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Pharmaceuticals, Volume 12, Issue 2 (June 2019)

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Cover Story (view full-size image) HIV-1 inhibition by the long-acting antiviral 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA). The [...] Read more.
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Open AccessReview
Psychotropic Drugs for the Management of Chronic Pain and Itch
Pharmaceuticals 2019, 12(2), 99; https://doi.org/10.3390/ph12020099
Received: 26 May 2019 / Revised: 19 June 2019 / Accepted: 21 June 2019 / Published: 24 June 2019
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Abstract
Clinical observations have shown that patients with chronic neuropathic pain or itch exhibit symptoms of increased anxiety, depression and cognitive impairment. Such patients need corrective therapy with antidepressants, antipsychotics or anticonvulsants. It is known that some psychotropic drugs are also effective for the [...] Read more.
Clinical observations have shown that patients with chronic neuropathic pain or itch exhibit symptoms of increased anxiety, depression and cognitive impairment. Such patients need corrective therapy with antidepressants, antipsychotics or anticonvulsants. It is known that some psychotropic drugs are also effective for the treatment of neuropathic pain and pruritus syndromes due to interaction with the secondary molecular targets. Our own clinical studies have identified antipruritic and/or analgesic efficacy of the following compounds: tianeptine (atypical tricyclic antidepressant), citalopram (selective serotonin reuptake inhibitor), mianserin (tetracyclic antidepressant), carbamazepine (anticonvulsant), trazodone (serotonin antagonist and reuptake inhibitor), and chlorprothixene (antipsychotic). Venlafaxine (serotonin-norepinephrine reuptake inhibitor) is known to have an analgesic effect too. The mechanism of such effect of these drugs is not fully understood. Herein we review and correlate the literature data on analgesic/antipruritic activity with pharmacological profile of these compounds. Full article
(This article belongs to the Special Issue The Story of Successful Drugs and Recent FDA-Approved Molecules)
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Open AccessArticle
Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells
Pharmaceuticals 2019, 12(2), 98; https://doi.org/10.3390/ph12020098
Received: 9 April 2019 / Revised: 5 June 2019 / Accepted: 6 June 2019 / Published: 21 June 2019
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Abstract
With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the [...] Read more.
With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and Aβ1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD. Full article
(This article belongs to the Special Issue Carbohydrates 2018)
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Open AccessReview
Lipid Metabolism as a Source of Druggable Targets for Antiviral Discovery against Zika and Other Flaviviruses
Pharmaceuticals 2019, 12(2), 97; https://doi.org/10.3390/ph12020097
Received: 14 May 2019 / Revised: 14 June 2019 / Accepted: 19 June 2019 / Published: 21 June 2019
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Abstract
The Zika virus (ZIKV) is a mosquito-borne flavivirus that can lead to birth defects (microcephaly), ocular lesions and neurological disorders (Guillain-Barré syndrome). There is no licensed vaccine or antiviral treatment against ZIKV infection. The effort to understand the complex interactions of ZIKV with [...] Read more.
The Zika virus (ZIKV) is a mosquito-borne flavivirus that can lead to birth defects (microcephaly), ocular lesions and neurological disorders (Guillain-Barré syndrome). There is no licensed vaccine or antiviral treatment against ZIKV infection. The effort to understand the complex interactions of ZIKV with cellular networks contributes to the identification of novel host-directed antiviral (HDA) candidates. Among the cellular pathways involved in infection, lipid metabolism gains attention. In ZIKV-infected cells lipid metabolism attributed to intracellular membrane remodeling, virion morphogenesis, autophagy modulation, innate immunity and inflammation. The key roles played by the cellular structures associated with lipid metabolism, such as peroxisomes and lipid droplets, are starting to be deciphered. Consequently, there is a wide variety of lipid-related antiviral strategies that are currently under consideration, which include an inhibition of sterol regulatory element-binding proteins (SREBP), the activation of adenosine-monophosphate activated kinase (AMPK), an inhibition of acetyl-Coenzyme A carboxylase (ACC), interference with sphingolipid metabolism, blockage of intracellular cholesterol trafficking, or a treatment with cholesterol derivatives. Remarkably, most of the HDAs identified in these studies are also effective against flaviviruses other than ZIKV (West Nile virus and dengue virus), supporting their broad-spectrum effect. Considering that lipid metabolism is one of the main cellular pathways suitable for pharmacological intervention, the idea of repositioning drugs targeting lipid metabolism as antiviral candidates is gaining force. Full article
(This article belongs to the Special Issue Zika Virus: Therapeutic Advances)
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Open AccessReview
Ferritin in Kidney and Vascular Related Diseases: Novel Roles for an Old Player
Pharmaceuticals 2019, 12(2), 96; https://doi.org/10.3390/ph12020096
Received: 30 April 2019 / Revised: 14 June 2019 / Accepted: 19 June 2019 / Published: 21 June 2019
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Abstract
Iron is at the forefront of a number of pivotal biological processes due to its ability to readily accept and donate electrons. However, this property may also catalyze the generation of free radicals with ensuing cellular and tissue toxicity. Accordingly, throughout evolution numerous [...] Read more.
