Pharmaceuticals

13 pages, 4124 KiB

Open AccessArticle

Comparison Study of Two Differently Clicked ¹⁸F-Folates—Lipophilicity Plays a Key Role

by Kathrin Kettenbach, Laura M. Reffert, Hanno Schieferstein, Stefanie Pektor, Raphael Eckert, Matthias Miederer, Frank Rösch and Tobias L. Ross

Pharmaceuticals 2018, 11(1), 30; https://doi.org/10.3390/ph11010030 - 17 Mar 2018

Cited by 12 | Viewed by 4676

Abstract

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable ¹⁸F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation [...] Read more.

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable ¹⁸F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel ¹⁸F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the ¹⁸F-folates was investigated. ¹⁸F-Ala-folate and ¹⁸F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked ¹⁸F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with ¹⁸F-DBCO-folate, ¹⁸F-Ala-folate (logD = −1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, ¹⁸F-Ala-folate is expected to be a promising candidate for FR-PET imaging. Full article

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26 pages, 4180 KiB

Open AccessArticle

Heterodimer Binding Scaffolds Recognition via the Analysis of Kinetically Hot Residues

by Ognjen Perišić

Pharmaceuticals 2018, 11(1), 29; https://doi.org/10.3390/ph11010029 - 16 Mar 2018

Cited by 3 | Viewed by 5193

Abstract

Physical interactions between proteins are often difficult to decipher. The aim of this paper is to present an algorithm that is designed to recognize binding patches and supporting structural scaffolds of interacting heterodimer proteins using the Gaussian Network Model (GNM). The recognition is [...] Read more.

Physical interactions between proteins are often difficult to decipher. The aim of this paper is to present an algorithm that is designed to recognize binding patches and supporting structural scaffolds of interacting heterodimer proteins using the Gaussian Network Model (GNM). The recognition is based on the (self) adjustable identification of kinetically hot residues and their connection to possible binding scaffolds. The kinetically hot residues are residues with the lowest entropy, i.e., the highest contribution to the weighted sum of the fastest modes per chain extracted via GNM. The algorithm adjusts the number of fast modes in the GNM’s weighted sum calculation using the ratio of predicted and expected numbers of target residues (contact and the neighboring first-layer residues). This approach produces very good results when applied to dimers with high protein sequence length ratios. The protocol’s ability to recognize near native decoys was compared to the ability of the residue-level statistical potential of Lu and Skolnick using the Sternberg and Vakser decoy dimers sets. The statistical potential produced better overall results, but in a number of cases its predicting ability was comparable, or even inferior, to the prediction ability of the adjustable GNM approach. The results presented in this paper suggest that in heterodimers at least one protein has interacting scaffold determined by the immovable, kinetically hot residues. In many cases, interacting proteins (especially if being of noticeably different sizes) either behave as a rigid lock and key or, presumably, exhibit the opposite dynamic behavior. While the binding surface of one protein is rigid and stable, its partner’s interacting scaffold is more flexible and adaptable. Full article

(This article belongs to the Special Issue Chemoinformatics and Drug Design)

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13 pages, 3579 KiB

Open AccessArticle

Low Molecular Weight Chitosan-Coated PLGA Nanoparticles for Pulmonary Delivery of Tobramycin for Cystic Fibrosis

by Nusaiba K. Al-Nemrawi, Nid’’A H. Alshraiedeh, Aref L. Zayed and Bashar M. Altaani

Pharmaceuticals 2018, 11(1), 28; https://doi.org/10.3390/ph11010028 - 8 Mar 2018

Cited by 69 | Viewed by 9783

Abstract

(1) Background: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Tobramycin were prepared using a solvent-evaporation method. (2) Methods: The NPs were coated with low molecular weight chitosan (LMWC) to enhance the mucoadhesiveness of PLGA-NPs. The following w/w ratios of tobramycin to [...] Read more.

(1) Background: Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with Tobramycin were prepared using a solvent-evaporation method. (2) Methods: The NPs were coated with low molecular weight chitosan (LMWC) to enhance the mucoadhesiveness of PLGA-NPs. The following w/w ratios of tobramycin to LMWC were prepared: control (0:0.50), F₀ (1:0.25), F₀.₅ (1:0.5), and F₁ (1:1). (3) Results: The results showed that the size of the particles increased from 220.7 nm to 575.77 nm as the concentration of LMWC used in the formulation increased. The surface charge was also affected by the amount of LMWC, where uncoated-PLGA nanoparticles had negative charges (−2.8 mV), while coated-PLGA NPs had positive charges (+33.47 to +50.13 mV). SEM confirmed the size and the spherical homogeneous morphology of the NPs. Coating the NPs with LMWC enhanced the mucoadhesive properties of the NPs and sustained the tobramycin release over two days. Finally, all NPs had antimicrobial activity that increased as the amount of LMWC increased. (4) Conclusion: In conclusion, the formulation of mucoadhesive, controlled-release, tobramycin-LMWC-PLGA nanoparticles for the treatment of P. aeruginosa in cystic fibrosis patients is possible, and their properties could be controlled by controlling the concentration of LMWC. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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9 pages, 1293 KiB

Open AccessEditorial

Glycosaminoglycans and Proteoglycans

by Vitor H. Pomin and Barbara Mulloy

Pharmaceuticals 2018, 11(1), 27; https://doi.org/10.3390/ph11010027 - 27 Feb 2018

Cited by 134 | Viewed by 14249

Abstract

In this editorial to MDPI Pharmaceuticals special issue “Glycosaminoglycans and Proteoglycans” we describe in outline the common structural features of glycosaminoglycans and the characteristics of proteoglycans, including the intracellular proteoglycan, serglycin, cell-surface proteoglycans, like syndecans and glypicans, and the extracellular matrix [...] Read more.

