Biomolecules

16 pages, 403 KiB

Open AccessEditor’s ChoiceReview

Polysaccharide-Based Formulations for Healing of Skin-Related Wound Infections: Lessons from Animal Models and Clinical Trials

by Diogo Marcelo Lima Ribeiro, Alexsander Rodrigues Carvalho Júnior, Gustavo Henrique Rodrigues Vale de Macedo, Vitor Lopes Chagas, Lucas dos Santos Silva, Brenda da Silva Cutrim, Deivid Martins Santos, Bruno Luis Lima Soares, Adrielle Zagmignan, Rita de Cássia Mendonça de Miranda, Priscilla Barbosa Sales de Albuquerque and Luís Cláudio Nascimento da Silva

Biomolecules 2020, 10(1), 63; https://doi.org/10.3390/biom10010063 - 30 Dec 2019

Cited by 74 | Viewed by 7799

Abstract

Skin injuries constitute a gateway for pathogenic bacteria that can be either part of tissue microbiota or acquired from the environmental. These microorganisms (such as Acinetobacter baumannii, Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus aureus) produce virulence factors that impair tissue integrity and [...] Read more.

Skin injuries constitute a gateway for pathogenic bacteria that can be either part of tissue microbiota or acquired from the environmental. These microorganisms (such as Acinetobacter baumannii, Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus aureus) produce virulence factors that impair tissue integrity and sustain the inflammatory phase leading for establishment of chronic wounds. The high levels of antimicrobial resistance have limited the therapeutic arsenal for combatting skin infections. Thus, the treatment of non-healing chronic wounds is a huge challenge for health services worldwide, imposing great socio-economic damage to the affected individuals. This scenario has encouraged the use of natural polymers, such as polysaccharide, in order to develop new formulations (membranes, nanoparticles, hydrogels, scaffolds) to be applied in the treatment of skin infections. In this non-exhaustive review, we discuss the applications of polysaccharide-based formulations in the healing of infected wounds in animal models and clinical trials. The formulations discussed in this review were prepared using alginate, cellulose, chitosan, and hyaluronic acid. In addition to have healing actions per se, these polysaccharide formulations can act as transdermal drug delivery systems, controlling the release of active ingredients (such as antimicrobial and healing agents). The papers show that these polysaccharides-based formulations are efficient in controlling infection and improve the healing, even in chronic infected wounds. These data should positively impact the design of new dressings to treat skin infections. Full article

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25 pages, 13439 KiB

Open AccessEditor’s ChoiceReview

Contribution of Non-Saccharomyces Yeasts to Wine Freshness. A Review

by Antonio Morata, Carlos Escott, María Antonia Bañuelos, Iris Loira, Juan Manuel del Fresno, Carmen González and José Antonio Suárez-Lepe

Biomolecules 2020, 10(1), 34; https://doi.org/10.3390/biom10010034 - 25 Dec 2019

Cited by 110 | Viewed by 10911

Abstract

Freshness, although it is a concept difficult to define in wines, can be understood as a combination of different circumstances. Organolepticwise, bluish red, floral and fruity, more acidic and full-bodied wines, are perceived as younger and fresher by consumers. In traditional winemaking processes, [...] Read more.

Freshness, although it is a concept difficult to define in wines, can be understood as a combination of different circumstances. Organolepticwise, bluish red, floral and fruity, more acidic and full-bodied wines, are perceived as younger and fresher by consumers. In traditional winemaking processes, these attributes are hard to boost if no other technology or biotechnology is involved. In this regard, the right selection of yeast strains plays an important role in meeting these parameters and obtaining wines with fresher profiles. Another approach in getting fresh wines is through the use of novel non-thermal technologies during winemaking. Herein, the contributions of non-Saccharomyces yeasts and emerging technologies to these parameters are reviewed and discussed. Full article

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

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14 pages, 927 KiB

Open AccessEditor’s ChoiceArticle

Thermal Processing for the Release of Phenolic Compounds from Wheat and Oat Bran

by Lavinia Florina Călinoiu and Dan Cristian Vodnar

Biomolecules 2020, 10(1), 21; https://doi.org/10.3390/biom10010021 - 22 Dec 2019

Cited by 102 | Viewed by 7027

Abstract

The aim of the present paper was to identify the major polyphenolic compounds and investigate the antioxidant, antimutagenic, and antimicrobial activities of industrially-derived cereal byproducts—wheat bran (WB) and oat bran (OB)—before (fresh) and after thermal processing (TP) (10 min, 80 °C), coupled with [...] Read more.

The aim of the present paper was to identify the major polyphenolic compounds and investigate the antioxidant, antimutagenic, and antimicrobial activities of industrially-derived cereal byproducts—wheat bran (WB) and oat bran (OB)—before (fresh) and after thermal processing (TP) (10 min, 80 °C), coupled with ultrasound-asssited extraction. The results showed that the thermal process improved the total phenolic content of WB by +22.49%, and of OB with +25.84%. After the TP, the phenolic concentration showed a significant relative percentage increase in the case of WB (ferulic acid +39.18%, vanillic acid +95.68%, apigenin–glucoside +71.96%, p-coumaric acid +71.91) and of OB (avenanthramide 2c +52.17%, dihydroxybenzoic acids +38.55%). The best antioxidant capacity was registered by OBTP followed by WBTP. The strongest antimicrobial inhibition was attributed to the WBTP sample. Both thermally processed matrices had strong antimutagenic activity toward S. typhimurium TA100. This thermal processing was tested on bran based on its practical application within the food industry, considering the design of different cereal byproducts derived from functional foods and nutraceuticals. Full article

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17 pages, 3163 KiB

Open AccessEditor’s ChoiceArticle

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

by Jan Wysocki, Arndt Schulze and Daniel Batlle

Biomolecules 2019, 9(12), 886; https://doi.org/10.3390/biom9120886 - 17 Dec 2019

Cited by 46 | Viewed by 7727

Abstract

ACE2 is a monocarboxypeptidase which generates Angiotensin (1–7) from Angiotensin II (1–8). Attempts to target the kidney Renin Angiotensin System using native ACE2 to treat kidney disease are hampered by its large molecular size, 100 kDa, which precludes its glomerular filtration and subsequent [...] Read more.

