Biomolecules

18 pages, 3220 KiB

Open AccessArticle

Identification of the Genetic Variation and Gene Exchange between Citrus Trifoliata and Citrus Clementina

by Tian-Jia Liu^†, Jing-Jing Zhou^†, Fa-Yi Chen^†, Zhi-Meng Gan, Yong-Ping Li, Jin-Zhi Zhang^* and Chun-Gen Hu^*

¹ Key Laboratory of Horticultural Plant Biology (Ministry of Education), College of Horticulture and Forestry Science, Huazhong Agricultural University, Wuhan 430070, China

^† These authors have contributed equally to this work.

Biomolecules 2018, 8(4), 182; https://doi.org/10.3390/biom8040182 - 19 Dec 2018

Cited by 9 | Viewed by 4059

Abstract

To identify the genetic variation between Citrus trifoliata and Citrus clementina, we performed genome resequencing on the two citrus species. Compared with the citrus reference genome, a total of 9,449,204 single-nucleotide polymorphisms (SNPs) and 846,615 insertion/deletion polymorphisms (InDels) were identified in the [...] Read more.

To identify the genetic variation between Citrus trifoliata and Citrus clementina, we performed genome resequencing on the two citrus species. Compared with the citrus reference genome, a total of 9,449,204 single-nucleotide polymorphisms (SNPs) and 846,615 insertion/deletion polymorphisms (InDels) were identified in the two citrus species, while 1,868,115 (19.77%) of the SNPs and 190,199 (22.47%) of the InDels from the two citrus species were located in the genic regions. Meanwhile, a total of 8,091,407 specific SNPs and 692,654 specific InDels were identified in the two citrus genotypes, yielding an average of 27.32 SNPs/kb and 2.34 InDels/kb. We identified and characterized the patterns of gene exchanges in the grafted citrus plants by using specific genetic variation from genome resequencing. A total of 4396 transporting genes across graft junctions was identified. Some specific genetic variation and mobile genes was also confirmed by Sanger sequencing. Furthermore, these mobile genes could move directionally or bidirectionally between the scions and the rootstocks. In addition, a total of 1581 and 2577 differentially expressed genes were found in the scions and the rootstocks after grafting compared with the control, respectively. These genetic variations provide fundamental information on the genetic basis of important traits between C. trifoliata and C. clementina, as the transport of genes would be applicable to horticulture crops. Full article

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11 pages, 1736 KiB

Open AccessArticle

Dual Specificity Phosphatase 6 Protects Neural Stem Cells from β-Amyloid-Induced Cytotoxicity through ERK1/2 Inactivation

by Wang Liao^1,2,†, Yuqiu Zheng^2,†, Wenli Fang², Shaowei Liao², Ying Xiong², Yi Li², Songhua Xiao², Xingcai Zhang^3,* and Jun Liu^2,*

¹ Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA

² Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510120, China

³ John A Paulson School of Engineering and Applied Science, Harvard University, Cambridge, MA 02138, USA

^† The first two authors contributed equally to this work.

Biomolecules 2018, 8(4), 181; https://doi.org/10.3390/biom8040181 - 19 Dec 2018

Cited by 24 | Viewed by 5181

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with limited treatment options and no cure. Beta-amyloid (Aβ) is a hallmark of AD that has potent neurotoxicity in neural stem cells (NSCs). Dual specificity phosphatase 6 (DUSP6) is a member of the mitogen-activated protein [...] Read more.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with limited treatment options and no cure. Beta-amyloid (Aβ) is a hallmark of AD that has potent neurotoxicity in neural stem cells (NSCs). Dual specificity phosphatase 6 (DUSP6) is a member of the mitogen-activated protein kinases (MAPKs), which is involved in regulating various physiological and pathological processes. Whether DUSP6 has a protective effect on Aβ-induced NSC injury remains to be explored. C17.2 neural stem cells were transfected with DUSP6-overexpressed plasmid. NSCs with or without DUSP6 overexpression were administrated with Aβ25–35 at various concentrations (i.e., 0, 2.5, 5 μM). DUSP6 expression after Aβ treatment was detected by Real-Time Polymerase Chain Reaction (RT-PCR) and Western blot and cell vitality was examined by the CCK8 assay. The oxidative stress (intracellular reactive oxygen species (ROS) and malondialdehyde (MDA)), endoplasmic reticulum stress (ER calcium level) and mitochondrial dysfunction (cytochrome c homeostasis) were tested. The expression of p-ERK1/2 and ERK1/2 were assayed by Western blot. Our results showed that Aβ decreased the expression of DUSP6 in a dose-dependent manner. The overexpression of DUSP6 increased the cell vitality of NSCs after Aβ treatment. Oxidative stress, ER stress, and mitochondrial dysfunction induced by Aβ could be restored by DUSP6 overexpression. Additionally, the Aβ-induced ERK1/2 activation was reversed. In summary, DUSP6 might have a neuroprotective effect on Aβ-induced cytotoxicity, probably via ERK1/2 activation. Full article

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

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17 pages, 1091 KiB

Open AccessReview

Combining Optical Approaches with Human Inducible Pluripotent Stem Cells in G Protein-Coupled Receptor Drug Screening and Development

by Kyla Bourque^†, Jace Jones-Tabah^†, Nourhen Mnasri, Ryan D. Martin and Terence E. Hébert^*

¹ Department of Pharmacology and Therapeutics, McGill University, Room 1303 McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montréal, QC H3G 1Y6, Canada

^† These authors contributed equally to this work.

Biomolecules 2018, 8(4), 180; https://doi.org/10.3390/biom8040180 - 18 Dec 2018

Cited by 3 | Viewed by 6091

Abstract

Drug discovery for G protein-coupled receptors (GPCRs) stands at an interesting juncture. Screening programs are slowly moving away from model heterologous cell systems such as human embryonic kidney (HEK) 293 cells to more relevant cellular, tissue and whole animal platforms. Investigators are now [...] Read more.

Drug discovery for G protein-coupled receptors (GPCRs) stands at an interesting juncture. Screening programs are slowly moving away from model heterologous cell systems such as human embryonic kidney (HEK) 293 cells to more relevant cellular, tissue and whole animal platforms. Investigators are now developing analytical approaches as means to undertake different aspects of drug discovery by scaling into increasingly more relevant models all the way down to the single cell level. Such approaches include cellular, tissue slice and whole animal models where biosensors that track signaling events and receptor conformational profiles can be used. Here, we review aspects of biosensor-based imaging approaches that might be used in inducible pluripotent stem cell (iPSC) and organoid models, and focus on how such models must be characterized in order to apply them in drug screening. Full article

(This article belongs to the Special Issue Biomolecules: Insights from Single Molecule, Single Cell, and Systems Biology Perspectives)

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5 pages, 207 KiB

Open AccessEditorial

Intrinsically Disordered Proteins and the Janus Challenge

by Prakash Kulkarni^1,* and Vladimir N. Uversky^2,3,*

¹ Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA

² Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA

³ Laboratory of New methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino 142290, Moscow Region, Russia

Biomolecules 2018, 8(4), 179; https://doi.org/10.3390/biom8040179 - 18 Dec 2018

Cited by 7 | Viewed by 5028

Abstract

To gain a new insight into the role of proteins in the origin of life on Earth, we present the Janus Challenge: identify an intrinsically disordered protein (IDP), naturally occurring or synthetic, that has catalytic activity. For example, such a catalytic IDP may [...] Read more.

To gain a new insight into the role of proteins in the origin of life on Earth, we present the Janus Challenge: identify an intrinsically disordered protein (IDP), naturally occurring or synthetic, that has catalytic activity. For example, such a catalytic IDP may perform condensation reactions to catalyze a peptide bond or a phosphodiester bond formation utilizing natural/un-natural amino acids or nucleotides, respectively. The IDP may also have autocatalytic, de novo synthesis, or self-replicative activity. Meeting this challenge may not only shed new light and provide an alternative to the RNA world hypothesis, but it may also serve as an impetus for technological advances with important biomedical applications. Full article

(This article belongs to the Collection Intrinsically Disordered Proteins)

10 pages, 1283 KiB

Open AccessReview

Transport Properties for Pharmaceutical Controlled-Release Systems: A Brief Review of the Importance of Their Study in Biological Systems

by Ana C. F. Ribeiro^1,* and Miguel A. Esteso^2,*

¹ Department of Chemistry, Coimbra Chemistry Centre, University of Coimbra, 3004-535 Coimbra, Portugal

² U.D. Química Física, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain

Biomolecules 2018, 8(4), 178; https://doi.org/10.3390/biom8040178 - 17 Dec 2018

Cited by 11 | Viewed by 3836

Abstract

The goal of this work was to comprehensive study the transport properties of controlled-release systems for the safe and reliable delivery of drugs. Special emphasis has been placed on the measurement of the diffusion of drugs, alone or in combination with carrier molecules [...] Read more.

