Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor.

Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.

Unveiling the hidden role of disulfidptosis in kidney renal clear cell carcinoma: a prognostic signature for personalized treatment.

The role of disulfidptosis in kidney renal clear cell carcinoma (KIRC) remains unknown. This study investigated disulfidptosis-related biomarkers for KIRC prognosis prediction and individualized treatment. KIRC patients were clustered by disulfidptosis profiles. Differential expression analysis, survival models, and machine learning were used to construct the disulfidptosis-related prognostic signature (DRPS). Characterizations of the tumor immune microenvironment, genetic drivers, drug sensitivity, and immunotherapy response were explored according to the DRPS risk stratification. Markers included in the signature were validated using single-cell, spatial transcriptomics, quantitative RT-qPCR, and immunohistochemistry. In the discovery cohort, we unveiled two clusters of KIRC patients that differed significantly in disulfidptosis regulator expressions and overall survival (OS). After multiple feature selection steps, a DRPS prognostic model with four features (CHAC1, COL7A1, FOXM1, SHOX2) was constructed and validated. Combined with clinical factors, the model demonstrated robust performance in the discovery and external validation cohorts (5-year AUC = 0.793 and 0.846, respectively). KIRC patients with high-risk scores are characterized by inferior OS, less tumor purity, and increased infiltrations of fibroblasts, M1 macrophages, and B cells. High-risk patients also have higher frequencies of BAP1 and AHNAK2 mutation. Besides, the correlation between the DRPS score and the chemotherapy-response signature indicated the potential effect of Gefitinib for high-risk patients. Among the signature genes, FOXM1 is highly expressed in cycling tumor cells and exhibits spatial aggregation, while others are expressed sparsely within tumor samples. The DRPS model enables improved clinical management and personalized KIRC therapy. The identified biomarkers and immune characteristics offer new mechanistic insight into disulfidptosis in KIRC.

Multimodal neuroimaging exploration of the mechanisms of sleep quality deterioration after SARS-CoV-2 Omicron infection.

BACKGROUND: To evaluate the neurological alterations induced by Omicron infection, to compare brain changes in chronic insomnia with those in exacerbated chronic insomnia in Omicron patients, and to examine individuals without insomnia alongside those with new-onset insomnia. METHODS: In this study, a total of 135 participants were recruited between January 11 and May 4, 2023, including 26 patients with chronic insomnia without exacerbation, 24 patients with chronic insomnia with exacerbation, 40 patients with no sleep disorder, and 30 patients with new-onset insomnia after infection with Omicron (a total of 120 participants with different sleep statuses after infection), as well as 15 healthy controls who were never infected with Omicron. Neuropsychiatric data, clinical symptoms, and multimodal magnetic resonance imaging data were collected. The gray matter thickness and T1, T2, proton density, and perivascular space values were analyzed. Associations between changes in multimodal magnetic resonance imaging findings and neuropsychiatric data were evaluated with correlation analyses. RESULTS: Compared with healthy controls, gray matter thickness changes were similar in the patients who have and do not have a history of chronic insomnia groups after infection, including an increase in cortical thickness near the parietal lobe and a reduction in cortical thickness in the frontal, occipital, and medial brain regions. Analyses showed a reduced gray matter thickness in patients with chronic insomnia compared with those with an aggravation of chronic insomnia post-Omicron infection, and a reduction was found in the right medial orbitofrontal region (mean [SD], 2.38 [0.17] vs. 2.67 [0.29] mm; P < 0.001). In the subgroups of Omicron patients experiencing sleep deterioration, patients with a history of chronic insomnia whose insomnia symptoms worsened after infection displayed heightened medial orbitofrontal cortical thickness and increased proton density values in various brain regions. Conversely, patients with good sleep quality who experienced a new onset of insomnia after infection exhibited reduced cortical thickness in pericalcarine regions and decreased proton density values. In new-onset insomnia patients post-Omicron infection, the thickness in the right pericalcarine was negatively correlated with the Self-rating Anxiety Scale (r = - 0.538, P = 0.002, PFDR = 0.004) and Self-rating Depression Scale (r = - 0.406, P = 0.026, PFDR = 0.026) scores. CONCLUSIONS: These findings help us understand the pathophysiological mechanisms involved when Omicron invades the nervous system and induces various forms of insomnia after infection. In the future, we will continue to pay attention to the dynamic changes in the brain related to insomnia caused by Omicron infection.

