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Medicines, Volume 6, Issue 3 (September 2019) – 25 articles

Cover Story (view full-size image): UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. We found that a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5-aza-2’-deoxycytidine (DAC) could slow melanoma cell growth. RNA sequence analysis revealed an increased number of differentially expressed genes in combination treatment. This included a key immunoregulatory cytokine associated with melanoma survival, C-C motif ligand 5 (CCL-5), validated using ELISA. These results indicate a potential combinatorial effect of a dietary antioxidant and an FDA-approved epigenetic drug in controlling melanoma cell growth. View this paper.
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18 pages, 472 KiB  
Review
Dietary Supplements on Controlling Multiple Sclerosis Symptoms and Relapses: Current Clinical Evidence and Future Perspectives
by Christina Tryfonos, Maria Mantzorou, Dimitris Fotiou, Michael Vrizas, Konstantinos Vadikolias, Eleni Pavlidou and Constantinos Giaginis
Medicines 2019, 6(3), 95; https://doi.org/10.3390/medicines6030095 - 12 Sep 2019
Cited by 16 | Viewed by 7853
Abstract
Background: Multiple sclerosis (MS) constitutes a chronic progressive demyelinating disease which negatively affects the central nervous system. MS symptoms detrimentally affect the quality of life, as well as the life expectancy of MS patients. In this aspect, the present study aims to critically [...] Read more.
Background: Multiple sclerosis (MS) constitutes a chronic progressive demyelinating disease which negatively affects the central nervous system. MS symptoms detrimentally affect the quality of life, as well as the life expectancy of MS patients. In this aspect, the present study aims to critically summarize and evaluate the currently available clinical studies focusing on the potential beneficial effects of dietary supplements on controlling MS symptomatology and relapse. Methods: PubMed database was comprehensively searched, using relative keywords to identify clinical trials that investigated the beneficial effects of dietary supplementation against MS symptomatology and progression. 40 clinical trials were found, which were divided into categories. Results: Nutritional status of MS patients, as well as supplementation have been suggested as potential factors affecting progression. Several substantial studies have documented a systematically high prevalence of vitamin A, B12 and D3 deficiency amongst MS patients. At present, clinical data have suggested that most of the dietary supplements under study may exert antioxidant and anti-inflammatory properties, improving depression symptomatology and quality of life overall. However, malnutrition risk in MS patients has not been adequately explored in order for more precise conclusions to be drawn. The supplements that may have a positive effect on MS are vitamins, fatty acids, antioxidants, phytochemicals and melatonin. Conclusions: Several dietary supplements may decrease inflammation and fatigue, also increasing also autoimmunity tolerance in MS patients, and thus improving quality of life and life expectancy. Currently, there is no effective clinical indication for applying dietary supplementation as complementary treatment against MS symptomatology. Full article
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24 pages, 502 KiB  
Review
Functional Foods and Bioactive Compounds: A Review of Its Possible Role on Weight Management and Obesity’s Metabolic Consequences
by Melina Konstantinidi and Antonios E. Koutelidakis
Medicines 2019, 6(3), 94; https://doi.org/10.3390/medicines6030094 - 9 Sep 2019
Cited by 108 | Viewed by 12805
Abstract
Background: Weight management and obesity prevention is a basic aim of health organizations in order to decrease the prevalence of various metabolic disorders. The aim of the present review article was the evaluation of the possible role of functional foods and their bioactive [...] Read more.
Background: Weight management and obesity prevention is a basic aim of health organizations in order to decrease the prevalence of various metabolic disorders. The aim of the present review article was the evaluation of the possible role of functional foods and their bioactive compounds as alternative way to promote weight management and prevent obesity and its metabolic consequences. Methods: Approximately 100 articles were selected from Scopus, PubMed, Google Scholar, and Science Direct, by using relative key words, and based mainly on recent animal, clinical or epidemiological studies. Results: The literature review highlighted the possible effect of specific functional foods such as coffee, green tea, berries, nuts, olive oil, pomegranate, avocado, and ginger. Specific bioactive compounds of those foods—such as caffeine, catechins, gallic acid, anthocyanins, ascorbic acid, polyphenols, oleuropein, capsaicin, and quercetin—may contribute to weight management, obesity prevention, and obesity’s metabolic consequences. The possible mechanisms include effect on satiety, lipid absorption, fatty acids beta oxidation, stimulation of thermogenesis, etc. Conclusions: Functional foods, as part of a balanced diet, could be useful in the direction of weight management and decrease of obesity’s’ metabolic consequences. However, the scientific evidence is unclear and in most cases controversial and more clinical and epidemiological studies are needed in order to further investigate the mechanisms of their possible effect. Full article
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9 pages, 526 KiB  
Article
Cervical Cancer Prevention in Racially Disparate Rural Populations
by Patti Olusola, Kia Ousley, Harrison Ndetan, Karan P. Singh, Hirendra Nath Banerjee and Santanu Dasgupta
Medicines 2019, 6(3), 93; https://doi.org/10.3390/medicines6030093 - 4 Sep 2019
Cited by 4 | Viewed by 3078
Abstract
Background: Undergoing a timely Pap smear, high-risk human papilloma virus (HPV)- and colposcopy-based testing can reduce HPV-associated cervical cancer (CC) development in women. However, in rural areas, women and minorities without insurance do not undergo periodic assessment and remain at greater risk of [...] Read more.
