The Kavaratamides: Discovery of Linear Lipodepsipeptides from the Marine Cyanobacterium Moorena bouillonii Using a Comparative Chemogeographic Analysis.

Kavaratamide A (1), a new linear lipodepsipeptide possessing an unusual isopropyl-O-methylpyrrolinone moiety, was discovered from the tropical marine filamentous cyanobacterium Moorena bouillonii collected from Kavaratti, India. A comparative chemogeographic analysis of M. bouillonii collected from six different geographical regions led to the prioritized isolation of this metabolite from India as distinctive among our data sets. AI-based structure annotation tools, including SMART 2.1 and DeepSAT, accelerated the structure elucidation by providing useful structural clues, and the full planar structure was elucidated based on comprehensive HRMS, MS/MS fragmentation, and NMR data interpretation. Subsequently, the absolute configuration of 1 was determined using advanced Marfey's analysis, modified Mosher's ester derivatization, and chiral-phase HPLC. The structures of kavaratamides B (2) and C (3) are proposed based on a detailed analysis of their MS/MS fragmentations. The biological activity of kavaratamide A was also investigated and found to show moderate cytotoxicity to the D283-medullablastoma cell line.

Outlining the Hidden Curriculum: Perspectives on Successfully Navigating Scientific Conferences.

Scientific conferences and meetings are valuable opportunities for researchers to network, communicate, and develop knowledge. For early career scientists, conferences can also be intimidating, confusing, and overwhelming, especially without having adequate preparation or experience. In this Perspective, we provide advice based on previous experiences navigating scientific meetings and conferences. These guidelines outline parts of the hidden curriculum around preparing for and attending meetings, navigating conference sessions, networking with other scientists, and participating in social activities while upholding a recommended code of conduct.

Structure and Biosynthesis of Hectoramide B, a Linear Depsipeptide from Marine Cyanobacterium Moorena producens JHB Discovered via Coculture with Candida albicans.

The tropical marine cyanobacterium Moorena producens JHB is a prolific source of secondary metabolites with potential biomedical utility. Previous studies on this strain led to the discovery of several novel compounds such as hectochlorins and jamaicamides. However, bioinformatic analyses of its genome indicate the presence of numerous cryptic biosynthetic gene clusters that have yet to be characterized. To potentially stimulate the production of novel compounds from this strain, it was cocultured with Candida albicans. From this experiment, we observed the increased production of a new compound that we characterize here as hectoramide B. Bioinformatic analysis of the M. producens JHB genome enabled the identification of a putative biosynthetic gene cluster responsible for hectoramide B biosynthesis. This work demonstrates that coculture competition experiments can be a valuable method to facilitate the discovery of novel natural products from cyanobacteria.

Irpetones A and B, Anti-Osteoclastic Heptaketides from a Marine Mesophotic Zone Ircinia Sponge-Associated Fungus Irpex sp. NBUF088.

Chemical investigation of Irpex sp. NBUF088, associated with an Ircinia sp. sponge located at an 84 m deep mesophotic zone, led to the discovery of two new heptaketides, named irpetones A (1) and B (2). Their structures were identified by analysis of spectroscopic data and quantum-chemical calculations. Compound 1 exhibited inhibition against the receptor activator of NF-κB ligand-induced osteoclastogenesis in bone marrow monocytes with an IC50 of 6.3 ± 0.2 µM, causing no notable cytotoxicity. It was also determined that 1 inhibited the phosphorylation of ERK1/2-JNK1/2-p38 MAPKs and the nuclear translocation of NF-κB, consequently suppressing the activation of MAPK and NF-κB signaling pathways induced by the NF-κB ligand.

Pestanoid A, a Rearranged Pimarane Diterpenoid Osteoclastogenesis Inhibitor from a Marine Mesophotic Zone Chalinidae Sponge-Associated Fungus, Pestalotiopsis sp. NBUF145.

One novel rearranged pimarane diterpenoid, pestanoid A (1), and two reported molecules, nodulisporenones A (2) and B (3), were discovered from Pestalotiopsis sp. NBUF145 fungus associated with a 62 m deep mesophotic ("twilight") zone Chalinidae sponge. The structures of 1-3 were identified by spectrometry, spectroscopy, quantum-chemical calculations, and X-ray crystallography. Compounds 1 and 2 inhibited bone marrow monocyte osteoclastogenesis in vitro with the IC50 values 4.2 ± 0.2 µM and 3.0 ± 0.4 µM, respectively, without observed cytotoxicity. Both 1 and 2 suppressed the receptor activator of NF-kB ligand-induced MAPK and NF-κB signaling by inhibiting the phosphorylation of ERK1/2-JNK1/2-p38 MAPKs and NF-κB nuclear translocation.