The goal of this work was to comprehensive study the transport properties of controlled-release systems for the safe and reliable delivery of drugs. Special emphasis has been placed on the measurement of the diffusion of drugs, alone or in combination with carrier molecules for enhanced solubility and facilitated transport. These studies have provided detailed comprehensive information—both kinetic and thermodynamic—for the design and operation of systems for the controlled release and delivery of drugs. Cyclodextrins are among the most important carriers used in these systems. The basis for their popularity is the ability of these materials to solubilize poorly soluble drugs, generally resulting in striking increases in their water solubilities. The techniques used in these investigations include pulse voltammetry, nuclear magnetic resonance (NMR) and Raman spectroscopy, ultrasonic relaxation, and dissolution kinetics. Transport in these systems is a mutual diffusion process involving coupled fluxes of drugs and carrier molecules driven by concentration gradients. Owing to a strong association in these multicomponent systems, it is not uncommon for a diffusing solute to drive substantial coupled fluxes of other solutes, mixed electrolytes, or polymers. Thus, diffusion data, including cross-diffusion coefficients for coupled transport, are essential in order to understand the rates of many processes involving mass transport driven by chemical concentration gradients, as crystal growth and dissolution, solubilization, membrane transport, and diffusion-limited chemical reactions are all relevant to the design of controlled-release systems. While numerous studies have been carried out on these systems, few have considered the transport behavior for controlled-release systems. To remedy this situation, we decided to measure mutual diffusion coefficients for coupled diffusion in a variety of drug–carrier solutions. In summary, the main objective of the present work was to understand the physical chemistry of carrier-mediated transport phenomena in systems of controlled drug release. Full article

(This article belongs to the Special Issue Transport Properties for Pharmaceutical Controlled-Release Systems)

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16 pages, 3733 KiB

Open AccessArticle

Administration of Enalapril Started Late in Life Attenuates Hypertrophy and Oxidative Stress Burden, Increases Mitochondrial Mass, and Modulates Mitochondrial Quality Control Signaling in the Rat Heart

by Anna Picca^1,2,†

, Giuseppe Sirago^3,†

, Vito Pesce³, Angela Maria Serena Lezza³, Riccardo Calvani^1,2,*

, Maurizio Bossola^1,4, Emanuele Rocco Villani², Francesco Landi^1,2, Christiaan Leeuwenburgh⁵, Roberto Bernabei^1,2, Christy S. Carter⁶ and Emanuele Marzetti¹

¹ Fondazione Policlinico Universitario “Agostino Gemelli” IRCSS, Università Cattolica del Sacro Cuore, L.go A. Gemelli 1, 00168 Rome, Italy

² Institute of Internal Medicine and Geriatrics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy

³ Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy

⁴ Institute of Surgical Sciences, Fondazione Policlinico Universitario “Agostino Gemelli” IRCSS, 00168 Rome, Italy

⁵ Department of Aging and Geriatric Research, Institute on Aging, Division of Biology of Aging, University of Florida, Gainesville, FL 32611, USA

⁶ Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, Nathan Shock Center of Excellence in the Basic Biology of Aging, University of Alabama at Birmingham, Birmingham, AL 35205, USA

^† These two authors contributed equally to this work.

Biomolecules 2018, 8(4), 177; https://doi.org/10.3390/biom8040177 - 17 Dec 2018

Cited by 20 | Viewed by 4913

Abstract

Mitochondrial dysfunction is a relevant mechanism in cardiac aging. Here, we investigated the effects of late-life enalapril administration at a non-antihypertensive dose on mitochondrial genomic stability, oxidative damage, and mitochondrial quality control (MQC) signaling in the hearts of aged rats. The protein expression [...] Read more.

Mitochondrial dysfunction is a relevant mechanism in cardiac aging. Here, we investigated the effects of late-life enalapril administration at a non-antihypertensive dose on mitochondrial genomic stability, oxidative damage, and mitochondrial quality control (MQC) signaling in the hearts of aged rats. The protein expression of selected mediators (i.e., mitochondrial antioxidant enzymes, energy metabolism, mitochondrial biogenesis, dynamics, and autophagy) was measured in old rats randomly assigned to receive enalapril (n = 8) or placebo (n = 8) from 24 to 27 months of age. We also assessed mitochondrial DNA (mtDNA) content, citrate synthase activity, oxidative lesions to protein and mtDNA (i.e., carbonyls and the abundance of mtDNA⁴⁸³⁴ deletion), and the mitochondrial transcription factor A (TFAM) binding to specific mtDNA regions. Enalapril attenuated cardiac hypertrophy and oxidative stress-derived damage (mtDNA oxidation, mtDNA⁴⁸³⁴ deletion, and protein carbonylation), while increasing mitochondrial antioxidant defenses. The binding of mitochondrial transcription factor A to mtDNA regions involved in replication and deletion generation was enhanced following enalapril administration. Increased mitochondrial mass as well as mitochondriogenesis and autophagy signaling were found in enalapril-treated rats. Late-life enalapril administration mitigates age-dependent cardiac hypertrophy and oxidative damage, while increasing mitochondrial mass and modulating MQC signaling. Further analyses are needed to conclusively establish whether enalapril may offer cardioprotection during aging. Full article

(This article belongs to the Special Issue Mitochondrial Diseases)

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20 pages, 973 KiB

Open AccessReview

Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function

by George A. Porter, Jr.^*

and Gisela Beutner

Department of Pediatrics, Division of Cardiology, University of Rochester School of Medicine, Rochester, NY 14642, USA

Biomolecules 2018, 8(4), 176; https://doi.org/10.3390/biom8040176 - 14 Dec 2018

Cited by 90 | Viewed by 11251

Abstract

Cyclophilin D (CyPD) is an important mitochondrial chaperone protein whose mechanism of action remains a mystery. It is well known for regulating mitochondrial function and coupling of the electron transport chain and ATP synthesis by controlling the mitochondrial permeability transition pore (PTP), but [...] Read more.

Cyclophilin D (CyPD) is an important mitochondrial chaperone protein whose mechanism of action remains a mystery. It is well known for regulating mitochondrial function and coupling of the electron transport chain and ATP synthesis by controlling the mitochondrial permeability transition pore (PTP), but more recent evidence suggests that it may regulate electron transport chain activity. Given its identification as a peptidyl-prolyl, cis-trans isomerase (PPIase), CyPD, is thought to be involved in mitochondrial protein folding, but very few reports demonstrate the presence of this activity. By contrast, CyPD may also perform a scaffolding function, as it binds to a number of important proteins in the mitochondrial matrix and inner mitochondrial membrane. From a clinical perspective, inhibiting CyPD to inhibit PTP opening protects against ischemia–reperfusion injury, making modulation of CyPD activity a potentially important therapeutic goal, but the lack of knowledge about the mechanisms of CyPD’s actions remains problematic for such therapies. Thus, the important yet enigmatic nature of CyPD somehow makes it a master regulator, yet a troublemaker, for mitochondrial function. Full article

(This article belongs to the Special Issue Evolving Functional Features of Peptidyl-Prolyl cis-trans Isomerases (PPIases) in Mono-Cellular versus Multi-Cellular Organisms)

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23 pages, 4561 KiB

Open AccessArticle

Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations

by Ana Correia^1,2, Dany Silva¹, Alexandra Correia^3,4,5, Manuel Vilanova^3,4,5

, Fátima Gärtner^2,3,6 and Nuno Vale^1,2,3,6,*

¹ Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal

² Department of Molecular Pathology and Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal

³ i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal

⁴ Department of Imuno-Physiology and Pharmacology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal

⁵ Institute of Molecular and Cell Biology (IBMC) of the University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal

⁶ Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal

Biomolecules 2018, 8(4), 175; https://doi.org/10.3390/biom8040175 - 14 Dec 2018

Cited by 33 | Viewed by 6420

Abstract

Cancer is a disease that affects and kills millions of people worldwide. Breast cancer, especially, has a high incidence and mortality, and is challenging to treat. Due to its high impact on the health sector, oncological therapy is the subject of an intense [...] Read more.

