Design, Synthesis, Structure-Activity Relationship, and Three-Dimensional Quantitative Structure-Activity Relationship of Fusarium Acid Derivatives and Analogues as Potential Fungicides.

In research related to fungicides, the development of compounds from natural products with high antifungal activity has attracted considerable attention. Fusaric acid (FA), an alkaloid isolated from the metabolites of Fusarium oxysporum, is an important precursor for developing pharmacologically active herbicides. In our previous work, we reported that FA has a wide range of inhibitory activities against 14 plant pathogenic fungi. In particular, it exhibited excellent antifugal effects on Colletotrichum higginsianum (EC50 = 31.7 µg/mL). Herein, to explore the practical application in the agricultural field, the design and synthesis of three series of FA derivatives and their inhibitory activities against plant pathogenic fungi were examined. Results demonstrated that the optimized FA derivatives had excellent inhibitory activities against C. higginsianum, Helminthosporium (Harpophora maydis), and Pyricularia grisea. In particular, the inhibitory activities were considerably improved when the 5-butyl groups of FA were substituted. The EC50 of C. higginsianum and P. grisea was only 1.2 and 12.0 µg/mL when 5-butylalkyl groups were substituted with 5-([1,1'-biphenyl]-4-yl) and 5-phenyl, respectively. Moreover, the safety index of target compounds, which was obtained from the treatment index of medicines, on rice seeds was evaluated. Finally, 16 leading compounds (H4, H22-H24, H27, H29, H30-H34, H37, H45, H50, H52, and H53) were obtained; they had considerable potential for additional modification and optimization as agricultural fungicides. Moreover, three-dimensional quantitative structure-activity relationship models were developed for obtaining a systematic structure-activity relationship profile to explore the possibility of more potent FA derivatives as novel fungicides.

A Quantitative Study of Micro and Macro Mechanical Parameters Based on the PFC3D Flat-Joint Model.

The flat-joint model, which constructs round particles as polygons, can suppress rotation after breakage between particles and simulate more larger compression and tension ratios than the linear parallel-bond model. The flat-joint contact model was chosen for this study to calibrate the rock for 3D experiments. In the unit experiments, the triaxial unit was loaded with flexible boundaries, and the influence of each microscopic parameter on the significance magnitude of the macroscopic parameters (modulus of elasticity E, Poisson's ratio ν, uniaxial compressive strength UCS, crack initiation strength σci, internal friction angle φ and uniaxial tensile strength TS) was analysed by ANOVA (Analysis of Variance) in an orthogonal experimental design. Among them, Eƒ, kƒ has a significant effect on E; Cƒ and kƒ have a significant effect on ν; Cƒ, σƒ and kƒ have a significant effect on UCS; Cƒ; σƒ and Eƒ have a significant effect on TS; Rsd has a significant effect on σci; and φf, Eƒ, kƒ, µƒ, and σƒ have a significant effect on φ. Regressions were then carried out to establish the equations for calculating the macroscopic parameters of the rock material so that the three-dimensional microscopic parameters of the PFC can be quantitatively analysed and calculated. The correctness of the establishment of the macroscopic equations was verified by comparing the numerical and damage patterns of uniaxial compression, Brazilian splitting, and triaxial experiments with those of numerical simulation units in the chamber.

Diabetes patients with comorbidities had unfavorable outcomes following COVID-19: A retrospective study.

BACKGROUND: Previous studies have shown that diabetes mellitus is a common comorbidity of coronavirus disease 2019 (COVID-19), but the effects of diabetes or anti-diabetic medication on the mortality of COVID-19 have not been well described. AIM: To investigate the outcome of different statuses (with or without comorbidity) and anti-diabetic medication use before admission of diabetic after COVID-19. METHODS: In this multicenter and retrospective study, we enrolled 1422 consecutive hospitalized patients from January 21, 2020, to March 25, 2020, at six hospitals in Hubei Province, China. The primary endpoint was in-hospital mortality. Epidemiological material, demographic information, clinical data, laboratory parameters, radiographic characteristics, treatment and outcome were extracted from electronic medical records using a standardized data collection form. Most of the laboratory data except fasting plasma glucose (FPG) were obtained in first hospitalization, and FPG was collected in the next day morning. Major clinical symptoms, vital signs at admission and comorbidities were collected. The treatment data included not only COVID-19 but also diabetes mellitus. The duration from the onset of symptoms to admission, illness severity, intensive care unit (ICU) admission, and length of hospital stay were also recorded. All data were checked by a team of sophisticated physicians. RESULTS: Patients with diabetes were 10 years older than non-diabetic patients [(39 - 64) vs (56 - 70), P < 0.001] and had a higher prevalence of comorbidities such as hypertension (55.5% vs 21.4%, P < 0.001), coronary heart disease (CHD) (9.9% vs 3.5%, P < 0.001), cerebrovascular disease (CVD) (3% vs 2.2%, P < 0.001), and chronic kidney disease (CKD) (4.7% vs 1.5%, P = 0.007). Mortality (13.6% vs 7.2%, P = 0.003) was more prevalent among the diabetes group. Further analysis revealed that patients with diabetes who took acarbose had a lower mortality rate (2.2% vs 26.1, P < 0.01). Multivariable Cox regression showed that male sex [hazard ratio (HR) 2.59 (1.68 - 3.99), P < 0.001], hypertension [HR 1.75 (1.18 - 2.60), P = 0.006), CKD [HR 4.55 (2.52-8.20), P < 0.001], CVD [HR 2.35 (1.27 - 4.33), P = 0.006], and age were risk factors for the COVID-19 mortality. Higher HRs were noted in those aged ≥ 65 (HR 11.8 [4.6 - 30.2], P < 0.001) vs 50-64 years (HR 5.86 [2.27 - 15.12], P < 0.001). The survival curve revealed that, compared with the diabetes only group, the mortality was increased in the diabetes with comorbidities group (P = 0.009) but was not significantly different from the non-comorbidity group (P = 0.59). CONCLUSION: Patients with diabetes had worse outcomes when suffering from COVID-19; however, the outcome was not associated with diabetes itself but with comorbidities. Furthermore, acarbose could reduce the mortality in diabetic.

