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Novel natural products (NPs) and their derivatives are important sources for drug discovery, which have been broadly applied in the fields of agriculture, livestock, and medicine, making the synthesis of NPs and their derivatives necessarily important. In recent years, biosynthesis technology has received increasing attention due to its high efficiency in the synthesis of high value-added novel products and its advantages of green, environmental protection, and controllability. In this review, the technological advances of biosynthesis strategies in the discovery of novel NPs and their derivatives are outlined, with an emphasis on two areas of host engineering and in vitro enzymatic synthesis. In terms of hosts engineering, multiple microorganisms, including Streptomyces, Aspergillus, and Penicillium, have been used as the biosynthetic gene clusters (BGCs) provider and host strain for the expression of BGCs to discover new compounds over the past years. In addition, the use of in vitro enzymatic synthesis strategy to generate novel compounds such as triterpenoid saponins and flavonoids is also hereby described. [ABSTRACT FROM AUTHOR]

Abstract The farnesoid X receptor (FXR) is a crucial therapeutic target for treating non-alcoholic steatohepatitis (NASH). Although obeticholic acid (OCA) as a FXR agonist presents good efficacy, the safety data such as severe pruritus should be carefully considered. To discover new medications, we screen and choose the optimal compounds from ZINC15 database that may agonistically interact with FXR. We utilized the DS19 software to assist us in conducting the computer-aided structure based virtual screening to discover potential FXR agonists. After LibDock scores were determined by screening, their absorption, distribution, metabolism, excretion and toxicity predictions were examined. To determine the binding affinity between the chosen drugs and FXR, molecule docking was utilized. Molecular dynamics simulation was utilized to evaluate the stabilization of the ligand-FXR complex in its native environment. Higher binding affinity and stability with FXR were observed for ZINC000013374322 and ZINC000006036327, as two novel natural compounds, with lower rodent carcinogenicity, Ames mutagenicity, no hepatotoxicity and non-inhibitors of CYP2D6. They could stably exist in the environment, possess favorable potential energy and exert pharmacological effects at lower doses. Furthermore, ZINC000006036327 had lower skin irritancy and sensitization potential compared to OCA, also suggest the possibility of improved skin itching occurrence. ZINC000013374322 and ZINC000006036327 were found to be the best leading compounds to be FXR agonists. They are chosen as safe candidates for FXR target medicine, which play comparable pharmacological effects at lower doses.

Antimicrobial resistance is a global threat, leading to an alarming increase in the prevalence of bacterial infections that can no longer be treated with available antibiotics. The World Health Organization estimates that by 2050 up to 10 million deaths peryear could be associated with antimicrobial resistance, which would equal the annual number of cancer deaths worldwide. To overcome this emerging crisis, novel anti-bacterial compounds are urgently needed. There are two possible approaches in the fight against bacterial infections: a) targeting structures within bacterial cells, similar to existing antibiotics; and/or b) targeting virulence factors rather than bacterial growth. Here, for the first time, we provide a comprehensive overview of the key steps in the evaluation of potential new anti-bacterial and/or anti-virulence compounds. The methods described in this review include: a) in silico methods for the evaluation of novel compounds; b) anti-bacterial assays (MIC, MBC, Time-kill); b) anti-virulence assays (anti-biofilm, anti-quorum sensing, anti-adhesion); and c) evaluation of safety aspects (cytotoxicity assay and Ames test). Overall, we provide a detailed description of the methods that are an essential tool for chemists, computational chemists, microbiologists, and toxicologists in the evaluation of potential novel antimicrobial compounds. These methods are cost-effective and have high predictive value. They are widely used in preclinical studies to identify new molecular candidates, for further investigation in animal and human trials. [ABSTRACT FROM AUTHOR]

The field of mycology has grown from an underappreciated subset of botany, to a valuable, modern scientific discipline. As this field of study has grown, there have been significant contributions to science, technology, and industry, highlighting the value of fungi in the modern era. This paper looks at the current research, along with the existing limitations, and suggests future areas where scientists can focus their efforts, in the field mycology. We show how fungi have become important emerging diseases in medical mycology. We discuss current trends and the potential of fungi in drug and novel compound discovery. We explore the current trends in phylogenomics, its potential, and outcomes and address the question of how phylogenomics can be applied in fungal ecology. In addition, the trends in functional genomics studies of fungi are discussed with their importance in unravelling the intricate mechanisms underlying fungal behaviour, interactions, and adaptations, paving the way for a comprehensive understanding of fungal biology. We look at the current research in building materials, how they can be used as carbon sinks, and how fungi can be used in biocircular economies. The numbers of fungi have always been of great interest and have often been written about and estimates have varied greatly. Thus, we discuss current trends and future research needs in order to obtain more reliable estimates. We address the aspects of machine learning (AI) and how it can be used in mycological research. Plant pathogens are affecting food production systems on a global scale, and as such, we look at the current trends and future research needed in this area, particularly in disease detection. We look at the latest data from High Throughput Sequencing studies and question if we are still gaining new knowledge at the same rate as before. A review of current trends in nanotechnology is provided and its future potential is addressed. The importance of Arbuscular Mycorrhizal Fungi is addressed and future trends are acknowledged. Fungal databases are becoming more and more important, and we therefore provide a review of the current major databases. Edible and medicinal fungi have a huge potential as food and medicines, especially in Asia and their prospects are discussed. Lifestyle changes in fungi (e.g., from endophytes, to pathogens, and/or saprobes) are also extremely important and a current research trend and are therefore addressed in this special issue of Fungal Diversity. [ABSTRACT FROM AUTHOR]

