Biomolecules

Review

27 pages, 2320 KiB

Open AccessEditor’s ChoiceReview

Fluctuations of Histone Chemical Modifications in Breast, Prostate, and Colorectal Cancer: An Implication of Phytochemicals as Defenders of Chromatin Equilibrium

by Marek Samec, Alena Liskova, Lenka Koklesova, Veronika Mestanova, Maria Franekova, Monika Kassayova, Bianka Bojkova, Sona Uramova, Pavol Zubor, Katarina Janikova, Jan Danko, Samson Mathews Samuel, Dietrich Büsselberg and Peter Kubatka

Biomolecules 2019, 9(12), 829; https://doi.org/10.3390/biom9120829 - 5 Dec 2019

Cited by 20 | Viewed by 6003

Abstract

Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell’s epigenome. The potential antineoplastic activity of plant natural substances mediated [...] Read more.

Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell’s epigenome. The potential antineoplastic activity of plant natural substances mediated by their action on posttranslational histone modifications (PHMs) is currently a highly evaluated area of cancer research. PHMs play an important role in maintaining chromatin structure and regulating gene expression. Aberrations in PHMs are directly linked to the process of carcinogenesis in cancer such as breast (BC), prostate (PC), and colorectal (CRC) cancer, common malignant diseases in terms of incidence and mortality among both men and women. This review summarizes the effects of plant phytochemicals (isolated or mixtures) on cancer-associated PHMs (mainly modulation of acetylation and methylation) resulting in alterations of chromatin structure that are related to the regulation of transcription activity of specific oncogenes, which are crucial in the development of BC, PC, and CRC. Significant effectiveness of natural compounds in the modulation of aberrant PHMs were confirmed by a number of in vitro or in vivo studies in preclinical cancer research. However, evidence concerning PHMs-modulating abilities of plant-based natural substances in clinical trials is insufficient. 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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35 pages, 6586 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Actual and Potential Aroma of Winemaking Grapes

by Vicente Ferreira and Ricardo Lopez

Biomolecules 2019, 9(12), 818; https://doi.org/10.3390/biom9120818 - 3 Dec 2019

Cited by 95 | Viewed by 8831

Abstract

This review intends to rationalize the knowledge related to the aroma of grapes and to the aroma of wine with specific origin in molecules formed in grapes. The actual flavor of grapes is formed by the few free aroma molecules already found in [...] Read more.

This review intends to rationalize the knowledge related to the aroma of grapes and to the aroma of wine with specific origin in molecules formed in grapes. The actual flavor of grapes is formed by the few free aroma molecules already found in the pulp and in the skin, plus by those aroma molecules quickly formed by enzymatic/catalytic reactions. The review covers key aroma components of aromatic grapes, raisins and raisinized grapes, and the aroma components responsible from green and vegetal notes. This knowledge is used to explain the flavor properties of neutral grapes. The aroma potential of grape is the consequence of five different systems/pools of specific aroma precursors that during fermentation and/or aging, release wine varietal aroma. In total, 27 relevant wine aroma compounds can be considered that proceed from grape specific precursors. Some of them are immediately formed during fermentation, while some others require long aging time to accumulate. Precursors are glycosides, glutathionyl and cysteinyl conjugates, and other non-volatile molecules. Full article

(This article belongs to the Special Issue Biochemistry of Wine and Beer)

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24 pages, 3892 KiB

Open AccessEditor’s ChoiceReview

Biomaterials for In Situ Tissue Regeneration: A Review

by Saba Abdulghani and Geoffrey R. Mitchell

Biomolecules 2019, 9(11), 750; https://doi.org/10.3390/biom9110750 - 19 Nov 2019

Cited by 148 | Viewed by 13171

Abstract

This review focuses on a somewhat unexplored strand of regenerative medicine, that is in situ tissue engineering. In this approach manufactured scaffolds are implanted in the injured region for regeneration within the patient. The scaffold is designed to attract cells to the required [...] Read more.

This review focuses on a somewhat unexplored strand of regenerative medicine, that is in situ tissue engineering. In this approach manufactured scaffolds are implanted in the injured region for regeneration within the patient. The scaffold is designed to attract cells to the required volume of regeneration to subsequently proliferate, differentiate, and as a consequence develop tissue within the scaffold which in time will degrade leaving just the regenerated tissue. This review highlights the wealth of information available from studies of ex-situ tissue engineering about the selection of materials for scaffolds. It is clear that there are great opportunities for the use of additive manufacturing to prepare complex personalized scaffolds and we speculate that by building on this knowledge and technology, the development of in situ tissue engineering could rapidly increase. Ex-situ tissue engineering is handicapped by the need to develop the tissue in a bioreactor where the conditions, however optimized, may not be optimum for accelerated growth and maintenance of the cell function. We identify that in both methodologies the prospect of tissue regeneration has created much promise but delivered little outside the scope of laboratory-based experiments. We propose that the design of the scaffolds and the materials selected remain at the heart of developments in this field and there is a clear need for predictive modelling which can be used in the design and optimization of materials and scaffolds. Full article