Iron is at the forefront of a number of pivotal biological processes due to its ability to readily accept and donate electrons. However, this property may also catalyze the generation of free radicals with ensuing cellular and tissue toxicity. Accordingly, throughout evolution numerous pathways and proteins have evolved to minimize the potential hazardous effects of iron cations and yet allow for readily available iron cations in a wide variety of fundamental metabolic processes. One of the extensively studied proteins in the context of systemic and cellular iron metabolisms is ferritin. While clinicians utilize serum ferritin to monitor body iron stores and inflammation, it is important to note that the vast majority of ferritin is located intracellularly. Intracellular ferritin is made of two different subunits (heavy and light chain) and plays an imperative role as a safe iron depot. In the past couple of decades our understanding of ferritin biology has remarkably improved. Additionally, a significant body of evidence has emerged describing the significance of the kidney in iron trafficking and homeostasis. Here, we briefly discuss some of the most important findings that relate to the role of iron and ferritin heavy chain in the context of kidney-related diseases and, in particular, vascular calcification, which is a frequent complication of chronic kidney disease. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview
Therapeutic Potential of Kappa Opioid Agonists
Pharmaceuticals 2019, 12(2), 95; https://doi.org/10.3390/ph12020095
Received: 25 May 2019 / Revised: 12 June 2019 / Accepted: 18 June 2019 / Published: 20 June 2019
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Abstract
Many original research articles have been published that describe findings and outline areas for the development of kappa-opioid agonists (KOAs) as novel drugs; however, a single review article that summarizes the broad potential for KOAs in drug development does not exist. It is [...] Read more.
Many original research articles have been published that describe findings and outline areas for the development of kappa-opioid agonists (KOAs) as novel drugs; however, a single review article that summarizes the broad potential for KOAs in drug development does not exist. It is well-established that KOAs demonstrate efficacy in pain attenuation; however, KOAs also have proven to be beneficial in treating a variety of novel but often overlapping conditions including cardiovascular disease, pruritus, nausea, inflammatory diseases, spinal anesthesia, stroke, hypoxic pulmonary hypertension, multiple sclerosis, addiction, and post-traumatic cartilage degeneration. This article summarizes key findings of KOAs and discusses the untapped therapeutic potential of KOAs in the treatment of many human diseases. Full article
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Open AccessReview
Ironing out Macrophage Immunometabolism
Pharmaceuticals 2019, 12(2), 94; https://doi.org/10.3390/ph12020094
Received: 31 May 2019 / Revised: 14 June 2019 / Accepted: 17 June 2019 / Published: 19 June 2019
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Abstract
Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. [...] Read more.
Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. In this context, iron metabolism has been recognized as an important component of macrophage plasticity. Since macrophages control the availability of this essential metal, changes in the expression of genes coding for the major proteins of iron metabolism may result in different iron availability for the macrophage itself and for other cells in the microenvironment. In this review, we discuss how macrophage iron can also play a role in immunometabolism. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview
Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease
Pharmaceuticals 2019, 12(2), 93; https://doi.org/10.3390/ph12020093
Received: 26 May 2019 / Revised: 14 June 2019 / Accepted: 17 June 2019 / Published: 19 June 2019
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Abstract
Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). [...] Read more.
Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessReview
CDK8-Novel Therapeutic Opportunities
Pharmaceuticals 2019, 12(2), 92; https://doi.org/10.3390/ph12020092
Received: 10 May 2019 / Revised: 11 June 2019 / Accepted: 17 June 2019 / Published: 19 June 2019
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Abstract
Improvements in cancer therapy frequently stem from the development of new small-molecule inhibitors, paralleled by the identification of biomarkers that can predict the treatment response. Recent evidence supports the idea that cyclin-dependent kinase 8 (CDK8) may represent a potential drug target for breast [...] Read more.
Improvements in cancer therapy frequently stem from the development of new small-molecule inhibitors, paralleled by the identification of biomarkers that can predict the treatment response. Recent evidence supports the idea that cyclin-dependent kinase 8 (CDK8) may represent a potential drug target for breast and prostate cancer, although no CDK8 inhibitors have entered the clinics. As the available inhibitors have been recently reviewed, we focus on the biological functions of CDK8 and provide an overview of the complexity of CDK8-dependent signaling throughout evolution and CDK8-dependent effects that may open novel treatment avenues. Full article
(This article belongs to the Special Issue Protein Kinases and Cancer)
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Open AccessArticle
Synthesis and Study of New Quinolineaminoethanols as Anti-Bacterial Drugs
Pharmaceuticals 2019, 12(2), 91; https://doi.org/10.3390/ph12020091
Received: 29 May 2019 / Revised: 12 June 2019 / Accepted: 14 June 2019 / Published: 18 June 2019
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Abstract
The lack of antibiotics with a novel mode of action associated with the spread of drug resistant bacteria make the fight against infectious diseases particularly challenging. A quinoline core is found in several anti-infectious drugs, such as mefloquine and bedaquiline. Two main objectives [...] Read more.
The lack of antibiotics with a novel mode of action associated with the spread of drug resistant bacteria make the fight against infectious diseases particularly challenging. A quinoline core is found in several anti-infectious drugs, such as mefloquine and bedaquiline. Two main objectives were set in this work. Firstly, we evaluated the anti-mycobacterial properties of the previous quinolines 3, which have been identified as good candidates against ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli) bacteria. Secondly, a new series 4 was designed and assessed against the same bacteria strains, taking the pair of enantiomers 3m/3n as the lead. More than twenty compounds 4 were prepared through a five-step asymmetric synthesis with good enantiomeric excesses (>90%). Interestingly, all compounds of series 3 were efficient on M. avium with MIC = 2–16 µg/mL, while series 4 was less active. Both series 3 and 4 were generally more active than mefloquine against the ESKAPEE bacteria. The quinolines 4 were either active against Gram-positive bacteria (MIC ≤ 4 µg/mL for 4c4h and 4k/4l) or E. coli (MIC = 32–64 µg/mL for 4q4v) according to the global lipophilicity of these compounds. Full article
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Open AccessArticle
Novel 11-Substituted Ellipticines as Potent Anticancer Agents with Divergent Activity against Cancer Cells
Pharmaceuticals 2019, 12(2), 90; https://doi.org/10.3390/ph12020090
Received: 19 May 2019 / Revised: 9 June 2019 / Accepted: 12 June 2019 / Published: 14 June 2019
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Abstract
Ellipticines have well documented anticancer activity, in particular with substitution at the 1-, 2-, 6- and 9-positions. However, due to limitations in synthesis and coherent screening methodology the full SAR profile of this anticancer class has not yet been achieved. In order to [...] Read more.