ACE2 is a monocarboxypeptidase which generates Angiotensin (1–7) from Angiotensin II (1–8). Attempts to target the kidney Renin Angiotensin System using native ACE2 to treat kidney disease are hampered by its large molecular size, 100 kDa, which precludes its glomerular filtration and subsequent tubular uptake. Here, we show that both urine and kidney lysates are capable of digesting native ACE2 into shorter proteins of ~60–75 kDa and then demonstrate that they are enzymatically very active. We then truncated the native ACE2 by design from the C-terminus to generate two short recombinant (r)ACE2 variants (1-605 and 1-619AA). These two truncates have a molecular size of ~70 kDa, as expected from the amino acid sequence and as shown by Western blot. ACE2 enzyme activity, measured using a specific substrate, was higher than that of the native rACE2 (1-740 AA). When infused to mice with genetic ACE2 deficiency, a single i.v. injection of 1-619 resulted in detectable ACE2 activity in urine, whereas infusion of the native ACE2 did not. Moreover, ACE2 activity was recovered in harvested kidneys from ACE2-deficient mice infused with 1-619, but not in controls (23.1 ± 4.3 RFU/µg creatinine/h and 1.96 ± 0.73 RFU/µg protein/hr, respectively). In addition, the kidneys of ACE2-null mice infused with 1-619 studied ex vivo formed more Ang (1–7) from exogenous Ang II than those infused with vehicle (AUC 8555 ± 1933 vs. 3439 ± 753 ng/mL, respectively, p < 0.05) further demonstrating the functional effect of increasing kidney ACE2 activity after the infusion of our short ACE2 1-619 variant. We conclude that our novel short recombinant ACE2 variants undergo glomerular filtration, which is associated with kidney uptake of enzymatically active proteins that can enhance the formation of Ang (1–7) from Ang II. These small ACE2 variants may offer a potentially useful approach to target kidney RAS overactivity to combat kidney injury. Full article

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

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17 pages, 834 KiB

Open AccessEditor’s ChoiceReview

A Sight to Wheat Bran: High Value-Added Products

by Agne Katileviciute, Gediminas Plakys, Aida Budreviciute, Kamil Onder, Samar Damiati and Rimantas Kodzius

Biomolecules 2019, 9(12), 887; https://doi.org/10.3390/biom9120887 - 17 Dec 2019

Cited by 81 | Viewed by 10769

Abstract

Recently more consideration has been given to the use of renewable materials and agricultural residues. Wheat production is increasing yearly and correspondingly, the volume of by-products from the wheat process is increasing, as well. It is important to find the use of the [...] Read more.

Recently more consideration has been given to the use of renewable materials and agricultural residues. Wheat production is increasing yearly and correspondingly, the volume of by-products from the wheat process is increasing, as well. It is important to find the use of the residuals for higher value-added products, and not just for the food industry or animal feed purposes as it is happening now. Agricultural residue of the roller milled wheat grain is a wheat bran description. The low-cost of wheat bran and its composition assortment provides a good source of substrate for various enzymes and organic acids production and other biotechnological applications. The main purpose of this review article is to look into recent trends, developments, and applications of wheat bran. Full article

(This article belongs to the Special Issue Application of Biotechnological Techniques Aimed to Obtain Bioactive Compounds from Food Industry By-Products)

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15 pages, 2675 KiB

Open AccessEditor’s ChoiceArticle

High-Fat Diet Affects Ceramide Content, Disturbs Mitochondrial Redox Balance, and Induces Apoptosis in the Submandibular Glands of Mice

by Anna Zalewska, Mateusz Maciejczyk, Julita Szulimowska, Monika Imierska and Agnieszka Błachnio-Zabielska

Biomolecules 2019, 9(12), 877; https://doi.org/10.3390/biom9120877 - 15 Dec 2019

Cited by 42 | Viewed by 4563

Abstract

This is the first study to investigate the relationship between ceramides, the mitochondrial respiratory system, oxidative stress, inflammation, and apoptosis in the submandibular gland mitochondria of mice with insulin resistance (IR). The experiment was conducted on 20 male C57BL/6 mice divided into two [...] Read more.

This is the first study to investigate the relationship between ceramides, the mitochondrial respiratory system, oxidative stress, inflammation, and apoptosis in the submandibular gland mitochondria of mice with insulin resistance (IR). The experiment was conducted on 20 male C57BL/6 mice divided into two equal groups: animals fed a high-fat diet (HFD; 60 kcal% fat) and animals fed a standard diet (10 kcal% fat). We have shown that feeding mice HFD induces systemic IR. We noticed that HFD feeding was accompanied by a significant increase in ceramide production (C18 1Cer, C18 Cer, C22 Cer, C24 1Cer, C24 Cer), higher activity of pro-oxidant enzymes (NADPH oxidase and xanthine oxidase), and weakened functioning of mitochondrial complexes in the submandibular glands of IR mice. In this group, we also observed a decrease in catalase and peroxidase activities, glutathione concentration, redox status, increased concentration of protein (advanced glycation end products, advanced oxidation protein products) and lipid (malondialdehyde, lipid hydroperoxide) peroxidation products, and enhanced production of tumor necrosis factor alpha (TNFα) and interleukin 2 (IL-2) as well as pro-apoptotic Bax in the submandibular gland mitochondria. In summary, HFD impairs salivary redox homeostasis and is responsible for enhanced oxidative damage and apoptosis in the submandibular gland mitochondria. The accumulation of some ceramides could boost free radical formation by affecting pro-oxidant enzymes and the mitochondrial respiratory chain. Full article

(This article belongs to the Special Issue Oxidative Stress and Mitochondrial Dysfunction in Human Diseases: Pathophysiology, Predictive Biomarkers, Therapeutic)

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25 pages, 2417 KiB

Open AccessEditor’s ChoiceReview

Fatty Acids of Marine Mollusks: Impact of Diet, Bacterial Symbiosis and Biosynthetic Potential

by Natalia V. Zhukova

Biomolecules 2019, 9(12), 857; https://doi.org/10.3390/biom9120857 - 11 Dec 2019

Cited by 56 | Viewed by 6689

Abstract

The n-3 and n-6 polyunsaturated fatty acid (PUFA) families are essential for important physiological processes. Their major source are marine ecosystems. The fatty acids (FAs) from phytoplankton, which are the primary producer of organic matter and PUFAs, are transferred into consumers via food [...] Read more.