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

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18 pages, 1971 KiB

Open AccessFeature PaperEditor’s ChoiceReview

A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment

by Linh Khanh Huynh, Christopher John Hipolito and Peter ten Dijke

Biomolecules 2019, 9(11), 743; https://doi.org/10.3390/biom9110743 - 17 Nov 2019

Cited by 130 | Viewed by 12418

Abstract

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages [...] Read more.

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-β can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-β in cancer cells are blocked, TGF-β signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-β signaling in cancer and summarize the clinical status of TGF-β signaling inhibitors that interfere with TGF−β bioavailability, TGF-β/receptor interaction, or TGF-β receptor kinase function. Moreover, we will discuss targeting of TGF-β signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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26 pages, 2934 KiB

Open AccessEditor’s ChoiceReview

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements

by Vaishali Aggarwal, Hardeep Singh Tuli, Ayşegül Varol, Falak Thakral, Mukerrem Betul Yerer, Katrin Sak, Mehmet Varol, Aklank Jain, Md. Asaduzzaman Khan and Gautam Sethi

Biomolecules 2019, 9(11), 735; https://doi.org/10.3390/biom9110735 - 13 Nov 2019

Cited by 776 | Viewed by 21087

Abstract

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor [...] Read more.

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies. Full article

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

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14 pages, 1265 KiB

Open AccessEditor’s ChoiceReview

Algae: Critical Sources of Very Long-Chain Polyunsaturated Fatty Acids

by John L. Harwood

Biomolecules 2019, 9(11), 708; https://doi.org/10.3390/biom9110708 - 6 Nov 2019

Cited by 103 | Viewed by 10669

Abstract

Polyunsaturated fatty acids (PUFAs), which are divided into n-3 and n-6 classes, are essential for good health in humans and many animals. They are metabolised to lipid mediators, such as eicosanoids, resolvins and protectins. Increasing interest has been paid to the 20 or [...] Read more.

Polyunsaturated fatty acids (PUFAs), which are divided into n-3 and n-6 classes, are essential for good health in humans and many animals. They are metabolised to lipid mediators, such as eicosanoids, resolvins and protectins. Increasing interest has been paid to the 20 or 22 carbon very long chain PUFAs, since these compounds can be used to form lipid mediators and, thus, avoid inefficient formation of dietary plant PUFAs. The ultimate sources of very long chain PUFAs are algae, which are consumed by fish and then by humans. In this review, I describe the biosynthesis of very long chain PUFAs by algae and how this synthesis can be manipulated for commercial purposes. Ultimately, the production of algal oils is critical for ecosystems worldwide, as well as for human dietary lipids. Full article

(This article belongs to the Special Issue Lipids of Marine Algae)

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17 pages, 1223 KiB

Open AccessEditor’s ChoiceReview

Cell Fate Control by Translation: mRNA Translation Initiation as a Therapeutic Target for Cancer Development and Stem Cell Fate Control

by Hyun-Jung Kim

Biomolecules 2019, 9(11), 665; https://doi.org/10.3390/biom9110665 - 29 Oct 2019

Cited by 14 | Viewed by 7996

Abstract

Translation of mRNA is an important process that controls cell behavior and gene regulation because proteins are the functional molecules that determine cell types and function. Cancer develops as a result of genetic mutations, which lead to the production of abnormal proteins and [...] Read more.

Translation of mRNA is an important process that controls cell behavior and gene regulation because proteins are the functional molecules that determine cell types and function. Cancer develops as a result of genetic mutations, which lead to the production of abnormal proteins and the dysregulation of translation, which in turn, leads to aberrant protein synthesis. In addition, the machinery that is involved in protein synthesis plays critical roles in stem cell fate determination. In the current review, recent advances in the understanding of translational control, especially translational initiation in cancer development and stem cell fate control, are described. Therapeutic targets of mRNA translation such as eIF4E, 4EBP, and eIF2, for cancer treatment or stem cell fate regulation are reviewed. Upstream signaling pathways that regulate and affect translation initiation were introduced. It is important to regulate the expression of protein for normal cell behavior and development. mRNA translation initiation is a key step to regulate protein synthesis, therefore, identifying and targeting molecules that are critical for protein synthesis is necessary and beneficial to develop cancer therapeutics and stem cells fate regulation. Full article

(This article belongs to the Special Issue New Insights on Translational Machinery in Protein Synthesis and Beyond)

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20 pages, 3272 KiB

Open AccessEditor’s ChoiceReview

The Roles of Notch Signaling in Liver Development and Disease

by Joshua M. Adams and Hamed Jafar-Nejad

Biomolecules 2019, 9(10), 608; https://doi.org/10.3390/biom9100608 - 14 Oct 2019

Cited by 62 | Viewed by 8009

Abstract

The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch [...] Read more.

