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1.
Potential natural inhibitors of xanthine oxidase and HMG-CoA reductase in cholesterol regulation: in silico analysis.
Marahatha, R, Basnet, S, Bhattarai, BR, Budhathoki, P, Aryal, B, Adhikari, B, Lamichhane, G, Poudel, DK, Parajuli, N
BMC complementary medicine and therapies. 2021;(1):1
Abstract
BACKGROUND Hypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced cholesterol levels, most of them have failed to meet potential drug candidates' requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup. METHODS Out of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were selected based on the IC50 values reported in in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-silico ADMET analysis was carried out to explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. RESULTS The molecular docking of amentoflavone (GOLD score 70.54, ∆G calc. = - 10.4 Kcal/mol) and ganomycin I (GOLD score 59.61, ∆G calc. = - 6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl (6' → 1″)-O-α-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use. CONCLUSION This computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.
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2.
Nanoreduction as a technology to exploit β-Glucan from cereal and fungal sources for enhancing its nutraceutical potential.
Ashraf, ZU, Shah, A, Gani, A, Gani, A, Masoodi, FA, Noor, N
Carbohydrate polymers. 2021;:117664
Abstract
β-Glucan nanoparticles were produced from cereal and fungal sources viz: oats, barley, and yeast using ball milling which is considered as a green technology. The β-glucan nanoparticles were evaluated using dynamic light scattering (DLS) and Fourier transform infra-spectroscopy (ATR-FTIR). The particle size, zeta potential, polydispersity index, antioxidant, anticancerous, antimicrobial and antihypertensive potential of β-glucan nanoparticles from different sources were also studied. The experimental results revealed that the average particle size for BN (Barley β-glucan nanoparticle), ON (Oats β-glucan nanoparticle), and YN (Yeast β-glucan nanoparticle) were 90.35, 83.55 and 77.44 nm and zeta potential were in the range of -27 to -6.3 mV. . There was an increase in antioxidant, antihyperglycemic and antihypertensive activity of BN, YN, and ON in comparison to native. Study reported increase in anticancerous activity upon size reduction. Also, antibacterial activity of BNT, ONT, YNT, BN, ON and YN against Gram-negative and Gram-positive (E.coli & Bacillus Subtilis) were studied. It was concluded that the β-glucan nanoparticles showed enhanced nutraceutical properties that might be due to the nanoreduction using green technology.
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3.
Surviving the odds: From perception to survival of fungal phytopathogens under host-generated oxidative burst.
Singh, Y, Nair, AM, Verma, PK
Plant communications. 2021;(3):100142
Abstract
Fungal phytopathogens pose a serious threat to global crop production. Only a handful of strategies are available to combat these fungal infections, and the increasing incidence of fungicide resistance is making the situation worse. Hence, the molecular understanding of plant-fungus interactions remains a primary focus of plant pathology. One of the hallmarks of host-pathogen interactions is the overproduction of reactive oxygen species (ROS) as a plant defense mechanism, collectively termed the oxidative burst. In general, high accumulation of ROS restricts the growth of pathogenic organisms by causing localized cell death around the site of infection. To survive the oxidative burst and achieve successful host colonization, fungal phytopathogens employ intricate mechanisms for ROS perception, ROS neutralization, and protection from ROS-mediated damage. Together, these countermeasures maintain the physiological redox homeostasis that is essential for cell viability. In addition to intracellular antioxidant systems, phytopathogenic fungi also deploy interesting effector-mediated mechanisms for extracellular ROS modulation. This aspect of plant-pathogen interactions is significantly under-studied and provides enormous scope for future research. These adaptive responses, broadly categorized into "escape" and "exploitation" mechanisms, are poorly understood. In this review, we discuss the oxidative stress response of filamentous fungi, their perception signaling, and recent insights that provide a comprehensive understanding of the distinct survival mechanisms of fungal pathogens in response to the host-generated oxidative burst.
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The genome of Geosiphon pyriformis reveals ancestral traits linked to the emergence of the arbuscular mycorrhizal symbiosis.
