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Biomolecules, Volume 10, Issue 8 (August 2020) – 114 articles

Cover Story (view full-size image): Zinc homeostasis is critical for bacterial survival and virulence. Extracellular zinc-binding proteins play an important role in this process. The ATP-binding cassette (ABC) transporter system AztABCD includes two periplasmic proteins, AztC and AztD. Both bind zinc with high affinity and specificity. Further, AztD can transfer zinc to AztC, which can then deliver the metal to the membrane permease (AztB) for import into the cell. These processes are highly specific and rely on conserved structural features of each protein. This work assesses the role of several flexible or unstructured sequences in zinc binding and transfer from AztD to AztC. The results provide insights into the dynamic nature of these processes and support a previously proposed structural model of transfer. View this paper.
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Review
Mitochondrial Potassium Channels as Druggable Targets
Biomolecules 2020, 10(8), 1200; https://doi.org/10.3390/biom10081200 - 18 Aug 2020
Cited by 16 | Viewed by 1703
Abstract
Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been [...] Read more.
Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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Article
The Protective Role of Decorin in Hepatic Metastasis of Colorectal Carcinoma
Biomolecules 2020, 10(8), 1199; https://doi.org/10.3390/biom10081199 - 18 Aug 2020
Cited by 2 | Viewed by 1363
Abstract
Decorin, the prototype member of the small leucine-rich proteoglycan gene family of extracellular matrix (ECM) proteins, acts as a powerful tumor suppressor by inducing the p21Waf1/Cip1 cyclin-dependent kinase inhibitor, as well as through its ability to directly bind and block the action [...] Read more.
Decorin, the prototype member of the small leucine-rich proteoglycan gene family of extracellular matrix (ECM) proteins, acts as a powerful tumor suppressor by inducing the p21Waf1/Cip1 cyclin-dependent kinase inhibitor, as well as through its ability to directly bind and block the action of several tyrosine kinase receptors. Our previous studies suggested that the lack of decorin promotes hepatic carcinogenesis in mice. Based on this, we set out to investigate whether excess decorin may protect against the liver metastases of colon carcinoma. We also analyzed the effect of decorin in tissue microarrays of human colon carcinoma liver metastasis and examined whether the tumor cells can directly influence the decorin production of myofibroblasts. In humans, low levels of decorin in the liver facilitated the development of colon carcinoma metastases in proportion with more aggressive phenotypes, indicating a possible antitumor action of the proteoglycan. In vitro, colon carcinoma cells inhibited decorin expression in LX2 hepatic stellate cells. Moreover, liver-targeted decorin delivery in mice effectively attenuated metastasis formation of colon cancer. Overexpressed decorin reduced the activity of multiple receptor tyrosine kinases (RTKs) including the epidermal growth factor receptor (EGFR), an important player in colorectal cancer (CRC) pathogenesis. Downstream of that, we observed weakened signaling of ERK1/2, PLCγ, Akt/mTOR, STAT and c-Jun pathways, while p38 MAPK/MSK/CREB and AMPK were upregulated culminating in enhanced p53 function. In conclusion, decorin may effectively inhibit metastatic tumor formation in the liver. Full article
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Article
CB2 Receptors and Neuron–Glia Interactions Modulate Neurotoxicity Generated by MAGL Inhibition
Biomolecules 2020, 10(8), 1198; https://doi.org/10.3390/biom10081198 - 18 Aug 2020
Cited by 3 | Viewed by 1048
Abstract
Monoacylglycerol lipase inhibition (MAGL) has emerged as an interesting therapeutic target for neurodegenerative disease treatment due to its ability to modulate the endocannabinoid system and to prevent the production of proinflammatory mediators. To obtain a beneficial response, it is necessary to understand how [...] Read more.
Monoacylglycerol lipase inhibition (MAGL) has emerged as an interesting therapeutic target for neurodegenerative disease treatment due to its ability to modulate the endocannabinoid system and to prevent the production of proinflammatory mediators. To obtain a beneficial response, it is necessary to understand how this inhibition affects the neuron–glia crosstalk and neuron viability. In this study, the effect of MAGL inhibition by KML29 was evaluated in two types of rat cortical primary cultures; mixed cultures, including neuron and glial cells, and neuron-enriched cultures. The risk of neuronal death was estimated by longitudinal survival analysis. The spontaneous neuronal risk of death in culture was higher in the absence of glial cells, a process that was enhanced by KML29 addition. In contrast, neuronal survival was not compromised by MAGL inhibition in the presence of glial cells. Blockade of cannabinoid type 2 (CB2) receptors expressed mainly by microglial cells did not affect the spontaneous neuronal death risk but decreased neuronal survival when KML29 was added. Modulation of cannabinoid type 1 (CB1) receptors did not affect neuronal survival. Our results show that neuron–glia interactions are essential for neuronal survival. CB2 receptors play a key role in these protective interactions when neurons are exposed to toxic conditions. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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Article
Plasmodium falciparum Knockout for the GPCR-Like PfSR25 Receptor Displays Greater Susceptibility to 1,2,3-Triazole Compounds That Block Malaria Parasite Development
Biomolecules 2020, 10(8), 1197; https://doi.org/10.3390/biom10081197 - 18 Aug 2020
Cited by 4 | Viewed by 1157
Abstract
The search for new compounds with antimalarial activity is urgent, as resistance to ones in the classical drug, has already been described in more than one continent. Compounds derived from 1,2,3-triazoles are effective against parasites and bacteria. Here, we evaluated the potential antimalarial [...] Read more.
