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Pharmaceuticals, Volume 15, Issue 9 (September 2022) – 128 articles

Cover Story (view full-size image): Retinoblastoma is a rare, sometimes hereditary, pediatric cancer. Depending on the stage of the disease, different therapeutic protocols are applied. In more advanced forms, surgical removal of the entire globe and its intraocular contents (enucleation) is necessary. In other cases, local treatments (laser, photocoagulation, cryotherapy, etc.) and conventional chemotherapy are used. To overcome the side-effects and reduced efficacy of chemotherapeutic drugs, nanodelivery systems have been developed. They allow for a sustained drug release and manage to reach the target site. This review regards the current use and advances of nanomedicine in the treatment of retinoblastoma, and it investigates nanoparticles containing conventional drugs and natural products. In addition, future developments in retinoblastoma treatment are discussed. View this paper
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14 pages, 1733 KiB  
Article
Sustainable Extraction, Chemical Profile, Cytotoxic and Antileishmanial Activities In-Vitro of Some Citrus Species Leaves Essential Oils
by Salwa Bouabdallah, Kevin Cianfaglione, Myriam Azzouz, Gaber El-Saber Batiha, Afrah Fahad Alkhuriji, Wafa Abdullah I. Al-Megrin, Mossadok Ben-Attia and Omayma A. Eldahshan
Pharmaceuticals 2022, 15(9), 1163; https://doi.org/10.3390/ph15091163 - 19 Sep 2022
Cited by 3 | Viewed by 2244
Abstract
Anti-leishmanial drugs extracted from natural sources have not been sufficiently explored in the literature. Until now, leishmaniasis treatments have been limited to synthetic and expensive drugs. This study investigated, for the first time, the anti-leishmanial efficacy of essential oils (EOs) from the leaves [...] Read more.
Anti-leishmanial drugs extracted from natural sources have not been sufficiently explored in the literature. Until now, leishmaniasis treatments have been limited to synthetic and expensive drugs. This study investigated, for the first time, the anti-leishmanial efficacy of essential oils (EOs) from the leaves of Citrus species (C. sinensis, C. limon, and C. clementina). Essential oils were extracted from three species by solvent free microwave extraction (SFME); in addition, lemon oil was also isolated by hydro-distillation (HD). These were investigated using gas chromatography coupled with mass spectrometry (GC–MS) and evaluated against Leishmania species, namely Leishmania major and Leishmania infantum, using a mitochondrial tetrazolium test (MTT) assay. The chemical compositions of Citrus limon EOs obtained by HD and SFME showed some differences. The identified peaks of C. limon (SFME) represented 93.96%, where linalool was the major peak (44.21%), followed by sabinene (14.22%) and ocimene (6.09%). While the hydro-distilled oil of C. limon contained geranial (30.08%), limonene (27.09%), and neral (22.87%) in the identified peaks (96.67%). The identified components of C. clementina leaves oil (68.54%) showed twenty-six compounds, where the predominant compound was geranial (42.40%), followed by neral (26.79%) and limonene (14.48%). However, 89.82% C. sinensis oil was identified, where the major peaks were for neral (27.52%), linalool (25.83%), and geranial (23.44%). HD oil of lemon showed the highest activity against L. major, with moderate toxicity on murine macrophage (RAW 264.7) cells, and possessed the best selectivity index on both Leishmanial species (SI: 3.68; 6.38), followed by C. clementina oil and C. limon using SFME (0.9 ± 0.29, 1.03 ± 0.27, and 1.13 ± 0.3), respectively. C. clementina oil induced the greatest activity on Leishmania infantum, followed by HD lemon and SFME lemon oils (0.32 ± 0.18, 0.52 ± 0.15, and 0.57 ± 0.09, respectively) when compared to Amphotericin B (0.80 ± 0.18 and 0.23 ± 0.13) as a positive control, on both species, respectively. Our study suggests a potent anti-leishmanial activity of lemon oil (HD) on L. major, followed by C. clementina. With the same potency on L. infantum shown by C. clementina oil, followed by HD lemon oil. This effect could be attributed to the major compounds of limonene, citral, and neral, as well as the synergistic effect of other different compounds. These observations could be a starting point for the building of new anti-leishmanial drugs from natural origins, and which combine different EOs containing Citrus cultivars. Full article
(This article belongs to the Section Natural Products)
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13 pages, 337 KiB  
Article
Evaluation of the Polyphenolic Composition and Bioactivities of Three Native Cabo Verde Medicinal Plants
by Anyse P. Essoh, Ângela Liberal, Ângela Fernandes, Maria Inês Dias, Carla Pereira, Filipa Mandim, Margarida Moldão-Martins, Pedro Cravo, Maria Paula Duarte, Mónica Moura, Maria M. Romeiras and Lillian Barros
Pharmaceuticals 2022, 15(9), 1162; https://doi.org/10.3390/ph15091162 - 19 Sep 2022
Cited by 6 | Viewed by 2498
Abstract
The use of medicinal plants in a variety of health conditions remains essential for the discovery of new treatments. The present study aimed to investigate the bioactive properties of three native plants from Cabo Verde Islands, namely Artemisia gorgonum Webb, Sideroxylon marginatum (Decne. [...] Read more.
The use of medicinal plants in a variety of health conditions remains essential for the discovery of new treatments. The present study aimed to investigate the bioactive properties of three native plants from Cabo Verde Islands, namely Artemisia gorgonum Webb, Sideroxylon marginatum (Decne. ex Webb) Cout., and Tamarix senegalensis DC., contributing to the characterization of less-known medicinal plants and their potential benefits for human health. Known compounds, such as kaempferol, quercetin, caffeyolquinic, and apigenin derivatives, among others, were detected in the plant species under study. Overall, all species demonstrated good antioxidant capacity, especially the ethanolic extracts of A. gorgonum (EC50 = 0.149 mg/mL) in TBARS assay. Moreover, the ethanolic extracts of the studied plants showed cytotoxic properties against tumor cells, and again the A. gorgonum extract proved to be the most effective in inhibiting tumor growth, mainly in the CaCO2 (GI50 = 17.3 μg/mL) and AGS (GI50 = 18.2 μg/mL) cell lines. Only the ethanolic extracts of T. senegalensis and S. marginatum demonstrated anti-inflammatory activity, albeit weak (EC50 = 35 and 43 μg/mL, respectively). The present study contributed to increased knowledge about the bioactive properties of these plants commonly used in traditional medicine, some of which was discussed for the first time, opening new perspectives for their use in a wider range of health conditions, especially in African countries, where access to modern health care is more limited. Full article
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22 pages, 2273 KiB  
Article
Albumin-Mediated Size Exclusion Chromatography: The Apparent Molecular Weight of PSMA Radioligands as Novel Parameter to Estimate Their Blood Clearance Kinetics
by Jan-Philip Kunert, Sebastian Fischer, Alexander Wurzer and Hans-Jürgen Wester
Pharmaceuticals 2022, 15(9), 1161; https://doi.org/10.3390/ph15091161 - 19 Sep 2022
Cited by 4 | Viewed by 2219
Abstract
A meticulously adjusted pharmacokinetic profile and especially fine-tuned blood clearance kinetics are key characteristics of therapeutic radiopharmaceuticals. We, therefore, aimed to develop a method that allowed the estimation of blood clearance kinetics in vitro. For this purpose, 177Lu-labeled PSMA radioligands were subjected [...] Read more.
