Acidic Cannabinoids Suppress Proinflammatory Cytokine Release by Blocking Store-operated Calcium Entry.

Cannabis sativa has long been known to affect numerous biological activities. Although plant extracts, purified cannabinoids, or synthetic cannabinoid analogs have shown therapeutic potential in pain, inflammation, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting, the underlying mechanisms of action remain ill-defined. In this study we provide the first comprehensive overview of the effects of whole-plant Cannabis extracts and various pure cannabinoids on store-operated calcium (Ca2+) entry (SOCE) in several different immune cell lines. Store-operated Ca2+ entry is one of the most significant Ca2+ influx mechanisms in immune cells, and it is critical for the activation of T lymphocytes, leading to the release of proinflammatory cytokines and mediating inflammation and T cell proliferation, key mechanisms for maintaining chronic pain. While the two major cannabinoids cannabidiol and trans-Δ9-tetrahydrocannabinol were largely ineffective in inhibiting SOCE, we report for the first time that several minor cannabinoids, mainly the carboxylic acid derivatives and particularly cannabigerolic acid, demonstrated high potency against SOCE by blocking calcium release-activated calcium currents. Moreover, we show that this inhibition of SOCE resulted in a decrease of nuclear factor of activated T-cells activation and Interleukin 2 production in human T lymphocytes. Taken together, these results indicate that cannabinoid-mediated inhibition of a proinflammatory target such as SOCE may at least partially explain the anti-inflammatory and analgesic effects of Cannabis.

The Natural Products Atlas: An Open Access Knowledge Base for Microbial Natural Products Discovery.

Despite rapid evolution in the area of microbial natural products chemistry, there is currently no open access database containing all microbially produced natural product structures. Lack of availability of these data is preventing the implementation of new technologies in natural products science. Specifically, development of new computational strategies for compound characterization and identification are being hampered by the lack of a comprehensive database of known compounds against which to compare experimental data. The creation of an open access, community-maintained database of microbial natural product structures would enable the development of new technologies in natural products discovery and improve the interoperability of existing natural products data resources. However, these data are spread unevenly throughout the historical scientific literature, including both journal articles and international patents. These documents have no standard format, are often not digitized as machine readable text, and are not publicly available. Further, none of these documents have associated structure files (e.g., MOL, InChI, or SMILES), instead containing images of structures. This makes extraction and formatting of relevant natural products data a formidable challenge. Using a combination of manual curation and automated data mining approaches we have created a database of microbial natural products (The Natural Products Atlas, www.npatlas.org) that includes 24 594 compounds and contains referenced data for structure, compound names, source organisms, isolation references, total syntheses, and instances of structural reassignment. This database is accompanied by an interactive web portal that permits searching by structure, substructure, and physical properties. The Web site also provides mechanisms for visualizing natural products chemical space and dashboards for displaying author and discovery timeline data. These interactive tools offer a powerful knowledge base for natural products discovery with a central interface for structure and property-based searching and presents new viewpoints on structural diversity in natural products. The Natural Products Atlas has been developed under FAIR principles (Findable, Accessible, Interoperable, and Reusable) and is integrated with other emerging natural product databases, including the Minimum Information About a Biosynthetic Gene Cluster (MIBiG) repository, and the Global Natural Products Social Molecular Networking (GNPS) platform. It is designed as a community-supported resource to provide a central repository for known natural product structures from microorganisms and is the first comprehensive, open access resource of this type. It is expected that the Natural Products Atlas will enable the development of new natural products discovery modalities and accelerate the process of structural characterization for complex natural products libraries.

Characterization of Leptazolines A-D, Polar Oxazolines from the Cyanobacterium Leptolyngbya sp., Reveals a Glitch with the "Willoughby-Hoye" Scripts for Calculating NMR Chemical Shifts.

The bioactivity-guided examination of a Leptolyngbya sp. led to the isolation of leptazolines A-D (1-4), from the culture media, along with two degradation products (5 and 6). Density functional theory nuclear magnetic resonance calculations established the relative configurations of 1 and 2 and revealed that the calculated shifts depended on the operating system when using the "Willoughby-Hoye" Python scripts to streamline the processing of the output files, a previously unrecognized flaw that could lead to incorrect conclusions.

Myrmenaphthol A, Isolated from a Hawaiian Sponge of the Genus Myrmekioderma.

Four compounds (1-4) were isolated from a Hawaiian sponge of the genus Myrmekioderma. Myrmenaphthol A (1) incorporates two unusual elements into an oxidized steroidal core: a naphthyl AB-ring system and a hydroxy group at C-2. A comparison of the experimental and predicted electronic circular dichroism (ECD) spectra of 1 assigned an S configuration to the lone stereocenter (ΔESI = 0.75; similarity factor 0.8137). Known compounds, cinanthrenol A (2), 3,4-dihydroxypregna-5,17-diene-10,2-carbolactone (3), and 3,4-dihydroxypregna-5,20-diene-10,2-carbolactone (4), were also isolated. Despite literature reports of competitive inhibition at nanomolar levels for 2, neither 2 nor the structurally related 1 showed any activity against estrogen receptors at the concentrations tested.