The search for new compounds with antimalarial activity is urgent, as resistance to ones in the classical drug, has already been described in more than one continent. Compounds derived from 1,2,3-triazoles are effective against parasites and bacteria. Here, we evaluated the potential antimalarial activity against the human malaria parasite Plasmodium falciparum in a culture of fifty-four triazole compounds derived from 1H-and 2H-1,2,3-triazole. We identified thirty-one compounds with potential antimalarial activity at concentrations in the micromolar order (µM) and IC50 values ranging from 2.80 µM (9) to 29.27 µM (21). Then, we selected some of these compounds to perform the same tests on the PfSR25- strain (knockout for P. falciparum G-protein coupled receptor-like, SR25). Our experiences with the PfSR25- strain showed that both compounds with higher antimalarial activity for the 3D7 strain and those with less activity resulted in lower IC50 values for the knockout strain. The cytotoxicity of the compounds was evaluated in human renal embryonic cells (HEK 293), using MTT assays. This demonstrated that the compounds with the highest activity (9, 13, 19, 22, 24, 29), showed no toxicity at the tested concentrations. Full article
(This article belongs to the Section Molecular Medicine)
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Article
A 3D Tissue Model of Traumatic Brain Injury with Excitotoxicity That Is Inhibited by Chronic Exposure to Gabapentinoids
Biomolecules 2020, 10(8), 1196; https://doi.org/10.3390/biom10081196 - 17 Aug 2020
Cited by 1 | Viewed by 1489
Abstract
Injury progression associated with cerebral laceration is insidious. Following the initial trauma, brain tissues become hyperexcitable, begetting further damage that compounds the initial impact over time. Clinicians have adopted several strategies to mitigate the effects of secondary brain injury; however, higher throughput screening [...] Read more.
Injury progression associated with cerebral laceration is insidious. Following the initial trauma, brain tissues become hyperexcitable, begetting further damage that compounds the initial impact over time. Clinicians have adopted several strategies to mitigate the effects of secondary brain injury; however, higher throughput screening tools with modular flexibility are needed to expedite mechanistic studies and drug discovery that will contribute to the enhanced protection, repair, and even the regeneration of neural tissues. Here we present a novel bioengineered cortical brain model of traumatic brain injury (TBI) that displays characteristics of primary and secondary injury, including an outwardly radiating cell death phenotype and increased glutamate release with excitotoxic features. DNA content and tissue function were normalized by high-concentration, chronic administrations of gabapentinoids. Additional experiments suggested that the treatment effects were likely neuroprotective rather than regenerative, as evidenced by the drug-mediated decreases in cell excitability and an absence of drug-induced proliferation. We conclude that the present model of traumatic brain injury demonstrates validity and can serve as a customizable experimental platform to assess the individual contribution of cell types on TBI progression, as well as to screen anti-excitotoxic and pro-regenerative compounds. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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Review
Grapevine Cane Extracts: Raw Plant Material, Extraction Methods, Quantification, and Applications
Biomolecules 2020, 10(8), 1195; https://doi.org/10.3390/biom10081195 - 17 Aug 2020
Cited by 5 | Viewed by 1773
Abstract
Grapevine canes are viticulture waste that is usually discarded without any further use. However, recent studies have shown that they contain significant concentrations of health-promoting compounds, such as stilbenes, secondary metabolites of plants produced as a response to biotic and abiotic stress from [...] Read more.
Grapevine canes are viticulture waste that is usually discarded without any further use. However, recent studies have shown that they contain significant concentrations of health-promoting compounds, such as stilbenes, secondary metabolites of plants produced as a response to biotic and abiotic stress from fungal disease or dryness. Stilbenes have been associated with antioxidant, anti-inflammatory, and anti-microbial properties and they have been tested as potential treatments of cardiovascular and neurological diseases, and even cancer, with promising results. Stilbenes have been described in the different genus of the Vitaceae family, the Vitis genera being one of the most widely studied due to its important applications and economic impact around the world. This review presents an in-depth study of the composition and concentration of stilbenes in grapevine canes. The results show that the concentration of stilbenes in grapevine canes is highly influenced by the Vitis genus and cultivar aspects (growing conditions, ultraviolet radiation, fungal attack, etc.). Different methods for extracting stilbenes from grapevine canes have been reviewed, and the extraction conditions have also been studied, underlining the advantages and disadvantages of each technique. After the stilbenes were extracted, they were analyzed to determine the stilbene composition and concentration. Analytical techniques have been employed with this aim, in most cases using liquid chromatography, coupled with others such as mass spectrometry and/or nuclear magnetic resonance to achieve the individual quantification. Finally, stilbene extracts may be applied in multiple fields based on their properties. The five most relevant are preservative, antifungal, insecticide, and biostimulant applications. The current state-of-the-art of the above applications and their prospects are discussed. Full article
(This article belongs to the Special Issue Biomolecules from Plant Residues)
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Article
Enhancement of Migration and Invasion of Gastric Cancer Cells by IQGAP3
Biomolecules 2020, 10(8), 1194; https://doi.org/10.3390/biom10081194 - 17 Aug 2020
Cited by 4 | Viewed by 1166
Abstract
Although gastric cancer is one of the most common causes of cancer death in the world, mechanisms underlying this type of tumor have not been fully understood. In this study, we found that IQGAP3, a member of the IQGAP gene family, was [...] Read more.
Although gastric cancer is one of the most common causes of cancer death in the world, mechanisms underlying this type of tumor have not been fully understood. In this study, we found that IQGAP3, a member of the IQGAP gene family, was significantly up-regulated in human gastric cancer starting from the early stages of tumor progression. Overexpression of IQGAP3 in 293T and NIH3T3 cells, which have no endogenous IQGAP3 expression, resulted in morphological change with multiple dendritic-like protrusions and enhanced migration. Overexpression of IQGAP3 also led to reduced cell–cell adhesion in 293T cells, likely as a result of its interactions with e-cadherin or β-catenin proteins. Additionally, IQGAP3 accumulated along the leading edge of migrating cells and at the cleavage furrow of dividing cells. In contrast, suppression of IQGAP3 by short-interfering RNA (siRNA) markedly reduced invasion and anchorage-independent growth of MKN1 and TMK-1 gastric cancer cells. We further confirmed that IQGAP3 interacted with Rho family GTPases, and had an important role in cytokinesis. Taken together, we demonstrated that IQGAP3 plays critical roles in migration and invasion of human gastric cancer cells, and regulates cytoskeletal remodeling, cell migration and adhesion. These findings may open a new avenue for the diagnosis and treatment of gastric cancer. Full article
(This article belongs to the Special Issue New Advances in Molecular Oncology)
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Review
Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases
Biomolecules 2020, 10(8), 1193; https://doi.org/10.3390/biom10081193 - 16 Aug 2020
Cited by 6 | Viewed by 1503
Abstract
Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression [...] Read more.
Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level. Full article
(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)
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Article
The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin
Biomolecules 2020, 10(8), 1192; https://doi.org/10.3390/biom10081192 - 16 Aug 2020
Cited by 2 | Viewed by 1566
Abstract
The intrinsically disordered protein α-synuclein (aSN) is, in its fibrillated state, the main component of Lewy bodies—hallmarks of Parkinson’s disease. Additional Lewy body components include glycosaminoglycans, including heparan sulfate proteoglycans. In humans, heparan sulfate has, in an age-dependent manner, shown increased levels of [...] Read more.
The intrinsically disordered protein α-synuclein (aSN) is, in its fibrillated state, the main component of Lewy bodies—hallmarks of Parkinson’s disease. Additional Lewy body components include glycosaminoglycans, including heparan sulfate proteoglycans. In humans, heparan sulfate has, in an age-dependent manner, shown increased levels of sulfation. Heparin, a highly sulfated glycosaminoglycan, is a relevant mimic for mature heparan sulfate and has been shown to influence aSN fibrillation. Here, we decompose the underlying properties of the interaction between heparin and aSN and the effect of heparin on fibrillation. Via the isolation of the first 61 residues of aSN, which lacked intrinsic fibrillation propensity, fibrillation could be induced by heparin, and access to the initial steps in fibrillation was possible. Here, structural changes with shifts from disorder via type I β-turns to β-sheets were revealed, correlating with an increase in the aSN1–61/heparin molar ratio. Fluorescence microscopy revealed that heparin and aSN1–61 co-exist in the final fibrils. We conclude that heparin can induce the fibrillation of aSN1–61, through binding to the N-terminal with an affinity that is higher in the truncated form of aSN. It does so by specifically modulating the structure of aSN via the formation of type I β-turn structures likely critical for triggering aSN fibrillation. Full article
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Article
Natural Polymeric Compound Based on High Thermal Stability Catechin from Green Tea
Biomolecules 2020, 10(8), 1191; https://doi.org/10.3390/biom10081191 - 16 Aug 2020
Cited by 9 | Viewed by 1083
Abstract
Catechin is a plant polyphenol with valuable antioxidant and health-promoting properties. Polymerization is one way to stabilize flavonoids and may cause changes in their specific properties. The aim of this study is to obtain a polymeric complex catechin compound with high thermal stability. [...] Read more.
Catechin is a plant polyphenol with valuable antioxidant and health-promoting properties. Polymerization is one way to stabilize flavonoids and may cause changes in their specific properties. The aim of this study is to obtain a polymeric complex catechin compound with high thermal stability. As a result of polymerization, a condensed and cross-linked catechin structure was obtained, which guaranteed high thermal resistance and, moreover, the phosphorus groups added in the second step of polymerization ensured that the compound obtained had thermal stability higher than natural condensed tannins. The first step of self-polymerization of (+)-catechin may be an easy way to obtain proanthocyanidins with greater antioxidant activity. The second step of the polymerization obtained a polymeric complex catechin compound that showed better thermal stability than catechin. This compound can potentially be used as a new pro-ecological thermal stabilizer. Full article
(This article belongs to the Special Issue Plant-Based Biomolecules—Potential Effects on Degenerative Diseases)
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Review
Proteomic and Bioinformatic Profiling of Transporters in Higher Plant Mitochondria
Biomolecules 2020, 10(8), 1190; https://doi.org/10.3390/biom10081190 - 16 Aug 2020
Cited by 3 | Viewed by 1159
Abstract
To function as a metabolic hub, plant mitochondria have to exchange a wide variety of metabolic intermediates as well as inorganic ions with the cytosol. As identified by proteomic profiling or as predicted by MU-LOC, a newly developed bioinformatics tool, Arabidopsis thaliana mitochondria [...] Read more.
To function as a metabolic hub, plant mitochondria have to exchange a wide variety of metabolic intermediates as well as inorganic ions with the cytosol. As identified by proteomic profiling or as predicted by MU-LOC, a newly developed bioinformatics tool, Arabidopsis thaliana mitochondria contain 128 or 143 different transporters, respectively. The largest group is the mitochondrial carrier family, which consists of symporters and antiporters catalyzing secondary active transport of organic acids, amino acids, and nucleotides across the inner mitochondrial membrane. An impressive 97% (58 out of 60) of all the known mitochondrial carrier family members in Arabidopsis have been experimentally identified in isolated mitochondria. In addition to many other secondary transporters, Arabidopsis mitochondria contain the ATP synthase transporters, the mitochondria protein translocase complexes (responsible for protein uptake across the outer and inner membrane), ATP-binding cassette (ABC) transporters, and a number of transporters and channels responsible for allowing water and inorganic ions to move across the inner membrane driven by their transmembrane electrochemical gradient. A few mitochondrial transporters are tissue-specific, development-specific, or stress-response specific, but this is a relatively unexplored area in proteomics that merits much more attention. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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Article
Free-Radical-Mediated Formation of Trans-Cardiolipin Isomers, Analytical Approaches for Lipidomics and Consequences of the Structural Organization of Membranes
Biomolecules 2020, 10(8), 1189; https://doi.org/10.3390/biom10081189 - 15 Aug 2020
Cited by 5 | Viewed by 1545
Abstract
Free-radical-mediated processes, such as peroxidation, isomerization and hydrogenation affecting fatty acid integrity and biological functions, have a trans-disciplinary relevance. Cardiolipins (CL, (1,3-diphosphatidyl-sn-glycerol)) and tetra-linoleoyl-CL are complex phospholipids, exclusively present in the Inner Mitochondrial Membrane (IMM) lipids, where they maintain membrane integrity [...] Read more.
