Biomolecules

19 pages, 3356 KiB

Open AccessArticle

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

by Agnieszka A. Kaczor, Katarzyna M. Targowska-Duda, Andrea G. Silva, Magda Kondej, Grażyna Biała and Marián Castro

Biomolecules 2020, 10(2), 349; https://doi.org/10.3390/biom10020349 - 24 Feb 2020

Cited by 14 | Viewed by 3420

Abstract

N-(2-hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol -1-yl)propyl]piperidine-4-carboxamide (D2AAK4) is a multitarget ligand of aminergic G protein-coupled receptors (GPCRs) identified in structure-based virtual screening. Here we present detailed in vitro, in silico and in vivo investigations of this virtual hit. D2AAK4 has an atypical antipsychotic profile [...] Read more.

N-(2-hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol -1-yl)propyl]piperidine-4-carboxamide (D2AAK4) is a multitarget ligand of aminergic G protein-coupled receptors (GPCRs) identified in structure-based virtual screening. Here we present detailed in vitro, in silico and in vivo investigations of this virtual hit. D2AAK4 has an atypical antipsychotic profile and low affinity to off-targets. It interacts with aminergic GPCRs, forming an electrostatic interaction between its protonatable nitrogen atom and the conserved Asp 3.32 of the receptors. At the dose of 100 mg/kg D2AAK4 decreases amphetamine-induced hyperactivity predictive of antipsychotic activity, improves memory consolidation in passive avoidance test and has anxiogenic properties in elevated plus maze test (EPM). Further optimization of the virtual hit D2AAK4 will be aimed to balance its multitarget profile and to obtain analogs with anxiolytic activity. Full article

(This article belongs to the Special Issue New Molecules: Towards the Drugs of the Future - Selected Papers from JMMC 2019)

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13 pages, 1834 KiB

Open AccessArticle

Sequencing and Analysis of the Genome of Propionibacterium freudenreichii T82 Strain: Importance for Industry

by Kamil Piwowarek, Edyta Lipińska, Elżbieta Hać-Szymańczuk, Marek Kieliszek and Anna Maria Kot

Biomolecules 2020, 10(2), 348; https://doi.org/10.3390/biom10020348 - 24 Feb 2020

Cited by 13 | Viewed by 4068

Abstract

The genome of Propionibacterium freudenreichii ssp. freudenreichii T82, which has a chromosome containing 2,585,340 nucleotides with 67.3% GC content (guanine-cytosine content), is described in this paper. The total number of genes is 2308, of which 2260 are protein-coding genes and 48 are RNA [...] Read more.

The genome of Propionibacterium freudenreichii ssp. freudenreichii T82, which has a chromosome containing 2,585,340 nucleotides with 67.3% GC content (guanine-cytosine content), is described in this paper. The total number of genes is 2308, of which 2260 are protein-coding genes and 48 are RNA genes. According to the genome analysis and the obtained results, the T82 strain can produce various compounds such as propionic acid, trehalose, glycogen, and B group vitamins (e.g., B6, B9, and B12). From protein-coding sequences (CDSs), genes related to stress adaptation, biosynthesis, metabolism, transport, secretion, and defense machinery were detected. In the genome of the T82 strain, sequences corresponding to the CRISPR loci (Clustered Regularly Interspaced Short Palindromic Repeats), antibiotic resistance, and restriction–modification system were found. Full article

(This article belongs to the Special Issue Visualizing the Genome)

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24 pages, 1776 KiB

Open AccessEditor’s ChoiceReview

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

by Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Julio Manuel Martinez-Moreno, Maria Monsalve, Adrian Mario Ramos, Maria Dolores Sanchez-Niño, Marta Ruiz-Ortega, Alberto Ortiz and Ana Belen Sanz

Biomolecules 2020, 10(2), 347; https://doi.org/10.3390/biom10020347 - 24 Feb 2020

Cited by 155 | Viewed by 21838

Abstract

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and [...] Read more.

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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12 pages, 2058 KiB

Open AccessArticle

Investigation of a Direct Interaction between miR4749 and the Tumor Suppressor p53 by Fluorescence, FRET and Molecular Modeling

by Anna Rita Bizzarri and Salvatore Cannistraro

Biomolecules 2020, 10(2), 346; https://doi.org/10.3390/biom10020346 - 22 Feb 2020

Cited by 8 | Viewed by 2921

Abstract

The interactions between the DNA binding domain (DBD) of the tumor suppressor p53 and miR4749, characterized by a high sequence similarity with the DNA Response Element (RE) of p53, was investigated by fluorescence spectroscopy combined with computational modeling and docking. Fluorescence quenching experiments [...] Read more.

The interactions between the DNA binding domain (DBD) of the tumor suppressor p53 and miR4749, characterized by a high sequence similarity with the DNA Response Element (RE) of p53, was investigated by fluorescence spectroscopy combined with computational modeling and docking. Fluorescence quenching experiments witnessed the formation of a specific complex between DBD and miR4749 with an affinity of about 10⁵ M. Förster Resonance Energy Transfer (FRET) allowed us to measure a distance of 3.9 ± 0.3 nm, between the lone tryptophan of DBD and an acceptor dye suitably bound to miR4749. Such information, combined with a computational modeling approach, allowed us to predict possible structures for the DBD-miR4749 complex. A successive docking refinement, complemented with binding free energy calculations, led us to single out a best model for the DBD-miR4749 complex. We found that the interaction of miR4749 involves the DBD L₃ loop and the H₁ helix, close to the Zn-finger motif; with this suggesting that miR4749 could directly inhibit the p53 interaction with DNA. These results might inspire new therapeutic strategies finalized to restore the p53 functional activity. Full article

(This article belongs to the Special Issue Recent Advances in p53)

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19 pages, 3846 KiB

Open AccessArticle

Antiproliferative Effect of Acridine Chalcone Is Mediated by Induction of Oxidative Stress

by Peter Takac, Martin Kello, Maria Vilkova, Janka Vaskova, Radka Michalkova, Gabriela Mojzisova and Jan Mojzis

Biomolecules 2020, 10(2), 345; https://doi.org/10.3390/biom10020345 - 22 Feb 2020

Cited by 36 | Viewed by 4133

Abstract

Chalcones are naturally occurring phytochemicals with diverse biological activities including antioxidant, antiproliferative, and anticancer effects. Some studies indicate that the antiproliferative effect of chalcones may be associated with their pro-oxidant effect. In the present study, we evaluated contribution of oxidative stress in the [...] Read more.