Two Novel Quassinoid Glycosides with Antiviral Activity from the Samara of Ailanthus altissima.

Phytochemistry investigations on Ailanthus altissima (Mill.) Swingle, a Simaroubaceae plant that is recognized as a traditional herbal medicine, have afforded various natural products, among which C20 quassinoid is the most attractive for their significant and diverse pharmacological and biological activities. Our continuous study has led to the isolation of two novel quassinoid glycosides, named chuglycosides J and K, together with fourteen known lignans from the samara of A. altissima. The new structures were elucidated based on comprehensive spectra data analysis. All of the compounds were evaluated for their anti-tobacco mosaic virus activity, among which chuglycosides J and K exhibited inhibitory effects against the virus multiplication with half maximal inhibitory concentration (IC50) values of 56.21 ± 1.86 and 137.74 ± 3.57 µM, respectively.

Candida in Lower Respiratory Tract Increases the Frequency of Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Retrospective Case-Control Study.

Objective: To explore impact of Candida on the acute exacerbation of chronic obstructive pulmonary disease (AECOPD) outcome. Methods: A retrospective, multi-center, case-control study was performed. Patients hospitalized for AECOPD in 25 centers during Jan 2011-Dec 2016 were enrolled. Data were collected, including demographic information, conditions during the stable phase of COPD, clinical characteristics of AECOPD, and follow-up information within 1 year after discharge. Univariate analysis and binary logistic regression were applied, and p < 0.05 was regarded as significant. Results: Totally 1,103 patients were analyzed, with 644 lower respiratory airway (LTR) Candida positive cases and 459 Candida negative controls. Long-term prognosis was significantly different between Candida positive and negative group, including the recurrent AECOPD within 180 days (75.5 vs. 6.6%, p < 0.001) and mortality within 1 year (6.9 vs. 0.4%, p < 0.001). Univariate logistic analysis showed that LTR Candida isolation was related to higher recurrence rate of AECOPD within 180 days and mortality within 1 year. Binary logistic regression analysis demonstrated that LTR Candida isolation was independently associated with recurrence of AECOPD within 180 days. Conclusions: LTR Candida isolation was associated with worse long-term prognosis of AECOPD and independently related to higher risks of recurrent AECOPD within 180 days.

Two new compounds from the fruit of Ailanthus altissima.

A new phenolic derivative, 4-hydroxyphenol-1-O-[6-O-(E)-feruloyl-ß-d-glucopyranosyl]-(1→6)-ß-d-glucopyranoside (1), and a new terpenylated coumarin, named altissimacoumarin H (2) were identified from the fruit of Ailanthus altissima (Mill.) Swingle (Simaroubaceae), together with ten known compounds (3-12), including two coumarins and eight phenylpropanoids. Their structures were determined on the basis of chemical method and spectroscopic data. Antiviral effect against Tobacco mosaic virus (TMV) of all the compounds obtained were evaluated using leaf-disc method.

Anti-Tobacco Mosaic Virus Quassinoids from Ailanthus altissima (Mill.) Swingle.

Quassinoids are bitter constituents characteristic of the family Simaroubaceae. A total of 18 C20 quassinoids, including nine new quassinoid glycosides, named chuglycosides A-I (1-6 and 8-10), were identified from the samara of Ailanthus altissima (Mill.) Swingle. All of the quassinoids showed potent anti-tobacco mosaic virus (TMV) activity. A preliminary structure-anti-TMV activity relationship of quassinoids was discussed. The effects of three quassinoids, including chaparrinone (12), glaucarubinone (15), and ailanthone (16), on the accumulation of TMV coat protein (CP) were studied by western blot analysis. Ailanthone (16) was further investigated for its influence on TMV spread in the Nicotiana benthamiana plant.