A meticulously adjusted pharmacokinetic profile and especially fine-tuned blood clearance kinetics are key characteristics of therapeutic radiopharmaceuticals. We, therefore, aimed to develop a method that allowed the estimation of blood clearance kinetics in vitro. For this purpose, 177Lu-labeled PSMA radioligands were subjected to a SEC column with human serum albumin (HSA) dissolved in a mobile phase. The HSA-mediated retention time of each PSMA ligand generated by this novel ‘albumin-mediated size exclusion chromatography’ (AMSEC) was converted to a ligand-specific apparent molecular weight (MWapp), and a normalization accounting for unspecific interactions between individual radioligands and the SEC column matrix was applied. The resulting normalized MWapp,norm. could serve to estimate the blood clearance of renally excreted radioligands by means of their influence on the highly size-selective process of glomerular filtration (GF). Based on the correlation between MW and the glomerular sieving coefficients (GSCs) of a set of plasma proteins, GSCcalc values were calculated to assess the relative differences in the expected GF/blood clearance kinetics in vivo and to select lead candidates among the evaluated radioligands. Significant differences in the MWapp,norm. and GSCcalc values, even for stereoisomers, were found, indicating that AMSEC might be a valuable and high-resolution tool for the preclinical selection of therapeutic lead compounds for clinical translation. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy (TRNT) in Modern Cancer Management)
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14 pages, 2686 KiB  
Article
Polyhydric Stigmastane-Type Steroids Derivative from Vernonia amygdalina and Their Anti-Neuroinflammatory Activity
by Xiangzhong Liu, Mi Zhou, Shoulun He, Qiannan Xu, Chunchun Du, Honghong Zhu, Ting Lin, Guanghui Wang, Wenjing Tian and Haifeng Chen
Pharmaceuticals 2022, 15(9), 1160; https://doi.org/10.3390/ph15091160 - 19 Sep 2022
Cited by 4 | Viewed by 1757
Abstract
Vernonia amygdalina Del. is a traditional medicinal plant and vegetable originating from tropical Africa. The phytochemical investigation of V. amygdalina led to eight undescribed polyhydric stigmastane-type steroids, vernonin M–T (18). Their gross structures and stereochemistry were elucidated by HR-ESI-MS, [...] Read more.
Vernonia amygdalina Del. is a traditional medicinal plant and vegetable originating from tropical Africa. The phytochemical investigation of V. amygdalina led to eight undescribed polyhydric stigmastane-type steroids, vernonin M–T (18). Their gross structures and stereochemistry were elucidated by HR-ESI-MS, 1D and 2D NMR spectra, X-ray diffraction, quantum chemical computation of the ECD spectrum, and the in situ dimolybdenum CD method. The anti-neuroinflammatory activity of the isolated compounds was performed in BV-2 microglia cells. As a result, compound 1 displayed a notable anti-neuroinflammatory effect via suppressing the LPS-induced IκB degradation and restricting the activation of the PI3K/AKT and p38 MAPK pathways. Full article
(This article belongs to the Section Natural Products)
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14 pages, 2462 KiB  
Article
Deconstructing Markush: Improving the R&D Efficiency Using Library Selection in Early Drug Discovery
by Leticia Manen-Freixa, José I. Borrell, Jordi Teixidó and Roger Estrada-Tejedor
Pharmaceuticals 2022, 15(9), 1159; https://doi.org/10.3390/ph15091159 - 18 Sep 2022
Cited by 1 | Viewed by 1814
Abstract
Most of the product patents claim a large number of compounds based on a Markush structure. However, the identification and optimization of new principal active ingredients is frequently driven by a simple Free Wilson approach, leading to a highly focused study only involving [...] Read more.
Most of the product patents claim a large number of compounds based on a Markush structure. However, the identification and optimization of new principal active ingredients is frequently driven by a simple Free Wilson approach, leading to a highly focused study only involving the chemical space nearby a hit compound. This fact raises the question: do the tested compounds described in patents really reflect the full molecular diversity described in the Markush structure? In this study, we contrast the performance of rational selection to conventional approaches in seven real-case patents, assessing their ability to describe the patent’s chemical space. Results demonstrate that the integration of computer-aided library selection methods in the early stages of the drug discovery process would boost the identification of new potential hits across the chemical space. Full article
(This article belongs to the Special Issue Structure and Ligand Based Drug Design)
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11 pages, 1905 KiB  
Article
Stability Study, Quantification Method and Pharmacokinetics Investigation of a Coumarin–Monoterpene Conjugate Possessing Antiviral Properties against Respiratory Syncytial Virus
by Arina G. Nemolochnova, Artem D. Rogachev, Olga P. Salnikova, Tatyana M. Khomenko, Konstantin P. Volcho, Olga I. Yarovaya, Alina V. Fatianova, Andrey G. Pokrovsky and Nariman F. Salakhutdinov
Pharmaceuticals 2022, 15(9), 1158; https://doi.org/10.3390/ph15091158 - 18 Sep 2022
Cited by 3 | Viewed by 1641
Abstract
The stability of a new coumarin derivative, agent K-142, bearing α-pinene residue and possessing antiviral activity against respiratory syncytial virus (RSV) was studied in whole mice blood in vitro, and a method for its quantification in this matrix was developed and validated. The [...] Read more.
The stability of a new coumarin derivative, agent K-142, bearing α-pinene residue and possessing antiviral activity against respiratory syncytial virus (RSV) was studied in whole mice blood in vitro, and a method for its quantification in this matrix was developed and validated. The sample preparation method was precipitation of whole blood with a mixture of 0.2 M ZnSO4 with MeOH (2:8 v/v) containing 2-adamantylamine hydrochloride as an internal standard (IS). Analysis was carried out by HPLC-MS/MS using reversed phase chromatography and a triple quadrupole mass spectrometer 6500 QTRAP (SCIEX) in multiple reaction monitoring (MRM) mode. The transitions 351.2 → 217.1 Da and 152.2 → 93.1/107.2 Da were monitored for K-142 and the IS, respectively. The method was validated in terms of selectivity, calibration curve, LLOQ, accuracy and precision, stability, recovery and carry over. The developed method was used for a pharmacokinetics study of the compound after its oral administration to mice at a dose of 20 mg/kg. Full article
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16 pages, 2770 KiB  
Article
Anti-Inflammatory Effects of Ang-(1-7) Bone-Targeting Conjugate in an Adjuvant-Induced Arthritis Rat Model
by Sana Khajeh pour, Arina Ranjit, Emma L. Summerill and Ali Aghazadeh-Habashi
Pharmaceuticals 2022, 15(9), 1157; https://doi.org/10.3390/ph15091157 - 17 Sep 2022
Cited by 3 | Viewed by 1578
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory condition of synovial joints that causes disability and systemic complications. Ang-(1-7), one of the main peptides in the renin-angiotensin (Ang) system (RAS), imposes its protective effects through Mas receptor (MasR) signaling. It has a short half-life, [...] Read more.
Rheumatoid arthritis (RA) is a chronic inflammatory condition of synovial joints that causes disability and systemic complications. Ang-(1-7), one of the main peptides in the renin-angiotensin (Ang) system (RAS), imposes its protective effects through Mas receptor (MasR) signaling. It has a short half-life, limiting its feasibility as a therapeutic agent. In this study, we evaluated the anti-inflammatory effects of Ang-(1-7)’s novel and stable conjugate (Ang. Conj.) by utilizing its affinity for bone through bisphosphonate (BP) moiety in an adjuvant-induced arthritis (AIA) rat model. The rats received subcutaneous injections of vehicle, plain Ang-(1-7), or an equivalent dose of Ang. Conj. The rats’ body weights, paws, and joints’ diameters were measured thrice weekly. After 14 days, the rats were euthanized, and the blood and tissue samples were harvested for further analysis of nitric oxide (NO) and RAS components’ gene and protein expression. The administration of Ang. Conj. reduced body weight loss, joint edema, and serum NO. Moreover, the Ang. Conj. treatment significantly reduced the classical arm components at peptide, enzyme, and receptor levels while augmenting them for the protective arm. The results of this study introduce a novel class of bone-targeting natural peptides for RA caused by an inflammation-induced imbalance in the activated RAS. Our results indicate that extending the half-life of Ang-(1-7) augments the RAS protective arm and exerts enhanced therapeutic effects in the AIA model in rats. Full article
(This article belongs to the Special Issue New Applications and Developments in Synthetic Peptide Chemistry)
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25 pages, 2202 KiB  
Article
LC–MS/MS Phytochemical Profiling, Antioxidant Activity, and Cytotoxicity of the Ethanolic Extract of Atriplex halimus L. against Breast Cancer Cell Lines: Computational Studies and Experimental Validation
by Amine Elbouzidi, Hayat Ouassou, Marouane Aherkou, Loubna Kharchoufa, Nada Meskali, Abdellah Baraich, Hamza Mechchate, Mohamed Bouhrim, Abderrazak Idir, Christophe Hano, Hassan Zrouri and Mohamed Addi
Pharmaceuticals 2022, 15(9), 1156; https://doi.org/10.3390/ph15091156 - 16 Sep 2022
Cited by 23 | Viewed by 3700
Abstract
Atriplex halimus L., also known as Mediterranean saltbush, and locally as “Lgtef”, an halophytic shrub, is used extensively to treat a wide variety of ailments in Morocco. The present study was undertaken to determine the antioxidant activity and cytotoxicity of the ethanolic extract [...] Read more.