Assessment of chronic allograft injury in renal transplantation using diffusional kurtosis imaging.

BACKGROUND: Chronic allograft injury (CAI) is a significant reason for which many grafts were lost. The study was conducted to assess the usefulness of diffusional kurtosis imaging (DKI) technology in the non-invasive assessment of CAI. METHODS: Between February 2019 and October 2019, 110 renal allograft recipients were included to analyze relevant DKI parameters. According to estimated glomerular filtration rate (eGFR) (mL/min/ 1.73 m2) level, they were divided to 3 groups: group 1, eGFR ≥ 60 (n = 10); group 2, eGFR 30-60 (n = 69); group 3, eGFR < 30 (n = 31). We performed DKI on a clinical 3T magnetic resonance imaging system. We measured the area of interest to determine the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) of the renal cortex and medulla. We performed a Pearson correlation analysis to determine the relationship between eGFR and the DKI parameters. We used the receiver operating characteristic curve to estimate the predicted values of DKI parameters in the CAI evaluation. We randomly selected five patients from group 2 for biopsy to confirm CAI. RESULTS: With the increase of creatinine, ADC, and MD of the cortex and medulla decrease, MK of the cortex and medulla gradually increase. Among the three different eGFR groups, significant differences were found in cortical and medullary MK (P = 0.039, P < 0.001, P < 0.001, respectively). Cortical and medullary ADC and MD are negatively correlated with eGFR (r = - 0.49, - 0.44, - 0.57, - 0.57, respectively; P < 0.001), while cortical and medullary MK are positively correlated with eGFR (r = 0.42, 0.38; P < 0.001). When 0.491 was set as the cutoff value, MK's CAI assessment showed 87% sensitivity and 100% specificity. All five patients randomly selected for biopsy from the second group confirmed glomerulosclerosis and tubular atrophy/interstitial fibrosis. CONCLUSION: The DKI technique is related to eGFR as allograft injury progresses and is expected to become a potential non-invasive method for evaluating CAI.

Butyric acid normalizes hyperglycemia caused by the tacrolimus-induced gut microbiota.

Approximately 33.6% of nondiabetic solid organ transplant recipients who received tacrolimus developed hyperglycemia. Whether the tacrolimus-induced gut microbiota is involved in the regulation of hyperglycemia has not been reported. Hyperglycemia was observed in a tacrolimus-treated mouse model, with reduction in taxonomic abundance of butyrate-producing bacteria and decreased butyric acid concentration in the cecum. This tacrolimus-induced glucose metabolic disorder was caused by the gut microbiota, as confirmed by a broad-spectrum antibiotic model. Furthermore, oral supplementation with butyrate, whether for remedy or prevention, significantly increased the butyric acid content in the cecum and arrested hyperglycemia through the regulation of glucose-regulating hormones, including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin, in serum. The butyrate-G-protein-coupled receptor 43-GLP-1 pathway in the intestinal crypts may be involved in the pathogenesis of normalization of hyperglycemia caused by the tacrolimus. Therefore, tacrolimus affects glucose metabolism through the butyrate-associated GLP-1 pathway in the gut, and oral supplementation with butyrate provides new insights for the prevention and treatment of tacrolimus-induced hyperglycemia in transplant recipients.

Identification of a three-long noncoding RNA prognostic model involved competitive endogenous RNA in kidney renal clear cell carcinoma.

