Neocryptolepine is an alkaloid isolated from traditional African herbal medicine Cryptolepis sanguinolenta, and its broad spectrum of biological activities has been illuminated in past decades. In ...this study, neocryptolepine and its derivatives (1–49) were designed and synthesized from economical and readily available starting materials. Their structures were confirmed by proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and mass spectrometry. The synthesized compounds were screened for their antifungal profile against six agriculturally important fungi Rhizoctonia solani, Botrytis cinerea (B. cinerea), Fusarium graminearum, Mycosphaerella melonis, Sclerotinia sclerotiorum, and Magnaporthe oryzae. The results of in vitro assay revealed that compounds 5, 21, 24, 35, 40, 45, and 47 presented remarkable antifungal activity against the fungi tested with EC50 values lower than 1 μg/mL. Significantly, compound 24 displayed the most effective inhibitory potency against B. cinerea (EC50 = 0.07 μg/mL), and the data from in vivo experiments revealed that compound 24 demonstrated comparable protective activity with the positive control boscalid. Preliminary mechanism studies indicated that compound 24 showed impressive spore germination inhibitory effectiveness and lower cytotoxicity than azoxystrobin, imparted on normal function of the cell membrane and cell wall, and arrested the normal function of the nucleus. Besides the excellent inhibitory activity against agriculturally important phytopathogenic fungi tested, the designed assemblage possesses several benefits with a high profile of variation in synthesized molecules, the ease of synthesis, and good cost-effectiveness of commercially available synthetic reagents, all of these have highlighted the potential worth of compound 24 as a new and highly efficient agricultural fungicide.
Based on the structural characteristics of the cryptolepine alkaloid, a series of new quindoline derivatives bearing various substituents were prepared and evaluated for their fungicidal and ...antibacterial activities. Bioassay results showed that compound D7 displayed superior in vitro fungicidal activities against Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum, and Rhizoctonia solani with EC50 values of 0.780, 3.62, 1.59, and 2.85 μg/mL, respectively. Compound A7 showed apparent antibacterial activities toward Xanthomonas oryzae pv. oryzae with a minimum inhibitory concentration (MIC) value of 3.12 μg/mL. Significantly, in vivo antifungal activity suggested that the curative effect (98.3%) of compound D7 was comparable to that of the positive control azoxystrobin (96.7%) at 100 μg/mL. Preliminary mechanistic studies showed that compound D7 might cause mycelial abnormality of S. sclerotiorum, cell membrane breakage, accumulation of reactive oxygen species (ROS), and inhibition of sclerotia formation. Therefore, compound D7 could be a novel broad-spectrum fungicidal candidate against plant fungal diseases.
Increasing number of resistant bacteria have emerged with the overuse of antibiotics, which indicates that the bacterial infection has become a global challenge. Furthermore, the pollution of ...antibiotics to the environment has become a serious threat to public health. It is known that toxins produced by bacteria are the main cause of bacterial infections. Photothermal therapy is an effective antibacterial approach. However, the photothermal reagents cannot eliminate bacterial toxins, and even some anti-bacterial materials are toxic. Here, we synthesized a biomimetic recycled nanoparticle, red blood cell (RBC) membrane-coated Fe3O4 nanoparticles (RBC@Fe3O4), as an antibacterial agent. The RBC@Fe3O4 nanoparticles act as nano-sponges to trap toxins and then kill them all with a photothermal effect. We can describe this process simply as a battle between two armies. Our strategy is to disarm the "enemy" so that we can easily kill the "enemy" who has no power, which results in enhancing the bactericidal efficacy. The toxin of methicillin-resistant Staphylococcus aureus (MRSA) was absorbed by RBC@Fe3O4in vitro. In addition, in vivo studies proved that the RBC@Fe3O4 nanoparticles confer obvious survival benefits against toxin-induced lethality by absorbing the toxin of MRSA. Furthermore, using a mouse model of MRSA wound infection, the RBC@Fe3O4 nanoparticles with laser irradiation were found to have a superior wound-healing effect. Simultaneously, the RBC@Fe3O4 nanoparticles could be recycled in a simple way without affecting the bactericidal efficacy. The highly biocompatible and recyclable RBC@Fe3O4 biomimetic nanoparticles based on photothermal therapy and bacterial toxin adsorption strategy are promising for treating bacterial infections.