The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch activity in proper liver development and function. Specifically, we discuss the latest discoveries on how Notch, in conjunction with other signaling pathways, aids in proper liver development, regeneration and repair. In addition, we review the latest in the role of Notch signaling in the pathogenesis of liver fibrosis and chronic liver disease. Finally, recent evidence has shed light on the emerging connection between Notch signaling and glucose and lipid metabolism. We hope that highlighting the major advances in the roles of Notch signaling in the liver will stimulate further research in this exciting field and generate additional ideas for therapeutic manipulation of the Notch pathway in liver 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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21 pages, 3200 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles of Lysyl Oxidases in the Cardiovascular System: New Concepts and Therapeutic Challenges

by José Martínez-González, Saray Varona, Laia Cañes, María Galán, Ana M Briones, Victoria Cachofeiro and Cristina Rodríguez

Biomolecules 2019, 9(10), 610; https://doi.org/10.3390/biom9100610 - 14 Oct 2019

Cited by 38 | Viewed by 6552

Abstract

Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. [...] Read more.

Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. Besides this structural role, in the last years, novel biological properties have been attributed to these enzymes, which can critically influence cardiovascular function. LOX and LOXLs control cell proliferation, migration, adhesion, differentiation, oxidative stress, and transcriptional regulation and, thereby, their dysregulation has been linked to a myriad of cardiovascular pathologies. Lysyl oxidase could modulate virtually all stages of the atherosclerotic process, from endothelial dysfunction and plaque progression to calcification and rupture of advanced and complicated plaques, and contributes to vascular stiffness in hypertension. The alteration of LOX/LOXLs expression underlies the development of other vascular pathologies characterized by a destructive remodeling of the ECM, such as aneurysm and artery dissections, and contributes to the adverse myocardial remodeling and dysfunction in hypertension, myocardial infarction, and obesity. This review examines the most recent advances in the study of LOX and LOXLs biology and their pathophysiological role in cardiovascular diseases with special emphasis on their potential as therapeutic targets. Full article

(This article belongs to the Special Issue Lysyl Oxidases: Novel Roles in Disease and Therapeutic Opportunities)

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28 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

Function, Regulation and Biological Roles of PI3Kγ Variants

by Bernd Nürnberg and Sandra Beer-Hammer

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

Cited by 29 | Viewed by 5224

Abstract

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

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

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

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26 pages, 2247 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 15 | Viewed by 6176

Abstract

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

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

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

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16 pages, 965 KiB

Open AccessEditor’s ChoiceReview

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

by Eric D. Salomaki and Martin Kolisko

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

Cited by 19 | Viewed by 6464

Abstract

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

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

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

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30 pages, 5117 KiB

Open AccessEditor’s ChoiceReview

Tannins: Prospectives and Actual Industrial Applications

by Antonio Pizzi

Biomolecules 2019, 9(8), 344; https://doi.org/10.3390/biom9080344 - 5 Aug 2019

Cited by 183 | Viewed by 12614

Abstract

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

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

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

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18 pages, 1060 KiB

Open AccessEditor’s ChoiceReview

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

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

Biomolecules 2019, 9(8), 331; https://doi.org/10.3390/biom9080331 - 1 Aug 2019

Cited by 9 | Viewed by 5127

Abstract

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

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

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

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22 pages, 8183 KiB

Open AccessEditor’s ChoiceReview

Metabolic Innovations Underpinning the Origin and Diversification of the Diatom Chloroplast

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

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

Cited by 27 | Viewed by 7048

Abstract

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

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

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

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25 pages, 1185 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 35 | Viewed by 8855

Abstract

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

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

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

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14 pages, 1151 KiB

Open AccessEditor’s ChoiceReview

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

by Sumeyye Cavdarli, Sophie Groux-Degroote and Philippe Delannoy

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

Cited by 50 | Viewed by 7059

Abstract

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

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

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

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23 pages, 2555 KiB

Open AccessEditor’s ChoiceReview

Flagella-Driven Motility of Bacteria

by Shuichi Nakamura and Tohru Minamino

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

Cited by 197 | Viewed by 24201

Abstract

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

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

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

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54 pages, 1623 KiB

Open AccessEditor’s ChoiceReview

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

by Marianna Tosato and Valerio Di Marco

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

Cited by 46 | Viewed by 8789

Abstract

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

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

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

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20 pages, 2390 KiB

Open AccessEditor’s ChoiceReview

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

by Pavel Pospíšil, Ankush Prasad and Marek Rác

Biomolecules 2019, 9(7), 258; https://doi.org/10.3390/biom9070258 - 5 Jul 2019

Cited by 69 | Viewed by 7461

Abstract

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

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

(This article belongs to the Section Cellular Biochemistry)

