Class Of Products Research Articles

Biostimulants with glycine betaine or kelp extract alleviate heat stress in red raspberry (Rubus idaeus)

Biostimulants are an emerging and innovative class of products that may mitigate the adverse effects of extreme heat, but research on their efficacy in fruit crops is limited. This study addressed this knowledge gap by evaluating the performance of three biostimulants, FRUIT ARMOR™, Optysil®, and KelpXpress™ [active ingredients glycine betaine, silicon, and kelp (Ascophyllum nodosum) extract, respectively] applied to three raspberry genotypes exposed to high temperatures (Tmax ≥ 35 °C/day) inside a glasshouse. ‘Meeker’ consistently maintained high chlorophyll fluorescence (Fv/Fm) and photosynthesis under control and biostimulant treatments. However, Fv/Fm and photosynthesis of WSU 2188 and ORUS 4715-2 increased when treated with FRUIT ARMOR™. KelpXpress™ also improved the Fv/Fm and photosynthesis of WSU 2188. ‘Meeker’ and WSU 2188 plants treated with FRUIT ARMOR™ and KelpXpress™ accumulated more anthocyanins and exhibited greater shoot and total biomass than ORUS 4715-2. Results demonstrate genotype and biostimulants vary in their ability to mitigate heat stress over time. Superior performance of ‘Meeker’ under control and biostimulant treatments manifested in improved heat tolerance. Biostimulants improved WSU 2188 and ORUS 4715-2 thermotolerance by improving PSII, photosynthetic, and antioxidative capacities. Results indicate biostimulants containing glycine betaine and kelp (Ascophyllum nodosum) extract enhance thermotolerance and may contribute to climate resiliency among commercial fruit crops exposed to heat stress.

Pseudopterosin Biosynthesis: Unravelling a Decades Old Problem in Animal Specialized Metabolism.

Soft corals are prolific producers of terpenoids, such as pseudopterosins. The exact biosynthetic pathway of these anti-inflammatory diterpene glycosides has eluded the scientific community for decades. Using a forward genetic approach, we have identified, cloned, and expressed the key genes involved in pseudopterosin biosynthesis. We characterized a unique class of multifunctional cytochrome P450 enzymes that catalyze a cascade reaction that produces a nearly mature natural product using a single enzyme. This clarifies the previously proposed biosynthetic pathways to pseudopterosin A and its relatives. The mechanism of the oxidative cascade was probed using in vivo feeding studies in Saccharomyces cerevisiae expressing heterologous coral genes. The cascade produces the pseudopterosin aglycone 7,8-dihydroxyerogorgiaene via elisabethatrienol and its epimer, starting from elisabethatriene. This discovery demonstrates the potential to produce this valuable class of natural products using fermentation.

Ring strain governs transmetalation behaviour at a tucked-in iron complex.

Studies that independently investigate [M]-C transmetalation reactions using two different metals are uncommon and yet understanding this reactivity is important to unlocking new synthetic approaches and product classes. Here, we show that the strained [Fe]-C complex, [(η6-C5Me4-CH2)Fe(diphosphine)] undergoes transmetalation with rhodium(I) and iridium(I) diolefin salts, leading to rapid Fe-C(sp3) bond cleavage and M-C(sp3) (M = Rh or Ir) bond generation.

Mining of antioxidant sesquiterpene lactones from the aerial parts of Saussurea involucrata with feature-based molecular network strategy.

Sesquiterpene lactones (SLs) are a class of natural products with diverse structural scaffoldings and biological activities, making them intriguing objects in the fields of pharmaceutical industry, drug development, and pharmacology. Herein, fifteen SLs, including eleven undescribed SLs compounds sauruintones A-K (1-8 and 13-15), were isolated and identified from the aerial parts of Saussurea involucrata. Their structures were characterized by using mass spectrometry, spectroscopic methods, computational calculations, and single crystal X-ray diffraction. The Feature-Based Molecular Network (FBMN) strategy was utilized for the annotation of SLs with their MS/MS fragmentation patterns. Most of the SLs exerted their protective effects against oxidative stress by enhancing the levels of antioxidant enzyme (CAT) and reducing the malondialdehyde (MDA) levels. Among them, compound 12 exhibited potent reactive oxygen species (ROS) inhibitory activities and enhanced the activities of CAT, superoxide dismutase (SOD), and glutathione peroxidase (GSH), and decreased the content of MDA at concentrations of 10-25 μM. Further RT-qPCR assays and western blot analysis revealed it reduced the level of ROS by activating the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway.