Ellipticines have well documented anticancer activity, in particular with substitution at the 1-, 2-, 6- and 9-positions. However, due to limitations in synthesis and coherent screening methodology the full SAR profile of this anticancer class has not yet been achieved. In order to address this shortfall, we have set out to explore the anticancer activity of this potent natural product by substitution. We currently describe the synthesis of novel 11-substituted ellipticines with two specific derivatives showing potency and diverging cellular growth effects. Full article
(This article belongs to the Special Issue Anticancer Drugs)
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Open AccessArticle
CK2 Pro-Survival Role in Prostate Cancer Is Mediated via Maintenance and Promotion of Androgen Receptor and NFκB p65 Expression
Pharmaceuticals 2019, 12(2), 89; https://doi.org/10.3390/ph12020089
Received: 4 May 2019 / Revised: 5 June 2019 / Accepted: 13 June 2019 / Published: 14 June 2019
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Abstract
The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, [...] Read more.
The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, and AR and NFκB are involved in the development and progression of prostate cancer, we investigated their interaction in benign and malignant prostate cells in the presence of altered CK2 expression. Our results show that elevation of CK2 levels caused increased levels of AR and NFκB p65 in prostate cells of different phenotypes. Analysis of TCGA PCa data indicated that AR and CK2α RNA expression are strongly correlated. Small molecule inhibition or molecular down-regulation of CK2 caused reduction in AR mRNA expression and protein levels in PCa cells and in orthotopic xenograft tumors by various pathways. Among these, regulation of AR protein stability plays a unifying role in CK2 maintenance of AR protein levels. Our results show induction of various endoplasmic reticulum stress signals after CK2 inhibition, which may play a role in the PCa cell death response. Of note, CK2 inhibition caused loss of cell viability in both parental and enzalutamide-resistant castrate-resistant PCa cells. The present work elucidates the specific link of CK2 to the pathogenesis of PCa in association with AR and NFκB expression; further, the observation that inhibition of CK2 can exert a growth inhibitory effect on therapy-resistant PCa cells emphasizes the potential utility of CK2 inhibition in patients who are on enzalutamide treatment for advanced cancer. Full article
(This article belongs to the Special Issue Protein Kinases and Cancer)
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Open AccessCorrection
Correction: Klingler, M., et al. Cholecystokinin-2 Receptor Targeting with Novel C-terminally Stabilized HYNIC-Minigastrin Analogs Radiolabeled with Technetium-99m. Pharmaceuticals 2019, 12, 13
Pharmaceuticals 2019, 12(2), 88; https://doi.org/10.3390/ph12020088
Received: 11 June 2019 / Accepted: 12 June 2019 / Published: 13 June 2019
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Abstract
In our paper [...] Full article
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Open AccessReview
Cysteine Cathepsin Protease Inhibition: An update on its Diagnostic, Prognostic and Therapeutic Potential in Cancer
Pharmaceuticals 2019, 12(2), 87; https://doi.org/10.3390/ph12020087
Received: 15 May 2019 / Revised: 6 June 2019 / Accepted: 8 June 2019 / Published: 11 June 2019
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Abstract
In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic [...] Read more.
In keeping with recent developments in basic research; the importance of the Cathepsins as targets in cancer therapy have taken on increasing importance and given rise to a number of key areas of interest in the clinical setting. In keeping with driving basic research in this area in a translational direction; recent findings have given rise to a number of exciting developments in the areas of cancer diagnosis; prognosis and therapeutic development. As a fast-moving area of research; the focus of this review brings together the latest findings and highlights the translational significance of these developments. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)
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Open AccessReview
Recent Developments in Peptidyl Diaryl Phoshonates as Inhibitors and Activity-Based Probes for Serine Proteases
Pharmaceuticals 2019, 12(2), 86; https://doi.org/10.3390/ph12020086
Received: 13 May 2019 / Revised: 6 June 2019 / Accepted: 8 June 2019 / Published: 10 June 2019
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Abstract
This review presents current achievements in peptidyl diaryl phosphonates as covalent, specific mechanism-based inhibitors of serine proteases. Along three decades diaryl phosphonates have emerged as invaluable tools in fundamental and applicative studies involving these hydrolases. Such an impact has been promoted by advantageous [...] Read more.