Retinoic Acid Receptor Is a Novel Therapeutic Target for Postoperative Cognitive Dysfunction.

Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterizing by cognitive impairments in the elderly after surgery. There is limited effective treatment available or clear pathological mechanisms known for this syndrome. In this study, a Connectivity Map (CMap) bioinformatics model of POCD was established by using differently expressed landmark genes in the serum samples of POCD and non-POCD patients from the only human transcriptome study. The predictability and reliability of this model were further supported by the positive CMap scores of known POCD inducers and the negative CMap scores of anti-POCD drug candidates. Most retinoic acid receptor (RAR) agonists were negatively associated with POCD in this CMap model, suggesting that RAR might be a novel target for POCD. Most importantly, acitretin, a clinically used RAR agonist, significantly inhibited surgery-induced cognitive impairments and prevented the reduction in RARα and RARα-target genes in the hippocampal regions of aged mice. The study denotes a reliable CMap bioinformatics model of POCD for future use and establishes that RAR is a novel therapeutic target for treating this clinical syndrome.

Metabolomics Approaches for the Diagnosis, Treatment, and Better Disease Management of Viral Infections.

Metabolomics is an analytical approach that involves profiling and comparing the metabolites present in biological samples. This scoping review article offers an overview of current metabolomics approaches and their utilization in evaluating metabolic changes in biological fluids that occur in response to viral infections. Here, we provide an overview of metabolomics methods including high-throughput analytical chemistry and multivariate data analysis to identify the specific metabolites associated with viral infections. This review also focuses on data interpretation and applications designed to improve our understanding of the pathogenesis of these viral diseases.

Structure and Biosynthesis of Hectoramide B, a Linear Depsipeptide from the Marine Cyanobacterium Moorena producens JHB Discovered via Co-culture with Candida albicans.

The tropical marine cyanobacterium Moorena producens JHB is a prolific source of secondary metabolites with potential biomedical utility. Previous studies of this strain led to the discovery of several novel compounds such as the hectochlorins and jamaicamides; however, bioinformatic analyses of its genome suggested that there were many more cryptic biosynthetic gene clusters yet to be characterized. To potentially stimulate the production of novel compounds from this strain, it was co-cultured with Candida albicans. From this experiment, we observed the increased production of a new compound that we characterize here as hectoramide B. Bioinformatic analysis of the M. producens JHB genome enabled the identification of a putative biosynthetic gene cluster responsible for hectoramide B biosynthesis. This work demonstrates that co-culture competition experiments can be a valuable method to facilitate the discovery of novel natural products from cyanobacteria.

Discrepancy of synaptic and microtubular protein phosphorylation in the hippocampus of APP/PS1 and MAPT×P301S transgenic mice at the early stage of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and is caused by multiple pathological factors, such as the overproduction of ß-amyloid (Aß) and the hyperphosphorylation of tau. However, there is limited knowledge of the mechanisms underlying AD pathogenesis and no effective biomarker for the early diagnosis of this disorder. Thus in this study, a quantitative phosphoproteomics analysis was performed to evaluate global protein phosphorylation in the hippocampus of Aß overexpressing APP/PS1 transgenic mice and tau overexpressing MAPT×P301S transgenic mice, two in vivo AD model systems. These animals, up to ten weeks old, do not exhibit cognitive dysfunctions and are widely used to simulate early-stage AD patients. The number of differentially phosphorylated proteins (DPPs) was greater for APP/PS1 transgenic mice than for MAPT×P301S transgenic mice. The function of the DPPs in APP/PS1 transgenic mice was mainly related to synapses, while the function of the DPPs in MAPT×P301S transgenic mice was mainly related to microtubules. In addition, an AD core network was established including seven phosphoproteins differentially expressed in both animal models, and the function of this core network was related to synapses and oxidative stress. The results of this study suggest that Aß and tau induce different protein phosphorylation profiles in the early stage of AD, leading to the dysfunctions in synapses and microtubule, respectively. And the detection of same DPPs in these animal models might be used for early AD diagnosis.