BACKGROUND: Long noncoding RNA (lncRNA) is generally identified as competing endogenous RNA (ceRNA) that plays a vital role in the pathogenesis of kidney renal clear cell carcinoma (KIRC), the most common subtype of renal cell carcinoma with poor prognosis and unclear pathogenesis. This study established a novel ceRNA network and thus identified a three-lncRNA prognostic model in KIRC patients. METHODS: Differentially expressed genes (DEGs) were screened out from The Cancer Genome Atlas (TCGA) database. The lncATLAS was applied to determine the differentially expressed lncRNAs (DElncRNAs) of the cytoplasm. The miRcode, miRDB, miRTarBase, and TargetScan databases were utilized to predict the interactions of DElncRNAs, DEmiRNAs, and DEmRNAs. Cytoscape was used to construct the ceRNA network. Then, a lncRNA prognostic model (LPM) was constructed based on ceRNA-related lncRNA that was significantly related to overall survival (OS), and its predictive ability was evaluated. Moreover, an LPM-based nomogram model was constructed. The significantly different expression of genes in the LPM was validated in an independent clinical cohort (N = 21) by quantitative RT-PCR. RESULTS: A novel ceRNA regulatory network, including 73 lncRNAs, 8 miRNAs, and 21 mRNAs was constructed. Functional enrichment analysis indicated that integral components of membrane and PI3K-Akt signaling pathway represented the most significant GO terms and pathway, respectively. The LPM established based on three lncRNAs (MIAT, LINC00460, and LINC00443) of great prognostic value from the ceRNA network was proven to be independent of conventional clinical parameters to differentiate patients with low or high risk of poor survival, with the AUC of 1-, 5- and 10-year OS were 0.723, 0.714 and 0.826 respectively. Furthermore, the nomogram showed a better predictive value in KIRC patients than individual prognostic parameters. The expression of MIAT and LINC00460 was significantly upregulated in the KIRC samples, while the expression of LINC00443 was significantly downregulated compared with the adjacent normal samples in the clinical cohort, TCGA, and GTEx. CONCLUSION: This LPM based on three-lncRNA could serve as an independent prognostic factor with a tremendous predictive ability for KIRC patients, and the identified novel ceRNA network may provide insight into the prognostic biomarkers and therapeutic targets of KIRC.

Ovule Development and in Planta Transformation of Paphiopedilum Maudiae by Agrobacterium-Mediated Ovary-Injection.

In this paper, the development of the Paphiopedilum Maudiae embryo sac at different developmental stages after pollination was assessed by confocal laser scanning microscopy. The mature seeds of P. Maudiae consisted of an exopleura and a spherical embryo, but without an endosperm, while the inner integument cells were absorbed by the developing embryo. The P. Maudiae embryo sac exhibited an Allium type of development. The time taken for the embryo to develop to a mature sac was 45-50 days after pollination (DAP) and most mature embryo sacs had completed fertilization and formed zygotes by about 50-54 DAP. In planta transformation was achieved by injection of the ovaries by Agrobacterium, resulting in 38 protocorms or seedlings after several rounds of hygromycin selection, corresponding to 2, 7, 5, 1, 3, 4, 9, and 7 plantlets from Agrobacterium-mediated ovary-injection at 30, 35, 42, 43, 45, 48, 50, and 53 DAP, respectively. Transformation efficiency was highest at 50 DAP (2.54%), followed by 2.48% at 53 DAP and 2.45% at 48 DAP. Four randomly selected hygromycin-resistant plants were GUS-positive after PCR analysis. Semi-quantitative PCR and quantitative real-time PCR analysis revealed the expression of the hpt gene in the leaves of eight hygromycin-resistant seedlings following Agrobacterium-mediated ovary-injection at 30, 35, 42, 43, 45, 48, 50, and 53 DAP, while hpt expression was not detected in the control. The best time to inject P. Maudiae ovaries in planta with Agrobacterium is 48-53 DAP, which corresponds to the period of fertilization. This protocol represents the first genetic transformation protocol for any Paphiopedilum species and will allow for expanded molecular breeding programs to introduce useful and interesting genes that can expand its ornamental and horticulturally important characteristics.

Kidney transplant outcomes in HIV-positive patients: a systematic review and meta-analysis.