Dark teas are prepared by a microbial fermentation process. Flavan-3-ol B-ring fission analogues (FBRFAs) are some of the key bioactive constituents that characterize dark teas. The precursors and ...the synthetic mechanism involved in the formation of FBRFAs are not known. Using a unique solid-state fermentation system with β-cyclodextrin inclusion complexation as well as targeted chromatographic isolation, spectroscopic identification, and Feature-based Molecular Networking on the Global Natural Products Social Molecular Networking web platform, we reveal that dihydromyricetin and the FBRFAs, including teadenol A and fuzhuanin A, are derived from epigallocatechin gallate upon exposure to fungal strains isolated from Fuzhuan brick tea. In particular, the strains from subphylum Pezizomycotina were key drivers for these B-/C-ring oxidation transformations. These are the same transformations seen during the fermentation process of dark teas. These discoveries set the stage to enrich dark teas and other food products for these health-promoting constituents.
Crop diseases caused by fungi threaten food security and exacerbate the food crisis. Inspired by the application of fungicide candidates from natural products in agrochemical discovery, a series of ...luotonin A derivatives were designed, synthesized, and evaluated for their antifungal activities against five plant fungi. Most of these compounds exhibited significant fungicidal activity against Botrytis cinerea in vitro with EC50 values less than 1 μg/mL. Among them, compounds w7, w8, w12, and w15 showed superior antifungal activity against B. cinerea with EC50 values of 0.036, 0.050, 0.042, and 0.048 μg/mL, respectively, which were more potent than boscalid (EC50 = 1.790 μg/mL). Preliminary mechanism studies revealed that compound w7 might pursue its antifungal activity by disrupting the fungal cell membrane and cell wall. Moreover, in vivo bioassay also indicated that compound w7 could be effective for the control of B. cinerea. The above results evidenced the potential of luotonin A derivatives as novel and promising candidate fungicides.
The solar radiation pressure acting on the sail surface provides a force, which depends on the deformation of the surface itself, and thus the coupling between the force and the deformation may lead ...to flutter. The panel flutter mechanism of two-dimensional solar sail subjected to solar radiation pressure is investigated in this study based on the traveling mode analysis. The partial differential equations governing the panel vibrations are truncated into a set of ordinary differential equations. Two types of flutter have been detected, namely, traditional coupled-mode flutter and novel coupled-direction flutter especially existing in two-dimensional cases. Varying mode shapes with solar radiation pressure and critical values have been studied by considering the eigenvalue problem. By studying the mode shapes in standing wave contour or traveling wave contour, the flutter phenomena have been described based on the mechanism of energy accumulation.
The emergence of resistant pathogens has increased the demand for alternative fungicides. The use of natural products as chemical scaffolds is a potential method for developing fungicides. HWY-289, a ...semisynthetic protoberberine derivative, demonstrated broad-spectrum and potent activities against phytopathogenic fungi, particularly Botrytis cinerea (with EC50 values of 1.34 μg/mL). SEM and TEM imaging indicated that HWY-289 altered the morphology of the mycelium and the internal structure of cells. Transcriptomics revealed that it could break down cellular walls through amino acid sugar and nucleotide sugar metabolism. In addition, it substantially decreased chitinase activity and chitin synthase gene (BcCHSV) expression by 53.03 and 82.18% at 1.5 μg/mL, respectively. Moreover, this impacted the permeability and integrity of cell membranes. Finally, HWY-289 also hindered energy metabolism, resulting in a significant reduction of ATP content, ATPase activities, and key enzyme activities in the TCA cycle. Therefore, HWY-289 may be a potential candidate for the development of plant fungicides.
