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Biomedicines
Volume 7
Issue 3
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Biomedicines, Volume 7, Issue 3 (September 2019) – 26 articles

Cover Story (view full-size image): Cover story: In the tumor microenvironment, nerve density is often increased, and it has recently been shown that there is a crosstalk between nerves and cancer cells. In short, various neurotransmitters secreted from nerve endings stimulate (cancer) stem cells and promote tumor growth. In turn, cancer cells can secrete neurotrophins, which promote axon growth from neuronal cells into cancer tissues. Targeting this crosstalk could be a promising therapeutic approach. View this paper.
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22 pages, 2719 KiB  
Article
Antihyperlipidemic and Antioxidant Effects of Averrhoa Carambola Extract in High-Fat Diet-Fed Rats
by Saleem H. Aladaileh, Sultan A. M. Saghir, Kisantini Murugesu, Amirin Sadikun, Ashfaq Ahmad, Gurjeet Kaur, Ayman M. Mahmoud and Vikneswaran Murugaiyah
Biomedicines 2019, 7(3), 72; https://doi.org/10.3390/biomedicines7030072 - 16 Sep 2019
Cited by 31 | Viewed by 7716
Abstract
The present study explored the antihyperlipidemic potential of a standardized methanolic extract of Averrhoa carambola (A. carambola) leaf (MEACL) in high-fat diet (HFD)-fed rats. The standardized MEACL was orally administered at different doses (250, 500, and 1000 mg/kg) to HFD-induced hyperlipidemic [...] Read more.
The present study explored the antihyperlipidemic potential of a standardized methanolic extract of Averrhoa carambola (A. carambola) leaf (MEACL) in high-fat diet (HFD)-fed rats. The standardized MEACL was orally administered at different doses (250, 500, and 1000 mg/kg) to HFD-induced hyperlipidemic rats for five weeks. Serum lipid profile, body weight changes, body mass index (BMI), daily food intake, relative organ weight, and histology of the liver were evaluated. In addition, the effect of MEACL on HMG-CoA reductase and pancreatic lipase activities as well as hepatic and fecal lipids was demonstrated. MEACL supplementation reduced serum lipids in HFD-fed rats in a dose-dependent manner. Histopathological scores revealed that 1000 mg/kg MEACL restored the damage to liver tissue in hyperlipidemic rats. MEACL decreased the body mass index (BMI), atherogenic index, and hepatic cholesterol and triglycerides and increased fecal cholesterol and bile acids in HFD-fed rats. Also, MEACL ameliorated lipid peroxidation and improved antioxidant defenses in the liver of HFD-fed rats. Furthermore, HMG-CoA reductase and lipase were suppressed by MEACL. In conclusion, this study shows the potential effect of MEACL to ameliorate hyperlipidemia and oxidative stress in HFD-fed rats. It prevented hepatic lipid accumulation and exerted an inhibitory effect on HMG-CoA reductase and lipase. Full article
(This article belongs to the Section Drug Discovery and Development)
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8 pages, 480 KiB  
Review
Zebrafish: A Powerful Model for Understanding the Functional Relevance of Noncoding Region Mutations in Human Genetic Diseases
by Anita Mann and Shipra Bhatia
Biomedicines 2019, 7(3), 71; https://doi.org/10.3390/biomedicines7030071 - 16 Sep 2019
Cited by 5 | Viewed by 3393
Abstract
Determining aetiology of genetic disorders caused by damaging mutations in protein-coding genes is well established. However, understanding how mutations in the vast stretches of the noncoding genome contribute to genetic abnormalities remains a huge challenge. Cis-regulatory elements (CREs) or enhancers are an important [...] Read more.
Determining aetiology of genetic disorders caused by damaging mutations in protein-coding genes is well established. However, understanding how mutations in the vast stretches of the noncoding genome contribute to genetic abnormalities remains a huge challenge. Cis-regulatory elements (CREs) or enhancers are an important class of noncoding elements. CREs function as the primary determinants of precise spatial and temporal regulation of their target genes during development by serving as docking sites for tissue-specific transcription factors. Although a large number of potential disease-associated CRE mutations are being identified in patients, lack of robust methods for mechanistically linking these mutations to disease phenotype is currently hampering the understanding of their roles in disease aetiology. Here, we have described the various systems available for testing the CRE potential of stretches of noncoding regions harbouring mutations implicated in human disease. We highlight advances in the field leading to the establishment of zebrafish as a powerful system for robust and cost-effective functional assays of CRE activity, enabling rapid identification of causal variants in regulatory regions and the validation of their role in disruption of appropriate gene expression. Full article
(This article belongs to the Special Issue Zebrafish Models for Development and Disease)
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15 pages, 15503 KiB  
Article
Induction of Urokinase Activity by Retinoic Acid in Two Cell Lines of Neuronal Origin
by Luka Horvat, Josip Madunić, Martina Grubar, Mariastefania Antica and Maja Matulić
Biomedicines 2019, 7(3), 70; https://doi.org/10.3390/biomedicines7030070 - 12 Sep 2019
Viewed by 3605
Abstract
Retinoic acid is one of the most well-known agents able to induce differentiation in several types of tumours. Unfortunately, most of the tumours are refractive to the differentiation cues. The aim of this investigation was to analyse the effects of prolonged treatment with [...] Read more.