A metabologenomics strategy for rapid discovery of polyketides derived from modular polyketide synthases.

Bioinformatics-guided metabolomics is a powerful means for the discovery of novel natural products. However, the application of such metabologenomics approaches on microbial polyketides, a prominent class of natural products with diverse bioactivities, remains largely hindered due to our limited understanding on the mass spectrometry behaviors of these metabolites. Here, we present a metabologenomics approach for the targeted discovery of polyketides biosynthesized by modular type I polyketide synthases. We developed the NegMDF workflow, which uses mass defect filtering (MDF) supported by bioinformatic structural prediction, to connect the biosynthetic gene clusters to corresponding metabolite ions obtained under negative ionization mode. The efficiency of the NegMDF workflow is illustrated by rapid characterization of 22 polyketides synthesized by three gene clusters from a well-characterized strain Streptomyces cattleya NRRL 8057, including cattleyatetronates, new members of polyketides containing a rare tetronate moiety. Our results showcase the effectiveness of the MDF-based metabologenomics workflow for analyzing microbial natural products, and will accelerate the genome mining of microbial polyketides.

2-Acylpyrrole-based alkaloids from the leaves of Sauropus spatulifolius and their α-glucosidase inhibitory activities.

Pyrrole alkaloids are a class of natural products with intriguing structures and promising biological actives. Within the Sauropus plants, these alkaloids are mainly present in Sauropus spatulifolius. An investigation of the leaves of S. spatulifoliuswas conducted to discover novel and bioactive pyrrole alkaloids. This study led to the identification of 38 alkaloids, including 21 new pyrrole alkaloids (1-5, 13, 16, 19-23, 26-31, 33, 35, and 36), along with 17 related analogues (6-12, 14, 15, 17, 18, 24, 25, 32, 34 37, and 38). The structures of the new compounds were elucidated by NMR, HRESIMS, electronic circular dichroism (ECD), and X-ray diffraction analysis. Notably, compounds 28-31 were identified as pyrrole alkaloids with unprecedented skeletons. Compounds 28 and 29 featured a 2-acylpyrrole alkaloid and a cinnamic acid heterodimers, while 30 and 31 possessed a pyrrolooxazinone scaffold with a 1,2-hexadecanediol moiety. These structures were rare in plants. Three compounds (27, 31, and 38) displayed α-glucosidase inhibitory activity. Particularly, compounds 27 (IC50: 320.3μM) and 31 (IC50: 153.7μM) exhibited stronger activity than that of acarbose (IC50: 545.9μM). Molecular docking studies showed the strong interactions of the three bioactive compounds with the α-glucosidase protein. Additionally, compounds 27, 31, and 38 showed significant effects on enhancing glucose consumption in HepG2 cells.

NaturePred: A Tool for Revolutionizing Natural Product Classification with Artificial Intelligence