Atriplex halimus L., also known as Mediterranean saltbush, and locally as “Lgtef”, an halophytic shrub, is used extensively to treat a wide variety of ailments in Morocco. The present study was undertaken to determine the antioxidant activity and cytotoxicity of the ethanolic extract of A. halimus leaves (AHEE). We first determined the phytochemical composition of AHEE using a liquid chromatography (LC)–tandem mass spectrometry (MS/MS) technique. The antioxidant activity was evaluated using different methods including DPPH scavenging capacity, β-carotene bleaching assay, ABTS scavenging, iron chelation, and the total antioxidant capacity assays. Cytotoxicity was investigated against human cancer breast cells lines MCF-7 and MDA-MB-231. The results showed that the components of the extract are composed of phenolic acids and flavonoids. The DPPH test showed strong scavenging capacity for the leaf extract (IC50 of 0.36 ± 0.05 mg/mL) in comparison to ascorbic acid (IC50 of 0.19 ± 0.02 mg/mL). The β-carotene test determined an IC50 of 2.91 ± 0.14 mg/mL. The IC50 values of ABTS, iron chelation, and TAC tests were 44.10 ± 2.92 TE µmol/mL, 27.40 ± 1.46 mg/mL, and 124 ± 1.27 µg AAE/mg, respectively. In vitro, the AHE extract showed significant inhibitory activity in all tested tumor cell lines, and the inhibition activity was found in a dose-dependent manner. Furthermore, computational techniques such as molecular docking and ADMET analysis were used in this work. Moreover, the physicochemical parameters related to the compounds’ pharmacokinetic indicators were evaluated, including absorption, distribution, metabolism, excretion, and toxicity prediction (Pro-Tox II). Full article
(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)
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15 pages, 1675 KiB  
Article
Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors
by Sofia Koustoulidou, Maryana Handula, Corrina de Ridder, Debra Stuurman, Savanne Beekman, Marion de Jong, Julie Nonnekens and Yann Seimbille
Pharmaceuticals 2022, 15(9), 1155; https://doi.org/10.3390/ph15091155 - 16 Sep 2022
Cited by 4 | Viewed by 2403
Abstract
Somatostatin receptor subtype 2 (SSTR2) has become an essential target for radionuclide therapy of neuroendocrine tumors (NETs). JR11 was introduced as a promising antagonist peptide to target SSTR2. However, due to its rapid blood clearance, a better pharmacokinetic profile is necessary for more [...] Read more.
Somatostatin receptor subtype 2 (SSTR2) has become an essential target for radionuclide therapy of neuroendocrine tumors (NETs). JR11 was introduced as a promising antagonist peptide to target SSTR2. However, due to its rapid blood clearance, a better pharmacokinetic profile is necessary for more effective treatment. Therefore, two JR11 analogs (8a and 8b), each carrying an albumin binding domain, were designed to prolong the blood residence time of JR11. Both compounds were labeled with lutetium-177 and evaluated via in vitro assays, followed by in vivo SPECT/CT imaging and ex vivo biodistribution studies. [177Lu]Lu-8a and [177Lu]Lu-8b were obtained with high radiochemical purity (>97%) and demonstrated excellent stability in PBS and mouse serum (>95%). [177Lu]Lu-8a showed better affinity towards human albumin compared to [177Lu]Lu-8b. Further, 8a and 8b exhibited binding affinities 30- and 48-fold lower, respectively, than that of the parent peptide JR11, along with high cell uptake and low internalization rate. SPECT/CT imaging verified high tumor accumulation for [177Lu]Lu-8a and [177Lu]Lu-JR11 at 4, 24, 48, and 72 h post-injection, but no tumor uptake was observed for [177Lu]Lu-8b. Ex vivo biodistribution studies revealed high and increasing tumor uptake for [177Lu]Lu-8a. However, its extended blood circulation led to an unfavorable biodistribution profile for radionuclide therapy. Full article
(This article belongs to the Special Issue Tumor-Targeting Radioligands for Molecular Imaging and Therapy)
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10 pages, 695 KiB  
Article
Response to Anti-PD1/L1 Antibodies in Advanced Urothelial Cancer in the ‘Real-Life’ Setting
by Moran Gadot, Ido Arad, Eshetu G. Atenafu, Meital Levartovsky, Orith Portnoy, Tima Davidson, Rachel Schor-Bardach, Raanan Berger and Raya Leibowitz
Pharmaceuticals 2022, 15(9), 1154; https://doi.org/10.3390/ph15091154 - 16 Sep 2022
Viewed by 1423
Abstract
Immune checkpoint inhibitors (ICIs) are now the standard of care for metastatic urothelial carcinoma (mUC) patients. Our aim was to describe the activity of ICIs in mUC and find the clinical parameters associated with response. This is a retrospective, single-center chart review of [...] Read more.
Immune checkpoint inhibitors (ICIs) are now the standard of care for metastatic urothelial carcinoma (mUC) patients. Our aim was to describe the activity of ICIs in mUC and find the clinical parameters associated with response. This is a retrospective, single-center chart review of mUC patients receiving ICIs. The overall survival (OS) was plotted using the Kaplan–Meier method and was compared using a log-rank test. Associations between the variables and responses were analyzed by univariate and multivariable analyses, using either logistic regression or a Chi-square/Fisher’s exact test. Ninety-four patients received ICIs, 85% of which were in the second line or beyond; the median age was 71.8 years, and 82% were men. Six (6.4%), 11 (11.7%), 7 (7.4%) and 70 (74.5%) patients achieved a complete response (CR), partial response (PR), mixed response/stable disease (M/SD) or progressive disease (PD), respectively. The median overall survival was 3.2 months for the entire cohort and was significantly different according to the response pattern—not reached, 32.3, 6.4 and 2.0 months for CR, PR, M/SD and PD, respectively. The response was not significantly associated with the line of treatment. ‘Site of metastasis’ was associated with the response, and the absolute neutrophil count was borderline associated with the response. In summary, we found a substantial variance in the potential benefit from ICIs in mUC, emphasizing the need for predictive biomarkers and frequent monitoring of mUC patients receiving ICIs. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitor in Cancer Therapy: Recent Advances)
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10 pages, 1088 KiB  
Review
From Snake Venoms to Therapeutics: A Focus on Natriuretic Peptides
by Wei Fong Ang, Cho Yeow Koh and R. Manjunatha Kini
Pharmaceuticals 2022, 15(9), 1153; https://doi.org/10.3390/ph15091153 - 16 Sep 2022
Cited by 4 | Viewed by 1896
Abstract
Snake venom is a cocktail of multifunctional biomolecules that has evolved with the purpose of capturing prey and for defense. These biomolecules are classified into different classes based on their functions. They include three-finger toxins, natriuretic peptides, phospholipases and metalloproteinases. The focus for [...] Read more.
Snake venom is a cocktail of multifunctional biomolecules that has evolved with the purpose of capturing prey and for defense. These biomolecules are classified into different classes based on their functions. They include three-finger toxins, natriuretic peptides, phospholipases and metalloproteinases. The focus for this review is on the natriuretic peptide (NP), which is an active component that can be isolated from the venoms of vipers and mambas. In these venoms, NPs contribute to the lowering of blood pressure, causing a rapid loss of consciousness in the prey such that its mobility is reduced, paralyzing the prey, and often death follows. Over the past 30 years since the discovery of the first NP in the venom of the green mamba, venom NPs have shown potential in the development of drug therapy for heart failure. Venom NPs have long half-lives, different pharmacological profiles, and may also possess different functions in comparison to the mammalian NPs. Understanding their mechanisms of action provides the strategies needed to develop new NPs for treatment of heart failure. This review summarizes the venom NPs that have been identified over the years and how they can be useful in drug development. Full article
(This article belongs to the Special Issue Drug Candidates from Venoms)
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12 pages, 2914 KiB  
Article
Development of Halogenated-Chalcones Bearing with Dimethoxy Phenyl Head as Monoamine Oxidase-B Inhibitors
by Nisha Abdul Rehuman, Jong Min Oh, Mohamed A. Abdelgawad, Eman A. M. Beshr, Mohammed A. S. Abourehab, Nicola Gambacorta, Orazio Nicolotti, Rakesh Kumar Jat, Hoon Kim and Bijo Mathew
Pharmaceuticals 2022, 15(9), 1152; https://doi.org/10.3390/ph15091152 - 16 Sep 2022
Cited by 11 | Viewed by 1681
Abstract
Two series of dimethoxy-halogenated chalcones (DM1DM20) were synthesized and tested for their ability to inhibit monoamine oxidase (MAOs). Compound DM2 exhibited the most significant inhibition against MAO-B with an IC50 value of 0.067 µM, followed by compound DM18 [...] Read more.