Retinoic acid is one of the most well-known agents able to induce differentiation in several types of tumours. Unfortunately, most of the tumours are refractive to the differentiation cues. The aim of this investigation was to analyse the effects of prolonged treatment with retinoic acid on two cell lines of neural origin refractive to differentiation. Cells were also treated with retinoic acid in combination with a poly(ADP-ribosyl) polymerase (PARP) inhibitor because PARP1 is a known chromatin modulator and can influence the process of differentiation. The main methods comprised tumour cell line culturing and treatment; analysis of RNA and protein expression after cell treatment; as well as analysis of urokinase activity, migration, and proliferation. Both cell lines continued to proliferate under the prolonged treatment and showed increase in urokinase plasminogen activator activity. Analysis of gene expression and cell phenotype revealed different mechanisms, which only in neuroblastoma H4 cells could indicate the process of epithelial-mesenchymal transition. The data collected indicate that the activity of the urokinase plasminogen activator, although belonging to an extracellular protease, does not necessary lead to epithelial-mesenchymal reprogramming and increase in cell migration but can have different outcomes depending on the intracellular milieu. Full article
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17 pages, 993 KiB  
Review
Temozolomide and Other Alkylating Agents in Glioblastoma Therapy
by Hannah Strobel, Tim Baisch, Rahel Fitzel, Katharina Schilberg, Markus D. Siegelin, Georg Karpel-Massler, Klaus-Michael Debatin and Mike-Andrew Westhoff
Biomedicines 2019, 7(3), 69; https://doi.org/10.3390/biomedicines7030069 - 9 Sep 2019
Cited by 155 | Viewed by 10688
Abstract
The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around [...] Read more.
The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk—or at least of the invading cells—by the blood brain barrier (BBB). TMZ crosses the BBB, but—unlike classic chemotherapeutics—does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences. Full article
(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)
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12 pages, 540 KiB  
Review
Alcoholic Liver Disease: Current Mechanistic Aspects with Focus on Their Clinical Relevance
by Rolf Teschke
Biomedicines 2019, 7(3), 68; https://doi.org/10.3390/biomedicines7030068 - 5 Sep 2019
Cited by 47 | Viewed by 6206
Abstract
The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition [...] Read more.
The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition as assumed for many decades but due to the ingested alcohol and its metabolic consequences although malnutrition may marginally contribute to disease aggravation. Ethanol is metabolized in the liver to the heavily reactive acetaldehyde via the alcohol dehydrogenase (ADH) and the cytochrome P450 isoform 2E1 of the microsomal ethanol-oxidizing system (MEOS). The resulting disturbances modify not only the liver parenchymal cells but also non-parenchymal cells such as Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These are activated by acetaldehyde, reactive oxygen species (ROS), and endotoxins, which are produced from bacteria in the gut and reach the liver due to gut leakage. A variety of intrahepatic signaling pathways and innate or acquired immune reactions are under discussion contributing to the pathogenesis of ALD via the five injurious hits responsible for disease aggravation. As some of the mechanistic steps are based on studies with in vitro cell systems or animal models, respective proposals for humans may be considered as tentative. However, sufficient evidence is provided for clinical risk factors that include the amount of alcohol used daily for more than a decade, gender differences with higher susceptibility of women, genetic predisposition, and preexisting liver disease. In essence, efforts within the last years were devoted to shed more light in the pathogenesis of ALD, much has been achieved but issues remain to what extent results obtained from experimental studies can be transferred to humans. Full article
(This article belongs to the Special Issue Alcoholic Liver Disease: Diagnostics and Therapeutics)
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12 pages, 1471 KiB  
Communication
Possible Uses of Plants of the Genus Asphodelus in Oral Medicine
by Mario Dioguardi, Pierpaolo Campanella, Armando Cocco, Claudia Arena, Giancarlo Malagnino, Diego Sovereto, Riccardo Aiuto, Luigi Laino, Enrica Laneve, Antonio Dioguardi, Khrystyna Zhurakivska and Lorenzo Lo Muzio
Biomedicines 2019, 7(3), 67; https://doi.org/10.3390/biomedicines7030067 - 2 Sep 2019
Cited by 4 | Viewed by 4028
Abstract
Among the many plants used in traditional medicine we have the plants of the genus Asphodelus, which are present in the Mediterranean area in North Africa and South East Asia, and have been used by indigenous peoples until recently for various pathologies, [...] Read more.
Among the many plants used in traditional medicine we have the plants of the genus Asphodelus, which are present in the Mediterranean area in North Africa and South East Asia, and have been used by indigenous peoples until recently for various pathologies, including: Psoriasis, alopecia areata, acne, burns, nephrolithiasis, toothache, and local inflammation. The scientific literature over the last five years has investigated the various effects of the metabolites extracted from plants of the genus Asphodelus, paying attention to the diuretic, antihypertensive, antimicrobial, anti-inflammatory, and antioxidant effects, and it also has begun to investigate the antitumor properties on tumor cell lines. Studies have been identified through bibliographic research on electronic databases. A total of 574 records were identified on the PubMed, Scopus, Web of Science, and EBSCO databases. After having proceeded to the screening of the articles with the application of the eligibility criteria (all the articles pertaining to the issue Asphodelus), we arrived at a number of 163 articles, and then after the elimination of overlaps, to 82 articles. There are 11 articles which investigate the possible uses of plants of the genus Asphodelus in oral medicine. In oral medicine, the possible uses investigated by the scientific literature are for the treatment of neoplastic (melanoma and oral cancer), viral (herpetic viruses), and microbial diseases (candida, bacteriosis, leishmaniasis), and in the affection of the skin. Full article
(This article belongs to the Section Drug Discovery and Development)
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37 pages, 650 KiB  
Review
Breaking Therapy Resistance: An Update on Oncolytic Newcastle Disease Virus for Improvements of Cancer Therapy
by Volker Schirrmacher, Stefaan van Gool and Wilfried Stuecker
Biomedicines 2019, 7(3), 66; https://doi.org/10.3390/biomedicines7030066 - 30 Aug 2019
Cited by 72 | Viewed by 8329
Abstract
Resistance to therapy is a major obstacle to cancer treatment. It may exist from the beginning, or it may develop during therapy. The review focusses on oncolytic Newcastle disease virus (NDV) as a biological agent with potential to break therapy resistance. This avian [...] Read more.
