Biomolecules

23 pages, 4983 KiB

Open AccessEditor’s ChoiceArticle

Temporin-SHa and Its Analogs as Potential Candidates for the Treatment of Helicobacter pylori

by Hamza Olleik, Elias Baydoun, Josette Perrier, Akram Hijazi, Josette Raymond, Marine Manzoni, Lucas Dupuis, Ghislain Pauleau, Yvain Goudard, Bruno de La Villéon, Géraldine Goin, Philippe Sockeel, Muhammad Iqbal Choudhary, Eric Di Pasquale, Muhammad Nadeem-ul-Haque, Hunain Ali, Arif Iftikhar Khan, Farzana Shaheen and Marc Maresca

Biomolecules 2019, 9(10), 598; https://doi.org/10.3390/biom9100598 - 11 Oct 2019

Cited by 11 | Viewed by 4863

Abstract

Helicobacterpylori is one of the most prevalent pathogens colonizing 50% of the world’s population and causing gastritis and gastric cancer. Even with triple and quadruple antibiotic therapies, H. pylori shows increased prevalence of resistance to conventional antibiotics and treatment failure. Due to [...] Read more.

Helicobacterpylori is one of the most prevalent pathogens colonizing 50% of the world’s population and causing gastritis and gastric cancer. Even with triple and quadruple antibiotic therapies, H. pylori shows increased prevalence of resistance to conventional antibiotics and treatment failure. Due to their pore-forming activity, antimicrobial peptides (AMP) are considered as a good alternative to conventional antibiotics, particularly in the case of resistant bacteria. In this study, temporin-SHa (a frog AMP) and its analogs obtained by Gly to Ala substitutions were tested against H. pylori. Results showed differences in the antibacterial activity and toxicity of the peptides in relation to the number and position of D-Ala substitution. Temporin-SHa and its analog NST1 were identified as the best molecules, both peptides being active on clinical resistant strains, killing 90–100% of bacteria in less than 1 h and showing low to no toxicity against human gastric cells and tissue. Importantly, the presence of gastric mucins did not prevent the antibacterial effect of temporin-SHa and NST1, NST1 being in addition resistant to pepsin. Taken together, our results demonstrated that temporin-SHa and its analog NST1 could be considered as potential candidates to treat H. pylori, particularly in the case of resistant strains. Full article

(This article belongs to the Special Issue Structure and Function of Antimicrobial Peptides)

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7 pages, 1269 KiB

Open AccessEditor’s ChoiceCommunication

Butyrylcholinesterase Protein Ends in the Pathogenesis of Alzheimer’s Disease—Could BCHE Genotyping Be Helpful in Alzheimer’s Therapy?

by Jacek Jasiecki and Bartosz Wasąg

Biomolecules 2019, 9(10), 592; https://doi.org/10.3390/biom9100592 - 09 Oct 2019

Cited by 36 | Viewed by 7682

Abstract

Late-onset Alzheimer’s disease (AD) is clinically characterized by a progressive decline of memory and other cognitive functions leading to the loss of the ability to perform everyday activities. Only a few drugs have been approved to treat AD dementia over the past century [...] Read more.

Late-onset Alzheimer’s disease (AD) is clinically characterized by a progressive decline of memory and other cognitive functions leading to the loss of the ability to perform everyday activities. Only a few drugs have been approved to treat AD dementia over the past century since the first AD patient was diagnosed. Drugs increasing the availability of neurotransmitters at synapses in the brain are used clinically in the treatment of AD dementia, and cholinesterase inhibitors (ChEIs) are the mainstay of the therapy. A detrimental effect on cognitive function has been reported in patients with pharmacological inhibition of acetylcholinesterase (AChE) by ChEIs and reduced butyrylcholinesterase (BChE) activity due to the single nucleotide polymorphisms. The BChE K-variant (rs1803274), the most common genetic variant of the BCHE gene, was thought to reduce enzyme activity reflecting the lower clinical response to rivastigmine in AD patients. During ChEIs therapy, patients carrying reduced-activity BChE do not present such improved attention like patients with the wild-type enzyme. On the other hand, alterations in the BCHE gene causing enzyme activity reduction may delay AD onset in patients at risk by preserving the level of cortical acetylcholine (ACh). Based on our previous results, we conclude that SNPs localized outside of the coding sequence, in 5’UTR (rs1126680) and/or intron 2 (rs55781031) of the BCHE gene, but not solely K-variant alteration (p.A539T) itself, are responsible for reduced enzyme activity. Therefore, we suspect that not BChE-K itself, but these coexisting SNPs (rs1126680 and rs55781031), could be associated with deleterious changes in cognitive decline in patients treated with ChEIs. Based on the results, we suggest that SNPs (rs1126680) and/or (rs55781031) genotyping should be performed to identify subjects at risk for lowered efficacy ChEIs therapy, and such patients should be treated with a lower rivastigmine dosage. Finally, our sequence analysis of the N-terminal end of N-BChE revealed evolutionarily conserved amino acid residues that can be involved in disulfide bond formation and anchoring of N-BChE in the cell membrane. Full article

(This article belongs to the Special Issue Cholinesterases in Alzheimer's Disease)

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14 pages, 2733 KiB

Open AccessEditor’s ChoiceArticle

Chitosan–Azide Nanoparticle Coating as a Degradation Barrier in Multilayered Polyelectrolyte Drug Delivery Systems

by Steffen Sydow, Armin Aniol, Christoph Hadler and Henning Menzel

Biomolecules 2019, 9(10), 573; https://doi.org/10.3390/biom9100573 - 05 Oct 2019

Cited by 17 | Viewed by 3422

Abstract

Therapeutics, proteins or drugs, can be encapsulated into multilayer systems prepared from chitosan (CS)/tripolyphosphat (TPP) nanogels and polyanions. Such multilayers can be built-up by Layer-by-Layer (LbL) deposition. For use as drug-releasing implant coating, these multilayers must meet high requirements in terms of stability. [...] Read more.

Therapeutics, proteins or drugs, can be encapsulated into multilayer systems prepared from chitosan (CS)/tripolyphosphat (TPP) nanogels and polyanions. Such multilayers can be built-up by Layer-by-Layer (LbL) deposition. For use as drug-releasing implant coating, these multilayers must meet high requirements in terms of stability. Therefore, photochemically crosslinkable chitosan arylazide (CS–Az) was synthesized and nanoparticles were generated by ionotropic gelation with TPP. The particles were characterized with regard to particle size and stability and were used to form the top-layer in multilayer films consisting of CS–TPP and three different polysaccharides as polyanions, namely alginate, chondroitin sulfate or hyaluronic acid, respectively. Subsequently, photo-crosslinking was performed by irradiation with UV light. The stability of these films was investigated under physiological conditions and the influence of the blocking layer on layer thickness was investigated by ellipsometry. Furthermore, the polyanion and the degree of acetylation (DA) of chitosan were identified as additional parameters that influence the film structure and stability. Multilayer systems blocked with the photo-crosslinked chitosan arylazide showed enhanced stability against degradation. Full article

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25 pages, 1637 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Antioxidant Enzyme-Mimetic Activity and Neuroprotective Effects of Cerium Oxide Nanoparticles Stabilized with Various Ratios of Citric Acid and EDTA

by Ana Y. Estevez, Mallikarjunarao Ganesana, John F. Trentini, James E. Olson, Guangze Li, Yvonne O. Boateng, Jennifer M. Lipps, Sarah E. R. Yablonski, William T. Donnelly, James C. Leiter and Joseph S. Erlichman

Biomolecules 2019, 9(10), 562; https://doi.org/10.3390/biom9100562 - 03 Oct 2019

Cited by 30 | Viewed by 4618

Abstract

Cerium oxide (CeO₂) nanoparticles (CeNPs) are potent antioxidants that are being explored as potential therapies for diseases in which oxidative stress plays an important pathological role. However, both beneficial and toxic effects of CeNPs have been reported, and the method of [...] Read more.

Cerium oxide (CeO₂) nanoparticles (CeNPs) are potent antioxidants that are being explored as potential therapies for diseases in which oxidative stress plays an important pathological role. However, both beneficial and toxic effects of CeNPs have been reported, and the method of synthesis as well as physico-chemical, biological, and environmental factors can impact the ultimate biological effects of CeNPs. In the present study, we explored the effect of different ratios of citric acid (CA) and EDTA (CA/EDTA), which are used as stabilizers during synthesis of CeNPs, on the antioxidant enzyme-mimetic and biological activity of the CeNPs. We separated the CeNPs into supernatant and pellet fractions and used commercially available enzymatic assays to measure the catalase-, superoxide dismutase (SOD)-, and oxidase-mimetic activity of each fraction. We tested the effects of these CeNPs in a mouse hippocampal brain slice model of ischemia to induce oxidative stress where the fluorescence indicator SYTOX green was used to assess cell death. Our results demonstrate that CeNPs stabilized with various ratios of CA/EDTA display different enzyme-mimetic activities. CeNPs with intermediate CA/EDTA stabilization ratios demonstrated greater neuroprotection in ischemic mouse brain slices, and the neuroprotective activity resides in the pellet fraction of the CeNPs. The neuroprotective effects of CeNPs stabilized with equal proportions of CA/EDTA (50/50) were also demonstrated in two other models of ischemia/reperfusion in mice and rats. Thus, CeNPs merit further development as a neuroprotective therapy for use in diseases associated with oxidative stress in the nervous system. Full article

(This article belongs to the Special Issue Biological Effects of Cerium Dioxide (CeO2) Nanoparticles in Health and Disease)

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28 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

Function, Regulation and Biological Roles of PI3Kγ Variants

by Bernd Nürnberg and Sandra Beer-Hammer

Biomolecules 2019, 9(9), 427; https://doi.org/10.3390/biom9090427 - 30 Aug 2019

Cited by 25 | Viewed by 4925

Abstract

Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. [...] Read more.

Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. PI3Kγ occur as two different heterodimeric variants: PI3Kγ (p87) and PI3Kγ (p101), which share the same p110γ catalytic subunit but differ in their associated non-catalytic subunit. Here we concentrate on specific PI3Kγ features including its regulation and biological functions. In particular, the roles of its non-catalytic subunits serving as the main regulators determining specificity of class IB PI3Kγ enzymes are highlighted. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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16 pages, 3049 KiB

Open AccessEditor’s ChoiceArticle

Beyond the Scavenging of Reactive Oxygen Species (ROS): Direct Effect of Cerium Oxide Nanoparticles in Reducing Fatty Acids Content in an In Vitro Model of Hepatocellular Steatosis

by Marina Parra-Robert, Eudald Casals, Nuria Massana, Muling Zeng, Meritxell Perramón, Guillermo Fernández-Varo, Manuel Morales-Ruiz, Víctor Puntes, Wladimiro Jiménez and Gregori Casals

Biomolecules 2019, 9(9), 425; https://doi.org/10.3390/biom9090425 - 29 Aug 2019

Cited by 32 | Viewed by 5538

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipids. Antisteatotic effects of cerium oxide nanoparticles (CeO₂NPs) have recently been shown in animal models of liver disease. However, it is unclear whether the activity of CeO₂NPs is [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipids. Antisteatotic effects of cerium oxide nanoparticles (CeO₂NPs) have recently been shown in animal models of liver disease. However, it is unclear whether the activity of CeO₂NPs is related solely to the decrease in oxidative stress or, in addition, they directly decrease liver fatty acid accumulation. To address this question, in this work, we used an in vitro model of hepatocellular steatosis, exposing HepG2 cells to oleic and palmitic acid. Cell uptake of CeO₂NPs and their effect on oxidative stress and viability of hepatic cells cultured with H₂O₂ were also evaluated. Results show that CeO₂NPs were uptaken by HepG2 cells and reduced oxidative stress and improved cell viability. Treatment with oleic and palmitic acid increased lipogenesis and the content of different fatty acids. CeO₂NPs reduced palmitic and stearic acid and most fatty acids consisting of more than 18 carbon atoms. These effects were associated with significant changes in elongase and desaturase activity. In conclusion, CeO₂NPs directly protected HepG2 cells from cell injury in oxidative stress conditions and reduced fatty acid content in steatotic conditions by inducing specific changes in fatty acid metabolism, thus showing potential in the treatment of NAFLD. Full article

(This article belongs to the Special Issue Biological Effects of Cerium Dioxide (CeO2) Nanoparticles in Health and Disease)

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14 pages, 3274 KiB

Open AccessEditor’s ChoiceArticle

The Inhibitory Effect of Cordycepin on the Proliferation of MCF-7 Breast Cancer Cells, and Its Mechanism: An Investigation Using Network Pharmacology-Based Analysis

by Dahae Lee, Won-Yung Lee, Kiwon Jung, Yong Sam Kwon, Daeyoung Kim, Gwi Seo Hwang, Chang-Eop Kim, Sullim Lee and Ki Sung Kang

Biomolecules 2019, 9(9), 414; https://doi.org/10.3390/biom9090414 - 26 Aug 2019

Cited by 27 | Viewed by 8006

Abstract

Cordyceps militaris is a well-known medicinal mushroom. It is non-toxic and has clinical health benefits including cancer inhibition. However, the anticancer effects of C. militaris cultured in brown rice on breast cancer have not yet been reported. In this study, we simultaneously investigated [...] Read more.

Cordyceps militaris is a well-known medicinal mushroom. It is non-toxic and has clinical health benefits including cancer inhibition. However, the anticancer effects of C. militaris cultured in brown rice on breast cancer have not yet been reported. In this study, we simultaneously investigated the anticancer effects of cordycepin and an extract of C. militaris cultured in brown rice on MCF-7 human breast cancer cells using a cell viability assay, cell staining with Hoechst 33342, and an image-based cytometric assay. The C. militaris concentrate exhibited significant MCF-7 cell inhibitory effects, and its IC₅₀ value was 73.48 µg/mL. Cordycepin also exhibited significant MCF-7 cell inhibitory effects, and its IC₅₀ value was 9.58 µM. We applied network pharmacological analysis to predict potential targets and pathways of cordycepin. The gene set enrichment analysis showed that the targets of cordycepin are mainly associated with the hedgehog signaling, apoptosis, p53 signaling, and estrogen signaling pathways. We further verified the predicted targets related to the apoptosis pathway using western blot analysis. The C. militaris concentrate and cordycepin exhibited the ability to induce apoptotic cell death by increasing the cleavage of caspase-7 -8, and -9, increasing the Bcl-2-associated X protein/ B-cell lymphoma 2 (Bax/Bcl-2) protein expression ratio, and decreasing the protein expression of X-linked inhibitor of apoptosis protein (XIAP) in MCF-7 cells. Consequently, the C. militaris concentrate and cordycepin exhibited significant anticancer effects through their ability to induce apoptosis in breast cancer cells. Full article

(This article belongs to the Special Issue Natural Products and Bionanotechnology for Cancer and Disease Treatment)

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26 pages, 2247 KiB

Open AccessEditor’s ChoiceReview

For Better or Worse: The Potential for Dose Limiting the On-Target Toxicity of PI 3-Kinase Inhibitors

by Christina M. Buchanan, Kate L. Lee and Peter R. Shepherd

Biomolecules 2019, 9(9), 402; https://doi.org/10.3390/biom9090402 - 22 Aug 2019

Cited by 15 | Viewed by 5936

Abstract

The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key [...] Read more.

The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key role PI 3-kinases play in many normal cell functions, there is significant potential for the disruption of essential cellular functions by PI 3-kinase inhibitors in normal tissues; so-called on-target drug toxicity. It is, therefore, no surprise that progress within the clinical development of PI 3-kinase inhibitors as single-agent anti-cancer therapies has been slowed by the difficulty of identifying a therapeutic window. The aim of this review is to place the cellular, tissue and whole-body effects of PI 3-kinase inhibition in the context of understanding the potential for dose limiting on-target toxicities and to introduce possible strategies to overcome these. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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15 pages, 2132 KiB

Open AccessEditor’s ChoiceArticle

Dose-Dependent Alterations to In Vitro Human Microbiota Composition and Butyrate Inhibition by a Supercritical Carbon Dioxide Hops Extract

by Paul A. Blatchford, Shanthi G. Parkar, Wendy Hopkins, John R. Ingram and Kevin H. Sutton

Biomolecules 2019, 9(9), 390; https://doi.org/10.3390/biom9090390 - 21 Aug 2019

Cited by 11 | Viewed by 3527

Abstract

Hop cones (Humulus lupulus L.) have been used throughout history as an additive in beer brewing and as herbal supplements with medicinal and culinary properties. The objective of this study was to ascertain the effect of a range of concentrations of a [...] Read more.

Hop cones (Humulus lupulus L.) have been used throughout history as an additive in beer brewing and as herbal supplements with medicinal and culinary properties. The objective of this study was to ascertain the effect of a range of concentrations of a supercritical CO₂ extract of hops on the composition and metabolism of human gut bacterial communities using in vitro batch culture systems. Fermentations were conducted over 24 h using a mixed human fecal inoculum. Microbial metabolism was assessed by measuring organic acid production and microbial community alterations were determined by 16S rRNA gene sequencing. Butyrate, an important short chain fatty acid in maintaining colonic well-being, decreased at elevated concentrations of hops, which may partly be accounted for by the concomitant reduction of Eubacterium and Coprococcus, known butyrate-producing genera, and also the inhibition of Bifidobacterium, a beneficial organism that has a butyrogenic effect through metabolic cross-feeding with intestinal commensals. The hops compounds also caused dose-dependent increases in the potentially pathogenic Enterobacteriaceae and potentially beneficial Akkermansia. Thus, hops compounds had a significant impact on the structure of the bacterial consortium, which warrants further study including human clinical trials. Full article

(This article belongs to the Special Issue Function of Microorganism in Food Production)

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16 pages, 965 KiB

Open AccessEditor’s ChoiceReview

There Is Treasure Everywhere: Reductive Plastid Evolution in Apicomplexa in Light of Their Close Relatives

by Eric D. Salomaki and Martin Kolisko

Biomolecules 2019, 9(8), 378; https://doi.org/10.3390/biom9080378 - 19 Aug 2019

Cited by 18 | Viewed by 6265

Abstract

The phylum Apicomplexa (Alveolates) comprises a group of host-associated protists, predominately intracellular parasites, including devastating parasites like Plasmodium falciparum, the causative agent of malaria. One of the more fascinating characteristics of Apicomplexa is their highly reduced (and occasionally lost) remnant plastid, termed [...] Read more.

The phylum Apicomplexa (Alveolates) comprises a group of host-associated protists, predominately intracellular parasites, including devastating parasites like Plasmodium falciparum, the causative agent of malaria. One of the more fascinating characteristics of Apicomplexa is their highly reduced (and occasionally lost) remnant plastid, termed the apicoplast. Four core metabolic pathways are retained in the apicoplast: heme synthesis, iron–sulfur cluster synthesis, isoprenoid synthesis, and fatty acid synthesis. It has been suggested that one or more of these pathways are essential for plastid and plastid genome retention. The past decade has witnessed the discovery of several apicomplexan relatives, and next-generation sequencing efforts are revealing that they retain variable plastid metabolic capacities. These data are providing clues about the core genes and pathways of reduced plastids, while at the same time further confounding our view on the evolutionary history of the apicoplast. Here, we examine the evolutionary history of the apicoplast, explore plastid metabolism in Apicomplexa and their close relatives, and propose that the differences among reduced plastids result from a game of endosymbiotic roulette. Continued exploration of the Apicomplexa and their relatives is sure to provide new insights into the evolution of the apicoplast and apicomplexans as a whole. Full article

(This article belongs to the Special Issue Evolutionary and Molecular Aspects of Plastid Endosymbioses)

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38 pages, 5465 KiB

Open AccessEditor’s ChoiceArticle

Thimet Oligopeptidase (EC 3.4.24.15) Key Functions Suggested by Knockout Mice Phenotype Characterization

by Nilton B. dos Santos, Roseane D. Franco, Rosana Camarini, Carolina D. Munhoz, Rosangela A. S. Eichler, Mayara C. F. Gewehr, Patricia Reckziegel, Ricardo P. Llanos, Camila S. Dale, Victoria R. O. da Silva, Vanessa F. Borges, Braulio H. F. Lima, Fernando Q. Cunha, Bruna Visniauskas, Jair R. Chagas, Sergio Tufik, Fernanda F. Peres, Vanessa C. Abilio, Jorge C. Florio, Leo K. Iwai, Vanessa Rioli, Benedito C. Presoto, Alessander O. Guimaraes, Joao B. Pesquero, Michael Bader, Leandro M. Castro and Emer S. Ferro Show full author list Hide full author list

Biomolecules 2019, 9(8), 382; https://doi.org/10.3390/biom9080382 - 19 Aug 2019

Cited by 21 | Viewed by 4880

Abstract

Thimet oligopeptidase (THOP1) is thought to be involved in neuropeptide metabolism, antigen presentation, neurodegeneration, and cancer. Herein, the generation of THOP1 C57BL/6 knockout mice (THOP1^−/−) is described showing that they are viable, have estrus cycle, fertility, and a number of puppies [...] Read more.

Thimet oligopeptidase (THOP1) is thought to be involved in neuropeptide metabolism, antigen presentation, neurodegeneration, and cancer. Herein, the generation of THOP1 C57BL/6 knockout mice (THOP1^−/−) is described showing that they are viable, have estrus cycle, fertility, and a number of puppies per litter similar to C57BL/6 wild type mice (WT). In specific brain regions, THOP1^-/- exhibit altered mRNA expression of proteasome beta5, serotonin 5HT2a receptor and dopamine D2 receptor, but not of neurolysin (NLN). Peptidomic analysis identifies differences in intracellular peptide ratios between THOP1^-/- and WT mice, which may affect normal cellular functioning. In an experimental model of multiple sclerosis THOP1^-/- mice present worse clinical behavior scores compared to WT mice, corroborating its possible involvement in neurodegenerative diseases. THOP1^-/- mice also exhibit better survival and improved behavior in a sepsis model, but also a greater peripheral pain sensitivity measured in the hot plate test after bradykinin administration in the paw. THOP1^-/- mice show depressive-like behavior, as well as attention and memory retention deficits. Altogether, these results reveal a role of THOP1 on specific behaviors, immune-stimulated neurodegeneration, and infection-induced inflammation. Full article

(This article belongs to the Section Cellular Biochemistry)

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14 pages, 4542 KiB

Open AccessEditor’s ChoiceArticle

Aortic Oxidative Stress, Inflammation and DNA Damage Following Pulmonary Exposure to Cerium Oxide Nanoparticles in a Rat Model of Vascular Injury

by Abderrahim Nemmar, Suhail Al-Salam, Sumaya Beegam, Priya Yuvaraju and Badreldin H. Ali

Biomolecules 2019, 9(8), 376; https://doi.org/10.3390/biom9080376 - 17 Aug 2019

Cited by 23 | Viewed by 4459

Abstract

Pulmonary exposure to cerium oxide nanoparticles (CeO₂ NPs) can occur either at the workplace, or due to their release in the environment. Inhaled CeO₂ NPs are known to cross the alveolar–capillary barrier and reach various parts of the body, including the [...] Read more.

