Pharmaceuticals

18 pages, 4494 KiB

Open AccessArticle

Antimicrobial Photodynamic Therapy in Combination with Nystatin in the Treatment of Experimental Oral Candidiasis Induced by Candida albicans Resistant to Fluconazole

by Karem Janeth Rimachi Hidalgo, Juliana Cabrini Carmello, Cláudia Carolina Jordão, Paula Aboud Barbugli, Carlos Alberto de Sousa Costa, Ewerton Garcia de Oliveira Mima and Ana Claudia Pavarina

Pharmaceuticals 2019, 12(3), 140; https://doi.org/10.3390/ph12030140 - 18 Sep 2019

Cited by 29 | Viewed by 4905

Abstract

Background: It has been demonstrated that azole-resistant strains of Candida albicans have a greater resistance to antimicrobial photodynamic therapy (aPDT) when compared to their more susceptible counterparts. For this reason, the present study evaluated the efficacy of aPDT, together with nystatin (NYS), in [...] Read more.

Background: It has been demonstrated that azole-resistant strains of Candida albicans have a greater resistance to antimicrobial photodynamic therapy (aPDT) when compared to their more susceptible counterparts. For this reason, the present study evaluated the efficacy of aPDT, together with nystatin (NYS), in the treatment of oral candidiasis in vivo. Methods: Mice were infected with fluconazole-resistant C. albicans (ATCC 96901). To perform the combined therapy, aPDT, mediated by Photodithazine (PDZ) and LED light, was used together with NYS. The efficacy of the treatments was evaluated by microbiological, macroscopic, histopathological and Confocal Scanning Laser Microscopy analyses of the lesions. The expression of p21 and p53, proteins associated with cell death, from the tongues of mice, was also performed. Results: The combined therapy reduced the fungal viability by around 2.6 log₁₀ and decreased the oral lesions and the inflammatory reaction. Additionally, it stimulated the production of p53 and p21. Conclusions: The combined therapy is a promising alternative treatment for oral candidiasis induced by C. albicans resistant to fluconazole. Full article

(This article belongs to the Special Issue Photodynamic Therapy 2019)

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12 pages, 5926 KiB

Open AccessArticle

Phosphonic Acid Analogues of Phenylglycine as Inhibitors of Aminopeptidases: Comparison of Porcine Aminopeptidase N, Bovine Leucine Aminopeptidase, Tomato Acidic Leucine Aminopeptidase and Aminopeptidase from Barley Seeds

by Weronika Wanat, Michał Talma, Małgorzata Pawełczak and Paweł Kafarski

Pharmaceuticals 2019, 12(3), 139; https://doi.org/10.3390/ph12030139 - 17 Sep 2019

Cited by 7 | Viewed by 4289

Abstract

The inhibitory activity of 14 racemic phosphonic acid analogs of phenylglycine, substituted in aromatic rings, towards porcine aminopeptidase N (pAPN) and barley seed aminopeptidase was determined experimentally. The obtained patterns of the inhibitory activity against the two enzymes were similar. The obtained data [...] Read more.

The inhibitory activity of 14 racemic phosphonic acid analogs of phenylglycine, substituted in aromatic rings, towards porcine aminopeptidase N (pAPN) and barley seed aminopeptidase was determined experimentally. The obtained patterns of the inhibitory activity against the two enzymes were similar. The obtained data served as a basis for studying the binding modes of these inhibitors by pAPN using molecular modeling. It was found that their aminophosphonate fragments were bound in a highly uniform manner and that the difference in their affinities most likely resulted from the mode of substitution of their phenyl rings. The obtained binding modes towards pAPN were compared, with these predicted for bovine lens leucine aminopeptidase (blLAP) and tomato acidic leucine aminopeptidase (tLAPA). The performed studies indicated that the binding manner of the phenylglycine analogs to biLAP and tLAPA are significantly similar and differ slightly from that predicted for pAPN. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs)

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13 pages, 433 KiB

Open AccessReview

The Efficacy of Iron Chelators for Removing Iron from Specific Brain Regions and the Pituitary—Ironing out the Brain

by Robert R. Crichton, Roberta J. Ward and Robert C. Hider

Pharmaceuticals 2019, 12(3), 138; https://doi.org/10.3390/ph12030138 - 17 Sep 2019

Cited by 26 | Viewed by 6043

Abstract

Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia patients, has become an essential therapy to prolong [...] Read more.

Iron chelation therapy, either subcutaneous or orally administered, has been used successfully in various clinical conditions. The removal of excess iron from various tissues, e.g., the liver spleen, heart, and the pituitary, in beta thalassemia patients, has become an essential therapy to prolong life. More recently, the use of deferiprone to chelate iron from various brain regions in Parkinson’s Disease and Friederich’s Ataxia has yielded encouraging results, although the side effects, in <2% of Parkinson’s Disease(PD) patients, have limited its long-term use. A new class of hydroxpyridinones has recently been synthesised, which showed no adverse effects in preliminary trials. A vital question remaining is whether inflammation may influence chelation efficacy, with a recent study suggesting that high levels of inflammation may diminish the ability of the chelator to bind the excess iron. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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28 pages, 4363 KiB

Open AccessReview

Metal-Based Complexes as Pharmaceuticals for Molecular Imaging of the Liver

by Julia Greiser, Wolfgang Weigand and Martin Freesmeyer

Pharmaceuticals 2019, 12(3), 137; https://doi.org/10.3390/ph12030137 - 16 Sep 2019

Cited by 12 | Viewed by 5742

Abstract

This article reviews the use of metal complexes as contrast agents (CA) and radiopharmaceuticals for the anatomical and functional imaging of the liver. The main focus was on two established imaging modalities: magnetic resonance imaging (MRI) and nuclear medicine, the latter including scintigraphy [...] Read more.

This article reviews the use of metal complexes as contrast agents (CA) and radiopharmaceuticals for the anatomical and functional imaging of the liver. The main focus was on two established imaging modalities: magnetic resonance imaging (MRI) and nuclear medicine, the latter including scintigraphy and positron emission tomography (PET). The review provides an overview on approved pharmaceuticals like Gd-based CA and ^99mTc-based radiometal complexes, and also on novel agents such as ⁶⁸Ga-based PET tracers. Metal complexes are presented by their imaging modality, with subsections focusing on their structure and mode of action. Uptake mechanisms, metabolism, and specificity are presented, in context with advantages and limitations of the diagnostic application and taking into account the respective imaging technique. Full article

(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)

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35 pages, 392 KiB

Open AccessReview

Cellular Mechanisms for Antinociception Produced by Oxytocin and Orexins in the Rat Spinal Lamina II—Comparison with Those of Other Endogenous Pain Modulators

by Eiichi Kumamoto

Pharmaceuticals 2019, 12(3), 136; https://doi.org/10.3390/ph12030136 - 16 Sep 2019

Cited by 9 | Viewed by 4453

Abstract

Much evidence indicates that hypothalamus-derived neuropeptides, oxytocin, orexins A and B, inhibit nociceptive transmission in the rat spinal dorsal horn. In order to unveil cellular mechanisms for this antinociception, the effects of the neuropeptides on synaptic transmission were examined in spinal lamina II [...] Read more.

