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[Background] Rusts and powdery mildews are severe fungal diseases of major crops worldwide, including cereals and legumes. They can be managed by chemical fungicide treatments, with negative consequences as environmental pollution and risk for human and animal health. Bioactive natural products could be the safest alternative for pest control. The family of anthraquinones, as well as analogue compounds containing an anthraquinone moiety or some modified anthraquinone rings, has been reported to exhibit certain antibiotic activity. Thus, the potential antifungal activity of some anthraquinones isolated from Ascochyta lentis, was assayed in this study for their effectiveness to reduce rust and powdery mildew diseases on pea and oat. Their effect on fungal development was macro- and microscopically assessed on inoculated leaves, and compared to the control achieved by the chemical fungicide (Tetraconazol 12.5% and Azoxystrobin 25%). In addition, the most promising compound was also tested at different concentrations in inoculated whole plants in order to evaluate its preventive and curative potential against fungal infection., [Results] All metabolites studied strongly reduced the development of rust and powdery mildews in both pea and oat, being pachybasin and lentiquinone C the most effective ones in hampering fungal spore germination and appressoria formation. Some of them also affected post-penetration events reducing colony size and number of haustoria per colony. Results were confirmed for pachybasin in whole plants assays, showing an efficacy similar to the commercial fungicide to control fungal diseases, both in preventive and curative applications. [Conclusions] Some fungal anthraquinones and close metabolites, especially pachybasin, could be very promising molecules with effective potential as antifungal agents against both rust and powdery mildew of both pea and oat. Some structure activity-relationships feature have also been evaluated. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., Financial support by projects PID2020-11466RB-100 of Spanish AEI and P20 00986 of Plan Andaluz Investigación are acknowledged.

Background X-linked dystonia parkinsonism (XDP) or "Lubag" is a genetic dystonia syndrome observed among Filipinos that can present with levodopa-responsive parkinsonism and abnormal dopamine transporter (DAT) imaging. Objective The aim of this study is to describe the results of skin biopsies for phosphorylated α-synuclein (P-SYN) in XDP. Method This study used the retrospective chart review. Results We report 6 patients who carried the XDP gene mutation with DAT imaging and skin biopsies to detect P-SYN. Five had segmental or multifocal dystonia and parkinsonism: 4 were levodopa-responsive and 1 non-levodopa-responsive. One patient was asymptomatic but had mild bradykinesia. Cutaneous P-SYN and abnormal DAT scans were noted in the 4 levodopa-responsive patients and 1 asymptomatic patient. Conclusion We report for the first time the presence of cutaneous P-SYN in XDP. Our findings suggest that XDP may be a hitherto-undescribed synucleinopathy or that some XDP patients may have concurrent Parkinson's disease.

Sphaeropsidin A (SphA) is a tetracyclic pimarane diterpene, first isolated as the main phytotoxin produced by Diplodia cupressi the causal agent of a severe canker disease of Italian cypress (Cupressus sempervirens L.). It was also produced, together with several analogues, by different pathogenic Diplodia species and other fungi and showed a broad array of biological activities suggesting its promising application in agriculture and medicine. The anticancer activity of SphA is very potent and cell specific. Recent studies have revealed its unique mode of action. This minireview reports the structures of SphA and its family of natural analogues, their biosynthetic origins, their fungal sources, and biological activities. The preparation of various SphA derivatives is also described as well as the results of structure-activity relationship (SAR) studies and on their potential practical applications.

Sesquitepenoids inuloxins A-D, belonging to different subgroups, were isolated from Dittrichia viscosa and showed potential biocontrol of some parasitic plants as Pelipanche, Orobanche, and Cuscuta species. The absolute configurations of the first three inuloxins A-C were previously determined by using experimental and computational chiroptical spectroscopic methods. The absolute configuration of inuloxin D remains to be established. The bioactive inuloxin E, closely related to inuloxin D, was recently isolated from the same plant organic extract. The same relative configuration of inuloxin D was assigned to inuloxin E by comparison of their NMR spectroscopic data. The absolute configurations of inuloxin D and inuloxin E are suggested in this work by analysis of the experimental and predicted chiroptical properties of the 4-O-acetyl derivative of inuloxin D.