Pulmonary exposure to cerium oxide nanoparticles (CeO₂ NPs) can occur either at the workplace, or due to their release in the environment. Inhaled CeO₂ NPs are known to cross the alveolar–capillary barrier and reach various parts of the body, including the vasculature. The anticancer drug cisplatin (CP) causes vascular damage. However, the effects CeO₂ NPs on vascular homeostasis in a rat model of CP-induced vascular injury remain unclear. Here, we assessed the impact and underlying mechanism of pulmonary exposure to CeO₂ NPs on aorta in rats given a single intraperitoneal injection of cisplatin (CP, 6 mg/kg) to induce vascular damage. Six days later, the rats were intratracheally instilled with either CeO₂ NPs (1 mg/kg) or saline (control), and various variables were studied 24 h thereafter in the aortic tissue. The concentration of reduced glutathione and the activity of catalase were significantly increased in the CP + CeO₂ NPs group compared with both the CP + saline and the CeO₂ NPs groups. The activity of superoxide dismutase was significantly decreased in the CP + CeO₂ NPs group compared with both the CP + saline and CeO₂ NPs groups. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2) by the nuclei of smooth muscles and endocardial cells assessed by immunohistochemistry was significantly augmented in CeO₂ NPs versus saline, in CP + saline versus saline, and in CP + CeO₂ NPs versus CeO₂ NPs. Moreover, the concentrations of total nitric oxide, lipid peroxidation and 8-hydroxy-2-deoxyguanosine were significantly elevated in the CP + CeO₂ NPs group compared with both the CP + saline and the CeO₂ NPs groups. Similarly, compared with both the CP + saline and CeO₂ NPs groups, the combination of CP and CeO₂ NPs significantly elevated the concentrations of interleukin-6 and tumour necrosis factor-α. Additionally, aortic DNA damage assessed by Comet assay was significantly increased in CeO₂ NPs compared with saline, and in CP + saline versus saline, and all these effects were significantly aggravated by the combination of CP and CeO₂ NPs. We conclude that pulmonary exposure to CeO₂ NPs aggravates vascular toxicity in animal model of vascular injury through mechanisms involving oxidative stress, Nrf2 expression, inflammation and DNA damage. Full article

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15 pages, 3867 KiB

Open AccessEditor’s ChoiceArticle

The Methodological Trends of Traditional Herbal Medicine Employing Network Pharmacology

by Won-Yung Lee, Choong-Yeol Lee, Youn-Sub Kim and Chang-Eop Kim

Biomolecules 2019, 9(8), 362; https://doi.org/10.3390/biom9080362 - 13 Aug 2019

Cited by 101 | Viewed by 11845

Abstract

Natural products, including traditional herbal medicine (THM), are known to exert their therapeutic effects by acting on multiple targets, so researchers have employed network pharmacology methods to decipher the potential mechanisms of THM. To conduct THM-network pharmacology (THM-NP) studies, researchers have employed different [...] Read more.

Natural products, including traditional herbal medicine (THM), are known to exert their therapeutic effects by acting on multiple targets, so researchers have employed network pharmacology methods to decipher the potential mechanisms of THM. To conduct THM-network pharmacology (THM-NP) studies, researchers have employed different tools and databases for constructing and analyzing herb–compound–target networks. In this study, we attempted to capture the methodological trends in THM-NP research. We identified the tools and databases employed to conduct THM-NP studies and visualized their combinatorial patterns. We also constructed co-author and affiliation networks to further understand how the methodologies are employed among researchers. The results showed that the number of THM-NP studies and employed databases/tools have been dramatically increased in the last decade, and there are characteristic patterns in combining methods of each analysis step in THM-NP studies. Overall, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was the most frequently employed network pharmacology database in THM-NP studies. Among the processes involved in THM-NP research, the methodology for constructing a compound–target network has shown the greatest change over time. In summary, our analysis describes comprehensive methodological trends and current ideas in research design for network pharmacology researchers. Full article

(This article belongs to the Special Issue Phytochemical Omics in Medicinal Plants)

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16 pages, 2179 KiB

Open AccessEditor’s ChoiceArticle

The Natural-Based Antitumor Compound T21 Decreases Survivin Levels through Potent STAT3 Inhibition in Lung Cancer Models

by David Martínez-García, Marta Pérez-Hernández, Luís Korrodi-Gregório, Roberto Quesada, Ricard Ramos, Núria Baixeras, Ricardo Pérez-Tomás and Vanessa Soto-Cerrato

Biomolecules 2019, 9(8), 361; https://doi.org/10.3390/biom9080361 - 13 Aug 2019

Cited by 21 | Viewed by 4840

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide; hence novel treatments for this malignancy are eagerly needed. Since natural-based compounds represent a rich source of novel chemical entities in drug discovery, we have focused our attention on tambjamines, natural compounds isolated [...] Read more.

Lung cancer is the leading cause of cancer-related deaths worldwide; hence novel treatments for this malignancy are eagerly needed. Since natural-based compounds represent a rich source of novel chemical entities in drug discovery, we have focused our attention on tambjamines, natural compounds isolated from marine invertebrates that have shown diverse pharmacological activities. Based on these structures, we have recently identified the novel indole-based tambjamine analog 21 (T21) as a promising antitumor agent, which modulates the expression of apoptotic proteins such as survivin. This antiapoptotic protein plays an important role in carcinogenesis and chemoresistance. In this work, we have elucidated the molecular mechanism by which the anticancer compound T21 exerts survivin inhibition and have validated this protein as a therapeutic target in different lung cancer models. T21 was able to reduce survivin protein levels in vitro by repressing its gene expression through the blockade of Janus kinase/Signal Transducer and Activator of Transcription-3 (JAK/STAT3)/survivin signaling pathway. Interestingly, this occurred even when the pathway was overstimulated with its ligand interleukin 6 (IL-6), which is frequently overexpressed in lung cancer patients who show poor clinical outcomes. Altogether, these results show T21 as a potent anticancer compound that effectively decreases survivin levels through STAT3 inhibition in lung cancer, appearing as a promising therapeutic drug for cancer treatment. Full article

(This article belongs to the Special Issue Novel Natural-based Biomolecules Discovery for Tackling Chronic Diseases)

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15 pages, 2773 KiB

Open AccessEditor’s ChoiceArticle

Cyclodextrins Can Entrap Zearalenone-14-Glucoside: Interaction of the Masked Mycotoxin with Cyclodextrins and Cyclodextrin Bead Polymer

by Zelma Faisal, Eszter Fliszár-Nyúl, Luca Dellafiora, Gianni Galaverna, Chiara Dall’Asta, Beáta Lemli, Sándor Kunsági-Máté, Lajos Szente and Miklós Poór

Biomolecules 2019, 9(8), 354; https://doi.org/10.3390/biom9080354 - 09 Aug 2019

Cited by 14 | Viewed by 4100

Abstract

Zearalenone (ZEN) is a Fusarium-derived xenoestrogenic mycotoxin. In plants, zearalenone-14-O-β-d-glucoside (Z14G) is the major conjugated metabolite of ZEN, and is a masked mycotoxin. Masked mycotoxins are plant-modified derivatives, which are not routinely screened in food and feed samples. [...] Read more.

Zearalenone (ZEN) is a Fusarium-derived xenoestrogenic mycotoxin. In plants, zearalenone-14-O-β-d-glucoside (Z14G) is the major conjugated metabolite of ZEN, and is a masked mycotoxin. Masked mycotoxins are plant-modified derivatives, which are not routinely screened in food and feed samples. Cyclodextrins (CDs) are cyclic oligosaccharides built up from D-glucopyranose units. CDs can form stable host–guest type complexes with lipophilic molecules (e.g., with some mycotoxins). In this study, the interaction of Z14G with native and chemically modified β- and γ-CDs was examined employing fluorescence spectroscopy and molecular modeling. Furthermore, the removal of Z14G from aqueous solution by insoluble β-CD bead polymer (BBP) was also tested. Our results demonstrate that Z14G forms the most stable complexes with γ-CDs under acidic and neutral conditions (K ≈ 10³ L/mol). Among the CDs tested, randomly methylated γ-CD induced the highest increase in the fluorescence of Z14G (7.1-fold) and formed the most stable complexes with the mycotoxin (K = 2 × 10³ L/mol). Furthermore, BBP considerably reduced the Z14G content of aqueous solution. Based on these observations, CD technology seems a promising tool to improve the fluorescence analytical detection of Z14G and to discover new mycotoxin binders which can also remove masked mycotoxins (e.g., Z14G). Full article

(This article belongs to the Special Issue Perspectives of Cyclodextrins)

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17 pages, 1613 KiB

Open AccessEditor’s ChoiceArticle

KDR (VEGFR2) Genetic Variants and Serum Levels in Patients with Rheumatoid Arthritis

by Agnieszka Paradowska-Gorycka, Barbara Stypinska, Andrzej Pawlik, Damian Malinowski, Katarzyna Romanowska-Prochnicka, Malgorzata Manczak and Marzena Olesinska

Biomolecules 2019, 9(8), 355; https://doi.org/10.3390/biom9080355 - 09 Aug 2019

Cited by 12 | Viewed by 3305

Abstract

We investigated kinase insert domain-containing receptor (KDR) polymorphisms and protein levels in relation to susceptibility to and severity of Rheumatoid Arthritis (RA). 641 RA patients and 340 controls (HC) were examined for the rs1870377 KDR variant by the polymerase chain reaction (PCR)-restriction fragment [...] Read more.

