16,671 research outputs found

    Distinct regulatory networks control toxin gene expression in elapid and viperid snakes

    Get PDF
    Background Venom systems are ideal models to study genetic regulatory mechanisms that underpin evolutionary novelty. Snake venom glands are thought to share a common origin, but there are major distinctions between venom toxins from the medically significant snake families Elapidae and Viperidae, and toxin gene regulatory investigations in elapid snakes have been limited. Here, we used high-throughput RNA-sequencing to profile gene expression and microRNAs between active (milked) and resting (unmilked) venom glands in an elapid (Eastern Brown Snake, Pseudonaja textilis), in addition to comparative genomics, to identify cis- and trans-acting regulation of venom production in an elapid in comparison to viperids (Crotalus viridis and C. tigris). Results Although there is conservation in high-level mechanistic pathways regulating venom production (unfolded protein response, Notch signaling and cholesterol homeostasis), there are differences in the regulation of histone methylation enzymes, transcription factors, and microRNAs in venom glands from these two snake families. Histone methyltransferases and transcription factor (TF) specificity protein 1 (Sp1) were highly upregulated in the milked elapid venom gland in comparison to the viperids, whereas nuclear factor I (NFI) TFs were upregulated after viperid venom milking. Sp1 and NFI cis-regulatory elements were common to toxin gene promoter regions, but many unique elements were also present between elapid and viperid toxins. The presence of Sp1 binding sites across multiple elapid toxin gene promoter regions that have been experimentally determined to regulate expression, in addition to upregulation of Sp1 after venom milking, suggests this transcription factor is involved in elapid toxin expression. microRNA profiles were distinctive between milked and unmilked venom glands for both snake families, and microRNAs were predicted to target a diversity of toxin transcripts in the elapid P. textilis venom gland, but only snake venom metalloproteinase transcripts in the viperid C. viridis venom gland. These results suggest differences in toxin gene posttranscriptional regulation between the elapid P. textilis and viperid C. viridis. Conclusions Our comparative transcriptomic and genomic analyses between toxin genes and isoforms in elapid and viperid snakes suggests independent toxin regulation between these two snake families, demonstrating multiple different regulatory mechanisms underpin a venomous phenotype

    Molecular properties, structure and chiral resolution of secondary metabolites from the leaves of <i>Viburnum chingii</i>

    No full text
    A chemical investigation of leaves of Viburnum chingii afforded eleven compounds, including one undescribed lignan (1), a pair of known phenylpropanoid enantiomers (2a/2b), and eight known lignans (3-10). Their structures were elucidated by detailed spectroscopic and comparative literature data analysis. The absolute configurations of compounds 1 was determined by comparing the experimental ECD data with the calculated values. The compounds 2a/2b were separated successfully by a chiral chromatographic column. In addition, the acetylcholinesterase (AChE) inhibitory activities of described compounds were evaluated.</p

    Paparan Pestisida Menginduksi Senesen Dini Pada Mesenchymal Stem Cell In Vitro

    Get PDF
    Pestisida merupakan senyawa kimia yang banyak digunakan sebagai pengendali hama pada aktivitas pertanian. Residu penggunaan pestisida ini dapat mengakibatkan polusi pada lingkungan perairan khususnya di sekitar lahan pertanian. Pestisida yang terakumulasi pada lingkungan perairan maupun hasil pertanian memberikan dampak buruk bagi manusia antara lain gangguan pada sistem organ, jaringan, perkembangan, dan pada tingkat sel mengarah ke senesen. Senesen merupakan suatu kondisi saat sel berhenti melakukan proliferasi. Sel yang mengalami senesen secara alami umumnya terjadi pada individu tua, sebagai respons terhadap pemendekan telomer. Senesen dini akibat paparan pestisida pada umumnya melibatkan mekanisme stres oksidatif, kerusakan DNA, dan disfungsi mitokondria. Senesen memicu penurunan fungsi organ yang mengakibatkan berbagai masalah kesehatan seperti kanker, osteoporosis, penyakit kardiovaskuler hingga demensia. Selain itu, senesen juga dapat menyebabkan berhentinya siklus sel punca antara lain pada mesenchymal stem cells (MSCs). Ulasan ini fokus membahas mekanisme senesen akibat paparan pestisida pada sel punca terutama MSCs. Metode yang digunakan yaitu koleksi data dan analisis dari jurnal terindeks Scopus dengan menggunakan VOSviewer. Berdasarkan hasil ulasan diketahui bahwa pestisida menginduksi senesen pada MSCs melalui jaras peningkatan konsentrasi ROS dalam sel dan penurunan aktivitas ALDH. Hal tersebut menyebabkan aktivasi p53, dan p21, yang kemudian akan menyebabkan hambatan pada CDK2 dan  pRB, berakibat pada  inaktivasi E2F serta induksi senesen. Senesen juga akan memberikan respons patofisiologis lain hingga efek tumorigenesis.