This review presents current achievements in peptidyl diaryl phosphonates as covalent, specific mechanism-based inhibitors of serine proteases. Along three decades diaryl phosphonates have emerged as invaluable tools in fundamental and applicative studies involving these hydrolases. Such an impact has been promoted by advantageous features that characterize the phosphonate compounds and their use. First, the synthesis is versatile and allows comprehensive structural modification and diversification. Accordingly, reactivity and specificity of these bioactive molecules can be easily controlled by appropriate adjustments of the side chains and the leaving groups. Secondly, the phosphonates target exclusively serine proteases and leave other oxygen and sulfur nucleophiles intact. Synthetic accessibility, lack of toxicity, and promising pharmacokinetic properties make them good drug candidates. In consequence, the utility of peptidyl diaryl phosphonates continuously increases and involves novel enzymatic targets and innovative aspects of application. For example, conjugation of the structures of specific inhibitors with reporter groups has become a convenient approach to construct activity-based molecular probes capable of monitoring location and distribution of serine proteases. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)
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Open AccessCommunication
1,2-Dihydroxyxanthone: Effect on A375-C5 Melanoma Cell Growth Associated with Interference with THP-1 Human Macrophage Activity
Pharmaceuticals 2019, 12(2), 85; https://doi.org/10.3390/ph12020085
Received: 30 April 2019 / Revised: 1 June 2019 / Accepted: 3 June 2019 / Published: 4 June 2019
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Abstract
Xanthones have been suggested as prospective candidates for cancer treatment. 1,2- dihydroxyxanthone (1,2-DHX) is known to interfere with the growth of several cancer cell lines. We investigated the effects of 1,2-DHX on the growth of the A375-C5 melanoma cell line and THP-1 human [...] Read more.
Xanthones have been suggested as prospective candidates for cancer treatment. 1,2- dihydroxyxanthone (1,2-DHX) is known to interfere with the growth of several cancer cell lines. We investigated the effects of 1,2-DHX on the growth of the A375-C5 melanoma cell line and THP-1 human macrophage activity. 1,2-DHX showed a moderate growth inhibition of A375-C5 melanoma cells (concentration that causes a 50% inhibition of cell growth (GI50) = 55.0 ± 2.3 µM), but strongly interfered with THP-1 human macrophage activity. Supernatants from lipopolysaccharide (LPS)-stimulated THP-1 macrophage cultures exposed to 1,2-DHX significantly increased growth inhibition of A375-C5 cells, when compared to supernatants from untreated LPS-stimulated macrophages or to direct treatment with 1,2-DHX only. 1,2-DHX decreased THP-1 secretion of interleukin-1β (IL-1β) and interleukin-10 (IL-10), but stimulated tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) production. This xanthone also inhibited nitric oxide (NO) production by RAW 264.7 murine macrophages, possibly through inhibition of inducible NO synthase production. In conclusion, these findings suggest a potential impact of 1,2-DHX in melanoma treatment, not only due to a direct effect on cancer cells but also by modulation of macrophage activity. Full article
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Open AccessReview
Developments in Carbohydrate-Based Cancer Therapeutics
Pharmaceuticals 2019, 12(2), 84; https://doi.org/10.3390/ph12020084
Received: 3 May 2019 / Revised: 24 May 2019 / Accepted: 29 May 2019 / Published: 4 June 2019
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Abstract
Cancer cells of diverse origins express extracellular tumor-specific carbohydrate antigens (TACAs) because of aberrant glycosylation. Overexpressed TACAs on the surface of tumor cells are considered biomarkers for cancer detection and have always been prioritized for the development of novel carbohydrate-based anti-cancer vaccines. In [...] Read more.
Cancer cells of diverse origins express extracellular tumor-specific carbohydrate antigens (TACAs) because of aberrant glycosylation. Overexpressed TACAs on the surface of tumor cells are considered biomarkers for cancer detection and have always been prioritized for the development of novel carbohydrate-based anti-cancer vaccines. In recent years, progress has been made in developing synthetic, carbohydrate-based antitumor vaccines to improve immune responses associated with targeting these specific antigens. Tumor cells also exhaust more energy for proliferation than normal cells, by consuming excessive amounts of glucose via overexpressed sugar binding or transporting receptors located in the cellular membrane. Furthermore, inspired by the Warburg effect, glycoconjugation strategies of anticancer drugs have gained considerable attention from the scientific community. This review highlights a small cohort of recent efforts which have been made in carbohydrate-based cancer treatments, including vaccine design and the development of glycoconjugate prodrugs, glycosidase inhibiting iminosugars, and early cancer diagnosis. Full article
(This article belongs to the Special Issue Carbohydrates 2018)
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Open AccessArticle
Voltammetric Evaluation of Diclofenac Tablets Samples through Carbon Black-Based Electrodes
Pharmaceuticals 2019, 12(2), 83; https://doi.org/10.3390/ph12020083
Received: 5 April 2019 / Revised: 2 May 2019 / Accepted: 8 May 2019 / Published: 4 June 2019
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Abstract
Diclofenac (DIC) is a non-steroidal anti-inflammatory drug of wide use around the world. Electroanalytical methods display a high analytical potential for application in pharmaceutical samples but the drawbacks concerning electrode fouling and reproducibility are of major concern. Henceforth, the aim of this work [...] Read more.
Diclofenac (DIC) is a non-steroidal anti-inflammatory drug of wide use around the world. Electroanalytical methods display a high analytical potential for application in pharmaceutical samples but the drawbacks concerning electrode fouling and reproducibility are of major concern. Henceforth, the aim of this work was to propose the use of alternative low-cost carbon black (CB) and ionic liquid (IL) matrix to modify the surface of pencil graphite electrodes (PGE) in order to quantify DIC in raw materials, intermediates, and final products, as well as in stability assays of tablets. The proposed method using CB+IL/PGE displayed good recovery (99.4%) as well as limits of detection (LOD) of 0.08 µmol L-1 and limits of quantification (LOQ) of 0.28 µmol L−1. CB+IL/PGE response was five times greater than the unmodified PGE. CB+IL-PGE stands as an interesting alternative for DIC assessment in different pharmaceutical samples. Full article
(This article belongs to the Special Issue Advanced Electrochemical Sensors in Drug Sensing)
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Open AccessArticle
De Novo Design and In Vitro Testing of Antimicrobial Peptides against Gram-Negative Bacteria
Pharmaceuticals 2019, 12(2), 82; https://doi.org/10.3390/ph12020082
Received: 19 April 2019 / Revised: 26 May 2019 / Accepted: 30 May 2019 / Published: 3 June 2019
Cited by 1 | Viewed by 617 | PDF Full-text (1909 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Antimicrobial peptides (AMPs) have been identified as a potentially new class of antibiotics to combat bacterial resistance to conventional drugs. The design of de novo AMPs with high therapeutic indexes, low cost of synthesis, high resistance to proteases and high bioavailability remains a [...] Read more.