Much evidence indicates that hypothalamus-derived neuropeptides, oxytocin, orexins A and B, inhibit nociceptive transmission in the rat spinal dorsal horn. In order to unveil cellular mechanisms for this antinociception, the effects of the neuropeptides on synaptic transmission were examined in spinal lamina II neurons that play a crucial role in antinociception produced by various analgesics by using the whole-cell patch-clamp technique and adult rat spinal cord slices. Oxytocin had no effect on glutamatergic excitatory transmission while producing a membrane depolarization, γ-aminobutyric acid (GABA)-ergic and glycinergic spontaneous inhibitory transmission enhancement. On the other hand, orexins A and B produced a membrane depolarization and/or a presynaptic spontaneous excitatory transmission enhancement. Like oxytocin, orexin A enhanced both GABAergic and glycinergic transmission, whereas orexin B facilitated glycinergic but not GABAergic transmission. These inhibitory transmission enhancements were due to action potential production. Oxytocin, orexins A and B activities were mediated by oxytocin, orexin-1 and orexin-2 receptors, respectively. This review article will mention cellular mechanisms for antinociception produced by oxytocin, orexins A and B, and discuss similarity and difference in antinociceptive mechanisms among the hypothalamic neuropeptides and other endogenous pain modulators (opioids, nociceptin, adenosine, adenosine 5’-triphosphate (ATP), noradrenaline, serotonin, dopamine, somatostatin, cannabinoids, galanin, substance P, bradykinin, neuropeptide Y and acetylcholine) exhibiting a change in membrane potential, excitatory or inhibitory transmission in the spinal lamina II neurons. Full article

23 pages, 17035 KiB

Open AccessReview

Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review

by Giulia Oliveira Timo, Rodrigo Souza Silva Valle dos Reis, Adriana Françozo de Melo, Thales Viana Labourdette Costa, Pérola de Oliveira Magalhães and Mauricio Homem-de-Mello

Pharmaceuticals 2019, 12(3), 135; https://doi.org/10.3390/ph12030135 - 16 Sep 2019

Cited by 10 | Viewed by 4556

Abstract

Mycobacterium tuberculosis (Mtb) is an endemic bacterium worldwide that causes tuberculosis (TB) and involves long-term treatment that is not always effective. In this context, several studies are trying to develop and evaluate new substances active against Mtb. In silico techniques are often used [...] Read more.

Mycobacterium tuberculosis (Mtb) is an endemic bacterium worldwide that causes tuberculosis (TB) and involves long-term treatment that is not always effective. In this context, several studies are trying to develop and evaluate new substances active against Mtb. In silico techniques are often used to predict the effects on some known target. We used a systematic approach to find and evaluate manuscripts that applied an in silico technique to find antimycobacterial molecules and tried to prove its predictive potential by testing them in vitro or in vivo. After searching three different databases and applying exclusion criteria, we were able to retrieve 46 documents. We found that they all follow a similar screening procedure, but few studies exploited equal targets, exploring the interaction of multiple ligands to 29 distinct enzymes. The following in vitro/vivo analysis showed that, although the virtual assays were able to decrease the number of molecules tested, saving time and money, virtual screening procedures still need to develop the correlation to more favorable in vitro outcomes. We find that the in silico approach has a good predictive power for in vitro results, but call for more studies to evaluate its clinical predictive possibilities. Full article

(This article belongs to the Special Issue New Tools for Medicinal Chemists)

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6 pages, 200 KiB

Open AccessEditorial

Special Issue “Anticancer Drugs”

by Mary J. Meegan and Niamh M. O’Boyle

Pharmaceuticals 2019, 12(3), 134; https://doi.org/10.3390/ph12030134 - 16 Sep 2019

Cited by 35 | Viewed by 6560

Abstract

The focus of this Special Issue of Pharmaceuticals is on the design, synthesis, and molecular mechanism of action of novel antitumor, drugs with a special emphasis on the relationship between the chemical structure and the biological activity of the molecules. This Special Issue [...] Read more.

The focus of this Special Issue of Pharmaceuticals is on the design, synthesis, and molecular mechanism of action of novel antitumor, drugs with a special emphasis on the relationship between the chemical structure and the biological activity of the molecules. This Special Issue also provides an understanding of the biologic and genotypic context in which targets are selected for oncology drug discovery, thus providing a rationalization for the biological activity of these drugs and guiding the design of more effective agents. In this Special Issue of Pharmaceuticals dedicated to anticancer drugs, we present a selection of preclinical research papers including both traditional chemotherapeutic agents and newer more targeted therapies and biological agents. We have included articles that report the design of small molecules with promising anticancer activity as tubulin inhibitors, vascular targeting agents, and topoisomerase targeting agents, alongside a comprehensive review of clinically successful antibody-drug conjugates used in cancer treatment. Full article

(This article belongs to the Special Issue Anticancer Drugs)

18 pages, 1727 KiB

Open AccessFeature PaperArticle

The Impact of Childhood Maltreatment on Intravenous Ketamine Outcomes for Adult Patients with Treatment-Resistant Depression

by Brittany O’Brien, Marijn Lijffijt, Allison Wells, Alan C. Swann and Sanjay J. Mathew

Pharmaceuticals 2019, 12(3), 133; https://doi.org/10.3390/ph12030133 - 11 Sep 2019

Cited by 18 | Viewed by 5373

Abstract

Childhood maltreatment is associated with a poor treatment response to conventional antidepressants and increased risk for treatment-resistant depression (TRD). The N-methyl-D-aspartate receptor (NDMAR) antagonist ketamine has been shown to rapidly improve symptoms of depression in patients with TRD. It is unknown if childhood [...] Read more.