Plants belonging to the Amaryllidaceae family are well known for their ornamental and medicinal use. Plant members of this group are distributed through both tropical and subtropical regions of the world and are dominant in Andean South America, the Mediterranean basin, and southern Africa. Amaryllidaceae plants have been demonstrated to be a good source of alkaloids with a large spectrum of biological activities, the latter being strictly related to the absolute stereochemistry of the alkaloid scaffold. Among them, great importance for practical applications in medicine has galanthamine, which has already spawned an Alzheimer's prescription drug as a potent and selective inhibitor of the enzyme acetylcholinesterase. Furthermore, lycorine as well as its related isocarbostyryl analogs narciclasine and pancratistatine have shown a strong anticancer activity in vitro against different solid tumors with malignant prognosis. This review addresses the assignment of the absolute configuration of several Amaryllidaceae alkaloids and its relationship with their biological activities.

Fusarium wilt caused by Fusarium oxysporum f. sp. pisi (Fop) is one of the major constraints of pea worldwide. Its control is difficult and is mainly based on the use of resistant cultivars. This study aimed to identify and characterize resistance mechanisms interfering with Fop spore germination, as an additional pre-penetration resistance mechanism little explored so far. For this, root exudates were collected from 12 pea accessions with differential responses to the disease, from resistant to susceptible, and their effects on Fop germination and growth were determined. While root exudates from most accessions stimulated Fop germination, the root exudates of three accessions, JI 1412, JI 2480 and P42, did not stimulate, or even inhibited, Fop germination. Although some additional compounds might be involved, the analysis showed that the most active metabolite was the pea phytoalexin pisatin. Pisatin was identified in the active fraction of pea root exudate extracts and its amount in the root exudates was negatively correlated with the extent of Fop germination. This suggests an important role of pisatin in the constitutive defence of pea against F. oxysporum.

Pyricularia grisea has been identified as a foliar pathogen on buffelgrass (Cenchrus ciliaris) in North America and was studied as a potential source of phytotoxins for buffelgrass control. Two monosubstituted hex-4-ene-2,3-diols, named pyriculins A and B, were isolated from its culture filtrate organic extract together with (10S,11S)-(−)-epipyriculol, trans-3,4-dihydro-3,4,8-trihydroxy-1(2H)-napthalenone, and (4S)-(+)-isosclerone. Pyriculins A and B were characterized by spectroscopic (essentially nuclear magnetic resonance [NMR], High-resolution electrospray ionization mass spectrometry [HRESIMS]) and chemical methods such as (4E)-1-(4-hydroxy-1,3-dihydroisobenzofuran-1-yl)hex-4-ene-2,3-diols. The relative and absolute configuration of these compounds was determined by a combination of spectroscopic (NMR, electronic circular dichroism [ECD]) and computational tools. When bioassayed in a buffelgrass coleoptile and radicle elongation test, (10S,11S)-(−)-epipyriculol proved to be the most toxic compound. Seed germination was much reduced and slowed with respect to the control and radicles failed to elongate. All five compounds delayed germination, but only (10S,11S)-(−)-epipyriculol was able to prevent radicle development of buffelgrass seedlings. It had no effect on coleoptile elongation, while the other four compounds caused significantly increased coleoptile development relative to the control.

BACKGROUND Rusts are a noxious group of plant diseases affecting major economically important crops. Crop protection is largely based on chemical control. There is a renewed interest in the discovery of natural products as alternatives to synthetic fungicides for control. In this study we tested two fungal metabolites, namely cyclopaldic acid and epi-epoformin, for their effectiveness in reducing early stages of development of two major rust fungi from the genera Puccinia and Uromyces, P. triticina and U. pisi. Spore germination and appressorium formation were assessed on pretreated detached leaves under controlled conditions. Cyclopaldic acid and epi-epoformin were also tested in infected plants in order to evaluate the level of control achieved by treatments both before and after inoculation. RESULTS Cyclopaldic acid and epi-epoformin were strongly effective in inhibiting fungal germination and penetration of both rust species studied. This effect was not dose dependent. These results were further confirmed in planta by spraying the metabolites on plant leaves, which reduced fungal developmental of U. pisi and P. triticina at values comparable with those obtained by application of the fungicide. CONCLUSION Our results further demonstrate the potential of fungal metabolites as natural alternatives to synthetic fungicides for the control of crop pathogens of economic importance as rusts. © 2016 Society of Chemical Industry