Two series of dimethoxy-halogenated chalcones (DM1DM20) were synthesized and tested for their ability to inhibit monoamine oxidase (MAOs). Compound DM2 exhibited the most significant inhibition against MAO-B with an IC50 value of 0.067 µM, followed by compound DM18 (IC50 = 0.118 µM), with selectivity index (SI) values of 93.88 and >338.98, respectively. However, none of the substances successfully inhibited MAO-A. The MAO-B inhibitors DM2 and DM18 were competitive and reversible, with Ki values of 0.032 ± 0.004 and 0.045 ± 0.001 µM, respectively. DM2 was non-toxic below 100 µg/mL in the cytotoxic test using the Vero epithelial cell line by the MTT method. According to molecular docking studies, DM2 and DM18 formed very similar conformations within the MAO-B binding pocket, with the ortho-chlorine and ortho-fluorine aromatic rings sandwiched between F168 and Y326. These conformations were predicted to show better interactions with the targeted MAO-B than MAO-A. In particular, the induced-fit docking of the dimethoxy phenyl ring of DM2 facing the hydrophobic pocket made up of FAD, Y398, and Y435 had an impact on F168 in the docking pocket. Taken together, DM2 and DM18 may be suitable candidates for treating neurodegenerative conditions such as Parkinson’s disease. Full article
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17 pages, 2032 KiB  
Review
Xylan Prebiotics and the Gut Microbiome Promote Health and Wellbeing: Potential Novel Roles for Pentosan Polysulfate
by Margaret M. Smith and James Melrose
Pharmaceuticals 2022, 15(9), 1151; https://doi.org/10.3390/ph15091151 - 16 Sep 2022
Cited by 2 | Viewed by 2985
Abstract
This narrative review highlights the complexities of the gut microbiome and health-promoting properties of prebiotic xylans metabolized by the gut microbiome. In animal husbandry, prebiotic xylans aid in the maintenance of a healthy gut microbiome. This prevents the colonization of the gut by [...] Read more.
This narrative review highlights the complexities of the gut microbiome and health-promoting properties of prebiotic xylans metabolized by the gut microbiome. In animal husbandry, prebiotic xylans aid in the maintenance of a healthy gut microbiome. This prevents the colonization of the gut by pathogenic organisms obviating the need for dietary antibiotic supplementation, a practice which has been used to maintain animal productivity but which has led to the emergence of antibiotic resistant bacteria that are passed up the food chain to humans. Seaweed xylan-based animal foodstuffs have been developed to eliminate ruminant green-house gas emissions by gut methanogens in ruminant animals, contributing to atmospheric pollution. Biotransformation of pentosan polysulfate by the gut microbiome converts this semi-synthetic sulfated disease-modifying anti-osteoarthritic heparinoid drug to a prebiotic metabolite that promotes gut health, further extending the therapeutic profile and utility of this therapeutic molecule. Xylans are prominent dietary cereal components of the human diet which travel through the gastrointestinal tract as non-digested dietary fibre since the human genome does not contain xylanolytic enzymes. The gut microbiota however digest xylans as a food source. Xylo-oligosaccharides generated in this digestive process have prebiotic health-promoting properties. Engineered commensal probiotic bacteria also have been developed which have been engineered to produce growth factors and other bioactive factors. A xylan protein induction system controls the secretion of these compounds by the commensal bacteria which can promote gut health or, if these prebiotic compounds are transported by the vagal nervous system, may also regulate the health of linked organ systems via the gut–brain, gut–lung and gut–stomach axes. Dietary xylans are thus emerging therapeutic compounds warranting further study in novel disease prevention protocols. Full article
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13 pages, 18443 KiB  
Article
Binding-Induced Diversity of a Human Telomeric G-Quadruplex Stability Phase Space
by Domen Oblak, San Hadži, Črtomir Podlipnik and Jurij Lah
Pharmaceuticals 2022, 15(9), 1150; https://doi.org/10.3390/ph15091150 - 15 Sep 2022
Cited by 1 | Viewed by 1391
Abstract
The structural polymorphism of G-quadruplex nucleic acids is an important factor in their recognition by proteins and small-molecule ligands. However, it is not clear why the binding of several ligands alters G-quadruplex topology. We addressed this question by following the (un)folding and binding [...] Read more.
The structural polymorphism of G-quadruplex nucleic acids is an important factor in their recognition by proteins and small-molecule ligands. However, it is not clear why the binding of several ligands alters G-quadruplex topology. We addressed this question by following the (un)folding and binding of the human telomeric fragment 5′-(GGGTTA)3GGGT-3′ (22GT) by calorimetry (DSC, ITC) and spectroscopy (CD). A thermodynamic analysis of the obtained data led to a detailed description of the topological phase space of stability (phase diagram) of 22GT and shows how it changes in the presence of a specific bisquinolinium ligand (360A). Various 1:1 and 2:1 ligand–quadruplex complexes were observed. With increasing temperature, the 1:1 complexes transformed into 2:1 complexes, which is attributed to the preferential binding of the ligand to the folding intermediates. Overall, the dissection of the thermodynamic parameters in combination with molecular modelling clarified the driving forces of the topological quadruplex transformations in a wide range of ligand concentrations and temperatures. Full article
(This article belongs to the Special Issue Nucleic Acids in Medicinal Chemistry)
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19 pages, 1461 KiB  
Review
Pharmacological Potential of Flavonoids against Neurotropic Viruses
by Juliana Helena Castro e Silva, Jéssica Teles Souza, Clarissa Schitine, Aníbal de Freitas Santos Júnior, Eduardo Muniz Santana Bastos and Silvia Lima Costa
Pharmaceuticals 2022, 15(9), 1149; https://doi.org/10.3390/ph15091149 - 15 Sep 2022
Cited by 5 | Viewed by 2077
Abstract
Flavonoids are a group of natural compounds that have been described in the literature as having anti-inflammatory, antioxidant, and neuroprotective compounds. Although they are considered versatile molecules, little has been discussed about their antiviral activities for neurotropic viruses. Hence, the present study aimed [...] Read more.
Flavonoids are a group of natural compounds that have been described in the literature as having anti-inflammatory, antioxidant, and neuroprotective compounds. Although they are considered versatile molecules, little has been discussed about their antiviral activities for neurotropic viruses. Hence, the present study aimed to investigate the pharmacological potential of flavonoids in the face of viruses that can affect the central nervous system (CNS). We carried out research from 2011 to 2021 using the Pubmed platform. The following were excluded: articles not in the English language, letters to editors, review articles and papers that did not include any experimental or clinical tests, and papers that showed antiviral activities against viruses that do not infect human beings. The inclusion criteria were in silico predictions and preclinical pharmacological studies, in vitro, in vivo and ex vivo, and clinical studies with flavonoids, flavonoid fractions and extracts that were active against neurotropic viruses. The search resulted in 205 articles that were sorted per virus type and discussed, considering the most cited antiviral activities. Our investigation shows the latest relevant data about flavonoids that have presented a wide range of actions against viruses that affect the CNS, mainly influenza, hepatitis C and others, such as the coronavirus, enterovirus, and arbovirus. Considering that these molecules present well-known anti-inflammatory and neuroprotective activities, using flavonoids that have demonstrated both neuroprotective and antiviral effects could be viewed as an alternative for therapy in the course of CNS infections. Full article
(This article belongs to the Special Issue Antiviral Compounds in Medicinal Plants)
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13 pages, 1161 KiB  
Article
Quality of Active versus Spontaneous Reporting of Adverse Drug Reactions in Pediatric Patients: Relevance for Pharmacovigilance and Knowledge in Pediatric Medical Care
by Anne T. M. Dittrich, Nori J. L. Smeets, Emma F. M. de Jong, Juliët L. Kämink, Yvet Kroeze, Jos M. Th. Draaisma, Eugène P. van Puijenbroek and D. Maroeska W. M. te Loo
Pharmaceuticals 2022, 15(9), 1148; https://doi.org/10.3390/ph15091148 - 14 Sep 2022
Cited by 3 | Viewed by 1653
Abstract
For drug safety in pediatric patients, knowledge about adverse drug reactions (ADRs) is essential to balance benefits and risks, especially because of the high incidence of off-label drug use. However, underreporting of ADRs is a serious problem, leading to a deficit in knowledge [...] Read more.