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17 pages, 1455 KiB

Open AccessEditor’s ChoiceReview

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

by Sviatlana Smolskaya and Yaroslav A. Andreev

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

Cited by 58 | Viewed by 9544

Abstract

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

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

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

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13 pages, 1202 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Hunt for Degrons of the 26S Proteasome

by Hadar Ella, Yuval Reiss and Tommer Ravid

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

Cited by 18 | Viewed by 5960

Abstract

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

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

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

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23 pages, 2750 KiB

Open AccessEditor’s ChoiceReview

Albumin Nanovectors in Cancer Therapy and Imaging

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

Biomolecules 2019, 9(6), 218; https://doi.org/10.3390/biom9060218 - 5 Jun 2019

Cited by 89 | Viewed by 8173

Abstract

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

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

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

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16 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

The Contribution of the 20S Proteasome to Proteostasis

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

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

Cited by 94 | Viewed by 12079

Abstract

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

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

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

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12 pages, 890 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 66 | Viewed by 6919

Abstract

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

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

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

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18 pages, 21619 KiB

Open AccessEditor’s ChoiceReview

HIV Vaccine Mystery and Viral Shell Disorder

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

Biomolecules 2019, 9(5), 178; https://doi.org/10.3390/biom9050178 - 8 May 2019

Cited by 38 | Viewed by 8184

Abstract

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

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

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

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22 pages, 2126 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins

by Supriyo Bhattacharya and Xingcheng Lin

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

Cited by 50 | Viewed by 7861

Abstract

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

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

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

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48 pages, 5225 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 21 | Viewed by 7530

Abstract

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

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

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

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32 pages, 827 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 42 | Viewed by 10779

Abstract

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

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

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

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35 pages, 8296 KiB

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Structural Determinants of Isoform Selectivity in PI3K Inhibitors

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

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

Cited by 54 | Viewed by 8845

Abstract

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

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

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

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54 pages, 30011 KiB

Open AccessEditor’s ChoiceReview

Phosphatases in Mitosis: Roles and Regulation

by Margarida Moura and Carlos Conde

Biomolecules 2019, 9(2), 55; https://doi.org/10.3390/biom9020055 - 7 Feb 2019

Cited by 54 | Viewed by 11889

Abstract

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

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

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

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20 pages, 2429 KiB

Open AccessEditor’s ChoiceReview

The Many Faces of FKBP51

by Andreas Hähle, Stephanie Merz, Christian Meyners and Felix Hausch

Biomolecules 2019, 9(1), 35; https://doi.org/10.3390/biom9010035 - 21 Jan 2019

Cited by 75 | Viewed by 10674

Abstract

The FK506-binding protein 51 (FKBP51) has emerged as a key regulator of endocrine stress responses in mammals and as a potential therapeutic target for stress-related disorders (depression, post-traumatic stress disorder), metabolic disorders (obesity and diabetes) and chronic pain. Recently, FKBP51 has been implicated [...] Read more.

The FK506-binding protein 51 (FKBP51) has emerged as a key regulator of endocrine stress responses in mammals and as a potential therapeutic target for stress-related disorders (depression, post-traumatic stress disorder), metabolic disorders (obesity and diabetes) and chronic pain. Recently, FKBP51 has been implicated in several cellular pathways and numerous interacting protein partners have been reported. However, no consensus on the underlying molecular mechanisms has yet emerged. Here, we review the protein interaction partners reported for FKBP51, the proposed pathways involved, their relevance to FKBP51’s physiological function(s), the interplay with other FKBPs, and implications for the development of FKBP51-directed drugs. 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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19 pages, 3111 KiB

Open AccessEditor’s ChoiceReview

Bio-Molecular Applications of Recent Developments in Optical Tweezers

by Dhawal Choudhary, Alessandro Mossa, Milind Jadhav and Ciro Cecconi

Biomolecules 2019, 9(1), 23; https://doi.org/10.3390/biom9010023 - 11 Jan 2019

Cited by 61 | Viewed by 9529

Abstract

In the past three decades, the ability to optically manipulate biomolecules has spurred a new era of medical and biophysical research. Optical tweezers (OT) have enabled experimenters to trap, sort, and probe cells, as well as discern the structural dynamics of proteins and [...] Read more.