Antimicrobial peptides (AMPs) have been identified as a potentially new class of antibiotics to combat bacterial resistance to conventional drugs. The design of de novo AMPs with high therapeutic indexes, low cost of synthesis, high resistance to proteases and high bioavailability remains a challenge. Such design requires computational modeling of antimicrobial properties. Currently, most computational methods cannot accurately calculate antimicrobial potency against particular strains of bacterial pathogens. We developed a tool for AMP prediction (Special Prediction (SP) tool) and made it available on our Web site (https://dbaasp.org/prediction). Based on this tool, a simple algorithm for the design of de novo AMPs (DSP) was created. We used DSP to design short peptides with high therapeutic indexes against gram-negative bacteria. The predicted peptides have been synthesized and tested in vitro against a panel of gram-negative bacteria, including drug resistant ones. Predicted activity against Escherichia coli ATCC 25922 was experimentally confirmed for 14 out of 15 peptides. Further improvements for designed peptides included the synthesis of D-enantiomers, which are traditionally used to increase resistance against proteases. One synthetic D-peptide (SP15D) possesses one of the lowest values of minimum inhibitory concentration (MIC) among all DBAASP database short peptides at the time of the submission of this article, while being highly stable against proteases and having a high therapeutic index. The mode of anti-bacterial action, assessed by fluorescence microscopy, shows that SP15D acts similarly to cell penetrating peptides. SP15D can be considered a promising candidate for the development of peptide antibiotics. We plan further exploratory studies with the SP tool, aiming at finding peptides which are active against other pathogenic organisms. Full article
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Open AccessArticle
Cardiolipin-Based Lipopolyplex Platform for the Delivery of Diverse Nucleic Acids into Gram-Negative Bacteria
Pharmaceuticals 2019, 12(2), 81; https://doi.org/10.3390/ph12020081
Received: 30 April 2019 / Revised: 20 May 2019 / Accepted: 24 May 2019 / Published: 28 May 2019
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Abstract
Antibiotic resistance is a growing public health concern. Because only a few novel classes of antibiotics have been developed in the last 40 years, such as the class of oxazolidinones, new antibacterial strategies are urgently needed (Coates, A.R. et al., 2011). Nucleic acid-based [...] Read more.
Antibiotic resistance is a growing public health concern. Because only a few novel classes of antibiotics have been developed in the last 40 years, such as the class of oxazolidinones, new antibacterial strategies are urgently needed (Coates, A.R. et al., 2011). Nucleic acid-based antibiotics are a new type of antimicrobials. However, free nucleic acids cannot spontaneously cross the bacterial cell wall and membrane; consequently, their intracellular delivery into bacteria needs to be assisted. Here, we introduce an original lipopolyplex system named liposome polymer nucleic acid (LPN), capable of versatile nucleic acid delivery into bacteria. We characterized LPN formed with significant therapeutic nucleic acids: 11 nt antisense single-stranded (ss) DNA and double-stranded (ds) DNA of 15 and 95 base pairs (bp), 9 kbp plasmid DNA (pDNA), and 1000 nt ssRNA. All these complexes were efficiently internalized by two different bacterial species, i.e., Escherichia coli and Pseudomonas aeruginosa, as shown by flow cytometry. Consistent with intracellular delivery, LPN prepared with an antisense oligonucleotide and directed against an essential gene, induced specific and important bacterial growth inhibition likely leading to a bactericidal effect. Our findings indicate that LPN is a versatile platform for efficient delivery of diverse nucleic acids into Gram-negative bacteria. Full article
(This article belongs to the Special Issue New Tools for Medicinal Chemists)
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Open AccessArticle
Synthetic Inhibitors of Snake Venom Enzymes: Thioesters Derived from 2-Sulfenyl Ethylacetate
Pharmaceuticals 2019, 12(2), 80; https://doi.org/10.3390/ph12020080
Received: 5 April 2019 / Revised: 26 April 2019 / Accepted: 6 May 2019 / Published: 23 May 2019
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Abstract
Snakebite envenomings are a global public health issue. The therapy based on the administration of animal-derived antivenoms has limited efficacy against the venom-induced local tissue damage, which often leads to permanent disability. Therefore, there is a need to find inhibitors against toxins responsible [...] Read more.