The n-3 and n-6 polyunsaturated fatty acid (PUFA) families are essential for important physiological processes. Their major source are marine ecosystems. The fatty acids (FAs) from phytoplankton, which are the primary producer of organic matter and PUFAs, are transferred into consumers via food webs. Mollusk FAs have attracted the attention of researchers that has been driven by their critical roles in aquatic ecology and their importance as sources of essential PUFAs. The main objective of this review is to focus on the most important factors and causes determining the biodiversity of the mollusk FAs, with an emphasis on the key relationship of these FAs with the food spectrum and trophic preference. The marker FAs of trophic sources are also of particular interest. The discovery of new symbioses involving invertebrates and bacteria, which are responsible for nutrition of the host, deserves special attention. The present paper also highlights recent research into the molecular and biochemical mechanisms of PUFA biosynthesis in marine mollusks. The biosynthetic capacities of marine mollusks require a well-grounded evaluation. Full article

(This article belongs to the Special Issue Fatty Acids in Natural Ecosystems and Human Nutrition)

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33 pages, 1639 KiB

Open AccessEditor’s ChoiceReview

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

by Samson Mathews Samuel, Elizabeth Varghese, Peter Kubatka, Chris R. Triggle and Dietrich Büsselberg

Biomolecules 2019, 9(12), 846; https://doi.org/10.3390/biom9120846 - 9 Dec 2019

Cited by 66 | Viewed by 9495

Abstract

Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast [...] Read more.

Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer. Full article

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

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26 pages, 4264 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Polysaccharide-Based Systems for Targeted Stem Cell Differentiation and Bone Regeneration

by Markus Witzler, Dominik Büchner, Sarah Hani Shoushrah, Patrick Babczyk, Juliana Baranova, Steffen Witzleben, Edda Tobiasch and Margit Schulze

Biomolecules 2019, 9(12), 840; https://doi.org/10.3390/biom9120840 - 6 Dec 2019

Cited by 43 | Viewed by 7088

Abstract

Bone tissue engineering is an ever-changing, rapidly evolving, and highly interdisciplinary field of study, where scientists try to mimic natural bone structure as closely as possible in order to facilitate bone healing. New insights from cell biology, specifically from mesenchymal stem cell differentiation [...] Read more.

Bone tissue engineering is an ever-changing, rapidly evolving, and highly interdisciplinary field of study, where scientists try to mimic natural bone structure as closely as possible in order to facilitate bone healing. New insights from cell biology, specifically from mesenchymal stem cell differentiation and signaling, lead to new approaches in bone regeneration. Novel scaffold and drug release materials based on polysaccharides gain increasing attention due to their wide availability and good biocompatibility to be used as hydrogels and/or hybrid components for drug release and tissue engineering. This article reviews the current state of the art, recent developments, and future perspectives in polysaccharide-based systems used for bone regeneration. Full article

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

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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 24 | Viewed by 6950

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 122 | Viewed by 10638

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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16 pages, 2590 KiB

Open AccessEditor’s ChoiceArticle

Deregulation of the Histone Lysine-Specific Demethylase 1 Is Involved in Human Hepatocellular Carcinoma

by Sangchul Kim, Amina Bolatkan, Syuzo Kaneko, Noriko Ikawa, Ken Asada, Masaaki Komatsu, Shinya Hayami, Hidenori Ojima, Nobutsugu Abe, Hiroki Yamaue and Ryuji Hamamoto

Biomolecules 2019, 9(12), 810; https://doi.org/10.3390/biom9120810 - 1 Dec 2019

Cited by 24 | Viewed by 5020

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Given that the standard-of-care for advanced liver cancer is limited, there is an urgent need to develop a novel molecular targeted therapy [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Given that the standard-of-care for advanced liver cancer is limited, there is an urgent need to develop a novel molecular targeted therapy to improve therapeutic outcomes for HCC. In order to tackle this issue, we conducted functional analysis of the histone lysine-specific demethylase (LSD1) to explore the possibility that this enzyme acts as a therapeutic target in HCC. According to immunohistochemical analysis, 232 of 303 (77%) HCC cases showed positive staining of LSD1 protein, and its expression was correlated with several clinicopathological characteristics, such as female gender, AFP (alpha-fetoprotein) levels, and HCV (hepatitis C virus) infectious. The survival curves for HCC using the Kaplan–Meier method and the log-rank test indicate that positive LSD1 protein expression was significantly associated with decreased rates of overall survival (OS) and disease-free survival (DFS); the multivariate analysis indicates that LSD1 expression was an independent prognostic factor for both OS and DFS in patients with HCC. In addition, knockout of LSD1 using the CRISPR/Cas9 system showed a significantly lower number of colony formation units (CFUs) and growth rate in both SNU-423 and SNU-475 HCC cell lines compared to the corresponding control cells. Moreover, LSD1 knockout decreased cells in S phase of SNU-423 and SNU-475 cells with increased levels of H3K4me1/2 and H3K9me1/2. Finally, we identified the signaling pathways regulated by LSD1 in HCC, including the retinoic acid (RA) pathway. Our findings imply that deregulation of LSD1 can be involved in HCC; further studies may explore the usefulness of LSD1 as a therapeutic target of HCC. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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15 pages, 1306 KiB

Open AccessEditor’s ChoiceArticle

Detection and Quantification of Milk Ingredients as Hidden Allergens in Meat Products by a Novel Specific Real-Time PCR Method

by Caterina Villa, Joana Costa and Isabel Mafra

Biomolecules 2019, 9(12), 804; https://doi.org/10.3390/biom9120804 - 29 Nov 2019

Cited by 15 | Viewed by 4637

Abstract

Milk ingredients are often included in a wide range of meat products, such as cooked hams and sausages, to improve technological characteristics. However, milk proteins are also important food allergens. The aim of this study was the development of a highly sensitive and [...] Read more.

Milk ingredients are often included in a wide range of meat products, such as cooked hams and sausages, to improve technological characteristics. However, milk proteins are also important food allergens. The aim of this study was the development of a highly sensitive and specific real-time PCR system targeting the 12S rRNA gene of Bos domesticus for the detection and quantification of milk as an allergenic ingredient in processed meat products. The method was able to achieve an absolute limit of detection (LOD) of 6 fg of milk DNA. Using a normalized approach (∆Ct method) for the detection of milk protein concentrate (MPC), it was possible to obtain sensitivities down to 0.01% (w/w) of MPC in model hams (raw and cooked) and autoclaved sausages, and 0.005% in raw sausage mixtures. The developed systems generally presented acceptable PCR performance parameters, being successfully validated with blind samples, applied to commercial samples, and further compared with an immunochemical assay. Trace amounts of milk material were quantified in two out of 13 samples, but the results mostly infer the excessive practice of the precautionary labeling. Full article

(This article belongs to the Special Issue Advances on Allergens Identification and Characterization)

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13 pages, 1855 KiB

Open AccessEditor’s ChoiceArticle

Hydrogen Sulfide Effects on the Survival of Lactobacilli with Emphasis on the Development of Inflammatory Bowel Diseases

by Ivan Kushkevych, Věra Kotrsová, Dani Dordević, Leona Buňková, Monika Vítězová and Amedeo Amedei

Biomolecules 2019, 9(12), 752; https://doi.org/10.3390/biom9120752 - 20 Nov 2019

Cited by 39 | Viewed by 7876

Abstract

The gut microbiota is a complex component of humans that depends on diet, host genome, and lifestyle. The background: The study purpose is to find relations between nutrition, intestinal lactic acid bacteria (LAB) from various environments (human, animal intestine, and yogurt) and sulfate-reducing [...] Read more.