For drug safety in pediatric patients, knowledge about adverse drug reactions (ADRs) is essential to balance benefits and risks, especially because of the high incidence of off-label drug use. However, underreporting of ADRs is a serious problem, leading to a deficit in knowledge affecting clinical practice. The aim of this study is to find a method by which we can improve the quantity of ADR reporting while maintaining or improving the quality of the ADR reports. This was done in several steps. First, health care providers were educated to increase awareness of ADRs. Thereafter, a novel active supporting system was introduced, where reporting ADRs was simplified; if clinical physicians suspected an ADR, they only had to send the name or hospital number of the patient, the observed ADR, and the suspected drug to a supportive team. This team collects all information needed about the possible ADR from the patient’s medical records and hospital charts. With this information, the supportive team fills in the forms necessary for reporting ADRs to the nationwide pharmacovigilance centre Lareb. With this system, the quantity of ADR reports from both inpatients and outpatients rose dramatically. Subsequently, the quality of the obtained ADR reports was measured using the ClinDoc and vigiGrade systems. This study shows there is no loss of quality of the ADR reports in the active reporting system compared to spontaneous reporting systems. Based on the data of the present study, we suggest that an active reporting system has the potential to increase our knowledge about ADRs in pediatric patients. Full article
(This article belongs to the Special Issue Pharmacology of Pediatric Medicines)
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15 pages, 1268 KiB  
Review
Montelukast and Acute Coronary Syndrome: The Endowed Drug
by Basil Mohammed Alomair, Hayder M. Al-kuraishy, Ali I. Al-Gareeb, Sadiq M. Al-Hamash, Michel De Waard, Jean-Marc Sabatier, Hebatallah M. Saad and Gaber El-Saber Batiha
Pharmaceuticals 2022, 15(9), 1147; https://doi.org/10.3390/ph15091147 - 14 Sep 2022
Cited by 20 | Viewed by 5989
Abstract
Acute coronary syndrome (ACS) is a set of signs and symptoms caused by a reduction of coronary blood flow with subsequent myocardial ischemia. ACS is associated with activation of the leukotriene (LT) pathway with subsequent releases of various LTs, including LTB4, LTC4, and [...] Read more.
Acute coronary syndrome (ACS) is a set of signs and symptoms caused by a reduction of coronary blood flow with subsequent myocardial ischemia. ACS is associated with activation of the leukotriene (LT) pathway with subsequent releases of various LTs, including LTB4, LTC4, and LTD4, which cause inflammatory changes and induction of immunothrombosis. LTs through cysteine leukotriene (CysLT) induce activation of platelets and clotting factors with succeeding coronary thrombosis. CysLT receptor (CysLTR) antagonists such as montelukast (MK) may reduce the risk of the development of ACS and associated complications through suppression of the activation of platelet and clotting factors. Thus, this critical review aimed to elucidate the possible protective role of MK in the management of ACS. The LT pathway is implicated in the pathogenesis of atherosclerosis, cardiac hypertrophy, and heart failure. Inhibition of the LT pathway and CysL1TR by MK might be effective in preventing cardiovascular complications. MK could be an effective novel therapy in the management of ACS through inhibition of pro-inflammatory CysLT1R and modulation of inflammatory signaling pathways. MK can attenuate thrombotic events by inhibiting platelet activation and clotting factors that are activated during the development of ACS. In conclusion, MK could be an effective agent in reducing the severity of ACS and associated complications. Experimental, preclinical, and clinical studies are recommended to confirm the potential therapeutic of MK in the management of ACS. Full article
(This article belongs to the Section Pharmacology)
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26 pages, 1021 KiB  
Review
Dilemmas in the Choice of Adequate Therapeutic Treatment in Patients with Acute Pulmonary Embolism—From Modern Recommendations to Clinical Application
by Ratko Lasica, Milika Asanin, Lazar Djukanovic, Nebojsa Radovanovic, Lidija Savic, Marija Polovina, Sanja Stankovic, Arsen Ristic, Marija Zdravkovic, Andjelka Lasica, Jelena Kravic and Jovan Perunicic
Pharmaceuticals 2022, 15(9), 1146; https://doi.org/10.3390/ph15091146 - 14 Sep 2022
Cited by 2 | Viewed by 3033
Abstract
Pulmonary thromboembolism is a very common cardiovascular disease, with a high mortality rate. Despite the clear guidelines, this disease still represents a great challenge both in diagnosis and treatment. The heterogeneous clinical picture, often without pathognomonic signs and symptoms, represents a huge differential [...] Read more.
Pulmonary thromboembolism is a very common cardiovascular disease, with a high mortality rate. Despite the clear guidelines, this disease still represents a great challenge both in diagnosis and treatment. The heterogeneous clinical picture, often without pathognomonic signs and symptoms, represents a huge differential diagnostic problem even for experienced doctors. The decisions surrounding this therapeutic regimen also represent a major dilemma in the group of patients who are hemodynamically stable at initial presentation and have signs of right ventricular (RV) dysfunction proven by echocardiography and positive biomarker values (pulmonary embolism of intermediate–high risk). Studies have shown conflicting results about the benefit of using fibrinolytic therapy in this group of patients until hemodynamic decompensation, due to the risk of major bleeding. The latest recommendations give preference to new oral anticoagulants (NOACs) compared to vitamin K antagonists (VKA), except for certain categories of patients (patients with antiphospholipid syndrome, mechanical valves, pregnancy). When using oral anticoagulant therapy, special attention should be paid to drug–drug interactions, which can lead to many complications, even to the death of the patient. Special population groups such as pregnant women, obese patients, patients with antiphospholipid syndrome and the incidence of cancer represent a great therapeutic challenge in the application of anticoagulant therapy. In these patients, not only must the effectiveness of the drugs be taken into account, but great attention must be paid to their safety and possible side effects, which is why a multidisciplinary approach is emphasized in order to provide the best therapeutic option. Full article
(This article belongs to the Section Pharmacology)
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17 pages, 1056 KiB  
Review
Role of Trientine in Hypertrophic Cardiomyopathy: A Review of Mechanistic Aspects
by Fitri Fareez Ramli, Syed Alhafiz Syed Hashim, Betty Raman, Masliza Mahmod and Yusof Kamisah
Pharmaceuticals 2022, 15(9), 1145; https://doi.org/10.3390/ph15091145 - 14 Sep 2022
Cited by 7 | Viewed by 2003
Abstract
Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson’s disease, demonstrates beneficial effects in patients with hypertrophic cardiomyopathy. This review aims to present the updated development [...] Read more.
Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson’s disease, demonstrates beneficial effects in patients with hypertrophic cardiomyopathy. This review aims to present the updated development of the roles of trientine in hypertrophic cardiomyopathy. The drug has been demonstrated in animal studies to restore myocardial intracellular copper content. However, its mechanisms for improving the medical condition remain unclear. Thus, comprehending its mechanistic aspects in cardiomyopathy is crucial and could help to expedite future research. Full article
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9 pages, 1956 KiB  
Article
Synthesis of Novel N4-Hydrocytidine Analogs as Potential Anti-SARS-CoV-2 Agents
by Franck Amblard, Julia C. LeCher, Ramyani De, Shu Ling Goh, Chengwei Li, Mahesh Kasthuri, Nicolas Biteau, Longhu Zhou, Zahira Tber, Jessica Downs-Bowen, Keivan Zandi and Raymond F. Schinazi
Pharmaceuticals 2022, 15(9), 1144; https://doi.org/10.3390/ph15091144 - 14 Sep 2022
Cited by 2 | Viewed by 1661
Abstract
Coronavirus disease 2019 (COVID-19) is an emerging global pandemic with severe morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molnupiravir, an ester prodrug form of N4-hydroxycytidine (NHC), was recently emergency-use approved for the treatment of early [...] Read more.