In this editorial to MDPI Pharmaceuticals special issue “Glycosaminoglycans and Proteoglycans” we describe in outline the common structural features of glycosaminoglycans and the characteristics of proteoglycans, including the intracellular proteoglycan, serglycin, cell-surface proteoglycans, like syndecans and glypicans, and the extracellular matrix proteoglycans, like aggrecan, perlecan, and small leucine-rich proteoglycans. The context in which the pharmaceutical uses of glycosaminoglycans and proteoglycans are presented in this special issue is given at the very end. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Proteoglycans)

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12 pages, 1690 KiB

Open AccessReview

Semi-Solid and Solid Dosage Forms for the Delivery of Phage Therapy to Epithelia

by Teagan L. Brown, Steve Petrovski, Hiu Tat Chan, Michael J. Angove and Joseph Tucci

Pharmaceuticals 2018, 11(1), 26; https://doi.org/10.3390/ph11010026 - 26 Feb 2018

Cited by 26 | Viewed by 8832

Abstract

The delivery of phages to epithelial surfaces for therapeutic outcomes is a realistic proposal, and indeed one which is being currently tested in clinical trials. This paper reviews some of the known research on formulation of phages into semi-solid dosage forms such as [...] Read more.

The delivery of phages to epithelial surfaces for therapeutic outcomes is a realistic proposal, and indeed one which is being currently tested in clinical trials. This paper reviews some of the known research on formulation of phages into semi-solid dosage forms such as creams, ointments and pastes, as well as solid dosage forms such as troches (or lozenges and pastilles) and suppositories/pessaries, for delivery to the epithelia. The efficacy and stability of these phage formulations is discussed, with a focus on selection of optimal semi-solid bases for phage delivery. Issues such as the need for standardisation of techniques for formulation as well as for assessment of efficacy are highlighted. These are important when trying to compare results from a range of experiments and across different delivery bases. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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19 pages, 4517 KiB

Open AccessFeature PaperArticle

Characterization of the Lytic Capability of a LysK-Like Endolysin, Lys-phiSA012, Derived from a Polyvalent Staphylococcus aureus Bacteriophage

by Jumpei Fujiki, Tomohiro Nakamura, Takaaki Furusawa, Hazuki Ohno, Hiromichi Takahashi, Junya Kitana, Masaru Usui, Hidetoshi Higuchi, Yasunori Tanji, Yutaka Tamura and Hidetomo Iwano

Pharmaceuticals 2018, 11(1), 25; https://doi.org/10.3390/ph11010025 - 24 Feb 2018

Cited by 31 | Viewed by 8650

Abstract

Antibiotic-resistant bacteria (ARB) have spread widely and rapidly, with their increased occurrence corresponding with the increased use of antibiotics. Infections caused by Staphylococcus aureus have a considerable negative impact on human and livestock health. Bacteriophages and their peptidoglycan hydrolytic enzymes (endolysins) have received [...] Read more.

Antibiotic-resistant bacteria (ARB) have spread widely and rapidly, with their increased occurrence corresponding with the increased use of antibiotics. Infections caused by Staphylococcus aureus have a considerable negative impact on human and livestock health. Bacteriophages and their peptidoglycan hydrolytic enzymes (endolysins) have received significant attention as novel approaches against ARB, including S. aureus. In the present study, we purified an endolysin, Lys-phiSA012, which harbors a cysteine/histidine-dependent amidohydrolase/peptidase (CHAP) domain, an amidase domain, and a SH3b cell wall binding domain, derived from a polyvalent S. aureus bacteriophage which we reported previously. We demonstrate that Lys-phiSA012 exhibits high lytic activity towards staphylococcal strains, including methicillin-resistant S. aureus (MRSA). Analysis of deletion mutants showed that only mutants possessing the CHAP and SH3b domains could lyse S. aureus, indicating that lytic activity of the CHAP domain depended on the SH3b domain. The presence of at least 1 mM Ca²⁺ and 100 µM Zn²⁺ enhanced the lytic activity of Lys-phiSA012 in a turbidity reduction assay. Furthermore, a minimum inhibitory concentration (MIC) assay showed that the addition of Lys-phiSA012 decreased the MIC of oxacillin. Our results suggest that endolysins are a promising approach for replacing current antimicrobial agents and may contribute to the proper use of antibiotics, leading to the reduction of ARB. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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13 pages, 2536 KiB

Open AccessArticle

Improved Syntheses of the mGlu₅ Antagonists MMPEP and MTEP Using Sonogashira Cross-Coupling

by Boshuai Mu, Linjing Mu, Roger Schibli, Simon M. Ametamey and Selena Milicevic Sephton

Pharmaceuticals 2018, 11(1), 24; https://doi.org/10.3390/ph11010024 - 20 Feb 2018

Viewed by 4159

Abstract

The Sonogashira cross-coupling, a key step in the syntheses of the mGlu₅ antagonists MMPEP and MTEP, provided an improved three-step method for the preparation of MMPEP in 62% overall yield. Using Spartan molecular modeling kit an explanation for the failure to employ [...] Read more.

The Sonogashira cross-coupling, a key step in the syntheses of the mGlu₅ antagonists MMPEP and MTEP, provided an improved three-step method for the preparation of MMPEP in 62% overall yield. Using Spartan molecular modeling kit an explanation for the failure to employ analogues method in the synthesis of MTEP was sought. The DFT calculations indicated that meaningful isolated yields were obtained when the HOMO energy of the aryl halide was lower than the HOMO energy of the respective alkyne. Full article

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24 pages, 15492 KiB

Open AccessArticle

A π-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors

by Alexander Schnitzler, Andreas Gratz, Andre Bollacke, Michael Weyrich, Uwe Kuckländer, Bernhard Wünsch, Claudia Götz, Karsten Niefind and Joachim Jose

Pharmaceuticals 2018, 11(1), 23; https://doi.org/10.3390/ph11010023 - 17 Feb 2018

Cited by 7 | Viewed by 5695

Abstract

Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol [...] Read more.

Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol (5) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC₅₀ values of 7 nM (4a) and 5 nM (5) and an apparent K_i value of 0.4 nM for both. Compounds 4a and 5 reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of 4a and 5 revealed an unexpected π-halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound 4b, with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency. Full article

(This article belongs to the Special Issue Choices of the Journal)

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15 pages, 9398 KiB

Open AccessArticle

A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study

by Francesco Gentile, Marco A. Deriu, Khaled Barakat, Andrea Danani and Jack Tuszynski

Pharmaceuticals 2018, 11(1), 22; https://doi.org/10.3390/ph11010022 - 16 Feb 2018

Cited by 3 | Viewed by 5186

Abstract

The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of [...] Read more.