Free-radical-mediated processes, such as peroxidation, isomerization and hydrogenation affecting fatty acid integrity and biological functions, have a trans-disciplinary relevance. Cardiolipins (CL, (1,3-diphosphatidyl-sn-glycerol)) and tetra-linoleoyl-CL are complex phospholipids, exclusively present in the Inner Mitochondrial Membrane (IMM) lipids, where they maintain membrane integrity and regulate enzyme functionalities. Peroxidation pathways and fatty acid remodeling are known causes of mitochondrial disfunctions and pathologies, including cancer. Free-radical-mediated isomerization with the change of the cis CL into geometrical trans isomers is an unknown process with possible consequences on the supramolecular membrane lipid organization. Here, the formation of mono-trans CL (MT-CL) and other trans CL isomers (T-CL) is reported using CL from bovine heart mitochondria and thiyl radicals generated by UV-photolysis from 2-mercaptoethanol. Analytical approaches for CL isomer separation and identification via 1H/13C NMR are provided, together with the chemical study of CL derivatization to fatty acid methyl esters (FAME), useful for lipidomics and metabolomics research. Kinetics information of the radical chain isomerization process was obtained using γ-irradiation conditions. The CL isomerization affected the structural organization of membranes, as tested by the reduction in unilamellar liposome diameter, and accompanied the well-known process of oxidative consumption induced by Fenton reagents. These results highlight a potential new molecular modification pathway of mitochondrial lipids with wide applications to membrane functions and biological consequences. Full article
(This article belongs to the Special Issue 2020 Feature Papers by Biomolecules’ Editorial Board Members)
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Review
C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins
Biomolecules 2020, 10(8), 1188; https://doi.org/10.3390/biom10081188 - 15 Aug 2020
Cited by 3 | Viewed by 1547
Abstract
A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites [...] Read more.
A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients’ families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients. Full article
(This article belongs to the Special Issue Prion Diseases: A Model for Neurodegenerative Disorders)
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Article
Naphthoquinone-Based Meroterpenoids from Marine-Derived Streptomyces sp. B9173
Biomolecules 2020, 10(8), 1187; https://doi.org/10.3390/biom10081187 - 15 Aug 2020
Cited by 4 | Viewed by 1097
Abstract
Naphthoquinone-based meroterpenoids are hybrid polyketide-terpenoid natural products with chemical diversity and a broad range of biological activities. Here, we report the isolation of a group of naphthoquinone-containing compounds from Streptomyces sp. B9173, and their structures were elucidated by using a combination of spectroscopic [...] Read more.
Naphthoquinone-based meroterpenoids are hybrid polyketide-terpenoid natural products with chemical diversity and a broad range of biological activities. Here, we report the isolation of a group of naphthoquinone-containing compounds from Streptomyces sp. B9173, and their structures were elucidated by using a combination of spectroscopic techniques, including 1D, 2D NMR, and high-resolution mass (HRMS) analysis. Seven flaviogeranin congeners or intermediates, three of which were new, have been derived from common naphthoquinone backbone and subsequent oxidation, methylation, prenylation, and amino group incorporation. Both flaviogeranin B1 (1) and B (2) contain an amino group which was incorporated into the C8 of 1,3,6,8-terhydroxynaphthalene (THN). Flaviogeranin D (3) contains an intact C-geranylgeranyl residue attached to the C2 of THN, while the O-geranylgeranyl group of 2 links with the hydroxyl on the C2 site of THN. Four compounds were selected and tested for antibacterial activity and cytotoxicity, with 3 and flaviogeranin C2 (5) displaying potent activity against selected bacteria and cancer cell lines. In light of the structure features of isolated compounds and the biosynthetic genes, a biosynthetic pathway of naphthoquinone-based flaviogeranins has been proposed. These isolated compounds not only extend the structural diversity but also represent new insights into the biosynthesis of naphthoquinone-based meroterpenoids. Full article
(This article belongs to the Special Issue Recent Advance of Actinomycetes)
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Article
Rapid Killing and Biofilm Inhibition of Multidrug-Resistant Acinetobacter baumannii Strains and Other Microbes by Iodoindoles
Biomolecules 2020, 10(8), 1186; https://doi.org/10.3390/biom10081186 - 14 Aug 2020
Cited by 11 | Viewed by 1283
Abstract
Multi-drug resistant Acinetobacter baumannii is well-known for its rapid acclimatization in hospital environments. The ability of the bacterium to endure desiccation and starvation on dry surfaces for up to a month results in outbreaks of health care-associated infections. Previously, indole and its derivatives [...] Read more.
Multi-drug resistant Acinetobacter baumannii is well-known for its rapid acclimatization in hospital environments. The ability of the bacterium to endure desiccation and starvation on dry surfaces for up to a month results in outbreaks of health care-associated infections. Previously, indole and its derivatives were shown to inhibit other persistent bacteria. We found that among 16 halogenated indoles, 5-iodoindole swiftly inhibited A. baumannii growth, constrained biofilm formation and motility, and killed the bacterium as effectively as commercial antibiotics such as ciprofloxacin, colistin, and gentamicin. 5-Iodoindole treatment was found to induce reactive oxygen species, resulting in loss of plasma membrane integrity and cell shrinkage. In addition, 5-iodoindole rapidly killed three Escherichia coli strains, Staphylococcus aureus, and the fungus Candida albicans, but did not inhibit the growth of Pseudomonas aeruginosa. This study indicates the mechanism responsible for the activities of 5-iodoindole warrants additional study to further characterize its bactericidal effects on antibiotic-resistant A. baumannii and other microbes. Full article
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Article
Synthesis and Characterization of Oxidized Polysaccharides for In Situ Forming Hydrogels
Biomolecules 2020, 10(8), 1185; https://doi.org/10.3390/biom10081185 - 14 Aug 2020
Cited by 6 | Viewed by 2937
Abstract
Polysaccharides are widely used as building blocks of scaffolds and hydrogels in tissue engineering, which may require their chemical modification to permit crosslinking. The goal of this study was to generate a library of oxidized alginate (oALG) and oxidized hyaluronic acid (oHA) that [...] Read more.
Polysaccharides are widely used as building blocks of scaffolds and hydrogels in tissue engineering, which may require their chemical modification to permit crosslinking. The goal of this study was to generate a library of oxidized alginate (oALG) and oxidized hyaluronic acid (oHA) that can be used for in situ gelling hydrogels by covalent reaction between aldehyde groups of the oxidized polysaccharides (oPS) and amino groups of carboxymethyl chitosan (CMC) through imine bond formation. Here, we studied the effect of sodium periodate concentration and reaction time on aldehyde content, molecular weight of derivatives and cytotoxicity of oPS towards 3T3-L1 fibroblasts. It was found that the molecular weights of all oPs decreased with oxidation and that the degree of oxidation was generally higher in oHA than in oALG. Studies showed that only oPs with an oxidation degree above 25% were cytotoxic. Initial studies were also done on the crosslinking of oPs with CMC showing with rheometry that rather soft gels were formed from higher oxidized oPs possessing a moderate cytotoxicity. The results of this study indicate the potential of oALG and oHA for use as in situ gelling hydrogels or inks in bioprinting for application in tissue engineering and controlled release. Full article
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Article
Biotechnological Valorization of Food Marine Wastes: Microbial Productions on Peptones Obtained from Aquaculture By-Products
Biomolecules 2020, 10(8), 1184; https://doi.org/10.3390/biom10081184 - 14 Aug 2020
Cited by 5 | Viewed by 1207
Abstract
Based on a biotechnological strategy, in the present work several peptones are produced from the Alcalase hydrolysis (0.1–0.2% v/w, 56–64 °C, pH 8.27–8.98, 3 h) and thermal processing (105 °C, 60 min) of wastes generated from the industrial processing of turbot, salmon, [...] Read more.