The TP53 and PTEN tumour suppressor genes are inactivated by nonsense mutations in a significant fraction of human tumours. TP53 nonsense mutant tumours account for approximately one million new cancer cases per year worldwide. We have screened chemical libraries with the aim of identifying compounds that induce translational readthrough and expression of full-length p53 protein in cells with nonsense mutation in this gene. Here we describe two novel compounds with readthrough activity, either alone or in combination with other known readthrough-promoting substances. Both compounds induced levels of full-length p53 in cells carrying R213X nonsense mutant TP53. Compound C47 showed synergy with the aminoglycoside antibiotic and known readthrough inducer G418, whereas compound C61 synergized with eukaryotic release factor 3 (eRF3) degraders CC−885 and CC−90009. C47 alone showed potent induction of full-length PTEN protein in cells with different PTEN nonsense mutations. These results may facilitate further development of novel targeted cancer therapy by pharmacological induction of translational readthrough.

Developing novel antipsychotic mechanisms of action and repurposing established compounds for the treatment of schizophrenia is of utmost importance to improve relevant symptom domains and to improve the risk/benefit ratio of antipsychotic compounds. Novel trial design concepts, pathophysiology-based targeted treatment approaches, or even the return to old values may improve schizophrenia outcomes in the future. In this review of the clinical trial landscape in schizophrenia, we present an overview of the challenges and gaps in current clinical trials and elaborate on potential solutions to improve the outcomes of people with schizophrenia. The classic parallel group design may limit substantial advantages in drug approval or repurposing. Collaborative approaches between regulatory authorities, industry, academia, and funding agencies are needed to overcome barriers in clinical schizophrenia research to allow for meaningful outcome improvements for the patients. [ABSTRACT FROM AUTHOR]

Chenopodium quinoa possesses remarkable nutritional value and adaptability to various agroecological conditions. Panicle architecture influences the number of spikelets and grains in a panicle, ultimately leading to productivity and yield. Therefore, this study aimed to investigate the metabolites, nutrients, and minerals in Chenopodium quinoa accessions of varying panicle architecture. Metabolic profiling using liquid chromatography-mass spectrometry (LC–MS) analysis identified seventeen metabolites, including flavonoids, phenolics, fatty acids, terpenoids, phenylbutenoid dimers, amino acids, and saccharides. Eight metabolic compounds were reported in this study for the first time in quinoa. Some metabolites were detected as differentially expressed. The compound (Z)-1-(2,4,5-trimethoxyphenyl) butadiene and chrysin were found only in SPrecm. Sodium ((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxtetrahydrofuran-2-yl) methyl hydrogen phosphate and elenolic acid were detected only in CHEN-33, and quercetin, 3-hydroxyphloretin-3'-C-glucoside, kurarinone, and rosmarinic acid were identified only in D-12175. Variable importance in projection (VIP) scores annotated ten metabolites contributing to variability. Mineral analysis using atomic absorption spectrophotometry indicated that the quantity of magnesium and calcium is high in D-12175. In comparison, SPrecm showed a high quantity of magnesium compared to CHEN-33, while CHEN-33 showed a high quantity of calcium compared to SPrecm. However, the proximate composition showed no significant difference among quinoa accessions. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance is a global threat, leading to an alarming increase in the prevalence of bacterial infections that can no longer be treated with available antibiotics. The World Health Organization estimates that by 2050 up to 10 million deaths per year could be associated with antimicrobial resistance, which would equal the annual number of cancer deaths worldwide. To overcome this emerging crisis, novel anti-bacterial compounds are urgently needed. There are two possible approaches in the fight against bacterial infections: a) targeting structures within bacterial cells, similar to existing antibiotics; and/or b) targeting virulence factors rather than bacterial growth. Here, for the first time, we provide a comprehensive overview of the key steps in the evaluation of potential new anti-bacterial and/or anti-virulence compounds. The methods described in this review include: a) in silico methods for the evaluation of novel compounds; b) anti-bacterial assays (MIC, MBC, Time-kill); b) anti-virulence assays (anti-biofilm, anti-quorum sensing, anti-adhesion); and c) evaluation of safety aspects (cytotoxicity assay and Ames test). Overall, we provide a detailed description of the methods that are an essential tool for chemists, computational chemists, microbiologists, and toxicologists in the evaluation of potential novel antimicrobial compounds. These methods are cost-effective and have high predictive value. They are widely used in preclinical studies to identify new molecular candidates, for further investigation in animal and human trials.

Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting antiinflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-kB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1b, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1P, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA. [ABSTRACT FROM AUTHOR]

Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kδ, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation. [ABSTRACT FROM AUTHOR]

This document is an editorial published in the journal Frontiers in Veterinary Science. It discusses the use of natural products and pseudo-natural products in combating disease-causing microorganisms in veterinary medicine. The livestock and poultry industry faces challenges from viral, bacterial, parasitic, and fungal infections, as well as synthetic antibiotics and drugs in animal feed. The editorial highlights the potential effectiveness of nanoparticles, plant-based products, essential oils, botanical substances, phytochemicals, and probiotics in preventing and treating infectious diseases in animals. The authors hope that the research presented in this topic will contribute to the development of new strategies for managing infectious diseases in livestock and poultry. [Extracted from the article]

The TP53 and PTEN tumour suppressor genes are inactivated by nonsense mutations in a significant fraction of human tumours. TP53 nonsense mutant tumours account for approximately one million new cancer cases per year worldwide. We have screened chemical libraries with the aim of identifying compounds that induce translational readthrough and expression of full-length p53 protein in cells with nonsense mutation in this gene. Here we describe two novel compounds with readthrough activity, either alone or in combination with other known readthrough-promoting substances. Both compounds induced levels of full-length p53 in cells carrying R213X nonsense mutant TP53. Compound C47 showed synergy with the aminoglycoside antibiotic and known readthrough inducer G418, whereas compound C61 synergized with eukaryotic release factor 3 (eRF3) degraders CC−885 and CC−90009. C47 alone showed potent induction of full-length PTEN protein in cells with different PTEN nonsense mutations. These results may facilitate further development of novel targeted cancer therapy by pharmacological induction of translational readthrough. [ABSTRACT FROM AUTHOR]

Aim. This study aims to identify novel compounds against the mutant structures of PSEN2 protein associated with Alzheimer's disease by molecular docking studies using molecular docking server. Materials and Methods. In this study, we retrieved the mutant structures of I149T, L238P and R284G mutations of PSEN2 protein from Dynamut, which predicted these mutations to have destabilizing effects on the PSEN2 protein and performed molecular docking with phytochemicals; Curcumin and Resveratrol using SWISS-DOCK. Results. The docked compounds were analyzed for binding energies. Conclusion. Thus, we have performed molecular docking of mutant structures of the PSEN2 protein with potential phytochemicals using the molecular docking web tool used in our study. These docked compounds may serve as an aid to drug development studies and unravel a potential cure for EOAD. [ABSTRACT FROM AUTHOR]

Aim. Molecular docking experiments employing a molecular docking server will be used to find novel drugs against mutant structures of the MAPT protein linked to Alzheimer's disease. Materials and Methods. In this study, we used SWISS-Attach to dock phytochemicals Curcumin and Resveratrol with mutant structures of MAPT protein V287I mutation, which were predicted to have destabilizing effects on the MAPT protein by Dynamut. Alzheimer's disease, EOAD, PSEN2, Mutant structures, Novel compounds, Molecular Docking, SWISS-DOCK. Sample size chosen for this study was 1 mutation for the MAPT gene. Results. The binding energies of the docked molecules were investigated. Conclusion. Using the molecular docking online tool that we employed in our investigation, we performed molecular docking of mutant MAPT protein structures with putative phytochemicals. These docked chemicals could help with medication development investigations and uncover a possible AD treatment. [ABSTRACT FROM AUTHOR]