Childhood maltreatment is associated with a poor treatment response to conventional antidepressants and increased risk for treatment-resistant depression (TRD). The N-methyl-D-aspartate receptor (NDMAR) antagonist ketamine has been shown to rapidly improve symptoms of depression in patients with TRD. It is unknown if childhood maltreatment could influence ketamine’s treatment response. We examined the relationship between childhood maltreatment using the Childhood Trauma Questionnaire (CTQ) and treatment response using the Quick Inventory of Depressive Symptoms–Self Report (QIDS-SR) in TRD patients receiving intravenous ketamine at a community outpatient clinic. We evaluated treatment response after a single infusion (n = 115) and a course of repeated infusions (n = 63). Repeated measures general linear models and Bayes factor (BF) showed significant decreases in QIDS-SR after the first and second infusions, which plateaued after the third infusion. Clinically significant childhood sexual abuse, physical abuse, and cumulative clinically significant maltreatment on multiple domains (maltreatment load) were associated with better treatment response to a single and repeated infusions. After repeated infusions, higher load was also associated with a higher remission rate. In contrast to conventional antidepressants, ketamine could be more effective in TRD patients with more childhood trauma burden, perhaps due to ketamine’s proposed ability to block trauma-associated behavioral sensitization. Full article

(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)

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29 pages, 3934 KiB

Open AccessReview

Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features

by L. Tom Vlasveld, Roel Janssen, Edouard Bardou-Jacquet, Hanka Venselaar, Houda Hamdi-Roze, Hal Drakesmith and Dorine W. Swinkels

Pharmaceuticals 2019, 12(3), 132; https://doi.org/10.3390/ph12030132 - 9 Sep 2019

Cited by 40 | Viewed by 6236

Abstract

Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin [...] Read more.

Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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12 pages, 1693 KiB

Open AccessArticle

Effect of 6-Shogaol on the Glucose Uptake and Survival of HT1080 Fibrosarcoma Cells

by Angie C. Romero-Arias, Luis G. Sequeda-Castañeda, Andres F. Aristizábal-Pachón and Ludis Morales

Pharmaceuticals 2019, 12(3), 131; https://doi.org/10.3390/ph12030131 - 9 Sep 2019

Cited by 5 | Viewed by 4944

Abstract

Ginger is a plant that is native to southern China. In the last decade and research on the components of ginger has significantly increased; of these components, 6-shogaol exhibits the greatest potential antitumor capacity. However, the molecular mechanism through which 6-shogaol exerts its [...] Read more.

Ginger is a plant that is native to southern China. In the last decade and research on the components of ginger has significantly increased; of these components, 6-shogaol exhibits the greatest potential antitumor capacity. However, the molecular mechanism through which 6-shogaol exerts its effects has not yet been elucidated. In this study, the effect of 6-shogaol on tumor cells that were derived from human fibrosarcoma (HT1080) was evaluated. Cell viability was determined by a (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay testing different concentrations of 6-shogaol (2.5–150 μM). Subsequently, the effect of 6-shogaol on reactive oxygen species (ROS) production, glucose uptake, and protein expression of the signaling pathway phosphatase and tensin homolog/ protein kinase B /mammalian target of rapamycin (PTEN/Akt/mTOR) was measured. 6-Shogaol reduced the viability of the tumor cells and caused an increase in ROS production, which was attenuated with the addition of N-acetylcysteine, and the recovery of cell viability was observed. The increase in ROS production in response to 6-shogaol was associated with cell death. Similarly, glucose uptake decreased with incremental concentrations of 6-shogaol, and an increase in the expression of mTOR-p and Akt-p proteins was observed; PTEN was active in all the treatments with 6-shogaol. Thus, the results suggest that cells activate uncontrolled signaling pathways, such as phosphoinositide 3-kinase (PI3K)/Akt/mTOR, among other alternative mechanisms of metabolic modulation and of survival in order to counteract the pro-oxidant effect of 6-shogaol and the decrease in glucose uptake. Interestingly, a differential response was observed when non-cancerous cells were treated with 6-shogaol. Full article

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12 pages, 778 KiB

Open AccessConcept Paper

Methylxanthines: Potential Therapeutic Agents for Glioblastoma

by Daniel Pérez-Pérez, Iannel Reyes-Vidal, Elda Georgina Chávez-Cortez, Julio Sotelo and Roxana Magaña-Maldonado

Pharmaceuticals 2019, 12(3), 130; https://doi.org/10.3390/ph12030130 - 7 Sep 2019

Cited by 9 | Viewed by 5368

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Currently, treatment is ineffective and the median overall survival is 20.9 months. The poor prognosis of GBM is a consequence of several altered signaling pathways that favor the proliferation and survival of [...] Read more.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Currently, treatment is ineffective and the median overall survival is 20.9 months. The poor prognosis of GBM is a consequence of several altered signaling pathways that favor the proliferation and survival of neoplastic cells. One of these pathways is the deregulation of phosphodiesterases (PDEs). These enzymes participate in the development of GBM and may have value as therapeutic targets to treat GBM. Methylxanthines (MXTs) such as caffeine, theophylline, and theobromine are PDE inhibitors and constitute a promising therapeutic anti-cancer agent against GBM. MTXs also regulate various cell processes such as proliferation, migration, cell death, and differentiation; these processes are related to cancer progression, making MXTs potential therapeutic agents in GBM. Full article

(This article belongs to the Collection Old Pharmaceuticals with New Applications)

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16 pages, 3285 KiB

Open AccessArticle

The Antitumor Didox Acts as an Iron Chelator in Hepatocellular Carcinoma Cells

by Michela Asperti, Luca Cantamessa, Simone Ghidinelli, Magdalena Gryzik, Andrea Denardo, Arianna Giacomini, Giovanna Longhi, Alessandro Fanzani, Paolo Arosio and Maura Poli

Pharmaceuticals 2019, 12(3), 129; https://doi.org/10.3390/ph12030129 - 2 Sep 2019

Cited by 10 | Viewed by 4902

Abstract

Ribonucleotide reductase (RR) is the rate-limiting enzyme that controls the deoxynucleotide triphosphate synthesis and it is an important target of cancer treatment, since it is expressed in tumor cells in proportion to their proliferation rate, their invasiveness and poor prognosis. Didox, a derivative [...] Read more.