Chalcones are naturally occurring phytochemicals with diverse biological activities including antioxidant, antiproliferative, and anticancer effects. Some studies indicate that the antiproliferative effect of chalcones may be associated with their pro-oxidant effect. In the present study, we evaluated contribution of oxidative stress in the antiproliferative effect of acridine chalcone 1C ((2 E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one) in human colorectal HCT116 cells. We demonstrated that chalcone 1C induced oxidative stress via increased reactive oxygen/nitrogen species (ROS/RNS) and superoxide production with a simultaneous weak adaptive activation of the cellular antioxidant defence mechanism. Furthermore, we also showed chalcone-induced mitochondrial dysfunction, DNA damage, and apoptosis induction. Moreover, activation of mitogen activated phosphokinase (MAPK) signalling pathway in 1C-treated cancer cells was also observed. On the other hand, co-treatment of cells with strong antioxidant, N-acetyl cysteine (NAC), significantly attenuated all of the above-mentioned effects of chalcone 1C, that is, decreased oxidant production, prevent mitochondrial dysfunction, DNA damage, and induction of apoptosis, as well as partially preventing the activation of MAPK signalling. Taken together, we documented the role of ROS in the antiproliferative/pro-apoptotic effects of acridine chalcone 1C. Moreover, these data suggest that this chalcone may be useful as a promising anti-cancer agent for treating colon cancer. Full article

(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)

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18 pages, 1923 KiB

Open AccessFeature PaperArticle

Solid γ-Cyclodextrin Inclusion Compound with Gingerols, a Multi-Component Guest: Preparation, Properties and Application in Yogurt

by Joana M. Pais, Bruna Pereira, Filipe A. Almeida Paz, Susana M. Cardoso and Susana S. Braga

Biomolecules 2020, 10(2), 344; https://doi.org/10.3390/biom10020344 - 22 Feb 2020

Cited by 14 | Viewed by 4634

Abstract

Gingerols from the rhizome of fresh ginger (Zingiber officinale) were obtained by a simple extraction, followed by purification. The gingerols extract was composed of 6-gingerol (54%), 8-gingerol (20%), and 10-gingerol (26%). It was included into γ-cyclodextrin by classic co-dissolution procedures. Solid-state [...] Read more.

Gingerols from the rhizome of fresh ginger (Zingiber officinale) were obtained by a simple extraction, followed by purification. The gingerols extract was composed of 6-gingerol (54%), 8-gingerol (20%), and 10-gingerol (26%). It was included into γ-cyclodextrin by classic co-dissolution procedures. Solid-state characterisation of γ-cyclodextrin·gingerols shows that this inclusion compound features 1:1 host-to-guest stoichiometry and that it is a microcrystalline powder with a crystalline cell that belongs to the tetragonal space group 42₁2, having the host molecules stacked in infinite channels where the gingerols are accommodated. In chimico studies with ABTS^•+ scavenging, NO^• scavenging, β-carotene peroxidation, and 5-LOX inhibition show that γ-cyclodextrin is a suitable carrier for gingerols, because it does not alter their reactivity towards these substances. Yogurt was tested as a matrix for the incorporation of gingerols and γ-cyclodextrin·gingerols into foodstuff. The colour of the fortified yogurt suffered little alterations. In the case of yogurt with the inclusion compound, γ-cyclodextrin·gingerols, as fortificant, these alterations were not perceptible to the naked eye. Moreover, yogurt with γ-cyclodextrin·gingerols showed a good antioxidant activity, thus being suitable for use in nutraceutical applications. Full article

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

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15 pages, 1353 KiB

Open AccessArticle

Biological Effects of Glucosinolate Degradation Products from Horseradish: A Horse that Wins the Race

by Marijana Popović, Ana Maravić, Vedrana Čikeš Čulić, Azra Đulović, Franko Burčul and Ivica Blažević

Biomolecules 2020, 10(2), 343; https://doi.org/10.3390/biom10020343 - 21 Feb 2020

Cited by 27 | Viewed by 3835

Abstract

Horseradish degradation products, mainly isothiocyanates (ITC) and nitriles, along with their precursors glucosinolates, were characterized by GC-MS and UHPLC-MS/MS, respectively. Volatiles from horseradish leaves and roots were isolated using microwave assisted-distillation (MAD), microwave hydrodiffusion and gravity (MHG) and hydrodistillation (HD). Allyl ITC was [...] Read more.

Horseradish degradation products, mainly isothiocyanates (ITC) and nitriles, along with their precursors glucosinolates, were characterized by GC-MS and UHPLC-MS/MS, respectively. Volatiles from horseradish leaves and roots were isolated using microwave assisted-distillation (MAD), microwave hydrodiffusion and gravity (MHG) and hydrodistillation (HD). Allyl ITC was predominant in the leaves regardless of the isolation method while MAD, MHG, and HD of the roots resulted in different yields of allyl ITC, 2-phenylethyl ITC, and their nitriles. The antimicrobial potential of roots volatiles and their main compounds was assessed against sixteen emerging food spoilage and opportunistic pathogens. The MHG isolate was the most active, inhibiting bacteria at minimal inhibitory concentrations (MICs) from only 3.75 to 30 µg/mL, and fungi at MIC₅₀ between <0.12 and 0.47 µg/mL. Cytotoxic activity of volatile isolates and their main compounds were tested against two human cancer cell lines using MTT assay after 72 h. The roots volatiles showed best cytotoxic activity (HD; IC₅₀ = 2.62 μg/mL) against human lung A549 and human bladder T24 cancer cell lines (HD; IC₅₀ = 0.57 μg/mL). Generally, 2-phenylethyl ITC, which was tested for its antimicrobial and cytotoxic activities along with two other major components allyl ITC and 3-phenylpropanenitrile, showed the best biological activities. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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13 pages, 2374 KiB

Open AccessArticle

Optimum Inhibition of Amphotericin-B-Resistant Candida albicans Strain in Single- and Mixed-Species Biofilms by Candida and Non-Candida Terpenoids

by Hidaya F. Z. Touil, Kebir Boucherit, Zahia Boucherit-Otmani, Ghalia Kohder, Mohamed Madkour and Sameh S. M. Soliman

Biomolecules 2020, 10(2), 342; https://doi.org/10.3390/biom10020342 - 21 Feb 2020

Cited by 15 | Viewed by 4215

Abstract

Candida albicans is one of the most common human fungal pathogens and represents the most important cause of opportunistic mycoses worldwide. Surgical devices including catheters are easily contaminated with C. albicans via its formation of drug-resistant biofilms. In this study, amphotericin-B-resistant C. albicans [...] Read more.