Background: Undergoing a timely Pap smear, high-risk human papilloma virus (HPV)- and colposcopy-based testing can reduce HPV-associated cervical cancer (CC) development in women. However, in rural areas, women and minorities without insurance do not undergo periodic assessment and remain at greater risk of HPV infection and CC. Methods: In this study, 173 women from rural East Texas with various ethnic backgrounds were examined thorough HPV/Pap-based testing and colposcopic assessment. Results: Of the 113 informative cases, 77% (87/113) were positive for high-risk HPV infection and 23% of subjects (26/113) were negative. Associations between HPV positivity with young age (p = 0.002), and a low number of pregnancy (p = 0.004) and births (p = 0.005) were evident. Women with long-term use of contraceptives (OR 1.93, 95% CI, 0.80–4.69) were associated with increased risk of HPV infection. African-American women had a higher risk of abnormal Pap outcome compared to Caucasians (OR 5.31, 95% CI, 0.67–42.0). HPV seemed to be a predictor of abnormal Pap outcome (OR 1.77, 95% CI, 0.48–6.44) in these subjects. Unmarried/widowed/divorced women had an increased abnormal Pap test outcome compared to married women or women living with a partner (p = 0.01), with over 278% increased odds (OR 3.78 at 95% CI, 1.29–11.10). Insured women undergoing periodic checkups were detected early with high-risk HPV infection and abnormal Pap test/colposcopic outcome. Conclusions: Comprehensive and timely screening of uninsured women and minorities in rural East Texas are warranted, which could potentially prevent the onset of HPV-associated CC. Full article
(This article belongs to the Special Issue Novel Therapeutic and Preventive Approaches for Cancer)
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21 pages, 1163 KiB  
Review
Early Stage Glycosylation Biomarkers in Alzheimer’s Disease
by Patricia Regan, Paula L. McClean, Thomas Smyth and Margaret Doherty
Medicines 2019, 6(3), 92; https://doi.org/10.3390/medicines6030092 - 3 Sep 2019
Cited by 16 | Viewed by 5276
Abstract
Alzheimer’s disease (AD) is of great cause for concern in our ageing population, which currently lacks diagnostic tools to permit accurate and timely diagnosis for affected individuals. The development of such tools could enable therapeutic interventions earlier in the disease course and thus [...] Read more.
Alzheimer’s disease (AD) is of great cause for concern in our ageing population, which currently lacks diagnostic tools to permit accurate and timely diagnosis for affected individuals. The development of such tools could enable therapeutic interventions earlier in the disease course and thus potentially reducing the debilitating effects of AD. Glycosylation is a common, and important, post translational modification of proteins implicated in a host of disease states resulting in a complex array of glycans being incorporated into biomolecules. Recent investigations of glycan profiles, in a wide range of conditions, has been made possible due to technological advances in the field enabling accurate glycoanalyses. Amyloid beta (Aβ) peptides, tau protein, and other important proteins involved in AD pathogenesis, have altered glycosylation profiles. Crucially, these abnormalities present early in the disease state, are present in the peripheral blood, and help to distinguish AD from other dementias. This review describes the aberrant glycome in AD, focusing on proteins implicated in development and progression, and elucidates the potential of glycome aberrations as early stage biomarkers of AD. Full article
(This article belongs to the Special Issue Application of Glycobiology in the Treatment of Diseases)
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16 pages, 1000 KiB  
Review
Pathological Mechanisms and Therapeutic Targets for Trigeminal Neuropathic Pain
by Pawan Bista and Wendy L. Imlach
Medicines 2019, 6(3), 91; https://doi.org/10.3390/medicines6030091 - 22 Aug 2019
Cited by 36 | Viewed by 16724
Abstract
Trigeminal neuropathic pain is a chronic pain condition caused by damage or inflammation of the trigeminal nerve or its branches, with both peripheral and central nervous system dysfunction contributing to the disorder. Trigeminal pain conditions present with diagnostic and therapeutic challenges to healthcare [...] Read more.
Trigeminal neuropathic pain is a chronic pain condition caused by damage or inflammation of the trigeminal nerve or its branches, with both peripheral and central nervous system dysfunction contributing to the disorder. Trigeminal pain conditions present with diagnostic and therapeutic challenges to healthcare providers and often require multiple therapeutic approaches for pain reduction. This review will provide the overview of pathophysiology in peripheral and central nociceptive circuits that are involved in neuropathic pain conditions involving the trigeminal nerve and the current therapeutics that are used to treat these disorders. Recent advances in treatment of trigeminal pain, including novel therapeutics that target ion channels and receptors, gene therapy and monoclonal antibodies that have shown great promise in preclinical studies and clinical trials will also be described. Full article
(This article belongs to the Special Issue Novel Agents and Complementary Therapies for Chronic Pain)
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14 pages, 2258 KiB  
Article
Investigation of Anthocyanins Stability from Pomegranate Juice (Punica Granatum L. Cv Ermioni) under a Simulated Digestion Process
by Chrysavgi Gardeli, Kalliopi Varela, Eleni Krokida and Athanasios Mallouchos
Medicines 2019, 6(3), 90; https://doi.org/10.3390/medicines6030090 - 20 Aug 2019
Cited by 16 | Viewed by 3724
Abstract
Background: Pomegranate gained a widespread popularity as a functional food due to the high content of bioactive components of the whole fruit, as well as its juice and extracts. There is a large amount of research that assigns them very important functions for [...] Read more.