The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of tubulin was reported. To investigate the possibility of an interaction between structural analogues of colchicine and the TLR7, a recent computational model for the dimeric form of the TLR7 receptor was used to determine a possible interaction with a colchicine derivative called CR42-24, active as a tubulin polymerization inhibitor. The estimated values of the binding energy of this molecule with respect to the TLR7 receptor were comparable to the energies of known binders as reported in a previous study. The binding to the TLR7 was further assessed by introducing genetic transformations in the TLR7 gene in cancer cell lines and exposing them to the compound. A negative shift of the IC50 value in terms of cell growth was observed in cell lines carrying the mutated TLR7 gene. The reported study suggests a possible interaction between TLR7 and a colchicine derivative, which can be explored for rational design of new drugs acting on this receptor by using a colchicine scaffold for additional modifications. Full article

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

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12 pages, 7422 KiB

Open AccessArticle

Pilocarpine-Induced Status Epilepticus Is Associated with P-Glycoprotein Induction in Cardiomyocytes, Electrocardiographic Changes, and Sudden Death

by Jerónimo Auzmendi, Bruno Buchholz, Jimena Salguero, Carlos Cañellas, Jazmín Kelly, Paula Men, Marcela Zubillaga, Alicia Rossi, Amalia Merelli, Ricardo J. Gelpi, Alberto J. Ramos and Alberto Lazarowski

Pharmaceuticals 2018, 11(1), 21; https://doi.org/10.3390/ph11010021 - 16 Feb 2018

Cited by 32 | Viewed by 5692

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in those patients suffering from refractory epilepsy (RE), with a 24-fold higher risk relative to the normal population. SUDEP risk increases with seizure frequency and/or seizure-duration as in RE and Status [...] Read more.

Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in those patients suffering from refractory epilepsy (RE), with a 24-fold higher risk relative to the normal population. SUDEP risk increases with seizure frequency and/or seizure-duration as in RE and Status Epilepticus (SE). P-glycoprotein (P-gp), the product of the multidrug resistant ABCB1-MDR-1 gene, is a detoxifying pump that extrudes drugs out of the cells and can confer pharmacoresistance to the expressing cells. Neurons and cardiomyocytes normally do not express P-gp, however, it is overexpressed in the brain of patients or in experimental models of RE and SE. P-gp was also detected after brain or cardiac hypoxia. We have previously demonstrated that repetitive pentylenetetrazole (PTZ)-induced seizures increase P-gp expression in the brain, which is associated with membrane depolarization in the hippocampus, and in the heart, which is associated with fatal SE. SE can produce hypoxic-ischemic altered cardiac rhythm (HIACR) and severe arrhythmias, and both are related with SUDEP. Here, we investigate whether SE induces the expression of hypoxia-inducible transcription factor (HIF)-1α and P-gp in cardiomyocytes, which is associated with altered heart rhythm, and if these changes are related with the spontaneous death rate. SE was induced in Wistar rats once a week for 3 weeks, by lithium-pilocarpine-paradigm. Electrocardiograms, HIF-1α, and P-gp expression in cardiomyocytes, were evaluated in basal conditions and 72 h after SE. All spontaneous deaths occurred 48 h after each SE was registered. We observed that repeated SE induced HIF-1α and P-gp expression in cardiomyocytes, electrocardiographic (ECG) changes, and a high rate of spontaneous death. Our results suggest that the highly accumulated burden of convulsive stress results in a hypoxic heart insult, where P-gp expression may play a depolarizing role in cardiomyocyte membranes and in the development of the ECG changes, such as QT interval prolongation, that could be related with SUDEP. We postulate that this mechanism could explain, in part, the higher SUDEP risk in patients with RE or SE. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications)

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13 pages, 1057 KiB

Open AccessArticle

Antimicrobial Peptides for Topical Treatment of Osteomyelitis and Implant-Related Infections: Study in the Spongy Bone

by Pavel Melicherčík, Ondřej Nešuta and Václav Čeřovský

Pharmaceuticals 2018, 11(1), 20; https://doi.org/10.3390/ph11010020 - 16 Feb 2018

Cited by 25 | Viewed by 4929

Abstract

We examined the benefits of short linear α-helical antimicrobial peptides (AMPs) invented in our laboratory for treating bone infection and preventing microbial biofilm formation on model implants due to causative microorganisms of osteomyelitis. For this purpose, we introduced a model of induced osteomyelitis [...] Read more.

We examined the benefits of short linear α-helical antimicrobial peptides (AMPs) invented in our laboratory for treating bone infection and preventing microbial biofilm formation on model implants due to causative microorganisms of osteomyelitis. For this purpose, we introduced a model of induced osteomyelitis that utilizes human femur heads obtained from the hospital after their replacement with artificial prostheses. We found that the focus of the infection set up in the spongy part of this bone treated with AMP-loaded calcium phosphate cement was eradicated much more effectively than was the focus treated with antibiotics such as vancomycin or gentamicin loaded into the same cement. This contradicts the minimum inhibitory concentrations (MIC) values of AMPs and antibiotics against some bacterial strains obtained in standard in vitro assays. The formation of microbial biofilm on implants made from poly(methylmethacrylate)-based bone cement loaded with AMP was evaluated after the implants’ removal from the infected bone sample. AMPs loaded in such model implants prevented microbial adhesion and subsequent formation of bacterial biofilm on their surface. Biofilms did form, on the other hand, on control implants made from the plain cement when these were implanted into the same infected bone sample. These results of the experiments performed in human bone tissue highlight the clinical potential of antimicrobial peptides for use in treating and preventing osteomyelitis caused by resistant pathogens. Full article

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15 pages, 11550 KiB

Open AccessArticle

Application of Nanoparticle Technology to Reduce the Anti-Microbial Resistance through β-Lactam Antibiotic-Polymer Inclusion Nano-Complex

by Constain H. Salamanca, Cristhian J. Yarce, Yony Roman, Andrés F. Davalos and Gustavo R. Rivera

Pharmaceuticals 2018, 11(1), 19; https://doi.org/10.3390/ph11010019 - 10 Feb 2018

Cited by 20 | Viewed by 5548

Abstract

Biocompatible polymeric materials with potential to form functional structures in association with different therapeutic molecules have a high potential for biological, medical and pharmaceutical applications. Therefore, the capability of the inclusion of nano-Complex formed between the sodium salt of poly(maleic acid-alt-octadecene) [...] Read more.