Background: The identification and classification of natural products are vital in drug discovery and bioactive compound exploration. Traditional methods are laborious and timeconsuming, necessitating innovative tools for accurate predictions using advanced AI techniques. Objectives: This paper presents NaturePred, a user-friendly tool designed to predict the class of natural products and calculate eight physicochemical properties of protein sequences. It aims to accurately predict five distinct classes of natural product biosynthetic gene clusters (BGCs): Polyketide Synthases (PKS), Non-ribosomal Peptide Synthetases (NRPS), Ribosomally Synthesized and Post- Translationally Modified Peptides (RiPPs), Terpenes, and PKS-NRPS Hybrids. It also addresses reliability in multi-class classification with a 90% confidence score threshold. Method: NaturePred offers three input options: single protein sequence, CSV file, or GenBank (.gbk) file. It uses a pipeline with a Natural Language Processing model based on TF-IDF (Term Frequency- Inverse Document Frequency) and a Logistic Regression classifier. Predictions are made if the confidence score exceeds 90%; otherwise, "None of the above class" is predicted. Evaluation with unseen data from the MiBIG database shows high accuracy (~96%) in assigning BGCs. Results: NaturePred provides accurate predictions with high confidence scores, demonstrating reliability across different datasets. It calculates eight physicochemical properties of protein sequences, offering valuable insights for further analysis. Conclusion: NaturePred's integrated features, including versatile input options, accurate predictions, and physicochemical property calculations, make it an indispensable tool in natural product research. By addressing classification challenges, NaturePred facilitates drug discovery and bioactive compound exploration, advancing the field. Tool available: (http://login1.cabgrid.res.in:5101/).

Expanding Polycyclic Tetramate Macrolactam (PoTeM) Core Structure Diversity by Chemo-Enzymatic Synthesis and Bioengineering.

Polycyclic tetramate macrolactams (PoTeMs) represent a growing class of bioactive natural products that are derived from a common tetramate polyene precursor, lysobacterene A, produced by an unusual bacterial iterative polyketide synthase (PKS) / non-ribosomal peptide synthetase (NRPS). The structural and functional diversity of PoTeMs is biosynthetically elaborated from lysobacterene A by pathway-specific cyclizing and modifying enzymes. This results in diverse core structure decoration and cyclization patterns. However, approaches to directly edit the PoTeM carbon skeleton are currently not existing. We thus set out to modify the PoTeM core structure by exchanging the natural L-ornithine-derived building block by L-lysine, hence extending macrocycle size by an additional CH2 group. We developed streamlined synthetic access to lysobacterene A and the corresponding extended analog and achieved cyclization of both precursors by the cognate PoTeM cyclases IkaBC in vitro. This chemo-enzymatic approach corroborated the catalytic competence of IkaBC to produce a larger macrolactam yielding homo-ikarugamycin. We thus engineered the adenylation domain active site of IkaA to directly accept L-lysine, which upon co-expression with IkaBC delivered a recombinant bacterial homo-ikarugamycin producer. Our work establishes an entirely new PoTeM structural framework and sets the stage for the biotechnological diversification of the PoTeM natural product class in general.

Biosynthesis of Depsides, Depsidones, and Diphenyl Ethers from Fungi and Lichens

Depsides are a class of natural products in which two or more (poly)phenolic acid derivatives are linked by an ester bond. Depsides and related natural products, such as depsidones and diphenyl ethers, are widespread in nature and exhibit a wide range of biological activities. Although their biosynthesis has attracted considerable research interest for many decades, it remained largely elusive until recently. Recent studies have revealed the molecular mechanisms underlying the biosynthesis of several depsides and related natural products, uncovering unique enzymatic chemistry in their biosynthetic pathways. This review summarizes the biosynthetic pathways and mechanisms for depsides, depsidones, and diphenyl ethers, focusing on fungi and lichens, which are the primary producers of these compounds.

Microbe Engineering to Provide Drimane-Type Building Blocks for Chiral Pool Synthesis of Meroterpenoids.

Drimane-type merosesquiterpenoids (DMT) are a class of natural products with diverse structures and broad biological activity. Classical DMT synthesis relies on atom-inefficient plant-derived chiral pool building blocks, while alternative drimane-type building blocks such as drimenol and albicanol offer more direct routes but face production challenges. In this study, we engineered a microbial platform for efficient production of these building blocks. By optimizing the PhoN-IPK system through rational engineering and incorporating a Nudix hydrolase, we achieved a drimenol production of 398 mg/L and high albicanol titers of 1805 mg/L in shake flasks and 3.5 g/L in a bioreactor. Structural analysis and molecular dynamics simulations of the engineered PhoN provided insights into its improved catalytic efficiency. We demonstrated the utility of this platform by synthesizing several DMT using albicanol as the starting material, reducing the number of synthetic steps and improving overall efficiency as compared to classical approaches.