Phenylpropionamides, Piperidine, and Phenolic Derivatives from the Fruit of Ailanthus altissima.

Four novel compounds-two phenylpropionamides, one piperidine, and one phenolic derivatives-were isolated and identified from the fruit of a medicinal plant, Ailanthus altissima (Mill.) Swingle (Simaroubaceae), together with one known phenylpropionamide, 13 known phenols, and 10 flavonoids. The structures of the new compounds were elucidated as 2-hydroxy-N-[(2-O-ß-d-glucopyranosyl)phenyl]propionamide (1), 2-hydroxy-N-[(2-O-ß-d-glucopyranosyl-(1→6)-ß-d-glucopyranosyl)phenyl]propionamide (2), 2ß-carboxyl-piperidine-4ß-acetic acid methyl ester (4), and 4-hydroxyphenyl-1-O-[6-(hydrogen-3-hydroxy-3-methylpentanedioate)]-ß-d-glucopyranoside (5) based on spectroscopic analysis. All the isolated compounds were evaluated for their inhibitory activity against Tobacco mosaic virus (TMV) using the leaf-disc method. Among the compounds isolated, arbutin (6), ß-d-glucopyranosyl-(1→6)-arbutin (7), 4-methoxyphenylacetic acid (10), and corilagin (18) showed moderate inhibition against TMV with IC50 values of 0.49, 0.51, 0.27, and 0.45 mM, respectively.

Metabolites Produced by an Endophytic Phomopsis sp. and Their Anti-TMV Activity.

The fermentation and isolation of metabolites produced by an endophytic fungus, which was identified as Phomopsis sp. FJBR-11, based on phylogenetic analysis, led to the identification of six compounds, including dothiorelones A-C, and H, and cytosporones C and U. Among these compounds, cytosporone U exhibited potent inhibitory activity against Tobacco mosaic virus (TMV). Moreover, the crude and a purified exopolysaccharide were proved to possess strong inhibitory effects against the virus infection.

A New Erythrinan Alkaloid Glycoside from the Seeds of Erythrina crista-galli.

A new Erythrina alkaloid glycoside, named erythraline-11ß-O-glucopyranoside, was isolated from the seeds of Erythrina crista-galli L., together with five known Erythrina alkaloids and an indole alkaloid. The structure of the new alkaloid glycoside was elucidated by spectroscopic methods, and all of the compounds were evaluated for their antiviral activity against tobacco mosaic virus.

Anti-TMV activity of malformin A1, a cyclic penta-peptide produced by an endophytic fungus Aspergillus tubingensis FJBJ11.

Plant-associated microorganisms are known to produce a variety of metabolites with novel structures and interesting biological activities. An endophytic fungus FJBJ11, isolated from the plant tissue of Brucea javanica (L.) Merr. (Simaroubaceae), was proven to be significantly effective in producing metabolites with anti-Tobacco mosaic virus (TMV) activities. The isolate was identified as Aspergillus tubingensis FJBJ11 based on morphological characteristics and ITS sequence. Bioassay-guided isolation led to the identification of a cycli penta-peptide, malformin A1, along with two cyclic dipeptides, cyclo (Gly-L-Pro) and cyclo (Ala-Leu). Malformin A1 showed potent inhibitory effect against the infection and replication of TMV with IC50 values of 19.7 and 45.4 µg·mL⁻¹, as tested using local lesion assay and leaf-disc method, respectively. The results indicated the potential use of malformin A1 as a leading compound or a promising candidate of new viricide.

Five new taraxerene-type triterpenes from the branch barks of Davidia involucrata.

Five new taraxerene-type triterpenes, 2-nor-D-friedoolean-14-en-28-ol (1), 2-nor-d-friedoolean-14-en-3α,28-diol (2), 6α-hydroxy-2-nor-D-friedoolean-14-en-3,21-dione (3), 6α,11α,29-trihydroxy-D-friedoolean-14-en-3,16,21-trione (4), and 6α,23,29-trihydroxy-D-friedoolean-14-en-3,16,21-trione (5), were isolated from the MeOH extract of the branch barks of Davidia involucrata, together with five known compounds. Their structures were elucidated by means of various spectroscopic analyses. Five of the identified compounds showed moderate cytotoxicities against the cell proliferation of SGC-7901, MCF-7, and BEL-7404.

Constituents from the seeds of Brucea javanica with inhibitory activity of Tobacco mosaic virus.

Three new constituents were obtained along with 10 known compounds from the seeds of Brucea javanica. The structures of these compounds were determined based on spectral and chemical evidence. These new compounds included a monoterpenoid glycoside and two sesquiterpenes. Bioactivity screening of these constituents showed that compounds 1, 3, 8, 9, and 13 with obvious activities in inhibiting multiplication of the Tobacco mosaic virus.