Ribonucleotide reductase (RR) is the rate-limiting enzyme that controls the deoxynucleotide triphosphate synthesis and it is an important target of cancer treatment, since it is expressed in tumor cells in proportion to their proliferation rate, their invasiveness and poor prognosis. Didox, a derivative of hydroxyurea (HU), is one of the most potent pharmaceutical inhibitors of this enzyme, with low in vivo side effects. It inhibits the activity of the subunit RRM2 and deoxyribonucleotides (dNTPs) synthesis, and it seems to show iron-chelating activity. In the present work, we mainly investigated the iron-chelating properties of didox using the HA22T/VGH cell line, as a model of hepatocellular carcinoma (HCC). We confirmed that didox induced cell death and that this effect was suppressed by iron supplementation. Interestingly, cell treatments with didox caused changes of cellular iron content, TfR1 and ferritin levels comparable to those caused by the iron chelators, deferoxamine (DFO) and deferiprone (DFP). Chemical studies showed that didox has an affinity binding to Fe³⁺ comparable to that of DFO and DFP, although with slower kinetic. Structural modeling indicated that didox is a bidentated iron chelator with two theoretical possible positions for the binding and among them that with the two hydroxyls of the catechol group acting as ligands is the more likely one. The iron chelating property of didox may contribute to its antitumor activity not only blocking the formation of the tyrosil radical on Tyr122 (such as HU) on RRM2 (essential for its activity) but also sequestering the iron needed by this enzyme and to the cell proliferation. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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8 pages, 1054 KiB

Open AccessCommunication

Phenolic Plant Extracts Versus Penicillin G: In Vitro Susceptibility of Staphylococcus aureus Isolated from Bovine Mastitis

by Fernanda Gomes, Maria Elisa Rodrigues, Natália Martins, Isabel C.F.R. Ferreira and Mariana Henriques

Pharmaceuticals 2019, 12(3), 128; https://doi.org/10.3390/ph12030128 - 31 Aug 2019

Cited by 9 | Viewed by 4192

Abstract

Antibiotics are the elective drugs in bovine mastitis (BM) treatment, despite their low rates of efficiency and effectiveness and increasing risk of pathogen resistance. In this sense, it is urgent to discover new and effective antimicrobial agents to apply in BM control and [...] Read more.

Antibiotics are the elective drugs in bovine mastitis (BM) treatment, despite their low rates of efficiency and effectiveness and increasing risk of pathogen resistance. In this sense, it is urgent to discover new and effective antimicrobial agents to apply in BM control and even treatment. Plant extracts have been widely recognized as a rich source of phytochemicals with antimicrobial potential. Thus, the present work aims to compare the bioactivity of Eucalyptus globulus and Juglans regia extracts against Staphylococcus aureus bovine mastitis strains with penicillin G. At non-toxic concentrations, E. globulus exerted a bacteriostatic effect in planktonic cells and J. regia had no antimicrobial activity. Penicillin G, at minimum inhibitory concentration (MIC), demonstrated bactericidal activity, but just for S. aureus 3, 5, 6 and ATCC 25923, while the other strains seem to have acquired resistance. On the other hand, E. globulus and penicillin G in combination demonstrated synergy, being the most effective approach against S. aureus 1, 2 and 4. Thus, penicillin alone and in combination with E. globulus or J. regia seems to be promissory strategies to control bovine mastitis infections. Full article

(This article belongs to the Special Issue Plant Phytochemicals on Drug Development)

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29 pages, 458 KiB

Open AccessReview

Therapeutic Advances Against ZIKV: A Quick Response, a Long Way to Go

by Juan-Carlos Saiz

Pharmaceuticals 2019, 12(3), 127; https://doi.org/10.3390/ph12030127 - 30 Aug 2019

Cited by 13 | Viewed by 5110

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus that spread throughout the American continent in 2015 causing considerable worldwide social and health alarm due to its association with ocular lesions and microcephaly in newborns, and Guillain–Barré syndrome (GBS) cases in adults. Nowadays, no licensed [...] Read more.

Zika virus (ZIKV) is a mosquito-borne flavivirus that spread throughout the American continent in 2015 causing considerable worldwide social and health alarm due to its association with ocular lesions and microcephaly in newborns, and Guillain–Barré syndrome (GBS) cases in adults. Nowadays, no licensed vaccines or antivirals are available against ZIKV, and thus, in this very short time, the scientific community has conducted enormous efforts to develop vaccines and antivirals. So that, different platforms (purified inactivated and live attenuated viruses, DNA and RNA nucleic acid based candidates, virus-like particles, subunit elements, and recombinant viruses) have been evaluated as vaccine candidates. Overall, these vaccines have shown the induction of vigorous humoral and cellular responses, the decrease of viremia and viral RNA levels in natural target organs, the prevention of vertical and sexual transmission, as well as that of ZIKV-associated malformations, and the protection of experimental animal models. Some of these vaccine candidates have already been assayed in clinical trials. Likewise, the search for antivirals have also been the focus of recent investigations, with dozens of compounds tested in cell culture and a few in animal models. Both direct acting antivirals (DAAs), directed to viral structural proteins and enzymes, and host acting antivirals (HAAs), directed to cellular factors affecting all steps of the viral life cycle (binding, entry, fusion, transcription, translation, replication, maturation, and egress), have been evaluated. It is expected that this huge collaborative effort will produce affordable and effective therapeutic and prophylactic tools to combat ZIKV and other related still unknown or nowadays neglected flaviviruses. Here, a comprehensive overview of the advances made in the development of therapeutic measures against ZIKV and the questions that still have to be faced are summarized. Full article

(This article belongs to the Special Issue Zika Virus: Therapeutic Advances)

26 pages, 740 KiB

Open AccessReview

Multilevel Impacts of Iron in the Brain: The Cross Talk between Neurophysiological Mechanisms, Cognition, and Social Behavior

by Ana Ferreira, Pedro Neves and Raffaella Gozzelino

Pharmaceuticals 2019, 12(3), 126; https://doi.org/10.3390/ph12030126 - 29 Aug 2019

Cited by 76 | Viewed by 12500

Abstract

Iron is a critical element for most organisms, which plays a fundamental role in the great majority of physiological processes. So much so, that disruption of iron homeostasis has severe multi-organ impacts with the brain being particularly sensitive to such modifications. More specifically, [...] Read more.

Iron is a critical element for most organisms, which plays a fundamental role in the great majority of physiological processes. So much so, that disruption of iron homeostasis has severe multi-organ impacts with the brain being particularly sensitive to such modifications. More specifically, disruption of iron homeostasis in the brain can affect neurophysiological mechanisms, cognition, and social behavior, which eventually contributes to the development of a diverse set of neuro-pathologies. This article starts by exploring the mechanisms of iron action in the brain and follows with a discussion on cognitive and behavioral implications of iron deficiency and overload and how these are framed by the social context. Subsequently, we scrutinize the implications of the disruption of iron homeostasis for the onset and progression of psychosocial disorders. Lastly, we discuss the links between biological, psychological, and social dimensions and outline potential avenues of research. The study of these interactions could ultimately contribute to a broader understanding of how individuals think and act under physiological and pathophysiological conditions. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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9 pages, 785 KiB

Open AccessReview

Iron Deficiency as a Therapeutic Target in Cardiovascular Disease

by Samira Lakhal-Littleton

Pharmaceuticals 2019, 12(3), 125; https://doi.org/10.3390/ph12030125 - 28 Aug 2019

Cited by 14 | Viewed by 5053

Abstract

Iron deficiency is the most common nutritional disorder in the world. It is prevalent amongst patients with cardiovascular disease, in whom it is associated with worse clinical outcomes. The benefits of iron supplementation have been established in chronic heart failure, but data on [...] Read more.