The biotransformation of natural compounds by fungal microorganisms is a complex biochemical process. Tandem whole-cell biotransformation offers a promising, alternative, and cost-effective method for modifying of bioactive novel compounds. This approach is particularly beneficial for structurally complex natural products that are difficult to be synthesized through traditional synthetic methods. Biotransformation also provides significant regio- and stereoselectivity, making it a valuable tool for the chemical modification of natural compounds. By utilizing microbial conversion reactions, the biological activity and structural diversity of natural products can be enhanced. In this review, we have summarized 282 novel metabolites resulting from microbial transformation by various microorganisms. We discussed the chemical structures and pharmacological properties of these novel biotransformation products. The review would assist scientists working in the fields of biotechnology, organic chemistry, medicinal chemistry, and pharmacology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Coffee cascara is the first and most significant by-product of the coffee processing industry, whose valorization has become an urgent priority to reduce harmful environmental impacts. This work aimed to provide an improved understanding of phytochemicals and polysaccharides in coffee cascara in order to offer information for the better evaluation of potential applications. Phytochemicals in 20 different coffee cascara samples were ultrasonically extracted and analyzed by HPLC-UV and HPLC-MS/MS. Four novel compounds were isolated for the first time from coffee cascara, including two still unknown tautomers (337 Da), and two dihydroflavonol glycosides (dihydromyricetin glycoside and dihydromyricetin rhamnosylglycoside). Their presence can contribute to the design of new value-added applications of coffee cascara. Chemical characterization of two polysaccharides from two of the coffee cascara pulp samples showed that they were mainly composed of homogalacturonan, with rhamnose and arabinose as minor neutral sugars. In addition, principal component analysis results indicated that coffee cultivar and/or country significantly impacted the phytochemical composition of coffee cascara, although differences may be reduced by the external environment and processing method. It is suggested that processing method should be carefully designed when generating coffee cascara from the same cultivar and country/farm. [ABSTRACT FROM AUTHOR]

Abstract Background The plant Cochlospermum tinctorium A. Rich is a sub-shrub that belongs to the family Cochlospermaceae. The plant has been used in traditional medicine for the treatment of malaria, rickets, stomachache, diarrhea, gastric ulcer, parasitic infestations, liver diseases, fever, pain, inflammation, infectious diseases, epilepsy, snake bite, burns, orchitis, labour, menstrual problems, and many other diseases. This review summarizes the traditional uses, phytochemistry, and pharmacological activities of Cochlospermum tinctorium. Main text To date, few bioactive molecules have been identified and isolated from the plant such as 7,3-dimethyldihydroquercelin, 5,4-dimethylquercelin, cochloxanthine, dihydrocochloxanthine, arjunolic acid, 3-O-E-p-coumaroylalphitolic acid, alphitolic acid, 1-hydroxytetradecan-3-one, 3-bisabolen, 2-tridecanone, 3-hexadecanone, 1-dodecanol, l-tetradecanol, 2-pentdecanone, 3-octadecanone, 1-hydroxy-3-hexadecanone, 1-nonadecanol, l-O-acetyl-3-hexadecanone, and l-hydroxy-3-oetadecanone. The literature related some of the reported ethnomedicinal uses of the plant to these compounds found in the different parts of the plant. Conclusion The comprehensive information documented in this review about the importance of the C. tinctorium may provide an opportunity for research advancement in drug discovery and a better understanding of the medicinal benefits of the plant.

Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kδ, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.

Abdullah MS Al-Hatmi,1–3 G Sybren de Hoog,2,3 Jacques F Meis3,4 1Ministry of Health, Directorate General of Health Services, Ibri, Oman; 2Westerdijk Fungal Biodiversity Institute, Utrecht, the Netherlands; 3Centre of Expertise in Mycology Radboud University Medical Centre/Canisius Wilhelmina Hospital, Nijmegen, the Netherlands; 4Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, the NetherlandsCorrespondence: Abdullah MS Al-HatmiDirectorate General of Health Services, PO Box 46, 516 Al-Akdhar, Ibri, OmanTel +968 25691905Fax +968 25691915Email abdullaalhatmi@gmail.comAbstract: The fungal genus Fusarium contains numerous plant pathogens causing considerable economic losses. In addition, Fusarium species are emerging as opportunistic human pathogens causing both superficial and systemic infections. Appropriate treatment of Fusarium infections in a clinical setting of neutropenia is currently not available. ESCMID and ECMM joint guidelines, following the majority of published studies, suggest early therapy with amphotericin B and voriconazole, in conjunction with surgical debridement and reversal of immunosuppression. In this review, we elaborate on the trans-kingdom pathogenicity of Fusarium. Intrinsic resistance to several antifungal drugs and the evolution of antifungal resistance over the years are highlighted. Recent studies present novel compounds that are effective against some pathogenic fungi including Fusarium. We discuss the robust and dynamic antifungal pipeline, including results from clinical trials as well as preclinical data that might appear beneficial for patients with invasive fusariosis.Keywords: Fusarium, trans-kingdom, novel compounds, antifungal pipeline, E1210, SCY-078, ASP2397, MGCD290, olorofim, AR-12, isavuconazole, efinaconazole, luliconazole