Resistance to therapy is a major obstacle to cancer treatment. It may exist from the beginning, or it may develop during therapy. The review focusses on oncolytic Newcastle disease virus (NDV) as a biological agent with potential to break therapy resistance. This avian virus combines, upon inoculation into non-permissive hosts such as human, 12 described anti-neoplastic effects with 11 described immune stimulatory properties. Fifty years of clinical application of NDV give witness to the high safety profile of this biological agent. In 2015, an important milestone was achieved, namely the successful production of NDV according to Good Manufacturing Practice (GMP). Based on this, IOZK in Cologne, Germany, obtained a GMP certificate for the production of a dendritic cell vaccine loaded with tumor antigens from a lysate of patient-derived tumor cells together with immunological danger signals from NDV for intracutaneous application. This update includes single case reports and retrospective analyses from patients treated at IOZK. The review also presents future perspectives, including the concept of in situ vaccination and the combination of NDV or other oncolytic viruses with checkpoint inhibitors. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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26 pages, 996 KiB  
Review
A Brief Review about the Role of Nanomaterials, Mineral-Organic Nanoparticles, and Extra-Bone Calcification in Promoting Carcinogenesis and Tumor Progression
by Marina Senchukova
Biomedicines 2019, 7(3), 65; https://doi.org/10.3390/biomedicines7030065 - 28 Aug 2019
Cited by 9 | Viewed by 4576
Abstract
People come in contact with a huge number of nanoparticles (NPs) throughout their lives, which can be of both natural and anthropogenic origin and are capable of entering the body through swallowing, skin penetration, or inhalation. In connection with the expanding use of [...] Read more.
People come in contact with a huge number of nanoparticles (NPs) throughout their lives, which can be of both natural and anthropogenic origin and are capable of entering the body through swallowing, skin penetration, or inhalation. In connection with the expanding use of nanomaterials in various industrial processes, the question of whether there is a need to study the potentially adverse effects of NPs on human health becomes increasingly important. Despite the fact that the nature and the extent of damage caused depends on the chemical and the physical characteristics of individual NPs, there are also general mechanisms related to their toxicity. These mechanisms include the ability of NPs to translocate to various organs through endocytosis, as well as their ability to stimulate the production of reactive oxygen species (ROS), leading to oxidative stress, inflammation, genotoxicity, metabolic changes, and potentially carcinogenesis. In this review, we discuss the main characteristics of NPs and the effects they cause at both cellular and tissue levels. We also focus on possible mechanisms that underlie the relationship of NPs with carcinogenesis. We briefly summarize the main concepts related to the role of endogenous mineral organic NPs in the development of various human diseases and their participation in extra-bone calcification. Considering data from both our studies and those published in scientific literature, we propose the revision of some ideas concerning extra-bone calcification, since it may be one of the factors associated with the initiation of the mechanisms of immunological tolerance. Full article
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10 pages, 1702 KiB  
Perspective
A Proposed Framework for Patient-Focused Policy at the U.S. Food and Drug Administration
by Carrie M. Kuehn
Biomedicines 2019, 7(3), 64; https://doi.org/10.3390/biomedicines7030064 - 27 Aug 2019
Cited by 7 | Viewed by 4756
Abstract
Medical product sponsors are encouraged to include the patient perspective in their medical product development strategy to inform product design, augment regulatory submissions, argue for alternative clinical trial designs, or to support indications in specific patient populations. The goal is to create a [...] Read more.
Medical product sponsors are encouraged to include the patient perspective in their medical product development strategy to inform product design, augment regulatory submissions, argue for alternative clinical trial designs, or to support indications in specific patient populations. The goal is to create a patient-focused ecosystem that enables industry to integrate the patient voice throughout the medical product lifecycle. To this end, the U. S. Food and Drug Administration (FDA) has published several guidance documents to provide industry with the expectations and opportunities for conducting patient-focused activities. From an industry perspective, the Center for Devices and Radiologic Health (CDRH) and the Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER) patient-focused policies are complementary. The basic tenets promoted in all FDA patient-focused guidance could apply across therapeutic areas. However, there remain differences in these guidance documents across FDA centers, and there is no framework in place to provide industry with consistent recommendations. Without a coordinated patient-focused policy from the FDA, there is the potential for confusion and a lack of consistency among industry and regulatory decision-makers. The objective of this paper was to propose an alternative framework for patient-focused policy at the FDA, which recognizes the potential for different types of patient input to be used across therapeutic areas and medical product types. Further, these policies need to provide greater clarity on how patient input data is used, so that sponsors may navigate the opportunities to use patient input regardless of the FDA center under which their product is regulated. Creating consistent, coherent, and transparent FDA patient-focused policy will encourage sponsors to obtain patient input more often and with greater certainty of the value that these data may have to their medical product strategies. Full article
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19 pages, 8963 KiB  
Article
Herbal Tea for the Management of Pharyngitis: Inhibition of Streptococcus pyogenes Growth and Biofilm Formation by Herbal Infusions
by Niluni M. Wijesundara and H. P. Vasantha Rupasinghe
Biomedicines 2019, 7(3), 63; https://doi.org/10.3390/biomedicines7030063 - 24 Aug 2019
Cited by 11 | Viewed by 9141
Abstract
Herbal teas are becoming popular as functional beverages due to their various health promotional properties. This study aimed at assessing 13 hot water infusions (HWIs) from different herbs against streptococcal pharyngitis (strep throat). Licorice root exhibited the lowest minimum inhibitory concentrations (MIC) of [...] Read more.