Palladium-Catalyzed Reductive and Redox-Neutral Cyclization Approach to the Southern Core of Avermectins.

The avermectins make up a biologically relevant class of complex natural products that continue to inspire the development of new strategies in chemical synthesis. Herein, we disclose a concise synthesis of the southern core of avermectin aglycon. The key hydrobenzofuran was forged by either reductive cyclization or cycloisomerization, both using a cationic palladium precatalyst. This hydropalladation strategy generated the hydrofuran ring under mild conditions, enabling the rapid construction of the tetra-substituted carbon stereocenter.

Assessing the Impact of the Leader Peptide in Protease Inhibition by the Microviridin Family of RiPPs.

Background: Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing class of natural products biosynthesized from a genetically encoded precursor peptide. RiPPs have attracted attention for the ability to generate and screen libraries of these compounds for useful biological activities. To facilitate this screening, it is useful to be able to do so with the leader peptide still present. We assessed the suitability of the microviridin family for these screening experiments by determining their activity with the leader peptide still present. Methods: Modified precursor peptides with the leader present were heterologously expressed in Escherichia coli. Their ability to inhibit elastase was tested with a fluorogenic substrate. HPLC was used to monitor degradation of the modified precursor peptides by elastase. SDS-PAGE was used to determine the ability of immobilized modified precursor peptide to pull down elastase. Results: We found that the fully modified precursor peptide of microviridin B can inhibit the serine protease elastase with a low nanomolar IC50, and that the fully modified precursor with an N-terminal His-tag can mediate interactions between elastase and Ni-NTA resin, all indicating leader peptide removal is not necessary for microviridins to bind their target proteases. Additionally, we found that a bicyclic variant was able to inhibit elastase with the leader peptide still present, although with a roughly 100-fold higher IC50 and being subject to hydrolysis by elastase. Conclusions: These results open a pathway to screening libraries of microviridin variants for improved protease inhibition or other characteristics that can serve as, or as inspirations for, new pharmaceuticals.

Bacterial Cytochrome P450 Catalyzed Macrocyclization of Ribosomal Peptides.

Macrocyclization is a vital process in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), significantly enhancing their structural diversity and biological activity. Universally found in living organisms, cytochrome P450 enzymes (P450s) are versatile catalysts that facilitate a wide array of chemical transformations and have recently been discovered to contribute to the expansion and complexity of the chemical spectrum of RiPPs. Particularly, P450-catalyzed biaryl-bridged RiPPs, characterized by highly modified structures, represent an intriguing but underexplored class of natural products, as demonstrated by the recent discovery of tryptorubin A, biarylitide and cittilin. These P450 enzymes demonstrate their versatility by facilitating peptide macrocyclization through the formation of carbon-carbon (C-C), carbon-nitrogen (C-N) and ether bonds between the side chains of tyrosine (Tyr), tryptophan (Trp) and histidine (His). This Review briefly highlights the latest progress in P450-catalyzed macrocyclization within RiPP biosynthesis, resulting in the generation of structurally complex RiPPs. These findings have expedited the discovery and detailed analysis of new P450s engaged in RiPP biosynthetic pathways.

Discovery of Non-Peptide GLP-1 Positive Allosteric Modulators from Natural Products: Virtual Screening, Molecular Dynamics, ADMET Profiling, Repurposing, and Chemical Scaffolds Identification.