In the past three decades, the ability to optically manipulate biomolecules has spurred a new era of medical and biophysical research. Optical tweezers (OT) have enabled experimenters to trap, sort, and probe cells, as well as discern the structural dynamics of proteins and nucleic acids at single molecule level. The steady improvement in OT’s resolving power has progressively pushed the envelope of their applications; there are, however, some inherent limitations that are prompting researchers to look for alternatives to the conventional techniques. To begin with, OT are restricted by their one-dimensional approach, which makes it difficult to conjure an exhaustive three-dimensional picture of biological systems. The high-intensity trapping laser can damage biological samples, a fact that restricts the feasibility of in vivo applications. Finally, direct manipulation of biological matter at nanometer scale remains a significant challenge for conventional OT. A significant amount of literature has been dedicated in the last 10 years to address the aforementioned shortcomings. Innovations in laser technology and advances in various other spheres of applied physics have been capitalized upon to evolve the next generation OT systems. In this review, we elucidate a few of these developments, with particular focus on their biological applications. The manipulation of nanoscopic objects has been achieved by means of plasmonic optical tweezers (POT), which utilize localized surface plasmons to generate optical traps with enhanced trapping potential, and photonic crystal optical tweezers (PhC OT), which attain the same goal by employing different photonic crystal geometries. Femtosecond optical tweezers (fs OT), constructed by replacing the continuous wave (cw) laser source with a femtosecond laser, promise to greatly reduce the damage to living samples. Finally, one way to transcend the one-dimensional nature of the data gained by OT is to couple them to the other large family of single molecule tools, i.e., fluorescence-based imaging techniques. We discuss the distinct advantages of the aforementioned techniques as well as the alternative experimental perspective they provide in comparison to conventional OT. Full article

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

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24 pages, 4138 KiB

Open AccessEditor’s ChoiceReview

Combination of Cell-Penetrating Peptides with Nanoparticles for Therapeutic Application: A Review

by Sara Silva, António J. Almeida and Nuno Vale

Biomolecules 2019, 9(1), 22; https://doi.org/10.3390/biom9010022 - 10 Jan 2019

Cited by 173 | Viewed by 14294

Abstract

Cell-penetrating peptides (CPPs), also known as protein translocation domains, membrane translocating sequences or Trojan peptides, are small molecules of 6 to 30 amino acid residues capable of penetrating biological barriers and cellular membranes. Furthermore, CPP have become an alternative strategy to overcome some [...] Read more.

Cell-penetrating peptides (CPPs), also known as protein translocation domains, membrane translocating sequences or Trojan peptides, are small molecules of 6 to 30 amino acid residues capable of penetrating biological barriers and cellular membranes. Furthermore, CPP have become an alternative strategy to overcome some of the current drug limitations and combat resistant strains since CPPs are capable of delivering different therapeutic molecules against a wide range of diseases. In this review, we address the recent conjugation of CPPs with nanoparticles, which constitutes a new class of delivery vectors with high pharmaceutical potential in a variety of diseases. Full article

(This article belongs to the Special Issue Multidrug Combinations)

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26 pages, 9208 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Structural and Functional Insights into Human Nuclear Cyclophilins

by Caroline Rajiv and Tara L. Davis

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

Cited by 30 | Viewed by 7188

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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15 pages, 1340 KiB

Open AccessEditor’s ChoiceReview

Single Molecule FRET: A Powerful Tool to Study Intrinsically Disordered Proteins

by Sharonda J. LeBlanc, Prakash Kulkarni and Keith R. Weninger

Biomolecules 2018, 8(4), 140; https://doi.org/10.3390/biom8040140 - 8 Nov 2018

Cited by 46 | Viewed by 7422

Abstract

Intrinsically disordered proteins (IDPs) are often modeled using ideas from polymer physics that suggest they smoothly explore all corners of configuration space. Experimental verification of this random, dynamic behavior is difficult as random fluctuations of IDPs cannot be synchronized across an ensemble. Single [...] Read more.

Intrinsically disordered proteins (IDPs) are often modeled using ideas from polymer physics that suggest they smoothly explore all corners of configuration space. Experimental verification of this random, dynamic behavior is difficult as random fluctuations of IDPs cannot be synchronized across an ensemble. Single molecule fluorescence (or Förster) resonance energy transfer (smFRET) is one of the few approaches that are sensitive to transient populations of sub-states within molecular ensembles. In some implementations, smFRET has sufficient time resolution to resolve transitions in IDP behaviors. Here we present experimental issues to consider when applying smFRET to study IDP configuration. We illustrate the power of applying smFRET to IDPs by discussing two cases in the literature of protein systems for which smFRET has successfully reported phosphorylation-induced modification (but not elimination) of the disordered properties that have been connected to impacts on the related biological function. The examples we discuss, PAGE4 and a disordered segment of the GluN2B subunit of the NMDA receptor, illustrate the great potential of smFRET to inform how IDP function can be regulated by controlling the detailed ensemble of disordered states within biological networks. Full article