We investigated kinase insert domain-containing receptor (KDR) polymorphisms and protein levels in relation to susceptibility to and severity of Rheumatoid Arthritis (RA). 641 RA patients and 340 controls (HC) were examined for the rs1870377 KDR variant by the polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method and for rs2305948 and rs2071559 KDR single nucleotide polymorphisms (SNPs) by TaqMan SNP genotyping assay. KDR serum levels were determined by enzyme-linked immunosorbent assay (ELISA). The rs1870377 KDR variant has shown association with RA under the codominant (p = 0.02, OR = 1.76, 95% CI = 1.09–2.85) and recessive models (p = 0.019, OR = 1.53, 95% CI = 1.07–2.20). KDR rs2305948 was associated with RA under the dominant model (p = 0.005, OR = 1.38, 95% CI = 1.10–1.73). Under the codominant model, the frequency of the rs2071559 TC and GG genotypes were lower in RA patients than in controls (p < 0.001, OR = 0.51, 95% CI = 0.37–0.69, and p = 0.002, OR = 0.57, 95% CI = 0.39–0.81). KDR rs2071559 T and rs2305948 A alleles were associated with RA (p = 0.001, OR = 0.60, 95% CI = 0.45–0.81 and p = 0.008, OR = 1.71, CI = 1.15–2.54). KDR rs2305948SNP was associated with Disease Activity Score (DAS)-28 score (p < 0.001), Visual Analog Scale (VAS) score (p < 0.001), number of swollen joints (p < 0.001), mean value of CRP (p < 0.001). A higher KDR serum level was found in RA patients than in HC (8018 pg/mL versus 7381 pg/mL, p = 0.002). Present results shed light on the role of KDR genetic variants in the severity of RA. Full article

(This article belongs to the Section Molecular Medicine)

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13 pages, 2415 KiB

Open AccessEditor’s ChoiceArticle

Accumulation of Amyloid Beta (Aβ) Peptide on Blood Vessel Walls in the Damaged Brain after Transient Middle Cerebral Artery Occlusion

by Antonio Henrique Martins, Astrid Zayas-Santiago, Yancy Ferrer-Acosta, Solianne M. Martinez-Jimenez, Lidia Zueva, Amanda Diaz-Garcia and Mikhail Inyushin

Biomolecules 2019, 9(8), 350; https://doi.org/10.3390/biom9080350 - 08 Aug 2019

Cited by 12 | Viewed by 6026

Abstract

It is well known that amyloid beta (Aβ) peptides are generated in blood vessels, released into the brain during thrombosis, and temporarily accumulate in this organ after injury. Here we demonstrate that 24 h after transient middle cerebral artery occlusion (tMCAO), one of [...] Read more.

It is well known that amyloid beta (Aβ) peptides are generated in blood vessels, released into the brain during thrombosis, and temporarily accumulate in this organ after injury. Here we demonstrate that 24 h after transient middle cerebral artery occlusion (tMCAO), one of the standard models of focal ischemic stroke, Aβ peptide accumulates in the brain, concentrating on the blood vessel walls. Because Aβ oligomers are known to induce significant damage to brain cells, they act as an additional damaging factor during ischemic stroke. Considering that they have been shown to form ion channels in cells, affecting osmotic balance, we used an Aβ peptide channel blocker, tromethamine (2-amino-2-(hydroxymethyl) propane-1,3-diol), to prevent this additional injury. Tromethamine injected 0.1 g/100 g body weight intraperitoneally at 5 min before tMCAO decreased water content in the damaged hemisphere, as measured by dry brain weight. Congo red staining, which binds only to Aβ oligomer plaques (amyloid), showed that there was no significant presence of plaques. Therefore, we suggest that Aβ peptide oligomers are responsible for some of the brain damage during stroke and that blockage of the ion channels that they form could be beneficial in treating this complex neurological syndrome. Full article

(This article belongs to the Section Molecular Medicine)

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8 pages, 1730 KiB

Open AccessEditor’s ChoiceCommunication

The Impact of Salts on the Ice Recrystallization Inhibition Activity of Antifreeze (Glyco)Proteins

by Romà Surís-Valls and Ilja K. Voets

Biomolecules 2019, 9(8), 347; https://doi.org/10.3390/biom9080347 - 06 Aug 2019

Cited by 18 | Viewed by 4590

Abstract

Antifreeze (glyco)proteins (AF(G)Ps) have received increasing attention as potential cryopreservation agents since their discovery in the 1970s. While cryopreservation strategies for specific cells (such as red blood cells) are successful and widely implemented, preservation of other cell types, tissues and whole organs remains [...] Read more.

Antifreeze (glyco)proteins (AF(G)Ps) have received increasing attention as potential cryopreservation agents since their discovery in the 1970s. While cryopreservation strategies for specific cells (such as red blood cells) are successful and widely implemented, preservation of other cell types, tissues and whole organs remains challenging. This is due to the multifactorial nature of the freeze-thaw damage, the complexity of preserving biological matter and the (country-to-country) variability of the employed procedures and regulations. AF(G)Ps are well-known for their ability to modulate ice crystal growth morphology and ice recrystallization inhibition (IRI), both of which are considered key contributors to freeze-thaw damage. To date, however, the impact of AF(G)Ps on cell survival remains at best partially understood as conflicting results on the benefits or disadvantages of including AF(G)P in cryopreservation strategies remain unelucidated. We hypothesize that variability in the additives in the cryopreservation media contributes to the observed discrepancies. To critically examine this idea, we monitored the inhibition of ice recrystallization by AF(G)P in the presence of various salts using a quantitative analysis of optical microscopy images via the Lifshitz-Slyozov-Wagner (LSW) theory for Oswald ripening. We found that the addition of salts, which are used in culture and cryopreservation media, enhances the IRI activity of AF(G)Ps, and that the magnitude of the enhancement was in line with the Hofmeister series. The size of ice crystals grown in AFGP_1–5 and type III AFP samples containing chloride, phosphate and citrate ions were statistically smaller after 90 min of incubation than crystals grown in the absence of these salts. The ice recrystallization rates (k_d) of AFGP_1–5 and type III AFP samples prepared at a fixed overall ionic strength of 100 mM progressively decreased following the Hofmeister series for anions. Our results demonstrate that the performance of AF(G)Ps is significantly influenced by additives present in common cryopreservation media. It is thus important to conduct excipient compatibility experiments to identify potential incompatibilities between additives and AF(G)Ps in cryopreservation formulations. Full article

(This article belongs to the Special Issue Antifreeze Protein: New Insight from Different Approaches)

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30 pages, 5117 KiB

Open AccessEditor’s ChoiceReview

Tannins: Prospectives and Actual Industrial Applications

by Antonio Pizzi

Biomolecules 2019, 9(8), 344; https://doi.org/10.3390/biom9080344 - 05 Aug 2019

Cited by 171 | Viewed by 11768

Abstract

The origin of tannins, their historical evolution, their different types, and their applications are described. Old and established applications are described, as well as the future applications which are being developed at present and that promise to have an industrial impact in the [...] Read more.

The origin of tannins, their historical evolution, their different types, and their applications are described. Old and established applications are described, as well as the future applications which are being developed at present and that promise to have an industrial impact in the future. The chemistry of some of these applications is discussed where it is essential to understand the tannins and their derivates role. The essential points of each application, their drawbacks, and their chance of industrial application are briefly discussed. The article presents historical applications of tannins, such as leather, or traditional medicine, and more recent applications. Full article

(This article belongs to the Special Issue Perspectives on Tannins)

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18 pages, 1060 KiB

Open AccessEditor’s ChoiceReview

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

by Bart Vanhaesebroeck, Benoit Bilanges, Ralitsa R. Madsen, Katie L. Dale, Evelyn Lau and Elina Vladimirou

Biomolecules 2019, 9(8), 331; https://doi.org/10.3390/biom9080331 - 01 Aug 2019

Cited by 7 | Viewed by 4892

Abstract

Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase that [...] Read more.

Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase that opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancer-cell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which—even if occurring in a low fraction of the cell population—might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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22 pages, 8183 KiB

Open AccessEditor’s ChoiceReview

Metabolic Innovations Underpinning the Origin and Diversification of the Diatom Chloroplast

by Tomomi Nonoyama, Elena Kazamia, Hermanus Nawaly, Xia Gao, Yoshinori Tsuji, Yusuke Matsuda, Chris Bowler, Tsuyoshi Tanaka and Richard G. Dorrell

Biomolecules 2019, 9(8), 322; https://doi.org/10.3390/biom9080322 - 30 Jul 2019

Cited by 27 | Viewed by 6765

Abstract

Of all the eukaryotic algal groups, diatoms make the most substantial contributions to photosynthesis in the contemporary ocean. Understanding the biological innovations that have occurred in the diatom chloroplast may provide us with explanations to the ecological success of this lineage and clues [...] Read more.

Of all the eukaryotic algal groups, diatoms make the most substantial contributions to photosynthesis in the contemporary ocean. Understanding the biological innovations that have occurred in the diatom chloroplast may provide us with explanations to the ecological success of this lineage and clues as to how best to exploit the biology of these organisms for biotechnology. In this paper, we use multi-species transcriptome datasets to compare chloroplast metabolism pathways in diatoms to other algal lineages. We identify possible diatom-specific innovations in chloroplast metabolism, including the completion of tocopherol synthesis via a chloroplast-targeted tocopherol cyclase, a complete chloroplast ornithine cycle, and chloroplast-targeted proteins involved in iron acquisition and CO₂ concentration not shared between diatoms and their closest relatives in the stramenopiles. We additionally present a detailed investigation of the chloroplast metabolism of the oil-producing diatom Fistulifera solaris, which is of industrial interest for biofuel production. These include modified amino acid and pyruvate hub metabolism that might enhance acetyl-coA production for chloroplast lipid biosynthesis and the presence of a chloroplast-localised squalene synthesis pathway unknown in other diatoms. Our data provides valuable insights into the biological adaptations underpinning an ecologically critical lineage, and how chloroplast metabolism can change even at a species level in extant algae. Full article

(This article belongs to the Special Issue Evolutionary and Molecular Aspects of Plastid Endosymbioses)

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25 pages, 1185 KiB

Open AccessEditor’s ChoiceReview

Cell Intrinsic and Extrinsic Mechanisms of Caveolin-1-Enhanced Metastasis

by America Campos, Renato Burgos-Ravanal, María Fernanda González, Ricardo Huilcaman, Lorena Lobos González and Andrew Frederick Geoffery Quest

Biomolecules 2019, 9(8), 314; https://doi.org/10.3390/biom9080314 - 29 Jul 2019

Cited by 35 | Viewed by 8530

Abstract

Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. [...] Read more.

Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. Different mechanisms are summarized illustrating how CAV1 promotes such traits upon expression in cancer cells (intrinsic mechanisms). More recently, it has become apparent that CAV1 is also a secreted protein that can be included into exosomes where it plays a significant role in determining cargo composition. Thus, we will also discuss how CAV1 containing exosomes from metastatic cells promote malignant traits in more benign recipient cells (extrinsic mechanisms). This ability appears, at least in part, attributable to the transfer of specific cargos present due to CAV1 rather than the transfer of CAV1 itself. The evolution of how our perception of CAV1 function has changed since its discovery is summarized graphically in a time line figure. Full article

(This article belongs to the Special Issue Beyond Lipid Rafts and Caveolae: From Caveolae Compartmentalization of Signal Transduction to Medicine)

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14 pages, 1151 KiB

Open AccessEditor’s ChoiceReview

Gangliosides: The Double-Edge Sword of Neuro-Ectodermal Derived Tumors

by Sumeyye Cavdarli, Sophie Groux-Degroote and Philippe Delannoy

Biomolecules 2019, 9(8), 311; https://doi.org/10.3390/biom9080311 - 27 Jul 2019

Cited by 48 | Viewed by 6732

Abstract

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are mostly localized at the plasma membrane in lipid raft domains and implicated in many cellular signaling pathways mostly by interacting with tyrosine kinase receptors. Gangliosides are divided into four series according to [...] Read more.