Candida albicans is one of the most common human fungal pathogens and represents the most important cause of opportunistic mycoses worldwide. Surgical devices including catheters are easily contaminated with C. albicans via its formation of drug-resistant biofilms. In this study, amphotericin-B-resistant C. albicans strains were isolated from surgical devices at an intensive care center. The objective of this study was to develop optimized effective inhibitory treatment of resistant C. albicans by terpenoids, known to be produced naturally as protective signals. Endogenously produced farnesol by C. albicans yeast and plant terpenoids, carvacrol, and cuminaldehyde were tested separately or in combination on amphotericin-B-resistant C. albicans in either single- or mixed-infections. The results showed that farnesol did not inhibit hyphae formation when associated with bacteria. Carvacrol and cuminaldehyde showed variable inhibitory effects on C. albicans yeast compared to hyphae formation. A combination of farnesol with carvacrol showed synergistic inhibitory activities not only on C. albicans yeast and hyphae, but also on biofilms formed from single- and mixed-species and at reduced doses. The combined terpenoids also showed biofilm-penetration capability. The aforementioned terpenoid combination will not only be useful in the treatment of different resistant Candida forms, but also in the safe prevention of biofilm formation. Full article

(This article belongs to the Special Issue Perspectives of Essential Oils)

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20 pages, 862 KiB

Open AccessReview

Effects of Salicylic Acid on the Metabolism of Mitochondrial Reactive Oxygen Species in Plants

by Péter Poór

Biomolecules 2020, 10(2), 341; https://doi.org/10.3390/biom10020341 - 21 Feb 2020

Cited by 59 | Viewed by 8254

Abstract

Different abiotic and biotic stresses lead to the production and accumulation of reactive oxygen species (ROS) in various cell organelles such as in mitochondria, resulting in oxidative stress, inducing defense responses or programmed cell death (PCD) in plants. In response to oxidative stress, [...] Read more.

Different abiotic and biotic stresses lead to the production and accumulation of reactive oxygen species (ROS) in various cell organelles such as in mitochondria, resulting in oxidative stress, inducing defense responses or programmed cell death (PCD) in plants. In response to oxidative stress, cells activate various cytoprotective responses, enhancing the antioxidant system, increasing the activity of alternative oxidase and degrading the oxidized proteins. Oxidative stress responses are orchestrated by several phytohormones such as salicylic acid (SA). The biomolecule SA is a key regulator in mitochondria-mediated defense signaling and PCD, but the mode of its action is not known in full detail. In this review, the current knowledge on the multifaceted role of SA in mitochondrial ROS metabolism is summarized to gain a better understanding of SA-regulated processes at the subcellular level in plant defense responses. Full article

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34 pages, 7528 KiB

Open AccessEditor’s ChoiceReview

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

by Simona Neri and Rosa Maria Borzì

Biomolecules 2020, 10(2), 340; https://doi.org/10.3390/biom10020340 - 21 Feb 2020

Cited by 79 | Viewed by 9529

Abstract

Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of [...] Read more.

Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of clinical conditions. MSC use frequently requires in vitro expansion, thus exposing cells to replicative senescence. Aging of MSCs (both in vivo and in vitro) can affect not only their replicative potential, but also their properties, like immunomodulation and secretory profile, thus possibly compromising their therapeutic effect. It is therefore of critical importance to unveil the underlying mechanisms of MSC senescence and to define shared methods to assess MSC aging status. The present review will focus on current scientific knowledge about MSC aging mechanisms, control and effects, including possible anti-aging treatments. Full article

(This article belongs to the Special Issue New Targets and Strategies in Regenerative Medicine)

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18 pages, 4145 KiB

Open AccessArticle

New Lipidyl-Cyclodextrins Obtained by Ring Opening of Methyl Oleate Epoxide Using Ball Milling

by Estefania Oliva, David Mathiron, Sébastien Rigaud, Eric Monflier, Emmanuel Sevin, Hervé Bricout, Sébastien Tilloy, Fabien Gosselet, Laurence Fenart, Véronique Bonnet, Serge Pilard and Florence Djedaini-Pilard

Biomolecules 2020, 10(2), 339; https://doi.org/10.3390/biom10020339 - 20 Feb 2020

Cited by 14 | Viewed by 4314

Abstract

Bearing grafts based on fatty esters derivatives, lipidyl-cyclodextrins (L-CDs) are compounds able to form water-soluble nano-objects. In this context, bicatenary biobased lipidic-cyclodextrins of low DS were easily synthesized from a fatty ester epoxide by means of alternative methods (ball-milling conditions, use of enzymes). [...] Read more.

Bearing grafts based on fatty esters derivatives, lipidyl-cyclodextrins (L-CDs) are compounds able to form water-soluble nano-objects. In this context, bicatenary biobased lipidic-cyclodextrins of low DS were easily synthesized from a fatty ester epoxide by means of alternative methods (ball-milling conditions, use of enzymes). The ring opening reaction of methyl oleate epoxide needs ball-milling and is highly specific of cyclodextrins in solventless conditions. L-CDs are thus composed of complex mixtures that were deciphered by an extensive structural analysis using mainly mass spectrometry and NMR spectroscopy. In addition, as part of their potential use as vectors of active drugs, these products were submitted to an integrity study on in vitro model of the blood-brain-barrier (BBB) and the intestinal epithelium. No toxicity has been observed, suggesting that applications for the vectorization of active ingredients can be expected. Full article

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

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22 pages, 4926 KiB

Open AccessArticle

Acorus gramineusand and Euodia ruticarpa Steam Distilled Essential Oils Exert Anti-Inflammatory Effects Through Decreasing Th1/Th2 and Pro-/Anti-Inflammatory Cytokine Secretion Ratios In Vitro

by Tzu-He Yeh and Jin-Yuarn Lin

Biomolecules 2020, 10(2), 338; https://doi.org/10.3390/biom10020338 - 19 Feb 2020

Cited by 24 | Viewed by 4016

Abstract

To clarify the effects of steam distilled essential oils (SDEO) from herbs used in traditional Chinese medicine on immune functions, two potential herbs, Acorus gramineusand (AG) and Euodia ruticarpa (ER) cultivated in Taiwan, were selected to assess their immunomodulatory effects using mouse primary [...] Read more.