Biocompatible polymeric materials with potential to form functional structures in association with different therapeutic molecules have a high potential for biological, medical and pharmaceutical applications. Therefore, the capability of the inclusion of nano-Complex formed between the sodium salt of poly(maleic acid-alt-octadecene) and a β-lactam drug (ampicillin trihydrate) to avoid the chemical and enzymatic degradation and enhance the biological activity were evaluated. PAM-18Na was produced and characterized, as reported previously. The formation of polymeric hydrophobic aggregates in aqueous solution was determined, using pyrene as a fluorescent probe. Furthermore, the formation of polymer-drug nano-complexes was characterized by Differential Scanning Calorimetry-DSC, viscometric, ultrafiltration/centrifugation assays, zeta potential and size measurements were determined by dynamic light scattering-DLS. The PAM-18Na capacity to avoid the chemical degradation was studied through stress stability tests. The enzymatic degradation was evaluated from a pure β-lactamase, while the biological degradation was determined by different β-lactamase producing Staphylococcus aureus strains. When ampicillin was associated with PAM-18Na, the half-life time in acidic conditions increased, whereas both the enzymatic degradation and the minimum inhibitory concentration decreased to a 90 and 75%, respectively. These results suggest a promissory capability of this polymer to protect the β-lactam drugs against chemical, enzymatic and biological degradation. Full article

(This article belongs to the Special Issue Nano Drug Carriers)

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32 pages, 9090 KiB

Open AccessMeeting Report

Third International Electronic Conference on Medicinal Chemistry (ECMC-3)

by Annie Mayence and Jean Jacques Vanden Eynde

Pharmaceuticals 2018, 11(1), 18; https://doi.org/10.3390/ph11010018 - 9 Feb 2018

Cited by 1 | Viewed by 6261

Abstract

The third International Electronic Conference on Medicinal Chemistry, organized and sponsored by MDPI AG, publisher, and the journal Pharmaceuticals, took place in November 2017 on the SciForum website (www.sciforum.net/conference/ecmc-3). Around 300 authors from 34 different countries participated at the event, which hosted [...] Read more.

The third International Electronic Conference on Medicinal Chemistry, organized and sponsored by MDPI AG, publisher, and the journal Pharmaceuticals, took place in November 2017 on the SciForum website (www.sciforum.net/conference/ecmc-3). Around 300 authors from 34 different countries participated at the event, which hosted more than 70 presentations, keynotes, videos, and posters. A short description of some works presented during that scientific meeting is disclosed in this report. Full article

(This article belongs to the Special Issue Selected Papers from the 3rd International Electronic Conference on Medicinal Chemistry)

18 pages, 2234 KiB

Open AccessFeature PaperReview

Interactions Between Epilepsy and Plasticity

by José J. Jarero-Basulto, Yadira Gasca-Martínez, Martha C. Rivera-Cervantes, Mónica E. Ureña-Guerrero, Alfredo I. Feria-Velasco and Carlos Beas-Zarate

Pharmaceuticals 2018, 11(1), 17; https://doi.org/10.3390/ph11010017 - 7 Feb 2018

Cited by 43 | Viewed by 7958

Abstract

Undoubtedly, one of the most interesting topics in the field of neuroscience is the ability of the central nervous system to respond to different stimuli (normal or pathological) by modifying its structure and function, either transiently or permanently, by generating neural cells and [...] Read more.

Undoubtedly, one of the most interesting topics in the field of neuroscience is the ability of the central nervous system to respond to different stimuli (normal or pathological) by modifying its structure and function, either transiently or permanently, by generating neural cells and new connections in a process known as neuroplasticity. According to the large amount of evidence reported in the literature, many stimuli, such as environmental pressures, changes in the internal dynamic steady state of the organism and even injuries or illnesses (e.g., epilepsy) may induce neuroplasticity. Epilepsy and neuroplasticity seem to be closely related, as the two processes could positively affect one another. Thus, in this review, we analysed some neuroplastic changes triggered in the hippocampus in response to seizure-induced neuronal damage and how these changes could lead to the establishment of temporal lobe epilepsy, the most common type of focal human epilepsy. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications)

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11 pages, 999 KiB

Open AccessArticle

Vitamin E Phosphate Nucleoside Prodrugs: A Platform for Intracellular Delivery of Monophosphorylated Nucleosides

by Richard Daifuku, Michael Koratich and Murray Stackhouse

Pharmaceuticals 2018, 11(1), 16; https://doi.org/10.3390/ph11010016 - 6 Feb 2018

Cited by 8 | Viewed by 6080

Abstract

Vitamin E phosphate (VEP) nucleoside prodrugs are designed to bypass two mechanisms of tumor resistance to therapeutic nucleosides: nucleoside transport and kinase downregulation. Certain isoforms of vitamin E (VE) have shown activity against solid and hematologic tumors and result in chemosensitization. Because gemcitabine [...] Read more.

Vitamin E phosphate (VEP) nucleoside prodrugs are designed to bypass two mechanisms of tumor resistance to therapeutic nucleosides: nucleoside transport and kinase downregulation. Certain isoforms of vitamin E (VE) have shown activity against solid and hematologic tumors and result in chemosensitization. Because gemcitabine is one of the most common chemotherapeutics for the treatment of cancer, it was used to demonstrate the constructs utility. Four different VE isoforms were conjugated with gemcitabine at the 5′ position. Two of these were δ-tocopherol-monophosphate (MP) gemcitabine (NUC050) and δ-tocotrienol-MP gemcitabine (NUC052). NUC050 was shown to be able to deliver gemcitabine-MP intracellularly by a nucleoside transport independent mechanism. Its half-life administered IV in mice was 3.9 h. In a mouse xenograft model of non-small cell lung cancer (NSCLC) NCI-H460, NUC050 at a dose of 40 mg/kg IV qwk × 4 resulted in significant inhibition to tumor growth on days 11–31 (p < 0.05) compared to saline control (SC). Median survival was 33 days (NUC050) vs. 25.5 days (SC) ((hazard ratio) HR = 0.24, p = 0.017). Further, NUC050 significantly inhibited tumor growth compared to historic data with gemcitabine at 135 mg/kg IV q5d × 3 on days 14–41 (p < 0.05). NUC052 was administered at a dose of 40 mg/kg IV qwk × 2 followed by 50 mg/kg qwk × 2. NUC052 resulted in inhibition to tumor growth on days 14–27 (p < 0.05) and median survival was 34 days (HR = 0.27, p = 0.033). NUC050 and NUC052 have been shown to be safe and effective in a mouse xenograft of NSCLC. Full article

(This article belongs to the Special Issue Selected Papers from the 3rd International Electronic Conference on Medicinal Chemistry)

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34 pages, 4659 KiB

Open AccessReview

Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules

by Maria João Gouveia, Paul J. Brindley, Fátima Gärtner, José M. Correia da Costa and Nuno Vale

Pharmaceuticals 2018, 11(1), 15; https://doi.org/10.3390/ph11010015 - 5 Feb 2018

Cited by 52 | Viewed by 9517

Abstract

Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated [...] Read more.

Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ. Full article

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

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19 pages, 745 KiB

Open AccessReview

Antibiotic Persistence as a Metabolic Adaptation: Stress, Metabolism, the Host, and New Directions

by Damien J. Cabral, Jenna I. Wurster and Peter Belenky

Pharmaceuticals 2018, 11(1), 14; https://doi.org/10.3390/ph11010014 - 1 Feb 2018

Cited by 62 | Viewed by 9288

Abstract

Persistence is a phenomenon during which a small fraction of a total bacterial population survives treatment with high concentrations of antibiotics for an extended period of time. In conjunction with biofilms, antibiotic persisters represent a major cause of recalcitrant and recurring infections, resulting [...] Read more.

Persistence is a phenomenon during which a small fraction of a total bacterial population survives treatment with high concentrations of antibiotics for an extended period of time. In conjunction with biofilms, antibiotic persisters represent a major cause of recalcitrant and recurring infections, resulting in significant morbidity and mortality. In this review, we discuss the clinical significance of persister cells and the central role of bacterial metabolism in their formation, specifically with respect to carbon catabolite repression, sugar metabolism, and growth regulation. Additionally, we will examine persister formation as an evolutionary strategy used to tolerate extended periods of stress and discuss some of the response mechanisms implicated in their formation. To date, the vast majority of the mechanistic research examining persistence has been conducted in artificial in vitro environments that are unlikely to be representative of host conditions. Throughout this review, we contextualize the existing body of literature by discussing how in vivo conditions may create ecological niches that facilitate the development of persistence. Lastly, we identify how the development of next-generation sequencing and other “big data” tools may enable researchers to examine persistence mechanisms within the host to expand our understanding of their clinical importance. Full article

(This article belongs to the Special Issue Bacterial Drug Persisters: Basis, Regulatory Events, and Role in Pathogenesis)

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19 pages, 3562 KiB

Open AccessReview

A Systematic Review and Meta-Analysis of the In Vivo Haemodynamic Effects of Δ⁹-Tetrahydrocannabinol

by Salahaden R. Sultan, Sophie A. Millar, Saoirse E. O’Sullivan and Timothy J. England

Pharmaceuticals 2018, 11(1), 13; https://doi.org/10.3390/ph11010013 - 31 Jan 2018

Cited by 19 | Viewed by 6633

Abstract

∆⁹-Tetrahydrocannabinol (THC) has complex effects on the cardiovascular system. We aimed to systematically review studies of THC and haemodynamic alterations. PubMed, Medline, and EMBASE were searched for relevant studies. Changes in blood pressure (BP), heart rate (HR), and blood flow (BF) [...] Read more.

∆⁹-Tetrahydrocannabinol (THC) has complex effects on the cardiovascular system. We aimed to systematically review studies of THC and haemodynamic alterations. PubMed, Medline, and EMBASE were searched for relevant studies. Changes in blood pressure (BP), heart rate (HR), and blood flow (BF) were analysed using the Cochrane Review Manager Software. Thirty-one studies met the eligibility criteria. Fourteen publications assessed BP (number, n = 541), 22 HR (n = 567), and 3 BF (n = 45). Acute THC dosing reduced BP and HR in anaesthetised animals (BP, mean difference (MD) −19.7 mmHg, p < 0.00001; HR, MD −53.49 bpm, p < 0.00001), conscious animals (BP, MD −12.3 mmHg, p = 0.0007; HR, MD −30.05 bpm, p < 0.00001), and animal models of stress or hypertension (BP, MD −61.37 mmHg, p = 0.03) and increased cerebral BF in murine stroke models (MD 32.35%, p < 0.00001). Chronic dosing increased BF in large arteries in anaesthetised animals (MD 21.95 mL/min, p = 0.05) and reduced BP in models of stress or hypertension (MD −22.09 mmHg, p < 0.00001). In humans, acute administration increased HR (MD 8.16 bpm, p < 0.00001). THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased BF in animals; and causing increased HR in humans. Data is limited, and further studies assessing THC-induced haemodynamic changes in humans should be considered. Full article

(This article belongs to the Special Issue Cannabinoids as Medicines)

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19 pages, 973 KiB

Open AccessFeature PaperReview

Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer’s Disease Treatment

by Rafaela Peron, Izabela Pereira Vatanabe, Patricia Regina Manzine, Antoni Camins and Márcia Regina Cominetti

Pharmaceuticals 2018, 11(1), 12; https://doi.org/10.3390/ph11010012 - 29 Jan 2018

Cited by 70 | Viewed by 11315

Abstract

ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the [...] Read more.

ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer’s disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications)

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16 pages, 920 KiB

Open AccessReview

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

by Jaume Folch, Miren Ettcheto, Oriol Busquets, Elena Sánchez-López, Rubén D. Castro-Torres, Ester Verdaguer, Patricia R. Manzine, Saghar Rabiei Poor, María Luisa García, Jordi Olloquequi, Carlos Beas-Zarate, Carme Auladell and Antoni Camins

Pharmaceuticals 2018, 11(1), 11; https://doi.org/10.3390/ph11010011 - 29 Jan 2018

Cited by 42 | Viewed by 13942

Abstract

Alzheimer’s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) [...] Read more.