Cytotoxic Sesquiterpenoid Quinones and Quinols, and an 11-Membered Heterocycle, Kauamide, from the Hawaiian Marine Sponge Dactylospongia elegans.

Several known sesquiterpenoid quinones and quinols (1-9), and kauamide (10), a new polyketide-peptide containing an 11-membered heterocycle, were isolated from the extracts of the Hawaiian marine sponge Dactylospongia elegans. The planar structure of 10 was determined from spectroscopic analyses, and its relative and absolute configurations were established from density functional theory (DFT) calculations of the GIAO NMR shielding tensors, and advanced Marfey's analysis of the N-MeLeu residue, respectively. Compounds 1 and 3 showed moderate inhibition of ß-secretase 1 (BACE1), whereas 1-9 exhibited moderate to potent inhibition of growth of human glioma (U251) cells. Compounds 1-2 and 4-7 were also active against human pancreatic carcinoma (Panc-1) cells.

Correction: The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research' by James B. McAlpine et al., Nat. Prod. Rep., 2018, DOI: .

The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

Areca nut extracts mobilize calcium and release pro-inflammatory cytokines from various immune cells.

Betel nut consumption has significant implications for the public health globally, as the wide-spread habit of Areca chewing throughout Asia and the Pacific is associated with a high prevalence of oral carcinoma and other diseases. Despite a clear causal association of betel nut chewing and oral mucosal diseases, the biological mechanisms that link Areca nut-contained molecules, inflammation and cancer remain underexplored. In this study we show that the whole Areca nut extract (ANE) is capable of mobilizing Ca2+ in various immune cell lines. Interestingly, none of the four major alkaloids or a range of other known constituents of Areca nut were able to induce such Ca2+ signals, suggesting that the active components might represent novel or so far unappreciated chemical structures. The separation of ANE into aqueous and organic fractions has further revealed that the calcium-mobilizing molecules are exclusively present in the aqueous extract. In addition, we found that these calcium signals are associated with the activation of several immune cell lines as shown by the release of pro-inflammatory cytokines and increased cell proliferation. These results indicate that calcium-mobilizing molecules present in the aqueous fraction of the Areca nut may critically contribute to the inflammatory disorders affecting betel nut chewers.

Evaluating the impacts of landscape positions and nitrogen fertilizer rates on dissolved organic carbon on switchgrass land seeded on marginally yielding cropland.

Dissolved organic carbon (DOC) through leaching into the soils is another mechanism of net C loss. It plays an important role in impacting the environment and impacted by soil and crop management practices. However, little is known about the impacts of landscape positions and nitrogen (N) fertilizer rates on DOC leaching in switchgrass (Panicum virgatum L.). This experimental design included three N fertilizer rates [0 (low); 56 (medium); 112 (high) kg N ha(-1)] and three landscape positions (shoulder, backslope and footslope). Daily average DOC contents at backslope were significantly lower than that at shoulder and footslope. The DOC contents from the plots that received medium N rate were also significantly lower than the plots that received low N rates. The interactions of landscape and N rates on DOC contents were different in every year from 2009 to 2014, however, no significant consistent trend of DOC contents was observed over time. Annual average DOC contents from the plots managed with low N rate were higher than those with high N rate. These contents at the footslope were higher than that at the shoulder position. Data show that there is a moderate positive relationship between the total average DOC contents and the total average switchgrass biomass yields. Overall, the DOC contents from leachate in the switchgrass land were significantly influenced by landscape positions and N rates. The N fertilization reduced DOC leaching contents in switchgrass field. The switchgrass could retain soil and environment sustainability to some extent. These findings will assist in understanding the mechanism of changes in DOC contents with various parameters in the natural environment and crop management systems. However, use of long-term data might help to better assess the effects of above factors on DOC leaching contents and loss in the switchgrass field in the future.

Enantioselective hydroformylation of N-vinyl carboxamides, allyl carbamates, and allyl ethers using chiral diazaphospholane ligands.

Rhodium complexes of diazaphospholane ligands catalyze the asymmetric hydroformylation of N-vinyl carboxamides, allyl ethers, and allyl carbamates; products include 1,2- and 1,3-aminoaldehydes and 1,3-alkoxyaldehydes. Using glass pressure bottles, short reaction times (generally less than 6 h), and low catalyst loading (commonly 0.5 mol %), 20 substrates are successfully converted to chiral aldehydes with useful regioselectivity and high enantioselectivity (up to 99% ee). Chiral Roche aldehyde is obtained with 97% ee from the hydroformylation of allyl silyl ethers. Commonly difficult substrates such as 1,1- and 1,2-disubstituted alkenes undergo effective hydroformylation with 89-97% ee and complete conversion for six examples. Palladium-catalyzed aerobic oxidative amination of allyl benzyl ether followed by enantioselective hydroformylation yields the ß(3)-aminoaldehyde with 74% ee.