(This article belongs to the Collection Intrinsically Disordered Proteins)

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11 pages, 646 KiB

Open AccessEditor’s ChoiceReview

Antioxidants: Positive or Negative Actors?

by Bahare Salehi, Miquel Martorell, Jack L. Arbiser, Antoni Sureda, Natália Martins, Pawan Kumar Maurya, Mehdi Sharifi-Rad, Pradeep Kumar and Javad Sharifi-Rad

Biomolecules 2018, 8(4), 124; https://doi.org/10.3390/biom8040124 (registering DOI) - 25 Oct 2018

Cited by 151 | Viewed by 12373

Abstract

The term “antioxidant” is one of the most confusing definitions in biological/medical sciences. In chemistry, “antioxidant” is simply conceived “a compound that removes reactive species, mainly those oxygen-derived”, while in a cell context, the conceptual definition of an antioxidant is poorly understood. Indeed, [...] Read more.

The term “antioxidant” is one of the most confusing definitions in biological/medical sciences. In chemistry, “antioxidant” is simply conceived “a compound that removes reactive species, mainly those oxygen-derived”, while in a cell context, the conceptual definition of an antioxidant is poorly understood. Indeed, non-clinically recommended antioxidants are often consumed in large amounts by the global population, based on the belief that cancer, inflammation and degenerative diseases are triggered by high oxygen levels (or reactive oxygen species) and that through blocking reactive species production, organic unbalances/disorders can be prevented and/or even treated. The popularity of these chemicals arises in part from the widespread public mistrust of allopathic medicine. In fact, reactive oxygen species play a dual role in dealing with different disorders, since they may contribute to disease onset and/or progression but may also play a key role in disease prevention. Further, the ability of the most commonly used supplements, such as vitamins C, E, selenium, and herbal supplements to decrease pathologic reactive oxygen species is not clearly established. Hence, the present review aims to provide a nuanced understanding of where current knowledge is and where it should go. Full article

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25 pages, 2548 KiB

Open AccessEditor’s ChoiceReview

Modeling Membrane Curvature Generation due to Membrane–Protein Interactions

by Haleh Alimohamadi and Padmini Rangamani

Biomolecules 2018, 8(4), 120; https://doi.org/10.3390/biom8040120 - 23 Oct 2018

Cited by 56 | Viewed by 9864

Abstract

To alter and adjust the shape of the plasma membrane, cells harness various mechanisms of curvature generation. Many of these curvature generation mechanisms rely on the interactions between peripheral membrane proteins, integral membrane proteins, and lipids in the bilayer membrane. Mathematical and computational [...] Read more.

To alter and adjust the shape of the plasma membrane, cells harness various mechanisms of curvature generation. Many of these curvature generation mechanisms rely on the interactions between peripheral membrane proteins, integral membrane proteins, and lipids in the bilayer membrane. Mathematical and computational modeling of membrane curvature generation has provided great insights into the physics underlying these processes. However, one of the challenges in modeling these processes is identifying the suitable constitutive relationships that describe the membrane free energy including protein distribution and curvature generation capability. Here, we review some of the commonly used continuum elastic membrane models that have been developed for this purpose and discuss their applications. Finally, we address some fundamental challenges that future theoretical methods need to overcome to push the boundaries of current model applications. Full article

(This article belongs to the Special Issue Cellular Membrane Domains and Organization)

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38 pages, 2790 KiB

Open AccessEditor’s ChoiceReview

Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding?

by Hélène Pollet, Louise Conrard, Anne-Sophie Cloos and Donatienne Tyteca

Biomolecules 2018, 8(3), 94; https://doi.org/10.3390/biom8030094 - 14 Sep 2018

Cited by 97 | Viewed by 10286

Abstract

Extracellular vesicles (EVs) contribute to several pathophysiological processes and appear as emerging targets for disease diagnosis and therapy. However, successful translation from bench to bedside requires deeper understanding of EVs, in particular their diversity, composition, biogenesis and shedding mechanisms. In this review, we [...] Read more.