Introduction: Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. In addition to its role as essential redox cofactor, NAD also functions as a substrate for NAD-consuming enzymes, regulating multiple cellular processes such as DNA repair and gene expression, fundamental to sustain energetic needs for tumor growth. In this sense, NAMPT over-expression represents a common strategy that several tumor types adopt to sustain NAD production. In addition to its enzymatic role, NAMPT behaves as cytokine-like protein with pro-inflammatory function. Increasing evidence demonstrated that NAMPT inhibition represents a promising anti-cancer strategy to deplete NAD and impair cellular metabolism in cancer conditions., Areas Covered: By using Espacenet, we collected the patents which identified new molecules, compounds, formulations and methods able to inhibit NAMPT from 2007 to date., Expert Opinion: Most of the collected patents focused the attention on the ability of different compounds to inhibit the enzymatic activity of NAMPT, lacking other important aspects related to the extracellular role of NAMPT and the ability of alternative enzymes to counteract NAMPT-mediated NAD depletion. It is necessary to consider also these aspects to promote novel strategies and create novel inhibitors and molecules useful as anti-cancer compounds.

Potently affecting human and animal brain and behavior, hallucinogenic drugs have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing laboratory rodents, the zebrafish ( Danio rerio ) is a powerful model organism for screening neuroactive drugs, including hallucinogens. Here, we tested four novel N -benzyl-2-phenylethylamine (NBPEA) derivatives with 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -F, -Cl, and -OCF 3 substitutions in the ortho position of the phenyl ring of the N -benzyl moiety (34H-NBF, 34H-NBCl, 24H-NBOMe(F), and 34H-NBOMe(F)), assessing their behavioral and neurochemical effects following chronic 14 day treatment in adult zebrafish. While the novel tank test behavioral data indicate anxiolytic-like effects of 24H-NBOMe(F) and 34H-NBOMe(F), neurochemical analyses reveal reduced brain norepinephrine by all four drugs, and (except 34H-NBCl) - reduced dopamine and serotonin levels. We also found reduced turnover rates for all three brain monoamines but unaltered levels of their respective metabolites. Collectively, these findings further our understanding of complex central behavioral and neurochemical effects of chronically administered novel NBPEAs and highlight the potential of zebrafish as a model for preclinical screening of small psychoactive molecules.

We investigate the onomasiological question of which words speakers actually use and produce when trying to convey an intended meaning. This is not limited to selecting the best-fitting available existing word, but also includes word formation, the coinage of novel words. In the first two experiments, we introduce the taboo game paradigm in which participants were instructed to produce a single-word substitution for different words so that others can later identify them. Using distributional semantic models with the capability to produce quantitative representations for existing and novel word responses, we find that (a) responses tend to be semantically close to the targets and (b) existing words were represented closer than novel words, but (c) even novel compounds were often closer than the targets' free associates. In a final third experiment, we find that other participants are more likely to guess the correct original word (a) for responses closer to the original targets, and (b) for novel compound responses as compared to existing word responses. This shows that the production of both existing and novel words can be accurately captured in a unified computational framework of the semantic mechanisms driving word choice. • We investigate which words exactly speakers use to express an intended meaning. • In the taboo game paradigm, speakers substitute a target with a single other word. • Participants are allowed or required to also produce novel words. • Existing and novel word responses are well captured in a single distributional framework. • Responses not well captured by this framework are also less informative for other speakers. [ABSTRACT FROM AUTHOR]

Elicitation by chemical means including heavy metals is one of a novel technique for drug discoveries. In this review, the effect of heavy metals on animal, plants and microorganisms for the production of novel compounds with the unique structures has been discussed. The number of parameters such as metal concentration, type, dose, treatment schedule, duration of metal exposure, and nutrient composition are significant factors altering the secondary metabolites production. The detailed illustrated diagram representing the mode of action of metal stress has also been discussed. This is the first article reporting all the novel compounds produced from plants and microorganisms in response to metal-stress with their pharmacological potential. This new technique opens the new way for drug discovery from natural products.

Coffee cascara is the first and most significant by-product of the coffee processing industry, whose valorization has become an urgent priority to reduce harmful environmental impacts. This work aimed to provide an improved understanding of phytochemicals and polysaccharides in coffee cascara in order to offer information for the better evaluation of potential applications. Phytochemicals in 20 different coffee cascara samples were ultrasonically extracted and analyzed by HPLC-UV and HPLC-MS/MS. Four novel compounds were isolated for the first time from coffee cascara, including two still unknown tautomers (337 Da), and two dihydroflavonol glycosides (dihydromyricetin glycoside and dihydromyricetin rhamnosylglycoside). Their presence can contribute to the design of new value-added applications of coffee cascara. Chemical characterization of two polysaccharides from two of the coffee cascara pulp samples showed that they were mainly composed of homogalacturonan, with rhamnose and arabinose as minor neutral sugars. In addition, principal component analysis results indicated that coffee cultivar and/or country significantly impacted the phytochemical composition of coffee cascara, although differences may be reduced by the external environment and processing method. It is suggested that processing method should be carefully designed when generating coffee cascara from the same cultivar and country/farm.