Hidden in the photograph: The myth of complete metabolic coverage possible in metabolomics investigations.

Since the late 1970s, many 'omics-style investigations have advanced our understanding of systems at all levels, from community level, through organismal, to individual cellular processes. Beginning with genomics and progressing through transcriptomics, proteomics and finally to metabolomics, the scope of interest shifts significantly from what is genetically possible to what is currently expressed, produced and measurable in a system. While the ideal goal of any 'omics investigation is to fully describe a system, loss of information occurs at each decision-making juncture. These losses are often not considered in the experimental planning stage but, when combined, they drastically affect the power of an investigation and the conclusions that can be drawn from it. Herein we discuss through the analogy of photography many of the decision-making junctures of metabolomics investigations and the resultant losses of information occurring at each.

Rose Bengal inhibits ß-amyloid oligomers-induced tau hyperphosphorylation via acting on Akt and CDK5 kinases.

RATIONALE: Tau hyperphosphorylation and aggregation is considered as a main pathological mechanism underlying Alzheimer's disease (AD). Rose Bengal (RB) is a synthetic dye used for disease diagnosis, which was reported to inhibit tau toxicity via inhibiting tau aggregation in Drosophila. However, it was unknown if RB could produce anti-AD effects in rodents. OBJECTIVES: The research aimed to investigate if and how RB could prevent ß-amyloid (Aß) oligomers-induced tau hyperphosphorylation in rodents. METHODS AND RESULTS: RB was tested in vitro (0.3-1 µM) and prevented Aß oligomers-induced tau hyperphosphorylation in PC12 cells. Moreover, RB (10-30 mg/kg, i.p.) effectively attenuated cognitive impairments induced by Aß oligomers in mice. Western blotting analysis demonstrated that RB significantly increased the expression of pSer473-Akt, pSer9-glycogen synthase kinase-3ß (GSK3ß) and reduced the expression of cyclin-dependent kinase 5 (CDK5) both in vitro and in vivo. Molecular docking analysis suggested that RB might directly interact with GSK3ß and CDK5 by acting on ATP binding sites. Gene Ontology enrichment analysis indicated that RB might act on protein phosphorylation pathways to inhibit tau hyperphosphorylation. CONCLUSIONS: RB was shown to inhibit tau neurotoxicity at least partially via inhibiting the activity of GSK3ß and CDK5, which is a novel neuroprotective mechanism besides the inhibition of tau aggregation. As tau hyperphosphorylation is an important target for AD therapy, this study also provided support for investigating the drug repurposing of RB as an anti-AD drug candidate.

Native metabolomics identifies the rivulariapeptolide family of protease inhibitors.

The identity and biological activity of most metabolites still remain unknown. A bottleneck in the exploration of metabolite structures and pharmaceutical activities is the compound purification needed for bioactivity assignments and downstream structure elucidation. To enable bioactivity-focused compound identification from complex mixtures, we develop a scalable native metabolomics approach that integrates non-targeted liquid chromatography tandem mass spectrometry and detection of protein binding via native mass spectrometry. A native metabolomics screen for protease inhibitors from an environmental cyanobacteria community reveals 30 chymotrypsin-binding cyclodepsipeptides. Guided by the native metabolomics results, we select and purify five of these compounds for full structure elucidation via tandem mass spectrometry, chemical derivatization, and nuclear magnetic resonance spectroscopy as well as evaluation of their biological activities. These results identify rivulariapeptolides as a family of serine protease inhibitors with nanomolar potency, highlighting native metabolomics as a promising approach for drug discovery, chemical ecology, and chemical biology studies.

Discovery of Novel Epoxyketone Peptides as Lipase Inhibitors.