Iron deficiency is the most common nutritional disorder in the world. It is prevalent amongst patients with cardiovascular disease, in whom it is associated with worse clinical outcomes. The benefits of iron supplementation have been established in chronic heart failure, but data on their effectiveness in other cardiovascular diseases are lacking or conflicting. Realising the potential of iron therapies in cardiovascular disease requires understanding of the mechanisms through which iron deficiency affects cardiovascular function, and the cell types in which such mechanisms operate. That understanding has been enhanced by recent insights into the roles of hepcidin and iron regulatory proteins (IRPs) in cellular iron homeostasis within cardiovascular cells. These studies identify intracellular iron deficiency within the cardiovascular tissue as an important contributor to the disease process, and present novel therapeutic strategies based on targeting the machinery of cellular iron homeostasis rather than direct iron supplementation. This review discusses these new insights and their wider implications for the treatment of cardiovascular diseases, focusing on two disease conditions: chronic heart failure and pulmonary arterial hypertension. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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16 pages, 6674 KiB

Open AccessArticle

Antitumor Mechanism of the Essential Oils from Two Succulent Plants in Multidrug Resistance Leukemia Cell

by Paola Poma, Manuela Labbozzetta, James A. McCubrey, Aro Vonjy Ramarosandratana, Maurizio Sajeva, Pietro Zito and Monica Notarbartolo

Pharmaceuticals 2019, 12(3), 124; https://doi.org/10.3390/ph12030124 - 26 Aug 2019

Cited by 12 | Viewed by 4950

Abstract

Drug resistance remains a major challenge in the treatment of cancer. The multiplicity of the drug resistance determinants raises the question about the optimal strategies to deal with them. Essential oils showed to inhibit the growth of different tumor cell types. Essential oils [...] Read more.

Drug resistance remains a major challenge in the treatment of cancer. The multiplicity of the drug resistance determinants raises the question about the optimal strategies to deal with them. Essential oils showed to inhibit the growth of different tumor cell types. Essential oils contain several chemical classes of compounds whose heterogeneity of active moieties can help prevent the development of drug resistance. In the present paper, we analyzed, by gas chromatography-mass spectrometry the chemical composition of the essential oil of the leaves of Kalanchoe beharensis obtained by hydrodistillation and compared the chemical composition of its essential oil with that of Cyphostemma juttae. Our results demonstrated the anticancer and proapoptotic activities of both species against acute myeloid leukemia on an in vitro model and its multidrug resistant variant involving NF-κB pathway. The essential oils of both species produced a significant decrease in many targets of NF-κB both at mRNA and protein levels. The results corroborate the idea that essential oils may be a good alternative to traditional drugs in the treatment of cancer, especially in drug resistant cancer. Full article

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13 pages, 1561 KiB

Open AccessFeature PaperConcept Paper

Unraveling Hepcidin Plasma Protein Binding: Evidence from Peritoneal Equilibration Testing

by Laura E. Diepeveen, Coby M. Laarakkers, Hilde P.E. Peters, Antonius E. van Herwaarden, Hans Groenewoud, Joanna IntHout, Jack F. Wetzels, Rachel P.L. van Swelm and Dorine W. Swinkels

Pharmaceuticals 2019, 12(3), 123; https://doi.org/10.3390/ph12030123 - 23 Aug 2019

Cited by 9 | Viewed by 3869

Abstract

Peptide hormone hepcidin regulates systemic iron metabolism and has been described to be partially bound to α2-macroglobulin and albumin in blood. However, the reported degree of hepcidin protein binding varies between <3% and ≈89%. Since protein-binding may influence hormone function and quantification, better [...] Read more.

Peptide hormone hepcidin regulates systemic iron metabolism and has been described to be partially bound to α2-macroglobulin and albumin in blood. However, the reported degree of hepcidin protein binding varies between <3% and ≈89%. Since protein-binding may influence hormone function and quantification, better insight into the degree of hepcidin protein binding is essential to fully understand the biological behavior of hepcidin and interpretation of its measurement in patients. Here, we used peritoneal dialysis to assess human hepcidin protein binding in a functional human setting for the first time. We measured freely circulating solutes in blood and peritoneal fluid of 14 patients with end-stage renal disease undergoing a peritoneal equilibration test to establish a curve describing the relation between molecular weight and peritoneal clearance. Calculated binding percentages of total cortisol and testosterone confirmed our model. The protein-bound fraction of hepcidin was calculated to be 40% (±23%). We, therefore, conclude that a substantial proportion of hepcidin is freely circulating. Although a large inter-individual variation in hepcidin clearance, besides patient-specific peritoneal transport characteristics, may have affected the accuracy of the determined binding percentage, we describe an important step towards unraveling human hepcidin plasma protein binding in vivo including the caveats that need further research. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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12 pages, 2254 KiB

Open AccessArticle

by Graça Porto, Eugénia Cruz, Maria José Teles and Maria de Sousa

Pharmaceuticals 2019, 12(3), 122; https://doi.org/10.3390/ph12030122 - 22 Aug 2019

Cited by 8 | Viewed by 5185

Abstract

The HFE gene (OMIM 235200), most commonly associated with the genetic iron overload disorder Hemochromatosis, was identified by Feder et al. in 1996, as a major histocompatibilty complex (MHC) class I like gene, first designated human leukocyte antigen-H (HLA-H). This discovery was thus [...] Read more.