The gut microbiota is a complex component of humans that depends on diet, host genome, and lifestyle. The background: The study purpose is to find relations between nutrition, intestinal lactic acid bacteria (LAB) from various environments (human, animal intestine, and yogurt) and sulfate-reducing microbial communities in the large intestine; to compare kinetic growth parameters of LAB; and to determine their sensitivity to different concentration of hydrogen sulfide produced by intestinal sulfate-reducing bacteria. Methods: Microbiological (isolation and identification), biochemical (electrophoresis), molecular biology methods (DNA isolation and PCR analysis), and statistical processing (average and standard error calculations) of the results were used. The results: The toxicity of hydrogen sulfide produced by sulfate-reducing bacteria, the survival of lactic acid bacteria, and minimal inhibitory concentrations (MIC) were determined. The measured hydrogen sulfide sensitivity values were the same for L. paracasei and L. reuteri (MIC > 1.1 mM). In addition, L. plantarum and L. fermentum showed also a similar sensitivity (MIC > 0.45 mM) but significantly (p < 0.05) lower than L. reuteri and L. paracasei (1.1 > 0.45 mM). L. paracasei and L. reuteri are more sensitive to hydrogen sulfide than L. fermentum and L. plantarum. L. pentosus was sensitive to the extremely low concentration of H₂S (MIC > 0.15 mM). Conclusions: The Lactobacillus species were significantly sensitive to hydrogen sulfide, which is a final metabolite of intestinal sulfate-reducing bacteria. The results are definitely helpful for a better understanding of complicated interaction among intestinal microbiota and nutrition. Full article

(This article belongs to the Special Issue Role of the Gut Microbiota in Immunity and Inflammatory Diseases)

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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 171 | Viewed by 15068

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 144 | Viewed by 14475

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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16 pages, 2235 KiB

Open AccessEditor’s ChoiceArticle

Total Phenolic and Flavonoid Content and Biological Activities of Extracts and Isolated Compounds of Cytisus villosus Pourr.

by Farida Larit, Francisco León, Samira Benyahia and Stephen J. Cutler

Biomolecules 2019, 9(11), 732; https://doi.org/10.3390/biom9110732 - 13 Nov 2019

Cited by 26 | Viewed by 6971

Abstract

The aim of this study was to evaluate the total phenolic and flavonoid content, and the in vitro antioxidant, anti-inflammatory, antibacterial, antifungal, antimalarial, cytotoxicity, and antiprotozoal activities of the Algerian plant Cytisus villosus Pourr. (Syn. Cytisus triflorus L’Hérit.). Additionally, the radioligand displacement affinity [...] Read more.

The aim of this study was to evaluate the total phenolic and flavonoid content, and the in vitro antioxidant, anti-inflammatory, antibacterial, antifungal, antimalarial, cytotoxicity, and antiprotozoal activities of the Algerian plant Cytisus villosus Pourr. (Syn. Cytisus triflorus L’Hérit.). Additionally, the radioligand displacement affinity on opioid and cannabinoid receptors was assessed for the extracts and isolated pure compounds. The hydro alcoholic extract of the aerial part of C. villosus was partitioned with chloroform (CHCl₃), ethyl acetate (EtOAc), and n-butanol (n-BuOH). The phenolic content of the C. villosus extracts was evaluated using a modified Folin–Ciocalteau method. The total flavonoid content was measured spectrometrically using the aluminum chloride colorimetric assay. The known flavonoids genistein (1), chrysin (2), chrysin-7-O-β-d-glucopyranoside (3), and 2″-O-α-l-rhamnosylorientin (4) were isolated. The antioxidant activities of the extracts and isolated compounds were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DDPH) and cellular antioxidant activity (CAA) assays. The plant extracts showed moderate antioxidant activity. EtOAc and n-BuOH extracts showed moderate anti-inflammatory activity through the inhibition of induced nitric oxide synthase (iNOS) with IC₅₀ values of 48 and 90 µg/mL, respectively. The isolated pure compounds 1 and 3 showed good inhibition of Inducible nitric oxide synthase (iNOS) with IC₅₀ values of 9 and 20 µg/mL, respectively. Compounds 1 and 2 exhibited lower inhibition of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) with IC₅₀ values of 28 and 38 µg/mL, respectively. Furthermore, the extracts and isolated pure compounds have been shown to exhibit low affinity for cannabinoid and opioid receptors. Finally, n-BuOH extract was a potent inhibitor of Trypanosoma brucei with IC₅₀ value of 7.99 µg/mL and IC₉₀ value of 12.61 µg/mL. The extracts and isolated compounds showed no antimicrobial, antimalarial nor antileishmanial activities. No cytotoxic effect was observed on cancer cell lines. The results highlight this species as a promising source of anti-inflammatory and antitrypanosomal agents. Full article

(This article belongs to the Special Issue Selected Papers from Bio.Natural Meeting 2019)

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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 938 | Viewed by 25987

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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20 pages, 9770 KiB

Open AccessEditor’s ChoiceArticle

The Potential Involvement of an ATP-Dependent Potassium Channel-Opening Mechanism in the Smooth Muscle Relaxant Properties of Tamarix dioica Roxb.

by Syeda Madiha Imtiaz, Ambreen Aleem, Fatima Saqib, Alexe Nicolae Ormenisan, Andrea Elena Neculau and Costin Vlad Anastasiu

Biomolecules 2019, 9(11), 722; https://doi.org/10.3390/biom9110722 - 10 Nov 2019

Cited by 26 | Viewed by 5356

Abstract

Background: Tamarix dioica is traditionally used to manage various disorders related to smooth muscle in the gastrointestinal, respiratory, and cardiovascular systems. This study was planned to establish a pharmacological basis for the uses of Tamarix dioica in certain medical conditions related to [...] Read more.