Snakebite envenomings are a global public health issue. The therapy based on the administration of animal-derived antivenoms has limited efficacy against the venom-induced local tissue damage, which often leads to permanent disability. Therefore, there is a need to find inhibitors against toxins responsible for local damage. This work aimed to synthesize thioesters derived from 2-sulfenyl ethylacetate and to evaluate the inhibitory effects on two snake venom toxins. Ethyl 2-((4-chlorobenzoyl)thio)acetate (I), Ethyl 2-((3-nitrobenzoyl)thio)acetate (II) and Ethyl 2-((4-nitrobenzoyl)thio)acetate (III) were synthesized and spectroscopically characterized. Computational calculations were performed to support the study. The inhibitory capacity of compounds (I–III) was evaluated on a phospholipase A2 (Cdcum6) isolated from the venom of the Colombian rattlesnake Crotalus durissus cumanensis and the P-I type metalloproteinase Batx-I isolated from Bothrops atrox. I–III inhibited PLA2 with IC50 values of 193.2, 305.4 and 132.7 µM, respectively. Otherwise, compounds II and III inhibited the proteolytic activity of Batx-I with IC50 of 2774 and 1879 µM. Molecular docking studies show that inhibition of PLA2 may be due to interactions of the studied compounds with amino acids in the catalytic site and the cofactor Ca2+. Probably, a blockage of the hydrophobic channel and some amino acids of the interfacial binding surface of PLA2 may occur. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)
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Open AccessReview
Targeting MMP-9 in Diabetic Foot Ulcers
Pharmaceuticals 2019, 12(2), 79; https://doi.org/10.3390/ph12020079
Received: 1 May 2019 / Revised: 15 May 2019 / Accepted: 18 May 2019 / Published: 22 May 2019
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Abstract
Diabetic foot ulcers (DFUs) are significant complications of diabetes and an unmet medical need. Matrix metalloproteinases (MMPs) play important roles in the pathology of wounds and in the wound healing process. However, because of the challenge in distinguishing active MMPs from the two [...] Read more.
Diabetic foot ulcers (DFUs) are significant complications of diabetes and an unmet medical need. Matrix metalloproteinases (MMPs) play important roles in the pathology of wounds and in the wound healing process. However, because of the challenge in distinguishing active MMPs from the two catalytically inactive forms of MMPs and the clinical failure of broad-spectrum MMP inhibitors in cancer, MMPs have not been a target for treatment of DFUs until recently. This review covers the discovery of active MMP-9 as the biochemical culprit in the recalcitrance of diabetic wounds to healing and targeting this proteinase as a novel approach for the treatment of DFUs. Active MMP-8 and MMP-9 were observed in mouse and human diabetic wounds using a batimastat affinity resin and proteomics. MMP-9 was shown to play a detrimental role in diabetic wound healing, whereas MMP-8 was beneficial. A new class of selective MMP-9 inhibitors shows clinical promise for the treatment of DFUs. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases)
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Open AccessBrief Report
Tegsedi (Inotersen): An Antisense Oligonucleotide Approved for the Treatment of Adult Patients with Hereditary Transthyretin Amyloidosis
Pharmaceuticals 2019, 12(2), 78; https://doi.org/10.3390/ph12020078
Received: 16 April 2019 / Revised: 16 May 2019 / Accepted: 17 May 2019 / Published: 21 May 2019
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Abstract
Tegsedi (Inotersen) is a chemically modified antisense oligonucleotide that inhibits the hepatic production of transthyretin (TTR). Several single-point mutations in TTR destabilize its structure, leading to the aggregation and accumulation of amyloid deposits in the nervous system, heart, kidneys and eyes. In July [...] Read more.
Tegsedi (Inotersen) is a chemically modified antisense oligonucleotide that inhibits the hepatic production of transthyretin (TTR). Several single-point mutations in TTR destabilize its structure, leading to the aggregation and accumulation of amyloid deposits in the nervous system, heart, kidneys and eyes. In July 2018, Tegsedi was approved by the European Commission for use in adults with stage one and two polyneuropathies. Later on, in October 2018, the FDA and Health Canada also approved its use for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults in the U.S. and Canada. Tegsedi was developed by Ionis Pharmaceuticals, the company that holds the global marketing license, together with its subsidiary Akcea Therapeutics. Full article
(This article belongs to the Special Issue The Story of Successful Drugs and Recent FDA-Approved Molecules)
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Open AccessReview
The Expanding Role of MT1-MMP in Cancer Progression
Pharmaceuticals 2019, 12(2), 77; https://doi.org/10.3390/ph12020077
Received: 1 May 2019 / Revised: 16 May 2019 / Accepted: 18 May 2019 / Published: 20 May 2019
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Abstract
For over 20 years, membrane type 1 matrix metalloproteinase (MT1-MMP) has been recognized as a key component in cancer progression. Initially, the primary roles assigned to MT1-MMP were the activation of proMMP-2 and degradation of fibrillar collagen. Proteomics has revealed a great array [...] Read more.
For over 20 years, membrane type 1 matrix metalloproteinase (MT1-MMP) has been recognized as a key component in cancer progression. Initially, the primary roles assigned to MT1-MMP were the activation of proMMP-2 and degradation of fibrillar collagen. Proteomics has revealed a great array of MT1-MMP substrates, and MT1-MMP selective inhibitors have allowed for a more complete mapping of MT1-MMP biological functions. MT1-MMP has extensive sheddase activities, is both a positive and negative regulator of angiogenesis, can act intracellularly and as a transcription factor, and modulates immune responses. We presently examine the multi-faceted role of MT1-MMP in cancer, with a consideration of how the diversity of MT1-MMP behaviors impacts the application of MT1-MMP inhibitors. Full article
(This article belongs to the Special Issue Matrix Metalloproteinases)
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Open AccessArticle
Magnetic Graphene Oxide Nanocarrier for Targeted Delivery of Cisplatin: A Perspective for Glioblastoma Treatment
Pharmaceuticals 2019, 12(2), 76; https://doi.org/10.3390/ph12020076
Received: 15 April 2019 / Revised: 10 May 2019 / Accepted: 16 May 2019 / Published: 18 May 2019
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Abstract
Selective vectorization of Cisplatin (CisPt) to Glioblastoma U87 cells was exploited by the fabrication of a hybrid nanocarrier composed of magnetic γ-Fe2O3 nanoparticles and nanographene oxide (NGO). The magnetic component, obtained by annealing magnetite Fe3O4 and characterized [...] Read more.