Cancer is a disease that affects and kills millions of people worldwide. Breast cancer, especially, has a high incidence and mortality, and is challenging to treat. Due to its high impact on the health sector, oncological therapy is the subject of an intense and very expensive research. To improve this therapy and reduce its costs, strategies such as drug repurposing and drug combinations have been extensively studied. Drug repurposing means giving new usefulness to drugs which are approved for the therapy of various diseases, but, in this case, are not approved for cancer therapy. On the other hand, the purpose of combining drugs is that the response that is obtained is more advantageous than the response obtained by the single drugs. Using drugs with potential to be repurposed, combined with 5-fluorouracil, the aim of this project was to investigate whether this combination led to therapeutic benefits, comparing with the isolated drugs. We started with a screening of the most promising drugs, with verapamil and itraconazole being chosen. Several cellular viability studies, cell death and proliferation studies, mainly in MCF-7 cells (Michigan Cancer Foundation-7, human breast adenocarcinoma cells) were performed. Studies were also carried out to understand the effect of the drugs at the level of possible therapeutic resistance, evaluating the epithelial-mesenchymal transition. Combining all the results, the conclusion is that the combination of verapamil and itraconazole with 5-fluorouracil had benefits, mainly by decreasing cell viability and proliferation. Furthermore, the combination of itraconazole and 5-fluorouracil seemed to be the most effective, being an interesting focus in future studies. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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16 pages, 298 KiB

Open AccessReview

Quantification of Lipids: Model, Reality, and Compromise

by Spiro Khoury^1,2

, Cécile Canlet^3,4, Marlène Z. Lacroix⁵, Olivier Berdeaux^1,2, Juliette Jouhet^2,6 and Justine Bertrand-Michel^2,7,*

¹ Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRA, Université Bourgogne Franche-Comté, 9E Boulevard Jeanne d’Arc, F-21000 Dijon, France

² French LipidomYstes Network, 31000 Toulouse, France

³ Toxalim, Research Centre in Food Toxicology, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, F-31027 Toulouse, France

⁴ Axiom Platform, MetaToul-MetaboHUB, National Infrastructure for Metabolomics and Fluxomics, F-31027 Toulouse, France

⁵ INTHERES, Université de Toulouse, INRA, ENVT, 31432 Toulouse, France

⁶ Laboratoire de Physiologie Cellulaire et Végétale, Université Grenoble Alpes, CNRS, INRA, CEA, 38000 Grenoble, France

⁷ MetaToul-Lipidomic Core Facility, MetaboHUB, I2MC U1048, Inserm, 31432 Toulouse, France

Biomolecules 2018, 8(4), 174; https://doi.org/10.3390/biom8040174 - 14 Dec 2018

Cited by 55 | Viewed by 8156

Abstract

Lipids are key molecules in various biological processes, thus their quantification is a crucial point in a lot of studies and should be taken into account in lipidomics development. This family is complex and presents a very large diversity of structures, so analyzing [...] Read more.

Lipids are key molecules in various biological processes, thus their quantification is a crucial point in a lot of studies and should be taken into account in lipidomics development. This family is complex and presents a very large diversity of structures, so analyzing and quantifying all this diversity is a real challenge. In this review, the different techniques to analyze lipids will be presented: from nuclear magnetic resonance (NMR) to mass spectrometry (with and without chromatography) including universal detectors. First of all, the state of the art of quantification, with the definitions of terms and protocol standardization, will be presented with quantitative lipidomics in mind, and then technical considerations and limitations of analytical chemistry’s tools, such as NMR, mass spectrometry and universal detectors, will be discussed, particularly in terms of absolute quantification. Full article

(This article belongs to the Special Issue Lipidomics)

25 pages, 8754 KiB

Open AccessReview

Recent Developments of Useful MALDI Matrices for the Mass Spectrometric Characterization of Lipids

by Jenny Leopold

, Yulia Popkova

, Kathrin M. Engel

and Jürgen Schiller^*

Faculty of Medicine, Institute for Medical Physics and Biophysics, Härtelstr. 16/18, Leipzig University, D-04107 Leipzig, Germany

Biomolecules 2018, 8(4), 173; https://doi.org/10.3390/biom8040173 - 13 Dec 2018

Cited by 156 | Viewed by 12562

Abstract

Matrix-assisted laser desorption/ionization (MALDI) is one of the most successful “soft” ionization methods in the field of mass spectrometry and enables the analysis of a broad range of molecules, including lipids. Although the details of the ionization process are still unknown, the importance [...] Read more.

Matrix-assisted laser desorption/ionization (MALDI) is one of the most successful “soft” ionization methods in the field of mass spectrometry and enables the analysis of a broad range of molecules, including lipids. Although the details of the ionization process are still unknown, the importance of the matrix is commonly accepted. Both, the development of and the search for useful matrices was, and still is, an empirical process, since properties like vacuum stability, high absorption at the laser wavelength, etc. have to be fulfilled by a compound to become a useful matrix. This review provides a survey of successfully used MALDI matrices for the lipid analyses of complex biological samples. The advantages and drawbacks of the established organic matrix molecules (cinnamic or benzoic acid derivatives), liquid crystalline matrices, and mixtures of common matrices will be discussed. Furthermore, we will deal with nanocrystalline matrices, which are most suitable to analyze small molecules, such as free fatty acids. It will be shown that the analysis of mixtures and the quantitative analysis of small molecules can be easily performed if the matrix is carefully selected. Finally, some basic principles of how useful matrix compounds can be “designed” de novo will be introduced. Full article

(This article belongs to the Special Issue Lipidomics)

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9 pages, 293 KiB

Open AccessReview

Effect of Coenzyme Q₁₀ Supplementation on Testosterone

by Saleem Ali Banihani

Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan

Biomolecules 2018, 8(4), 172; https://doi.org/10.3390/biom8040172 - 13 Dec 2018

Cited by 39 | Viewed by 9647

Abstract

Enhancing testosterone production in males is a continuous research direction for many scientists in the field, due to its role as a principal sex hormone and as a crucial modulator of well-being and general health in humans. Since 1978, there have been more [...] Read more.

Enhancing testosterone production in males is a continuous research direction for many scientists in the field, due to its role as a principal sex hormone and as a crucial modulator of well-being and general health in humans. Since 1978, there have been more than 30 studies that have connected coenzyme Q₁₀ and testosterone. Such a link is attributable to the vigorous biological role of coenzyme Q₁₀ as a crucial member in the energy production route in humans and animals, which is thought to have a positive influence on testosterone production, and hence on infertility, particularly male infertility. However, this connection has not yet been deliberated. The present work systematically reviews and summarizes the influence of coenzyme Q₁₀ supplementation on testosterone. To accomplish this purpose, the Scopus, PubMed, and Web of Science databases were searched using the keywords “coenzyme Q₁₀” versus “testosterone” for English language papers from November 1978 through October 2018. Relevant articles were also discussed and included to address an integral discussion. In summary, to date the studies conducted on human males reveal insignificant effects of coenzyme Q₁₀ supplementation on testosterone. Similarly, rather than the reproductive toxicity studies, the studies conducted on animals did not show any positive influence of coenzyme Q₁₀ on testosterone. However, coenzyme Q₁₀ supplementation was found to ameliorate the reduction in testosterone induced by chemical reproductive toxicants, mainly by neutralizing the damaging effect of the generated free radicals. However, collectively these findings require further confirmation by additional research studies. Full article

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11 pages, 1809 KiB

Open AccessArticle

Anticancer Activity of Polysaccharides Produced from Glycerol and Crude Glycerol by an Endophytic Fungus Chaetomium globosum CGMCC 6882 on Human Lung Cancer A549 Cells

by Zichao Wang^1,*

, Peizhang Chen¹, Ning Tao¹, Huiru Zhang^1,*, Ruifang Li¹, Xiaobei Zhan², Fuzhuan Wang¹ and Yingben Shen³

¹ College of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China

² The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China

³ Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA

Biomolecules 2018, 8(4), 171; https://doi.org/10.3390/biom8040171 - 11 Dec 2018

Cited by 31 | Viewed by 4467

Abstract

Two polysaccharides were produced by Chaetomium globosum CGMCC 6882 from glycerol (GCP-1) and crude glycerol (GCP-2). Chemical characteristics results showed GCP-1 and GCP-2 were similar polysaccharides, but the molecular weights of GCP-1 and GCP-2 were 5.340 × 10⁴ Da and 3.105 × [...] Read more.