BACKGROUND: Kidney transplantation is now a viable alternative to dialysis in HIV-positive patients who achieve good immunovirological control with the currently available antiretroviral therapy regimens. This systematic review and meta-analysis investigate the published evidence of outcome and risk of kidney transplantation in HIV-positive patients following the PRISMA guidelines. METHODS: Searches of PubMed, the Cochrane Library and EMBASE identified 27 cohort studies and 1670 case series evaluating the survival of HIV-positive kidney transplant patients published between July 2003 and May 2018. The regimens for induction, maintenance therapy and highly active antiretroviral therapy, acute rejection, patient and graft survival, CD4 count and infectious complications were recorded. We evaluated the patient survival and graft survival at 1 and 3 years respectively, acute rejection rate and also other infectious complications by using a random-effects analysis. RESULTS: At 1 year, patient survival was 0.97 (95% CI 0.95; 0.98), graft survival was 0.91 (95% CI 0.88; 0.94), acute rejection was 0.33 (95% CI 0.28; 0.38), and infectious complications was 0.41 (95% CI 0.34; 0.50), and at 3 years, patient survival was 0.94 (95% CI 0.90; 0.97) and graft survival was 0.81 (95% CI 0.74; 0.87). CONCLUSIONS: With careful selection and evaluation, kidney transplantation can be performed with good outcomes in HIV-positive patients.

Use of intravoxel incoherent motion imaging to monitor a rat kidney chronic allograft damage model.

BACKGROUND: Chronic allograft damage (CAD) is the leading cause of long-term graft dysfunction. A noninvasive method that can diagnose CAD early and monitor its development is needed. METHODS: Kidneys from Fisher rats were transplanted into Lewis rats to establish a CAD model (n = 20). The control group underwent syngeneic kidney transplantation (n = 20). The serum creatinine of the rats was monitored. At 4, 12, and 20 weeks after modeling, a magnetic resonance imaging (MRI) examination was performed. The apparent diffusion coefficient (ADC), pseudo diffusion coefficient (D*), true diffusion coefficient (D) and perfusion fraction (f) of the two groups were analyzed. Chronic allograft damage index (CADI) scoring was used to evaluate the transplanted kidney specimens. Immunohistochemistry was used to detect the expression of fibrosis markers in the transplanted kidney tissues and to analyze their correlations with all MRI parameters. RESULTS: The transplanted kidneys in the experimental group developed CAD changes before the appearance of elevated creatinine. The MRI parameters in the experimental group [ADC (1.460 ± 0.109 VS 2.095 ± 0.319, P < 0.001), D (1.435 ± 0.102 VS 1.969 ± 0.305, P < 0.001), and f (26.532 ± 2.136 VS 32.255 ± 4.013, P < 0.001)] decreased, and D* (20.950 ± 2.273 VS 21.415 ± 1.598, P = 0.131) was not significantly different from those in the control group. ADC, D and f were negatively correlated with the CADI and the α-SMA and vimentin expression levels. CONCLUSION: Intravoxel incoherent motion (IVIM) imaging could detect CAD earlier than creatinine and reflect the degree of fibrosis in grafts quantitatively.

Residues, dissipation kinetics, and dietary intake risk assessment of two fungicides in grape and soil.

The residue behavior and dietary intake risk of two fungicides (dimethomorph and pyraclostrobin) in grape (Vitis vinifera L.) were investigated from field trials. A modified quick, easy, cheap, effective, rugged, and safe method for simultaneously determining dimethomorph and pyraclostrobin residues in grape and soil was established using high performance liquid chromatography-tandem mass spectrometry. The average recoveries of dimethomorph and pyraclostrobin in the grape and soil matrices varied from 76.88% to 97.05%, with relative standard deviations of 1.73%-10.38%. The degradation half-lives of dimethomorph and pyraclostrobin were 7.3-12.0 days and 3.6-7.0 days in grape and soil, respectively. The terminal residues of dimethomorph and pyraclostrobin in the two matrices were 0.05-0.87 mg/kg. For dietary exposure risk assessments, all of the hazard quotient and hazard quotient index values were below 100%, which indicated that the suspending agents of dimethomorph and pyraclostrobin were sprayed on grape at the recommended dosages with no significant potential risks for Chinese consumers. This study provides a reference for analytically evaluating residual degradation behavior and dietary intake risk of two fungicides under field conditions.