The HFE gene (OMIM 235200), most commonly associated with the genetic iron overload disorder Hemochromatosis, was identified by Feder et al. in 1996, as a major histocompatibilty complex (MHC) class I like gene, first designated human leukocyte antigen-H (HLA-H). This discovery was thus accomplished 20 years after the realization of the first link between the then “idiopathic” hemochromatosis and the human leukocyte antigens (HLA). The availability of a good genetic marker in subjects homozygous for the C282Y variant in HFE (hereditary Fe), the reliability in serum markers such as transferrin saturation and serum ferritin, plus the establishment of noninvasive methods for the estimation of hepatic iron overload, all transformed hemochromatosis into a unique age related disease where prevention became the major goal. We were challenged by the finding of iron overload in a 9-year-old boy homozygous for the C282Y HFE variant, with two brothers aged 11 and 5 also homozygous for the mutation. We report a 20 year follow-up during which the three boys were seen yearly with serial determinations of iron parameters and lymphocyte counts. This paper is divided in three sections: Learning, applying, and questioning. The result is the illustration of hemochromatosis as an age related disease in the transition from childhood to adult life and the confirmation of the inextricable link between iron overload and the cells of the immune system. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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9 pages, 2711 KiB

Open AccessArticle

Cell Adhesive Character of Phenylboronic Acid-Modified Insulin and Its Potential as Long-Acting Insulin

by Yui Ohno, Momoko Kawakami, Tomohiro Seki, Ryotaro Miki, Toshinobu Seki and Yuya Egawa

Pharmaceuticals 2019, 12(3), 121; https://doi.org/10.3390/ph12030121 - 19 Aug 2019

Cited by 7 | Viewed by 3835

Abstract

Phenylboronic acid (PBA) derivatives have attracted substantial attention owing to their unique character of forming dynamic covalent bonds with polyol compounds. Recent studies have shown interactions between PBA and sugar chains on the cell surface; they have interesting applications for sensors and drug [...] Read more.

Phenylboronic acid (PBA) derivatives have attracted substantial attention owing to their unique character of forming dynamic covalent bonds with polyol compounds. Recent studies have shown interactions between PBA and sugar chains on the cell surface; they have interesting applications for sensors and drug delivery systems. In this study, we prepared phenylboronic acid-modified insulin (PBA-Ins) to evaluate its glucose-lowering activity and cell adhesiveness. In the case of intravenous injection, PBA-Ins showed longer glucose-lowering activity than native insulin. We hypothesized that this prolonged effect was the result of the interaction between the PBA moiety and sugar chains on the cell surface. Red blood cells (RBCs) were used as a cell model, and we confirmed PBA-Ins’s affinity for RBCs, which induced RBC agglutination. Interestingly, using an alternative PBA-Ins administration route markedly changed its glucose-lowering activity. Unlike the intravenous injection of PBA-Ins, the subcutaneous injection showed a small effect on glucose level, which indicated that a small amount of PBA-Ins was absorbed into the bloodstream. This suggested the importance of investigating the interaction between the PBA moiety and many types of cells, such as adipocytes, in subcutaneous tissues. Full article

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16 pages, 553 KiB

Open AccessReview

Impairment of the Developing Human Brain in Iron Deficiency: Correlations to Findings in Experimental Animals and Prospects for Early Intervention Therapy

by Veronika Markova, Charlotte Holm, Anja Bisgaard Pinborg, Lars Lykke Thomsen and Torben Moos

Pharmaceuticals 2019, 12(3), 120; https://doi.org/10.3390/ph12030120 - 14 Aug 2019

Cited by 21 | Viewed by 4449

Abstract

Due to the necessity of iron for a variety of cellular functions, the developing mammalian organism is vulnerable to iron deficiency, hence causing structural abnormalities and physiological malfunctioning in organs, which are particularly dependent on adequate iron stores, such as the brain. In [...] Read more.

Due to the necessity of iron for a variety of cellular functions, the developing mammalian organism is vulnerable to iron deficiency, hence causing structural abnormalities and physiological malfunctioning in organs, which are particularly dependent on adequate iron stores, such as the brain. In early embryonic life, iron is already needed for proper development of the brain with the proliferation, migration, and differentiation of neuro-progenitor cells. This is underpinned by the widespread expression of transferrin receptors in the developing brain, which, in later life, is restricted to cells of the blood–brain and blood–cerebrospinal fluid barriers and neuronal cells, hence ensuring a sustained iron supply to the brain, even in the fully developed brain. In embryonic human life, iron deficiency is thought to result in a lower brain weight, with the impaired formation of myelin. Studies of fully developed infants that have experienced iron deficiency during development reveal the chronic and irreversible impairment of cognitive, memory, and motor skills, indicating widespread effects on the human brain. This review highlights the major findings of recent decades on the effects of gestational and lactational iron deficiency on the developing human brain. The findings are correlated to findings of experimental animals ranging from rodents to domestic pigs and non-human primates. The results point towards significant effects of iron deficiency on the developing brain. Evidence would be stronger with more studies addressing the human brain in real-time and the development of blood biomarkers of cerebral disturbance in iron deficiency. Cerebral iron deficiency is expected to be curable with iron substitution therapy, as the brain, privileged by the cerebral vascular transferrin receptor expression, is expected to facilitate iron extraction from the circulation and enable transport further into the brain. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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21 pages, 1241 KiB

Open AccessReview

Role of Dietary Flavonoids in Iron Homeostasis

by Marija Lesjak and Surjit K. S. Srai

Pharmaceuticals 2019, 12(3), 119; https://doi.org/10.3390/ph12030119 - 8 Aug 2019

Cited by 39 | Viewed by 10437

Abstract

Balancing systemic iron levels within narrow limits is critical for human health, as both iron deficiency and overload lead to serious disorders. There are no known physiologically controlled pathways to eliminate iron from the body and therefore iron homeostasis is maintained by modifying [...] Read more.

Balancing systemic iron levels within narrow limits is critical for human health, as both iron deficiency and overload lead to serious disorders. There are no known physiologically controlled pathways to eliminate iron from the body and therefore iron homeostasis is maintained by modifying dietary iron absorption. Several dietary factors, such as flavonoids, are known to greatly affect iron absorption. Recent evidence suggests that flavonoids can affect iron status by regulating expression and activity of proteins involved the systemic regulation of iron metabolism and iron absorption. We provide an overview of the links between different dietary flavonoids and iron homeostasis together with the mechanism of flavonoids effect on iron metabolism. In addition, we also discuss the clinical relevance of state-of-the-art knowledge regarding therapeutic potential that flavonoids may have for conditions that are low in iron such as anaemia or iron overload diseases. Full article

(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)

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18 pages, 671 KiB

Open AccessReview

Matrix Metalloproteinase in Abdominal Aortic Aneurysm and Aortic Dissection

by Eithne M. Maguire, Stuart W. A. Pearce, Rui Xiao, Aung Y. Oo and Qingzhong Xiao

Pharmaceuticals 2019, 12(3), 118; https://doi.org/10.3390/ph12030118 - 6 Aug 2019

Cited by 115 | Viewed by 8372

Abstract

Abdominal Aortic Aneurysm (AAA) affects 4–5% of men over 65, and Aortic Dissection (AD) is a life-threatening aortic pathology associated with high morbidity and mortality. Initiators of AAA and AD include smoking and arterial hypertension, whilst key pathophysiological features of AAA and AD [...] Read more.