Obesity is the most common nutritional disorder in the developed world and is associated with important comorbidities. Pancreatic lipase (PL) inhibitors play a key role in the metabolism of human fat. A series of novel epoxyketones peptide derivatives were investigated for their pancreatic lipase inhibitory activity. The epoxyketone moiety is a well-known reactive electrophile group that has been used as part of proteasome inhibitors in cancer therapy, and it is widely believed that these are very selective for targeting the proteasome active site. Here we investigated various peptide derivatives with an epoxide warhead for their anti-lipase activity. The assessment of these novel epoxyketones was performed by an in-house method that we developed for rapid screening and identification of lipase inhibitors using GC-FID. Herein, we present a novel anti-lipase pharmacophore based on epoxyketone peptide derivatives that showed potent anti-lipase activity. Many of these derivatives had comparable or more potent activity than the clinically used lipase inhibitors such as orlistat. In addition, the lipase appears to be inhibited by a wide range of epoxyketone analogues regardless of the configuration of the epoxide in the epoxyketone moiety. The presented data in this study shows the first example of the use of epoxyketone peptides as novel lipase inhibitors.

Polysubstituted Cyclopentene Benzamides and Dianthramide Alkaloids from Delphinium anthriscifolium Hance.

Thirteen new benzamide alkaloids, delphiniumines A-M (1-13), together with one known analogue (14), were isolated from Delphinium anthriscifolium Hance. All of the structures were determined by spectroscopic and spectrometric analyses. Absolute configuration for 1 was established using experimental and calculated ECD data, as well as by X-ray crystallography analysis. Compound 1 possesses a previously undescribed polysubstituted cyclopentene carbon framework. Compound 2 was isolated as an artifact from 1 during the extraction process. Compound 7 is glycosylated with a ß-D-glucose unit. Compound 13 bears a chlorine substituent. At a concentration of 10 µM, compounds 6, 8, and 10-12 suppressed LPS-induced NO production in RAW264.7 cells with inhibition rates ranging from 40.3% to 78.8%.

Acremocholone, an Anti-Vibrio Steroid from the Marine Mesophotic Zone Ciocalypta Sponge-Associated Fungus Acremonium sp. NBUF150.

Mesophotic coral ecosystems (MCEs) represent an underexplored source of intriguing natural products. Efforts to discover bioactive metabolites from sponge-associated fungi in MCEs identified a new steroid, acremocholone (1) and its three known analogs (2-4), from Acremonium sp. NBUF150. The Acremonium sp. NBUF150 was isolated from a Ciocalypta sponge located 70 m deep within the South China Sea. The planar structures and absolute configuration of 1-4 were determined from NMR-derived spectroscopic data, HR-ESI-MS, and X-ray crystallography. Compound 1 exhibited antimicrobial inhibition against Vibrio scophthalmi, V. shilonii and V. brasiliensis at minimum inhibitory concentrations of 8 µg/mL; compound 2 inhibited V. shilonii and V. brasiliensis at 8 and 32 µg/mL, respectively, and compound 4 inhibited growth of V. brasiliensis at 16 µg/mL. Sponge associated fungi from MCEs represent a promising resource of anti-Vibrio drug leads for aquaculture use.

Targeted Isolation of Two New Anti-inflammatory and UV-A Protective Dipyrroloquinones from the Sponge-associated Fungus Aspergillus tamarii MCCF102.

In following up on observed in vitro anti-inflammatory activity of the organic extract of the marine sponge-derived fungus Aspergillus tamarii MCCF102, two new dipyrrolobenzoquinones, terreusinone B and C (1: and 2: ), were discovered along with the known analogue, terreusinone (3: ). The structures of 1: -3: were determined by spectroscopic and spectrometric analyses, along with chemical inter-conversion. In vitro testing on lipopolysaccharide (LPS) stimulated RAW 264.7 murine macrophage cells revealed that 1: -3: exhibit anti-inflammatory activity by inhibiting nitric oxide production in a dose-dependent manner (IC50 < 1 µM) without any cytotoxicity observed at the same concentrations. Due to this and the UV-A absorptive properties imparted by the highly conjugated structures of these molecules, the potential for using 1: -3: or related analogues as natural sunscreen components is suggested. Gene sequencing and informatics biosynthetic gene cluster comparisons were insufficient to confidently elucidate the biosynthetic origins of these compounds, possibly suggesting the occurrence of a gene cluster not detected in the initial sequencing or a non-canonical pathway that should be further investigated.

Targeted Discovery of Amantamide B, an Ion Channel Modulating Nonapeptide from a South China Sea Oscillatoria Cyanobacterium.