Herbal teas are becoming popular as functional beverages due to their various health promotional properties. This study aimed at assessing 13 hot water infusions (HWIs) from different herbs against streptococcal pharyngitis (strep throat). Licorice root exhibited the lowest minimum inhibitory concentrations (MIC) of 1.56 mg/mL, followed by barberry root, thyme, and oregano flowering shoots, with a MIC of 3.13 mg/mL. At their respective minimum bactericidal concentrations (MBC), licorice showed the bactericidal effect on S. pyogenes within 12 h after exposure while others need 24 h for a similar outcome. The HWIs exhibited inhibitory activity on biofilm formation, ranging from 1.56 to 6.25 mg/mL, which confirmed by ruptured cells or clusters of dead cell debris observed in scanning electron microscope (SEM). Overall, non-toxic concentrations of efficacious HWIs from licorice root, barberry root, thyme, and oregano flowering shoots may provide potential sources for developing herbal teas or biomedicine for the management of S. pyogenes infections. Full article
(This article belongs to the Section Drug Discovery and Development)
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28 pages, 5385 KiB  
Review
The Glucosinolates: A Sulphur Glucoside Family of Mustard Anti-Tumour and Antimicrobial Phytochemicals of Potential Therapeutic Application
by James Melrose
Biomedicines 2019, 7(3), 62; https://doi.org/10.3390/biomedicines7030062 - 19 Aug 2019
Cited by 65 | Viewed by 10575
Abstract
This study reviewed aspects of the biology of two members of the glucosinolate family, namely sinigrin and glucoraphanin and their anti-tumour and antimicrobial properties. Sinigrin and glucoraphanin are converted by the β-sulphoglucosidase myrosinase or the gut microbiota into their bioactive forms, allyl isothiocyanate [...] Read more.
This study reviewed aspects of the biology of two members of the glucosinolate family, namely sinigrin and glucoraphanin and their anti-tumour and antimicrobial properties. Sinigrin and glucoraphanin are converted by the β-sulphoglucosidase myrosinase or the gut microbiota into their bioactive forms, allyl isothiocyanate (AITC) and sulphoraphanin (SFN) which constitute part of a sophisticated defence system plants developed over several hundred million years of evolution to protect them from parasitic attack from aphids, ticks, bacteria or nematodes. Delivery of these components from consumption of cruciferous vegetables rich in the glucosinolates also delivers many other members of the glucosinolate family so the dietary AITCs and SFN do not act in isolation. In vitro experiments with purified AITC and SFN have demonstrated their therapeutic utility as antimicrobials against a range of clinically important bacteria and fungi. AITC and SFN are as potent as Vancomycin in the treatment of bacteria listed by the World Health Organisation as antibiotic-resistant “priority pathogens” and also act as anti-cancer agents through the induction of phase II antioxidant enzymes which inactivate potential carcinogens. Glucosinolates may be useful in the treatment of biofilms formed on medical implants and catheters by problematic pathogenic bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus and are potent antimicrobials against a range of clinically important bacteria and fungi. The glucosinolates have also been applied in the prevention of bacterial and fungal spoilage of food products in advanced atmospheric packaging technology which improves the shelf-life of these products. Full article
(This article belongs to the Section Drug Discovery and Development)
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18 pages, 874 KiB  
Review
Perspective on Adenoviruses: Epidemiology, Pathogenicity, and Gene Therapy
by Brennetta J. Crenshaw, Leandra B. Jones, Courtnee’ R. Bell, Sanjay Kumar and Qiana L. Matthews
Biomedicines 2019, 7(3), 61; https://doi.org/10.3390/biomedicines7030061 - 19 Aug 2019
Cited by 70 | Viewed by 9593
Abstract
Human adenoviruses are large (150 MDa) doubled-stranded DNA viruses that cause respiratory infections. These viruses are particularly pathogenic in healthy and immune-compromised individuals, and currently, no adenovirus vaccine is available for the general public. The purpose of this review is to describe (i) [...] Read more.
Human adenoviruses are large (150 MDa) doubled-stranded DNA viruses that cause respiratory infections. These viruses are particularly pathogenic in healthy and immune-compromised individuals, and currently, no adenovirus vaccine is available for the general public. The purpose of this review is to describe (i) the epidemiology and pathogenicity of human adenoviruses, (ii) the biological role of adenovirus vectors in gene therapy applications, and (iii) the potential role of exosomes in adenoviral infections. Full article
(This article belongs to the Special Issue Adenoviruses: From Virus to Medicine)
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27 pages, 2001 KiB  
Review
A Classic Herbal Formula Guizhi Fuling Wan for Menopausal Hot Flushes: From Experimental Findings to Clinical Applications
by Mingdi Li, Andrew Hung, Hong Li and Angela Wei Hong Yang
Biomedicines 2019, 7(3), 60; https://doi.org/10.3390/biomedicines7030060 - 18 Aug 2019
Cited by 14 | Viewed by 6075
Abstract
A classic herbal formula Guizhi Fuling Wan (GFW) has been used for managing menopausal hot flushes (MHFs), but the evidence across different study types has not been systematically summarized. This project investigated the clinical effects, phytochemistry, pharmacodynamics, and potential mechanisms of actions of [...] Read more.
A classic herbal formula Guizhi Fuling Wan (GFW) has been used for managing menopausal hot flushes (MHFs), but the evidence across different study types has not been systematically summarized. This project investigated the clinical effects, phytochemistry, pharmacodynamics, and potential mechanisms of actions of GFW on the causative target proteins potentially driving MHFs. Twenty English and Chinese databases were searched for relevant clinical and experimental studies. A total of 12,988 studies were identified, of which 46 were included. Seven clinical studies demonstrated GFW had no statistically significant changes in the frequency and severity of MHFs; however, it could improve peripheral blood flow in the fingertips, jaw, and toes. Thirty-five studies on phytochemistry identified 169 chemical compounds of GFW. Four experimental studies revealed GFW’s therapeutic effects (e.g., normalize calcitonin gene-related peptide (CGRP) level) and potential target protein/cytokine (estrogen receptor beta (ESR2) with genetic variation, CGRP receptor, and interleukin-8) on MHFs. Therapeutic effects across different study types were inconsistent, possibly due to the dose difference and genotype variety of ESR2 in the human population. Further clinical and experimental studies, as well as biochemical investigation on the mechanisms of actions of GFW, are recommended. Full article
(This article belongs to the Section Drug Discovery and Development)
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22 pages, 5342 KiB  
Article
Vindoline—A Natural Product from Catharanthus Roseus Reduces Hyperlipidemia and Renal Pathophysiology in Experimental Type 2 Diabetes
by Oluwafemi Omoniyi Oguntibeju, Yapo Aboua and Mediline Goboza
Biomedicines 2019, 7(3), 59; https://doi.org/10.3390/biomedicines7030059 - 13 Aug 2019
Cited by 20 | Viewed by 5303
Abstract
Cardiovascular diseases (CVDs) and kidney diseases in diabetes are linked to increased mortality and morbidity. The aim of this study was to evaluate the effect of vindoline derived from Catharanthus roseus in diabetes-induced CVDs and kidney disease through assessing inflammation, oxidative stress, hyperlipidaemia [...] Read more.