Speakers of languages with synchronically productive compounding systems, such as English, are likely to encounter new compounds on a daily basis. These can only be useful for communication if speakers are able to rapidly compose their meanings. However, while compositional meanings can be obtained for some novel compounds such as bridgemill, this is far harder for others such as radiosauce ; accordingly, processing speed should be affected by the ease of such a compositional process. To rigorously test this hypothesis, we employed a fully implemented computational model based on distributional semantics to quantitatively measure the degree of semantic compositionality of novel compounds. In two large-scale studies, we collected timed sensibility judgements and lexical decisions for hundreds of morphologically structured nonwords in English. Response times were predicted by the constituents' semantic contribution to the compositional process, with slower rejections for more compositional nonwords. We found no indication of a difference in these compositional effects between the tasks, suggesting that speakers automatically engage in a compositional process whenever they encounter morphologically structured stimuli, even when it is not required by the task at hand. Such compositional effects in the processing of novel compounds have important implications for studies that employ such stimuli as filler material or "nonwords," as response times for these items can differ greatly depending on their compositionality. [ABSTRACT FROM AUTHOR]

Malaria is an old disease and continues to be a major health problem in many countries. In spite of decrement in morbidity and mortality due to malaria, the transmission is still active throughout the world. Hence, appropriate treatment is needed to handle malaria in addition to preventive measures. However, unavailability of new drugs and the occurrence of resistant Plasmodium strains toward many conventional antimalarial drugs including artemisinins are the major obstacles in combating malaria infection. Thus, experts from all directions of our planet are in search of novel compounds, and many new chemical entities, such as artefenomel, ferroquine, KAE609, KAF156, DSM265, methylene blue, MMV39048, DDD107498, SJ733, and MMV253, have been under drug development process. While many agents are in the pipeline, most of them are not able to kill both gametocytes and hypnozoites. [ABSTRACT FROM AUTHOR]

Introduction Cancer continues to pose a significant challenge in medical research. Phytochemicals derived from plants have emerged as a promising avenue for pioneering drug discovery due to their potential for reduced toxicity. The phosphatidylinositol 3-kinase (PI3K) pathway has gained recognition as a pivotal signaling pathway with implications across multiple facets of cancer initiation and progression. This study focuses on the virtual screening of phytochemicals from Schinus molle , evaluating their potential as inhibitors of PI3K, a crucial target in cancer therapy. Methods and materials The present study involved a comprehensive in silico screening of phytochemicals derived from S. molle. The screening process encompassed various parameters, such as drug-likeness, pharmacokinetics, molecular docking, toxicity analysis, bioavailability assessment, and molecular target exploration. The primary objective of this systematic approach was to identify potential lead compounds. The study aimed to provide a detailed understanding of the molecular properties of the phytochemicals and their potential as drug candidates. Results Upon analyzing 18 compounds, two compounds were noteworthy. Beta-spathulene and kaempferol demonstrated significant affinity for PI3K and favorable attributes concerning drug-likeness, pharmacokinetics, and bioavailability. Conclusion While our computational investigation lays a promising foundation, it is essential to emphasize that further experimental studies, including in vitro and in vivo experiments, are imperative to validate the action of these lead compounds., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kumar et al.)

This paper investigates how structure emerges in a young language, focusing on compounding in two young sign languages, Israeli Sign Language (ISL) and Al-Sayyid Bedouin Sign Language (ABSL). We focus on novel compounds (tokens invented on the spot) to ensure that we are studying a productive process and to avoid issues contingent with lexicalization. We found that both languages make use both of compounding and size-and-shape classifier constructions (SASS-constructions), but ISL and ABSL have conventionalized different structures and the structures they do use are conventionalized to different degrees. We discuss the similarities and differences of those constructions in ISL and ABSL in the context of structure emergence and language evolution.

The exponential growth of emerging multidrug-resistant microorganisms, including foodborne pathogens affecting the shelf-life and quality of foods, has recently increased the needs of the food industry to search for novel, natural and eco-friendly antimicrobial agents. Macroalgae are a bio-diverse group distributed worldwide, known to produce multiple compounds of diverse chemical nature, different to those produced by terrestrial plants. These novel compounds have shown promising health benefits when incorporated into foods, including antimicrobial properties. This review aims to provide an overview of the general methods and novel compounds with antimicrobial properties recently isolated and characterized from macroalgae, emphasizing the molecular pathways of their antimicrobial mechanisms of action. The current scientific evidence on the use of macroalgae or macroalgal extracts to increase the shelf-life of foods and prevent the development of foodborne pathogens in real food products and their influence on the sensory attributes of multiple foods (i.e., meat, dairy, beverages, fish and bakery products) will also be discussed, together with the main challenges and future trends of the use of marine natural products as antimicrobials.