Coronavirus disease 2019 (COVID-19) is an emerging global pandemic with severe morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molnupiravir, an ester prodrug form of N4-hydroxycytidine (NHC), was recently emergency-use approved for the treatment of early SARS-CoV-2 infections. Herein, we report the synthesis and evaluation of a series of novel NHC analogs. Full article
(This article belongs to the Special Issue Small Molecules Targeting Viral Polymerases)
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8 pages, 487 KiB  
Review
Healing Potential of Propolis in Skin Wounds Evidenced by Clinical Studies
by Cristiano da Rosa, Ian Lucas Bueno, Ana Clara Martins Quaresma and Giovanna Barbarini Longato
Pharmaceuticals 2022, 15(9), 1143; https://doi.org/10.3390/ph15091143 - 14 Sep 2022
Cited by 13 | Viewed by 3066
Abstract
Propolis has been used since ancient times for the treatment of skin diseases and, currently, its pharmacological potential for healing and repairing various types of wounds is widely cited in the literature. The healing properties of propolis are mainly attributed to its composition [...] Read more.
Propolis has been used since ancient times for the treatment of skin diseases and, currently, its pharmacological potential for healing and repairing various types of wounds is widely cited in the literature. The healing properties of propolis are mainly attributed to its composition which is rich in phenolic compounds, and propolis has aroused the interest of the pharmaceutical industry as a low-cost product as compared with other treatments and medications; however, most of the published data refer to its effects in vitro and in vivo and, so far, few clinical studies have been carried out proving its therapeutic efficacy. In this article, we aimed to review clinical trail data published in Portuguese, Spanish, and English, in Scielo, PubMed, Google Scholar, Medline, and Lilacs between 1990 and 2021 on the clinical use of propolis for skin ulcers. The potential of propolis as an alternative healing treatment for skin wounds such as diabetic, venous, and surgical wounds, as well as wounds caused by burns, etc., is mainly due to its evidenced properties such as antimicrobial, anti-inflammatory, analgesic, and angiogenesis promoter effects. However, there is a need to standardize the type of administration and the concentration of propolis for each type of wound. Furthermore, further clinical studies are essential to add information about propolis safety and for obtaining the best possible therapeutic benefits from its use. Full article
(This article belongs to the Special Issue Feature Reviews in Natural Products)
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28 pages, 8086 KiB  
Article
Nanoparticulate System for the Transdermal Delivery of Catechin as an Antihypercholesterol: In Vitro and In Vivo Evaluations
by Soraya Ratnawulan Mita, Marline Abdassah, Unang Supratman, Yoshihito Shiono, Driyanti Rahayu, Iyan Sopyan and Gofarana Wilar
Pharmaceuticals 2022, 15(9), 1142; https://doi.org/10.3390/ph15091142 - 13 Sep 2022
Cited by 6 | Viewed by 1847
Abstract
Gambir (Uncaria gambir, Roxb.) contains catechins that is often empirically used to treat various diseases. Catechins can reduce cholesterol levels by inhibiting coenzyme HMG-CoA reductase that plays a role in cholesterol metabolism. Research has been carried out covering the optimization of [...] Read more.
Gambir (Uncaria gambir, Roxb.) contains catechins that is often empirically used to treat various diseases. Catechins can reduce cholesterol levels by inhibiting coenzyme HMG-CoA reductase that plays a role in cholesterol metabolism. Research has been carried out covering the optimization of transethosomal catechins, the formulation of Transethosomal Catechin Gel (TCG) and Non-Transethosomal Catechin Gel (NTCG), which were then tested for catechin permeation from these gel preparations in vitro using Franz’s diffusion cell with PTFE membranes. The anti-hypercholesterol activity test was carried out with Simvastatin orally as a positive control using 25 male Wistar rats (Rattus norvegicus). The catechin transetosomes have a size of 176.1 ± 5.8 nm, Zeta potential −11.6 ± 5.28, and Entrapment Efficacy of 96.77% ± 0.05. The result of cumulative catechins that permeated from TCG and NTCG were and 172.454 ± 5.287 and 112.741 ± 2.241 μg respectively. Permeation test graphs showed similar permeation and flux profiles. TCG can reduce total cholesterol and LDL (Low Density Lipoprotein) values in rats by 39.77% and 51.52% respectively during 14 days of use. Full article
(This article belongs to the Special Issue Polyphenols and their Nanoformulations: Challenges and Opportunities)
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24 pages, 2769 KiB  
Article
In Silico Prediction of Anti-Infective and Cell-Penetrating Peptides from Thalassophryne nattereri Natterin Toxins
by Gabrielle Lupeti De Cena, Bruna Vitória Scavassa and Katia Conceição
Pharmaceuticals 2022, 15(9), 1141; https://doi.org/10.3390/ph15091141 - 13 Sep 2022
Cited by 6 | Viewed by 2535
Abstract
The therapeutic potential of venom-derived peptides, such as bioactive peptides (BAPs), is determined by specificity, stability, and pharmacokinetics properties. BAPs, including anti-infective or antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), share several physicochemical characteristics and are potential alternatives to antibiotic-based therapies and drug [...] Read more.
The therapeutic potential of venom-derived peptides, such as bioactive peptides (BAPs), is determined by specificity, stability, and pharmacokinetics properties. BAPs, including anti-infective or antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs), share several physicochemical characteristics and are potential alternatives to antibiotic-based therapies and drug delivery systems, respectively. This study used in silico methods to predict AMPs and CPPs derived from natterins from the venomous fish Thalassophryne nattereri. Fifty-seven BAPs (19 AMPs, 8 CPPs, and 30 AMPs/CPPs) were identified using the web servers CAMP, AMPA, AmpGram, C2Pred, and CellPPD. The physicochemical properties were analyzed using ProtParam, PepCalc, and DispHred tools. The membrane-binding potential and cellular location of each peptide were analyzed using the Boman index by APD3, and TMHMM web servers. All CPPs and two AMPs showed high membrane-binding potential. Fifty-four peptides were located in the plasma membrane. Peptide immunogenicity, toxicity, allergenicity, and ADMET parameters were evaluated using several web servers. Sixteen antiviral peptides and 37 anticancer peptides were predicted using the web servers Meta-iAVP and ACPred. Secondary structures and helical wheel projections were predicted using the PEP-FOLD3 and Heliquest web servers. Fifteen peptides are potential lead compounds and were selected to be further synthesized and tested experimentally in vitro to validate the in silico screening. The use of computer-aided design for predicting peptide structure and activity is fast and cost-effective and facilitates the design of potent therapeutic peptides. The results demonstrate that toxins form a natural biotechnological platform in drug discovery, and the presence of CPP and AMP sequences in toxin families opens new possibilities in toxin biochemistry research. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)
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15 pages, 2786 KiB  
Article
Attenuated Risk Association of End-Stage Kidney Disease with Metformin in Type 2 Diabetes with eGFR Categories 1–4
by Aimin Yang, Eric S. H. Lau, Hongjiang Wu, Ronald C. W. Ma, Alice P. S. Kong, Wing Yee So, Andrea O. Y. Luk, Amy W. C. Fu, Juliana C. N. Chan and Elaine Chow
Pharmaceuticals 2022, 15(9), 1140; https://doi.org/10.3390/ph15091140 - 13 Sep 2022
Cited by 7 | Viewed by 2570
Abstract
Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a global burden, while the renoprotective effects of metformin remain controversial. In a population-based cohort (2002–2018) including 96,643 patients with T2D observed for 0.7 million person-years, we estimated the risk association of metformin and [...] Read more.
Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a global burden, while the renoprotective effects of metformin remain controversial. In a population-based cohort (2002–2018) including 96,643 patients with T2D observed for 0.7 million person-years, we estimated the risk association of metformin and its dose-relationship with ESKD in a propensity-score overlap-weighting (PS-OW) cohort by eGFR categories. Amongst 96,643, 83,881 (86.8%) had eGFR-G1/G2 (≥60 mL/min/1.73 m2), 8762 (9.1%) had eGFR-G3a (≥45–60 mL/min/1.73 m2), 3051 (3.2%) had eGFR-G3b (≥30–45 mL/min/1.73 m2), and 949 (1.0%) had eGFR-G4 (≥15–30 mL/min/1.73 m2). The respective proportions of metformin users in these eGFR categories were 95.1%, 81.9%, 53.8%, and 20.8%. In the PS-OW cohort with 88,771 new-metformin and 7872 other oral glucose-lowering-drugs (OGLDs) users, the respective incidence rates of ESKD were 2.8 versus 22.4/1000 person-years. Metformin use associated with reduced risk of ESKD (hazard ratio (HR) = 0.43 [95% CI: 0.35–0.52] in eGFR-G1/G2, 0.64 [0.52–0.79] in eGFR-G3a, 0.67 [0.56–0.80] in eGFR-G3b, and 0.63 [0.48–0.83] in eGFR-G4). Metformin use was associated with reduced or neutral risk of major adverse cardiovascular events (MACE) (7.2 versus 16.0/1000 person-years) and all-cause mortality (14.6 versus 65.1/1000 person-years). Time-weighted mean daily metformin dose was 1000 mg in eGFR-G1/G2, 850 mg in eGFR-G3a, 650 mg in eGFR-G3b, and 500 mg in eGFR-G4. In a subcohort of 14,766 patients observed for 0.1 million person-years, the respective incidence rates of lactic acidosis and HR in metformin users and non-users were 42.5 versus 226.4 events/100,000 person-years (p = 0.03) for eGFR-G1/G2 (HR = 0.57, 0.25–1.30) and 54.5 versus 300.6 events/100,000 person-years (p = 0.01) for eGFR-G3/G4 (HR = 0.49, 0.19–1.30). These real-world data underscore the major benefits and low risk of lactic acidosis with metformin use down to an eGFR of 30 mL/min/1.73 m2 and possibly even 15 mL/min/1.73 m2, while reinforcing the importance of dose adjustment and frequent monitoring of eGFR. Full article
(This article belongs to the Special Issue Drugs for Diabetes: From Pharmacology to Clinical Application)
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11 pages, 2566 KiB  
Article
Construction and Validation of an Oxaliplatin-Resistant Gene Signature in Colorectal Cancer Patients Who Underwent Chemotherapy
by Yixin Yin, Siqi Li, Xinqiang Liang, Kezhi Li, Mingzhi Xie and Bangli Hu
Pharmaceuticals 2022, 15(9), 1139; https://doi.org/10.3390/ph15091139 - 13 Sep 2022
Cited by 4 | Viewed by 1593
Abstract
Aberrant expression of genes contributes to the chemoresistance of colorectal cancer (CRC) treatment. This study aimed to identify genes associated with the chemoresistance of oxaliplatin-based chemotherapy in CRC patients and to construct a signature. Oxaliplatin resistance-related genes were screened by analyzing the gene [...] Read more.
Aberrant expression of genes contributes to the chemoresistance of colorectal cancer (CRC) treatment. This study aimed to identify genes associated with the chemoresistance of oxaliplatin-based chemotherapy in CRC patients and to construct a signature. Oxaliplatin resistance-related genes were screened by analyzing the gene profiles of cell lines and tissue samples that underwent oxaliplatin-based treatment. Oxaliplatin resistance-related genes were used to establish a signature. The association of the signature had clinical significance, so the prognostic value of the signature was analyzed. Independent cohorts and CRC cell lines were used to validate the value of the gene signature and the oxaliplatin-resistant genes. There were 64 oxaliplatin resistance-related genes identified after overlapping the genes from the dataset of oxaliplatin-treated CRC cells and the dataset of patients treated with oxaliplatin-based chemotherapy. A gene signature based on five oxaliplatin resistance-related genes was established. This gene signature effectively predicted the prognosis of CRC patients who underwent chemotherapy. No significant associations were found between the gene mutations and survival of the patients; however, two genes were associated with microsatellite instability status. Two external independent cohorts and CRC cell line experiments validated the prognostic values of the signature and expression of the genes after oxaliplatin treatment. In conclusion, the oxaliplatin resistance-related gene signature involving five genes was a novel biomarker for the prediction of the chemotherapy response and prognosis of CRC patients who underwent oxaliplatin-based chemotherapy. Full article
(This article belongs to the Special Issue Pharmacotherapy for Colorectal Cancer)
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15 pages, 1404 KiB  
Communication
Novel Effective Fluorinated Benzothiophene-Indole Hybrid Antibacterials against S. aureus and MRSA Strains
by Marius Seethaler, Tobias Hertlein, Elisa Hopke, Paul Köhling, Knut Ohlsen, Michael Lalk and Andreas Hilgeroth
Pharmaceuticals 2022, 15(9), 1138; https://doi.org/10.3390/ph15091138 - 13 Sep 2022
Cited by 4 | Viewed by 1435
Abstract
Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds [...] Read more.
Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds to combat antibacterial drug resistance. The synthesis of novel drugs from natural sources is mostly cost-intensive due to those drugs’ complicated structures. Therefore, it is necessary to find novel antibacterials by simple synthesis to become more attractive for industrial production. We succeeded in the discovery of four antibacterial compound (sub)classes accessible in a simple one-pot reaction based on fluorinated benzothiophene-indole hybrids. They have been evaluated against various S. aureus and MRSA strains. Structure- and substituent-dependent activities have been found within the (sub)classes and promising lead compounds have been identified. In addition, bacterial pyruvate kinase was found to be the molecular target of the active compounds. In conclusion, simple one-pot synthesis of benzothiophene-indoles represents a promising strategy for the search of novel antimicrobial compounds. Full article
(This article belongs to the Special Issue Novel Antibacterial Agents 2022)
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22 pages, 6153 KiB  
Article
Antiproliferative and Apoptotic Effects of Graphene Oxide @AlFu MOF Based Saponin Natural Product on OSCC Line
by Seyyed Mojtaba Mousavi, Seyyed Alireza Hashemi, Yasmin Ghahramani, Rouhollah Azhdari, Khadijeh Yousefi, Ahmad Gholami, Fatemeh Fallahi Nezhad, Neralla Vijayakameswara Rao, Navid Omidifar and Wei-Hung Chiang
Pharmaceuticals 2022, 15(9), 1137; https://doi.org/10.3390/ph15091137 - 12 Sep 2022
Cited by 15 | Viewed by 2490
Abstract
The increasing rate of oral squamous cell carcinoma (OSCC) and the undesirable side effects of anticancer agents have enhanced the demand for the development of efficient, detectable, and targeted anticancer systems. Saponins are a diverse family of natural glycosides that have recently been [...] Read more.