Two polysaccharides were produced by Chaetomium globosum CGMCC 6882 from glycerol (GCP-1) and crude glycerol (GCP-2). Chemical characteristics results showed GCP-1 and GCP-2 were similar polysaccharides, but the molecular weights of GCP-1 and GCP-2 were 5.340 × 10⁴ Da and 3.105 × 10⁴ Da, respectively. Viabilities of A549 cells after treatment with GCP-1 and GCP-2 were 49% and 39% compared to the control group. Meanwhile, flow cytometry results indicated that GCP-1 and GCP-2 could induce 17.79% and 24.28% of A549 cells to apoptosis with 200 μg/mL concentration treated for 24 h. RT-PCR results suggested that GCP-1 and GCP-2 could be used as potential and effective apoptosis inducers on A549 cells by increasing BAX, CASPASE-3, CASPASE-9, TIMP-1, TIMP-2 expression and decreasing BCL-2 expression. This research provided an innovative approach to using a byproduct of biodiesel production (crude glycerol) to produce polysaccharides of potential medicinal benefit. Full article

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

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15 pages, 391 KiB

Open AccessReview

Role of HIF-1α in Alcohol-Mediated Multiple Organ Dysfunction

by Niya L. Morris^1,2 and Samantha M. Yeligar^1,2,*

¹ Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA 30322, USA

² Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Atlanta Veterans Affairs Health Care System, Decatur, GA 30033, USA

Biomolecules 2018, 8(4), 170; https://doi.org/10.3390/biom8040170 - 10 Dec 2018

Cited by 24 | Viewed by 4949

Abstract

Excess alcohol consumption is a global crisis contributing to over 3 million alcohol-related deaths per year worldwide and economic costs exceeding $200 billion dollars, which include productivity losses, healthcare, and other effects (e.g., property damages). Both clinical and experimental models have shown that [...] Read more.

Excess alcohol consumption is a global crisis contributing to over 3 million alcohol-related deaths per year worldwide and economic costs exceeding $200 billion dollars, which include productivity losses, healthcare, and other effects (e.g., property damages). Both clinical and experimental models have shown that excessive alcohol consumption results in multiple organ injury. Although alcohol metabolism occurs primarily in the liver, alcohol exposure can lead to pathophysiological conditions in multiple organs and tissues, including the brain, lungs, adipose, liver, and intestines. Understanding the mechanisms by which alcohol-mediated organ dysfunction occurs could help to identify new therapeutic approaches to mitigate the detrimental effects of alcohol misuse. Hypoxia-inducible factor (HIF)-1 is a transcription factor comprised of HIF-1α and HIF-1β subunits that play a critical role in alcohol-mediated organ dysfunction. This review provides a comprehensive analysis of recent studies examining the relationship between HIF-1α and alcohol consumption as it relates to multiple organ injury and potential therapies to mitigate alcohol’s effects. Full article

(This article belongs to the Special Issue Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)

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10 pages, 782 KiB

Open AccessArticle

Clinical Significance of Serum NEDD9 Levels in Patients with Pancreatic Cancer

by Cigdem Usul Afsar^1,*, Mehmet Karabulut², Senem Karabulut³, Safiye Tokgoz Ozal⁴, Murat Cikot², Murat Serilmez⁵

and Faruk Tas³

¹ Acıbadem Bakırkoy Hospital, Department of Internal Medicine and Medical Oncology, Medical Faculty, Acıbadem Mehmet Ali Aydınlar University, Zeytinlik Mah. Halit Ziya Usaklıgil Cad. No: 1, Bakırkoy, 34140 Istanbul, Turkey

² Department of General Surgery, Bakırkoy Dr Sadi Konuk Education and Research Hospital, Health Sciences University, 34147 Istanbul, Turkey

³ Department of Medical Oncology, Institute of Oncology, Istanbul University, 34452 Fatih/Istanbul, Turkey

⁴ Department of Radiology, Bakırkoy Dr Sadi Konuk Education and Research Hospital, Health Sciences University, 34147 Istanbul, Turkey

⁵ Department of Basic Oncology, Institute of Oncology, Istanbul University, 34452 Istanbul, Turkey

Biomolecules 2018, 8(4), 169; https://doi.org/10.3390/biom8040169 - 10 Dec 2018

Cited by 9 | Viewed by 3850

Abstract

Introduction: Pancreatic cancer (PC) is a lethal malignancy. Various diagnostic, predictive, and prognostic biomarkers have been evaluated. This study was conducted to investigate the serum levels of neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) in patients with PC and the relationship [...] Read more.

Introduction: Pancreatic cancer (PC) is a lethal malignancy. Various diagnostic, predictive, and prognostic biomarkers have been evaluated. This study was conducted to investigate the serum levels of neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) in patients with PC and the relationship between tumor progression and known prognostic parameters. Materials and Methods: Serum samples were obtained on first admission before any treatment. Serum NEDD9 levels were determined using enzyme-linked immunosorbent assay (ELISA). Age- and sex-matched healthy controls were included in the analysis. Results: In a three year period, 32 patients with a pathologically-confirmed diagnosis of PC were enrolled in this study. The median age at diagnosis was 61 years, range 38 to 84 years; the majority of the patients in the group were men (n = 20, 62.5%). The tumor was located in the head of pancreas in 21 (65.6%) patients. Forty-one percent of 17 metastatic patients who received palliative CTx (chemotherapy) were CTx-responsive. The baseline serum NEDD9 levels were significantly higher in patients with PA than in the control group (p = 0.03). Median OS of the whole group were 27 ± 7.3 weeks. Alcohol intake, performance status, and LDH levels were found to be significant prognostic factors (p = 0.006, p < 0.001, and p < 0.001, respectively). However, serum NEDD9 levels had no significantly effect on progression free survival (PFS) and overall survival (OS) (p = 0.71 and p = 0.58, respectively). Conclusions: NEDD9 is identified as a secretory biomarker for PC but it has no prognostic role. Full article

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1 pages, 139 KiB

Open AccessErratum

Erratum: Traghella, I.; et al. Nontraditional Cardiovascular Biomarkers and Risk Factors: Rationale and Future Perspectives. Biomolecules 2018, 8, 40

by Irene Traghella¹, Francesca Mastorci², Alessia Pepe¹, Alessandro Pingitore² and Cristina Vassalle^1,*

¹ Fondazione G. Monasterio CNR-Regione Toscana and Institute of Clinical Physiology, CNR San Cataldo Research Area, via Moruzzi, 1, 56124 Pisa, Italy

² Institute of Clinical Physiology, CNR San Cataldo Research Area, via Moruzzi, 1, 56124 Pisa, Italy

Biomolecules 2018, 8(4), 168; https://doi.org/10.3390/biom8040168 - 10 Dec 2018

Cited by 3 | Viewed by 2646

Abstract

The authors wish to make the following change in their paper [...] Full article

(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)

11 pages, 3100 KiB

Open AccessArticle

Effect of Adipose-Derived Stem Cells and Their Exo as Adjunctive Therapy to Nonsurgical Periodontal Treatment: A Histologic and Histomorphometric Study in Rats

by Ebtehal Mohammed^1,*, Eman Khalil² and Dina Sabry³

¹ Lecturer of Oral Medicine, Oral diagnosis and Periodontology, Faculty of Dentistry, Beni Suef University, Beni Suef 62511, Egypt

² Lecturer of Oral Medicine, Oral diagnosis and Periodontology, Faculty of Dentistry, British University, Cairo 11837, Egypt

³ Professor of Biochemistry, Faculty of Medicine, Cairo University, Cairo 11562, Egypt

Biomolecules 2018, 8(4), 167; https://doi.org/10.3390/biom8040167 - 10 Dec 2018

Cited by 84 | Viewed by 5847

Abstract

Scaling and root planing (SRP) is of limited value in many cases, so adjunctive treatment was applied to augment its outcome. Adipose-derived stem/stromal cells (ADSCs) were investigated in periodontal regeneration with promising results. However, they have safety concerns. The exosomes (Exo.), which are [...] Read more.