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are mostly localized at the plasma membrane in lipid raft domains and implicated in many cellular signaling pathways mostly by interacting with tyrosine kinase receptors. Gangliosides are divided into four series according to the number of sialic acid residues, which can be also modified by O-acetylation. Both ganglioside expression and sialic acid modifications can be modified in pathological conditions such as cancer, which can induce either pro-cancerous or anti-cancerous effects. In this review, we summarize the specific functions of gangliosides in neuro-ectodermal derived tumors, and their roles in reprogramming the lipidomic profile of cell membrane occurring with the induction of epithelial-mesenchymal transition. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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18 pages, 1140 KiB

Open AccessEditor’s ChoiceArticle

Role of Transmembrane Proteins for Phase Separation and Domain Registration in Asymmetric Lipid Bilayers

by Guilherme Volpe Bossa, Sean Gunderson, Rachel Downing and Sylvio May

Biomolecules 2019, 9(8), 303; https://doi.org/10.3390/biom9080303 - 25 Jul 2019

Cited by 5 | Viewed by 3218

Abstract

It is well known that the formation and spatial correlation of lipid domains in the two apposed leaflets of a bilayer are influenced by weak lipid–lipid interactions across the bilayer’s midplane. Transmembrane proteins span through both leaflets and thus offer an alternative domain [...] Read more.

It is well known that the formation and spatial correlation of lipid domains in the two apposed leaflets of a bilayer are influenced by weak lipid–lipid interactions across the bilayer’s midplane. Transmembrane proteins span through both leaflets and thus offer an alternative domain coupling mechanism. Using a mean-field approximation of a simple bilayer-type lattice model, with two two-dimensional lattices stacked one on top of the other, we explore the role of this “structural” inter-leaflet coupling for the ability of a lipid membrane to phase separate and form spatially correlated domains. We present calculated phase diagrams for various effective lipid–lipid and lipid–protein interaction strengths in membranes that contain a binary lipid mixture in each leaflet plus a small amount of added transmembrane proteins. The influence of the transmembrane nature of the proteins is assessed by a comparison with “peripheral” proteins, which result from the separation of one single integral protein into two independent units that are no longer structurally connected across the bilayer. We demonstrate that the ability of membrane-spanning proteins to facilitate domain formation requires sufficiently strong lipid–protein interactions. Weak lipid–protein interactions generally tend to inhibit phase separation in a similar manner for transmembrane as for peripheral proteins. Full article

(This article belongs to the Special Issue Plasma Membrane Lipid Domains As a Favorable Environment for Protein:Lipid Interactions?)

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14 pages, 2850 KiB

Open AccessEditor’s ChoiceArticle

Embryonic Exposure to Bisphenol A Impairs Primordial Germ Cell Migration without Jeopardizing Male Breeding Capacity

by Marta Lombó, Lidia Getino-Álvarez, Alexandra Depincé, Catherine Labbé and María Paz Herráez

Biomolecules 2019, 9(8), 307; https://doi.org/10.3390/biom9080307 - 25 Jul 2019

Cited by 25 | Viewed by 5535

Abstract

A large amount of chemicals are released to the environment each year. Among them, bisphenol A (BPA) is of utmost concern since it interferes with the reproductive system of wild organisms due to its capacity to bind to hormone receptors. Additionally, BPA epigenotoxic [...] Read more.

A large amount of chemicals are released to the environment each year. Among them, bisphenol A (BPA) is of utmost concern since it interferes with the reproductive system of wild organisms due to its capacity to bind to hormone receptors. Additionally, BPA epigenotoxic activity is known to affect basic processes during embryonic life. However, its effects on primordial germ cells (PGCs) proliferation and migration, both mechanisms being crucial for gametogenesis, remain unknown. To investigate the effects of BPA on PGCs migration and eventual testicle development, zebrafish embryos were exposed to 100, 2000 and 4000 µg/L BPA during the first 24 h of development. Vasa immunostaining of PGCs revealed that exposure to 2000 and 4000 µg/L BPA impaired their migration to the genital ridge. Two pivotal genes of PGCs migration (cxcr4b and sdf1a) were highly dysregulated in embryos exposed to these doses, whereas DNA methylation and epigenetic marks in PGCs and their surrounding somatic cells were not altered. Once embryos reached adulthood, the morphometric study of their gonads revealed that, despite the reduced number of PGCs which colonized the genital ridges, normal testicles were developed. Although H3K9ac decreased in the sperm from treated fishes, it did not affect the progeny development. Full article

(This article belongs to the Special Issue Relevant Biomolecules for Germ Cells and Fertilization)

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16 pages, 2195 KiB

Open AccessEditor’s ChoiceArticle

Caveolin-1 Endows Order in Cholesterol-Rich Detergent Resistant Membranes

by Carla Raggi, Marco Diociaiuti, Giulio Caracciolo, Federica Fratini, Luca Fantozzi, Giovanni Piccaro, Katia Fecchi, Elisabetta Pizzi, Giuseppe Marano, Fiorella Ciaffoni, Elena Bravo, Maria L. Fiani and Massimo Sargiacomo

Biomolecules 2019, 9(7), 287; https://doi.org/10.3390/biom9070287 - 17 Jul 2019

Cited by 12 | Viewed by 4428

Abstract

Cholesterol-enriched functional portions of plasma membranes, such as caveolae and rafts, were isolated from lungs of wild-type (WT) and caveolin-1 knockout (Cav-1 KO) mice within detergent resistant membranes (DRMs). To gain insight into their molecular composition we performed proteomic and lipid analysis on [...] Read more.

Cholesterol-enriched functional portions of plasma membranes, such as caveolae and rafts, were isolated from lungs of wild-type (WT) and caveolin-1 knockout (Cav-1 KO) mice within detergent resistant membranes (DRMs). To gain insight into their molecular composition we performed proteomic and lipid analysis on WT and Cav-1 KO-DRMs that showed predicted variations of proteomic profiles and negligible differences in lipid composition, while Langmuir monolayer technique and small and wide-angle X-ray scattering (SAXS-WAXS) were here originally introduced to study DRMs biophysical association state. Langmuir analysis of Cav-1 containing DRMs displayed an isotherm with a clear-cut feature, suggesting the coexistence of the liquid-ordered (L_o) phase typical of the raft structure, namely “cholesterol-rich L_o phase”, with a phase fully missing in Cav-1 KO that we named “caveolin-induced L_o phase”. Furthermore, while the sole lipid component of both WT and KO-DRMs showed qualitatively similar isotherm configuration, the reinsertion of recombinant Cav-1 into WT-DRMs lipids restored the WT-DRM pattern. X-ray diffraction results confirmed that Cav-1 causes the formation of a “caveolin-induced L_o phase”, as suggested by Langmuir experiments, allowing us to speculate about a possible structural model. These results show that the unique molecular link between Cav-1 and cholesterol can spur functional order in a lipid bilayer strictly derived from biological sources. Full article

(This article belongs to the Special Issue Beyond Lipid Rafts and Caveolae: From Caveolae Compartmentalization of Signal Transduction to Medicine)

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23 pages, 2555 KiB

Open AccessEditor’s ChoiceReview

Flagella-Driven Motility of Bacteria

by Shuichi Nakamura and Tohru Minamino

Biomolecules 2019, 9(7), 279; https://doi.org/10.3390/biom9070279 - 14 Jul 2019

Cited by 186 | Viewed by 23013

Abstract

The bacterial flagellum is a helical filamentous organelle responsible for motility. In bacterial species possessing flagella at the cell exterior, the long helical flagellar filament acts as a molecular screw to generate thrust. Meanwhile, the flagella of spirochetes reside within the periplasmic space [...] Read more.

The bacterial flagellum is a helical filamentous organelle responsible for motility. In bacterial species possessing flagella at the cell exterior, the long helical flagellar filament acts as a molecular screw to generate thrust. Meanwhile, the flagella of spirochetes reside within the periplasmic space and not only act as a cytoskeleton to determine the helicity of the cell body, but also rotate or undulate the helical cell body for propulsion. Despite structural diversity of the flagella among bacterial species, flagellated bacteria share a common rotary nanomachine, namely the flagellar motor, which is located at the base of the filament. The flagellar motor is composed of a rotor ring complex and multiple transmembrane stator units and converts the ion flux through an ion channel of each stator unit into the mechanical work required for motor rotation. Intracellular chemotactic signaling pathways regulate the direction of flagella-driven motility in response to changes in the environments, allowing bacteria to migrate towards more desirable environments for their survival. Recent experimental and theoretical studies have been deepening our understanding of the molecular mechanisms of the flagellar motor. In this review article, we describe the current understanding of the structure and dynamics of the bacterial flagellum. Full article

(This article belongs to the Special Issue Perspectives on Bacterial Flagellar Motor)

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17 pages, 2970 KiB

Open AccessEditor’s ChoiceArticle

A Sesquiterpenoid from Farfarae Flos Induces Apoptosis of MDA-MB-231 Human Breast Cancer Cells through Inhibition of JAK–STAT3 Signaling

by Hyeri Jang, Hyejin Ko, Kwangho Song and Yeong Shik Kim

Biomolecules 2019, 9(7), 278; https://doi.org/10.3390/biom9070278 - 13 Jul 2019

Cited by 21 | Viewed by 4627

Abstract

Triple-negative breast cancers (TNBCs) are hard-to-treat breast tumors with poor prognosis, which need to be treated by chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in proliferation, metastasis, and invasion of cancer cells. Therefore, research on searching [...] Read more.

Triple-negative breast cancers (TNBCs) are hard-to-treat breast tumors with poor prognosis, which need to be treated by chemotherapy. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in proliferation, metastasis, and invasion of cancer cells. Therefore, research on searching for promising compounds with metabolism that suppress phosphorylation or transcription of STAT3 in TNBC cells is important. Farfarae Flos is well known as a traditional medicine for treating inflammation. However, few studies have shown that sesquiterpenoids from Farfarae Flos have an anticancer effect. In this study, efficient separation methods and an MTT assay were conducted to isolate an anticancer compound from Farfarae Flos against TNBC MDA-MB-231 cells. Here, 7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a compound isolated from Farfarae Flos showed a potent cytotoxic effect on MDA-MB-231 cells. ECN inhibited JAK–STAT3 signaling and suppressed the expression of STAT3 target genes. In addition, ECN induced apoptosis through both extrinsic and intrinsic pathways. Furthermore, we investigated that ECN inhibited the growth of tumors by intraperitoneal administration in mice injected with MDA-MB-231 cells. Therefore, ECN can be an effective chemotherapeutic agent for breast cancer treatment. Full article

(This article belongs to the Special Issue Antitumor Agents from Natural Sources)

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54 pages, 1623 KiB

Open AccessEditor’s ChoiceReview

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

by Marianna Tosato and Valerio Di Marco

Biomolecules 2019, 9(7), 269; https://doi.org/10.3390/biom9070269 - 09 Jul 2019

Cited by 44 | Viewed by 8465

Abstract

The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson’s disease (PD) therapy in the year range 2014–2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or [...] Read more.

The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson’s disease (PD) therapy in the year range 2014–2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compounds has been collected or, if not experimentally available, has been estimated from similar molecules. Stoichiometries and stability constants of the complexes have been reported; values of the cologarithm of the concentration of free metal ion at equilibrium (pM), and of the dissociation constant K_d (both computed at pH = 7.4 and at total metal and ligand concentrations of 10⁻⁶ and 10⁻⁵ mol/L, respectively), charge and stoichiometry of the most abundant metal–ligand complexes existing at physiological conditions, have been obtained. A rigorous definition of the reported amounts is given, the possible usefulness of this data is described, and the need to characterize the metal–ligand speciation of PD drugs is underlined. Full article

(This article belongs to the Special Issue Advances in Parkinson's Disease Drugs)

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20 pages, 2390 KiB

Open AccessEditor’s ChoiceReview

Mechanism of the Formation of Electronically Excited Species by Oxidative Metabolic Processes: Role of Reactive Oxygen Species

by Pavel Pospíšil, Ankush Prasad and Marek Rác

Biomolecules 2019, 9(7), 258; https://doi.org/10.3390/biom9070258 - 05 Jul 2019

Cited by 62 | Viewed by 7162

Abstract

It is well known that biological systems, such as microorganisms, plants, and animals, including human beings, form spontaneous electronically excited species through oxidative metabolic processes. Though the mechanism responsible for the formation of electronically excited species is still not clearly understood, several lines [...] Read more.