The increasing rate of oral squamous cell carcinoma (OSCC) and the undesirable side effects of anticancer agents have enhanced the demand for the development of efficient, detectable, and targeted anticancer systems. Saponins are a diverse family of natural glycosides that have recently been evaluated as an effective compound for the targeted therapy of squamous cell carcinoma. Due to their porous nature and stable structure, metal–organic frameworks (MOFs) are a well-known substance form for various biological applications, such as drug delivery. In this study, we fabricated a novel hybrid, highly porous and low-toxic saponin-loaded nanostructure by modifying graphene oxide (GO)/reduced GO (rGO) with aluminum fumarate (AlFu) as MOF core–shell nanocomposite. The characterization of the nanostructures was investigated by FTIR, TEM, EDX, FESEM, and BET. MTT assay was used to investigate the anticancer activity of these compounds on OSCC and PDL normal dental cells. The effect of the nanocomposites on OSCC was then investigated by studying apoptosis and necrosis using flow cytometry. The GO/rGO was decorated with a saponin–AlFu mixture to further investigate cytotoxicity. The results of the MTT assay showed that PDL cells treated with AlFu–GO–saponin at a concentration of 250 μg/mL had a viability of 74.46 ± 16.02%, while OSCC cells treated with this sample at a similar concentration had a viability of only 38.35 ± 19.9%. The anticancer effect of this nanostructure on OSCC was clearly demonstrated. Moreover, the number of apoptotic cells in the AlFu–GO–saponin and AlFu–rGO–saponin groups was 10.98 ± 2.36%–26.90 ± 3.24% and 15.9 ± 4.08%–29.88 ± 0.41%, respectively, compared with 2.52 ± 0.78%–1.31 ± 0.62% in the untreated group. This significant increase in apoptotic effect observed with AlFu–rGO–saponin was also reflected in the significant anticancer effect of saponin-loaded nanostructures. Therefore, this study suggests that an effective saponin delivery system protocol for the precise design and fabrication of anticancer nanostructures for OSCC therapy should be performed prior to in vivo evaluations. Full article
(This article belongs to the Section Pharmaceutical Technology)
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17 pages, 2477 KiB  
Article
Molecular Insight into Mycobacterium tuberculosis Resistance to Nitrofuranyl Amides Gained through Metagenomics-like Analysis of Spontaneous Mutants
by Igor Mokrousov, Ivaylo Slavchev, Natalia Solovieva, Marine Dogonadze, Anna Vyazovaya, Violeta Valcheva, Aleksey Masharsky, Olesya Belopolskaya, Simeon Dimitrov, Viacheslav Zhuravlev, Isabel Portugal, João Perdigão and Georgi M. Dobrikov
Pharmaceuticals 2022, 15(9), 1136; https://doi.org/10.3390/ph15091136 - 12 Sep 2022
Cited by 3 | Viewed by 1787
Abstract
We performed synthesis of new nitrofuranyl amides and investigated their anti-TB activity and primary genetic response of mycobacteria through whole-genome sequencing (WGS) of spontaneous resistant mutants. The in vitro activity was assessed on reference strain Mycobacterium tuberculosis H37Rv. The most active compound 11 [...] Read more.
We performed synthesis of new nitrofuranyl amides and investigated their anti-TB activity and primary genetic response of mycobacteria through whole-genome sequencing (WGS) of spontaneous resistant mutants. The in vitro activity was assessed on reference strain Mycobacterium tuberculosis H37Rv. The most active compound 11 was used for in vitro selection of spontaneous resistant mutants. The same mutations in six genes were detected in bacterial cultures grown under increased concentrations of 11 (2×, 4×, 8× MIC). The mutant positions were presented as mixed wild type and mutant alleles while increasing the concentration of the compound led to the semi-proportional and significant increase in mutant alleles. The identified genes belong to different categories and pathways. Some of them were previously reported as mediating drug resistance or drug tolerance, and counteracting oxidative and nitrosative stress, in particular: Rv0224c, fbiC, iniA, and Rv1592c. Gene-set interaction analysis revealed a certain weak interaction for gene pairs Rv1592–Rv1639c and Rv1592–Rv0224c. To conclude, this study experimentally demonstrated a multifaceted primary genetic response of M. tuberculosis to the action of nitrofurans. All three 11-treated subcultures independently presented the same six SNPs, which suggests their non-random occurrence and likely causative relationship between compound action and possible resistance mechanism. Full article
(This article belongs to the Section Medicinal Chemistry)
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20 pages, 5861 KiB  
Article
Preparation of Solid Self-Nanoemulsifying Drug Delivery Systems (S-SNEDDS) by Co-Extrusion of Liquid SNEDDS and Polymeric Carriers—A New and Promising Formulation Approach to Improve the Solubility of Poorly Water-Soluble Drugs
by Fabian-Pascal Schmied, Alexander Bernhardt and Sandra Klein
Pharmaceuticals 2022, 15(9), 1135; https://doi.org/10.3390/ph15091135 - 11 Sep 2022
Cited by 9 | Viewed by 2921
Abstract
The present study focused on a new formulation approach to improving the solubility of drugs with poor aqueous solubility. A hot melt extrusion (HME) process was applied to prepare drug-loaded solid self-nanoemulsifying drug delivery systems (S-SNEDDS) by co-extrusion of liquid SNEDDS (L-SNEDDS) and [...] Read more.
The present study focused on a new formulation approach to improving the solubility of drugs with poor aqueous solubility. A hot melt extrusion (HME) process was applied to prepare drug-loaded solid self-nanoemulsifying drug delivery systems (S-SNEDDS) by co-extrusion of liquid SNEDDS (L-SNEDDS) and different polymeric carriers. Experiments were performed with L-SNEDDS formulations containing celecoxib, efavirenz or fenofibrate as model drugs. A major objective was to identify a polymeric carrier and process parameters that would enable the preparation of stable S-SNEDDS without impairing the release behavior and storage stability of the L-SNEDDS used and, if possible, even improving them further. In addition to commercially available (co)polymers already used in the field of HME, a particular focus was on the evaluation of different variants of a recently developed aminomethacrylate-based copolymer (ModE) that differed in Mw. Immediately after preparation, the L-SNEDDS and S-SNEDDS formulations were tested for amorphicity by differential scanning calorimetry. Furthermore, solubility and dissolution tests were performed. In addition, the storage stability was investigated at 30 °C/65% RH over a period of three and six months, respectively. In all cases, amorphous formulations were obtained and, especially for the model drug celecoxib, S-SNEDDS were developed that maintained the rapid and complete drug release of the underlying L-SNEDDS even over an extended storage period. Overall, the data obtained in this study suggest that the presented S-SNEDDS approach is very promising, provided that drug-loaded L-SNEDDS are co-processed with a suitable polymeric carrier. In the case of celecoxib, the E-173 variant of the novel ModE copolymer proved to be a novel polymeric carrier with great potential for application in S-SNEDDS. The presented approach will, therefore, be pursued in future studies to establish S-SNEDDS as an alternative formulation to other amorphous systems. Full article
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23 pages, 8281 KiB  
Article
New Sulfamethoxazole Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors: Design, Synthesis, Cytotoxic Activity and Molecular Modeling
by Mohamed A. Abdelgawad, Syed N. A. Bukhari, Arafa Musa, Mohammed Elmowafy, Mohammed H. Elkomy, AbdElAziz. A. Nayl, Ahmed H. El-Ghorab, Ibrahim Hotan Alsohaimi, Mohamed Sadek Abdel-Bakky, Ibrahim O. Althobaiti, Hamud A. Altaleb, Hany A. Omar, Ahmed H. Abdelazeem, Mohamed A. Zaki, Mohamed E. Shaker and Heba A. H. Elshemy
Pharmaceuticals 2022, 15(9), 1134; https://doi.org/10.3390/ph15091134 - 10 Sep 2022
Cited by 3 | Viewed by 2702
Abstract
In this study new sulphamethoxazole derivatives (S1S4, S6S12, and S14S22) were designed and synthesized and their structures were fully characterized and validated using NMR, mass, and IR spectroscopy, as well as elemental analyses. [...] Read more.
In this study new sulphamethoxazole derivatives (S1S4, S6S12, and S14S22) were designed and synthesized and their structures were fully characterized and validated using NMR, mass, and IR spectroscopy, as well as elemental analyses. All new derivatives (S1S22) were assayed against human carbonic anhydrase (hCAs IX and XII) for their inhibitory activities. hCAs IX and XII were chosen due to the fact that CAIX expression is recognized as a hypoxia marker with a poor prognosis in breast cancer. When compared to Dorzolamide HCl as a standard reference, derivatives S2, S3, S8, S9, and S15 had the most effective inhibition with low IC50 values. The active compounds were further evaluated against hCAs I and II inhibitory activity and compounds S8, S9 and S15 showed the least inhibitory effect compared to the reference standard, acetazolamide, indicating that their effect in normal cells is the lowest. Cell viability tests for the selected compounds were carried out on MCF7 (normoxia and hypoxia) and on the normal breast cell line (MCF10a) with Staurosporine as a standard. The results showed that compound S15 had a highly potent cytotoxic effect. Furthermore, cell cycle analysis results showed that compound S15 triggered cell cycle arrest and apoptosis in G1/S of MCF7 cancer cells. Finally, molecular docking was performed to point out the possible explanation for the vital structural features and key-interactions exerted by our ligands with hCAs IX and XII that might share additional designs and highlight possible leads for a hopeful anticancer agent. Consequently, sulphamethoxazole Derivative S15 could be the potential lead for emerging selective cytotoxic compounds directing h CAs IX and XII. Full article
(This article belongs to the Section Medicinal Chemistry)
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