To clarify the effects of steam distilled essential oils (SDEO) from herbs used in traditional Chinese medicine on immune functions, two potential herbs, Acorus gramineusand (AG) and Euodia ruticarpa (ER) cultivated in Taiwan, were selected to assess their immunomodulatory effects using mouse primary splenocytes and peritoneal macrophages. T helper type 1 lymphocytes (Th1) (IL-2), Th2 (IL-5), pro-inflammatory (TNF-α) and anti-inflammatory (IL-10) cytokines secreted by correspondent immune cells treated with SDEO samples were determined using enzyme-linked immunosorbent assay. The total amounts of potential phytochemicals, including total flavonoids, polyphenols and saponins, in these two selected SDEOs were measured and correlated with cytokine levels secreted by immune cells. Our results evidenced that ER SDEO is rich in total flavonoids, polyphenols and saponins. Treatments with AG and ER SDEO significantly (p < 0.05) increased IL-5/IL-2 (Th2/Th1) cytokine secretion ratios by splenocytes, suggesting that both AG and ER SDEO have the Th2-polarization property and anti-inflammatory potential. In addition, AG and ER SDEO, particularly ER SDEO, markedly decreased TNF-α/IL-10 secretion ratios by macrophages in the absence or presence of lipopolysaccharide (LPS), exhibiting substantial effects on spontaneous and LPS-induced inflammation. Significant correlations were found between the total polyphenols, flavonoids or saponins content in the two selected SDEOs and Th1/Th2 immune balance or anti-inflammatory ability in linear, non-linear or biphasic manners, respectively. In conclusion, our results suggest that AG and ER, particularly ER, SDEO have immunomodulatory potential in shifting the Th1/Th2 balance toward Th2 polarization in splenocytes and inhibiting inflammation in macrophages in the absence or presence of LPS. Full article

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

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20 pages, 963 KiB

Open AccessReview

Pathological Crosstalk between Metastatic Breast Cancer Cells and the Bone Microenvironment

by Jennifer Zarrer, Marie-Therese Haider, Daniel J. Smit and Hanna Taipaleenmäki

Biomolecules 2020, 10(2), 337; https://doi.org/10.3390/biom10020337 - 19 Feb 2020

Cited by 36 | Viewed by 6441

Abstract

Bone is the most common metastatic site in breast cancer. Upon arrival to the bone, disseminated tumor cells can undergo a period of dormancy but often eventually grow and hijack the bone microenvironment. The bone marrow microenvironment consists of multiple cell types including [...] Read more.

Bone is the most common metastatic site in breast cancer. Upon arrival to the bone, disseminated tumor cells can undergo a period of dormancy but often eventually grow and hijack the bone microenvironment. The bone marrow microenvironment consists of multiple cell types including the bone cells, adipocytes, endothelial cells, and nerve cells that all have crucial functions in the maintenance of bone homeostasis. Tumor cells severely disturb the tightly controlled cellular and molecular interactions in the bone marrow fueling their own survival and growth. While the role of bone resorbing osteoclasts in breast cancer bone metastases is well established, the function of other bone cells, as well as adipocytes, endothelial cells, and nerve cells is less understood. In this review, we discuss the composition of the physiological bone microenvironment and how the presence of tumor cells influences the microenvironment, creating a pathological crosstalk between the cells. A better understanding of the cellular and molecular events that occur in the metastatic bone microenvironment could facilitate the identification of novel cellular targets to treat this devastating disease. Full article

(This article belongs to the Special Issue Connecting the Bone with Other Organs: A Reciprocal Cross-Talk)

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14 pages, 3506 KiB

Open AccessArticle

Cinnamomum verum Bark Extract Mediated Green Synthesis of ZnO Nanoparticles and Their Antibacterial Potentiality

by Mohammad Azam Ansari, Mahadevamurthy Murali, Daruka Prasad, Mohammad A. Alzohairy, Ahmad Almatroudi, Mohammad N. Alomary, Arakere Chunchegowda Udayashankar, Sudarshana Brijesh Singh, Sarah Mousa Maadi Asiri, Bagepalli Shivaram Ashwini, Hittanahallikoppal Gajendramurthy Gowtham, Nataraj Kalegowda, Kestur Nagaraj Amruthesh, Thimappa Ramachandrappa Lakshmeesha and Siddapura Ramachandrappa Niranjana

Biomolecules 2020, 10(2), 336; https://doi.org/10.3390/biom10020336 - 19 Feb 2020

Cited by 108 | Viewed by 7290

Abstract

Cinnamomum verum plant extract mediated propellant chemistry route was used for the green synthesis of zinc oxide nanoparticles. Prepared samples were confirmed for their nano regime using advanced characterization techniques such as powder X-ray diffraction and microscopic techniques such as scanning electron microscopy [...] Read more.

Cinnamomum verum plant extract mediated propellant chemistry route was used for the green synthesis of zinc oxide nanoparticles. Prepared samples were confirmed for their nano regime using advanced characterization techniques such as powder X-ray diffraction and microscopic techniques such as scanning electron microscopy and transmission electron microscopy. The energy band gap of the green synthesized zinc oxide (ZnO)-nanoparticles (NPs) were found between 3.25–3.28 eV. Fourier transmission infrared spectroscopy shows the presence of Zn-O bond within the wave number of 500 cm⁻¹. SEM images show the specific agglomeration of particles which was also confirmed by TEM studies. The green synthesized ZnO-NPs inhibited the growth of Escherichia coli and Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 125 µg mL⁻¹ and 62.5 µg mL⁻¹, respectively. The results indicate the prepared ZnO-NPs can be used as a potential antimicrobial agent against harmful pathogens. Full article

(This article belongs to the Special Issue Plant-based green synthesis of nanoparticles: production, characterization and applications)

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17 pages, 1031 KiB

Open AccessReview

The Challenge of Disease-Modifying Therapies in Parkinson’s Disease: Role of CSF Biomarkers

by Federico Paolini Paoletti, Lorenzo Gaetani and Lucilla Parnetti

Biomolecules 2020, 10(2), 335; https://doi.org/10.3390/biom10020335 - 19 Feb 2020

Cited by 25 | Viewed by 5989

Abstract

The development of disease modifying strategies in Parkinson’s disease (PD) largely depends on the ability to identify suitable populations after accurate diagnostic work-up. Therefore, patient molecular profiling and disease subtyping are mandatory. Thus far, in clinical trials, PD has been considered to be [...] Read more.