Background: Pomegranate gained a widespread popularity as a functional food due to the high content of bioactive components of the whole fruit, as well as its juice and extracts. There is a large amount of research that assigns them very important functions for the human organism. Methods: The anthocyanins (ACNs) of pomegranate juice (PJ) from the Ermioni variety are quantitatively identified and their stability under a simulated digestion process (SDP) is investigated. ACNs, as well as phenolic compounds, were isolated through solid phase extraction and determined using high-performance liquid chromatography in every stage of the SDP. Total phenolics, total monomeric ACNs, polymeric color and antioxidant activity were also determined in pomegranate juice and during the digestion process. Results: The predominant anthocyanin was Cy-3-glucoside followed by the corresponding 3,5-diglucoside, which accounted for 40.8% and 27.4% of the total ACN content, respectively. About 65% of the total monomeric ACN content remained intact by the end of the simulated digestion process. Conclusions: The PJ of the Ermioni variety seems to retain a large amount of the bioactive compounds after the SDP. The antioxidant activity and total phenolic content (TPC) remain almost stable during the SDP, suggesting that the products formed during ACN degradation maintain the antioxidant activity of the parent molecule. Full article
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17 pages, 2494 KiB  
Article
Methylamine Activates Glucose Uptake in Human Adipocytes Without Overpassing Action of Insulin or Stimulating its Secretion in Pancreatic Islets
by Christian Carpéné, Pascale Mauriège, Nathalie Boulet, Simon Biron, Jean-Louis Grolleau, Maria José Garcia-Barrado and Mari Carmen Iglesias-Osma
Medicines 2019, 6(3), 89; https://doi.org/10.3390/medicines6030089 - 12 Aug 2019
Cited by 8 | Viewed by 3478
Abstract
Background: Methylamine, a natural soluble amine present in foods, is known to be a substrate of primary amine oxidase (PrAO) widely expressed in animal tissues. Methylamine has been reported to activate glucose transport in fat cells and to facilitate glucose disposal in rabbits [...] Read more.
Background: Methylamine, a natural soluble amine present in foods, is known to be a substrate of primary amine oxidase (PrAO) widely expressed in animal tissues. Methylamine has been reported to activate glucose transport in fat cells and to facilitate glucose disposal in rabbits but the interests and limits of such insulin-mimicking actions have not been further explored. This work aimed to perform a preclinical study of the inter-individual variations of these biological properties to study the putative link between PrAO activity and insulin resistance. Methods: Methylamine was tested on human adipocyte preparations and in rabbit pancreatic islets to determine its influence on glucose uptake and insulin release, respectively. PrAO activity and related responses were determined in adipose tissues obtained from two cohorts of non-obese and obese women. Results: Adipose tissue PrAO activity was negatively correlated with insulin resistance in high-risk obese women. PrAO-dependent activation of glucose uptake was negatively correlated with body mass index and reflected the decrease of insulin responsiveness of human fat cells with increasing obesity. Methylamine exhibited antilipolytic properties in adipocytes but was unable to directly activate insulin secretion in isolated pancreatic islets. Conclusions: PrAO activation by its substrates, e.g., methylamine, increases glucose utilization in human adipocytes in a manner that is linked to insulin responsiveness. Methylamine/PrAO interaction can therefore contribute to adipose tissue enlargement but should be considered as potentially useful for diabetes prevention since it could limit lipotoxicity and facilitate glucose handling, at the expense of favoring healthy fat accumulation. Full article
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10 pages, 832 KiB  
Article
Inpatient Burden of Prurigo Nodularis in the United States
by Katherine A. Whang, Sewon Kang and Shawn G. Kwatra
Medicines 2019, 6(3), 88; https://doi.org/10.3390/medicines6030088 - 11 Aug 2019
Cited by 35 | Viewed by 6152
Abstract
Background: Although prurigo nodularis (PN) has a significant burden of disease, little is known about its epidemiology and disease burden within the United States. We describe the characteristics of hospitalized patients diagnosed with PN and assess the factors associated with hospitalization. Methods: We [...] Read more.
Background: Although prurigo nodularis (PN) has a significant burden of disease, little is known about its epidemiology and disease burden within the United States. We describe the characteristics of hospitalized patients diagnosed with PN and assess the factors associated with hospitalization. Methods: We performed a cross-sectional study of the 2016 National Inpatient Sample, a representative sample of 20% of hospital discharges nationally. Results: Patients diagnosed with PN accounted for 3.7 inpatient visits per 100,000 discharges nationally in 2016. Patients with PN were more likely to be black (odds ratio (OR) 4.43, 95% CI (3.33–6.08), p < 0.001) or Asian (OR 3.44, 95% CI (1.39–5.08), p = 0.003) compared with white patients. Patients diagnosed with PN had both a longer length of hospital stay (mean ± SD, 6.51 ± 0.37 days vs. 4.62 ± 0.02 days, p < 0.001) and higher cost of care ($14,772 ± $964 vs. $11,728 ± $106, p < 0.001) compared with patients without PN. Patients with PN were significantly more likely to be admitted for HIV complications (OR 78.2, 95% CI (46.4–131.8), p < 0.001). PN contributes to increased inpatient cost of care and length of hospitalization. Conclusions: There are racial disparities associated with hospital admission of patients diagnosed with PN. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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14 pages, 3973 KiB  
Article
Robot-Controlled Acupuncture—An Innovative Step towards Modernization of the Ancient Traditional Medical Treatment Method
by Kun-Chan Lan and Gerhard Litscher
Medicines 2019, 6(3), 87; https://doi.org/10.3390/medicines6030087 - 10 Aug 2019
Cited by 23 | Viewed by 5566
Abstract
Background: For several years now, research teams worldwide have been conducting high-tech research on the development of acupuncture robots. In this article, the design of such an acupuncture robot is presented. Methods: Robot-controlled acupuncture (RCA) equipment consists of three components: (a) Acupuncture point [...] Read more.