Based on a biotechnological strategy, in the present work several peptones are produced from the Alcalase hydrolysis (0.1–0.2% v/w, 56–64 °C, pH 8.27–8.98, 3 h) and thermal processing (105 °C, 60 min) of wastes generated from the industrial processing of turbot, salmon, trout, seabream and seabass. These peptones were included (in the range of 2.6–11 g/L of soluble protein) as main source of organic nitrogen (protein substrates) in low-cost media for the culture of lactic acid bacteria (LAB), marine probiotic bacteria (MPB) and ubiquitous Gram+ bacteria. In most cases, batch fermentations conducted in aquaculture peptone media led to the best growth, metabolic productions and yields. Nevertheless, no significant differences between aquaculture peptones and commercial media were generally observed. Kinetic parameters from a logistic equation and used for cultures modeling were applied with the purpose of comparing the bioproduction outcomes. In economical terms, the validity of the aquaculture peptones as substitutives of the peptones (meat extract, casitone, etc.) from commercial media was also compared. The decreasing of the costs for LAB bioproductions ranged between 3–4 times and the growth costs of MPB and Gram+ bacteria were improved more than 70 and 15 times, respectively, in relation to those found in control commercial media. Full article
(This article belongs to the Special Issue Function of Microorganism in Food Production)
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Article
A Transmembrane Histidine Kinase Functions as a pH Sensor
Biomolecules 2020, 10(8), 1183; https://doi.org/10.3390/biom10081183 - 14 Aug 2020
Cited by 3 | Viewed by 1135
Abstract
The two-component system DesK-DesR regulates the synthesis of unsaturated fatty acids in the soil bacteria Bacillus subtilis. This system is activated at low temperature and maintains membrane lipid fluidity upon temperature variations. Here, we found that DesK—the transmembrane histidine kinase—also responds to [...] Read more.
The two-component system DesK-DesR regulates the synthesis of unsaturated fatty acids in the soil bacteria Bacillus subtilis. This system is activated at low temperature and maintains membrane lipid fluidity upon temperature variations. Here, we found that DesK—the transmembrane histidine kinase—also responds to pH and studied the mechanism of pH sensing. We propose that a helix linking the transmembrane region with the cytoplasmic catalytic domain is involved in pH sensing. This helix contains several glutamate, lysine, and arginine residues At neutral pH, the linker forms an alpha helix that is stabilized by hydrogen bonds in the i, i + 4 register and thus favors the kinase state. At low pH, protonation of glutamate residues breaks salt bridges, which results in helix destabilization and interruption of signaling. This mechanism inhibits unsaturated fatty acid synthesis and rigidifies the membrane when Bacillus grows in acidic conditions. Full article
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Article
Rapid Ex-Vivo Ciliogenesis and Dose-Dependent Effect of Notch Inhibition on Ciliogenesis of Respiratory Epithelia
Biomolecules 2020, 10(8), 1182; https://doi.org/10.3390/biom10081182 - 14 Aug 2020
Viewed by 1074
Abstract
Background: Cilia are actin based cellular protrusions conserved from algae to complex multicellular organisms like Homo sapiens. Respiratory motile cilia line epithelial cells of the tracheobronchial tree, beat in a synchronous, metachronal wave, moving inhaled pollutants and pathogens cephalad. Their role in [...] Read more.
Background: Cilia are actin based cellular protrusions conserved from algae to complex multicellular organisms like Homo sapiens. Respiratory motile cilia line epithelial cells of the tracheobronchial tree, beat in a synchronous, metachronal wave, moving inhaled pollutants and pathogens cephalad. Their role in both congenital disorders like primary ciliary dyskinesia (PCD) to acquired disorders like chronic obstructive pulmonary disease (COPD) continues to evolve. In this current body of work we outline a protocol optimized to reciliate human nasal epithelial cells and mouse tracheal cells in vitro. Using this protocol, we knocked down known cilia genes, as well as use a small molecule inhibitor of Notch, N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl Ester (DAPT), to assess the effect of these on ciliogenesis in order to show the validity of our protocol. Methods: Tracheas were harvested from wild-type, adult C57B6 mice, pronase digested and sloughed off epithelial cells grown to confluence in stationary culture on rat-tail collagen coated wells. Upon reaching confluence, collagen was digested and cells placed suspension culture protocol to reciliate the cells. Using this suspension culture protocol, we employed siRNA gene knockdown to assay gene functions required for airway ciliogenesis. Knock down of Dynein axonemal heavy chain 5 (Dnah5), a ciliary structural protein, was confirmed using immunostaining. Mouse tracheal cells were treated in suspension with varying doses of DAPT, an inhibitor of Notch, with the purpose of evaluating its effect and dose response on ciliogenesis. The optimum dose was then used on reciliating human nasal epithelial cells. Results: siRNA knockdown of Foxj1 prevented ciliation, consistent with its role as a master regulator of motile cilia. Knockdown of Dnai1 and Dnah5 resulted in immotile cilia, and Cand1 knockdown, a centrosome protein known to regulate centrosome amplification, inhibited airway ciliogenesis. Dnah5 knockdown was confirmed with significantly decreased immunostaining of cilia for this protein. Inhibiting Notch signaling by inhibiting gamma secretase with DAPT enhanced the percentage of ciliation, and resulted in longer cilia that beat with higher frequency in both mouse and human airway epithelia. Conclusions: Modifying existing reciliation protocols to suit both human nasal epithelial and mouse tracheal tissue, we have shown that knockdown of known cilia-related genes have the expected effects. Additionally, we have demonstrated the optimal dosage for significantly improving reciliation of airway epithelia using DAPT. Given that cilia length and function are significantly compromised in COPD, these findings open up interesting avenues for further exploration. Full article
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Review
Histamine Intolerance: The Current State of the Art
Biomolecules 2020, 10(8), 1181; https://doi.org/10.3390/biom10081181 - 14 Aug 2020
Cited by 21 | Viewed by 9242
Abstract
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown [...] Read more.