Selective vectorization of Cisplatin (CisPt) to Glioblastoma U87 cells was exploited by the fabrication of a hybrid nanocarrier composed of magnetic γ-Fe2O3 nanoparticles and nanographene oxide (NGO). The magnetic component, obtained by annealing magnetite Fe3O4 and characterized by XRD measurements, was combined with NGO sheets prepared via a modified Hummer’s method. The morphological and thermogravimetric analysis proved the effective binding of γ-Fe2O3 nanoparticles onto NGO layers. The magnetization measured under magnetic fields up to 7 Tesla at room temperature revealed superparamagnetic-like behavior with a maximum value of MS = 15 emu/g and coercivity HC ≈ 0 Oe within experimental error. The nanohybrid was found to possess high affinity towards CisPt, and a rather slow fractional release profile of 80% after 250 h. Negligible toxicity was observed for empty nanoparticles, while the retainment of CisPt anticancer activity upon loading into the carrier was observed, together with the possibility to spatially control the drug delivery at a target site. Full article
(This article belongs to the Special Issue Anticancer Drugs)
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Open AccessReview
Iron Supplementation Therapy, A Friend and Foe of Mycobacterial Infections?
Pharmaceuticals 2019, 12(2), 75; https://doi.org/10.3390/ph12020075
Received: 28 April 2019 / Revised: 14 May 2019 / Accepted: 15 May 2019 / Published: 17 May 2019
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Abstract
Iron is an essential element that is required for oxygen transfer, redox, and metabolic activities in mammals and bacteria. Mycobacteria, some of the most prevalent infectious agents in the world, require iron as growth factor. Mycobacterial-infected hosts set up a series of defense [...] Read more.
Iron is an essential element that is required for oxygen transfer, redox, and metabolic activities in mammals and bacteria. Mycobacteria, some of the most prevalent infectious agents in the world, require iron as growth factor. Mycobacterial-infected hosts set up a series of defense mechanisms, including systemic iron restriction and cellular iron distribution, whereas mycobacteria have developed sophisticated strategies to acquire iron from their hosts and to protect themselves from iron’s harmful effects. Therefore, it is assumed that host iron and iron-binding proteins, and natural or synthetic chelators would be keys targets to inhibit mycobacterial proliferation and may have a therapeutic potential. Beyond this hypothesis, recent evidence indicates a host protective effect of iron against mycobacterial infections likely through promoting remodeled immune response. In this review, we discuss experimental procedures and clinical observations that highlight the role of the immune response against mycobacteria under various iron availability conditions. In addition, we discuss the clinical relevance of our knowledge regarding host susceptibility to mycobacteria in the context of iron availability and suggest future directions for research on the relationship between host iron and the immune response and the use of iron as a therapeutic agent. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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Open AccessArticle
Retinal Gene Distribution and Functionality Implicated in Inherited Retinal Degenerations Can Reveal Disease-Relevant Pathways for Pharmacologic Intervention
Pharmaceuticals 2019, 12(2), 74; https://doi.org/10.3390/ph12020074
Received: 16 April 2019 / Revised: 8 May 2019 / Accepted: 15 May 2019 / Published: 17 May 2019
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Abstract
The advent of genetic therapies for inherited retinal diseases (IRDs) has spurred the need for precise diagnosis and understanding of pathways for therapeutic targeting. The majority of IRDs that are clinically diagnosed, however, lack an identifiable mutation in established disease-causing loci and thus [...] Read more.
The advent of genetic therapies for inherited retinal diseases (IRDs) has spurred the need for precise diagnosis and understanding of pathways for therapeutic targeting. The majority of IRDs that are clinically diagnosed, however, lack an identifiable mutation in established disease-causing loci and thus can be investigated with limited rational drug discovery methods. Transcriptome profiling of the retina can reveal the functional state of the tissue, and geographic profiling can uncover the various clinical phenotypic presentations of IRDs and aid in pharmaceutical intervention. In this investigation, we detail the retinal geographic expression of known retinal disease-causing genes in the primate retina and functional targetable pathways in specific IRDs. Understanding the genetic basis as well as the resulting functional consequences will assist in the discovery of future therapeutic interventions and provide novel insights to medicinal chemists. Herein, we report that, despite the genetic heterogeneity of retinal diseases, potential functional pathways can be elucidated for therapeutic targeting and be used for predictive phenotypic and genotypic modeling of novel IRD presentations. Full article
(This article belongs to the Special Issue New Tools for Medicinal Chemists)
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Open AccessMeeting Report
26th Annual GP2A Medicinal Chemistry Conference & 32nd Journées Franco-Belges de Pharmacochimie
Pharmaceuticals 2019, 12(2), 73; https://doi.org/10.3390/ph12020073
Received: 7 May 2019 / Accepted: 10 May 2019 / Published: 16 May 2019
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Abstract
As a joint meeting, the 26th Medicinal Chemistry Conference of GP2A and 32nd Journées Franco-Belges de Pharmacochimie took place between 13th and 15th June at Asnelles sur Mer (Normandie, France), providing a unique opportunity for a wide group of European medicinal chemists to [...] Read more.