Amantamide B (1) is a new linear nonapeptide analogue of the cyanobacterial natural product amantamide A (2), and both have methyl ester and butanamide termini. These compounds were discovered in this study from the organic extract of a tropical marine filamentous cyanobacterium, Oscillatoria sp., collected around the Paracel Islands in the South China Sea. The use of LC-MS/MS molecular networking for sample prioritization and as an analytical dereplication tool facilitated the targeted isolation of 1 and 2. These molecules were characterized by spectroscopy and spectrometry, and configurational assignments were determined using chemical degradation and chiral-phase HPLC analysis. Compounds 1 and 2 modulated spontaneous calcium oscillations without notable cytotoxicity at 10 µM in short duration in vitro testing on primary cultured neocortical neurons, a model system that evaluates neuronal excitability and/or the potential activity on Ca2+ signaling. Both molecules were also found to be moderately cytotoxic in longer duration bioassays, with in vitro IC50 values of 1-10 µM against CCRF-CEM human T lymphoblastoid cells and U937 human histiocytic lymphoma cells. These formerly undiscovered bioactivities of known compound 2 expand upon its previously reported function as a selective CXCR7 agonist among 168 GPCR targets.

Fucoxanthin has potential for therapeutic efficacy in neurodegenerative disorders by acting on multiple targets.

Fucoxanthin, one of the most abundant carotenoids from edible brown seaweeds, for years has been used as a bioactive dietary supplement and functional food ingredient. Recently, fucoxanthin was reported to penetrate the blood-brain barrier, and was superior to other carotenoids to exert anti-neurodegenerative disorder effects via acting on multiple targets, including amyloid protein aggregation, oxidative stress, neuroinflammation, neuronal loss, neurotransmission dysregulation and gut microbiota disorder. However, the concentration of fucoxanthin required for in vivo neuroprotective effects is somewhat high, and the poor bioavailability of this molecule might prevent its clinical use. As such, new strategies have been introduced to overcome these obstacles, and may help to develop fucoxanthin as a novel lead for neurodegenerative disorders. Moreover, it has been shown that some metabolites of fucoxanthin may produce potent in vivo neuroprotective effects. Altogether, these studies suggest the possibility for future development of fucoxanthin as a one-compound-multiple-target or pro-drug type pharmaceutical or nutraceutical treatment for neurodegenerative disorders.Trial registration: ClinicalTrials.gov identifier: NCT03625284.Trial registration: ClinicalTrials.gov identifier: NCT02875392.Trial registration: ClinicalTrials.gov identifier: NCT03613740.Trial registration: ClinicalTrials.gov identifier: NCT04761406.

Cadinane Sesquiterpenoids and Their Glycosides from Alangium chinense That Inhibit Spontaneous Calcium Oscillations.

Nine new cadinane sesquiterpenoids, alanenses A-I (1-9), were isolated from the leaves of Alangium chinense together with three previously reported analogues (10-12). The structures of these molecules were elucidated by interpretation of spectroscopic and spectrometric data. Absolute configurations were established by the comparison of experimental and calculated ECD data, chemical degradation studies for sugar moieties, and a single-crystal X-ray diffraction analysis. Compounds 1 and 2 were isolated as racemates, and enantiopurification was achieved by chiral HPLC. Compounds 3-5 are glycosylated cadinanes bearing a ß-d-glucose unit, while compounds 6-9 incorporate a hydroxymethyl group in either the free form or additional ring fusion. The structure of compound 11 was originally misassigned and later revised using additional NMR data. The corrected structure is here supported by X-ray single-crystal analysis. Compounds 1 and 2 inhibit spontaneous calcium channel oscillations at low micromolar concentrations.

Targeted Isolation of a Cytotoxic Cyclic Hexadepsipeptide from the Mesophotic Zone Sponge-Associated Fungus Cymostachys sp. NBUF082.

LC-MS/MS-based molecular networking facilitated the targeted isolation of a new cyclic hexadepsipeptide, cymodepsipeptide (1), and two known analogues, RF-2691A (2) and RF-2691B (3), from the fungus Cymostachys sp. NBUF082 that was derived from a mesophotic zone Aaptos sponge collected near Apo Island. The constitution and configuration of 1 was elucidated through 1D and 2D NMR-spectroscopy, high resolution mass-spectrometry, and chemical degradations including Marfey's analysis and chiral HPLC. It was observed that 1 was moderately cytotoxic against CCRF-CEM human acute lymphocytic leukemia cells in vitro with the IC50 value of 9.2 ± 1.1 µM.