the structural framework of the target compound, the corresponding compound exhibits significant inhibitory activity against fungi.

Impact of Phenamacril on the Growth and Development of Fusarium pseudograminearum and Control of Crown Rot of Wheat.

Fusarium pseudograminearum is the dominant pathogen causing Fusarium crown rot (FCR) of wheat. Phenamacril is a 2-cyanoacrylate fungicide, having a control effect on diseases caused by Fusarium spp. The objective of this study was to investigate the inhibitory effect of phenamacril on F. pseudograminearum and its control efficacy against FCR. The results showed that phenamacril had a strong inhibitory effect on the mycelial growth of F. pseudograminearum, EC50 values of phenamacril to 63 tested strains were in the range of 0.0998 to 0.5672 µg/ml, and the average EC50 value was 0.3403 ± 0.0872 µg/ml and could be used as the baseline sensitivity of F. pseudograminearum to phenamacril. Phenamacril reduced the germination rate of conidia of F. pseudograminearum, and the EC50 value was 5.0273 to 26.4814 µg/ml. In addition, we found that phenamacril had a teratogenic effect on conidia and blastotubules, which increased the ratio of conidial germination from the middle cells and showed high efficacy on the sporulation quantity of F. pseudograminearum with an EC50 value in the range of 0.0770 to 0.1064 µg/ml. There was no significant correlation between the sensitivity of F. pseudograminearum to phenamacril and its sensitivity to fludioxonil, carbendazim, tebuconazole, and kresoxim-methyl. In vitro and greenhouse assays showed that the treatment with 0.125 µl of active ingredient per gram recorded the best control effect on wheat crown rot, reaching 87.8 and 77.3%, respectively. In two experimental sites in Luoyang, phenamacril also had great control effect against FCR, reaching 83.9%. It was proven that phenamacril has a superior control effect against FCR. This study has laid a foundation for the study of the mechanism of action of phenamacril against F. pseudograminearum and provided a theoretical basis for the application of phenamacril to control FCR.

Comparison of Prognostic Scores for Patients with COVID-19 Presenting with Dyspnea in the Emergency Department.

BACKGROUND: Easy-to-use bedside risk assessment is crucial for patients with COVID-19 in the overcrowded emergency department (ED). OBJECTIVE: The aim of this study was to explore the prognostic ability of ratio of percutaneous oxygen saturation (SpO2) to fraction of inspired oxygen (FiO2) (S/F); ratio of SpO2/FiO2 to respiratory rate (ROX); National Early Warning Score (NEWS); quick Sequential Organ Failure Assessment (qSOFA); and confusion, respiratory rate, blood pressure, and age ≥ 65 years (CRB-65) in patients with COVID-19 presenting with dyspnea to the ED. METHODS: In this retrospective observational study, clinical and demographic details of patients with COVID-19 were obtained at ED admission. S/F, ROX, NEWS, CRB-65, and qSOFA scores were calculated at the time of ED arrival. Accuracy of these five indices to predict the need for invasive mechanical ventilation (IMV) within 48 h, intensive care unit (ICU) admission, and early (7-day) mortality were determined using receiver operating characteristic curves. RESULTS: A total of 375 patients were included in this study. Fifty patients (13.3%) required IMV within 48 h and 58 patients (15.5%) were transferred to the ICU. Seven-day mortality was 6.7% and 28-day mortality was 18.1%. Among all five scores determined from patient data on ED admission, ROX, S/F, and NEWS presented greater discriminatory performance than CRB-65 and qSOFA in predicting IMV within 48 h, ICU admission, and early mortality. CONCLUSIONS: Emergency physicians can effectively use S/F, ROX, and NEWS scores for rapid risk stratification of patients with COVID-19 infection. Moreover, from the perspective of simplicity and ease of calculation, we recommend the use of the S/F ratio.

Using biological information to analyze potential miRNA-mRNA regulatory networks in the plasma of patients with non-small cell lung cancer.