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies. In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some uncertainties historically associated to histamine intoxication outbreaks that may be better explained by the existence of interindividual susceptibility to ingested histamine. Full article
(This article belongs to the Special Issue New Developments in Histamine Research)
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Article
Association between Circular RNA CDR1as and Post-Infarction Cardiac Function in Pig Ischemic Heart Failure: Influence of the Anti-Fibrotic Natural Compounds Bufalin and Lycorine
Biomolecules 2020, 10(8), 1180; https://doi.org/10.3390/biom10081180 - 14 Aug 2020
Cited by 10 | Viewed by 1299
Abstract
Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine [...] Read more.
Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine by downregulating miRNA-671-5p, associated with a theoretic increase in the tissue level of circRNA CDR1as. Accordingly, we hypothesized that both anti-fibrotic drugs may inhibit focal myocardial fibrosis of the remodeled left ventricle (LV) also in a translational large animal model of heart failure (HF). Domestic pigs were repeatedly treated with subcutaneous injections of either bufalin, lycorine, or saline, (n = 5/group) between days 7–21 post acute myocardial infarction (AMI). At the 2-month follow-up, both bufalin and lycorine led to significantly reduced cardiac fibrosis. Bufalin treatment additionally led to smaller end-diastolic volumes, higher LV ejection fraction (EF), and increased expression of CDR1as of the AMI region. Elevated tissue levels of the circRNA CDR1as in the AMI region of the pig heart correlated significantly with LV and right ventricular EF, LV stroke volume, and negatively with infarct size. In conclusion, we successfully identified the circRNA CDR1as in pig hearts and show a significant association with improved LV and RV function by anti-fibrotic therapies in a translational animal model of HF. Full article
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Article
Dietary Supplementation with Sugar Beet Fructooligosaccharides and Garlic Residues Promotes Growth of Beneficial Bacteria and Increases Weight Gain in Neonatal Lambs
Biomolecules 2020, 10(8), 1179; https://doi.org/10.3390/biom10081179 - 13 Aug 2020
Cited by 1 | Viewed by 1419
Abstract
The proper development of the early gastrointestinal tract (GIT) microbiota is critical for newborn ruminants. This microbiota is susceptible to modification by diverse external factors (such as diet) that can lead to long-lasting results when occurring in young ruminants. Dietary supplementation with prebiotics, [...] Read more.
The proper development of the early gastrointestinal tract (GIT) microbiota is critical for newborn ruminants. This microbiota is susceptible to modification by diverse external factors (such as diet) that can lead to long-lasting results when occurring in young ruminants. Dietary supplementation with prebiotics, ingredients nondigestible and nonabsorbable by the host that stimulate the growth of beneficial GIT bacteria, has been applied worldwide as a potential approach in order to improve ruminant health and production yields. However, how prebiotics affect the GIT microbiota during ruminants’ early life is still poorly understood. We investigated the effect of milk supplementation with a combination of two well-known prebiotics, fructooligosaccharides (FOS) from sugar beet and garlic residues (all together named as “additive”), exerted on preweaned lamb growth and the composition of their fecal microbiota, by using 16S rRNA gene amplicon high-throughput sequencing. The results showed a significant increase in the mean daily weight gain of lambs fed with the additive. Lamb fecal microbiota was also influenced by the additive intake, as additive-diet lambs showed lower bacterial diversity and were significantly more abundant in Bifidobacterium, Enterococcus, Lactobacillus and Veillonella. These bacteria have been previously reported to confer beneficial properties to the ruminant, including promotion of growth and health status, and our results showed that they were strongly linked to the additive intake and the increased weight gain of lambs. This study points out the combination of FOS from sugar beet and garlic residues as a potential prebiotic to be used in young ruminants’ nutrition in order to improve production yields. Full article
(This article belongs to the Special Issue Function of Microorganism in Food Production)
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Article
Alanyl-Glutamine Restores Tight Junction Organization after Disruption by a Conventional Peritoneal Dialysis Fluid
Biomolecules 2020, 10(8), 1178; https://doi.org/10.3390/biom10081178 - 13 Aug 2020
Cited by 4 | Viewed by 1232
Abstract
Understanding and targeting the molecular basis of peritoneal solute and protein transport is essential to improve peritoneal dialysis (PD) efficacy and patient outcome. Supplementation of PD fluids (PDF) with alanyl-glutamine (AlaGln) increased small solute transport and reduced peritoneal protein loss in a recent [...] Read more.
Understanding and targeting the molecular basis of peritoneal solute and protein transport is essential to improve peritoneal dialysis (PD) efficacy and patient outcome. Supplementation of PD fluids (PDF) with alanyl-glutamine (AlaGln) increased small solute transport and reduced peritoneal protein loss in a recent clinical trial. Transepithelial resistance and 10 kDa and 70 kDa dextran transport were measured in primary human endothelial cells (HUVEC) exposed to conventional acidic, glucose degradation products (GDP) containing PDF (CPDF) and to low GDP containing PDF (LPDF) with and without AlaGln. Zonula occludens-1 (ZO-1) and claudin-5 were quantified by Western blot and immunofluorescence and in mice exposed to saline and CPDF for 7 weeks by digital imaging analyses. Spatial clustering of ZO-1 molecules was assessed by single molecule localization microscopy. AlaGln increased transepithelial resistance, and in CPDF exposed HUVEC decreased dextran transport rates and preserved claudin-5 and ZO-1 abundance. Endothelial clustering of membrane bound ZO-1 was higher in CPDF supplemented with AlaGln. In mice, arteriolar endothelial claudin-5 was reduced in CPDF, but restored with AlaGln, while mesothelial claudin-5 abundance was unchanged. AlaGln supplementation seals the peritoneal endothelial barrier, and when supplemented to conventional PD fluid increases claudin-5 and ZO-1 abundance and clustering of ZO-1 in the endothelial cell membrane. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Peritoneal Membrane Pathophysiology)
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Article
Contactin-1 Is Reduced in Cerebrospinal Fluid of Parkinson’s Disease Patients and Is Present within Lewy Bodies
Biomolecules 2020, 10(8), 1177; https://doi.org/10.3390/biom10081177 - 12 Aug 2020
Cited by 2 | Viewed by 1340
Abstract
Synaptic degeneration is an early phenomenon in Parkinson’s disease (PD) pathogenesis. We aimed to investigate whether levels of synaptic proteins contactin-1 and contactin-2 in cerebrospinal fluid (CSF) of PD patients are reduced compared to dementia with Lewy bodies (DLB) patients and controls and [...] Read more.