Alzheimer’s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors. Full article

(This article belongs to the Special Issue Epilepsy and Neurodegeneration: Current Therapeutic Implications)

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11 pages, 1417 KiB

Open AccessArticle

Self-Assembled Supramolecular Nanoparticles Improve the Cytotoxic Efficacy of CK2 Inhibitor THN7

by Abdelhamid Nacereddine, Andre Bollacke, Eszter Róka, Christelle Marminon, Zouhair Bouaziz, Ferenc Fenyvesi, Ildikó Katalin Bácskay, Joachim Jose, Florent Perret and Marc Le Borgne

Pharmaceuticals 2018, 11(1), 10; https://doi.org/10.3390/ph11010010 - 26 Jan 2018

Cited by 7 | Viewed by 4711

Abstract

Since the approval of imatinib in 2001, kinase inhibitors have revolutionized cancer therapies. Inside this family of phosphotransferases, casein kinase 2 (CK2) is of great interest and numerous scaffolds have been investigated to design CK2 inhibitors. Recently, functionalized indeno[1,2-b]indoles have been [...] Read more.

Since the approval of imatinib in 2001, kinase inhibitors have revolutionized cancer therapies. Inside this family of phosphotransferases, casein kinase 2 (CK2) is of great interest and numerous scaffolds have been investigated to design CK2 inhibitors. Recently, functionalized indeno[1,2-b]indoles have been revealed to have high potency against human cancer cell lines such as MCF-7 breast carcinoma and A-427 lung carcinoma. 4-Methoxy-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (THN7), identified as a potent inhibitor of CK2 (IC₅₀ = 71 nM), was selected for an encapsulation study in order to evaluate its antiproliferative activity as THN7-loaded cyclodextrin nanoparticles. Four α-cyclodextrins (α-CDs) were selected to encapsulate THN7 and all experiments indicated that the nanoencapsulation of this CK2 inhibitor in α-CDs was successful. No additional surface-active agent was used during the nanoformulation process. Nanoparticles formed between THN7 and α-C₆H₁₃ amphiphilic derivative gave the best results in terms of encapsulation rate (% of associated drug = 35%), with a stability constant (K₁₁) of 298 mol·L⁻¹ and a size of 132 nm. Hemolytic activity of the four α-CDs was determined before the in cellulo evaluation and the α-C₆H₁₃ derivative gave the lowest value of hemolytic potency (HC₅₀ = 1.93 mol·L⁻¹). Only the THN7-loaded cyclodextrin nanoparticles showing less toxicity on human erythrocytes (α-C₆H₁₃, α-C₈H₁₇ and α-C₄H₉) were tested against A-427 cells. All drug-loaded nanoparticles caused more cytotoxicity against A-427 cells than THN7 alone. Based on these results, the use of amphiphilic CD nanoparticles could be considered as a drug delivery system for indeno[1,2-b]indoles, allowing an optimized bioavailability and offering perspectives for the in vivo development of CK2 inhibitors. Full article

(This article belongs to the Special Issue Choices of the Journal)

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16 pages, 3304 KiB

Open AccessArticle

Improved Intranasal Retentivity and Transnasal Absorption Enhancement by PEGylated Poly-l-ornithine

by Yusuke Kamiya, Tsutomu Yamaki, Shigehiro Omori, Masaki Uchida, Kazuo Ohtake, Mitsutoshi Kimura, Hiroshi Yamazaki and Hideshi Natsume

Pharmaceuticals 2018, 11(1), 9; https://doi.org/10.3390/ph11010009 - 25 Jan 2018

Cited by 9 | Viewed by 4282

Abstract

We reported that the introduction of polyethylene glycol (PEG) to poly-l-ornithine (PLO), which is an homopolymeric basic amino acid having absorption-enhancement ability, prolonged retention time in an in vitro inclined plate test, probably due to an increase in viscosity caused by [...] Read more.

We reported that the introduction of polyethylene glycol (PEG) to poly-l-ornithine (PLO), which is an homopolymeric basic amino acid having absorption-enhancement ability, prolonged retention time in an in vitro inclined plate test, probably due to an increase in viscosity caused by PEGylation. The aim of the present study is to investigate whether the introduction of PEG chains to PLO improves intranasal retention and transnasal absorption in vivo. We performed intranasal administration experiments using PLO and PEG-PLO with a model drug, fluorescein isothiocyanate dextran (FD-4), in rats under closed and open systems. In the open system, transition of plasma FD-4 concentration after co-administration with unmodified PLO was low, and the area under the plasma concentration-time curve (AUC) decreased to about 60% of that in the closed system. In contrast, the AUC after co-administration with PEG-PLO in the open system was about 90% of that in the closed system, and the transition of plasma FD-4 concentration and FD-4 absorption profile were similar to those of the closed system. These findings indicate that introducing PEG chains to homopolymeric basic amino acids (HPBAAs) is a very useful method for developing a functional absorption enhancer that can exhibit an efficient in vivo absorption-enhancing effect. Full article

(This article belongs to the Special Issue Polyethylene Glycol (PEG) and PEGylation in Pharmacy)

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18 pages, 7327 KiB

Open AccessArticle

In Silico Study, Synthesis, and Cytotoxic Activities of Porphyrin Derivatives

by Fransiska Kurniawan, Youhei Miura, Rahmana Emran Kartasasmita, Naoki Yoshioka, Abdul Mutalib and Daryono Hadi Tjahjono

Pharmaceuticals 2018, 11(1), 8; https://doi.org/10.3390/ph11010008 - 20 Jan 2018

Cited by 16 | Viewed by 8663

Abstract

Five known porphyrins, 5,10,15,20-tetrakis(p-tolyl)porphyrin (TTP), 5,10,15,20-tetrakis(p-bromophenyl)porphyrin (TBrPP), 5,10,15,20-tetrakis(p-aminophenyl)porphyrin (TAPP), 5,10,15-tris(tolyl)-20-mono(p-nitrophenyl)porphyrin (TrTMNP), 5,10,15-tris(tolyl)-20-mono(p-aminophenyl)porphyrin (TrTMAP), and three novel porphyrin derivatives, 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di(p-tolyl)porphyrin [...] Read more.