Background: For several years now, research teams worldwide have been conducting high-tech research on the development of acupuncture robots. In this article, the design of such an acupuncture robot is presented. Methods: Robot-controlled acupuncture (RCA) equipment consists of three components: (a) Acupuncture point localization, (b) acupuncture point stimulation through a robotic arm, and (c) automated detection of a deqi event for the efficacy of acupuncture point stimulation. Results: This system is under development at the Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan. Acupuncture point localization and acupuncture point stimulation through a robotic arm works well; however, automated detection of a deqi sensation is still under development. Conclusions: RCA has become a reality and is no longer a distant vision. Full article
(This article belongs to the Special Issue Innovative Laser Medicine and Traditional Acupuncture Therapy)
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13 pages, 2837 KiB  
Article
A Visualization Tool for Cryo-EM Protein Validation with an Unsupervised Machine Learning Model in Chimera Platform
by Lin Chen, Brandon Baker, Eduardo Santos, Michell Sheep and Darius Daftarian
Medicines 2019, 6(3), 86; https://doi.org/10.3390/medicines6030086 - 6 Aug 2019
Cited by 1 | Viewed by 4674
Abstract
Background: Cryo-electron microscopy (cryo-EM) has become a major technique for protein structure determination. However, due to the low quality of cryo-EM density maps, many protein structures derived from cryo-EM contain outliers introduced during the modeling process. The current protein model validation system lacks [...] Read more.
Background: Cryo-electron microscopy (cryo-EM) has become a major technique for protein structure determination. However, due to the low quality of cryo-EM density maps, many protein structures derived from cryo-EM contain outliers introduced during the modeling process. The current protein model validation system lacks identification features for cryo-EM proteins making it not enough to identify outliers in cryo-EM proteins. Methods: This study introduces an efficient unsupervised outlier detection model for validating protein models built from cryo-EM technique. The current model uses a high-resolution X-ray dataset (<1.5 Å) as the reference dataset. The distal block distance, side-chain length, phi, psi, and first chi angle of the residues in the reference dataset are collected and saved as a database of the histogram-based outlier score (HBOS). The HBOS value of the residues in target cryo-EM proteins can be read from this HBOS database. Results: Protein residues with a HBOS value greater than ten are labeled as outliers by default. Four datasets containing proteins derived from cryo-EM density maps were tested with this probabilistic anomaly detection model. Conclusions: According to the proposed model, a visualization assistant tool was designed for Chimera, a protein visualization platform. Full article
(This article belongs to the Special Issue Novel Therapeutic and Preventive Approaches for Cancer)
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15 pages, 3414 KiB  
Review
A Short Review of Iron Metabolism and Pathophysiology of Iron Disorders
by Andronicos Yiannikourides and Gladys O. Latunde-Dada
Medicines 2019, 6(3), 85; https://doi.org/10.3390/medicines6030085 - 5 Aug 2019
Cited by 108 | Viewed by 34401
Abstract
Iron is a vital trace element for humans, as it plays a crucial role in oxygen transport, oxidative metabolism, cellular proliferation, and many catalytic reactions. To be beneficial, the amount of iron in the human body needs to be maintained within the ideal [...] Read more.
Iron is a vital trace element for humans, as it plays a crucial role in oxygen transport, oxidative metabolism, cellular proliferation, and many catalytic reactions. To be beneficial, the amount of iron in the human body needs to be maintained within the ideal range. Iron metabolism is one of the most complex processes involving many organs and tissues, the interaction of which is critical for iron homeostasis. No active mechanism for iron excretion exists. Therefore, the amount of iron absorbed by the intestine is tightly controlled to balance the daily losses. The bone marrow is the prime iron consumer in the body, being the site for erythropoiesis, while the reticuloendothelial system is responsible for iron recycling through erythrocyte phagocytosis. The liver has important synthetic, storing, and regulatory functions in iron homeostasis. Among the numerous proteins involved in iron metabolism, hepcidin is a liver-derived peptide hormone, which is the master regulator of iron metabolism. This hormone acts in many target tissues and regulates systemic iron levels through a negative feedback mechanism. Hepcidin synthesis is controlled by several factors such as iron levels, anaemia, infection, inflammation, and erythropoietic activity. In addition to systemic control, iron balance mechanisms also exist at the cellular level and include the interaction between iron-regulatory proteins and iron-responsive elements. Genetic and acquired diseases of the tissues involved in iron metabolism cause a dysregulation of the iron cycle. Consequently, iron deficiency or excess can result, both of which have detrimental effects on the organism. Full article
(This article belongs to the Section Endocrinology and Metabolic Disorders)
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7 pages, 558 KiB  
Article
Pruritus Associated with Commonly Prescribed Medications in a Tertiary Care Center
by Amy H. Huang, Benjamin H. Kaffenberger, Adam Reich, Jacek C. Szepietowski, Sonja Ständer and Shawn G. Kwatra
Medicines 2019, 6(3), 84; https://doi.org/10.3390/medicines6030084 - 4 Aug 2019
Cited by 11 | Viewed by 6337
Abstract
Background: Sparse data are available on rates of drug-induced pruritus, a well-recognized adverse reaction. We sought to assess relative rates of pruritus associated with commonly prescribed medications. Methods: Using the electronic medical record system EPIC, retrospective data were collected on patients seen at [...] Read more.