It is well known that biological systems, such as microorganisms, plants, and animals, including human beings, form spontaneous electronically excited species through oxidative metabolic processes. Though the mechanism responsible for the formation of electronically excited species is still not clearly understood, several lines of evidence suggest that reactive oxygen species (ROS) are involved in the formation of electronically excited species. This review attempts to describe the role of ROS in the formation of electronically excited species during oxidative metabolic processes. Briefly, the oxidation of biomolecules, such as lipids, proteins, and nucleic acids by ROS initiates a cascade of reactions that leads to the formation of triplet excited carbonyls formed by the decomposition of cyclic (1,2-dioxetane) and linear (tetroxide) high-energy intermediates. When chromophores are in proximity to triplet excited carbonyls, the triplet-singlet and triplet-triplet energy transfers from triplet excited carbonyls to chromophores result in the formation of singlet and triplet excited chromophores, respectively. Alternatively, when molecular oxygen is present, the triplet-singlet energy transfer from triplet excited carbonyls to molecular oxygen initiates the formation of singlet oxygen. Understanding the mechanism of the formation of electronically excited species allows us to use electronically excited species as a marker for oxidative metabolic processes in cells. Full article

(This article belongs to the Section Cellular Biochemistry)

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17 pages, 1455 KiB

Open AccessEditor’s ChoiceReview

Site-Specific Incorporation of Unnatural Amino Acids into Escherichia coli Recombinant Protein: Methodology Development and Recent Achievement

by Sviatlana Smolskaya and Yaroslav A. Andreev

Biomolecules 2019, 9(7), 255; https://doi.org/10.3390/biom9070255 - 28 Jun 2019

Cited by 55 | Viewed by 9135

Abstract

More than two decades ago a general method to genetically encode noncanonical or unnatural amino acids (NAAs) with diverse physical, chemical, or biological properties in bacteria, yeast, animals and mammalian cells was developed. More than 200 NAAs have been incorporated into recombinant proteins [...] Read more.

More than two decades ago a general method to genetically encode noncanonical or unnatural amino acids (NAAs) with diverse physical, chemical, or biological properties in bacteria, yeast, animals and mammalian cells was developed. More than 200 NAAs have been incorporated into recombinant proteins by means of non-endogenous aminoacyl-tRNA synthetase (aa-RS)/tRNA pair, an orthogonal pair, that directs site-specific incorporation of NAA encoded by a unique codon. The most established method to genetically encode NAAs in Escherichia coli is based on the usage of the desired mutant of Methanocaldococcus janaschii tyrosyl-tRNA synthetase (MjTyrRS) and cognate suppressor tRNA. The amber codon, the least-used stop codon in E. coli, assigns NAA. Until very recently the genetic code expansion technology suffered from a low yield of targeted proteins due to both incompatibilities of orthogonal pair with host cell translational machinery and the competition of suppressor tRNA with release factor (RF) for binding to nonsense codons. Here we describe the latest progress made to enhance nonsense suppression in E. coli with the emphasis on the improved expression vectors encoding for an orthogonal aa-RA/tRNA pair, enhancement of aa-RS and suppressor tRNA efficiency, the evolution of orthogonal EF-Tu and attempts to reduce the effect of RF1. Full article

(This article belongs to the Section Synthetic Biology and Bioengineering)

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18 pages, 4254 KiB

Open AccessEditor’s ChoiceArticle

Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor

by Kouji Fukuyama, Ryo Kato, Masahiko Murata, Takashi Shiroyama and Motohiro Okada

Biomolecules 2019, 9(6), 234; https://doi.org/10.3390/biom9060234 - 17 Jun 2019

Cited by 55 | Viewed by 6467

Abstract

Pharmacological mechanisms of gold-standard antipsychotics against treatment-refractory schizophrenia, such as clozapine (CLZ), remain unclear. We aimed to explore the mechanisms of CLZ by investigating the effects of MK801 and CLZ on tripartite synaptic transmission in the thalamocortical glutamatergic pathway using multi-probe microdialysis and [...] Read more.

Pharmacological mechanisms of gold-standard antipsychotics against treatment-refractory schizophrenia, such as clozapine (CLZ), remain unclear. We aimed to explore the mechanisms of CLZ by investigating the effects of MK801 and CLZ on tripartite synaptic transmission in the thalamocortical glutamatergic pathway using multi-probe microdialysis and primary cultured astrocytes. l-glutamate release in the medial prefrontal cortex (mPFC) was unaffected by local MK801 administration into mPFC but was enhanced in the mediodorsal thalamic nucleus (MDTN) and reticular thalamic nucleus (RTN) via GABAergic disinhibition in the RTN–MDTN pathway. The local administration of therapeutically relevant concentrations of CLZ into mPFC and MDTN increased and did not affect mPFC l-glutamate release. The local administration of the therapeutically relevant concentration of CLZ into mPFC reduced MK801-induced mPFC l-glutamate release via presynaptic group III metabotropic glutamate receptor (III-mGluR) activation. However, toxic concentrations of CLZ activated l-glutamate release associated with hemichannels. This study demonstrated that RTN is a candidate generator region in which impaired N-methyl-d-aspartate (NMDA)/glutamate receptors likely produce thalamocortical hyperglutamatergic transmission. Additionally, we identified several mechanisms of CLZ relating to its superiority in treatment-resistant schizophrenia and its severe adverse effects: (1) the prevention of thalamocortical hyperglutamatergic transmission via activation of mPFC presynaptic III-mGluR and (2) activation of astroglial l-glutamate release associated with hemichannels. These actions may contribute to the unique clinical profile of CLZ. Full article

(This article belongs to the Special Issue NMDA Receptor in Health and Diseases)

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13 pages, 1202 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Hunt for Degrons of the 26S Proteasome

by Hadar Ella, Yuval Reiss and Tommer Ravid

Biomolecules 2019, 9(6), 230; https://doi.org/10.3390/biom9060230 - 13 Jun 2019

Cited by 18 | Viewed by 5717

Abstract

Since the discovery of ubiquitin conjugation as a cellular mechanism that triggers proteasomal degradation, the mode of substrate recognition by the ubiquitin-ligation system has been the holy grail of research in the field. This entails the discovery of recognition determinants within protein substrates, [...] Read more.

Since the discovery of ubiquitin conjugation as a cellular mechanism that triggers proteasomal degradation, the mode of substrate recognition by the ubiquitin-ligation system has been the holy grail of research in the field. This entails the discovery of recognition determinants within protein substrates, which are part of a degron, and explicit E3 ubiquitin (Ub)-protein ligases that trigger their degradation. Indeed, many protein substrates and their cognate E3′s have been discovered in the past 40 years. In the course of these studies, various degrons have been randomly identified, most of which are acquired through post-translational modification, typically, but not exclusively, protein phosphorylation. Nevertheless, acquired degrons cannot account for the vast diversity in cellular protein half-life times. Obviously, regulation of the proteome is largely determined by inherent degrons, that is, determinants integral to the protein structure. Inherent degrons are difficult to predict since they consist of diverse sequence and secondary structure features. Therefore, unbiased methods have been employed for their discovery. This review describes the history of degron discovery methods, including the development of high throughput screening methods, state of the art data acquisition and data analysis. Additionally, it summarizes major discoveries that led to the identification of cognate E3 ligases and hitherto unrecognized complexities of degron function. Finally, we discuss future perspectives and what still needs to be accomplished towards achieving the goal of understanding how the eukaryotic proteome is regulated via coordinated action of components of the ubiquitin-proteasome system. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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23 pages, 2750 KiB

Open AccessEditor’s ChoiceReview

Albumin Nanovectors in Cancer Therapy and Imaging

by Alessandro Parodi, Jiaxing Miao, Surinder M. Soond, Magdalena Rudzińska and Andrey A. Zamyatnin

Biomolecules 2019, 9(6), 218; https://doi.org/10.3390/biom9060218 - 05 Jun 2019

Cited by 83 | Viewed by 7767

Abstract

Albumin nanovectors represent one of the most promising carriers recently generated because of the cost-effectiveness of their fabrication, biocompatibility, safety, and versatility in delivering hydrophilic and hydrophobic therapeutics and diagnostic agents. In this review, we describe and discuss the recent advances in how [...] Read more.

Albumin nanovectors represent one of the most promising carriers recently generated because of the cost-effectiveness of their fabrication, biocompatibility, safety, and versatility in delivering hydrophilic and hydrophobic therapeutics and diagnostic agents. In this review, we describe and discuss the recent advances in how this technology has been harnessed for drug delivery in cancer, evaluating the commonly used synthesis protocols and considering the key factors that determine the biological transport and the effectiveness of such technology. With this in mind, we highlight how clinical and experimental albumin-based delivery nanoplatforms may be designed for tackling tumor progression or improving the currently established diagnostic procedures. Full article

(This article belongs to the Special Issue Nanoparticles for Cancer Therapy)

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18 pages, 2490 KiB

Open AccessEditor’s ChoiceArticle

Amantadine Combines Astroglial System Xc⁻ Activation with Glutamate/NMDA Receptor Inhibition

by Tomosuke Nakano, Toshiki Hasegawa, Dai Suzuki, Eishi Motomura and Motohiro Okada

Biomolecules 2019, 9(5), 191; https://doi.org/10.3390/biom9050191 - 17 May 2019

Cited by 36 | Viewed by 5283

Abstract

A glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA) exhibits a broad spectrum of clinically important properties, including antiviral, antiparkinsonian, neuroprotective, neuro-reparative and cognitive-enhancing effects. However, both clinical and pre-clinical studies have demonstrated that noncompetitive NMDA-R antagonists induce severe schizophrenia-like cognitive deficits. Therefore, this study [...] Read more.

A glutamate/NMDA receptor (NMDA-R) antagonist, amantadine (AMA) exhibits a broad spectrum of clinically important properties, including antiviral, antiparkinsonian, neuroprotective, neuro-reparative and cognitive-enhancing effects. However, both clinical and pre-clinical studies have demonstrated that noncompetitive NMDA-R antagonists induce severe schizophrenia-like cognitive deficits. Therefore, this study aims to clarify the clinical discrepancy between AMA and noncompetitive NMDA-R antagonists by comparing the effects of AMA with those of a noncompetitive NMDA-R antagonist, MK801, on rat tripartite glutamatergic synaptic transmission using microdialysis and primary cultured astrocytes. Microdialysis study demonstrated that the stimulatory effects of AMA on L-glutamate release differed from those of MK801 in the globus pallidus, entorhinal cortex and entopeduncular nucleus. The stimulatory effect of AMA on L-glutamate release was modulated by activation of cystine/glutamate antiporter (Sxc). Primary cultured astrocytes study demonstrated that AMA also enhanced glutathione synthesis via Sxc activation. Furthermore, carbon-monoxide induced damage of the astroglial glutathione synthesis system was repaired by AMA but not MK801. Additionally, glutamate/AMPA receptor (AMPA-R) antagonist, perampanel enhanced the protective effects of AMA. The findings of microdialysis and cultured astrocyte studies suggest that a combination of Sxc activation with inhibitions of ionotropic glutamate receptors contributes to neuroprotective, neuro-reparative and cognitive-enhancing activities that can mitigate several neuropsychiatric disorders. Full article

(This article belongs to the Special Issue NMDA Receptor in Health and Diseases)

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16 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

The Contribution of the 20S Proteasome to Proteostasis

by Fanindra Kumar Deshmukh, Dana Yaffe, Maya A. Olshina, Gili Ben-Nissan and Michal Sharon

Biomolecules 2019, 9(5), 190; https://doi.org/10.3390/biom9050190 - 16 May 2019

Cited by 90 | Viewed by 11381

Abstract

The last decade has seen accumulating evidence of various proteins being degraded by the core 20S proteasome, without its regulatory particle(s). Here, we will describe recent advances in our knowledge of the functional aspects of the 20S proteasome, exploring several different systems and [...] Read more.