Background: Tamarix dioica is traditionally used to manage various disorders related to smooth muscle in the gastrointestinal, respiratory, and cardiovascular systems. This study was planned to establish a pharmacological basis for the uses of Tamarix dioica in certain medical conditions related to the digestive, respiratory, and cardiovascular systems, and to explore the underlying mechanisms. Methods: A phytochemical study was performed by preliminary methods, followed by HPLC-DAD and spectrometric methods. In vivo evaluation of a crude hydromethanolic extract of T. dioica (TdCr) was done with a castor-oil-provoked diarrheal model in rats to determine its antidiarrheal effect. Ex vivo experiments were done by using isolated tissues to determine the effects on smooth and cardiac muscles and explore the possible mechanisms. Results: TdCr tested positive for flavonoids, saponins, phenols, and tannins as methanolic solvable constituents in a preliminary study. The maximum quantity of gallic acid equivalent (GAE), phenolic, and quercetin equivalent (QE) flavonoid content found was 146 ± 0.001 μg GAE/mg extract and 36.17 ± 2.35 μg QE/mg extract. Quantification based on HPLC-DAD (reverse phase) exposed the presence of rutin at the highest concentration, followed by catechin, gallic acid, myricetin, kaempferol, and apigenin in TdCr. In vivo experiments showed the significant antidiarrheal effect of TdCr (100, 200, and 400 mg/kg) in the diarrheal (castor-oil-provoked) model. Ex vivo experiments revealed spasmolytic, bronchodilatory, and vasorelaxant activities as well as partial cardiac depressant activity, which may be potentiated by a potassium channel opener mechanism, similar to that of cromakalim. The potassium channel (K_ATP channel)-opening activity was further confirmed by repeating the experiments in glibenclamide-pretreated tissues. Conclusions: In vivo and ex vivo studies of T. dioica provided evidence of the antidiarrheal, spasmolytic, bronchodilator, vasorelaxant, and partial cardiodepressant properties facilitated through the opening of the K_ATP channel. Full article

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

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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 133 | Viewed by 12498

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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18 pages, 3250 KiB

Open AccessEditor’s ChoiceArticle

Zika and Flavivirus Shell Disorder: Virulence and Fetal Morbidity

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

Biomolecules 2019, 9(11), 710; https://doi.org/10.3390/biom9110710 - 6 Nov 2019

Cited by 24 | Viewed by 4665

Abstract

Zika virus (ZIKV) was first discovered in 1947 in Africa. Since then, sporadic ZIKV infections of humans have been reported in Africa and Asia. For a long time, this virus was mostly unnoticed due to its mild symptoms and low fatality rates. However, [...] Read more.

Zika virus (ZIKV) was first discovered in 1947 in Africa. Since then, sporadic ZIKV infections of humans have been reported in Africa and Asia. For a long time, this virus was mostly unnoticed due to its mild symptoms and low fatality rates. However, during the 2015–2016 epidemic in Central and South America, when millions of people were infected, it was discovered that ZIKV causes microcephaly in the babies of mothers infected during pregnancy. An examination of the M and C proteins of the ZIKV shell using the disorder predictor PONDR VLXT revealed that the M protein contains relatively high disorder levels comparable only to those of the yellow fever virus (YFV). On the other hand, the disorder levels in the C protein are relatively low, which can account for the low case fatality rate (CFR) of this virus in contrast to the more virulent YFV, which is characterized by high disorder in its C protein. A larger variation was found in the percentage of intrinsic disorder (PID) in the C protein of various ZIKV strains. Strains of African lineage are characterized by higher PIDs. Using both in vivo and in vitro experiments, laboratories have also previously shown that strains of African origin have a greater potential to inflict higher fetal morbidity than do strains of Asian lineage, with dengue-2 virus (DENV-2) having the least potential. Strong correlations were found between the potential to inflict fetal morbidity and shell disorder in ZIKV (r² = 0.9) and DENV-2 (DENV-2 + ZIKV, r² = 0.8). A strong correlation between CFR and PID was also observed when ZIKV was included in an analysis of sets of shell proteins from a variety of flaviviruses (r² = 0.8). These observations have potential implications for antiviral vaccine development and for the design of cancer therapeutics in terms of developing therapeutic viruses that penetrate hard-to-reach organs. Full article

(This article belongs to the Special Issue Biomolecular Structure and Drug Design. Advances in Therapy against Neglected Infectious Diseases)

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16 pages, 1937 KiB

Open AccessEditor’s ChoiceArticle

Cytokinin Detection during the Dictyostelium discoideum Life Cycle: Profiles Are Dynamic and Affect Cell Growth and Spore Germination

by Megan M. Aoki, Anna B. Kisiala, Shaojun Li, Naomi L. Stock, Craig R. Brunetti, Robert J. Huber and R. J. Neil Emery

Biomolecules 2019, 9(11), 702; https://doi.org/10.3390/biom9110702 - 5 Nov 2019

Cited by 19 | Viewed by 8526

Abstract

Cytokinins (CKs) are a family of evolutionarily conserved growth regulating hormones. While CKs are well-characterized in plant systems, these N⁶-substituted adenine derivatives are found in a variety of organisms beyond plants, including bacteria, fungi, mammals, and the social amoeba, Dictyostelium discoideum [...] Read more.

Cytokinins (CKs) are a family of evolutionarily conserved growth regulating hormones. While CKs are well-characterized in plant systems, these N⁶-substituted adenine derivatives are found in a variety of organisms beyond plants, including bacteria, fungi, mammals, and the social amoeba, Dictyostelium discoideum. Within Dictyostelium, CKs have only been studied in the late developmental stages of the life cycle, where they promote spore encapsulation and dormancy. In this study, we used ultra high-performance liquid chromatography-positive electrospray ionization-high resolution tandem mass spectrometry (UHPLC-(ESI+)-HRMS/MS) to profile CKs during the Dictyostelium life cycle: growth, aggregation, mound, slug, fruiting body, and germination. Comprehensive profiling revealed that Dictyostelium produces 6 CK forms (cis-Zeatin (cZ), discadenine (DA), N⁶-isopentenyladenine (iP), N⁶-isopentenyladenine-9-riboside (iPR), N⁶-isopentenyladenine-9-riboside-5′ phosphate (iPRP), and 2-methylthio-N⁶-isopentenyladenine (2MeSiP)) in varying abundance across the sampled life cycle stages, thus laying the foundation for the CK biosynthesis pathway to be defined in this organism. Interestingly, iP-type CKs were the most dominant CK analytes detected during growth and aggregation. Exogenous treatment of AX3 cells with various CK types revealed that iP was the only CK to promote the proliferation of cells in culture. In support of previous studies, metabolomics data revealed that DA is one of the most significantly upregulated small molecules during Dictyostelium development, and our data indicates that total CK levels are highest during germination. While much remains to be explored in Dictyostelium, this research offers new insight into the nature of CK biosynthesis, secretion, and function during Dictyostelium growth, development, and spore germination. Full article