Background: Sparse data are available on rates of drug-induced pruritus, a well-recognized adverse reaction. We sought to assess relative rates of pruritus associated with commonly prescribed medications. Methods: Using the electronic medical record system EPIC, retrospective data were collected on patients seen at Johns Hopkins who received a medication of interest in a five-year period (2013–2018). Sequential criteria were used to identify the subpopulation who presented with a chief complaint of “pruritus” or diagnosis of “itching” within three months of receiving drugs. Results: We identified 9802 patients with pruritus after drug initiation and 1,085,404 patients without. A higher proportion of those with pruritus were female (70%) than those without (58%), p < 0.001. Patients in both groups were most commonly 50 to 79 years old. A higher proportion of patients with pruritus were black (40%) compared to those without (23%), p < 0.001. In this study, the highest rates of pruritus were observed with heparin (1.11%), trimethoprim-sulfamethoxazole (1.06%), and calcium channel blockers (0.92%). Psychiatric/neurologic drugs used to treat pruritus were associated with low rates of itch. Conclusions: Certain cardiovascular and antimicrobial agents are associated with increased frequencies of pruritus. This knowledge may guide providers in clinical selection of commonly used agents to minimize adverse effects associated with reduced compliance. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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5 pages, 239 KiB  
Perspective
Perspectives on Interval Exercise Interventions for Non-Alcoholic Fatty Liver Disease
by Hidetaka Hamasaki
Medicines 2019, 6(3), 83; https://doi.org/10.3390/medicines6030083 - 1 Aug 2019
Cited by 8 | Viewed by 3714
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an increased risk of type 2 diabetes, cardiovascular disease, cirrhosis, and liver cancer. Exercise therapy is the most effective treatment for patients with NAFLD. High-intensity interval training [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an increased risk of type 2 diabetes, cardiovascular disease, cirrhosis, and liver cancer. Exercise therapy is the most effective treatment for patients with NAFLD. High-intensity interval training (HIIT) is attracting attention as a time-efficient and an effective exercise modality for treating patients with NAFLD. Previous studies have shown that HIIT can reduce fat mass, visceral adipose tissue, and intrahepatic lipid levels and improve hepatic stiffness. HIIT may be an optimal exercise therapy to improve NAFLD in patients with a lack of time. Full article
136 pages, 2350 KiB  
Review
Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications
by Ugo Testa, Germana Castelli and Elvira Pelosi
Medicines 2019, 6(3), 82; https://doi.org/10.3390/medicines6030082 - 30 Jul 2019
Cited by 65 | Viewed by 11717
Abstract
Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with [...] Read more.
Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis. Full article
(This article belongs to the Section Cancer Biology and Anticancer Therapeutics)
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10 pages, 1345 KiB  
Article
Arctium lappa Extract Suppresses Inflammation and Inhibits Melanoma Progression
by Bruno A. C. Nascimento, Luiz G. Gardinassi, Inaê M. G. Silveira, Marília G. Gallucci, Mariana A. Tomé, Júlia Fernanda D. Oliveira, Mirella R. A. Moreira, Alyne F. G. Meirelles, Lúcia H. Faccioli, Cristiane Tefé-Silva and Karina F. Zoccal
Medicines 2019, 6(3), 81; https://doi.org/10.3390/medicines6030081 - 29 Jul 2019
Cited by 8 | Viewed by 4364
Abstract
Background: Arctium lappa has been used as popular medicinal herb and health supplement in Chinese societies. Bioactive components from A. lappa have attracted the attention of researchers due to their promising therapeutic effects. In this study, we investigated the effects of A. lappa [...] Read more.
Background: Arctium lappa has been used as popular medicinal herb and health supplement in Chinese societies. Bioactive components from A. lappa have attracted the attention of researchers due to their promising therapeutic effects. In this study, we investigated the effects of A. lappa hydroalcoholic extract (Alhe) during different models of inflammation, in vivo. Methods: The anti-inflammatory activity was evaluated through the air pouch model. For this, mice received an inflammatory stimulus with lipopolysaccharide (LPS) and were later injected with Alhe. To assess anti-tumoral activity, the animals were inoculated with B16F10 cells and injected with Alhe every 5 days, along the course of 30 days. Controls were submitted to the same conditions and injected with the vehicle. Peritoneal or air pouch fluids were collected to evaluate leukocyte counting or cellular activation via quantification of cytokines and nitric oxide. Results: Alhe injection reduced the neutrophil influx and production of inflammatory mediators in inflammatory foci after LPS or tumor challenges. Furthermore, Alhe injection reduced tumor growth and enhanced mice survival. Conclusions: Collectively, these data suggest that Alhe regulates immune cell migration and activation, which correlates with favorable outcome in mouse models of acute inflammation and melanoma progression. Full article
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26 pages, 2043 KiB  
Review
Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends
by Giancarlo Ghiselli
Medicines 2019, 6(3), 80; https://doi.org/10.3390/medicines6030080 - 29 Jul 2019
Cited by 15 | Viewed by 4544
Abstract
The polyanionic nature and the ability to interact with proteins with different affinities are properties of sulfated glycosaminoglycans (GAGs) that determine their biological function. In designing drugs affecting the interaction of proteins with GAGs the challenge has been to generate agents with high [...] Read more.