Abstract Elicitation by chemical means including heavy metals is one of a novel technique for drug discoveries. In this review, the effect of heavy metals on animal, plants and microorganisms for the production of novel compounds with the unique structures has been discussed. The number of parameters such as metal concentration, type, dose, treatment schedule, duration of metal exposure, and nutrient composition are significant factors altering the secondary metabolites production. The detailed illustrated diagram representing the mode of action of metal stress has also been discussed. This is the first article reporting all the novel compounds produced from plants and microorganisms in response to metal-stress with their pharmacological potential. This new technique opens the new way for drug discovery from natural products. [ABSTRACT FROM AUTHOR]

Every year, hundreds of new compounds are discovered from the metabolites of marine organisms. Finding new and useful compounds is one of the crucial drivers for this field of research. Here we describe the statistics of bioactive compounds discovered from marine organisms from 1985 to 2012. This work is based on our database, which contains information on more than 15,000 chemical substances including 4196 bioactive marine natural products. We performed a comprehensive statistical analysis to understand the characteristics of the novel bioactive compounds and detail temporal trends, chemical structures, species distribution, and research progress. We hope this meta-analysis will provide useful information for research into the bioactivity of marine natural products and drug development.

This study explores formal aspects and functions of 420 novel noun-noun (NN) compounds in diary data from three Swedish children (1;9-6;11). With regard to form, the data show that the children’s compounds respect target head order, allow for a small amount of internal inflection, and, in more than half of the cases where a liaison form is required, are properly formed. Most of the compounds concatenate two nouns (without the presence of liaison forms), as is the general case for Swedish NN compounds. With regard to function, the data permit us to distinguish three main functions of the coinages: I. Novel compound instead of established term, II. Novel compound for novel category, and III. Novel compound for specific entity. Type I involves attempts to target conventional compounds by relying either on perceptual or functional features or on recalled semantic, phonological, and/or morphological cues. Type II is innovative compounding par excellence: detailed discriminations and fantasy concepts are named. Type III divides into anaphoric and deictic uses as well as what we call appropriation, i.e. naming a specific entity. Types II and III are functions displayed by novel compounds in general. In conclusion, the three children seem to master the central facets of NN compounds, formally and functionally. Furthermore, compound production can constitute a simple and efficient means for young children to maximize and build more structure into their lexicon. [ABSTRACT FROM AUTHOR]

We examined how noun–noun compounds and their syntactic properties are lexically stored and processed in speech production. Using gender-marked determiner primes (dermasc, diefem, dasneut [the]) in a picture naming task, we tested for specific effects from determiners congruent with either the modifier or the head of the compound target (e.g., Teemasckannefem [teapot]) to examine whether the constituents are processed independently at the syntactic level. Experiment 1 assessed effects of auditory gender-marked determiner primes in bare noun picture naming, and Experiment 2 assessed effects of visual gender-marked determiner primes in determiner–noun picture naming. Three prime conditions were implemented: (a) head-congruent determiner (e.g., diefem), (b) modifier-congruent determiner (e.g., dermasc), and (c) incongruent determiner (e.g., dasneuter). We observed a facilitation effect of head congruency but no effect of modifier congruency. In Experiment 3, participants produced novel noun–noun compounds in response to two pictures, demanding independent processing of head and modifier at the syntactic level. Now, head and modifier congruency effects were obtained, demonstrating the general sensitivity of our task. Our data support the notion of a single-lemma representation of lexically stored compound nouns in the German production lexicon. [ABSTRACT FROM AUTHOR]

In many languages, compounding is a fundamental process for the generation of novel words. When this process is productive (as, e.g., in English), native speakers can juxtapose two words to create novel compounds that can be readily understood by other speakers. The present paper proposes a large-scale, data-driven computational system for compound semantic processing based on distributional semantics, the CAOSS model (Compounding as Abstract Operation in Semantic Space). In CAOSS, word meanings are represented as vectors encoding their lexical co-occurrences in a reference corpus. Given two constituent words, their composed representation (the compound) is computed by using matrices representing the abstract properties of constituent roles (modifier vs. head). The matrices are also induced through examples of language usage. The model is then validated against behavioral results concerning the processing of novel compounds, and in particular relational effects on response latencies. The effects of relational priming and relational dominance are considered. CAOSS predictions are shown to pattern with previous results, in terms of both the impact of relational information and the dissociations related to the different constituent roles. The simulations indicate that relational information is implicitly reflected in language usage, suggesting that human speakers can learn these aspects from language experience and automatically apply them to the processing of new word combinations. The present model is flexible enough to emulate this procedure, suggesting that relational effects might emerge as a by-product of nuanced operations across distributional patterns. [ABSTRACT FROM AUTHOR]