Cardiovascular diseases (CVDs) and kidney diseases in diabetes are linked to increased mortality and morbidity. The aim of this study was to evaluate the effect of vindoline derived from Catharanthus roseus in diabetes-induced CVDs and kidney disease through assessing inflammation, oxidative stress, hyperlipidaemia and kidney function parameters. Type 2 diabetes was induced in male Wistar rats by 10% fructose water intake for two weeks, followed by a single intraperitoneal injection of 40 mg/kg body weight of streptozotocin (STZ). Six groups (n = 8) of randomly divided rats received vindoline (20 mg/kg) or glibenclamide (5 mg/kg) daily for 6 weeks via oral gavage. Lipid profile markers and markers of atherogenic index were decreased in diabetic rats after treatment with vindoline and glibenclamide. The levels of urea were significantly increased in the diabetic control group (13.66 ± 0.9) compared to the diabetic groups treated with vindoline and glibenclamide (10.62 ± 0.6 and 10.82 ± 0.8), respectively. Vindoline did not significantly alter the levels of inflammatory cytokines; however glibenclamide lowered the levels of TNF-α in kidney and heart tissues. Vindoline improved the ferric reducing antioxidant power in diabetic hearts, while superoxide dismutase (SOD) oxygen radical absorbance capacity was increased in the kidneys. Lipid peroxidation was reduced when compared to the diabetic controls. Vindoline restored the structure of the renal parenchyma and was accompanied by significant decrease in the expression of caspase 9 in diabetic rats when compared to the diabetic controls. Full article
(This article belongs to the Section Drug Discovery and Development)
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9 pages, 670 KiB  
Review
Role of Muscarinic Acetylcholine Signaling in Gastrointestinal Cancers
by Mitsuru Konishi, Yoku Hayakawa and Kazuhiko Koike
Biomedicines 2019, 7(3), 58; https://doi.org/10.3390/biomedicines7030058 - 10 Aug 2019
Cited by 20 | Viewed by 6139
Abstract
In the tumor microenvironment, various stromal and immune cells accumulate and interact with cancer cells to contribute to tumor progression. Among stromal players, nerves have recently been recognized as key regulators of tumor growth. More neurotransmitters, such as catecholamines and acetylcholine (ACh), are [...] Read more.
In the tumor microenvironment, various stromal and immune cells accumulate and interact with cancer cells to contribute to tumor progression. Among stromal players, nerves have recently been recognized as key regulators of tumor growth. More neurotransmitters, such as catecholamines and acetylcholine (ACh), are present in tumors, as the cells that secrete neurotransmitters accumulate by the release of neurotrophic factors from cancer cells. In this short review, we focus on the role of nerve signaling in gastrointestinal (GI) cancers. Given that muscarinic acetylcholine receptor signaling seems to be a dominant regulator of GI stem cells and cancers, we review the function and mechanism of the muscarinic ACh pathway as a regulator of GI cancer progression. Accumulating evidence suggests that ACh, which is secreted from nerves and tuft cells, stimulates GI epithelial stem cells and contributes to cancer progression via muscarinic receptors. Full article
(This article belongs to the Special Issue Gastric Cancer Research: From Basic Science to the Clinic)
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12 pages, 2205 KiB  
Article
Olfactory Stimulation Effect of Aldehydes, Nonanal, and Decanal on the Human Electroencephalographic Activity, According to Nostril Variation
by Minju Kim, Kandhasamy Sowndhararajan, Hae Jin Choi, Se Jin Park and Songmun Kim
Biomedicines 2019, 7(3), 57; https://doi.org/10.3390/biomedicines7030057 - 31 Jul 2019
Cited by 24 | Viewed by 4288
Abstract
Fragrances play a pivotal role in humans’ psychological and physiological functions through the olfactory system. Aldehydes are important organic compounds with a variety of fragrance notes. Particularly, nonanal (C9) and decanal (C10) aldehydes are important natural fragrant components used to enhance floral, as [...] Read more.
Fragrances play a pivotal role in humans’ psychological and physiological functions through the olfactory system. Aldehydes are important organic compounds with a variety of fragrance notes. Particularly, nonanal (C9) and decanal (C10) aldehydes are important natural fragrant components used to enhance floral, as well as citrus notes in perfumery products. In general, each nostril of the human nose is tuned to smell certain odor molecules better than others due to slight turbinate swelling between the nostrils. Hence, the objective of the present investigation was aimed to evaluate the influence of binasal and uninasal inhalations of C9 and C10 aldehydes on human electroencephalographic (EEG) activity. Twenty healthy participants (10 males and 10 females) participated in this study. The EEG readings were recorded from 8 electrodes (QEEG-8 system) according to the International 10-20 System. The results revealed that C10 exposure exhibited significantly different EEG changes, during binasal and uninasal inhalations. In different brain regions, C10 odor markedly decreased the absolute alpha and absolute beta power spectra. In regards to C9 odor, significant changes of EEG power spectra were noticed only during binasal inhalation. In addition, C10 mainly produced changes at the left parietal site (P3) than other brain sites. In conclusion, the variations in EEG activities of C9 and C10 aldehydes might be owing to their characteristic fragrance quality, as well as the influence of nostril differences. Full article
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23 pages, 538 KiB  
Review
Diagnosis and Management of Progressive Multiple Sclerosis
by Gabrielle Macaron and Daniel Ontaneda
Biomedicines 2019, 7(3), 56; https://doi.org/10.3390/biomedicines7030056 - 29 Jul 2019
Cited by 55 | Viewed by 10136
Abstract
Multiple sclerosis is a chronic autoimmune disease of the central nervous system that results in varying degrees of disability. Progressive multiple sclerosis, characterized by a steady increase in neurological disability independently of relapses, can occur from onset (primary progressive) or after a relapsing–remitting [...] Read more.