BACKGROUND: Lung cancer is the most common malignant tumor, and it has a high mortality rate. However, the study of miRNA-mRNA regulatory networks in the plasma of patients with non-small cell lung cancer (NSCLC) is insufficient. Therefore, this study explored the differential expression of mRNA and miRNA in the plasma of NSCLC patients. METHODS: The Gene Expression Omnibus (GEO) database was used to download microarray datasets, and the differentially expressed miRNAs (DEMs) were analyzed. We predicted transcription factors and target genes of the DEMs by using FunRich software and the TargetScanHuman database, respectively. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for GO annotation and KEGG enrichment analysis of downstream target genes. We constructed protein-protein interaction (PPI) and DEM-hub gene networks using the STRING database and Cytoscape software. The GSE20189 dataset was used to screen out the key hub gene. Using The Cancer Genome Atlas (TCGA) and UALCAN databases to analyze the expression and prognosis of the key hub gene and DEMs. Then, GSE17681 and GSE137140 datasets were used to validate DEMs expression. Finally, the receiver operating characteristic (ROC) curve was used to verify the ability of the DEMs to distinguish lung cancer patients from healthy patients. RESULTS: Four upregulated candidate DEMs (hsa-miR199a-5p, hsa-miR-186-5p, hsa-miR-328-3p, and hsa-let-7d-3p) were screened from 3 databases, and 6 upstream transcription factors and 2253 downstream target genes were predicted. These genes were mainly enriched in cancer pathways and PI3k-Akt pathways. Among the top 30 hub genes, the expression of KLHL3 was consistent with the GSE20189 dataset. Except for let-7d-3p, the expression of other DEMs and KLHL3 in tissues were consistent with those in plasma. LUSC patients with high let-7d-3p expression had poor overall survival rates (OS). External validation demonstrated that the expression of hsa-miR-199a-5p and hsa-miR-186-5p in peripheral blood of NSCLC patients was higher than the healthy controls. The ROC curve confirmed that the DEMs could better distinguish lung cancer patients from healthy people. CONCLUSION: The results showed that miR-199a-5p and miR-186-5p may be noninvasive diagnostic biomarkers for NSCLC patients. MiR-199a-5p-KLHL3 may be involved in the occurrence and development of NSCLC.

Synthesis of Hinokitiol Sulfonate Derivatives and Their Anti-Oomycete and Nematicidal Activities.

In order to explore novel natural product-based anti-oomycete and nematicidal agents, sixteen unreported 2-sulfonyloxyhinokitiol derivatives were prepared using the principle of active splicing, and structurally confirmed by proton nuclear magnetic resonance (1 H-NMR), carbon-13 nuclear magnetic resonance (13 C-NMR), high-resolution mass spectrometry (HRMS), and melting point. Moreover, we evaluated the title compounds as anti-oomycete and nematicidal agents against two serious agricultural pests of Phytophthora capsici and Meloidogyne incongnita. Among the sixteen hinokitiol esters tested: (1) Compounds 3a and 3m exhibited the most potent anti-oomycete activity compared to zoxamide against P. capsici, and the median effective concentration (EC50 ) values of 3a, 3m, and zoxamide were 18.64, 21.11, and 23.15 mg/L, respectively; Further studies showed that the existence of seven membered ring and carbonyl group was the necessary condition for the high anti-oomycete activity of hinokitiol. (2) Compounds 3n and 3p exhibited more promising nematicidal activity than hinokitiol, and the median lethal concentration (LC50 ) values of 3n, 3p and 1 against M. incongnita were 0.2111, 0.2079, and 0.3933 mg/L, respectively. This result will pave the way for further modification of hinokitiol to develop potential new fungicides and nematicides.

Synthesis and Anti-Oomycete Preliminary Mechanism of Sulfonate Derivatives of Ethyl Maltol.

To discover novel molecules with unique mechanism against plant pathogenic oomycetes, sixteen new sulfonate derivatives of ethyl maltol (3a-p) were synthesized by structural modification of 2-ethyl-3-hydroxy-4H-pyran-4-one, and their anti-oomycete activity against a serious agricultural disease, Phytophthora capsici Leonian was determined in this study. Among all tested compounds, derivatives 3e, 3m and 3p exhibited the most potent anti-oomycete activity against P. capsici with EC50 values of 19.40, 21.04 and 31.10 mg/L, respectively; especially 3e and 3m showed the best promising and pronounced anti-oomycete activity than zoxamide (EC50 =26.87 mg/L). The results further proved that 4-tert-butylphenylsulfonyl group, 3-nitro-4-chlorophenylsulfonyl group and 8-quinolinesulfonyl group introduced at the hydroxy position of ethyl maltol or maltol were necessary for obtaining the most potent compounds. Further mechanism studies of P. capsici treated with 3e demonstrated that this compound can affect the growth of mycelia by disrupting the integrity of the membrane, and the higher the concentration of the compound is, the greater the degree of membrane integrity damage. These important results will pave the way for further modification of ethyl maltol to develop potential new fungicides.

Synthesis and Anti-Oomycete Activity of Sulfonate Derivatives of Fenjuntong.

In order to discover highly active fungicides, sixteen novel sulfonate derivatives of Fenjuntong were synthesized by structural modification of 2'-hydroxybutyrophenone, and their anti-oomycete activity against Phytophthora capsici Leonian was determined in this study. Among all tested compounds, compound 3b displayed more significant anti-oomycete activity than the precursor Fenjuntong against P. capsici, and the EC50 values of 3b and Fenjuntong were 84.50 and 517.25 mg/L, respectively. By comparing the anti-oomycete activity of compounds 3a-p, I-a-p, and II-a-p, the following conclusions were drawn: (1) Hydroxy group is well tolerated, and sulfonylation of hydroxy group enhances its anti-oomycete activity. (2) The proper length of the ketone carbonyl chain is very important for their anti-oomycete activity. (3) The presence of a site methoxy group in the structural skeleton is closely related to the anti-oomycete activity. These important results will pave the way for further modification of Fenjuntong to develop potential new fungicides.