(This article belongs to the Section Molecular Biology)

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16 pages, 4128 KiB

Open AccessEditor’s ChoiceArticle

Natural Bis-Benzylisoquinoline Alkaloids-Tetrandrine, Fangchinoline, and Cepharanthine, Inhibit Human Coronavirus OC43 Infection of MRC-5 Human Lung Cells

by Dong Eon Kim, Jung Sun Min, Min Seong Jang, Jun Young Lee, Young Sup Shin, Chul Min Park, Jong Hwan Song, Hyoung Rae Kim, Seungtaek Kim, Young-Hee Jin and Sunoh Kwon

Biomolecules 2019, 9(11), 696; https://doi.org/10.3390/biom9110696 - 4 Nov 2019

Cited by 243 | Viewed by 13408

Abstract

Stephania tetrandra and other related species of Menispermaceae are the major sources of the bis-benzylisoquinoline alkaloids tetrandrine (TET), fangchinoline (FAN), and cepharanthine (CEP). Although the pharmacological properties of these compounds include anticancer and anti-inflammatory activities, the antiviral effects of these compounds against human [...] Read more.

Stephania tetrandra and other related species of Menispermaceae are the major sources of the bis-benzylisoquinoline alkaloids tetrandrine (TET), fangchinoline (FAN), and cepharanthine (CEP). Although the pharmacological properties of these compounds include anticancer and anti-inflammatory activities, the antiviral effects of these compounds against human coronavirus (HCoV) remain unclear. Hence, the aims of the current study were to assess the antiviral activities of TET, FAN, and CEP and to elucidate the underlying mechanisms in HCoV-OC43-infected MRC-5 human lung cells. These compounds significantly inhibited virus-induced cell death at the early stage of virus infection. TET, FAN, and CEP treatment dramatically suppressed the replication of HCoV-OC43 as well as inhibited viral S and N protein expression. The virus-induced host response was reduced by compound treatment as compared with the vehicle control. Taken together, these findings demonstrate that TET, FAN, and CEP are potential natural antiviral agents for the prevention and treatment of HCoV-OC43 infection. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 2780 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells

by Daniel Janitschke, Christopher Nelke, Anna Andrea Lauer, Liesa Regner, Jakob Winkler, Andrea Thiel, Heike Sabine Grimm, Tobias Hartmann and Marcus Otto Walter Grimm

Biomolecules 2019, 9(11), 689; https://doi.org/10.3390/biom9110689 - 2 Nov 2019

Cited by 25 | Viewed by 7400

Abstract

Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine. Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial properties in neurodegenerative diseases, however, the [...] Read more.

Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine. Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial properties in neurodegenerative diseases, however, the mechanisms of action are not completely understood. Here we investigate the effect of the naturally occurring caffeine, theobromine and theophylline and the synthetic propentofylline and pentoxifylline on processes involved in Alzheimer’s disease (AD). All MTXs decreased amyloid-β (Aβ) level by shifting the amyloid precursor protein (APP) processing from the Aβ-producing amyloidogenic to the non-amyloidogenic pathway. The α-secretase activity was elevated whereas β-secretase activity was decreased. Breaking down the molecular mechanism, caffeine increased protein stability of the major α-secretase ADAM10, downregulated BACE1 expression and directly decreased β-secretase activity. Additionally, APP expression was reduced. In line with literature, MTXs reduced oxidative stress, decreased cholesterol and a decreased in Aβ1-42 aggregation. In conclusion, all MTXs act via the pleiotropic mechanism resulting in decreased Aβ and show beneficial properties with respect to AD in neuroblastoma cells. However, the observed effect strength was moderate, suggesting that MTXs should be integrated in a healthy diet rather than be used exclusively to treat or prevent AD. Full article

(This article belongs to the Special Issue 2019 Feature Papers by Biomolecules’ Editorial Board Members)

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14 pages, 4080 KiB

Open AccessEditor’s ChoiceArticle

Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer

by Yu-Min Huang, Chia-Hsiung Cheng, Shiow-Lin Pan, Pei-Ming Yang, Ding-Yen Lin and Kuen-Haur Lee

Biomolecules 2019, 9(11), 688; https://doi.org/10.3390/biom9110688 - 2 Nov 2019

Cited by 26 | Viewed by 4827

Abstract

Human high-mobility group A2 (HMGA2) encodes for a non-histone chromatin protein which influences a variety of biological processes, including the cell cycle process, apoptosis, the DNA damage repair process, and epithelial–mesenchymal transition. The accumulated evidence suggests that high expression of HMGA2 is related [...] Read more.

Human high-mobility group A2 (HMGA2) encodes for a non-histone chromatin protein which influences a variety of biological processes, including the cell cycle process, apoptosis, the DNA damage repair process, and epithelial–mesenchymal transition. The accumulated evidence suggests that high expression of HMGA2 is related to tumor progression, poor prognosis, and a poor response to therapy. Thus, HMGA2 is an important molecular target for many types of malignancies. Our recent studies revealed the positive connections between heat shock protein 90 (Hsp90) and HMGA2 and that the Hsp90 inhibitor has therapeutic potential to inhibit HMGA2-triggered tumorigenesis. However, 43% of patients suffered visual disturbances in a phase I trial of the second-generation Hsp90 inhibitor, NVP-AUY922. To identify a specific inhibitor to target HMGA2, the Gene Expression Omnibus (GEO) database and the Library of Integrated Network-based Cellular Signatures (LINCS) L1000platform were both analyzed. We identified the approved small-molecule antifungal agent ciclopirox (CPX) as a novel potential inhibitor of HMGA2. In addition, CPX induces cytotoxicity of colorectal cancer (CRC) cells by induction of cell cycle arrest and apoptosis in vitro and in vivo through direct interaction with the AT-hook motif (a small DNA-binding protein motif) of HMGA2. In conclusion, this study is the first to report that CPX is a novel potential inhibitor of HMGA2 using a drug-repurposing approach, which can provide a potential therapeutic intervention in CRC patients. Full article

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24 pages, 8916 KiB

Open AccessEditor’s ChoiceArticle

Preparation of Chitosan/Poly(Vinyl Alcohol) Nanocomposite Films Incorporated with Oxidized Carbon Nano-Onions (Multi-Layer Fullerenes) for Tissue-Engineering Applications

by Carlos David Grande Tovar, Jorge Iván Castro, Carlos Humberto Valencia, Diana Paola Navia Porras, José Herminsul Mina Hernandez, Mayra Eliana Valencia, José Daniel Velásquez and Manuel N. Chaur

Biomolecules 2019, 9(11), 684; https://doi.org/10.3390/biom9110684 - 1 Nov 2019

Cited by 31 | Viewed by 6600

Abstract

Recently, tissue engineering became a very important medical alternative in patients who need to regenerate damaged or lost tissues through the use of scaffolds that support cell adhesion and proliferation. Carbon nanomaterials (carbon nanotubes, fullerenes, multi-wall fullerenes, and graphene) became a very important [...] Read more.