    A review of the effects of mushrooms on mood and neurocognitive health across the lifespan

    Get PDF
    Mushrooms contain bioactive compounds with documented antioxidant and anti-inflammatory actions. Here, we present a systematic evaluation of epidemiological and clinical studies that investigate the role of mushrooms, either as a separate or integral dietary component, on neurocognition and mood. Following a search of four databases, a total of 34 human studies examining the effect of different mushrooms across varying age cohorts and health statuses were selected for inclusion. Epidemiological studies included in this review (n = 24) revealed a significant benefit of dietary patterns that included mushrooms of any species on cognition and mood in both healthy and compromised populations. However, the results obtained from intervention studies (n = 10) were mixed. Studies mainly investigated LionÔÇÖs Mane (Hericium erinaceus), showing some enhancement of mood and cognitive function in middle-aged and older adults. Further acute and chronic human intervention studies are needed, using adequate sample sizes, employing appropriately sensitive neurocognitive tests, and investigating a range of dietary mushrooms, to confirm the effects of mushroom supplementation on neurocognition and mood in humans

    Assessment of the impacts of GABA and AChE targeting pesticides on freshwater invertebrate family richness in English rivers

    Get PDF
    Globally, riverine system biodiversity is threatened by a range of stressors, spanning pollution, sedimentation, alterations to water flow, and climate change. Pesticides have been associated with population level impacts on freshwater invertebrates for acute high-level exposures, but far less is known about the chronic impact of episodic exposure to specific classes of pesticides or their mixtures. Here we employed the use of the UK Environment Agency's monitoring datasets over 40 years (covering years 1980 to 2019) to assess the impacts of AChE (acetylcholinesterase) and GABA (gamma-aminobutyric acid) receptor targeting pesticides on invertebrate family richness at English river sites. Concentrations of AChE and GABA pesticides toxic to freshwater invertebrates occurred (measured) across 18 of the 66 river sites assessed. For one of the three river sites (all found in the Midlands region of England) where data recorded over the past 40 years were sufficient for robust modelling studies, both AChE and GABA pesticides associated with invertebrate family richness. Here, where AChE total pesticide concentrations were classified as high, 46 of 64 invertebrate families were absent, and where GABA total pesticide concentration were classified as high, 16 of 64 invertebrate families were absent. Using a combination of field evidence and laboratory toxicity thresholds for population relevant endpoints we identify families of invertebrates most at risk in the selected English rivers to AChE and GABA pesticides. We, furthermore, provide strong evidence that the absence of the invertebrate family Polycentropodidae (caddisfly) from one field site is due to exposure effects to AChE pesticides

    Artemisia absinthium L.: Chemical composition and biological activity : diploma thesis

    No full text
    Cilj ovog rada bio je izolirati i odrediti kemijski sastav eteri─Źnih ulja pelina (Artemisia absinthium L.) sakupljenih na razli─Źitim lokalitetima te u razli─Źitim sezonama, ispitati sposobnost inhibicije eteri─Źnih ulja na djelovanje enzima acetilkolinesteraze, butirilkolinesteraze i ╬▒-glukozidaze te istra┼żiti antioksidacijsku aktivnost. Predominantni spojevi eteri─Źnog ulja pelina iz Sinja su cis-sabinil-acetat i cis-epoksi-ocimen, eteri─Źnog ulja pelina iz Mostara su cis-epoksi-ocimen i cis-krizantemil-acetat, eteri─Źnog ulja pelina iz Zaboka su trans-tujon i cis- epoksi-ocimen te ulja pelina iz Obrovca je cis-epoksi-ocimen. Kod svih analiziranih uzoraka ulja ove biljke sabrane na razli─Źitim lokacijama i u razli─Źitim sezonama branja kao dominantne komponente ulja javljaju se oksidirani monoterpenski spojevi-monoterpenoidi. Eteri─Źna ulja biljke A. absinthium L. pokazuju umjerenu ili slabu sposobnost inhibicije enzima AChE i BChE, ne inhibiraju ili umjereno inhibiraju enzim ╬▒-glukozidazu, pokazuju slab redukcijski potencijal i ne pokazuju sposobnost hvatanja slobodnih DPPH radikala.The aim of this study was to isolate and determine the chemical composition of essential oils of wormwood (Artemisia absinthium L.) collected at different sites and in different seasons, to examine the ability to inhibit essential oils on the enzymes acetylcholinesterase, butyrylcholinesterase and ╬▒-glucosidase and to investigate antioxidant activity. The predominant compounds of wormwood essential oil from Sinj are cis-sabinyl-acetate and cis-epoxy-ocimen, wormwood essential oil from Mostar are cis-epoxy-ocimen and cis-chrysanthemum-acetate, wormwood essential oil from Zabok are trans-thujone and cis-epoxy-ocimen and oils wormwood from Obrovac is cis-epoxy-ocimen. In all analyzed oil samples of this plant collected at different locations and in different harvesting seasons, oxidized monoterpene compounds-monoterpenoids appear as the dominant oil components. The essential oils of A. absinthium L. show moderate or weak ability to inhibit the enzymes AChE and BChE, do not inhibit or moderately inhibit the enzyme ╬▒-glucosidase, show weak reduction potential and do not show the ability to capture free DPPH radicals