Scaling and root planing (SRP) is of limited value in many cases, so adjunctive treatment was applied to augment its outcome. Adipose-derived stem/stromal cells (ADSCs) were investigated in periodontal regeneration with promising results. However, they have safety concerns. The exosomes (Exo.), which are extracellular vesicles mediating the action of stem/stromal cells, represent a new approach to overcome these concerns. Ligature-induced periodontitis was induced in 50 rats for 14 days, and they were divided into control (5 healthy rats for histologic comparison), SRP group, ADSCs group, and Exo. group, with evaluation intervals at 2 days, and 2 and 4 weeks, including 5 rats in each interval for each group. The specimens were evaluated for histologic description (H&E), histochemical study (Masson trichrome), and histomorphometric study, to evaluate the area % of newly formed tissues. The Exo. group revealed the best results in all intervals with significantly higher area % of newly formed tissues, followed by ADSCs and, finally, SRP. Both Exo. and ADSCs showed organized newly formed tissues with the Exo. group obtaining comparable histologic results to the normal, healthy tissues by 4 weeks. Adipose-derived stem/stromal cells and their Exo. represent a promising adjunctive treatment to SRP. Full article

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8 pages, 386 KiB

Open AccessCommunication

High-Throughput Screen Identifying the Thiosemicarbazone NSC319726 Compound as a Potent Antimicrobial Lead Against Resistant Strains of Escherichia coli

by Carmen Sadaka^1,*

, Peter Damborg²

and Jeffrey L. Watts^2,*

¹ Department of Veterinary and Animal Sciences, University of Copenhagen, Stigboejlen 4, 1870 Frederiksberg C, Denmark

² Zoetis Global Therapeutics Research, 333 Portage Street, Kalamazoo, MI 49007, USA

Biomolecules 2018, 8(4), 166; https://doi.org/10.3390/biom8040166 - 7 Dec 2018

Cited by 5 | Viewed by 4468

Abstract

Antibiotic discovery is vital when considering the increasing antimicrobial resistance threat. The aim of this work was to provide a high-throughput screen (HTS) assay using multidrug-resistant Escherichia coli strains to enable further research into antimicrobial lead discovery and identify novel antimicrobials. This study [...] Read more.

Antibiotic discovery is vital when considering the increasing antimicrobial resistance threat. The aim of this work was to provide a high-throughput screen (HTS) assay using multidrug-resistant Escherichia coli strains to enable further research into antimicrobial lead discovery and identify novel antimicrobials. This study describes a primary HTS of a diverse library of 7884 small molecules against a susceptible E. coli strain. A secondary screening of 112 molecules against four E. coli strains with different susceptibility profiles revealed NSC319726 as a potential antimicrobial lead serving as a novel template. NSC319726 is a good candidate for an analoguing program. Full article

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15 pages, 1404 KiB

Open AccessArticle

RNA Sequencing Provides Insights into the Regulation of Solanesol Biosynthesis in Nicotiana tabacum Induced by Moderately High Temperature

by Ning Yan^1,*, Yongmei Du¹, Hongbo Zhang¹, Zhongfeng Zhang¹, Xinmin Liu¹, John Shi² and Yanhua Liu^1,*

¹ Tobacco Research Institute of Chinese Academy of Agricultural Sciences, Qingdao 266101, China

² Guelph Food Research Center, Agriculture and Agri-Food Canada, Guelph, ON N1G 5C9, Canada

Biomolecules 2018, 8(4), 165; https://doi.org/10.3390/biom8040165 - 7 Dec 2018

Cited by 6 | Viewed by 4247

Abstract

Solanesol is a terpene alcohol composed of nine isoprene units that mainly accumulates in solanaceous plants, especially tobacco (Nicotiana tabacum). The present study aimed to investigate the regulation of solanesol accumulation in tobacco leaves induced by moderately high temperature (MHT). Exposure [...] Read more.

Solanesol is a terpene alcohol composed of nine isoprene units that mainly accumulates in solanaceous plants, especially tobacco (Nicotiana tabacum). The present study aimed to investigate the regulation of solanesol accumulation in tobacco leaves induced by moderately high temperature (MHT). Exposure to MHT resulted in a significant increase in solanesol content, dry weight, and net photosynthetic rate in tobacco leaves. In MHT-exposed tobacco leaves, 492 and 1440 genes were significantly up- and downregulated, respectively, as revealed by RNA-sequencing. Functional enrichment analysis revealed that most of the differentially expressed genes (DEGs) were mainly related to secondary metabolite biosynthesis, metabolic pathway, carbohydrate metabolism, lipid metabolism, hydrolase activity, catalytic activity, and oxidation-reduction process. Moreover, 122 transcription factors of DEGs were divided into 22 families. Significant upregulation of N. tabacum 3-hydroxy-3-methylglutaryl-CoA reductase (NtHMGR), 1-deoxy-d-xylulose 5-phosphate reductoisomerase (NtDXR), geranylgeranyl diphosphate synthase (NtGGPS), and solanesyl diphosphate synthase (NtSPS) and significant downregulation of N. tabacum 1-deoxy-d-xylulose 5-phosphate synthase (NtDXS) and farnesyl diphosphate synthase (NtFPS) transcription upon MHT exposure were monitored by quantitative real-time PCR (qRT-PCR). This study indicated that solanesol accumulation in tobacco leaves can be manipulated through regulation of the environmental temperature and established a basis for further elucidation of the molecular mechanism of temperature regulation of solanesol accumulation. Full article

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11 pages, 2045 KiB

Open AccessArticle

Association of Genetic Variation at AQP4 Locus with Vascular Depression

by Anna L. Westermair^1,†

, Matthias Munz^2,3,4,5,†

, Anja Schaich¹, Stefan Nitsche^2,3,4, Bastian Willenborg¹, Loreto M. Muñoz Venegas^2,3,4

, Christina Willenborg^2,3,4, Heribert Schunkert^6,7, Ulrich Schweiger¹

and Jeanette Erdmann^2,3,4,*

¹ Department of Psychiatry and Psychotherapy, University Medical Center Schleswig-Holstein—Campus Lübeck, 23562 Lübeck, Germany

² Institute for Cardiogenetics, University of Lübeck, 23562 Lübeck, Germany

³ DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany

⁴ University Heart Center Lübeck, 23562 Lübeck, Germany

⁵ Department of Periodontology and Synoptic Dentistry, Institute of Health, Institute for Dental and Craniofacial Sciences, Charité–University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, 10117 Berlin, Germany

⁶ German Heart Center Munich, Technical University Munich, 80636 Munich, Germany

⁷ DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80636 Munich, Germany

^† These authors contributed equally to this work.

Biomolecules 2018, 8(4), 164; https://doi.org/10.3390/biom8040164 - 5 Dec 2018

Cited by 15 | Viewed by 6192

Abstract

Despite its substantial clinical importance, specific genetic variants associated with depression have not yet been identified. We sought to identify genetic variants associated with depression by (a) focusing on a more homogenous subsample (vascular depression) and (b) applying a three-stage approach. First, we [...] Read more.