Over the past two decades infections due to antibiotic-resistant bacteria have escalated world-wide, affecting patient morbidity, mortality, and health care costs. Among these bacteria, Enterococcus faecium and Enterococcus faecalis represent opportunistic nosocomial pathogens that cause difficult-to-treat infections because of intrinsic and acquired resistance to a plethora of antibiotics. In recent years, a number of novel antimicrobial compound classes have been discovered and developed that target Gram-positive bacteria, including E. faecium and E. faecalis. These new antibacterial agents include teixobactin (targeting lipid II and lipid III), lipopeptides derived from nisin (targeting lipid II), dimeric vancomycin analogues (targeting lipid II), sortase transpeptidase inhibitors (targeting the sortase enzyme), alanine racemase inhibitors, lipoteichoic acid synthesis inhibitors (targeting LtaS), various oxazolidinones (targeting the bacterial ribosome), and tarocins (interfering with teichoic acid biosynthesis). The targets of these novel compounds and mode of action make them very promising for further antimicrobial drug development and future treatment of Gram-positive bacterial infections. Here we review current knowledge of the most favorable anti-enterococcal compounds along with their implicated modes of action and efficacy in animal models to project their possible future use in the clinical setting. [ABSTRACT FROM AUTHOR]

Antibiotic-resistant bacteria are a major health concern and honey may provide an alternative to antibiotic use under certain conditions. The antimicrobial action of six Scottish honeys and Manuka Medihoney ® was compared against antibiotic-resistant Acinetobacter calcoaceticus, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli . Certain Scottish honeys, such as Highland and Portobello honey 2011, were comparable in effectiveness to the established antimicrobial Medihoney ® , inhibiting growth to <1 compared to 10 log 10 CFU/ml in the control. Heather honey was the next most active while Blossom honeys were less active. Bacteria were inhibited by a sugar-matched control, but to a lesser extent, indicating that antimicrobial activity was associated with non-sugar components, such as polyphenols. However, total phenol content or antioxidant capacity did not correlate with antimicrobial activity. Liquid chromatography-mass spectrometric analysis revealed that the composition of polyphenol and non-polyphenol components differed between honeys. In addition, candidate components that could be associated with antimicrobial activity were noted including novel fatty diacid glycoside derivatives not previously identified in honeys. [ABSTRACT FROM AUTHOR]

Within this retrospective single-center study, we analyzed the survival of 320 multiple myeloma (MM) patients receiving melphalan high-dose chemotherapy (HDCT) and either single (n = 286) or tandem (n = 34) autologous stem cell transplantation (ASCT) from 1996 to 2012. Additionally, the impact of novel induction regimens was assessed. Median follow-up was 67 months, median overall survival (OS) 62 months, median progression-free survival (PFS) 33 months (95% CI 27-39), and treatment-related death (TRD) 3%. Multivariate analysis revealed age ≥ 60 years ( p = 0.03) and stage 3 according to the International Staging System (p = 0.006) as adverse risk factors regarding PFS. Median OS was significantly better in newly diagnosed MM patients receiving induction therapy with novel agents, e.g., bortezomib, thalidomide, or lenalidomide, compared with a traditional regimen (69 vs. 58 months; p = 0.01). More patients achieved at least a very good partial remission in the period from 2005 to 2012 than from 1996 to 2004 (65 vs. 30%; p < 0.001), with a longer median OS in the later period (71 vs. 52 months, p = 0.027). In conclusion, our analysis confirms HDCT-ASCT as an effective therapeutic strategy in an unselected large myeloma patient cohort with a low TRD rate and improved prognosis due to novel induction strategies. [ABSTRACT FROM AUTHOR]

Bioprospecting for new marine natural products (NPs) has increased significantly over the last decades, leading to an unprecedented discovery of new molecules. Marine invertebrates have been the most important source of these NPs, with researchers commonly targeting particular taxonomic groups, marine regions and/or molecules from specific chemical groups. The present review focuses on new NPs identified from marine invertebrates between 2000 and 2009, and performs a detailed analysis on: (1) the chemical groups of these NPs; (2) the association of particular chemical groups to specific marine invertebrate taxa; and (3) the yielding of molecules from the same chemical group from organisms occurring in a particular geographic region. Our survey revealed an increasing number of new terpenoids being discovered between 2000 and 2009, contrasting with the decreasing trend in the discovery of new alkaloids and aliphatic molecules. Overall, no particular association was identified between marine invertebrate taxa and chemical groups of new NPs. Nonetheless, it is worth noting that most NPs recorded from cnidarians and mollusks were terpenoids, while most NPs identified in echinoderms were aliphatic compounds or carbohydrates. The geographical trends observed in our study do not support the idea of particular chemical groups of new NPs being associated with marine invertebrates from any specific geographical region, as NPs from different chemical groups were commonly distributed worldwide.