BackgroundThe disparity in prevalence of infectious diseases across the globe is common knowledge. Vitamin D receptor (VDR)-mediated toll-like receptor (TLR) 2/1 signaling produces antimicrobial peptides, which is critical as a first line of defense in innate immunity. Numerous studies disclosed the independent role of genetic polymorphisms in this pathway, vitamin D status or season and more recently epigenetics, as factors contributing to infectious disease predisposition. Few studies address the interaction between environment, genetics, and epigenetics. Here, we hypothesized that VDR-mediated TLR2/1 signaling is influenced by a combination of environment, epigenetics and genetics, collectively influencing differential innate immunity.MethodsHealthy Black and White South Africans (n = 100) donated blood, while ultraviolet index (UVI) was recorded for the duration of the study. LC-MS/MS supported 25(OH)D3 quantification. Monocyte/macrophage cultures, supplemented with/without 1,25(OH)2D3, were activated with the TLR2/1 elicitor, Pam3CSK4. VDR, cathelicidin antimicrobial peptide, hCAP-18, and 25-hydroxyvitamin D3-24-hydroxylase expression were quantified by RT-qPCR or flow cytometry. Pyrosequencing facilitated VDR methylation analysis and single-nucleotide polymorphism (SNP) genotyping in regions pinpointed through a bioinformatics workflow.ResultsSeason interacted with race showing 25(OH)D3 deficiency in Blacks. UVI correlated with 25(OH)D3 and VDR methylation, likely influencing race differences in the latter. Regarding the TLR2/1 pathway, race differences in SNP genotype distribution were confirmed and functional analysis of VDR-mediated signaling showed interaction between race, season, and 25(OH)D3 status. Multivariate OPLS-DA mirrored several interactions between UVI, 25(OH)D3 status, DNA sequence, and methylation variants. Methylation of the third cytosine-phosphate-guanine dinucleotide (CpG) in the promoter CpG island (CGI) 1062, CGI 1062 CpG 3, significantly discriminated a 5.7-fold above average mean in VDR protein level upon TLR2/1 elicitation, the variation of which was further influenced by 25(OH)D3 status and the VDR SNP TaqI.ConclusionRegulation of VDR-mediated TLR2/1 signaling is multifactorial, involving interaction between environment [UVI and consequent 25(OH)D3 status], epigenetics (VDR methylation at key regulatory sites), and genetics (TLR1, TIRAP, and VDR SNPs).
In response to abiotic stresses, plants mount comprehensive stress-specific responses which mediate signal transduction cascades, transcription of relevant responsive genes and the accumulation of numerous different stress-specific transcripts and metabolites, as well as coordinated stress-specific biochemical and physiological readjustments. These natural mechanisms employed by plants are however not always sufficient to ensure plant survival under abiotic stress conditions. Biostimulants such as plant growth-promoting rhizobacteria (PGPR) formulation are emerging as novel strategies for improving crop quality, yield and resilience against adverse environmental conditions. However, to successfully formulate these microbial-based biostimulants and design efficient application programs, the understanding of molecular and physiological mechanisms that govern biostimulant-plant interactions is imperatively required. Systems biology approaches, such as metabolomics, can unravel insights on the complex network of plant-PGPR interactions allowing for the identification of molecular targets responsible for improved growth and crop quality. Thus, this review highlights the current models on plant defence responses to abiotic stresses, from perception to the activation of cellular and molecular events. It further highlights the current knowledge on the application of microbial biostimulants and the use of epigenetics and metabolomics approaches to elucidate mechanisms of action of microbial biostimulants.
Systematic solvent screening using highthroughput solvothermal syntheses with bismuth nitrate pentahydrate and 1,2,4,5-tetrakis-(4-carboxyphenyl)benzene (H 4 TCPB) led to three new porous Bi-metal−organic frameworksCompounds CAU-31, -32, and -33 were synthesized in CH 3 OH, CH 3 OH/DMF, and DMF/toluene, respectively. The crystal structures were determined using electron diffraction and single-crystal X-ray diffraction in combination with the Rietveld method. The structures of CAU-31 and CAU-32 are composed of isolated Bi 3+ ions as the inorganic building unit (IBU), which are connected by the linker ions to form a layered structure with inclined interpenetration and a three-dimensional anionic network, respectively. The IBU of CAU-33 consists of infinite bismuth-oxo rods forming a three-dimensional network by connection of the organic linkers. For CAU-33 structural flexibility was observed, and two phases denoted αand β-CAU-33 could be isolated.