Malar C, M, Krüger, M, Krüger, C, Wang, Y, Stajich, JE, Keller, J, Chen, ECH, Yildirir, G, Villeneuve-Laroche, M, Roux, C, et al
Current biology : CB. 2021;(7):1570-1577.e4
Abstract
Arbuscular mycorrhizal fungi (AMF) (subphylum Glomeromycotina)1 are among the most prominent symbionts and form the Arbuscular Mycorrhizal symbiosis (AMS) with over 70% of known land plants.2,3 AMS allows plants to efficiently acquire poorly soluble soil nutrients4 and AMF to receive photosynthetically fixed carbohydrates. This plant-fungus symbiosis dates back more than 400 million years5 and is thought to be one of the key innovations that allowed the colonization of lands by plants.6 Genomic and genetic analyses of diverse plant species started to reveal the molecular mechanisms that allowed the evolution of this symbiosis on the host side, but how and when AMS abilities emerged in AMF remain elusive. Comparative phylogenomics could be used to understand the evolution of AMS.7,8 However, the availability of genome data covering basal AMF phylogenetic nodes (Archaeosporales, Paraglomerales) is presently based on fragmentary protein coding datasets.9Geosiphon pyriformis (Archaeosporales) is the only fungus known to produce endosymbiosis with nitrogen-fixing cyanobacteria (Nostoc punctiforme) presumably representing the ancestral AMF state.10-12 Unlike other AMF, it forms long fungal cells ("bladders") that enclose cyanobacteria. Once in the bladder, the cyanobacteria are photosynthetically active and fix nitrogen, receiving inorganic nutrients and water from the fungus. Arguably, G. pyriformis represents an ideal candidate to investigate the origin of AMS and the emergence of a unique endosymbiosis. Here, we aimed to advance knowledge in these questions by sequencing the genome of G. pyriformis, using a re-discovered isolate.
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Snow mold of winter cereals: a complex disease and a challenge for resistance breeding.
Ponomareva, ML, Gorshkov, VY, Ponomarev, SN, Korzun, V, Miedaner, T
TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik. 2021;(2):419-433
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Abstract
Snow mold resistance is a complex quantitative trait highly affected by environmental conditions during winter that must be addressed by resistance breeding. Snow mold resistance in winter cereals is an important trait for many countries in the Northern Hemisphere. The disease is caused by at least four complexes of soilborne fungi and oomycetes of which Microdochium nivale and M. majus are among the most common pathogens. They have a broad host range covering all winter and spring cereals and can basically affect all plant growth stages and organs. Their attack leads to a low germination rate, and/or pre- and post-emergence death of seedlings after winter and, depending on largely unknown environmental conditions, also to foot rot, leaf blight, and head blight. Resistance in winter wheat and triticale is governed by a multitude of quantitative trait loci (QTL) with mainly additive effects highly affected by genotype × environment interaction. Snow mold resistance interacts with winter hardiness in a complex way leading to a co-localization of resistance QTLs with QTLs/genes for freezing tolerance. In practical breeding, a multistep procedure is necessary with (1) freezing tolerance tests, (2) climate chamber tests for snow mold resistance, and (3) field tests in locations with and without regularly occurring snow cover. In the future, resistance sources should be genetically characterized also in rye by QTL mapping or genome-wide association studies. The development of genomic selection procedures should be prioritized in breeding research.
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Glucose - The X factor for the survival of human fungal pathogens and disease progression in the host.
Qadri, H, Qureshi, MF, Mir, MA, Shah, AH
Microbiological research. 2021;:126725
Abstract
The incidence of human fungal infections is increasing due to the expansion of the immunocompromised patient population. The continuous use of different antifungal agents has eventually resulted in the establishment of resistant fungal species. The fungal pathogens unfold multiple resistance strategies to successfully tackle the effect of different antifungal agents. For the successful colonization and establishment of infection inside the host, the pathogenic fungi switch to the process of metabolic flexibility to regulate distinct nutrient uptake systems as well as to modulate their metabolism accordingly. Glucose the most favourable carbon source helps carry out the important survival and niche colonization processes. Adopting glucose as the center, this review has been put forward to provide an outline of the important processes like growth, the progression of infection, and the metabolism regulated by glucose, affecting the pathogenicity and virulence traits in the human pathogenic fungi. This could help in the identification of better treatment options and appropriate target-oriented antifungal drugs based on the glucose-regulated pathways and processes. In the article, we have also presented a summary of the novel studies and findings pointing to glucose-based potential therapeutic avenues to be explored to tackle the problem of globally increasing multidrug-resistant human fungal infections.
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Heat stress in macrofungi: effects and response mechanisms.