The polyanionic nature and the ability to interact with proteins with different affinities are properties of sulfated glycosaminoglycans (GAGs) that determine their biological function. In designing drugs affecting the interaction of proteins with GAGs the challenge has been to generate agents with high binding specificity. The example to emulated has been a heparin-derived pentasaccharide that binds to antithrombin-III with high affinity. However, the portability of this model to other biological situations is questioned on several accounts. Because of their structural flexibility, oligosaccharides with different sulfation and uronic acid conformation can display the same binding proficiency to different proteins and produce comparable biological effects. This circumstance represents a formidable obstacle to the design of drugs based on the heparin scaffold. The conceptual framework discussed in this article is that through a direct intervention on the heparin-binding functionality of proteins is possible to achieve a high degree of action specificity. This objective is currently pursued through two strategies. The first makes use of small molecules for which in the text we provide examples from past and present literature concerning angiogenic factors and enzymes. The second approach entails the mutagenesis of the GAG-binding site of proteins as a means to generate a new class of biologics of therapeutic interest. Full article
(This article belongs to the Special Issue Application of Glycobiology in the Treatment of Diseases)
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16 pages, 4633 KiB  
Article
A Review of Bioinformatics Tools to Understand Acetaminophen-Alcohol Interaction
by Bryan Hedgpeth, Roy Missall, Anna Bambaci, Matthew Smolen, Sevgi Yavuz, Jessica Cottrell, Tinchun Chu and Sulie L. Chang
Medicines 2019, 6(3), 79; https://doi.org/10.3390/medicines6030079 - 25 Jul 2019
Cited by 3 | Viewed by 4985
Abstract
Background: Drug-ethanol interaction can result in hepatotoxicity. The liver is capable of metabolizing both acetaminophen and ethanol; however, severe acute or moderate chronic simultaneous exposure can cause cell and tissue damage. Therapeutic doses can become harmful if gene activity is altered via competition [...] Read more.
Background: Drug-ethanol interaction can result in hepatotoxicity. The liver is capable of metabolizing both acetaminophen and ethanol; however, severe acute or moderate chronic simultaneous exposure can cause cell and tissue damage. Therapeutic doses can become harmful if gene activity is altered via competition for metabolic pathways. Simultaneous intake of ethanol and acetaminophen results in overactive CYP2E1 and depletion of glutathione, leaving NAPQI to build up in the liver. NAPQI is a hepatotoxic substance typically neutralized by glutathione. Methods: Bioinformatics tools including PharmGKB, Chemical Annotation Retrieval Toolkit, Transcriptome Analysis Console 4.0 (TAC), wikipathways, STRING, and Ingenuity Pathway Analysis (IPA) were used to explore interactive metabolic pathways of ethanol-acetaminophen exposure as a proof of concept for assessing drug-drug or drug-alcohol interactions. Results: As the ethanol-acetaminophen comparison indicates, bioinformatics tools may be used to understand interactive pathways following exposure to ethanol and acetaminophen, with potential extrapolation to other drug-drug/drug-ethanol interactions. Conclusions: Direct interactive effects were not able to be confirmed through this bioinformatics study due to the lack of existing ethanol-acetaminophen simultaneous exposure data. This work suggests that a battery of software applications should be used to assess interactive effects. Full article
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3 pages, 234 KiB  
Editorial
Natural Compounds as New Cancer Treatments
by Enrique Barrajón-Catalán
Medicines 2019, 6(3), 78; https://doi.org/10.3390/medicines6030078 - 23 Jul 2019
Cited by 2 | Viewed by 2599
Abstract
Cancer is still a global challenge worldwide with a high impact not only on human health, causing morbidity and mortality, but also on economics [...] Full article
(This article belongs to the Special Issue Natural Compounds as New Cancer Treatments)
17 pages, 2522 KiB  
Review
CO2 Transoral Laser Microsurgery in Benign, Premalignant and Malignant (Tis, T1, T2) Lesion of the Glottis. A Literature Review
by Carlos Miguel Chiesa-Estomba, Jose Angel González-García, Ekhiñe Larruscain, Christian Calvo-Henríquez, Miguel Mayo-Yáñez and Jon A Sistiaga-Suarez
Medicines 2019, 6(3), 77; https://doi.org/10.3390/medicines6030077 - 22 Jul 2019
Cited by 11 | Viewed by 6410
Abstract
Carbon Dioxide transoral laser microsurgery represents a reliable option for the treatment of early glottic carcinoma (Tis–T2), with good functional and oncological outcomes, nowadays representing one of the main options in larynx preservation protocols. The development and improvement of laser devices means surgeons [...] Read more.