A new 3-substituted-5-diazenylcyclopentendione named kongiidiazadione was isolated from culture filtrates of Diaporthe kongii, associated with stem cankers on sunflower in Australia. Kongiidiazadione was characterized by spectroscopic (essentially nuclear magnetic resonance [NMR] and high-resolution, electrospray ionization, mass spectrometry [HRESIMS]) methods as (-)-5-diazenyl-3-hydroxymethyl-cyclopent-3-en-1,2-dione. The stereochemistry of the diazenyl group was determined by IR spectroscopy, while the (R) absolute configuration at C(5) was assigned by computational analysis of its electronic circular dichroism (ECD) spectrum. When assayed on leaf disks of different plant species at 5 mM, the kongiidiazadione had a differential impact, causing clear necrosis, in particular to Helianthus annuus. Moreover, kongiidiazadione proved to have a weak antibacterial activity against gram-positive Bacillus amyloliquefaciens.

Although fungi produce highly structurally diverse metabolites, many of which have served as excellent sources of pharmaceuticals, no fungi-derived agent has been approved as a cancer drug so far. This is despite a tremendous amount of research being aimed at the identification of fungal metabolites with promising anticancer activities. This review discusses the results of clinical testing of fungal metabolites and their synthetic derivatives, with the goal to evaluate how far we are from an approved cancer drug of fungal origin. Also, because in vivo studies in animal models are predictive of the efficacy and toxicity of a given compound in a clinical situation, literature describing animal cancer testing of compounds of fungal origin is reviewed as well. Agents showing the potential to advance to clinical trials are also identified. Finally, the technological challenges involved in the exploitation of fungal biodiversity and procurement of sufficient quantities of clinical candidates are discussed, and potential solutions that could be pursued by researchers are highlighted.

Ungeremine (UNG) is an alkaloid typically isolated from Pancratium maritimum or synthesized by the oxidation of lycorine. This antifungal alkaloid was incorporated into electrospun nanofibers based on blends of poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG). The effect of the UNG on the structure, morphology, and thermal properties of the fibers was evaluated, and the release of the alkaloid from the fibers was quantified. Studies on the release of the UNG for the nanofibers show that the release rate is related to the amount and distribution of the PEG in the nanofiber matrix. Initial burst release of the antifungal alkaloid is related to the PEG in the nanofibers, where after a sustained release occurs indicating that the UNG is present in both the PLA and PEG domains in the nanofibers.

The Amaryllidaceae alkaloid bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine's natural crinine-type congeners, were evaluated in vitro against a panel of cancer cell lines with various levels of resistance to pro-apoptotic stimuli. Bulbispermine, haemanthamine, and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited notable growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion; they displayed similar potencies in both cell types, indicating that the induction of apoptosis is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis-resistant cancers and glioblastoma in particular.

Phytotoxic microbial metabolites produced by certain phytopathogenic fungi and bacteria, and a group of phytotoxic plant metabolites including Amaryllidacea alkaloids and some derivatives of these compounds were evaluated for algicide, bactericide, insecticide, fungicide, and herbicide activities in order to discover natural compounds for potential use in the management and control of several important agricultural and household structural pests. Among the various compounds evaluated: i) ophiobolin A was found to be the most promising for potential use as a selective algicide; ii) ungeremine was discovered to be bactericidal against certain species of fish pathogenic bacteria; iii) cycasin caused significant mortality in termites; iv) cavoxin, ophiobolin A, and sphaeropsidin A were most active towards species of plant pathogenic fungi; and v) lycorine and some of its analogues (1-O-acetyllycorine and lycorine chlorohydrate) were highly phytotoxic in the herbicide bioassay. Our results further demonstrated that plants and microbes can provide a diverse and natural source of compounds with potential use as pesticides.

Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through the targeting of eEF1A elongation factor with narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC50 growth inhibitory values between 30–100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, narciclasine also significantly improves (P=0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEF1A targeting with narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (≥200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that narciclasine directly binds to human recombinant and yeast-purified eEF1A in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEF1A is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of narciclasine.—Van Goietsenoven, G., Hutton, J., Becker, J.-P., Lallemand, B., Robert, F., Lefranc, F., Pirker, C., Vandenbussche, G., Van Antwerpen, P., Evidente, A., Berger, W., Prévost, M., Pelletier, J., Kiss, R., Goss Kinzy, T., Kornienko, A., Mathieu, V. Targeting of eEF1A with Amaryllidaceae isocarbostyrils as a strategy to combat melanomas.