Abdominal Aortic Aneurysm (AAA) affects 4–5% of men over 65, and Aortic Dissection (AD) is a life-threatening aortic pathology associated with high morbidity and mortality. Initiators of AAA and AD include smoking and arterial hypertension, whilst key pathophysiological features of AAA and AD include chronic inflammation, hypoxia, and large modifications to the extra cellular matrix (ECM). As it stands, only surgical methods are available for preventing aortic rupture in patients, which often presents difficulties for recovery. No pharmacological treatment is available, as such researchers are attempting to understand the cellular and molecular pathophysiology of AAA and AD. Upregulation of matrix metalloproteinase (MMPs), particularly MMP-2 and MMP-9, has been identified as a key event occurring during aneurysmal growth. As such, several animal models of AAA and AD have been used to investigate the therapeutic potential of suppressing MMP-2 and MMP-9 activity as well as modulating the activity of other MMPs, and TIMPs involved in the pathology. Whilst several studies have offered promising results, targeted delivery of MMP inhibition still needs to be developed in order to avoid surgery in high risk patients. Full article

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14 pages, 2351 KiB

Open AccessArticle

Stereoselective Anti-Cancer Activities of Ginsenoside Rg3 on Triple Negative Breast Cancer Cell Models

by Maryam Nakhjavani, Helen M. Palethorpe, Yoko Tomita, Eric Smith, Timothy J. Price, Andrea J. Yool, Jinxin V. Pei, Amanda R. Townsend and Jennifer E. Hardingham

Pharmaceuticals 2019, 12(3), 117; https://doi.org/10.3390/ph12030117 - 1 Aug 2019

Cited by 41 | Viewed by 5905

Abstract

Ginsenoside Rg3 (Rg3) has two epimers, 20(S)-ginsenoside Rg3 (SRg3) and 20(R)-ginsenoside Rg3 (RRg3), and while Rg3 itself has been reported to have anti-cancer properties, few studies have been reported on the anti-cancer effects of the different epimers. The aim was to investigate the [...] Read more.

Ginsenoside Rg3 (Rg3) has two epimers, 20(S)-ginsenoside Rg3 (SRg3) and 20(R)-ginsenoside Rg3 (RRg3), and while Rg3 itself has been reported to have anti-cancer properties, few studies have been reported on the anti-cancer effects of the different epimers. The aim was to investigate the stereoselective effects of the Rg3 epimers on triple negative breast cancer (TNBC) cell lines, tested using cell-based assays for proliferation, apoptosis, cell cycle arrest, migration and invasion. Molecular docking showed that Rg3 interacted with the aquaporin 1 (AQP1) water channel (binding score −9.4 kJ mol⁻¹). The Xenopus laevis oocyte expression system was used to study the effect of Rg3 epimers on the AQP1 water permeability. The AQP1 expression in TNBC cell lines was compared with quantitative-polymerase chain reaction (PCR). The results showed that only SRg3 inhibited the AQP1 water flux and inhibited the proliferation of MDA-MB-231 (100 μM), due to cell cycle arrest at G0/G1. SRg3 inhibited the chemoattractant-induced migration of MDA-MB-231. The AQP1 expression in MDA-MB-231 was higher than in HCC1143 or DU4475 cell lines. These results suggest a role for AQP1 in the proliferation and chemoattractant-induced migration of this cell line. Compared to SRg3, RRg3 had more potency and efficacy, inhibiting the migration and invasion of MDA-MB-231. Rg3 has stereoselective anti-cancer effects in the AQP1 high-expressing cell line MDA-MB-231. Full article

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10 pages, 4012 KiB

Open AccessArticle

Electrochemical Characterization of Central Action Tricyclic Drugs by Voltammetric Techniques and Density Functional Theory Calculations

by Edson Silvio Batista Rodrigues, Isaac Yves Lopes de Macêdo, Larissa Lesley da Silva Lima, Douglas Vieira Thomaz, Carlos Eduardo Peixoto da Cunha, Mayk Teles de Oliveira, Nara Ballaminut, Morgana Fernandes Alecrim, Murilo Ferreira de Carvalho, Bruna Guimarães Isecke, Karla Carneiro de Siqueira Leite, Fabio Bahls Machado, Freddy Fernandes Guimarães, Ricardo Menegatti, Vernon Somerset and Eric de Souza Gil

Pharmaceuticals 2019, 12(3), 116; https://doi.org/10.3390/ph12030116 - 1 Aug 2019

Cited by 10 | Viewed by 5464

Abstract

This work details the study of the redox behavior of the drugs cyclobenzaprine (CBP), amitriptyline (AMP) and nortriptyline (NOR) through voltammetric methods and computational chemistry. Results obtained in this study show that the amine moiety of each compound is more likely to undergo [...] Read more.

This work details the study of the redox behavior of the drugs cyclobenzaprine (CBP), amitriptyline (AMP) and nortriptyline (NOR) through voltammetric methods and computational chemistry. Results obtained in this study show that the amine moiety of each compound is more likely to undergo oxidation at 1a at E_p1a ≈ 0.69, 0.79, 0.93 V (vs. Ag/AgCl/KClsat) for CBP, AMP and NOR, respectively. Moreover, CBP presented a second peak, 2a at E_p2a ≈ 0.98 V (vs. Ag/AgCl/KClsat) at pH 7.0. Furthermore, the electronic structure calculation results corroborate the electrochemical assays regarding the HOMO energies of the lowest energy conformers of each molecule. The mechanism for each anodic process is proposed according to electroanalytical and computational chemistry findings, which show evidence that the methods herein employed may be a valuable alternative to study the redox behavior of structurally similar drugs. Full article

(This article belongs to the Special Issue Molecular Dynamics in Drug Design)

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7 pages, 2374 KiB

Open AccessBrief Report

Tafenoquine: A 2018 Novel FDA-Approved Prodrug for the Radical Cure of Plasmodium vivax Malaria and Prophylaxis of Malaria

by Annie Mayence and Jean Jacques Vanden Eynde

Pharmaceuticals 2019, 12(3), 115; https://doi.org/10.3390/ph12030115 - 30 Jul 2019

Cited by 15 | Viewed by 7295

Abstract

Tafenoquine (an 8-aminoquinoline) was approved by the Food and Drug Administration (FDA) in 2018 for the radical cure of Plasmodium vivax malaria and preventive action against malaria. Despite the fact that the mechanism of action of the drug remains unclear, all studies indicated [...] Read more.