Simultaneous determination and method validation of clethodim and its metabolites clethodim sulfoxide and clethodim sulfone in tobacco by LC-MS/MS.

A simple method was developed and validated for the simultaneous determination of clethodim, clethodim sulfoxide, and clethodim sulfone in soil and tobacco by liquid chromatography with tandem mass spectrometry. The three target compounds were extracted from tobacco and soil with acetonitrile, and the extracts were purified using octadecyl silane. The proposed method showed satisfactory linearity (R2 ≥ 0.9973) for the target compounds. The limits of detection and quantitation of the three analytes in all matrices were 0.024-0.06 and 0.08-0.2 mg/kg, respectively. The recovery was tested in blank soil and tobacco leaf samples and calculated to be 74.8-104.4% with relative standard deviations of 1.9-12.1%. The developed method was successfully applied to the analysis of residues of clethodim, clethodim sulfoxide and clethodim sulfone in real soil and tobacco samples. The results indicated that the developed method can meet the requirements for the analysis of trace amounts of all three analytes in soil and tobacco.

Simultaneous determination and method validation of difenoconazole, propiconazole and pyraclostrobin in pepper and soil by LC-MS/MS in field trial samples from three provinces, China.

A liquid chromatography-electrospray ionization tandem mass spectrometry method was developed for simple and accurate detection of the fungicides difenoconazole, propiconazole and pyraclostrobin in peppers and soil. Three fungicides residues were extracted from samples by acetonitrile and cleaned up by dispersive solid-phase extraction before instrumental analysis. The accuracy and precision of the method were evaluated by conducting an intra- and inter-day recovery experiment. The limits of quantification and detection of difenoconazole, propiconazole and pyraclostrobin in pepper and soil were 0.005 and 0.0015 mg/kg, respectively. The recoveries were investigated by spiking pepper and soil at three levels, and were found to be in the ranges 79.62-103.15% for difenoconazole, 85.94-103.35% for propiconazole and 80.14-97.69% for pyraclostrobin, with relative standard deviations <6.5%. Field experiments were conducted in three locations in China. The half-lives of difenoconazole, propiconazole and pyraclostrobin were 5.3-11.5 days in peppers and 6.1-32.5 days in soil. At harvest, pepper samples were found to contain difenoconazole, propiconazole and pyraclostrobin well below the maximum residue limits of European Union at the interval of 21 days after last application following the recommended dosage.

Label-free quantitative proteomics analysis of Cytosinpeptidemycin responses in southern rice black-streaked dwarf virus-infected rice.

Southern rice black-streaked dwarf virus (SRBSDV), a genus Fijivirus of the family Reoviridae, could result in the significant crop losses because being short of an effective controlling measures. Cytosinpeptidemycin, a microbial pesticides developed by China, displayed a wide antiviral activity against many plant viruses. However, its underlying mechanism remains unclear. In this study, a total of 2321 proteins were identified using label-free proteomics technology. Compared with the treatment of SRBSDV-infected rice, 84 and 207 proteins were detected to be up-regulated and only presented in treatment group of SDBSDV-infected rice pre-treated by Cytosinpeptidemycin, which were partially enriched to stress and defense response, such as pathogenesis-related protein 5 (PR-5), pathogenesis-related protein 10 (PR-10) and heat shock protein (Hsp protein). Meanwhile, the real-time quantitative PCR (RT-qPCR) showed that Cytosinpeptidemycin could also up-regulate some resistance genes, and these results indicated a similar trends with the data of the label-free proteomics. Moreover, Cytosinpeptidemycin could enhance the defense enzymatic activities of peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT). These data offer a more comprehensive view about the response of SRBSDV-infected rice triggered by Cytosinpeptidemycin in the level of the proteome, mRNA and enzymatic activity.

Characterization and antifungal activity against Pestalotiopsis of a fusaricidin-type compound produced by Paenibacillus polymyxa Y-1.