Five known porphyrins, 5,10,15,20-tetrakis(p-tolyl)porphyrin (TTP), 5,10,15,20-tetrakis(p-bromophenyl)porphyrin (TBrPP), 5,10,15,20-tetrakis(p-aminophenyl)porphyrin (TAPP), 5,10,15-tris(tolyl)-20-mono(p-nitrophenyl)porphyrin (TrTMNP), 5,10,15-tris(tolyl)-20-mono(p-aminophenyl)porphyrin (TrTMAP), and three novel porphyrin derivatives, 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di(p-tolyl)porphyrin (DBECPDTP), 5,10-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-15,20-di-(methylpyrazole-4-yl)porphyrin (cDBECPDPzP), 5,15-di-[bis(3,4-ethylcarboxymethylenoxy)phenyl]-10,20-di-(methylpyrazole-4-yl)porphyrin (DBECPDPzP), were used to study their interaction with protein targets (in silico study), and were synthesized. Their cytotoxic activities against cancer cell lines were tested using 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromide (MTT) assay. The interaction of porphyrin derivatives with carbonic anhydrase IX (CAIX) and REV-ERBβ proteins were studied by molecular docking and molecular dynamic simulation. In silico study results reveal that DBECPDPzP and TrTMNP showed the highest binding interaction with REV- ERBβ and CAIX, respectively, and both complexes of DBECPDPzP-REV-ERBβ and TrTMNP-CAIX showed good and comparable stability during molecular dynamic simulation. The studied porphyrins have selective growth inhibition activities against tested cancer cells and are categorized as marginally active compounds based on their IC₅₀. Full article

(This article belongs to the Special Issue Chemoinformatics and Drug Design)

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11 pages, 2126 KiB

Open AccessArticle

Effects of Polymethoxyflavonoids on Bone Loss Induced by Estrogen Deficiency and by LPS-Dependent Inflammation in Mice

by Shigeru Matsumoto, Tsukasa Tominari, Chiho Matsumoto, Shosei Yoshinouchi, Ryota Ichimaru, Kenta Watanabe, Michiko Hirata, Florian M. W. Grundler, Chisato Miyaura and Masaki Inada

Pharmaceuticals 2018, 11(1), 7; https://doi.org/10.3390/ph11010007 - 20 Jan 2018

Cited by 18 | Viewed by 5710

Abstract

Polymethoxyflavonoids (PMFs) are a family of the natural compounds that mainly compise nobiletin, tangeretin, heptamethoxyflavone (HMF), and tetramethoxyflavone (TMF) in citrus fruits. PMFs have shown various biological functions, including anti-oxidative effects. We previously showed that nobiletin, tangeretin, and HMF all inhibited interleukin (IL)-1-mediated [...] Read more.

Polymethoxyflavonoids (PMFs) are a family of the natural compounds that mainly compise nobiletin, tangeretin, heptamethoxyflavone (HMF), and tetramethoxyflavone (TMF) in citrus fruits. PMFs have shown various biological functions, including anti-oxidative effects. We previously showed that nobiletin, tangeretin, and HMF all inhibited interleukin (IL)-1-mediated osteoclast differentiation via the inhibition of prostaglandin E2 synthesis. In this study, we created an original mixture of PMFs (nobiletin, tangeretin, HMF, and TMF) and examined whether or not PMFs exhibit co-operative inhibitory effects on osteoclastogenesis and bone resorption. In a coculture of bone marrow cells and osteoblasts, PMFs dose-dependently inhibited IL-1-induced osteoclast differentiation and bone resorption. The optimum concentration of PMFs was lower than that of nobiletin alone in the suppression of osteoclast differentiation, suggesting that the potency of PMFs was stronger than that of nobiletin in vitro. The oral administration of PMFs recovered the femoral bone loss induced by estrogen deficiency in ovariectomized mice. We further tested the effects of PMFs on lipopolysaccharide-induced bone resorption in mouse alveolar bone. In an ex vivo experimental model for periodontitis, PMFs significantly suppressed the bone-resorbing activity in organ cultures of mouse alveolar bone. These results indicate that a mixture of purified nobiletin, tangeretin, HMF, and TMF exhibits a co-operative inhibitory effect for the protection against bone loss in a mouse model of bone disease, suggesting that PMFs may be potential candidates for the prevention of bone resorption diseases, such as osteoporosis and periodontitis. Full article

(This article belongs to the Special Issue Tissue-Protective Agents: New Drugs and Technologies)

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9 pages, 1294 KiB

Open AccessArticle

Gastroprotective Effects of Sulphated Polysaccharides from the Alga Caulerpa mexicana Reducing Ethanol-Induced Gastric Damage

by José Gerardo Carneiro, Ticiana De Brito Lima Holanda, Ana Luíza Gomes Quinderé, Annyta Fernandes Frota, Vitória Virgínia Magalhães Soares, Rayane Siqueira de Sousa, Manuela Araújo Carneiro, Dainesy Santos Martins, Antoniella Souza Gomes Duarte and Norma Maria Barros Benevides

Pharmaceuticals 2018, 11(1), 6; https://doi.org/10.3390/ph11010006 - 20 Jan 2018

Cited by 22 | Viewed by 4474

Abstract

The development of the gastric lesion is complex and the result of the imbalance between aggressive and protective factors, involving the generation of free radicals and disturbance in nitric oxide (NO) production. Sulphated polysaccharides (SP), from marine algae, are widely used in biotechnological [...] Read more.

The development of the gastric lesion is complex and the result of the imbalance between aggressive and protective factors, involving the generation of free radicals and disturbance in nitric oxide (NO) production. Sulphated polysaccharides (SP), from marine algae, are widely used in biotechnological and pharmaceutical areas. In this study, we evaluated the effects of SP from the green marine alga Caulerpa mexicana (Cm-SP) in ethanol-induced gastric damage models in mice. Cm-SP (2, 20, or 200 mg/kg), administered p.o., significantly reduced gastric damage, and these effects were inhibited through pretreatment with indomethacin. Cm-SP (200 mg/kg) prevented the ethanol-induced decline in glutathione and restored its normal level. Moreover, it was able to normalize the elevated thiobarbituric acid reactive substance levels. However, Cm-SP did not show any significant effects on NO₂/NO₃ level, when compared to the ethanol group. The pretreatment with L- NAME induced gastric mucosal damage and did not inhibit the gastroprotective effect of Cm-SP (200 mg/kg). In conclusion, the gastroprotective effects of Cm-SP in mice involve prostaglandins and reduction in the oxidative stress and are independent of NO. Full article

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4 pages, 181 KiB

Open AccessEditorial

Acknowledgement to Reviewers of Pharmaceuticals in 2017

by Pharmaceuticals Editorial Office

Pharmaceuticals 2018, 11(1), 5; https://doi.org/10.3390/ph11010005 - 10 Jan 2018

Viewed by 2965

Abstract

Peer review is an essential part in the publication process, ensuring that Pharmaceuticals maintains high quality standards for its published papers[...] Full article

8 pages, 764 KiB

Open AccessFeature PaperReview

Endolysosomal Cation Channels and Cancer—A Link with Great Potential

by Christian Grimm, Karin Bartel, Angelika M. Vollmar and Martin Biel

Pharmaceuticals 2018, 11(1), 4; https://doi.org/10.3390/ph11010004 - 5 Jan 2018

Cited by 49 | Viewed by 7631

Abstract

The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell [...] Read more.