The development of disease modifying strategies in Parkinson’s disease (PD) largely depends on the ability to identify suitable populations after accurate diagnostic work-up. Therefore, patient molecular profiling and disease subtyping are mandatory. Thus far, in clinical trials, PD has been considered to be a “single entity”. Conversely, in front of the common feature of nigro-striatal degeneration, PD is pathogenically heterogeneous with a series of several biological and molecular pathways that differently contribute to clinical development and progression. Currently available diagnostic criteria for PD mainly rely on clinical features and imaging biomarkers, thus missing to identify the contribution of pathophysiological pathways, also failing to catch abnormalities occurring in the early stages of disease. Cerebrospinal fluid (CSF) is a promising source of biomarkers, with the high potential for reflecting early changes occurring in PD brain. In this review, we provide an overview on CSF biomarkers in PD, discussing their association with different molecular pathways involved either in pathophysiology or progression in detail. Their potential application in the field of disease modifying treatments is also discussed. Full article

(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)

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15 pages, 2441 KiB

Open AccessArticle

Anti-Infectives Restore ORKAMBI^® Rescue of F508del-CFTR Function in Human Bronchial Epithelial Cells Infected with Clinical Strains of P. aeruginosa

by Onofrio Laselva, Tracy A. Stone, Christine E. Bear and Charles M. Deber

Biomolecules 2020, 10(2), 334; https://doi.org/10.3390/biom10020334 - 19 Feb 2020

Cited by 31 | Viewed by 3813

Abstract

Chronic infection and inflammation are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. ORKAMBI^® (Lumacaftor-Ivacaftor) is an approved combination therapy for Cystic Fibrosis (CF) patients bearing the most common mutation, F508del, in the cystic fibrosis conductance regulator (CFTR) [...] Read more.

Chronic infection and inflammation are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. ORKAMBI^® (Lumacaftor-Ivacaftor) is an approved combination therapy for Cystic Fibrosis (CF) patients bearing the most common mutation, F508del, in the cystic fibrosis conductance regulator (CFTR) protein. It has been previously shown that ORKAMBI^®-mediated rescue of CFTR is reduced by a pre-existing Pseudomonas aeruginosa infection. Here, we show that the infection of F508del-CFTR human bronchial epithelial (HBE) cells with lab strain and four different clinical strains of P. aeruginosa, isolated from the lung sputum of CF patients, decreases CFTR function in a strain-specific manner by 48 to 88%. The treatment of infected cells with antibiotic tobramycin or cationic antimicrobial peptide 6K-F17 was found to decrease clinical strain bacterial growth on HBE cells and restore ORKAMBI^®-mediated rescue of F508del-CFTR function. Further, 6K-F17 was found to downregulate the expression of pro-inflammatory cytokines, interleukin (IL)-8, IL-6, and tumor necrosis factor-α in infected HBE cells. The results provide strong evidence for a combination therapy approach involving CFTR modulators and anti-infectives (i.e., tobramycin and/or 6K-F17) to improve their overall efficacy in CF patients. Full article

(This article belongs to the Section Chemical Biology)

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15 pages, 1379 KiB

Open AccessArticle

Characterization of a Novel Mannose-Binding Lectin with Antiviral Activities from Red Alga, Grateloupia chiangii

by Hyun-Ju Hwang, Jin-Wook Han, Hancheol Jeon, Kichul Cho, Ju-hee Kim, Dae-Sung Lee and Jong Won Han

Biomolecules 2020, 10(2), 333; https://doi.org/10.3390/biom10020333 - 19 Feb 2020

Cited by 33 | Viewed by 4926

Abstract

Lectins have the ability to bind specific carbohydrates and they have potential applications as medical and pharmacological agents. The unique structure and usefulness of red algal lectin have been reported, but these lectins are limited to a few marine algal groups. In this [...] Read more.

Lectins have the ability to bind specific carbohydrates and they have potential applications as medical and pharmacological agents. The unique structure and usefulness of red algal lectin have been reported, but these lectins are limited to a few marine algal groups. In this study, a novel mannose-binding lectin from Grateloupia chiangii (G. chiangii lectin, GCL) was purified using antiviral screens and affinity chromatography. We characterized the molecular weight, agglutination activity, hemagglutination activity, and heat stability of GCL. To determine the carbohydrate specificity, a glycan microarray was performed. GCL showed strong binding affinity for Maltohexaose-β-Sp1 and Maltoheptaose-β-Sp1 with weak affinity for other monosaccharides and preferred binding to high-mannan structures. The N-terminal sequence and peptide sequence of GCL were determined using an Edman degradation method and LC-MS/MS, and the cDNA and peptide sequences were deduced. GCL was shown to consist of 231 amino acids (24.9 kDa) and the N-terminus methionine was eliminated after translation. GCL possessed a tandem repeat structure of six domains, similar to the other red algal lectins. The mannose binding properties and tandem repeat structure of GCL may confer it the potential to act as an antiviral agent for protection against viral infection. Full article

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18 pages, 808 KiB

Open AccessFeature PaperReview

Notch Signaling in Skeletal Development, Homeostasis and Pathogenesis

by Jennifer T. Zieba, Yi-Ting Chen, Brendan H. Lee and Yangjin Bae

Biomolecules 2020, 10(2), 332; https://doi.org/10.3390/biom10020332 - 19 Feb 2020

Cited by 51 | Viewed by 6235

Abstract

Skeletal development is a complex process which requires the tight regulation of gene activation and suppression in response to local signaling pathways. Among these pathways, Notch signaling is implicated in governing cell fate determination, proliferation, differentiation and apoptosis of skeletal cells-osteoblasts, osteoclasts, osteocytes [...] Read more.

Skeletal development is a complex process which requires the tight regulation of gene activation and suppression in response to local signaling pathways. Among these pathways, Notch signaling is implicated in governing cell fate determination, proliferation, differentiation and apoptosis of skeletal cells-osteoblasts, osteoclasts, osteocytes and chondrocytes. Moreover, human genetic mutations in Notch components emphasize the critical roles of Notch signaling in skeletal development and homeostasis. In this review, we focus on the physiological roles of Notch signaling in skeletogenesis, postnatal bone and cartilage homeostasis and fracture repair. We also discuss the pathological gain- and loss-of-function of Notch signaling in bone and cartilage, resulting in osteosarcoma and age-related degenerative diseases, such as osteoporosis and osteoarthritis. Understanding the physiological and pathological function of Notch signaling in skeletal tissues using animal models and human genetics will provide new insights into disease pathogenesis and offer novel approaches for the treatment of bone/cartilage diseases. Full article

(This article belongs to the Special Issue Cell Type- and Context-Specific Roles and Regulation of Notch Signaling)

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3 pages, 164 KiB

Open AccessEditorial

Rigidity of the Outer Shell Predicted by a Protein Intrinsic Disorder Model Sheds Light on the COVID-19 (Wuhan-2019-nCoV) Infectivity

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

Biomolecules 2020, 10(2), 331; https://doi.org/10.3390/biom10020331 - 19 Feb 2020

Cited by 52 | Viewed by 16642

Abstract

The world is currently witnessing an outbreak of a new coronavirus spreading quickly across China and affecting at least 24 other countries. With almost 65,000 infected, a worldwide death toll of at least 1370 (as of 14 February 2020), and with the potential [...] Read more.