Extracellular vesicles (EVs) contribute to several pathophysiological processes and appear as emerging targets for disease diagnosis and therapy. However, successful translation from bench to bedside requires deeper understanding of EVs, in particular their diversity, composition, biogenesis and shedding mechanisms. In this review, we focus on plasma membrane-derived microvesicles (MVs), far less appreciated than exosomes. We integrate documented mechanisms involved in MV biogenesis and shedding, focusing on the red blood cell as a model. We then provide a perspective for the relevance of plasma membrane lipid composition and biophysical properties in microvesiculation on red blood cells but also platelets, immune and nervous cells as well as tumor cells. Although only a few data are available in this respect, most of them appear to converge to the idea that modulation of plasma membrane lipid content, transversal asymmetry and lateral heterogeneity in lipid domains may play a significant role in the vesiculation process. We suggest that lipid domains may represent platforms for inclusion/exclusion of membrane lipids and proteins into MVs and that MVs could originate from distinct domains during physiological processes and disease evolution. Full article

(This article belongs to the Special Issue Cellular Membrane Domains and Organization)

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17 pages, 722 KiB

Open AccessEditor’s ChoiceReview

Molecular Modeling Applied to Nucleic Acid-Based Molecule Development

by Arne Krüger, Flávia M. Zimbres, Thales Kronenberger and Carsten Wrenger

Biomolecules 2018, 8(3), 83; https://doi.org/10.3390/biom8030083 - 27 Aug 2018

Cited by 21 | Viewed by 8262

Abstract

Molecular modeling by means of docking and molecular dynamics (MD) has become an integral part of early drug discovery projects, enabling the screening and enrichment of large libraries of small molecules. In the past decades, special emphasis was drawn to nucleic acid (NA)-based [...] Read more.

Molecular modeling by means of docking and molecular dynamics (MD) has become an integral part of early drug discovery projects, enabling the screening and enrichment of large libraries of small molecules. In the past decades, special emphasis was drawn to nucleic acid (NA)-based molecules in the fields of therapy, diagnosis, and drug delivery. Research has increased dramatically with the advent of the SELEX (systematic evolution of ligands by exponential enrichment) technique, which results in single-stranded DNA or RNA sequences that bind with high affinity and specificity to their targets. Herein, we discuss the role and contribution of docking and MD to the development and optimization of new nucleic acid-based molecules. This review focuses on the different approaches currently available for molecular modeling applied to NA interaction with proteins. We discuss topics ranging from structure prediction to docking and MD, highlighting their main advantages and limitations and the influence of flexibility on their calculations. Full article

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14 pages, 1443 KiB

Open AccessEditor’s ChoiceReview

The Many Faces of Amphipathic Helices

by Manuel Giménez-Andrés, Alenka Čopič and Bruno Antonny

Biomolecules 2018, 8(3), 45; https://doi.org/10.3390/biom8030045 - 5 Jul 2018

Cited by 115 | Viewed by 12080

Abstract

Amphipathic helices (AHs), a secondary feature found in many proteins, are defined by their structure and by the segregation of hydrophobic and polar residues between two faces of the helix. This segregation allows AHs to adsorb at polar–apolar interfaces such as the lipid [...] Read more.

Amphipathic helices (AHs), a secondary feature found in many proteins, are defined by their structure and by the segregation of hydrophobic and polar residues between two faces of the helix. This segregation allows AHs to adsorb at polar–apolar interfaces such as the lipid surfaces of cellular organelles. Using various examples, we discuss here how variations within this general scheme impart membrane-interacting AHs with different interfacial properties. Among the key parameters are: (i) the size of hydrophobic residues and their density per helical turn; (ii) the nature, the charge, and the distribution of polar residues; and (iii) the length of the AH. Depending on how these parameters are tuned, AHs can deform lipid bilayers, sense membrane curvature, recognize specific lipids, coat lipid droplets, or protect membranes from stress. Via these diverse mechanisms, AHs play important roles in many cellular processes. Full article

(This article belongs to the Special Issue Cellular Membrane Domains and Organization)

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9 pages, 804 KiB

Open AccessEditor’s ChoiceReview

Protein–Phospholipid Interaction Motifs: A Focus on Phosphatidic Acid

by Emeline Tanguy, Nawal Kassas and Nicolas Vitale

Biomolecules 2018, 8(2), 20; https://doi.org/10.3390/biom8020020 - 23 Apr 2018

Cited by 53 | Viewed by 8699

Abstract

Cellular membranes are composed of thousands of different lipids usually maintained within a narrow range of concentrations. In addition to their well-known structural and metabolic roles, signaling functions for many lipids have also emerged over the last two decades. The latter largely depend [...] Read more.