Dendrobium nobile (D. nobile) is a valuable Chinese herbal medicine. The discovery of microbial resources from has provided a wealth of raw materials. Stalk rot, which is caused by Pestalotiopsis, is one of the most serious diseases of D nobile and has resulted in serious losses in production. However, an effective method for the prevention and control of stalk rot remains lacking. In this study, we aimed to identify a biocontrol strain against Pestalotiopsis. We isolated Paenibacillus polymyxa Y-1, an endophytic bacterium, from the stem of D. nobile. Three pairs of active metabolites isolated from this bacterium were identified as fusaricidin compounds. We then investigated the mechanism of fusaricidin compounds on Pestalotiopsis via proteomics. Proteomics data showed that the compounds mainly inhibit energy generation in the respiratory chain and amino acid biosynthesis of Pestalotiopsis.

Simultaneous determination and risk assessment of metalaxyl and azoxystrobin in potato by liquid chromatography with tandem mass spectrometry.

A liquid chromatography with tandem mass spectrometry method was developed and validated to simultaneously determine metalaxyl and azoxystrobin in soil, potato, and potato foliage samples. The samples were extracted by 20 mL of acetonitrile and purified with dispersive solid-phase extraction using octadecyl silane as sorbent. The method showed good linearity (determination coefficients ≥ 0.9926) for metalaxyl (2.5-500 ng/mL) and azoxystrobin (5-1000 ng/mL). The limits of detection and quantification for both fungicides were 1.5-20 µg/kg. The average recoveries in soil, potato, and potato foliage were 83.07-92.87% for metalaxyl and 82.71-98.53% for azoxystrobin. The intra- and inter-day relative standard deviations were all less than 9%. The method was successfully applied on the residual analysis of metalaxyl and azoxystrobin in field trial samples. The results showed that the concentrations of metalaxyl and azoxystrobin in potato samples collected from Guizhou and Hunan were below 50 and 100 µg/kg (maximum residue limit set by China), respectively, at 5 days after the last application. When following the recommended application manual, metalaxyl and azoxystrobin do not present health concerns to the population because the risk quotients are far below 100%. All the above data could help and promote the safe and proper use of metalaxyl and azoxystrobin in potato.

Synthesis, antiviral activity, and molecular docking study of trans-ferulic acid derivatives containing acylhydrazone moiety.

In this study, we report the synthesis and antiviral activity of trans-ferulic acid derivatives containing acylhydrazone moiety. Biological tests demonstrated that most target compounds showed potent antiviral activity against tobacco mosaic virus (TMV). Compound D4 showed remarkable inactivating activity with EC50 value of 36.59µg/mL, which was obviously superior to ribavirin (126.05µg/mL). Molecular docking results revealed that compound D4 exhibited the optimal combining capacity with five hydrogen bonds to different amino-acid residues of TMV coat protein (TMV-CP). Docking results were consistent with the inactivating activity of target compounds against TMV.

Synthesis and Antiviral Activity of Novel 1,4-Pentadien-3-one Derivatives Containing a 1,3,4-Thiadiazole Moiety.

1,4-Pentadien-3-one derivatives derived from curcumin possess excellent inhibitory activity against plant viruses. On the basis of this finding, a series of novel 1,4-pentadien-3-one derivatives containing a 1,3,4-thiadiazole moiety were designed and synthesized, and their structures confirmed by IR, ¹H-NMR, and 13C-NMR spectroscopy and elemental analysis. The antiviral activities of the title compounds were evaluated against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo. The assay results showed that most of compounds had remarkable antiviral activities against TMV and CMV, among which compounds 4b, 4h, 4i, 4k, 4o, and 4q exhibited good curative, protection, and inactivation activity against TMV. Compounds 4h, 4i, 4k, 4l, 4o, and 4q exhibited excellent protection activity against TMV, with EC50 values of 105.01, 254.77, 135.38, 297.40, 248.18, and 129.87 µg/mL, respectively, which were superior to that of ribavirin (457.25 µg/mL). In addition, preliminary SARs indicated that small electron-withdrawing groups on the aromatic ring were favorable for anti-TMV activity. This finding suggests that 1,4-pentadien-3-one derivatives containing a 1,3,4-thiadiazole moiety may be considered as potential lead structures for discovering new antiviral agents.