    Synthesis, antibacterial, and antibiofilm activities of pulmonarin B analogues

    Get PDF
    New analogues of pulmonarin B were synthesized from (3,5-dibromo-4-hydroxyphenyl)acetic acid derivatives, and their antibacterial and antibiofilm activities against E. coli, S. aureus, and P. aeruginosa were evaluated. The antibacterial activity of synthesized ammonium salts against the methicillin-resistant strain of S. aureus 222 depends on the length of the alkyl chain. Bis-quaternary ammonium salt 5 demonstrated better activity against S. aureus 222, E. coli 311, and P. aeruginosa 449 compared to mono-alkylated derivatives. Analogues of pulmonarin B 5 and 4d reduced S. aureus 222 biofilm formation by 74.5% and 89.4%, respectively. In addition, compound 4c turned out to be the most active against the biofilm formation of P. aeruginosa 449 (biomass decreased by 39.8%)

    Unveiling the Full Dynamical and Reactivity Profiles of Acetylcholinesterase: A Comprehensive All-Atom Investigation

    No full text
    Acetylcholinesterase is one of the most significant known serine hydrolases that governs the mammalian nervous system. Its high-rate speed, operating at the diffusion limit, combined with its buried active site feature, has made it a subject of extensive research over the last decades. Despite several studies focused on atomistic details of the different steps, a comprehensive theoretical investigation of the entire catalytic cycle has not yet been reported. In this work, we present an intuitive workflow aiming at describing the full dynamical and reactive profiles of AChE by coupling extensive steered molecular dynamics simulations for ligand diffusion and hybrid quantum mechanics/molecular mechanics computations to decipher the complete reactivity of the substrate within the enzyme. This comprehensive approach provides a broader view of the interconnections between each step that would not be readily accessible if the two steps were studied independently. Our simulations reveal that although individual steps do not indicate any strong limiting step, a solvent water molecule reorganization between the acylation and deacylation processes through the reactivity results in an energy cost of 20 kcal/mol. The observed barrier surpasses all others and discloses insights into a strong polarization effect acting on water molecules near the active site. An AMOEBA polarizable molecular dynamics simulation tends to confirm this assumption by capturing a substantial dipole moment (3.10 D) on the water molecule closest to the reaction site. These results shed light on the crucial correlation between this high-energy water reorganization and the polarization of confined water molecules. Consequently, carefully considering and modeling buried (polarizable) water molecules are of paramount importance when modeling full enzymatic activity. Therefore, this work will also provide valuable insights for future research on related enzymes with buried active sites

    Rational design for novel heterocyclic based Donepezil analogs for AlzheimerÔÇÖs disease: an in silico approach

    No full text
    AlzheimerÔÇÖs disease (AD) is a progressive neurodegenerative disease and has devastating impacts on the elderly population. During the last two decades, there has been a significant focus on developing effective and safe treatments for AD. Acetylcholinesterase (AChE) has been identified as one of the primary therapeutic targets for developing drug candidates for AD. However, there is still a need for more efficient therapies. In this study, our aim is to design a new series of heterocyclic-based AChE inhibitors inspired by a standard drug. Here, we carried out molecular docking, drug-likeliness characteristics, and molecular dynamics (MD) to predict important pharmacophore features and understand the inhibitory mechanism of the designed inhibitors towards the AChE. We have designed 112 new derivatives by replacing the piperidine moiety of Donepezil with the different five and six-membered heterocyclic rings and selected 15 compounds that show higher or comparable docking scores as compared to standard Donepezil and pose no risk for carcinogenicity. Furthermore, MD results imply the structural stability of the selected docked complexes and seven exhibit a stronger binding affinity towards the AChE than Donepezil. Thus, heterocyclic-based derivatives based on oxazole, pyrazole, and tetrahydropyran may be potential therapeutic candidates for AD. Our structure-based drug design approach allows us to identify and gain insight into the structural stability of the inhibitor-protein complex and the inhibition mechanism of the newly designed inhibitors. The present finding might be an initial selection for developing a new inhibitor for AD and provide a direction for further experiments on its biological activities. Communicated by Ramaswamy H. Sarma</p
    • ÔÇŽ
    corecore