Caudal-type homeobox protein 2 (CDX-2) is an intestine-specific transcription factor (TF), with a polymorphic binding site (Cdx-2, rs11568820, A/G) in the vitamin D receptor gene (VDR). The molecular mechanism underlying Cdx-2 association with conditions like osteoporosis, which depends on intestinal VDR expression and calcium absorption, is believed to be due to higher affinity of CDX-2 for the ancestral A allele compared to the G allele. However, it is unclear why the polymorphism is associated with diseases like tuberculosis, which is dependent on VDR expression in immune cells that do not express CDX-2. This study aimed to explain Cdx-2 variant association with immune-related conditions. We hypothesised that the effect of Cdx-2 polymorphism on VDR expression in monocytes/macrophages, devoid of the CDX-2 TF, is indirect and dependent on circulating 25(OH)D and VDR methylation. Primary monocyte/macrophages from healthy donors (n = 100) were activated though TLR2/1 elicitation. VDR mRNA and 25(OH)D were quantified by RT-qPCR and LC-MS/MS, respectively. Genotyping and methylation analysis were done by pyrosequencing. AA vs. AG/GG showed reduced levels of 25(OH)D (P < 0.010), higher VDR promoter methylation (P < 0.050) and lower VDR mRNA induction (P < 0.050). Analysis of covariance confirmed that the effect of Cdx-2 variants depends primarily on VDR methylation. Thus, VDR methylation may confound association studies linking VDR polymorphisms to disease.
Microbial-based biostimulants are emerging as effective strategies to improve agricultural productivity; however, the modes of action of such formulations are still largely unknown. Thus, herein we report elucidated metabolic reconfigurations in maize (Zea mays) leaves associated with growth promotion and drought stress tolerance induced by a microbial-based biostimulant, a Bacillus consortium. Morphophysiological measurements revealed that the biostimulant induced a significant increase in biomass and enzymatic regulators of oxidative stress. Furthermore, the targeted metabolomics approach revealed differential quantitative profiles in amino acid-, phytohormone-, flavonoid- and phenolic acid levels in plants treated with the biostimulant under well-watered, mild, and severe drought stress conditions. These metabolic alterations were complemented with gene expression and global DNA methylation profiles. Thus, the postulated framework, describing biostimulant-induced metabolic events in maize plants, provides actionable knowledge necessary for industries and farmers to confidently and innovatively explore, design and fully implement microbial-based formulations and strategies into agronomic practices for sustainable agriculture and food production.
According to the World Health Organisation South Africa has the third highest tuberculosis (TB) incidence in the world, with an estimated 60 % incident cases having both TB and HIV. The South African National Tuberculosis Association (SANTA) recognized the importance of nutrition in the prevention and management of TB by including feeding schemes in community outreach programs. Vitamin D enhances innate immunity against mycobacterial infection through the antimicrobial peptide, cathelicidin. We reviewed studies on vitamin D status, its link with TB, and potential use in therapy in multiethnic South Africa with sunlight as primary source of vitamin D. Ethnicity, season, disease state, latitude, and urbanization are critical factors to be considered in vitamin D supplementation for prevention and treatment of TB.
Glutathione transferases (GSTs) are the main detoxification enzymes in schistosomes. These parasitic enzymes tend to be upregulated during drug treatment, with Schistosoma haematobium being one of the species that mainly affect humans. There is a lack of complete sequence information on the closely related bovis and haematobium 26-kDa GST isoforms in any database. Consequently, we engineered a pseudo-26-kDa S. bovis/haematobium GST (Sbh26GST) to understand structure–function relations and ligandin activity towards selected potential ligands. Sbh26GST was overexpressed in Escherichia coli as an MBP-fusion protein, purified to homogeneity and catalyzed 1-chloro-2,4-dinitrobenzene-glutathione (CDNB-GSH) conjugation activity, with a specific activity of 13 μmol/min/mg. This activity decreased by ~95% in the presence of bromosulfophthalein (BSP), which showed an IC50 of 27 µM. Additionally, enzyme kinetics revealed that BSP acts as a non-competitive inhibitor relative to GSH. Spectroscopic studies affirmed that Sbh26GST adopts the canonical GST structure, which is predominantly α-helical. Further extrinsic 8-anilino-1-naphthalenesulfonate (ANS) spectroscopy illustrated that BSP, praziquantel (PZQ), and artemisinin (ART) might preferentially bind at the dimer interface or in proximity to the hydrophobic substrate-binding site of the enzyme. The Sbh26GST-BSP interaction is both enthalpically and entropically driven, with a stoichiometry of one BSP molecule per Sbh26GST dimer. Enzyme stability appeared enhanced in the presence of BSP and GSH. Induced fit ligand docking affirmed the spectroscopic, thermodynamic, and molecular modelling results. In conclusion, BSP is a potent inhibitor of Sbh26GST and could potentially be rationalized as a treatment for schistosomiasis.
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