Carbon Dioxide transoral laser microsurgery represents a reliable option for the treatment of early glottic carcinoma (Tis–T2), with good functional and oncological outcomes, nowadays representing one of the main options in larynx preservation protocols. The development and improvement of laser devices means surgeons are able to use more precise instruments compared with classic cold dissection in laser-assisted phonosurgery. Secondary effects on voice, swallowing, or quality of life as well as complications have been well documented. Also, with the introduction of a new proposal for staging systems following the principle of the three-dimensional map of isoprognostic zones, the use of narrow-band imaging in clinical evaluation and intraoperative, and the implementation of diffusion-weighted magnetic resonance during preoperative evaluation, the development of new tools to improve surgical quality and preliminary reports regarding the use of carbon dioxide laser in transoral robotic surgery suggests an exciting future for this technique. Full article
(This article belongs to the Special Issue Innovative Laser Medicine and Traditional Acupuncture Therapy)
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14 pages, 1633 KiB  
Review
Breaking the Itch–Scratch Cycle: Topical Options for the Management of Chronic Cutaneous Itch in Atopic Dermatitis
by Ian P. Harrison and Fabrizio Spada
Medicines 2019, 6(3), 76; https://doi.org/10.3390/medicines6030076 - 18 Jul 2019
Cited by 19 | Viewed by 9014
Abstract
Chronic itch is an unpleasant sensation that triggers a desire to scratch that lasts for six weeks or more. It is a major diagnostic symptom of myriad diseases, including atopic dermatitis for which it is the most prominent feature. Chronic itch can be [...] Read more.
Chronic itch is an unpleasant sensation that triggers a desire to scratch that lasts for six weeks or more. It is a major diagnostic symptom of myriad diseases, including atopic dermatitis for which it is the most prominent feature. Chronic itch can be hugely debilitating for the sufferer, damaging in terms of both the monetary cost of treatment and its socioeconomic effects, and few treatment options exist that can adequately control it. Corticosteroids remain the first line treatment strategy for atopic dermatitis, but due to the risks associated with long-term use of corticosteroids, and the drawbacks of other topical options such as topical calcineurin inhibitors and capsaicin, topical options for itch management that are efficacious and can be used indefinitely are needed. In this review, we detail the pathophysiology of chronic pruritus, its key features, and the disease most commonly associated with it. We also assess the role of the skin and its components in maintaining a healthy barrier function, thus reducing dryness and the itch sensation. Lastly, we briefly detail examples of topical options for the management of chronic pruritus that can be used indefinitely, overcoming the risk associated with long-term use of corticosteroids. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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7 pages, 242 KiB  
Article
Intra-Articular Laser Treatment Plus Platelet Rich Plasma (PRP) Significantly Reduces Pain in Many Patients Who Had Failed Prior PRP Treatment
by Chadwick C. Prodromos, Susan Finkle, Alexander Dawes and Angelo Dizon
Medicines 2019, 6(3), 75; https://doi.org/10.3390/medicines6030075 - 16 Jul 2019
Cited by 4 | Viewed by 3750
Abstract
Background: In our practice, Platelet Rich Plasma (PRP) injections effectively reduce pain in most, but not all, arthritic patients. When PRP treatment fails, joint replacement surgery is often the only good alternative. Surface Low-Level-Laser-Therapy (LLLT) has not been helpful for osteoarthrosis in our [...] Read more.
Background: In our practice, Platelet Rich Plasma (PRP) injections effectively reduce pain in most, but not all, arthritic patients. When PRP treatment fails, joint replacement surgery is often the only good alternative. Surface Low-Level-Laser-Therapy (LLLT) has not been helpful for osteoarthrosis in our experience. We hypothesized that intra-articular laser (IAL) treatment combined with PRP would improve results in patients with prior ineffective PRP treatment. Methods: We offered Intra-articular Low-Level-Laser-Therapy (IAL) treatment simultaneously with repeat PRP injection to patients who had received no benefit from PRP alone. They were the treatment and also historical control group since all had failed PRP treatment alone. Thirty joints were treated: 22 knees, 4 hips, 2 shoulder glenohumeral joints and 2 first carpo-metacarpal (1st CMC). Results: No adverse events were seen at any time after treatment in any patient. Twenty-eight joints were available for re-evaluation: ≥ 40% improvement was seen in 46% (6 months), 32% (12 months) and 32% (24 months) post-treatment. Mean SANE scores improved significantly at 1 and 2 years. Thirteen patients failed treatment and had joint replacement. Conclusions: PRP with IAL allowed avoidance of surgery and good pain control at least two years post-treatment in nearly half of patients who had failed PRP treatment alone. Full article
(This article belongs to the Special Issue Innovative Laser Medicine and Traditional Acupuncture Therapy)
20 pages, 308 KiB  
Review
Novel Delivery Systems for Checkpoint Inhibitors
by Purushottam Lamichhane, Rahul Deshmukh, Julie A. Brown, Silvia Jakubski, Priyanka Parajuli, Todd Nolan, Dewan Raja, Mary Badawy, Thomas Yoon, Mark Zmiyiwsky and Narottam Lamichhane
Medicines 2019, 6(3), 74; https://doi.org/10.3390/medicines6030074 - 11 Jul 2019
Cited by 19 | Viewed by 5450
Abstract
Checkpoint inhibition (CPI) therapies have been proven to be powerful clinical tools in treating cancers. FDA approvals and ongoing clinical development of checkpoint inhibitors for treatment of various cancers highlight the immense potential of checkpoint inhibitors as anti-cancer therapeutics. The occurrence of immune-related [...] Read more.