Despite its substantial clinical importance, specific genetic variants associated with depression have not yet been identified. We sought to identify genetic variants associated with depression by (a) focusing on a more homogenous subsample (vascular depression) and (b) applying a three-stage approach. First, we contacted 730 participants with a confirmed atherosclerotic disease (coronary artery disease) from a population-based study population (German Myocardial Infarction Family Study IV) for psychiatric assessment with the Mini International Neuropsychiatric Interview. Second, we genotyped these patients using genome-wide single nucleotide polymorphism (SNP) arrays. Third, we characterized the SNP via in-silico analysis. The final sample consisted of 342 patients (78.3% male, age = 63.2 ± 9.9 years), 22.8% with a severe depressive disorder. Variant rs528732638 on chromosome 18q11.2 was a genome-wide significant variant and was associated with 3.6-fold increase in the odds of lifetime depression. The locus belongs to a linkage disequilibrium block showing expression quantitative trait loci effects on three putative cis-regulated genes, including the aquaporin 4 (AQP4) locus. AQP4 is already known to mediate the formation of ischemic edema in the brain and heart, increasing the size and extent of resulting lesions. Our findings indicate that AQP4 may also play a role in the etiopathology of vascular depression. Full article

(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)

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14 pages, 1765 KiB

Open AccessArticle

Triptolide Decreases Cell Proliferation and Induces Cell Death in Triple Negative MDA-MB-231 Breast Cancer Cells

by Elizabeth Varghese¹, Samson Mathews Samuel¹

, Sharon Varghese¹

, Sohaila Cheema²

, Ravinder Mamtani² and Dietrich Büsselberg^1,*

¹ Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P. O. Box 24144, Doha, Qatar

² Institute for Population Health, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, P. O. Box 24144, Doha, Qatar

Biomolecules 2018, 8(4), 163; https://doi.org/10.3390/biom8040163 - 5 Dec 2018

Cited by 34 | Viewed by 7324

Abstract

Triple negative breast cancers (TNBCs) do not respond to conventional estrogen receptor/progesterone receptor/human epidermal growth factor receptor-2 targeted interventions due to the absence of the respective receptor targets. They are aggressive, exhibit early recurrence, metastasize, are more invasive in nature, and develop drug [...] Read more.

Triple negative breast cancers (TNBCs) do not respond to conventional estrogen receptor/progesterone receptor/human epidermal growth factor receptor-2 targeted interventions due to the absence of the respective receptor targets. They are aggressive, exhibit early recurrence, metastasize, are more invasive in nature, and develop drug resistance. Some plant-derived substances have been screened and have gained attention as efficient anticancer drugs for TNBCs with few adverse effects. Here, we evaluate triptolide (concentrations in the range of 100 pM to 10 µM), a di-terpene tri-epoxide isolated from thunder god vine for its efficacy as anticancer drug in MDA-MB-231 TNBC cells. Cell proliferation and viability were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay and trypan blue exclusion assay, respectively. A flow cytometry-based apoptosis assay was performed by using fluorescein isothiocyanate (FITC)-conjugated annexin V and propidium iodide (PI). Western blotting was performed to determine the levels of apoptotic and autophagy proteins such as caspase 3, LC3B and SQSTM1/p62. Results indicate that in 72 h of 1 nM triptolide treatment, the percentage of cell proliferation in MDA-MB-231 cells declined to 49 ± 18.9% (mean ± standard deviation (SD)), whereas the proliferation rate did not drop below 80% in MCF-7 cells (non-TNBC cells which express the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) even at the highest concentration tested (10 µM). The MDA-MB-468 cells showed a similar trend to MDA-MB-231 cells. Furthermore, triptolide treatment for 72 h significantly decreased cell viability at concentrations above 10 nM. Apoptotic cell death assay in 72 h triptolide-treated MDA-MB-231 cells revealed 29.3 ± 10.57% of early apoptotic cells in comparison to the control group (4.61 ± 2.24%). Cell cycle analysis indicated accumulation of cells in sub G₀/G₁ phase, indicating apoptosis. Western blot analysis in the 25 nM triptolide treatment group revealed induction of autophagy as shown by a significant decrease in the levels of autophagy marker p62 (by 0.2-fold p < 0.0001) and with an increase in the levels of LC3B-II (by 8-fold p < 0.05). An increase in the levels of the apoptotic marker cleaved caspase 3 (by 4-fold p < 0.05) was also observed in triptolide treated MDA-MB-231 cells. Our data shows that triptolide could be an efficient anticancer agent in the treatment of TNBCs. Full article

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17 pages, 1552 KiB

Open AccessArticle

pH-Induced Folding of the Caspase-Cleaved Par-4 Tumor Suppressor: Evidence of Structure Outside of the Coiled Coil Domain

by Andrea M. Clark, Komala Ponniah, Meghan S. Warden, Emily M. Raitt, Andrea C. Yawn and Steven M. Pascal^*

Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529, USA

Biomolecules 2018, 8(4), 162; https://doi.org/10.3390/biom8040162 - 4 Dec 2018

Cited by 9 | Viewed by 5057

Abstract

Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par-4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer’s disease. Cleavage of Par-4 by caspase-3 [...] Read more.

Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par-4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer’s disease. Cleavage of Par-4 by caspase-3 activates tumor suppression via formation of an approximately 25 kDa fragment (cl-Par-4) that enters the nucleus and inhibits Bcl-2 and NF-ƙB, which function in pro-survival pathways. Here, we have investigated the structure of cl-Par-4 using biophysical techniques including circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and intrinsic tyrosine fluorescence. The results demonstrate pH-dependent folding of cl-Par-4, with high disorder and aggregation at neutral pH, but a largely folded, non-aggregated conformation at acidic pH. Full article

(This article belongs to the Collection Intrinsically Disordered Proteins)

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26 pages, 9208 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Structural and Functional Insights into Human Nuclear Cyclophilins

by Caroline Rajiv^1,2 and Tara L. Davis^1,3,*

¹ Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA

² Janssen Pharmaceuticals Inc., 22-21062, 1400 McKean Rd, Spring House, PA 19477, USA

³ FORMA Therapeutics, 550 Arsenal St. Ste. 100, Boston, MA 02472, USA

Biomolecules 2018, 8(4), 161; https://doi.org/10.3390/biom8040161 - 4 Dec 2018

Cited by 37 | Viewed by 8155

Abstract

The peptidyl prolyl isomerases (PPI) of the cyclophilin type are distributed throughout human cells, including eight found solely in the nucleus. Nuclear cyclophilins are involved in complexes that regulate chromatin modification, transcription, and pre-mRNA splicing. This review collects what is known about the [...] Read more.

The peptidyl prolyl isomerases (PPI) of the cyclophilin type are distributed throughout human cells, including eight found solely in the nucleus. Nuclear cyclophilins are involved in complexes that regulate chromatin modification, transcription, and pre-mRNA splicing. This review collects what is known about the eight human nuclear cyclophilins: peptidyl prolyl isomerase H (PPIH), peptidyl prolyl isomerase E (PPIE), peptidyl prolyl isomerase-like 1 (PPIL1), peptidyl prolyl isomerase-like 2 (PPIL2), peptidyl prolyl isomerase-like 3 (PPIL3), peptidyl prolyl isomerase G (PPIG), spliceosome-associated protein CWC27 homolog (CWC27), and peptidyl prolyl isomerase domain and WD repeat-containing protein 1 (PPWD1). Each “spliceophilin” is evaluated in relation to the spliceosomal complex in which it has been studied, and current work studying the biological roles of these cyclophilins in the nucleus are discussed. The eight human splicing complexes available in the Protein Data Bank (PDB) are analyzed from the viewpoint of the human spliceophilins. Future directions in structural and cellular biology, and the importance of developing spliceophilin-specific inhibitors, are considered. Full article

(This article belongs to the Special Issue Evolving Functional Features of Peptidyl-Prolyl cis-trans Isomerases (PPIases) in Mono-Cellular versus Multi-Cellular Organisms)

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14 pages, 1877 KiB

Open AccessReview

Regulation of Cellular Metabolism through Phase Separation of Enzymes

by Manoël Prouteau^1,2 and Robbie Loewith^1,2,3,*

¹ Department of Molecular Biology, University of Geneva, 30 Quai Ernest-Ansermet, CH1211 Geneva, Switzerland

² Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, 30 Quai Ernest-Ansermet, CH1211 Geneva, Switzerland

³ Swiss National Centre for Competence in Research (NCCR) in Chemical Biology, University of Geneva, Sciences II, Room 3-308, 30 Quai Ernest-Ansermet, CH1211 Geneva, Switzerland

Biomolecules 2018, 8(4), 160; https://doi.org/10.3390/biom8040160 - 3 Dec 2018

Cited by 77 | Viewed by 9502

Abstract

Metabolism is the sum of the life-giving chemical processes that occur within a cell. Proper regulation of these processes is essential for all organisms to thrive and prosper. When external factors are too extreme, or if internal regulation is corrupted through genetic or [...] Read more.