Synaptic degeneration is an early phenomenon in Parkinson’s disease (PD) pathogenesis. We aimed to investigate whether levels of synaptic proteins contactin-1 and contactin-2 in cerebrospinal fluid (CSF) of PD patients are reduced compared to dementia with Lewy bodies (DLB) patients and controls and to evaluate their relationship with α-synuclein aggregation. Contactin-1 and -2 were measured in CSF from PD patients (n = 58), DLB patients (n = 72) and age-matched controls (n = 90). Contactin concentration differences between diagnostic groups were assessed by general linear models adjusted for age and sex. Contactin immunoreactivity was characterized in postmortem substantia nigra, hippocampus and entorhinal cortex tissue of PD patients (n = 4) and controls (n = 4), and its relation to α-syn aggregation was evaluated using confocal laser scanning microscopy. Contactin-1 levels were lower in PD patients (42 (36–49) pg/mL) compared to controls (52 (44–58) pg/mL, p = 0.003) and DLB patients (56 (46–67) pg/mL, p = 0.001). Contactin-2 levels were similar across all diagnostic groups. Within the PD patient group, contactin-1 correlated with t-α-syn, tTau and pTau (r = 0.30–0.50, p < 0.05), whereas contactin-2 only correlated with t-α-syn (r = 0.34, p = 0.03). Contactin-1 and -2 were observed within nigral and cortical Lewy bodies and clustered within bulgy Lewy neurites in PD brains. A decrease in CSF contactin-1 may reflect synaptic degeneration underlying Lewy body pathology in PD. Full article
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Review
The Role of Fe, Zn, and Cu in Pregnancy
Biomolecules 2020, 10(8), 1176; https://doi.org/10.3390/biom10081176 - 12 Aug 2020
Cited by 10 | Viewed by 1956
Abstract
Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein [...] Read more.
Iron (Fe), copper (Cu), and zinc (Zn) are microelements essential for the proper functioning of living organisms. These elements participatein many processes, including cellular metabolism and antioxidant and anti-inflammatory defenses, and also influence enzyme activity, regulate gene expression, and take part in protein synthesis. Fe, Cu, and Zn have a significant impact on the health of pregnant women and in the development of the fetus, as well as on the health of the newborn. A proper concentration of these elements in the body of women during pregnancy reduces the risk of complications such as anemia, induced hypertension, low birth weight, preeclampsia, and postnatal complications. The interactions between Fe, Cu, and Zn influence their availability due to their similar physicochemical properties. This most often occurs during intestinal absorption, where metal ions compete for binding sites with transport compounds. Additionally, the relationships between these ions have a great influence on the course of reactions in the tissues, as well as on their excretion, which can be stimulated or delayed. This review aims to summarize reports on the influence of Fe, Cu, and Zn on the course of single and multiple pregnancies, and to discuss the interdependencies and mechanisms occurring between Fe, Cu, and Zn. Full article
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Article
DNA Phosphorothioate Modifications Are Widely Distributed in the Human Microbiome
Biomolecules 2020, 10(8), 1175; https://doi.org/10.3390/biom10081175 - 12 Aug 2020
Cited by 7 | Viewed by 1269
Abstract
The DNA phosphorothioate (PT) modification existing in many prokaryotes, including bacterial pathogens and commensals, confers multiple characteristics, including restricting gene transfer, influencing the global transcriptional response, and reducing fitness during exposure to chemical mediators of inflammation. While PT-containing bacteria have been investigated in [...] Read more.
The DNA phosphorothioate (PT) modification existing in many prokaryotes, including bacterial pathogens and commensals, confers multiple characteristics, including restricting gene transfer, influencing the global transcriptional response, and reducing fitness during exposure to chemical mediators of inflammation. While PT-containing bacteria have been investigated in a variety of environments, they have not been studied in the human microbiome. Here, we investigated the distribution of PT-harboring strains and verified their existence in the human microbiome. We found over 2000 PT gene-containing strains distributed in different body sites, especially in the gastrointestinal tract. PT-modifying genes are preferentially distributed within several genera, including Pseudomonas, Clostridioides, and Escherichia, with phylogenic diversities. We also assessed the PT modification patterns and found six new PT-linked dinucleotides (CpsG, CpsT, ApsG, TpsG, GpsC, ApsT) in human fecal DNA. To further investigate the PT in the human gut microbiome, we analyzed the abundance of PT-modifying genes and quantified the PT-linked dinucleotides in the fecal DNA. These results confirmed that human microbiome is a rich reservoir for PT-containing microbes and contains a wide variety of PT modification patterns. Full article
(This article belongs to the Section Molecular Biology)
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Review
Peroxisomal Cofactor Transport
Biomolecules 2020, 10(8), 1174; https://doi.org/10.3390/biom10081174 - 12 Aug 2020
Cited by 4 | Viewed by 1159
Abstract
Peroxisomes are eukaryotic organelles that are essential for growth and development. They are highly metabolically active and house many biochemical reactions, including lipid metabolism and synthesis of signaling molecules. Most of these metabolic pathways are shared with other compartments, such as Endoplasmic reticulum [...] Read more.