Checkpoint inhibition (CPI) therapies have been proven to be powerful clinical tools in treating cancers. FDA approvals and ongoing clinical development of checkpoint inhibitors for treatment of various cancers highlight the immense potential of checkpoint inhibitors as anti-cancer therapeutics. The occurrence of immune-related adverse events, however, is a major hindrance to the efficacy and use of checkpoint inhibitors as systemic therapies in a wide range of patients. Hence, methods of sustained and tumor-targeted delivery of checkpoint inhibitors are likely to improve efficacy while also decreasing toxic side effects. In this review, we summarize the findings of the studies that evaluated methods of tumor-targeted delivery of checkpoint inhibitors, review their strengths and weaknesses, and discuss the outlook for therapeutic use of these delivery methods. Full article
(This article belongs to the Section Cancer Biology and Anticancer Therapeutics)
5 pages, 502 KiB  
Letter
Mirtazapine for the Treatment of Chronic Pruritus
by Raveena Khanna, Emily Boozalis, Micah Belzberg, John G. Zampella and Shawn G. Kwatra
Medicines 2019, 6(3), 73; https://doi.org/10.3390/medicines6030073 - 6 Jul 2019
Cited by 16 | Viewed by 4649
Abstract
Background: Chronic pruritus is a debilitating condition associated with a wide range of dermatologic, systemic and psychogenic etiologies. In patients with chronic pruritus that is refractory to conventional therapy, symptoms can significantly decrease quality of life by contributing to anxiety, sleep disturbances, and [...] Read more.
Background: Chronic pruritus is a debilitating condition associated with a wide range of dermatologic, systemic and psychogenic etiologies. In patients with chronic pruritus that is refractory to conventional therapy, symptoms can significantly decrease quality of life by contributing to anxiety, sleep disturbances, and in many cases depression. Recent studies have demonstrated the effectiveness of mirtazapine in relieving chronic itch that is refractory to standard first-line therapies. Methods: We searched PubMed for English-language articles containing the words (“pruritus” or “itch”) AND “antidepressant” and then conducted a systematic review of the current literature to summarize the efficacy of mirtazapine in treating chronic itch. Results: All studies reported a reduction in itch intensity following the administration of mirtazapine. Conclusion: Collectively, these studies suggest the potential for mirtazapine to relieve chronic itch attributed to dermatological causes and malignancies. As, such mirtazapine may be an option for patients with chronic pruritus that is refractory to typical first-line treatments. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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15 pages, 799 KiB  
Article
Chronic Pruritus Responding to Dupilumab—A Case Series
by Lisa L. Zhai, Kevin T. Savage, Connie C. Qiu, Annie Jin, Rodrigo Valdes-Rodriguez and Nicholas K. Mollanazar
Medicines 2019, 6(3), 72; https://doi.org/10.3390/medicines6030072 - 29 Jun 2019
Cited by 48 | Viewed by 7984
Abstract
Background: Chronic pruritus is defined as itch lasting for greater than six weeks. Pruritus is a burdensome manifestation of several internal and external disease states with a significant impact on quality of life. Dupilumab has shown promise in treating a number of conditions [...] Read more.
Background: Chronic pruritus is defined as itch lasting for greater than six weeks. Pruritus is a burdensome manifestation of several internal and external disease states with a significant impact on quality of life. Dupilumab has shown promise in treating a number of conditions including atopic dermatitis (AD) and asthma. Its success in reducing pruritus in AD has generated interest regarding its potential application in other pruritic conditions, such as chronic pruritus of unknown origin, uremic pruritus, and pruigo nodularis. Methods: In this retrospective analysis, we present a series of 20 recalcitrant pruritus patients seen at a tertiary center treated with off-label dupilumab at standard AD dosing. Results: Dupilumab was successful at reducing itch in all treated patients, leading to complete resolution in 12/20 patients and an overall mean NRSi reduction of 7.55. Dupilumab was well tolerated with no significant adverse effects. Conclusions: Our case series suggests dupilumab may be a safe and efficacious therapeutic option in several pruritic conditions and demonstrates the need for further studies to better ascertain its place in the pruritus treatment armamentarium. Full article
(This article belongs to the Special Issue Pathogenesis and Treatment of Chronic Pruritus)
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18 pages, 2033 KiB  
Article
Effect of Sulforaphane and 5-Aza-2’-Deoxycytidine on Melanoma Cell Growth
by Tung-chin Chiang, Brian Koss, L. Joseph Su, Charity L. Washam, Stephanie D. Byrum, Aaron Storey and Alan J. Tackett
Medicines 2019, 6(3), 71; https://doi.org/10.3390/medicines6030071 - 27 Jun 2019
Cited by 6 | Viewed by 3722
Abstract
Background: UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. Accordingly, we explored whether a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5-aza-2’-deoxycytidine (DAC) [...] Read more.
Background: UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. Accordingly, we explored whether a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5-aza-2’-deoxycytidine (DAC) could slow melanoma cell growth. SFN is a natural bioactivated product of the cruciferous family, while DAC is a DNA methyltransferase inhibitor. Methods: Melanoma cell growth characteristics, gene transcription profiles, and histone epigenetic modifications were measured after single and combination treatments with SFN and DAC. Results: We detected melanoma cell growth inhibition and specific changes in gene expression profiles upon combinational treatments with SFN and DAC, while no significant alterations in histone epigenetic modifications were observed. Dysregulated gene transcription of a key immunoregulator cytokine—C-C motif ligand 5 (CCL-5)—was validated. Conclusions: These results indicate a potential combinatorial effect of a dietary antioxidant and an FDA-approved epigenetic drug in controlling melanoma cell growth. Full article
(This article belongs to the Special Issue Natural Compounds as New Cancer Treatments)
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