A time-dependent Density Functional Theory (TDDFT) computational simulation of the electronic circular dichroism (ECD) spectrum of the phytotoxin scytalone (1), produced by different plant pathogenic fungi and involved in melanin production, was undertaken with the aim to establish a nonempirical correlation between the spectrum and the absolute configuration of this compound. In fact, very low optical rotation data of 1 do not afford a reliable absolute configuration assignment while, on the contrary, the use of ECD can provide a useful tool for its stereochemical description. This structurally simple molecule displayed a considerable molecular flexibility, which made it mandatory to obtain an accurate conformers distribution to get a good reproduction of the experimental ECD spectrum. Only the application of an implicit integral equation formalism Polarizable Continuum Model (IEF-PCM) solvation model in the calculations allowed us to properly describe the conformer populations and finally obtain a more than satisfactory spectral simulation. Chirality 26:502–508, 2014. © 2014 Wiley Periodicals, Inc.

Summary Various Orobanche species are weedy and cause severe reduction in the yields of many important crops. The seeds of these parasitic weeds may remain dormant in the soil for many years until germination is stimulated by the release of a chemical signal from a host plant. In order to determine the effects of fenugreek root exudate on the induction of Orobanche crenata, Orobanche ramosa and Orobanche foetida seed germination, root exudate was collected from hydroponically grown fenugreek seedlings. Fractionation patterns obtained from column and thin layer chromatography of the fenugreek root exudate showed a set of metabolites differing in their polarity with stimulatory activity on Orobanche seed germination. The crude root exudate stimulated both O. ramosa and O. crenata seed germination to the same level caused by the synthetic germination stimulant GR24 at 10 mg L−1. It also stimulated O. foetida seed germination which did not respond to GR24. Active fractions of root exudate stimulated the germination of Orobanche species differentially.

The chemical structure of lipid A from the lipopolysaccharide of the mushroom-associated bacterium Pseudomonas reactans, a pathogen of cultivated mushroom, was elucidated by compositional analysis and spectroscopic methods (MALDI-TOF and two-dimensional NMR). The sugar backbone was composed of the beta-(1'--6)-linked d-glucosamine disaccharide 1-phosphate. The lipid A fraction showed remarkable heterogeneity with respect to the fatty acid and phosphate composition. The major species are hexacylated and pentacylated lipid A, bearing the (R)-3-hydroxydodecanoic acid [C12:0 (3OH)] in amide linkage and a (R)-3-hydroxydecanoic [C10:0 (3OH)] in ester linkage while the secondary fatty acids are present as C12:0 and/or C12:0 (2-OH). A nonstoichiometric phosphate substitution at position C-4' of the distal 2-deoxy-2-amino-glucose was detected. Interestingly, the pentacyl lipid A is lacking a primary fatty acid, namely the C10:0 (3-OH) at position C-3'. The potential biological meaning of this peculiar lipid A is also discussed.

A simple and rapid HPLC method, using a high-density C18 column, has been developed for the quantitative analysis of fusaric and dehydrofusaric acids and their methyl esters in the methanol extract of lyophilised culture filtrates of species of Fusarium. The method has been used to determine the content of these metabolites in two strains of Fusarium oxysporum and in strains of F. nygamai and F. udum. Fusaric acid has been isolated and identified from a strain of F. udum for the first time. Copyright © 2002 John Wiley & Sons, Ltd.

Phytotoxins are secondary microbial metabolites that play an essential role in the development of disease symptoms induced by fungi on host plants. Although phytotoxins can cause extensive-and in some cases devastating-damage to agricultural crops, they can also represent an important tool to develop natural herbicides when produced by fungi and plants to inhibit the growth and spread of weeds. An alternative strategy to biologically control parasitic plants is based on the use of plant and fungal metabolites, which stimulate seed germination in the absence of the host plant. Nontoxigenic fungi also produce bioactive metabolites with potential fungicide and insecticide activity, and could be applied for crop protection. All these metabolites represent important tools to develop eco-friendly pesticides. This review deals with the relationships between the biological activity of some phytotoxins, seed germination stimulants, fungicides and insecticides, and their stereochemistry.

The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.