As a joint meeting, the 26th Medicinal Chemistry Conference of GP2A and 32nd Journées Franco-Belges de Pharmacochimie took place between 13th and 15th June at Asnelles sur Mer (Normandie, France), providing a unique opportunity for a wide group of European medicinal chemists to engage. Topics included chemical tools for medicinal chemistry, protein-protein interactions, epigenetics, natural product-inspired molecules, computer-aided drug design, and new strategies for the design and development of drugs. Abstracts of invited lectures, proffered young researcher communications, flash communications and posters presented during the meeting are collected in this report. Full article
Open AccessArticle
Colloidal Silver Induces Cytoskeleton Reorganization and E-Cadherin Recruitment at Cell-Cell Contacts in HaCaT Cells
Pharmaceuticals 2019, 12(2), 72; https://doi.org/10.3390/ph12020072
Received: 11 April 2019 / Revised: 8 May 2019 / Accepted: 14 May 2019 / Published: 15 May 2019
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Abstract
Up until the first half of the 20th century, silver found significant employment in medical applications, particularly in the healing of open wounds, thanks to its antibacterial and antifungal properties. Wound repair is a complex and dynamic biological process regulated by several pathways [...] Read more.
Up until the first half of the 20th century, silver found significant employment in medical applications, particularly in the healing of open wounds, thanks to its antibacterial and antifungal properties. Wound repair is a complex and dynamic biological process regulated by several pathways that cooperate to restore tissue integrity and homeostasis. To facilitate healing, injuries need to be promptly treated. Recently, the interest in alternatives to antibiotics has been raised given the widespread phenomenon of antibiotic resistance. Among these alternatives, the use of silver appears to be a valid option, so a resurgence in its use has been recently observed. In particular, in contrast to ionic silver, colloidal silver, a suspension of metallic silver particles, shows antibacterial activity displaying less or no toxicity. However, the human health risks associated with exposure to silver nanoparticles (NP) appear to be conflicted, and some studies have suggested that it could be toxic in different cellular contexts. These potentially harmful effects of silver NP depend on various parameters including NP size, which commonly range from 1 to 100 nm. In this study, we analyzed the effect of a colloidal silver preparation composed of very small and homogeneous nanoparticles of 0.62 nm size, smaller than those previously tested. We found no adverse effect on the cell proliferation of HaCaT cells, even at high NP concentration. Time-lapse microscopy and indirect immunofluorescence experiments demonstrated that this preparation of colloidal silver strongly increased cell migration, re-modeled the cytoskeleton, and caused recruitment of E-cadherin at cell-cell junctions of human cultured keratinocytes. Full article
(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)
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Open AccessArticle
VitalSign6: A Primary Care First (PCP-First) Model for Universal Screening and Measurement-Based Care for Depression
Pharmaceuticals 2019, 12(2), 71; https://doi.org/10.3390/ph12020071
Received: 28 February 2019 / Revised: 3 May 2019 / Accepted: 8 May 2019 / Published: 14 May 2019
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Abstract
Major depressive disorder affects one in five adults in the United States. While practice guidelines recommend universal screening for depression in primary care settings, clinical outcomes suffer in the absence of optimal models to manage those who screen positive for depression. The current [...] Read more.
Major depressive disorder affects one in five adults in the United States. While practice guidelines recommend universal screening for depression in primary care settings, clinical outcomes suffer in the absence of optimal models to manage those who screen positive for depression. The current practice of employing additional mental health professionals perpetuates the assumption that primary care providers (PCP) cannot effectively manage depression, which is not feasible, due to the added costs and shortage of mental health professionals. We have extended our previous work, which demonstrated similar treatment outcomes for depression in primary care and psychiatric settings, using measurement-based care (MBC) by developing a model, called Primary Care First (PCP-First), that empowers PCPs to effectively manage depression in their patients. This model incorporates health information technology tools, through an electronic health records (EHR) integrated web-application and facilitates the following five components: (1) Screening (2) diagnosis (3) treatment selection (4) treatment implementation and (5) treatment revision. We have implemented this model as part of a quality improvement project, called VitalSign6, and will measure its success using the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) framework. In this report, we provide the background and rationale of the PCP-First model and the operationalization of VitalSign6 project. Full article
(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)
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Open AccessCommunication
Deregulation of Hepatic Mek1/2–Erk1/2 Signaling Module in Iron Overload Conditions
Pharmaceuticals 2019, 12(2), 70; https://doi.org/10.3390/ph12020070
Received: 25 February 2019 / Revised: 30 April 2019 / Accepted: 5 May 2019 / Published: 7 May 2019
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Abstract
The liver, through the production of iron hormone hepcidin, controls body iron levels. High liver iron levels and deregulated hepcidin expression are commonly observed in many liver diseases including highly prevalent genetic iron overload disorders. In spite of a number of breakthrough investigations [...] Read more.
The liver, through the production of iron hormone hepcidin, controls body iron levels. High liver iron levels and deregulated hepcidin expression are commonly observed in many liver diseases including highly prevalent genetic iron overload disorders. In spite of a number of breakthrough investigations into the signals that control hepcidin expression, little progress has been made towards investigations into intracellular signaling in the liver under excess of iron. This study examined hepatic signaling pathways underlying acquired and genetic iron overload conditions. Our data demonstrate that hepatic iron overload associates with a decline in the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) kinase (Mek1/2) pathway by selectively affecting the phosphorylation of Erk1/2. We propose that Mek1/2-Erk1/2 signaling is uncoupled from iron-Bmp-Smad-mediated hepcidin induction and that it may contribute to a number of liver pathologies in addition to toxic effects of iron. We believe that our findings will advance the understanding of cellular signaling events in the liver during iron overload of different etiologies. Full article
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
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