Metabolism is the sum of the life-giving chemical processes that occur within a cell. Proper regulation of these processes is essential for all organisms to thrive and prosper. When external factors are too extreme, or if internal regulation is corrupted through genetic or epigenetic changes, metabolic homeostasis is no longer achievable and diseases such as metabolic syndrome or cancer, aging, and, ultimately, death ensue. Metabolic reactions are catalyzed by proteins, and the in vitro kinetic properties of these enzymes have been studied by biochemists for many decades. These efforts led to the appreciation that enzyme activities can be acutely regulated and that this regulation is critical to metabolic homeostasis. Regulation can be mediated through allosteric interactions with metabolites themselves or via post-translational modifications triggered by intracellular signal transduction pathways. More recently, enzyme regulation has attracted the attention of cell biologists who noticed that change in growth conditions often triggers the condensation of diffusely localized enzymes into one or more discrete foci, easily visible by light microscopy. This reorganization from a soluble to a condensed state is best described as a phase separation. As summarized in this review, stimulus-induced phase separation has now been observed for dozens of enzymes suggesting that this could represent a widespread mode of activity regulation, rather than, or in addition to, a storage form of temporarily superfluous enzymes. Building on our recent structure determination of TOROIDs (TORc1 Organized in Inhibited Domain), the condensate formed by the protein kinase Target Of Rapamycin Complex 1 (TORC1), we will highlight that the molecular organization of enzyme condensates can vary dramatically and that future work aimed at the structural characterization of enzyme condensates will be critical to understand how phase separation regulates enzyme activity and consequently metabolic homeostasis. This information may ultimately facilitate the design of strategies to target the assembly or disassembly of specific enzymes condensates as a therapeutic approach to restore metabolic homeostasis in certain diseases. Full article

(This article belongs to the Special Issue TOR Signaling Pathway)

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19 pages, 1683 KiB

Open AccessReview

Overview of Bile Acids Signaling and Perspective on the Signal of Ursodeoxycholic Acid, the Most Hydrophilic Bile Acid, in the Heart

by Noorul Izzati Hanafi¹

, Anis Syamimi Mohamed¹, Siti Hamimah Sheikh Abdul Kadir^1,2,*

and Mohd Hafiz Dzarfan Othman³

¹ Institute of Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia

² Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia

³ Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, Johor Bharu 81310, Johor, Malaysia

Biomolecules 2018, 8(4), 159; https://doi.org/10.3390/biom8040159 - 27 Nov 2018

Cited by 98 | Viewed by 12809

Abstract

Bile acids (BA) are classically known as an important agent in lipid absorption and cholesterol metabolism. Nowadays, their role in glucose regulation and energy homeostasis are widely reported. BAs are involved in various cellular signaling pathways, such as protein kinase cascades, cyclic AMP [...] Read more.

Bile acids (BA) are classically known as an important agent in lipid absorption and cholesterol metabolism. Nowadays, their role in glucose regulation and energy homeostasis are widely reported. BAs are involved in various cellular signaling pathways, such as protein kinase cascades, cyclic AMP (cAMP) synthesis, and calcium mobilization. They are ligands for several nuclear hormone receptors, including farnesoid X-receptor (FXR). Recently, BAs have been shown to bind to muscarinic receptor and Takeda G-protein-coupled receptor 5 (TGR5), both G-protein-coupled receptor (GPCR), independent of the nuclear hormone receptors. Moreover, BA signals have also been elucidated in other nonclassical BA pathways, such as sphingosine-1-posphate and BK (large conductance calcium- and voltage activated potassium) channels. Hydrophobic BAs have been proven to affect heart rate and its contraction. Elevated BAs are associated with arrhythmias in adults and fetal heart, and altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile, in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase in serum bile acid concentrations. In contrast, the most hydrophilic BA, known as ursodeoxycholic acid (UDCA), has been found to be beneficial in improving peripheral blood flow in chronic heart failure patients and in protecting the heart against reperfusion injury. This review provides an overview of BA signaling, with the main emphasis on past and present perspectives on UDCA signals in the heart. Full article

(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)

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15 pages, 584 KiB

Open AccessArticle

Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species

by Ludwig Lausser^1,†, Lea Siegle^1,†

, Wolfgang Rottbauer², Derk Frank^3,4,‡, Steffen Just^2,‡ and Hans A. Kestler^1,*,‡

¹ Institute of Medical Systems Biology, Ulm University, 89069 Ulm, Germany

² Department of Internal Medicine II, Ulm University, 89081 Ulm, Germany

³ Department of Internal Medicine III (Cardiology and Angiology) UKSH, Campus Kiel, 24105 Kiel, Germany

⁴ DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany

^† These authors contributed equally to this work.

^‡ These authors are joint senior authors of this work.

Biomolecules 2018, 8(4), 158; https://doi.org/10.3390/biom8040158 - 26 Nov 2018

Cited by 1 | Viewed by 5598

Abstract

Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract [...] Read more.

Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract but precise high-level characterization of experimental findings. In this work, we provide a large-scale analysis of seven weak contractility/heart failure genotypes of the model organism zebrafish which all share a weak contractility phenotype. In supervised classification experiments, we screen for discriminative patterns that distinguish between observable phenotypes (homozygous mutant individuals) as well as wild-type (homozygous wild-types) and carriers (heterozygous individuals). As the method of choice we use semantic multi-classifier systems, a knowledge-based approach which constructs hypotheses from a predefined vocabulary of high-level terms (e.g., Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or Gene Ontology (GO) terms). Evaluating these models leads to a compact description of the underlying processes and guides the screening for new molecular markers of heart failure. Furthermore, we were able to independently corroborate the identified processes in Wistar rats. Full article

(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)

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16 pages, 613 KiB

Open AccessReview

Myosins in Osteoclast Formation and Function

by Beth S. Lee

Department of Physiology and Cell Biology, The Ohio State University College of Medicine, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA

Biomolecules 2018, 8(4), 157; https://doi.org/10.3390/biom8040157 - 22 Nov 2018

Cited by 27 | Viewed by 6140

Abstract

Skeletal quantity and quality are determined by processes of bone modeling and remodeling, which are undertaken by cells that build and resorb bone as they respond to mechanical, hormonal, and other external and internal signals. As the sole bone resorptive cell type, osteoclasts [...] Read more.

Skeletal quantity and quality are determined by processes of bone modeling and remodeling, which are undertaken by cells that build and resorb bone as they respond to mechanical, hormonal, and other external and internal signals. As the sole bone resorptive cell type, osteoclasts possess a remarkably dynamic actin cytoskeleton that drives their function in this enterprise. Actin rearrangements guide osteoclasts’ capacity for precursor fusion during differentiation, for migration across bone surfaces and sensing of their composition, and for generation of unique actin superstructures required for the resorptive process. In this regard, it is not surprising that myosins, the superfamily of actin-based motor proteins, play key roles in osteoclast physiology. This review briefly summarizes current knowledge of the osteoclast actin cytoskeleton and describes myosins’ roles in osteoclast differentiation, migration, and actin superstructure patterning. Full article

(This article belongs to the Special Issue Key Biomolecules in Bone Resorption)

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6 pages, 1108 KiB

Open AccessFeature PaperArticle

Distribution of Glycerophospholipids in the Adult Human Lens

by Jo Ann Seng¹, Jessica R. Nealon^2,3, Stephen J. Blanksby⁴ and Todd W. Mitchell^2,3,*

¹ School of Chemistry, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia

² School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia

³ Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia

⁴ Central Analytical Research Facility, Institute for Future Environments, Queensland University of Technology, Brisbane, QLD 4000, Australia

Biomolecules 2018, 8(4), 156; https://doi.org/10.3390/biom8040156 - 22 Nov 2018

Cited by 7 | Viewed by 3717

Abstract

In humans, the age of fibre cells differs across the ocular lens, ranging from those formed before birth in the core of the lens to those formed just prior to death in the outer cortex. The distribution of glycerophospholipids in the adult human [...] Read more.