Recently, tissue engineering became a very important medical alternative in patients who need to regenerate damaged or lost tissues through the use of scaffolds that support cell adhesion and proliferation. Carbon nanomaterials (carbon nanotubes, fullerenes, multi-wall fullerenes, and graphene) became a very important alternative to reinforce the mechanical, thermal, and antimicrobial properties of several biopolymers. In this work, five different formulations of chitosan/poly(vinyl alcohol)/oxidized carbon nano-onions (CS/PVA/ox-CNO) were used to prepare biodegradable scaffolds with potential biomedical applications. Film characterization consisted of Fourier-transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), tension strength, Young’s modulus, X-ray diffraction spectroscopy (XRD), scanning electron microscopy (SEM), and energy-dispersive spectroscopy (EDS). The degradation in a simulated body fluid (FBS) demonstrated that all the formulations lost between 75% and 80% of their weight after 15 days of treatment, but the degradation decreased with the ox-CNO content. In vivo tests after 90 days of subdermal implantation of the nanocomposite films in Wistar rats’ tissue demonstrated good biocompatibility without allergenic reactions or pus formation. There was a good correlation between FBS hydrolytic degradation and degradation in vivo for all the samples, since the ox-CNO content increased the stability of the material. All these results indicate the potential of the CS/PVA/ox-CNO nanocomposite films in tissue engineering, especially for long-term applications. Full article

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12 pages, 2159 KiB

Open AccessEditor’s ChoiceArticle

Illuminating Clues of Cancer Buried in Prostate MR Image: Deep Learning and Expert Approaches

by Jun Akatsuka, Yoichiro Yamamoto, Tetsuro Sekine, Yasushi Numata, Hiromu Morikawa, Kotaro Tsutsumi, Masato Yanagi, Yuki Endo, Hayato Takeda, Tatsuro Hayashi, Masao Ueki, Gen Tamiya, Ichiro Maeda, Manabu Fukumoto, Akira Shimizu, Toyonori Tsuzuki, Go Kimura and Yukihiro Kondo

Biomolecules 2019, 9(11), 673; https://doi.org/10.3390/biom9110673 - 30 Oct 2019

Cited by 25 | Viewed by 7494

Abstract

Deep learning algorithms have achieved great success in cancer image classification. However, it is imperative to understand the differences between the deep learning and human approaches. Using an explainable model, we aimed to compare the deep learning-focused regions of magnetic resonance (MR) images [...] Read more.

Deep learning algorithms have achieved great success in cancer image classification. However, it is imperative to understand the differences between the deep learning and human approaches. Using an explainable model, we aimed to compare the deep learning-focused regions of magnetic resonance (MR) images with cancerous locations identified by radiologists and pathologists. First, 307 prostate MR images were classified using a well-established deep neural network without locational information of cancers. Subsequently, we assessed whether the deep learning-focused regions overlapped the radiologist-identified targets. Furthermore, pathologists provided histopathological diagnoses on 896 pathological images, and we compared the deep learning-focused regions with the genuine cancer locations through 3D reconstruction of pathological images. The area under the curve (AUC) for MR images classification was sufficiently high (AUC = 0.90, 95% confidence interval 0.87–0.94). Deep learning-focused regions overlapped radiologist-identified targets by 70.5% and pathologist-identified cancer locations by 72.1%. Lymphocyte aggregation and dilated prostatic ducts were observed in non-cancerous regions focused by deep learning. Deep learning algorithms can achieve highly accurate image classification without necessarily identifying radiological targets or cancer locations. Deep learning may find clues that can help a clinical diagnosis even if the cancer is not visible. Full article

(This article belongs to the Special Issue Application of Artificial Intelligence for Medical Research)

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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 18 | Viewed by 8922

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, 4795 KiB

Open AccessEditor’s ChoiceArticle

Anthocyanins from Hibiscus syriacus L. Inhibit Melanogenesis by Activating the ERK Signaling Pathway

by Wisurumuni Arachchilage Hasitha Maduranga Karunarathne, Ilandarage Menu Neelaka Molagoda, Sang Rul Park, Jeong Woon Kim, Oh-Kyu Lee, Hae Yun Kwon, Matan Oren, Yung Hyun Choi, Hyung Won Ryu, Sei-Ryang Oh, Wol Soon Jo, Kyoung Tae Lee and Gi-Young Kim

Biomolecules 2019, 9(11), 645; https://doi.org/10.3390/biom9110645 - 24 Oct 2019

Cited by 36 | Viewed by 5900

Abstract

Hibiscus syriacus L. exhibited promising potential as a new source of food and colorants containing various anthocyanins. However, the function of anthocyanins from H. syriacus L. has not been investigated. In the current study, we evaluated whether anthocyanins from the H. syriacus L. [...] Read more.

Hibiscus syriacus L. exhibited promising potential as a new source of food and colorants containing various anthocyanins. However, the function of anthocyanins from H. syriacus L. has not been investigated. In the current study, we evaluated whether anthocyanins from the H. syriacus L. varieties Pulsae and Paektanshim (PS and PTS) inhibit melanin biogenesis. B16F10 cells and zebrafish larvae were exposed to PS and PTS in the presence or absence of α-melanocyte-stimulating hormone (α-MSH), and melanin contents accompanied by its regulating genes and proteins were analyzed. PS and PTS moderately downregulated mushroom tyrosinase activity in vitro, but significantly decreased extracellular and intracellular melanin production in B16F10 cells, and inhibited α-MSH-induced expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. PS and PTS also attenuated pigmentation in α-MSH-stimulated zebrafish larvae. Furthermore, PS and PTS activated the phosphorylation of extracellular signal-regulated kinase (ERK), whereas PD98059, a specific ERK inhibitor, completely reversed PS- and PTS-mediated anti-melanogenic activity in B16F10 cells and zebrafish larvae, which indicates that PS- and PTS-mediated anti-melanogenic activity is due to ERK activation. Moreover, chromatography data showed that PS and PTS possessed 17 identical anthocyanins as a negative regulator of ERK. These findings suggested that anthocyanins from PS and PTS inhibited melanogenesis in vitro and in vivo by activating the ERK signaling pathway. Full article

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17 pages, 6400 KiB

Open AccessEditor’s ChoiceArticle

Disclosing the Impact of Carcinogenic SF3b Mutations on Pre-mRNA Recognition Via All-Atom Simulations

by Jure Borišek, Andrea Saltalamacchia, Anna Gallì, Giulia Palermo, Elisabetta Molteni, Luca Malcovati and Alessandra Magistrato

Biomolecules 2019, 9(10), 633; https://doi.org/10.3390/biom9100633 - 21 Oct 2019

Cited by 24 | Viewed by 5221

Abstract

The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3’-splice-site (3’SS). Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered [...] Read more.