The ability to understand how Parkinson's disease neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in Parkinson's disease dementia. The overall purpose of this project was to study the small-amplitude cortical myoclonus in Parkinson's disease as an in vivo model of focal cortical dysfunction secondary to Parkinson's disease neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in Parkinson's disease is linked to abnormal levels of α-synuclein in the primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures. The primary motor cortex was evaluated for 11 Parkinson's disease subjects with and 8 without electrophysiologically confirmed cortical myoclonus (the Parkinson's disease + myoclonus group and the Parkinson's disease group, respectively) who had premortem movement and cognitive testing. Similarly assessed 9 controls were used for comparison. Measurements for α-synuclein, Aβ-42 peptide, and other biochemical measures were made in the primary motor cortex. A 36% increase in α-synuclein was found in the motor cortex of Parkinson's disease + myoclonus cases when compared with Parkinson's disease without myoclonus. This occurred without significant differences in insoluble α-synuclein, phosphorylated to total α-synuclein ratio, or Aβ-42 peptide levels. Higher total motor cortex α-synuclein levels significantly correlated with the presence of cortical myoclonus but did not correlate with multiple clinical or pathological findings. These results suggest an association between elevated α-synuclein and the dysfunctional physiology arising from the motor cortex in Parkinson's disease + myoclonus cases. Alzheimer's disease pathology was not associated with cortical myoclonus in Parkinson's disease. Cortical myoclonus arising from the motor cortex is a model to study cortical dysfunction in Parkinson's disease. © 2011 Movement Disorder Society

This work was supported by a grant from the Italian Ministry of University and Research (MIUR) and by the Spanish project AGL2008-01239, contribution DISSPAPA No. 237.

Summary Two phytotoxic metabolites, p-hydroxybenzaldehyde and indol-3-aldehyde, were isolated and identified by spectroscopic methods from solid cultures of Discula quercina, an endophytic fungal pathogen frequently associated with oak decline in Italy. In addition, the fungus produced an unusual acyclic keto acid as a major metabolite, which was identified by spectroscopic and chemical methods as 5-oxo-6E,8E-octadecadienoic acid. In leaf puncture assays on Quercus suber and Q. ilex leaves, indol-3-aldehyde proved to be more toxic than p-hydroxybenzaldehyde, while 5-oxo-6E,8E-octadecadienoic acid was inactive even at the highest concentration used (1 mg ml−1). Although indol-3-aldehyde is a known microbial metabolite, its phytotoxic activity has hitherto not been reported. This report is the first to describe the production of phytotoxic compounds by D. quercina.

Restless legs syndrome is a common disoder that may interrupt sleep and has been reported to produce daytime fatigue and/or mood changes. This study assessed whether patients with RLS have more cognitive dysfunction and depression than individuals of the same age and education who do not have RLS. The study showed that older individuals with mild RLS for at least 1 year do not have cognitive dysfunction and are not depressed compared with a control group of similar age and education.

Putaminoxin and pinolidoxin, two structurally related nonenolides, isolated respectively from organic extracts of Phoma putaminum and Aschochyta pinodes cultures, together with some of their natural analogs and synthetic derivatives, were used in a structure-activity relationship study. Their phytotoxic, antifungal and zootoxic activities were assayed with the aim to find compounds with potential herbicidal properties. The strongest phytotoxic compounds proved to be putaminoxin and pinolidoxin, whose activity appeared to be correlated to the integrity of the nonenolide ring and to the presence of both the hydroxy groups and the unmodified propyl side chain. None of the assayed nonenolides showed antifungal activity, whereas pinolidoxin analogs and derivatives showed high to weak zootoxicity.

Ralstonia solanacearum is one of the most devastating phytopathogenic bacteria, in particular its race 3. This microorganism is the causal agent of destructive diseases of different crops including tomato and potato. An important aspect of the interaction between this pathogen, and the host and non-host plants was its biochemical and molecular basis. Thus, the lipopolysaccharides (LPS) were extracted from the R. solanacearum cell wall, purified, and the O-specific polysaccharide (OPS) was isolated and chemically characterized by compositional analyses and NMR spectroscopy. The OPS was constituted of two linear polymers of an approximate ratio of 3 : 1, both of which were built up from three rhamnose and one N-acetylglucosamine residues and differed only in the substitution of one rhamnose residue. The LPS inhibited the hypersensitivity reaction (HR) in non-host tobacco plants and induced localized resistance in host potato plants, both of which were pre-treated with the LPS before being inoculated with the pathogen. A cDNA-AFLP approach was used to study transcriptome variation during the resistant and susceptible interactions. This revealed the presence of metabolites specifically expressed in the S. commersonii-resistant genotypes, which could be involved in the plant-pathogen incompatible reaction. Furthermore, a specific EST collection of the Ralstonia-potato interaction has been built up.