Multiple sclerosis is a chronic autoimmune disease of the central nervous system that results in varying degrees of disability. Progressive multiple sclerosis, characterized by a steady increase in neurological disability independently of relapses, can occur from onset (primary progressive) or after a relapsing–remitting course (secondary progressive). As opposed to active inflammation seen in the relapsing–remitting phases of the disease, the gradual worsening of disability in progressive multiple sclerosis results from complex immune mechanisms and neurodegeneration. A few anti-inflammatory disease-modifying therapies with a modest but significant effect on measures of disease progression have been approved for the treatment of progressive multiple sclerosis. The treatment effect of anti-inflammatory agents is particularly observed in the subgroup of patients with younger age and evidence of disease activity. For this reason, a significant effort is underway to develop molecules with the potential to induce myelin repair or halt the degenerative process. Appropriate trial methodology and the development of clinically meaningful disability outcome measures along with imaging and biological biomarkers of progression have a significant impact on the ability to measure the efficacy of potential medications that may reverse disease progression. In this issue, we will review current evidence on the physiopathology, diagnosis, measurement of disability, and treatment of progressive multiple sclerosis. Full article
(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment)
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15 pages, 11061 KiB  
Review
A Mini-Review: Clinical Development and Potential of Aptamers for Thrombotic Events Treatment and Monitoring
by Alex T. Ponce and Ka Lok Hong
Biomedicines 2019, 7(3), 55; https://doi.org/10.3390/biomedicines7030055 - 26 Jul 2019
Cited by 26 | Viewed by 4691
Abstract
The unique opportunity for aptamer uses in thrombotic events has sparked a considerable amount of research in the area. The short half-lives of unmodified aptamers in vivo remain one of the major challenges in therapeutic aptamers. Much of the incremental successful therapeutic aptamer [...] Read more.
The unique opportunity for aptamer uses in thrombotic events has sparked a considerable amount of research in the area. The short half-lives of unmodified aptamers in vivo remain one of the major challenges in therapeutic aptamers. Much of the incremental successful therapeutic aptamer stories were due to modifications in the aptamer bases. This mini-review briefly summarizes the successes and challenges in the clinical development of aptamers for thrombotic events, and highlights some of the most recent developments in using aptamers for anticoagulation monitoring. Full article
(This article belongs to the Special Issue Engineering Aptamers for Biomedical Applications II)
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15 pages, 1892 KiB  
Review
Management of Bleeding from Unresectable Gastric Cancer
by Hideaki Kawabata, Misuzu Hitomi and Shigehiro Motoi
Biomedicines 2019, 7(3), 54; https://doi.org/10.3390/biomedicines7030054 - 24 Jul 2019
Cited by 21 | Viewed by 9446
Abstract
Bleeding from unresectable gastric cancer (URGC) is not a rare complication. Two major ways in which the management of this issue differs from the management of benign lesions are the high rate of rebleeding after successful hemostasis and that not only endoscopic therapy [...] Read more.
Bleeding from unresectable gastric cancer (URGC) is not a rare complication. Two major ways in which the management of this issue differs from the management of benign lesions are the high rate of rebleeding after successful hemostasis and that not only endoscopic therapy (ET) and transcatheter arterial embolization (TAE) but palliative radiotherapy (PRT) can be applied in the clinical setting. However, there are no specific guidelines concerning the management of URGC with bleeding. We herein discuss strategies for managing bleeding from URGC. A high rate of initial hemostasis for active bleeding is expected when using various ET modalities properly. If ET fails in patients with hemostatic instability, emergent TAE is considered in order to avoid a life-threating condition due to massive bleeding. Early PRT, especially, regimens with a high biologically effective dose (BED) of ≥39 Gy should be considered not only for patients with hemostatic failure but also for those with successful hemostasis and inactive hemorrhage, as longer duration of response with few complications can be expected. Further prospective, comparative studies considering not only the hemostatic efficacy of these modalities but the patients’ quality of life are needed in order to establish treatment strategies for bleeding from URGC. Full article
(This article belongs to the Special Issue Gastric Cancer Research: From Basic Science to the Clinic)
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12 pages, 789 KiB  
Review
A Brief Overview of the Antitumoral Actions of Leelamine
by Myriam Merarchi, Young Yun Jung, Lu Fan, Gautam Sethi and Kwang Seok Ahn
Biomedicines 2019, 7(3), 53; https://doi.org/10.3390/biomedicines7030053 - 19 Jul 2019
Cited by 16 | Viewed by 4693
Abstract
For the last couple of decades, natural products, either applied singly or in conjunction with other cancer therapies including chemotherapy and radiotherapy, have allowed us to combat different types of human cancers through the inhibition of their initiation and progression. The principal sources [...] Read more.