The world is currently witnessing an outbreak of a new coronavirus spreading quickly across China and affecting at least 24 other countries. With almost 65,000 infected, a worldwide death toll of at least 1370 (as of 14 February 2020), and with the potential to affect up to two-thirds of the world population, COVID-19 is considered by the World Health Organization (WHO) to be a global health emergency. The speed of spread and infectivity of COVID-19 (also known as Wuhan-2019-nCoV) are dramatically exceeding those of the Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). In fact, since September 2012, the WHO has been notified of 2494 laboratory-confirmed cases of infection with MERS-CoV, whereas the 2002–2003 epidemic of SARS affected 26 countries and resulted in more than 8000 cases. Therefore, although SARS, MERS, and COVID-19 are all the result of coronaviral infections, the causes of the coronaviruses differ dramatically in their transmissibility. It is likely that these differences in infectivity of coronaviruses can be attributed to the differences in the rigidity of their shells which can be evaluated using computational tools for predicting intrinsic disorder predisposition of the corresponding viral proteins. Full article

19 pages, 1609 KiB

Open AccessReview

NAD⁺ Metabolism and Regulation: Lessons From Yeast

by Trevor Croft, Padmaja Venkatakrishnan and Su-Ju Lin

Biomolecules 2020, 10(2), 330; https://doi.org/10.3390/biom10020330 - 19 Feb 2020

Cited by 35 | Viewed by 11550

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite involved in various cellular processes. The cellular NAD⁺ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. NAD⁺ metabolism is an emerging therapeutic target for [...] Read more.

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite involved in various cellular processes. The cellular NAD⁺ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. NAD⁺ metabolism is an emerging therapeutic target for several human disorders including diabetes, cancer, and neuron degeneration. Factors regulating NAD⁺ homeostasis have remained incompletely understood due to the dynamic nature and complexity of NAD⁺ metabolism. Recent studies using the genetically tractable budding yeast Saccharomyces cerevisiae have identified novel NAD⁺ homeostasis factors. These findings help provide a molecular basis for how may NAD⁺ and NAD⁺ homeostasis factors contribute to the maintenance and regulation of cellular function. Here we summarize major NAD⁺ biosynthesis pathways, selected cellular processes that closely connect with and contribute to NAD⁺ homeostasis, and regulation of NAD⁺ metabolism by nutrient-sensing signaling pathways. We also extend the discussions to include possible implications of NAD⁺ homeostasis factors in human disorders. Understanding the cross-regulation and interconnections of NAD⁺ precursors and associated cellular pathways will help elucidate the mechanisms of the complex regulation of NAD⁺ homeostasis. These studies may also contribute to the development of effective NAD⁺-based therapeutic strategies specific for different types of NAD⁺ deficiency related disorders. Full article

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

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16 pages, 1693 KiB

Open AccessArticle

Effects of Cannabis Use on the Protein and Lipid Profile of Olfactory Neuroepithelium Cells from Schizophrenia Patients Studied by Synchrotron-Based FTIR Spectroscopy

by Sergi Saladrigas-Manjón, Tanja Dučić, Liliana Galindo, Cristina Fernández-Avilés, Víctor Pérez, Rafael de la Torre and Patricia Robledo

Biomolecules 2020, 10(2), 329; https://doi.org/10.3390/biom10020329 - 19 Feb 2020

Cited by 7 | Viewed by 3527

Abstract

Schizophrenia (SCZ) is a neurodevelopmental disorder with a high genetic component, but the presence of environmental stressors can be important for its onset and progression. Cannabis use can be a major risk factor for developing SCZ. However, despite the available data on the [...] Read more.

Schizophrenia (SCZ) is a neurodevelopmental disorder with a high genetic component, but the presence of environmental stressors can be important for its onset and progression. Cannabis use can be a major risk factor for developing SCZ. However, despite the available data on the neurobiological underpinnings of SCZ, there is an important lack of studies in human neuronal tissue and living cells addressing the effects of cannabis in SCZ patients. In this study, we analysed the most relevant bio-macromolecular constituents in olfactory neuroepithelium (ON) cells of healthy controls non-cannabis users, healthy cannabis users, SCZ patients non-cannabis users, and SCZ patients cannabis users using Synchrotron Radiation-Fourier Transform Infrared (SR-FTIR) spectrometry and microscopy. Our results revealed that SCZ patients non-cannabis users, and healthy cannabis users exhibit similar alterations in the macromolecular profile of ON cells, including disruption in lipid composition, increased lipid membrane renewal rate and lipid peroxidation, altered proteins containing more β-sheet structures, and showed an increase in DNA and histone methylation. Notably, these alterations were not observed in SCZ patients who use cannabis regularly. These data suggest a differential effect of cannabis in healthy controls and in SCZ patients in terms of the macromolecular constituents of ON cells. Full article

(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)

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13 pages, 2020 KiB

Open AccessArticle

Seasonal and Antioxidant Evaluation of Essential Oil from Eugenia uniflora L., Curzerene-Rich, Thermally Produced in Situ

by Jamile S. da Costa, Adenilson S. Barroso, Rosa Helena V. Mourão, Joyce Kelly R. da Silva, José Guilherme S. Maia and Pablo Luis B. Figueiredo

Biomolecules 2020, 10(2), 328; https://doi.org/10.3390/biom10020328 - 19 Feb 2020

Cited by 45 | Viewed by 4410

Abstract

The essential oil of Eugenia uniflora has been attributed anti-depressive, antinociceptive, antileishmanial, larvicidal, antioxidant, antibacterial, and antifungal activities. It is known that the cultivation of this plant can be affected by seasonality, promoting alteration in the oil composition and its biological activities. This [...] Read more.