In humans, the age of fibre cells differs across the ocular lens, ranging from those formed before birth in the core of the lens to those formed just prior to death in the outer cortex. The distribution of glycerophospholipids in the adult human lens should reflect this range; however, limited data currently exists to confirm this hypothesis. Accordingly, this study aimed to determine the distribution of glycerophospholipids in adult human lens using mass spectrometry imaging. To achieve this, 20-µm thick slices of two human lenses, aged 51 and 67 were analysed by matrix-assisted laser desorption ionisation imaging mass spectrometry. The data clearly indicate that intact glycerophospholipids such as phosphatidylethanolamine, phosphatidylserine, and phosphatidic acid are mainly present in the outer cortex region, corresponding to the youngest fibre cells, while lyso-phosphatidylethanolamine, likely produced by the degradation of phosphatidylethanolamine, is present in the nucleus (older fibre cells). This study adds further evidence to the relationship between fibre cell age and glycerophospholipid composition. Full article

(This article belongs to the Special Issue Lipidomics)

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23 pages, 4061 KiB

Open AccessArticle

The Effect of Edible Chitosan Coatings Incorporated with Thymus capitatus Essential Oil on the Shelf-Life of Strawberry (Fragaria x ananassa) during Cold Storage

by Keydis Martínez¹, Marta Ortiz¹, Alberto Albis¹

, Clara Gilma Gutiérrez Castañeda², Mayra Eliana Valencia³

and Carlos David Grande Tovar^4,*

¹ Programa de Ingeniería Química, Facultad de Ingeniería, Universidad del Atlántico, Carrera 30 Número 8-49, Puerto Colombia 081008, Colombia

² Programa de Microbiología, Facultad de Ciencias Exactas y Naturales, Universidad Libre seccional Barranquilla, km. 7 vía a, Puerto Colombia 081008, Colombia

³ Escuela de Ingeniería de Materiales, Facultad de Ingeniería, Universidad del Valle, Calle 13 Número 100-00, Santiago de Cali 760032, Colombia

⁴ Programa de Química, Facultad de Ciencias, Universidad del Atlántico, Carrera 30 Número 8-49, Puerto Colombia 081008, Colombia

Biomolecules 2018, 8(4), 155; https://doi.org/10.3390/biom8040155 - 21 Nov 2018

Cited by 116 | Viewed by 8452

Abstract

The strawberry is a fruit appreciated in the food industry for its high content of bioactive compounds. However, it is considered a highly perishable fruit, generally attacked by pests of phytopathogenic origin, which decreases its shelf-life. Normally, to diminish the losses caused by [...] Read more.

The strawberry is a fruit appreciated in the food industry for its high content of bioactive compounds. However, it is considered a highly perishable fruit, generally attacked by pests of phytopathogenic origin, which decreases its shelf-life. Normally, to diminish the losses caused by pathogenic microbes, coatings of polysaccharides in combination with natural products like essential oils are applied. In this work, we describe the effect of edible coatings from chitosan (CT) incorporating Thymus capitatus essential oil (TCEO), applied to strawberries stored under refrigeration conditions (5 ± 0.5 °C). Different concentrations of TCEO were applied to chitosan coatings, with different effects on the physical and microbiological properties of the strawberries. All the products had greater acceptance and quality than the controls, being more effective those with essential oil incorporation. It is noteworthy that all the essential oil treatments lead to an increase in the shelf-life of strawberries of up to 15 days. Scanning electron microscopy (SEM) analysis of the microstructure showed a decrease in compactness with TCEO introduction, but without compromising food preservation after 15 days. In addition, treated strawberries delayed the loss of physicochemical and antioxidant properties, due to protection against the microbial development of aerobic mesophylls, molds, and yeasts. Full article

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12 pages, 975 KiB

Open AccessArticle

Squalene Found in Alpine Grassland Soils under a Harsh Environment in the Tibetan Plateau, China

by Xuyang Lu^1,2, Shuqin Ma^3,*, Youchao Chen⁴, Degyi Yangzom⁵ and Hongmao Jiang^1,6

¹ Institute of Mountain Hazards and Environment, Chinese Academy of Sciences, Chengdu 610041, China

² Key Laboratory of Mountain Surface Processes and Ecological Regulation, Chinese Academy of Sciences, Chengdu 610041, China

³ College of Tourism, Henan Normal University, Xinxiang 453007, China

⁴ Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan 430074, China

⁵ Ecological Monitoring & Research Center, Tibetan Environment Monitoring Station, Lhasa 850000, China

⁶ University of Chinese Academy of Sciences, Beijing 100049, China

Biomolecules 2018, 8(4), 154; https://doi.org/10.3390/biom8040154 - 20 Nov 2018

Cited by 15 | Viewed by 4454

Abstract

Squalene is found in a large number of plants, animals, and microorganisms, as well as other sources, playing an important role as an intermediate in sterol biosynthesis. It is used widely in the food, cosmetics, and medicine industries because of its antioxidant, antistatic, [...] Read more.

Squalene is found in a large number of plants, animals, and microorganisms, as well as other sources, playing an important role as an intermediate in sterol biosynthesis. It is used widely in the food, cosmetics, and medicine industries because of its antioxidant, antistatic, and anti-carcinogenic properties. A higher natural squalene component of lipids is usually reported as being isolated to organisms living in harsh environments. In the Tibetan Plateau, which is characterized by high altitude, strong solar radiation, drought, low temperatures, and thin air, the squalene component was identified in five alpine grasslands soils using the pyrolysis gas chromatography–mass spectrometry (Py-GC/MS) technique. The relative abundance of squalene ranged from 0.93% to 10.66% in soils from the five alpine grasslands, with the highest value found in alpine desert and the lowest in alpine meadow. Furthermore, the relative abundance of squalene in alpine grassland soils was significantly negatively associated with soil chemical/microbial characteristics. These results indicate that the extreme environmental conditions of the Tibetan Plateau may stimulate the microbial biosynthesis of squalene, and the harsher the environment, the higher the relative abundance of soil squalene. Full article

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

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12 pages, 1909 KiB

Open AccessArticle

Therapeutic Chemical Screen Identifies Phosphatase Inhibitors to Reconstitute PKB Phosphorylation and Cardiac Contractility in ILK-Deficient Zebrafish

by Alexander Pott^1,†

, Maryam Shahid^1,†, Doreen Köhler², Christian Pylatiuk³, Karolina Weinmann¹, Steffen Just^1,*,‡ and Wolfgang Rottbauer^1,*,‡

¹ Department of Internal Medicine II, Ulm University, Albert-Einstein-Allee 23, D-89081 Ulm, Germany

² Department of Internal Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany

³ Institute of Applied Computer Science, Karlsruhe Institute of Technology, D-76344 Eggenstein-Leopoldshafen, Germany

^† These authors contributed equally to this work.

^‡ These authors contributed equally to this work.

Biomolecules 2018, 8(4), 153; https://doi.org/10.3390/biom8040153 - 19 Nov 2018

Cited by 11 | Viewed by 6052

Abstract

Patients with inherited dilated cardiomyopathy (DCM) often suffer from severe heart failure based on impaired cardiac contractility leading to increased morbidity and mortality. Integrin-linked kinase (ILK) as a part of the cardiac mechanical stretch sensor was found to be an essential genetic regulator [...] Read more.

Patients with inherited dilated cardiomyopathy (DCM) often suffer from severe heart failure based on impaired cardiac contractility leading to increased morbidity and mortality. Integrin-linked kinase (ILK) as a part of the cardiac mechanical stretch sensor was found to be an essential genetic regulator of cardiac contractility. Integrin-linked kinase localizes to z-disks and costameres in vertebrate hearts and regulates the activity of the signaling molecule protein kinase B (PKB/Akt) by controlling its phosphorylation. Despite identification of several potential drug targets in the ILK signaling pathway, pharmacological treatment strategies to restore contractile function in ILK-dependent cardiomyopathies have not been established yet. In recent years, the zebrafish has emerged as a valuable experimental system to model human cardiomyopathies as well as a powerful tool for the straightforward high-throughput in vivo small compound screening of therapeutically active substances. Using the ILK deficient zebrafish heart failure mutant main squeeze (msq), which shows reduced PKB phosphorylation and thereby impaired cardiac contractile force, we identified here, in an automated small compound screen, the protein phosphatase inhibitors calyculin A and okadaic acid significantly restoring myocardial contractile function by reconstituting PKB phosphorylation in msq ILK-deficient zebrafish embryos. Full article

(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)

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