For the last couple of decades, natural products, either applied singly or in conjunction with other cancer therapies including chemotherapy and radiotherapy, have allowed us to combat different types of human cancers through the inhibition of their initiation and progression. The principal sources of these useful compounds are isolated from plants that were described in traditional medicines for their curative potential. Leelamine, derived from the bark of pine trees, was previously reported as having a weak agonistic effect on cannabinoid receptors and limited inhibitory effects on pyruvate dehydrogenase kinases (PDKs). It has been reported to possess a strong lysosomotropic property; this feature enables its assembly inside the acidic compartments within a cell, such as lysosomes, which may eventually hinder endocytosis. In this review, we briefly highlight the varied antineoplastic actions of leelamine that have found implications in pharmacological research, and the numerous intracellular targets affected by this agent that can effectively negate the oncogenic process. Full article
(This article belongs to the Section Drug Discovery and Development)
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18 pages, 1579 KiB  
Article
Differential Roles of Dendritic Cells in Expanding CD4 T Cells in Sepsis
by Samuel Darkwah, Nodoka Nago, Michael G. Appiah, Phyoe Kyawe Myint, Eiji Kawamoto, Motomu Shimaoka and Eun Jeong Park
Biomedicines 2019, 7(3), 52; https://doi.org/10.3390/biomedicines7030052 - 18 Jul 2019
Cited by 13 | Viewed by 5269
Abstract
Sepsis is a systemically dysregulated inflammatory syndrome, in which dendritic cells (DCs) play a critical role in coordinating aberrant immunity. The aim of this study is to shed light on the differential roles played by systemic versus mucosal DCs in regulating immune responses [...] Read more.
Sepsis is a systemically dysregulated inflammatory syndrome, in which dendritic cells (DCs) play a critical role in coordinating aberrant immunity. The aim of this study is to shed light on the differential roles played by systemic versus mucosal DCs in regulating immune responses in sepsis. We identified a differential impact of the systemic and mucosal DCs on proliferating allogenic CD4 T cells in a mouse model of sepsis. Despite the fact that the frequency of CD4 T cells was reduced in septic mice, septic mesenteric lymph node (MLN) DCs proved superior to septic spleen (SP) DCs in expanding allogeneic CD4 T cells. Moreover, septic MLN DCs markedly augmented the surface expression of MHC class II and CD40, as well as the messaging of interleukin-1β (IL-1β). Interestingly, IL-1β-treated CD4 T cells expanded in a dose-dependent manner, suggesting that this cytokine acts as a key mediator of MLN DCs in promoting septic inflammation. Thus, mucosal and systemic DCs were found to be functionally different in the way CD4 T cells respond during sepsis. Our study provides a molecular basis for DC activity, which can be differential in nature depending on location, whereby it induces septic inflammation or immune-paralysis. Full article
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11 pages, 6733 KiB  
Communication
Biofunctional Textiles for Aging Skin
by Pierfrancesco Morganti, Gianluca Morganti and Claudia Colao
Biomedicines 2019, 7(3), 51; https://doi.org/10.3390/biomedicines7030051 - 17 Jul 2019
Cited by 36 | Viewed by 5652
Abstract
The skin is the largest organ in the human body, acting as the first protective barrier against the external environment aggression, such as UV rays and atmospheric nanoparticulate pollutants. On the one hand, the skin employs different antioxidant agents to protect its natural [...] Read more.
The skin is the largest organ in the human body, acting as the first protective barrier against the external environment aggression, such as UV rays and atmospheric nanoparticulate pollutants. On the one hand, the skin employs different antioxidant agents to protect its natural oxidative balance. On the other hand, ageing phenomena are the main cause of skin barrier damages, leading to a disequilibrium in the physiological redox system. Thus, the necessity to find new innovative cosmetic means, such as biodegradable non-woven tissues able to load, carry and release active ingredients in the right skin layers. These innovative cosmetic tissues can not only protect the skin from toxic environmental agents, but may balance the natural skin barrier, also acting as anti-aging agents when their fibers are bound to the right ingredients. The proposed tissues, consisting of polysaccharide natural fibers made of chitin nanofibrils and nanochitin, seem to be an ideal candidate for the production of new and effective biofunctional textiles, also because they are able to mimic the skin’s extra cellular matrix (ECM) when electrospun. These innovative cosmeceuticals have shown the possibility of being used for food formulations as well as for topic anti-aging agents, having shown an interesting repairing effectiveness on skin and also on hair. Thus, they could be used both as active ingredient and as skin smart active carriers in substitution of normal emulsions, being also biodegradable, free of chemicals, and obtainable from waste material. Full article
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10 pages, 3320 KiB  
Communication
The Function of Lgr5+ Cells in the Gastric Antrum Does Not Require Fzd7 or Myc In Vivo
by Dustin Flanagan, Nick Barker, Matthias Ernst, Elizabeth Vincan and Toby Phesse
Biomedicines 2019, 7(3), 50; https://doi.org/10.3390/biomedicines7030050 - 8 Jul 2019
Cited by 2 | Viewed by 4722
Abstract
The extreme chemical and mechanical forces endured by the gastrointestinal tract drive a constant renewal of the epithelial lining. Stem cells of the intestine and stomach, marked by the cell surface receptor Lgr5, preserve the cellular status-quo of their respective tissues through [...] Read more.
The extreme chemical and mechanical forces endured by the gastrointestinal tract drive a constant renewal of the epithelial lining. Stem cells of the intestine and stomach, marked by the cell surface receptor Lgr5, preserve the cellular status-quo of their respective tissues through receipt and integration of multiple cues from the surrounding niche. Wnt signalling is a critical niche component for gastrointestinal stem cells and we have previously shown that the Wnt receptor, Frizzled-7 (Fzd7), is required for gastric homeostasis and the function of Lgr5+ intestinal stem cells. Additionally, we have previously shown a requirement for the Wnt target gene Myc in intestinal homeostasis, regeneration and tumourigenesis. However, it is unknown whether Fzd7 or Myc have conserved functions in gastric Lgr5+ stem cells. Here we show that gastric Lgr5+ stem cells do not require Fzd7 or Myc and are able to maintain epithelial homeostasis, highlighting key differences in the way Wnt regulates homeostasis and Lgr5+ stem cells in the stomach compared to the intestinal epithelium. Furthermore, deletion of Myc throughout the epithelium of the gastric antrum has no deleterious effects suggesting therapeutic targeting of Myc in gastric cancer patients will be well tolerated by the surrounding normal tissue. Full article
(This article belongs to the Special Issue Gastric Cancer Research: From Basic Science to the Clinic)
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12 pages, 1867 KiB  
Article
Physicochemical and Biological Examination of Two Glatiramer Acetate Products
by Arthur Komlosh, Vera Weinstein, Pippa Loupe, Tal Hasson, Bracha Timan, Attila Konya, Jessica Alexander, Sigal Melamed-Gal and Steffen Nock
Biomedicines 2019, 7(3), 49; https://doi.org/10.3390/biomedicines7030049 - 3 Jul 2019
Cited by 12 | Viewed by 4684
Abstract
Herein we compared 40 mg/mL lots of the active ingredient, glatiramer acetate, manufactured by Mylan/Natco to the active ingredient, glatiramer acetate in Copaxone (Teva Pharmaceuticals, Ltd., Netanya Israel) using physicochemical (PCC) methods and biological assays. No differences were seen between the Mylan/Natco and [...] Read more.