Luo, L, Zhang, S, Wu, J, Sun, X, Ma, A
Applied microbiology and biotechnology. 2021;(20):7567-7576
Abstract
Temperature is one of the key factors that affects the growth and development of macrofungi. Heat stress not only negatively affects the morphology and growth rate of macrofungi, but also destroys cell structures and influences cell metabolism. Due to loosed structure of cell walls and increased membrane fluidity, which caused by heat stress, the outflow of intracellular nutrients makes macrofungi more vulnerable to invasion by pathogens. Macrofungi accumulate reactive oxygen species (ROS), Ca2+, and nitric oxide (NO) when heat-stressed, which transmit and amplify the heat stimulation signal through intracellular signal transduction pathways. Through regulation of some transcription factors including heat response factors (HSFs), POZCP26 and MYB, macrofungi respond to heat stress by different mechanisms. In this paper, we present mechanisms used by macrofungi to adapt and survive under heat stress conditions, including antioxidant defense systems that eliminate the excess ROS, increase in trehalose levels that prevent enzymes and proteins deformation, and stabilize cell structures and heat shock proteins (HSPs) that repair damaged proteins and synthesis of auxins, which increase the activity of antioxidant enzymes. All of these help macrofungi resist and adapt to heat stress. KEY POINTS • The effects of heat stress on macrofungal growth and development were described. • The respond mechanisms to heat stress in macrofungi were summarized. • The further research directions of heat stress in macrofungi were discussed.
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8.
Versatile effectors of phytopathogenic fungi target host immunity.
Tariqjaveed, M, Mateen, A, Wang, S, Qiu, S, Zheng, X, Zhang, J, Bhadauria, V, Sun, W
Journal of integrative plant biology. 2021;(11):1856-1873
Abstract
Phytopathogenic fungi secrete a large arsenal of effector molecules, including proteinaceous effectors, small RNAs, phytohormones and derivatives thereof. The pathogenicity of fungal pathogens is primarily determined by these effectors that are secreted into host cells to undermine innate immunity, as well as to facilitate the acquisition of nutrients for their in planta growth and proliferation. After conventional and non-conventional secretion, fungal effectors are translocated into different subcellular compartments of the host cells to interfere with various biological processes. In extracellular spaces, apoplastic effectors cope with physical and chemical barriers to break the first line of plant defenses. Intracellular effectors target essential immune components on the plasma membrane, in the cytosol, including cytosolic organelles, and in the nucleus to suppress host immunity and reprogram host physiology, favoring pathogen colonization. In this review, we comprehensively summarize the recent advances in fungal effector biology, with a focus on the versatile virulence functions of fungal effectors in promoting pathogen infection and colonization. A perspective of future research on fungal effector biology is also discussed.
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Microorganisms: A Potential Source of Bioactive Molecules for Antioxidant Applications.
Rani, A, Saini, KC, Bast, F, Mehariya, S, Bhatia, SK, Lavecchia, R, Zuorro, A
Molecules (Basel, Switzerland). 2021;(4)
Abstract
Oxidative stress originates from an elevated intracellular level of free oxygen radicals that cause lipid peroxidation, protein denaturation, DNA hydroxylation, and apoptosis, ultimately impairing cell viability. Antioxidants scavenge free radicals and reduce oxidative stress, which further helps to prevent cellular damage. Medicinal plants, fruits, and spices are the primary sources of antioxidants from time immemorial. In contrast to plants, microorganisms can be used as a source of antioxidants with the advantage of fast growth under controlled conditions. Further, microbe-based antioxidants are nontoxic, noncarcinogenic, and biodegradable as compared to synthetic antioxidants. The present review aims to summarize the current state of the research on the antioxidant activity of microorganisms including actinomycetes, bacteria, fungi, protozoa, microalgae, and yeast, which produce a variety of antioxidant compounds, i.e., carotenoids, polyphenols, vitamins, and sterol, etc. Special emphasis is given to the mechanisms and signaling pathways followed by antioxidants to scavenge Reactive Oxygen Species (ROS), especially for those antioxidant compounds that have been scarcely investigated so far.
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10.
Exploiting Structural Modelling Tools to Explore Host-Translocated Effector Proteins.
Amoozadeh, S, Johnston, J, Meisrimler, CN
International journal of molecular sciences. 2021;(23)
Abstract
Oomycete and fungal interactions with plants can be neutral, symbiotic or pathogenic with different impact on plant health and fitness. Both fungi and oomycetes can generate so-called effector proteins in order to successfully colonize the host plant. These proteins modify stress pathways, developmental processes and the innate immune system to the microbes' benefit, with a very different outcome for the plant. Investigating the biological and functional roles of effectors during plant-microbe interactions are accessible through bioinformatics and experimental approaches. The next generation protein modeling software RoseTTafold and AlphaFold2 have made significant progress in defining the 3D-structure of proteins by utilizing novel machine-learning algorithms using amino acid sequences as their only input. As these two methods rely on super computers, Google Colabfold alternatives have received significant attention, making the approaches more accessible to users. Here, we focus on current structural biology, sequence motif and domain knowledge of effector proteins from filamentous microbes and discuss the broader use of novel modelling strategies, namely AlphaFold2 and RoseTTafold, in the field of effector biology. Finally, we compare the original programs and their Colab versions to assess current strengths, ease of access, limitations and future applications.