Peroxisomes are eukaryotic organelles that are essential for growth and development. They are highly metabolically active and house many biochemical reactions, including lipid metabolism and synthesis of signaling molecules. Most of these metabolic pathways are shared with other compartments, such as Endoplasmic reticulum (ER), mitochondria, and plastids. Peroxisomes, in common with all other cellular organelles are dependent on a wide range of cofactors, such as adenosine 5′-triphosphate (ATP), Coenzyme A (CoA), and nicotinamide adenine dinucleotide (NAD). The availability of the peroxisomal cofactor pool controls peroxisome function. The levels of these cofactors available for peroxisomal metabolism is determined by the balance between synthesis, import, export, binding, and degradation. Since the final steps of cofactor synthesis are thought to be located in the cytosol, cofactors must be imported into peroxisomes. This review gives an overview about our current knowledge of the permeability of the peroxisomal membrane with the focus on ATP, CoA, and NAD. Several members of the mitochondrial carrier family are located in peroxisomes, catalyzing the transfer of these organic cofactors across the peroxisomal membrane. Most of the functions of these peroxisomal cofactor transporters are known from studies in yeast, humans, and plants. Parallels and differences between the transporters in the different organisms are discussed here. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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Article
Computational Identification and Characterization of New microRNAs in Human Platelets Stored in a Blood Bank
Biomolecules 2020, 10(8), 1173; https://doi.org/10.3390/biom10081173 - 12 Aug 2020
Cited by 2 | Viewed by 1095
Abstract
Platelet concentrate (PC) transfusions are widely used to save the lives of patients who experience acute blood loss. MicroRNAs (miRNAs) comprise a class of molecules with a biological role which is relevant to the understanding of storage lesions in blood banks. We used [...] Read more.
Platelet concentrate (PC) transfusions are widely used to save the lives of patients who experience acute blood loss. MicroRNAs (miRNAs) comprise a class of molecules with a biological role which is relevant to the understanding of storage lesions in blood banks. We used a new approach to identify miRNAs in normal human platelet sRNA-Seq data from the GSE61856 repository. We identified a comprehensive miRNA expression profile, where we detected 20 of these transcripts potentially expressed in PCs stored for seven days, which had their expression levels analyzed with simulations of computational biology. Our results identified a new collection of miRNAs (miR-486-5p, miR-92a-3p, miR-103a-3p, miR-151a-3p, miR-181a-5p, and miR-221-3p) that showed a sensitivity expression pattern due to biological platelet changes during storage, confirmed by additional quantitative real-time polymerase chain reaction (qPCR) validation on 100 PC units from 500 healthy donors. We also identified that these miRNAs could transfer regulatory information on platelets, such as members of the let-7 family, by regulating the YOD1 gene, which is a deubiquitinating enzyme highly expressed in platelet hyperactivity. Our results also showed that the target genes of these miRNAs play important roles in signaling pathways, cell cycle, stress response, platelet activation and cancer. In summary, the miRNAs described in this study, have a promising application in transfusion medicine as potential biomarkers to also measure the quality and viability of the PC during storage in blood banks. Full article
(This article belongs to the Special Issue microRNA Biomarkers in Clinical Study)
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Review
Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia
Biomolecules 2020, 10(8), 1172; https://doi.org/10.3390/biom10081172 - 11 Aug 2020
Viewed by 1574
Abstract
Schizophrenia is a chronic and disabling psychiatric disorder characterized by disturbances of thought, cognition, and behavior. Despite massive research efforts to date, the etiology and pathophysiology of schizophrenia remain largely unknown. The difficulty of brain research is largely a result of complex interactions [...] Read more.
Schizophrenia is a chronic and disabling psychiatric disorder characterized by disturbances of thought, cognition, and behavior. Despite massive research efforts to date, the etiology and pathophysiology of schizophrenia remain largely unknown. The difficulty of brain research is largely a result of complex interactions between contributory factors at different scales: susceptible gene variants (molecular scale), synaptopathies (synaptic, dendritic, and cell scales), and alterations in neuronal circuits (circuit scale), which together result in behavioral manifestations (individual scale). It is likely that each scale affects the others, from the microscale to the mesoscale to the macroscale, and vice versa. Thus, to consider the intricate complexity of schizophrenia across multiple layers, we introduce a multi-scale, hierarchical view of the nature of this disorder, focusing especially on N-methyl-D-aspartate-type glutamate receptors (NMDARs). The reason for placing emphasis on NMDAR is its clinical relevance to schizophrenia, as well as its diverse functions in neurons, including the robust supralinear synaptic integration provided by N-methyl-D-aspartate-type glutamate (NMDA) spikes and the Ca2+ permeability of the NMDAR, which facilitates synaptic plasticity via various calcium-dependent proteins. Here, we review recent evidence implicating NMDARs in the pathophysiology of schizophrenia from the multi-scale perspective. We also discuss recent advances from optical techniques, which provide a powerful tool for uncovering the mechanisms of NMDAR synaptic pathology and their relationships, with subsequent behavioral manifestations. Full article
(This article belongs to the Special Issue NMDA Receptor in Health and Diseases)
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Article
Targeting Endothelial Dysfunction in Eight Extreme-Critically Ill Patients with COVID-19 Using the Anti-Adrenomedullin Antibody Adrecizumab (HAM8101)
Biomolecules 2020, 10(8), 1171; https://doi.org/10.3390/biom10081171 - 11 Aug 2020
Cited by 9 | Viewed by 2395
Abstract
Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a “treatment on a [...] Read more.
Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a “treatment on a named-patient basis” approach, Adrecizumab was administered to eight extreme-critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). The patients received a single dose of Adrecizumab, which was administered between 1 and 3 days after the initiation of mechanical ventilation. The SOFA (median 12.5) and SAPS-II (median 39) scores clearly documented the population at highest risk. Moreover, six of the patients suffered from acute renal failure, of whom five needed renal replacement therapy. The length of follow-up ranged between 13 and 27 days. Following the Adrecizumab administration, one patient in the low-dose group died at day 4 due to fulminant pulmonary embolism, while four were in stable condition, and three were discharged from the intensive care unit (ICU). Within 12 days, the SOFA score, as well as the disease severity score (range 0–16, mirroring critical resources in the ICU, with higher scores indicating more severe illness), decreased in five out of the seven surviving patients (in all high-dose patients). The PaO2/FiO2 increased within 12 days, while the inflammatory parameters C-reactive protein, procalcitonin, and interleukin-6 decreased. Importantly, the mortality was lower than expected and calculated by the SOFA score. In conclusion, in this preliminary uncontrolled case series of eight shock patients with life-threatening COVID-19 and ARDS, the administration of Adrecizumab was followed by a favorable outcome. Although the non-controlled design and the small sample size preclude any definitive statement about the potential efficacy of Adrecizumab in critically ill COVID-19 patients, the results of this case series are encouraging. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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