Cellular membranes are composed of thousands of different lipids usually maintained within a narrow range of concentrations. In addition to their well-known structural and metabolic roles, signaling functions for many lipids have also emerged over the last two decades. The latter largely depend on the ability of particular classes of lipids to interact specifically with a great variety of proteins and to regulate their localization and activity. Among these lipids, phosphatidic acid (PA) plays a unique role in a large repertoire of cellular activities, most likely in relation to its unique biophysical properties. However, until recently, only incomplete information was available to model the interaction between PA and its protein partners. The development of new liposome-based assays as well as molecular dynamic simulation are now providing novel information. We will review the different factors that have shown to modulate the capacity of PA to interact with specific domains in target proteins. Full article

(This article belongs to the Special Issue Cellular Membrane Domains and Organization)

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18 pages, 932 KiB

Open AccessEditor’s ChoiceReview

p53-Mediated Molecular Control of Autophagy in Tumor Cells

by Maria Mrakovcic and Leopold F. Fröhlich

Biomolecules 2018, 8(2), 14; https://doi.org/10.3390/biom8020014 - 21 Mar 2018

Cited by 133 | Viewed by 11498

Abstract

Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell’s energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development [...] Read more.

Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell’s energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development of tumors. In recent years, the suppression of autophagy in combination with chemotherapeutic treatment has been approached as a novel therapy in cancer treatment. However, depending on the type of cancer and context, interference with the autophagic machinery can either promote or disrupt tumorigenesis. Therefore, disclosure of the major signaling pathways that regulate autophagy and control tumorigenesis is crucial. To date, several tumor suppressor proteins and oncogenes have emerged as eminent regulators of autophagy whose depletion or mutation favor tumor formation. The mammalian cell “janitor” p53 belongs to one of these tumor suppressors that are most commonly mutated in human tumors. Experimental evidence over the last decade convincingly reports that p53 can act as either an activator or an inhibitor of autophagy depending on its subcellular localization and its mode of action. This finding gains particular significance as p53 deficiency or mutant variants of p53 that accumulate in the cytoplasm of tumor cells enable activation of autophagy. Accordingly, we recently identified p53 as a molecular hub that regulates autophagy and apoptosis in histone deacetylase inhibitor-treated uterine sarcoma cells. In light of this novel experimental evidence, in this review, we focus on p53 signaling as a mediator of the autophagic pathway in tumor cells. Full article

(This article belongs to the Special Issue p53 Pathway in Cancer Progression and Cancer Therapy)

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24 pages, 2144 KiB

Open AccessEditor’s ChoiceReview

Antimicrobial Peptides: Diversity, Mechanism of Action and Strategies to Improve the Activity and Biocompatibility In Vivo

by Prashant Kumar, Jayachandran N. Kizhakkedathu and Suzana K. Straus

Biomolecules 2018, 8(1), 4; https://doi.org/10.3390/biom8010004 - 19 Jan 2018

Cited by 768 | Viewed by 40461

Abstract

Antibiotic resistance is projected as one of the greatest threats to human health in the future and hence alternatives are being explored to combat resistance. Antimicrobial peptides (AMPs) have shown great promise, because use of AMPs leads bacteria to develop no or low [...] Read more.

Antibiotic resistance is projected as one of the greatest threats to human health in the future and hence alternatives are being explored to combat resistance. Antimicrobial peptides (AMPs) have shown great promise, because use of AMPs leads bacteria to develop no or low resistance. In this review, we discuss the diversity, history and the various mechanisms of action of AMPs. Although many AMPs have reached clinical trials, to date not many have been approved by the US Food and Drug Administration (FDA) due to issues with toxicity, protease cleavage and short half-life. Some of the recent strategies developed to improve the activity and biocompatibility of AMPs, such as chemical modifications and the use of delivery systems, are also reviewed in this article. Full article

(This article belongs to the Special Issue Antimicrobial Peptides: Development, Conjugation, and Beyond)

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17 pages, 2771 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles for VEGF-D in Human Disease

by Steven A. Stacker and Marc G. Achen

Biomolecules 2018, 8(1), 1; https://doi.org/10.3390/biom8010001 - 4 Jan 2018

Cited by 68 | Viewed by 10492

Abstract

Blood vessels and lymphatic vessels are located in many tissues and organs throughout the body, and play important roles in a wide variety of prevalent diseases in humans. Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that can promote the remodeling of [...] Read more.

Blood vessels and lymphatic vessels are located in many tissues and organs throughout the body, and play important roles in a wide variety of prevalent diseases in humans. Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that can promote the remodeling of blood vessels and lymphatics in development and disease. Recent fundamental and translational studies have provided insight into the molecular mechanisms by which VEGF-D exerts its effects in human disease. Hence this protein is now of interest as a therapeutic and/or diagnostic target, or as a potential therapeutic agent, in a diversity of indications in cardiovascular medicine, cancer and the devastating pulmonary condition lymphangioleiomyomatosis. This has led to clinical trial programs to assess the effect of targeting VEGF-D signaling pathways, or delivering VEGF-D, in angina, cancer and ocular indications. This review summarizes our understanding of VEGF-D signaling in human disease, which is largely based on animal disease models and clinicopathological studies, and provides information about the outcomes of recent clinical trials testing agonists or antagonists of VEGF-D signaling. Full article

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