Autophagy maintains cellular homeostasis by degrading organelles, proteins, and lipids in lysosomes. Autophagy is involved in the innate and adaptive immune responses to a variety of pathogens. Some ...viruses can hijack host autophagy to enhance their replication. However, the role of autophagy in porcine reproductive and respiratory syndrome virus (PRRSV) infection is unclear. Here, we show that N-Myc downstream-regulated gene 1 (
) deficiency induced autophagy, which facilitated PRRSV replication by regulating lipid metabolism. NDRG1 mRNA is expressed ubiquitously in most porcine tissues and most strongly in white adipose tissue. PRRSV infection downregulated the expression of NDRG1 mRNA and protein, while NDRG1 deficiency contributed to PRRSV RNA replication and progeny virus assembly. NDRG1 deficiency reduced the number of intracellular lipid droplets (LDs), but the expression levels of key genes in lipogenesis and lipolysis were not altered. Our results also show that NDRG1 deficiency promoted autophagy and increased the subsequent yields of hydrolyzed free fatty acids (FFAs). The reduced LD numbers, increased FFA levels, and enhanced PRRSV replication were abrogated in the presence of an autophagy inhibitor. Overall, our findings suggest that NDRG1 plays a negative role in PRRSV replication by suppressing autophagy and LD degradation.
Porcine reproductive and respiratory syndrome virus (PRRSV), an enveloped single-positive-stranded RNA virus, causes acute respiratory distress in piglets and reproductive failure in sows. It has led to tremendous economic losses in the swine industry worldwide since it was first documented in the late 1980s. Vaccination is currently the major strategy used to control the disease. However, conventional vaccines and other strategies do not provide satisfactory or sustainable prevention. Therefore, safe and effective strategies to control PRRSV are urgently required. The significance of our research is that we demonstrate a previously unreported relationship between PRRSV, NDRG1, and lipophagy in the context of viral infection. Furthermore, our data point to a new role for NDRG1 in autophagy and lipid metabolism. Thus, NDRG1 and lipophagy will have significant implications for understanding PRRSV pathogenesis for developing new therapeutics.
Plant diseases caused by phytopathogenic fungi reduce the yield and quality of crops. To develop novel antifungal agents, we designed and synthesized eight series of quinazolinone derivatives and ...evaluated their anti-phytopathogenic fungal activity. The bioassay results revealed that compounds KZL-15, KZL-22, 5b, 6b, 6c, 8e, and 8f exhibited remarkable antifungal activity in vitro. Especially, compound 6c displayed the highest bioactivity against Sclerotinia sclerotiorum, Pellicularia sasakii, Fusarium graminearum, and Fusarium oxysporum, displaying appreciable IC50 values (50% inhibitory concentration) of 2.46, 2.94, 6.03, and 11.9 μg/mL, respectively. A further mechanism interrogation revealed abnormal mycelia, damaged organelles, and changed permeability of cell membranes in S. sclerotiorum treated with compound 6c. In addition, the in vivo bioassay indicated that compound 6c possessed comparable curative and protective effects (87.3 and 90.7%, respectively) to the positive control azoxystrobin (89.5 and 91.2%, respectively) at 100 μg/mL concentration against S. sclerotiorum. This work validated the potential of compound 6c as a new and promising fungicide candidate, contributing to the exploration of potent antifungal agents.
Enlightened from our previous work of structural simplification of quinine and innovative application of natural products against phytopathogenic fungi, lead structure ...2,8-bis(trifluoromethyl)-4-quinolinol (3) was selected to be a candidate and its diversified design, synthesis, and antifungal evaluation were carried out. All of the synthesized compounds Aa1–Db1 were evaluated for their antifungal activity against four agriculturally important fungi, Botrytis cinerea, Fusarium graminearum, Rhizoctonia solani, and Sclerotinia sclerotiorum. Results showed that compounds Ac3, Ac4, Ac7, Ac9, Ac12, Bb1, Bb10, Bb11, Bb13, Cb1. and Cb3 exhibited a good antifungal effect, especially Ac12 had the most potent activity with EC50 values of 0.52 and 0.50 μg/mL against S. sclerotiorum and B. cinerea, respectively, which were more potent than those of the lead compound 3 (1.72 and 1.89 μg/mL) and commercial fungicides azoxystrobin (both >30 μg/mL) and 8-hydroxyquinoline (2.12 and 5.28 μg/mL). Moreover, compound Ac12 displayed excellent in vivo antifungal activity, which was comparable in activity to the commercial fungicide boscalid. The preliminary mechanism revealed that compound Ac12 might cause an abnormal morphology of cell membranes, an increase in membrane permeability, and release of cellular contents. These results indicated that compound Ac12 displayed superior in vitro and in vivo fungicidal activities and could be a potential fungicidal candidate against plant fungal diseases.
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