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. Methods: This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation. The database, obtained from the Coconut website, was filtered according to a set of physicochemical descriptors, then was shape screened against the crystal ligand conformation. This filtered database consisting of 26,325 compounds was used for virtual screening against the GLP-1 allosteric site. Results: The results identified ten best hits with the XP score ranging from -9.6 to -7.6 and MM-GBSA scores ranging from -50.8 to -32.4 and another 58 hits from docked pose filter and a second round of XP docking and MM-GBSA calculation followed by molecular dynamics. The analysis of results identified hits from various natural products (NPs) classes, to whom attributed antidiabetic and anti-obesity effects have been previously reported. The results also pointed to β-lactam antibiotics that may be evaluated in drug repurposing studies for off-target effects. The calculated ADMET properties for those hits revealed suitable profiles for further development in terms of bioavailability and toxicity. Conclusions: The current study identified several NPs as potential GLP-1 positive allosteric modulators and revealed common structural scaffolds including peptidomimetics, lactams, coumarins, and sulfonamides with peptidomimetics being the most prominent especially in indole and coumarin cores.

Improved self-training-based distant label denoising method for cybersecurity entity extractions.

The task of named entity recognition (NER) plays a crucial role in extracting cybersecurity-related information. Existing approaches for cybersecurity entity extraction predominantly rely on manual labelling data, resulting in labour-intensive processes due to the lack of a cybersecurity-specific corpus. In this paper, we propose an improved self-training-based distant label denoising method for cybersecurity entity extraction. Firstly, we create two domain dictionaries of cybersecurity. Then, an algorithm that combines reverse maximum matching and part-of-speech tagging restrictions is proposed, for generating distant labels for the cybersecurity domain corpus. Lastly, we propose a high-confidence text selection method and an improved self-training algorithm that incorporates a teacher-student model and weight update constraints, for exploring the true labels of low-confidence text using a model trained on high-confidence text, thereby reducing the noise in the distant annotation data. Experimental results demonstrate that the cybersecurity distantly-labelled data we obtained is of high quality. Additionally, the proposed constrained self-training algorithm effectively improves the F1 score of several state-of-the-art NER models on this dataset, yielding a 3.5% improvement for the Vendor class and a 3.35% improvement for the Product class.

Naturally Occurring Cleistanthane Diterpenoids and Their Biological Activities.

Cleistanthane diterpenoids, an important class of active natural products, are characterized by a 6/6/6 tricycle system and contain a variety of functional groups. Studies have shown that cleistanthane diterpenoids are widespread in various higher plants and endophytic fungi and exhibit a wide range of biological activities. This review provides extensive coverage of naturally occurring cleistanthane diterpenoids discovered from 1973 to 2024 and sheds light on the sources, structures, biological effects, and primary molecular mechanisms of them and provides a useful reference for the further study and development of these compounds.

Enzymatic epimerization of monoterpene indole alkaloids in Kratom.

Monoterpene indole alkaloids (MIAs) are a large, structurally diverse class of bioactive natural products. These compounds are biosynthetically derived from a stereoselective Pictet-Spengler condensation that generates a tetrahydro-β-carboline scaffold characterized by a 3 S stereocenter. However, a subset of MIAs contain a non-canonical 3 R stereocenter. Herein, we report the basis for 3 R -MIA biosynthesis in Mitragyna speciosa (Kratom). We discover the presence of the iminium species, 20 S -3-dehydrocorynantheidine, which led us to hypothesize that isomerization of 3 S to 3 R occurs by oxidation and stereoselective reduction downstream of the initial Pictet-Spengler condensation. Isotopologue feeding experiments implicated young leaves and stems as the sites for pathway biosynthesis, facilitating the identification of an oxidase/reductase pair that catalyzes this epimerization. This enzyme pair has broad substrate specificity, suggesting that the oxidase and reductase may be responsible for the formation of many 3 R -MIAs and downstream spirooxindole alkaloids in Kratom. These enzymes allow biocatalytic access to a range of previously inaccessible pharmacologically active compounds.

Sorbent-Based Sampling With Two-Stage Trapping/Desorption Coupled to Comprehensive Two-Dimensional Gas Chromatography and Mass Spectrometry for Terpenoids Profiling in Cannabis.