The last decade has seen accumulating evidence of various proteins being degraded by the core 20S proteasome, without its regulatory particle(s). Here, we will describe recent advances in our knowledge of the functional aspects of the 20S proteasome, exploring several different systems and processes. These include neuronal communication, post-translational processing, oxidative stress, intrinsically disordered protein regulation, and extracellular proteasomes. Taken together, these findings suggest that the 20S proteasome, like the well-studied 26S proteasome, is involved in multiple biological processes. Clarifying our understanding of its workings calls for a transformation in our perception of 20S proteasome-mediated degradation—no longer as a passive and marginal path, but rather as an independent, coordinated biological process. Nevertheless, in spite of impressive progress made thus far, the field still lags far behind the front lines of 26S proteasome research. Therefore, we also touch on the gaps in our knowledge of the 20S proteasome that remain to be bridged in the future. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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12 pages, 890 KiB

Open AccessEditor’s ChoiceReview

The Use of Antifreeze Proteins in the Cryopreservation of Gametes and Embryos

by Vanesa Robles, David G. Valcarce and Marta F. Riesco

Biomolecules 2019, 9(5), 181; https://doi.org/10.3390/biom9050181 - 09 May 2019

Cited by 61 | Viewed by 6597

Abstract

The cryopreservation of gametes and embryos is a technique widely used in reproductive biology. This technology helps in the reproductive management of domesticated animals, and it is an important tool for gene banking and for human-assisted reproductive technologies. Antifreeze proteins are naturally present [...] Read more.

The cryopreservation of gametes and embryos is a technique widely used in reproductive biology. This technology helps in the reproductive management of domesticated animals, and it is an important tool for gene banking and for human-assisted reproductive technologies. Antifreeze proteins are naturally present in several organisms exposed to subzero temperatures. The ability for these proteins to inhibit ice recrystallization together with their ability to interact with biological membranes makes them interesting molecules to be used in cryopreservation protocols. This mini-review provides a general overview about the use of antifreeze proteins to improve the short and long term storage of gametes and embryos. Full article

(This article belongs to the Special Issue Antifreeze Protein: New Insight from Different Approaches)

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18 pages, 21619 KiB

Open AccessEditor’s ChoiceReview

HIV Vaccine Mystery and Viral Shell Disorder

by Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster and Vladimir N. Uversky

Biomolecules 2019, 9(5), 178; https://doi.org/10.3390/biom9050178 - 08 May 2019

Cited by 37 | Viewed by 7930

Abstract

Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the [...] Read more.

Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), was found in 1973. We reported earlier the highly disordered nature of proteins in outer shells of the HIV, HCV, and HSV. Such levels of disorder are completely absent among the classical viruses, such as smallpox, rabies, yellow fever, and polio viruses, for which efficient vaccines were discovered. This review analyzes the physiology and shell disorder of the various related and non-related viruses to argue that EIAV and the classical viruses need harder shells to survive during harsher conditions of non-sexual transmissions, thus making them vulnerable to antibody detection and neutralization. In contrast, the outer shell of the HIV-1 (with its preferential sexual transmission) is highly disordered, thereby allowing large scale motions of its surface glycoproteins and making it difficult for antibodies to bind to them. The theoretical underpinning of this concept is retrospectively traced to a classical 1920s experiment by the legendary scientist, Oswald Avery. This concept of viral shapeshifting has implications for improved treatment of cancer and infections via immune evasion. Full article

(This article belongs to the Special Issue HIV: ART and Immune Activation)

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16 pages, 4215 KiB

Open AccessEditor’s ChoiceArticle

Novel Galiellalactone Analogues Can Target STAT3 Phosphorylation and Cause Apoptosis in Triple-Negative Breast Cancer

by Hyejin Ko, Jong Hyun Lee, Hyun Su Kim, Taewoo Kim, Young Taek Han, Young-Ger Suh, Jaemoo Chun, Yeong Shik Kim and Kwang Seok Ahn

Biomolecules 2019, 9(5), 170; https://doi.org/10.3390/biom9050170 - 03 May 2019

Cited by 22 | Viewed by 4206

Abstract

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) has been documented in various malignancies including triple-negative breast cancers (TNBCs). The STAT3 transcription factor can regulate the different important hallmarks of tumor cells, and thus, targeting it can be a potential [...] Read more.

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) has been documented in various malignancies including triple-negative breast cancers (TNBCs). The STAT3 transcription factor can regulate the different important hallmarks of tumor cells, and thus, targeting it can be a potential strategy for treating TNBC, for which only limited therapeutic options are available. In this study, we analyzed the possible effect of (-)-galiellalactone and its novel analogues, SG-1709 and SG-1721, and determined whether these agents exerted their antineoplastic effects by suppressing the STAT3 signaling pathway in TNBC cells. The two analogues, SG-1709 and SG-1721, inhibited both constitutive as well as inducible STAT3 phosphorylation at tyrosine 705 more effectively than (-)-galiellalactone, which indicates that the analogues are more potent STAT3 blockers. Moreover, SG-1721 not only inhibited nuclear translocation and DNA binding of STAT3 but also induced apoptosis, and decreased expression of diverse oncogenic proteins. Interestingly, SG-1721 also exhibited an enhanced apoptotic effect when combined with radiotherapy. Furthermore, in vivo administration of SG-1721 significantly attenuated breast xenograft tumor growth via decreasing levels of p-STAT3. Therefore, SG-1721 may be a promising candidate for further application as a pharmacological agent that can target STAT3 protein in treating TNBC. Full article

(This article belongs to the Special Issue Antitumor Agents from Natural Sources)

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20 pages, 11087 KiB

Open AccessEditor’s ChoiceArticle

Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions

by Carolina Cragnell, Lasse Staby, Samuel Lenton, Birthe B. Kragelund and Marie Skepö

Biomolecules 2019, 9(5), 168; https://doi.org/10.3390/biom9050168 - 30 Apr 2019

Cited by 22 | Viewed by 5148

Abstract

Intrinsically disordered proteins (IDPs) can form functional oligomers and in some cases, insoluble disease related aggregates. It is therefore vital to understand processes and mechanisms that control pathway distribution. Divalent cations including Zn²⁺ can initiate IDP oligomerisation through the interaction with histidine [...] Read more.

Intrinsically disordered proteins (IDPs) can form functional oligomers and in some cases, insoluble disease related aggregates. It is therefore vital to understand processes and mechanisms that control pathway distribution. Divalent cations including Zn²⁺ can initiate IDP oligomerisation through the interaction with histidine residues but the mechanisms of doing so are far from understood. Here we apply a multi-disciplinary approach using small angle X-ray scattering, nuclear magnetic resonance spectroscopy, calorimetry and computations to show that that saliva protein Histatin 5 forms highly dynamic oligomers in the presence of Zn²⁺. The process is critically dependent upon interaction between Zn²⁺ ions and distinct histidine rich binding motifs which allows for thermodynamic switching between states. We propose a molecular mechanism of oligomerisation, which may be generally applicable to other histidine rich IDPs. Finally, as Histatin 5 is an important saliva component, we suggest that Zn²⁺ induced oligomerisation may be crucial for maintaining saliva homeostasis. Full article

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19 pages, 1253 KiB

Open AccessEditor’s ChoiceArticle

Promoter Hypermethylation of Tumor-Suppressor Genes p16^INK4a, RASSF1A, TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers

by Chamikara Liyanage, Asanga Wathupola, Sanjayan Muraleetharan, Kanthi Perera, Chamindie Punyadeera and Preethi Udagama

Biomolecules 2019, 9(4), 148; https://doi.org/10.3390/biom9040148 - 12 Apr 2019

Cited by 47 | Viewed by 8090

Abstract

Silencing of tumor-suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis; hence, TSGs may serve as early tumor biomarkers. We determined the promoter methylation levels of p16^INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs in salivary DNA [...] Read more.

Silencing of tumor-suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis; hence, TSGs may serve as early tumor biomarkers. We determined the promoter methylation levels of p16^INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs in salivary DNA from oral cancer (OC) and oropharyngeal cancer (OPC) patients, using methylation-specific PCR coupled with densitometry analysis. We assessed the association between DNA methylation of individual TSGs with OC and OPC risk factors. The performance and the clinical validity of this quadruple-methylation marker panel were evaluated in discriminating OC and OPC patients from healthy controls using the CombiROC web tool. Our study reports that RASSF1A, TIMP3, and PCQAP/MED15 TSGs were significantly hypermethylated in OC and OPC cases compared to healthy controls. DNA methylation levels of TSGs were significantly augmented by smoking, alcohol use, and betel quid chewing, indicating the fact that frequent exposure to risk factors may drive oral and oropharyngeal carcinogenesis through TSG promoter hypermethylation. Also, this quadruple-methylation marker panel of p16^INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs demonstrated excellent diagnostic accuracy in the early detection of OC at 91.7% sensitivity and 92.3% specificity and of OPC at 99.8% sensitivity and 92.1% specificity from healthy controls. Full article

(This article belongs to the Special Issue Biomarkers for Cancer)

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22 pages, 2126 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins

by Supriyo Bhattacharya and Xingcheng Lin

Biomolecules 2019, 9(4), 146; https://doi.org/10.3390/biom9040146 - 11 Apr 2019

Cited by 48 | Viewed by 7609

Abstract

Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This [...] Read more.

Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This enables the IDPs to signal through multiple signaling pathways and serve as scaffolds for multi-protein complexes. The challenge in studying IDPs experimentally stems from their disordered nature. Nuclear magnetic resonance (NMR), circular dichroism, small angle X-ray scattering, and single molecule Förster resonance energy transfer (FRET) can give the local structural information and overall dimension of IDPs, but seldom provide a unified picture of the whole protein. To understand the conformational dynamics of IDPs and how their structural ensembles recognize multiple binding partners and small molecule inhibitors, knowledge-based and physics-based sampling techniques are utilized in-silico, guided by experimental structural data. However, efficient sampling of the IDP conformational ensemble requires traversing the numerous degrees of freedom in the IDP energy landscape, as well as force-fields that accurately model the protein and solvent interactions. In this review, we have provided an overview of the current state of computational methods for studying IDP structure and dynamics and discussed the major challenges faced in this field. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)

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48 pages, 5225 KiB

Open AccessEditor’s ChoiceReview

Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson’s Disease

by Fabio Del Bello, Mario Giannella, Gianfabio Giorgioni, Alessandro Piergentili and Wilma Quaglia

Biomolecules 2019, 9(4), 142; https://doi.org/10.3390/biom9040142 - 09 Apr 2019

Cited by 19 | Viewed by 7223

Abstract

Levodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). However, although it represents the “gold standard” of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, [...] Read more.

Levodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). However, although it represents the “gold standard” of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic drugs are being developed to optimize the treatment response. This review focuses on recent investigations about non-dopaminergic central nervous system (CNS) receptor ligands that have been identified to have therapeutic potential for the treatment of motor and non-motor symptoms of PD. In a different way, such agents may contribute to extending LD response and/or ameliorate LD-induced side effects. Full article

(This article belongs to the Special Issue Advances in Parkinson's Disease Drugs)

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13 pages, 2056 KiB

Open AccessEditor’s ChoiceArticle

Quantification of Fecal Short Chain Fatty Acids by Liquid Chromatography Tandem Mass Spectrometry—Investigation of Pre-Analytic Stability

by Gerhard Liebisch, Josef Ecker, Sebastian Roth, Sabine Schweizer, Veronika Öttl, Hans-Frieder Schött, Hongsup Yoon, Dirk Haller, Ernst Holler, Ralph Burkhardt and Silke Matysik

Biomolecules 2019, 9(4), 121; https://doi.org/10.3390/biom9040121 - 28 Mar 2019

Cited by 59 | Viewed by 11180

Abstract

Short chain fatty acids (SCFAs) are generated by the degradation and fermentation of complex carbohydrates, (i.e., dietary fiber) by the gut microbiota relevant for microbe–host communication. Here, we present a method for the quantification of SCFAs in fecal samples by liquid chromatography tandem [...] Read more.

Short chain fatty acids (SCFAs) are generated by the degradation and fermentation of complex carbohydrates, (i.e., dietary fiber) by the gut microbiota relevant for microbe–host communication. Here, we present a method for the quantification of SCFAs in fecal samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) upon derivatization to 3-nitrophenylhydrazones (3NPH). The method includes acetate, propionate, butyrate, and isobutyrate with a run time of 4 min. The reproducible (coefficients of variation (CV) below 10%) quantification of SCFAs in human fecal samples was achieved by the application of stable isotope labelled internal standards. The specificity was demonstrated by the introduction of a quantifier and qualifier ions. The method was applied to investigate the pre-analytic stability of SCFAs in human feces. Concentrations of SCFA may change substantially within hours; the degree and kinetics of these changes revealed huge differences between the donors. The fecal SCFA level could be preserved by the addition of organic solvents like isopropanol. An analysis of the colon content of mice either treated with antibiotics or fed with a diet containing a non-degradable and -fermentable fiber source showed decreased SCFA concentrations. In summary, this fast and reproducible method for the quantification of SCFA in fecal samples provides a valuable tool for both basic research and large-scale studies. Full article

(This article belongs to the Special Issue Lipidomics)

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32 pages, 827 KiB

Open AccessEditor’s ChoiceReview

Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences

by Kateřina Melková, Vojtěch Zapletal, Subhash Narasimhan, Séverine Jansen, Jozef Hritz, Rostislav Škrabana, Markus Zweckstetter, Malene Ringkjøbing Jensen, Martin Blackledge and Lukáš Žídek

Biomolecules 2019, 9(3), 105; https://doi.org/10.3390/biom9030105 - 16 Mar 2019

Cited by 41 | Viewed by 10361

Abstract

The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic [...] Read more.

The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic resonance and cryo-electron microscopy recently revealed propensities of MAPs to form transient local structures and long-range contacts in the free state, and conformations adopted in complexes with microtubules and filamentous actin, as well as in pathological aggregates. In this paper, we compare the longest, 441-residue brain isoform of tau (tau40), and a 467-residue isoform of MAP2, known as MAP2c. For both molecules, we present transient structural motifs revealed by conformational analysis of experimental data obtained for free soluble forms of the proteins. We show that many of the short sequence motifs that exhibit transient structural features are linked to functional properties, manifested by specific interactions. The transient structural motifs can be therefore classified as molecular recognition elements of tau40 and MAP2c. Their interactions are further regulated by post-translational modifications, in particular phosphorylation. The structure-function analysis also explains differences between biological activities of tau40 and MAP2c. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)

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35 pages, 8296 KiB

Open AccessEditor’s ChoiceReview

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

by Michelle S. Miller, Philip E. Thompson and Sandra B. Gabelli

Biomolecules 2019, 9(3), 82; https://doi.org/10.3390/biom9030082 - 26 Feb 2019

Cited by 54 | Viewed by 8426

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ have unique, non-redundant physiological roles and as such, isoform selectivity has been a [...] Read more.

Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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17 pages, 7507 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Molecular Crowding Tunes Material States of Ribonucleoprotein Condensates

by Taranpreet Kaur, Ibraheem Alshareedah, Wei Wang, Jason Ngo, Mahdi Muhammad Moosa and Priya R. Banerjee

Biomolecules 2019, 9(2), 71; https://doi.org/10.3390/biom9020071 - 19 Feb 2019

Cited by 72 | Viewed by 16802

Abstract

Ribonucleoprotein (RNP) granules are membraneless liquid condensates that dynamically form, dissolve, and mature into a gel-like state in response to a changing cellular environment. RNP condensation is largely governed by promiscuous attractive inter-chain interactions mediated by low-complexity domains (LCDs). Using an archetypal disordered [...] Read more.

Ribonucleoprotein (RNP) granules are membraneless liquid condensates that dynamically form, dissolve, and mature into a gel-like state in response to a changing cellular environment. RNP condensation is largely governed by promiscuous attractive inter-chain interactions mediated by low-complexity domains (LCDs). Using an archetypal disordered RNP, fused in sarcoma (FUS), here we study how molecular crowding impacts the RNP liquid condensation. We observe that the liquid–liquid coexistence boundary of FUS is lowered by polymer crowders, consistent with an excluded volume model. With increasing bulk crowder concentration, the RNP partition increases and the diffusion rate decreases in the condensed phase. Furthermore, we show that RNP condensates undergo substantial hardening wherein protein-dense droplets transition from viscous fluid to viscoelastic gel-like states in a crowder concentration-dependent manner. Utilizing two distinct LCDs that broadly represent commonly occurring sequence motifs driving RNP phase transitions, we reveal that the impact of crowding is largely independent of LCD charge and sequence patterns. These results are consistent with a thermodynamic model of crowder-mediated depletion interaction, which suggests that inter-RNP attraction is enhanced by molecular crowding. The depletion force is likely to play a key role in tuning the physical properties of RNP condensates within the crowded cellular space. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)

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54 pages, 30011 KiB

Open AccessEditor’s ChoiceReview

Phosphatases in Mitosis: Roles and Regulation

by Margarida Moura and Carlos Conde

Biomolecules 2019, 9(2), 55; https://doi.org/10.3390/biom9020055 - 07 Feb 2019

Cited by 52 | Viewed by 11481

Abstract

Mitosis requires extensive rearrangement of cellular architecture and of subcellular structures so that replicated chromosomes can bind correctly to spindle microtubules and segregate towards opposite poles. This process originates two new daughter nuclei with equal genetic content and relies on highly-dynamic and tightly [...] Read more.

Mitosis requires extensive rearrangement of cellular architecture and of subcellular structures so that replicated chromosomes can bind correctly to spindle microtubules and segregate towards opposite poles. This process originates two new daughter nuclei with equal genetic content and relies on highly-dynamic and tightly regulated phosphorylation of numerous cell cycle proteins. A burst in protein phosphorylation orchestrated by several conserved kinases occurs as cells go into and progress through mitosis. The opposing dephosphorylation events are catalyzed by a small set of protein phosphatases, whose importance for the accuracy of mitosis is becoming increasingly appreciated. This review will focus on the established and emerging roles of mitotic phosphatases, describe their structural and biochemical properties, and discuss recent advances in understanding the regulation of phosphatase activity and function. Full article

(This article belongs to the Special Issue Cytoskeleton and Regulation of Mitosis)

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14 pages, 2579 KiB

Open AccessEditor’s ChoiceArticle

High-Throughput Screening of Lipidomic Adaptations in Cultured Cells

by Aike Jeucken and Jos F. Brouwers

Biomolecules 2019, 9(2), 42; https://doi.org/10.3390/biom9020042 - 24 Jan 2019

Cited by 13 | Viewed by 4535

Abstract

High-throughput screening of biologically active substances in cell cultures remains challenging despite great progress in contemporary lipidomic techniques. These experiments generate large amounts of data that are translated into lipid fingerprints. The subsequent visualization of lipidomic changes is key to meaningful interpretation of [...] Read more.

High-throughput screening of biologically active substances in cell cultures remains challenging despite great progress in contemporary lipidomic techniques. These experiments generate large amounts of data that are translated into lipid fingerprints. The subsequent visualization of lipidomic changes is key to meaningful interpretation of experimental results. As a demonstration of a rapid and versatile pipeline for lipidomic analysis, we cultured HeLa cells in 96-well format for four days in the presence or absence of various inhibitors of lipid metabolic pathways. Visualization of the data by principle component analysis revealed a high reproducibility of the method, as well as drug specific changes to the lipidome. Construction of heatmaps and networks revealed the similarities and differences between the effects of different drugs at the lipid species level. Clusters of related lipid species that might represent distinct membrane domains emerged after correlation analysis of the complete dataset. Taken together, we present a lipidomic platform for high-throughput lipidomic analysis of cultured cell lines. Full article

(This article belongs to the Special Issue Lipidomics)

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17 pages, 6710 KiB

Open AccessEditor’s ChoiceArticle

NP-Scout: Machine Learning Approach for the Quantification and Visualization of the Natural Product-Likeness of Small Molecules

by Ya Chen, Conrad Stork, Steffen Hirte and Johannes Kirchmair

Biomolecules 2019, 9(2), 43; https://doi.org/10.3390/biom9020043 - 24 Jan 2019

Cited by 44 | Viewed by 8526

Abstract

Natural products (NPs) remain the most prolific resource for the development of small-molecule drugs. Here we report a new machine learning approach that allows the identification of natural products with high accuracy. The method also generates similarity maps, which highlight atoms that contribute [...] Read more.

Natural products (NPs) remain the most prolific resource for the development of small-molecule drugs. Here we report a new machine learning approach that allows the identification of natural products with high accuracy. The method also generates similarity maps, which highlight atoms that contribute significantly to the classification of small molecules as a natural product or synthetic molecule. The method can hence be utilized to (i) identify natural products in large molecular libraries, (ii) quantify the natural product-likeness of small molecules, and (iii) visualize atoms in small molecules that are characteristic of natural products or synthetic molecules. The models are based on random forest classifiers trained on data sets consisting of more than 265,000 to 322,000 natural products and synthetic molecules. Two-dimensional molecular descriptors, MACCS keys and Morgan2 fingerprints were explored. On an independent test set the models reached areas under the receiver operating characteristic curve (AUC) of 0.997 and Matthews correlation coefficients (MCCs) of 0.954 and higher. The method was further tested on data from the Dictionary of Natural Products, ChEMBL and other resources. The best-performing models are accessible as a free web service at http://npscout.zbh.uni-hamburg.de/npscout. Full article

(This article belongs to the Special Issue New Approaches for the Discovery of Pharmacologically-Active Natural Compounds)

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