The spliceosome accurately promotes precursor messenger-RNA splicing by recognizing specific noncoding intronic tracts including the branch point sequence (BPS) and the 3’-splice-site (3’SS). Mutations of Hsh155 (yeast)/SF3B1 (human), which is a protein of the SF3b factor involved in BPS recognition and induces altered BPS binding and 3’SS selection, lead to mis-spliced mRNA transcripts. Although these mutations recur in hematologic malignancies, the mechanism by which they change gene expression remains unclear. In this study, multi-microsecond-long molecular-dynamics simulations of eighth distinct ∼700,000 atom models of the spliceosome Bact complex, and gene sequencing of SF3B1, disclose that these carcinogenic isoforms destabilize intron binding and/or affect the functional dynamics of Hsh155/SF3B1 only when binding non-consensus BPSs, as opposed to the non-pathogenic variants newly annotated here. This pinpoints a cross-talk between the distal Hsh155 mutation and BPS recognition sites. Our outcomes unprecedentedly contribute to elucidating the principles of pre-mRNA recognition, which provides critical insights on the mechanism underlying constitutive/alternative/aberrant splicing. Full article

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11 pages, 1945 KiB

Open AccessEditor’s ChoiceArticle

Identification and Isolation of Active Compounds from Astragalus membranaceus that Improve Insulin Secretion by Regulating Pancreatic β-Cell Metabolism

by Dahae Lee, Da Hye Lee, Sungyoul Choi, Jin Su Lee, Dae Sik Jang and Ki Sung Kang

Biomolecules 2019, 9(10), 618; https://doi.org/10.3390/biom9100618 - 17 Oct 2019

Cited by 19 | Viewed by 5384

Abstract

In type 2 diabetes (T2D), insufficient secretion of insulin from the pancreatic β-cells contributes to high blood glucose levels, associated with metabolic dysregulation. Interest in natural products to complement or replace existing antidiabetic medications has increased. In this study, we examined the effect [...] Read more.

In type 2 diabetes (T2D), insufficient secretion of insulin from the pancreatic β-cells contributes to high blood glucose levels, associated with metabolic dysregulation. Interest in natural products to complement or replace existing antidiabetic medications has increased. In this study, we examined the effect of Astragalus membranaceus extract (ASME) and its compounds 1–9 on glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. ASME and compounds 1–9 isolated from A. membranaceus stimulated insulin secretion in INS-1 cells without inducing cytotoxicity. A further experiment showed that compounds 2, 3, and 5 enhanced the phosphorylation of total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt, and activated pancreatic and duodenal homeobox-1 (PDX-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ), which are associated with β-cell function and insulin secretion. The data suggest that two isoflavonoids (2 and 3) and a nucleoside (compound 5), isolated from the roots of A. membranaceus, have the potential to improve insulin secretion in β-cells, representing the first step towards the development of potent antidiabetic drugs. Full article

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

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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 82 | Viewed by 9288

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 45 | Viewed by 7730

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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20 pages, 2719 KiB

Open AccessEditor’s ChoiceArticle

Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

by Aayushi Srivastava, Abhishek Kumar, Sara Giangiobbe, Elena Bonora, Kari Hemminki, Asta Försti and Obul Reddy Bandapalli

Biomolecules 2019, 9(10), 605; https://doi.org/10.3390/biom9100605 - 13 Oct 2019

Cited by 26 | Viewed by 6762

Abstract

Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC [...] Read more.

Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 5′ or 3′ untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC. Full article

(This article belongs to the Special Issue Systems Genomics Approaches for Understanding Multi-omics Data)

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23 pages, 4983 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 14 | Viewed by 5839

Abstract

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

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

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

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7 pages, 1269 KiB

Open AccessEditor’s ChoiceCommunication

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

by Jacek Jasiecki and Bartosz Wasąg

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

Cited by 52 | Viewed by 9048

Abstract

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

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

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

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14 pages, 2733 KiB

Open AccessEditor’s ChoiceArticle

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

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

Biomolecules 2019, 9(10), 573; https://doi.org/10.3390/biom9100573 - 5 Oct 2019

Cited by 19 | Viewed by 4070

Abstract

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

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

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25 pages, 1637 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

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

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

Biomolecules 2019, 9(10), 562; https://doi.org/10.3390/biom9100562 - 3 Oct 2019

Cited by 38 | Viewed by 5742

Abstract

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

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

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

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28 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

Function, Regulation and Biological Roles of PI3Kγ Variants

by Bernd Nürnberg and Sandra Beer-Hammer

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

Cited by 39 | Viewed by 6169

Abstract

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

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

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

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16 pages, 3049 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 39 | Viewed by 6395

Abstract

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

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

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

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14 pages, 3274 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 35 | Viewed by 9584

Abstract

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

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

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

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26 pages, 2247 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 16 | Viewed by 6933

Abstract

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

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

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

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15 pages, 2132 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 11 | Viewed by 4160

Abstract

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

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

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

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16 pages, 965 KiB

Open AccessEditor’s ChoiceReview

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

by Eric D. Salomaki and Martin Kolisko

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

Cited by 25 | Viewed by 7279

Abstract

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

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

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

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38 pages, 5465 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 23 | Viewed by 5867

Abstract

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

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

(This article belongs to the Section Cellular Biochemistry)

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14 pages, 4542 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 30 | Viewed by 5176

Abstract

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

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

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16 pages, 2179 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 25 | Viewed by 5553

Abstract

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

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

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

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15 pages, 3867 KiB

Open AccessEditor’s ChoiceArticle

The Methodological Trends of Traditional Herbal Medicine Employing Network Pharmacology

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

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

Cited by 135 | Viewed by 13853

Abstract

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

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

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

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15 pages, 2773 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 17 | Viewed by 4865

Abstract

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

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

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

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17 pages, 1613 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 16 | Viewed by 4035

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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