Risk assessment and monitoring of dinotefuran and its metabolites for Chinese consumption of apples.

Residues of dinotefuran and its metabolites, 1-methyl-3-(tetrahydro-3-furylmethyl)urea (UF) and 1-methyl-3-(tetrahydro-3-furylmethyl)guanidine (DN), in apple were investigated using a "QuEChERS" (quick, easy, cheap, effective, rugged, safe) pretreatment and liquid chromatography-tandem mass spectrometry. Limits of detection (LODs) and quantification (LOQs) of dinotefuran, UF, and DN in apples were 0.011-0.960 and 0.037-3.200 µg/kg, respectively. The average recoveries of dinotefuran, UF, and DN in apple ranged from 70.0 to 83.6% with relative standard deviations less than 13%. A formulation of 20% water-dispersible dinotefuran granules was sprayed at 1-1.5-fold the recommended dose 3-4 times on apple trees. Total terminal residues of dinotefuran in apple were less than 2 mg/kg, which is the maximum residue limit (MRL) set by Japan. When following the recommended application guidelines, dinotefuran is unlikely to present significant health concerns to the Chinese population because the risk quotient (RQ) is less than 100%. This work could provide guidance for the safe use of dinotefuran and serve as a reference for the establishment of a maximum residue limit of dinotefuran in apple in China.

Novel hydrazone derivatives containing pyridine amide moiety: Design, synthesis, and insecticidal activity.

A series of novel hydrazone derivatives containing pyridine amide moiety were designed, synthesized, and evaluated for their insecticidal activity. Bioassays indicated that some of the target compounds exhibited good insecticidal activities against Nilaparvata lugens (N. lugens), Plutella xylostella (P. xylostella), Mythimna separata (M. separata), Helicoverpa armigera (H. armigera), Pyrausta nubilalis (P. nubilalis), and Culex pipiens pallens (C. pipiens pallens). In particular, compound 5j revealed excellent insecticidal activity against C. pipiens pallens, with the 50% lethal concentration (LC50) and the 95% lethal concentration (LC95) values of 2.44 and 5.76 mg/L, respectively, which were similar to those of chlorpyrifos (3.26 and 6.98 mg/L, respectively), tebufenozide (1.22 and 2.49 mg/L, respectively), and RH-5849 (2.61 and 6.37 mg/L, respectively). These results indicated that hydrazone derivatives containing pyridine amide moiety could be developed as novel and promising insecticides.

Synthesis, antiviral activity, 3D-QSAR, and interaction mechanisms study of novel malonate derivatives containing quinazolin-4(3H)-one moiety.

A series of novel malonate derivatives containing quinazolin-4(3H)-one moiety were synthesized and evaluated for their antiviral activities against cucumber mosaic virus (CMV). Results indicated that the title compounds exhibited good antiviral activities. Notably, compounds g15, g16, g17, and g18 exhibited excellent curative activities in vivo against CMV, with 50% effective concentration (EC50) values of 208.36, 153.78, 181.47, and 164.72µg/mL, respectively, which were better than that of Ningnanmycin (256.35µg/mL) and Ribavirin (523.34µg/mL). Moreover, statistically valid three-dimensional quantitative structure-activity relationship (3D-QSAR) models with good correlation and predictive power were obtained with comparative molecular field analysis (CoMFA) steric and electrostatic fields (r(2)=0.990, q(2)=0.577) and comparative molecular similarity indices analysis (CoMSIA) with combined steric, electrostatic, hydrophobic and hydrogen bond acceptor fields (r(2)=0.977, q(2)=0.516), respectively. Based on those models, compound g25 was designed, synthesized, and showed better curative activity (146.30µg/mL) than that of compound g16. The interaction of between cucumber mosaic virus coat protein (CMV CP) and g25 with 1:1.83 ratio is typically spontaneous and exothermic with micromole binding affinity by isothermal titration calorimetry (ITC) and fluorescence spectroscopy investigation.