Tafenoquine (an 8-aminoquinoline) was approved by the Food and Drug Administration (FDA) in 2018 for the radical cure of Plasmodium vivax malaria and preventive action against malaria. Despite the fact that the mechanism of action of the drug remains unclear, all studies indicated that a metabolite is responsible for its efficacy. Routes for the preparation of the drug are described. Full article

(This article belongs to the Special Issue The Story of Successful Drugs and Recent FDA-Approved Molecules)

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8 pages, 1840 KiB

Open AccessReview

Lutathera^®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy

by Ute Hennrich and Klaus Kopka

Pharmaceuticals 2019, 12(3), 114; https://doi.org/10.3390/ph12030114 - 29 Jul 2019

Cited by 254 | Viewed by 17430

Abstract

As the first radiopharmaceutical for Peptide Receptor Radionuclide Therapy (PRRT), Lutathera^® was approved by the EMA in 2017 and the FDA in 2018 for the treatment of somatostatin receptor (SSTR) positive gastroenteropancreatic neuroendocrine tumors. Using the concept of PRRT, Lutathera^® combines [...] Read more.

As the first radiopharmaceutical for Peptide Receptor Radionuclide Therapy (PRRT), Lutathera^® was approved by the EMA in 2017 and the FDA in 2018 for the treatment of somatostatin receptor (SSTR) positive gastroenteropancreatic neuroendocrine tumors. Using the concept of PRRT, Lutathera^® combines the radionuclide ¹⁷⁷Lu with the somatostatin analogue DOTA-TATE, thus delivering ionizing radiation specifically to tumor cells expressing somatostatin receptors. As a result, DNA single- and double-strand breaks are provoked, in case of double-strand breaks leading to cell death of the tumor and its SSTR-positive lesions. Full article

(This article belongs to the Special Issue The Story of Successful Drugs and Recent FDA-Approved Molecules)

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23 pages, 2682 KiB

Open AccessReview

Novel Treatment Targets Based on Insights in the Etiology of Depression: Role of IL-6 Trans-Signaling and Stress-Induced Elevation of Glutamate and ATP

by Hans O. Kalkman

Pharmaceuticals 2019, 12(3), 113; https://doi.org/10.3390/ph12030113 - 29 Jul 2019

Cited by 22 | Viewed by 8782

Abstract

Inflammation and psychological stress are risk factors for major depression and suicide. Both increase central glutamate levels and activate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Both factors also affect the function of the chloride transporters, Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2), and [...] Read more.

Inflammation and psychological stress are risk factors for major depression and suicide. Both increase central glutamate levels and activate the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Both factors also affect the function of the chloride transporters, Na-K-Cl-cotransporter-1 (NKCC1) and K-Cl-cotransporter-2 (KCC2), and provoke interleukin-6 (IL-6) trans-signaling. This leads to measurable increases in circulating corticosteroids, catecholamines, anxiety, somatic and psychological symptoms, and a decline in cognitive functions. Recognition of the sequence of pathological events allows the prediction of novel targets for therapeutic intervention. Amongst others, these include blockade of the big-K potassium channel, blockade of the P2X4 channel, TYK2-kinase inhibition, noradrenaline α2B-receptor antagonism, nicotinic α7-receptor stimulation, and the Sgp130Fc antibody. A better understanding of downstream processes evoked by inflammation and stress also allows suggestions for tentatively better biomarkers (e.g., SERPINA3N, MARCKS, or ¹³C-tryptophan metabolism). Full article

(This article belongs to the Special Issue Antidepressants: Mechanistic Insights and Future Directions)

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12 pages, 3019 KiB

Open AccessArticle

Larvicidal and Enzymatic Inhibition Effects of Annona Muricata Seed Extract and Main Constituent Annonacin against Aedes Aegypti and Aedes Albopictus (Diptera: Culicidae)

by Alzeir Machado Rodrigues, Antonio Adailson Sousa Silva, Cleonilda Claita Carneiro Pinto, Dayanne Lima dos Santos, José Claudio Carneiro de Freitas, Victor Emanuel Pessoa Martins and Selene Maia de Morais

Pharmaceuticals 2019, 12(3), 112; https://doi.org/10.3390/ph12030112 - 26 Jul 2019

Cited by 16 | Viewed by 5713

Abstract

The mosquitoes Aedes aegypti and Aedes albopictus are vectors of arboviruses that cause dengue, zika and chikungunya. Bioactive compounds from plants are environmentally sustainable alternatives to control these vectors and thus the arboviruses transmitted by them. The present study evaluated the larvicidal activity [...] Read more.

The mosquitoes Aedes aegypti and Aedes albopictus are vectors of arboviruses that cause dengue, zika and chikungunya. Bioactive compounds from plants are environmentally sustainable alternatives to control these vectors and thus the arboviruses transmitted by them. The present study evaluated the larvicidal activity of an acetogenin-rich fraction (ACERF) and its main constituent annonacin obtained from Annona muricata seeds on Ae. aegypti and Ae. albopictus. The larvicidal assays were performed using different concentrations to calculate the LC₅₀ and LC₉₀ values observed 24 h after exposure to the treatment. Annonacin was more active against Ae. aegypti (LC₅₀ 2.65 μg·mL⁻¹) in comparison with Ae. albopictus (LC₅₀ 8.34 μg·mL⁻¹). In contrast, the acetogenin-rich fraction was more active against Ae. albopictus (LC₅₀ 3.41 μg·mL⁻¹) than Ae. aegypti (LC₅₀ 12.41 μg·mL⁻¹). ACERF and annonacin treated larvae of Ae. aegypti and Ae. albopictus showed significant differences in the inhibition of their metabolic enzymes when compared to untreated larvae. The results demonstrate the relevant larvicidal action of the acetogenin-rich fraction and annonacin showing the potential to develop new products for the control of Ae. aegypti and Ae. albopictus. Full article

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3 pages, 146 KiB

Open AccessEditorial

Special Issue “Targets, Tracers and Translation Novel Radiopharmaceuticals Boost Nuclear Medicine”

by Gerald Reischl

Pharmaceuticals 2019, 12(3), 111; https://doi.org/10.3390/ph12030111 - 18 Jul 2019

Cited by 3 | Viewed by 3477

Abstract

This is the fourth Special Issue in Pharmaceuticals within the last six years dealing with aspects of radiopharmaceutical sciences [...] Full article

(This article belongs to the Special Issue Targets, Tracers and Translation – Novel Radiopharmaceuticals Boost Nuclear Medicine)

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Pharmaceuticals, Volume 12, Issue 3 (September 2019) – 41 articles

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