The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell death signaling, tumor growth, and cancer progression. In addition, it plays a critical role in autophagy, and the autophagy-lysosome pathway is intimately associated with the hallmarks of cancer, such as escaping cell death pathways, evading immune surveillance, and deregulating metabolism. The function of endolysosomes is critically dependent on both soluble and endolysosomal membrane proteins such as ion channels and transporters. Cation channels found in the ES include members of the TRP (transient receptor potential) channel superfamily, namely TRPML channels (mucolipins) as well as two-pore channels (TPCs). In recent studies, these channels have been found to play crucial roles in endolysosomal trafficking, lysosomal exocytosis, and autophagy. Mutation or loss of these channel proteins can impact multiple endolysosomal trafficking pathways. A role for TPCs in cancer cell migration and metastasis, linked to distinct defects in endolysosomal trafficking such as integrin trafficking, has been recently established. In this review, we give an overview on the function of lysosomes in cancer with a particular focus on the roles which TPCs and TRPML channels play in the ES and how this can affect cancer cells. Full article

(This article belongs to the Special Issue Transient Receptor Potential Ion Channels as Targets in Anti-Cancer Therapies)

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18 pages, 823 KiB

Open AccessArticle

Antimicrobial and Antibiofilm Activity of UP-5, an Ultrashort Antimicrobial Peptide Designed Using Only Arginine and Biphenylalanine

by Ammar Almaaytah, Mohammed T. Qaoud, Gubran Khalil Mohammed, Ahmad Abualhaijaa, Daniel Knappe, Ralf Hoffmann and Qosay Al-Balas

Pharmaceuticals 2018, 11(1), 3; https://doi.org/10.3390/ph11010003 - 2 Jan 2018

Cited by 42 | Viewed by 6561

Abstract

The recent upsurge of multidrug resistant bacteria (MDRB) among global communities has become one of the most serious challenges facing health professionals and the human population worldwide. Cationic ultrashort antimicrobial peptides (USAMPs) are a promising group of molecules that meet the required criteria [...] Read more.

The recent upsurge of multidrug resistant bacteria (MDRB) among global communities has become one of the most serious challenges facing health professionals and the human population worldwide. Cationic ultrashort antimicrobial peptides (USAMPs) are a promising group of molecules that meet the required criteria of novel antimicrobial drug development. UP-5, a novel penta-peptide, displayed significant antimicrobial activities against various standard and clinical isolates of MDRB. UP-5 displayed MICs values within the range of (10–15 μM) and (55–65 μM) against Gram-positive and Gram-negative bacteria, respectively. Furthermore, UP-5 displayed antibiofilm activity with minimum biofilm eradication concentration (MBEC) value as equal to twofold higher than MIC value. At the same inhibitory concentrations, UP-5 exhibited very low or negligible toxicity toward human erythrocytes and mammalian cells. Combining UP-5 with conventional antibiotics led to a synergistic or additive mode of action that resulted in the reduction of the MIC values for some of the antibiotics by 99.7% along a significant drop in MIC values of the peptide. The stability profile of UP-5 was evaluated in full mouse plasma and serum with results indicating a more stable pattern in plasma. The present study indicates that USAMPs are promising antimicrobial agents that can avoid the negative characteristics of conventional antimicrobial peptides. Additionally, USAMPs exhibit good to moderate activity against MDRB, negligible toxicity, and synergistic outcomes in combination with conventional antimicrobial agents. Full article

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Open AccessReview

Roles of Heat Shock Proteins in Apoptosis, Oxidative Stress, Human Inflammatory Diseases, and Cancer

by Paul Chukwudi Ikwegbue, Priscilla Masamba, Babatunji Emmanuel Oyinloye and Abidemi Paul Kappo

Pharmaceuticals 2018, 11(1), 2; https://doi.org/10.3390/ph11010002 - 23 Dec 2017

Cited by 211 | Viewed by 16076

Abstract

Heat shock proteins (HSPs) play cytoprotective activities under pathological conditions through the initiation of protein folding, repair, refolding of misfolded peptides, and possible degradation of irreparable proteins. Excessive apoptosis, resulting from increased reactive oxygen species (ROS) cellular levels and subsequent amplified inflammatory reactions, [...] Read more.

Heat shock proteins (HSPs) play cytoprotective activities under pathological conditions through the initiation of protein folding, repair, refolding of misfolded peptides, and possible degradation of irreparable proteins. Excessive apoptosis, resulting from increased reactive oxygen species (ROS) cellular levels and subsequent amplified inflammatory reactions, is well known in the pathogenesis and progression of several human inflammatory diseases (HIDs) and cancer. Under normal physiological conditions, ROS levels and inflammatory reactions are kept in check for the cellular benefits of fighting off infectious agents through antioxidant mechanisms; however, this balance can be disrupted under pathological conditions, thus leading to oxidative stress and massive cellular destruction. Therefore, it becomes apparent that the interplay between oxidant-apoptosis-inflammation is critical in the dysfunction of the antioxidant system and, most importantly, in the progression of HIDs. Hence, there is a need to maintain careful balance between the oxidant-antioxidant inflammatory status in the human body. HSPs are known to modulate the effects of inflammation cascades leading to the endogenous generation of ROS and intrinsic apoptosis through inhibition of pro-inflammatory factors, thereby playing crucial roles in the pathogenesis of HIDs and cancer. We propose that careful induction of HSPs in HIDs and cancer, especially prior to inflammation, will provide good therapeutics in the management and treatment of HIDs and cancer. Full article

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