Cannabis inflorescences represent an important source of many high-value bioactive specialized metabolites, among which the family of terpenes or terpenoids that are the largest classes of natural products known. Besides their biological activities either alone or synergistic with other terpenoids and/or cannabinoids, they are responsible for their distinctive flavour. In this study, we exploited the separation power and identification capabilities of comprehensive two-dimensional gas chromatography coupled to mass spectrometry (GC×GC-MS) for the profiling of terpenes and terpenoids in cannabis inflorescences. The dynamic headspace (DHS) used herein for the extraction was chosen for its sensitivity, portability, suitability, as well as its versatility of sampling various natural products, including plant raw materials and different plant parts. The enrichment method and the following desorption into the GC were developed and optimized on both standards and real samples considering different sorbent traps (i.e. Tenax-TA, Carbotrap T420, Carbotrap 202), and evaluating key performance values. Analyte coverage, recovery and response reproducibility were used for the evaluation of the best performing thermal desorption tube. Considering terpenoids profiling on cannabis inflorescences, satisfactory extraction performance was observed with both Tenax-TA and Carbotrap T420. However, Tenax-TA provided a wider analyte coverage beyond the class of terpenoids, thus can be better suited for non-targeted analysis. On the other hand, peak width, peak height, peak quality and resolution were considered for the optimization of the chromatographic process, and more specifically the injection process, demonstrating the benefit of a secondary trapping/desorption stage with a cryotrap. Finally, considering the final DHSE-TD-GC×GC-MS conditions, terpenes and terpenoids were profiled in real-world cannabis inflorescences, highlighting the differences among the chemovars.

A comprehensive review on oral nicotine pouches: Available scientific evidence and future research needs.

Oral nicotine pouches (ONPs) are an emergent class of tobacco products that, unlike conventional oral smokeless tobacco products, contain a nicotine powder instead of tobacco leaves. This review synthesizes available data on ONPs in key research domains including survey studies, marketing/advertising studies, chemical characterization and in vitro studies, and clinical studies. Research findings relevant for ONP regulations are summarized, including who uses these products and why, how marketing tactics influence appeal and use intentions, what harmful and potentially harmful constituents they contain, and what acute effects they have on humans. Taken together, the current data suggest that ONPs likely produce less harm to individual users than conventional tobacco products (e.g., moist snuff, cigarettes) and can acutely suppress nicotine/tobacco withdrawal symptoms among current cigarette smokers. Thus, ONPs may be a viable harm reduction option for individuals who switch completely to using them from conventional products. However, randomized controlled trials are needed to determine if established tobacco users would use ONPs long term, and more independent academic research is needed given that most ONP studies to date are tobacco industry-funded. Additionally, ONPs have qualities (e.g., flavors, marketing claims of "tobacco free") that could increase appeal among youth and young adults, and these products can deliver nicotine at levels sufficient to cause dependence; widespread adoption of ONPs among otherwise nicotine-naive individuals may reduce their net public health benefit. This review concludes by suggesting future research directions necessary to increase scientific understanding of ONPs and inform regulations for these increasingly popular products. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Natural Products as Inhibitors of Coronavirus: An Update

Abstract: In the past couple of decades, several corona virus infections have alarmed the world claiming deaths of huge population over the globe. Effective anti-viral agents have been researched for treatment of COVID-19 infection. Vaccination has come up as an ultimate prevention against SARS-CoV-2virus as many vaccines have been recommended by WHO to be used for prevention from COVID-19. Alternative treatment strategies to combat infection include drug repurposing as well as supportive therapies. Traditional medicines being used from ancient times for different disease conditions provide a wealth of chemical diversity. Different classes of natural products are being utilized to study their antiviral properties and contributed in past for different viral diseases. The aim of current review is to enumerate different secondary metabolites and their pharmacophoric features against corona viruses that can be further optimized to develop more potent inhibitors specific to SARS-CoV-2. This review systematically evaluates natural products and their synthetic/ semisynthetic analogs belonging to terpenoids, polyphenols, saponins, and alkaloids having antiviral activity against coronaviruses. The information obtained from scope of Indian medicinal plants is also discussed which may be evaluated in future against SARS-CoV-2. Thus, it is proposed that the natural products may be used to develop potential inhibitors using the knowledge gained from similar studies to prevent morbidity and mortalities due to SARS-CoV-2.