The essential oil of Eugenia uniflora has been attributed anti-depressive, antinociceptive, antileishmanial, larvicidal, antioxidant, antibacterial, and antifungal activities. It is known that the cultivation of this plant can be affected by seasonality, promoting alteration in the oil composition and its biological activities. This study aims to perform the annual evaluation of the curzerene-type oil of E. uniflora and determine its antioxidant activity. The oil yield from the dry season (1.4 ± 0.6%) did not differ statistically from that of the rainy season (1.8 ± 0.8%). Curzerene, an oxygenated sesquiterpene, was the principal constituent, and its percentage showed no significant difference between the two periods: dry (42.7% ± 6.1) and rainy (40.8 ± 5.9%). Principal component and hierarchical cluster analyses presented a high level of similarity between the monthly samples of the oils. Also, in the annual study, the yield and composition of the oils did not present a significant correlation with the climatic variables. The antioxidant activity of the oils showed inhibition of DPPH radicals with an average value of 55.0 ± 6.6%. The high curzerene content in the monthly oils of E. uniflora suggests their potential for use as a future phytotherapeutic alternative. Full article

(This article belongs to the Special Issue Perspectives of Essential Oils)

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13 pages, 3743 KiB

Open AccessArticle

Characterization of the CRM Gene Family and Elucidating the Function of OsCFM2 in Rice

by Qiang Zhang, Lan Shen, Deyong Ren, Jiang Hu, Li Zhu, Zhenyu Gao, Guangheng Zhang, Longbiao Guo, Dali Zeng and Qian Qian

Biomolecules 2020, 10(2), 327; https://doi.org/10.3390/biom10020327 - 18 Feb 2020

Cited by 13 | Viewed by 3339

Abstract

The chloroplast RNA splicing and ribosome maturation (CRM) domain-containing proteins regulate the expression of chloroplast or mitochondrial genes that influence plant growth and development. Although 14 CRM domain proteins have previously been identified in rice, there are few studies of these gene expression [...] Read more.

The chloroplast RNA splicing and ribosome maturation (CRM) domain-containing proteins regulate the expression of chloroplast or mitochondrial genes that influence plant growth and development. Although 14 CRM domain proteins have previously been identified in rice, there are few studies of these gene expression patterns in various tissues and under abiotic stress. In our study, we found that 14 CRM domain-containing proteins have a conservative motif1. Under salt stress, the expression levels of 14 CRM genes were downregulated. However, under drought and cold stress, the expression level of some CRM genes was increased. The analysis of gene expression patterns showed that 14 CRM genes were expressed in all tissues but especially highly expressed in leaves. In addition, we analyzed the functions of OsCFM2 and found that this protein influences chloroplast development by regulating the splicing of a group I and five group II introns. Our study provides information for the function analysis of CRM domain-containing proteins in rice. Full article

(This article belongs to the Section Molecular Biology)

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9 pages, 1804 KiB

Open AccessArticle

Reduced Local Response to Corticosteroids in Eosinophilic Chronic Rhinosinusitis with Asthma

by Yoshiki Kobayashi, Akira Kanda, Yasutaka Yun, Dan Van Bui, Kensuke Suzuki, Shunsuke Sawada, Mikiya Asako and Hiroshi Iwai

Biomolecules 2020, 10(2), 326; https://doi.org/10.3390/biom10020326 - 18 Feb 2020

Cited by 15 | Viewed by 4186

Abstract

Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is recognized as a refractory eosinophilic disorder characterized by both upper and lower airway inflammation. In some severe cases, disease control is poor, likely due to local steroid insensitivity. In this [...] Read more.

Eosinophilic chronic rhinosinusitis (ECRS), a subgroup of chronic rhinosinusitis with nasal polyps, is recognized as a refractory eosinophilic disorder characterized by both upper and lower airway inflammation. In some severe cases, disease control is poor, likely due to local steroid insensitivity. In this study, we focused on protein phosphatase 2A (PP2A), a key factor regulating glucocorticoid receptor (GR) nuclear translocation, and examined its association with local responses to corticosteroids in eosinophilic airway inflammation. Our results indicated reduced responses to corticosteroids in nasal epithelial cells from ECRS patients with asthma, which were also associated with decreased PP2A mRNA expression. Eosinophil peroxidase stimulates elevated PP2A phosphorylation levels, reducing PP2A protein expression and activity. In addition, mRNA levels of inflammatory mediators (TSLP, IL-25, IL-33, CCL4, CCL5, CCL11, and CCL26) associated with eosinophilic airway inflammation in epithelial cells were increased in nasal polyps (eosinophil-rich areas) compared with those in uncinate process tissues (eosinophil-poor areas) from the same patients. PP2A reduction by siRNA reduced GR nuclear translocation, whereas PP2A overexpression by plasmid transfection, or PP2A activation by formoterol, enhanced GR nuclear translocation. Collectively, our findings indicate that PP2A may represent a promising therapeutic target in refractory eosinophilic airway inflammation characterized by local steroid insensitivity. Full article

(This article belongs to the Special Issue Eosinophilic Inflammation)

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16 pages, 2665 KiB

Open AccessFeature PaperReview

Current Advances in Allosteric Modulation of Muscarinic Receptors

by Jan Jakubik and Esam E. El-Fakahany

Biomolecules 2020, 10(2), 325; https://doi.org/10.3390/biom10020325 - 18 Feb 2020

Cited by 30 | Viewed by 5923

Abstract

Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated [...] Read more.

Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer’s disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)

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16 pages, 3278 KiB

Open AccessArticle

2α-Hydroxyeudesma-4,11(13)-Dien-8β,12-Olide Isolated from Inula britannica Induces Apoptosis in Diffuse Large B-cell Lymphoma Cells

by Dae Kil Jang, Ik-Soo Lee, Han-Seung Shin and Hee Min Yoo

Biomolecules 2020, 10(2), 324; https://doi.org/10.3390/biom10020324 - 18 Feb 2020

Cited by 15 | Viewed by 3866

Abstract

2α-Hydroxyeudesma-4,11(13)-dien-8β,12-olide (HEDO), a eudesmane-type sesquiterpene lactone belonging to large group of plant terpenoids isolated from Inula britannica, displays cytotoxic activity against diffuse large B cell lymphoma cells in vitro. However, the molecular mechanism of the anticancer effect remains unclear. In this study, [...] Read more.