Herein we compared 40 mg/mL lots of the active ingredient, glatiramer acetate, manufactured by Mylan/Natco to the active ingredient, glatiramer acetate in Copaxone (Teva Pharmaceuticals, Ltd., Netanya Israel) using physicochemical (PCC) methods and biological assays. No differences were seen between the Mylan/Natco and Teva lots with some low resolution release PCC assays (amino acid analysis, molecular weight distribution, interaction with Coomassie Brilliant Blue G-250). Changes in polydispersity between Mylan/Natco and Copaxone lots were found using size exclusion chromatography and the high resolution PCC method, known as Viscotek, and suggestive of a disparity in the homogeneity of mixture, with a shift towards high molecular weight polypeptides. Using RPLC-2D MALLS, 5 out of 8 Mylan/Natco lots fell outside the Copaxone range, containing a high molecular weight and high hydrophobicity subpopulation of polypeptides not found in Copaxone lots. Cation exchange chromatography showed differences in the surface charge distribution between the Copaxone and Mylan/Natco lots. The Mylan/Natco lots were found to be within Copaxone specifications for the EAE model, monoclonal and polyclonal binding assays and the in vitro cytotoxicity assay, however higher IL-2 secretion was shown for three Mylan/Natco lots in a potency assay. These observations provide data to inform the ongoing scientific discussion about the comparability of glatiramer acetate in Copaxone and follow-on products. Full article
(This article belongs to the Special Issue Peptides of Natural Origins as Leads for Drug Discovery: From Native Structures to Peptidomimetics, Peptide-Conjugates, and Peptide-Nanoparticles)
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6 pages, 2993 KiB  
Case Report
Zimmermann-Laband-1 Syndrome: Clinical, Histological, and Proteomic Findings of a 3-Year-Old Patient with Hereditary Gingival Fibromatosis
by Federica Guglielmi, Edoardo Staderini, Federica Iavarone, Laura Di Tonno and Patrizia Gallenzi
Biomedicines 2019, 7(3), 48; https://doi.org/10.3390/biomedicines7030048 - 29 Jun 2019
Cited by 14 | Viewed by 5139
Abstract
Background: Zimmermann-Laband-1 syndrome (ZLS-1; OMIM# 135500) is a rare genetic disorder whose oral pathognomonic sign is the development of progressive, diffuse, and severe gingival hypertrophy. Most children with abnormally gingival hyperplasia may also present multiple unerupted teeth and skeletal deformities of maxillary arches [...] Read more.
Background: Zimmermann-Laband-1 syndrome (ZLS-1; OMIM# 135500) is a rare genetic disorder whose oral pathognomonic sign is the development of progressive, diffuse, and severe gingival hypertrophy. Most children with abnormally gingival hyperplasia may also present multiple unerupted teeth and skeletal deformities of maxillary arches (i.e., skeletal anterior open bite). Despite phenotypic variability of the clinical spectrum, gingival fibromatosis is the hallmark of ZLS-1. Method: In this study, we report a 3-year-old male patient with a ZLS-1-related gingival overgrowth and failure of eruption of the deciduous teeth in the molar area. Surgical excision was performed under general anesthesia. Results: At three weeks follow-up, esthetics was significantly improved in terms of gingival appearance, and teeth eruption allowed an adequate masticatory function. Conclusion: In severe cases, surgical removal of the hyperplasic fibrous tissue may be required to expose unerupted teeth and establish a proper gingival contour. Surgical excision under general anesthesia is an elective procedure for patients with special needs, mental disability, as well as young and adult patients with dental anxiety type II and IV associated with poor oral health. Full article
(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy)
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12 pages, 351 KiB  
Article
Comparative Evaluation of Endotoxin Activity Level and Various Biomarkers for Infection and Outcome of ICU-Admitted Patients
by Toshiaki Ikeda, Hidenobu Kamohara, Shingo Suda, Takeo Nagura, Mikiko Tomino, Masatoshi Sugi and Zen’ichiro Wajima
Biomedicines 2019, 7(3), 47; https://doi.org/10.3390/biomedicines7030047 - 29 Jun 2019
Cited by 12 | Viewed by 4162
Abstract
Here, we concurrently measured the endotoxin activity (EA) level and levels of multiple biomarkers in patient blood obtained within 24 h after being admitted into the intensive care unit (ICU) and analyzed whether there were links between these markers and their associations with [...] Read more.
Here, we concurrently measured the endotoxin activity (EA) level and levels of multiple biomarkers in patient blood obtained within 24 h after being admitted into the intensive care unit (ICU) and analyzed whether there were links between these markers and their associations with patient conditions and outcomes. The EA levels highly correlated with disease severity and patient survival, and showed a significant positive association with levels of lactate, procalcitonin, presepsin, and interleukin-6. Notably, the EA level was the marker that most highly correlated with the results of blood culture, and the presepsin level was the marker most highly correlated with the survival outcome at 28 days. Thus, the optimal biomarker should be selected based on whether it will be used to discriminate the presence of an infection or to predict survival. Full article
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