2α-Hydroxyeudesma-4,11(13)-dien-8β,12-olide (HEDO), a eudesmane-type sesquiterpene lactone belonging to large group of plant terpenoids isolated from Inula britannica, displays cytotoxic activity against diffuse large B cell lymphoma cells in vitro. However, the molecular mechanism of the anticancer effect remains unclear. In this study, we showed that HEDO inhibits cell growth by inducing apoptosis in lymphoma cell lines through its antiproliferative activity. HEDO increases the depolarization of mitochondrial membrane potential and upregulated intracellular reactive oxygen species (ROS). Furthermore, we examined the cell cycle effect, and our results provided evidence that the arrest of the cell cycle at the SubG0/G1 phase plays an important role in the ability of HEDO to inhibit cell growth in Ontario Cancer Institute (OCI)-LY3 lymphoma cells by preventing nuclear factor-kappa B (NF-κB) signaling. In addition, HEDO induced apoptosis by instigating the activation of Bcl-2-associated X (BAX) and cleaved caspase-3, decreasing B-cell lymphoma 2 (BCL2), B-cell lymphoma-extra large (BCL-XL), and procaspase 3 expression levels. Based on these findings, we suggest that HEDO has potential as an anticancer drug of lymphoma by inducing ROS-dependent accumulation of SubG0/G1 arrest and apoptosis in OCI-LY3 cells. Full article

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

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26 pages, 3716 KiB

Open AccessReview

Hydrogen Sulfide in Pharmacotherapy, Beyond the Hydrogen Sulfide-Donors

by Ewelina Zaorska, Lenka Tomasova, Dominik Koszelewski, Ryszard Ostaszewski and Marcin Ufnal

Biomolecules 2020, 10(2), 323; https://doi.org/10.3390/biom10020323 - 18 Feb 2020

Cited by 78 | Viewed by 9678

Abstract

Hydrogen sulfide (H₂S) is one of the important biological mediators involved in physiological and pathological processes in mammals. Recently developed H₂S donors show promising effects against several pathological processes in preclinical and early clinical studies. For example, H₂ [...] Read more.

Hydrogen sulfide (H₂S) is one of the important biological mediators involved in physiological and pathological processes in mammals. Recently developed H₂S donors show promising effects against several pathological processes in preclinical and early clinical studies. For example, H₂S donors have been found to be effective in the prevention of gastrointestinal ulcers during anti-inflammatory treatment. Notably, there are well-established medicines used for the treatment of a variety of diseases, whose chemical structure contains sulfur moieties and may release H₂S. Hence, the therapeutic effect of these drugs may be partly the result of the release of H₂S occurring during drug metabolism and/or the effect of these drugs on the production of endogenous hydrogen sulfide. In this work, we review data regarding sulfur drugs commonly used in clinical practice that can support the hypothesis about H₂S-dependent pharmacotherapeutic effects of these drugs. Full article

(This article belongs to the Special Issue H₂S, Polysulfides, and Enzymes: Physiological and Pathological Aspects)

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24 pages, 7685 KiB

Open AccessEditor’s ChoiceArticle

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast

by Leticia Pollo-Oliveira, Roland Klassen, Nick Davis, Akif Ciftci, Jo Marie Bacusmo, Maria Martinelli, Michael S. DeMott, Thomas J. Begley, Peter C. Dedon, Raffael Schaffrath and Valérie de Crécy-Lagard

Biomolecules 2020, 10(2), 322; https://doi.org/10.3390/biom10020322 - 18 Feb 2020

Cited by 17 | Viewed by 6399

Abstract

Modifications found in the Anticodon Stem Loop (ASL) of tRNAs play important roles in regulating translational speed and accuracy. Threonylcarbamoyl adenosine (t⁶A37) and 5-methoxycarbonyl methyl-2-thiouridine (mcm⁵s²U34) are critical ASL modifications that have been linked to several human [...] Read more.

Modifications found in the Anticodon Stem Loop (ASL) of tRNAs play important roles in regulating translational speed and accuracy. Threonylcarbamoyl adenosine (t⁶A37) and 5-methoxycarbonyl methyl-2-thiouridine (mcm⁵s²U34) are critical ASL modifications that have been linked to several human diseases. The model yeast Saccharomyces cerevisiae is viable despite the absence of both modifications, growth is however greatly impaired. The major observed consequence is a subsequent increase in protein aggregates and aberrant morphology. Proteomic analysis of the t⁶A-deficient strain (sua5 mutant) revealed a global mistranslation leading to protein aggregation without regard to physicochemical properties or t⁶A-dependent or biased codon usage in parent genes. However, loss of sua5 led to increased expression of soluble proteins for mitochondrial function, protein quality processing/trafficking, oxidative stress response, and energy homeostasis. These results point to a global function for t⁶A in protein homeostasis very similar to mcm⁵/s²U modifications. Full article

(This article belongs to the Collection RNA Modifications)

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40 pages, 8279 KiB

Open AccessArticle

The Relevance of Thimet Oligopeptidase in the Regulation of Energy Metabolism and Diet-Induced Obesity

by Mayara C. F. Gewehr, Alexandre A. S. Teixeira, Bruna A. C. Santos, Luana A. Biondo, Fábio C. Gozzo, Amanda M. Cordibello, Rosangela A. S. Eichler, Patrícia Reckziegel, Renée N. O. Da Silva, Nilton B. Dos Santos, Niels O. S. Camara, Angela Castoldi, Maria L. M. Barreto-Chaves, Camila S. Dale, Nathalia Senger, Joanna D. C. C. Lima, Marilia C. L. Seelaender, Aline C. Inada, Eliana H. Akamine, Leandro M. Castro, Alice C. Rodrigues, José C. Rosa Neto and Emer S. Ferro Show full author list Hide full author list

Biomolecules 2020, 10(2), 321; https://doi.org/10.3390/biom10020321 - 17 Feb 2020

Cited by 14 | Viewed by 5033

Abstract

Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging [...] Read more.

Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1^−/−) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1^−/− and WT mice ingested similar chow and calories; however, the THOP1^−/− mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1^−/− mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1^−/− fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1^−/− mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action. Full article

(This article belongs to the Section Cellular Biochemistry)

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21 pages, 2655 KiB

Open AccessEditor’s ChoiceReview

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

by Shuya Kasai, Sunao Shimizu, Yota Tatara, Junsei Mimura and Ken Itoh

Biomolecules 2020, 10(2), 320; https://doi.org/10.3390/biom10020320 - 17 Feb 2020

Cited by 318 | Viewed by 23217

Abstract

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence [...] Read more.

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS. Full article

(This article belongs to the Special Issue Emerging Role of Mitochondrial Reactive Oxygen Species in Cellular Signaling)

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