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Pharmaceuticals, Volume 16, Issue 5 (May 2023) – 142 articles

Cover Story (view full-size image): G-protein-coupled receptors (GPCRs) represent valid molecular targets for directing peptide radioligands to malignant lesions. Diagnosis (γ-emitters: SPECT, β+-emitters: PET) and therapy (α, β-, Auger e- emitters: PRRT) are combined in a new promising “radiotheranostics” approach. Radiolabeled somatostatin analogs are widely used in neuroendocrine tumor patients, whereas peptide radioligands targeting other GPCRs in different tumors include bombesin, gastrin and exendin analogs. A recent switch from internalizing GPCR agonists to antagonists led to better pharmacokinetics and higher biosafety. GPCR antagonists do not activate their target receptor and do not elicit acute adverse effects when injected into patients. We herein discuss the challenges and opportunities of modern peptide radiotheranostics, focusing on GPCR antagonists. View this paper
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27 pages, 3323 KiB  
Review
Carboxymethylated Gums and Derivatization: Strategies and Significance in Drug Delivery and Tissue Engineering
by Madhuri Baghel, Kalyani Sakure, Tapan Kumar Giri, Sabyasachi Maiti, Kartik T. Nakhate, Shreesh Ojha, Charu Sharma, Yogeeta Agrawal, Sameer Goyal and Hemant Badwaik
Pharmaceuticals 2023, 16(5), 776; https://doi.org/10.3390/ph16050776 - 22 May 2023
Cited by 5 | Viewed by 2295
Abstract
Natural polysaccharides have been widely exploited in drug delivery and tissue engineering research. They exhibit excellent biocompatibility and fewer adverse effects; however, it is challenging to assess their bioactivities to that of manufactured synthetics because of their intrinsic physicochemical characteristics. Studies showed that [...] Read more.
Natural polysaccharides have been widely exploited in drug delivery and tissue engineering research. They exhibit excellent biocompatibility and fewer adverse effects; however, it is challenging to assess their bioactivities to that of manufactured synthetics because of their intrinsic physicochemical characteristics. Studies showed that the carboxymethylation of polysaccharides considerably increases the aqueous solubility and bioactivities of inherent polysaccharides and offers structural diversity, but it also has some limitations that can be resolved by derivatization or the grafting of carboxymethylated gums. The swelling ratio, flocculation capacity, viscosity, partition coefficient, metal absorption properties, and thermosensitivity of natural polysaccharides have been improved as a result of these changes. In order to create better and functionally enhanced polysaccharides, researchers have modified the structures and properties of carboxymethylated gums. This review summarizes the various ways of modifying carboxymethylated gums, explores the impact that molecular modifications have on their physicochemical characteristics and bioactivities, and sheds light on various applications for the derivatives of carboxymethylated polysaccharides. Full article
(This article belongs to the Section Pharmaceutical Technology)
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20 pages, 2018 KiB  
Review
The Genus Dacryodes Vahl.: Ethnobotany, Phytochemistry and Biological Activities
by Leseho Swana, Bienvenu Tsakem, Jacqueline V. Tembu, Rémy B. Teponno, Joy T. Folahan, Jarmo-Charles Kalinski, Alexandros Polyzois, Guy Kamatou, Louis P. Sandjo, Jean Christopher Chamcheu and Xavier Siwe-Noundou
Pharmaceuticals 2023, 16(5), 775; https://doi.org/10.3390/ph16050775 - 22 May 2023
Viewed by 2440
Abstract
Dacryodes Vahl. species, belonging to the Burseraceae family, are widely used in traditional medicine in tropical regions to treat a range of ailments including malaria, wounds, tonsillitis, and ringworms. This review discusses the distribution, ethnobotanical uses, phytochemistry, and bioactivities of Dacryodes species. The [...] Read more.
Dacryodes Vahl. species, belonging to the Burseraceae family, are widely used in traditional medicine in tropical regions to treat a range of ailments including malaria, wounds, tonsillitis, and ringworms. This review discusses the distribution, ethnobotanical uses, phytochemistry, and bioactivities of Dacryodes species. The intent is to spur future research into isolating and identifying key active principles, secondary metabolites, and crude extracts, and evaluating their pharmacological and toxicological effects, as well as the mechanism of actions to understand their medicinal benefits. A systematic review of scientific electronic databases from 1963 to 2022 including Scifinder, Scopus, Pubmed, Springer Link, ResearchGate, Ethnobotany Research and Applications, Google Scholar, and ScienceDirect was conducted with a focus on Dacryodes edulis (G.Don) H.J. Lam and Dacryodes rostrata (Blume) H.J. Lam. Pharmacological data revealed that D. edulis isolates contain secondary metabolites and other phytochemical groups belonging to the terpenoids class with anti-microbial, anticancer, antidiabetic, antiinflammatory and hepatoprotective activities, highlighting its pharmacological potential in the therapy or management of diverse cancers, cardiovascular, and neurological diseases. Thus, phytochemicals and standardized extracts from D. edulis could offer safer and cost-effective chemopreventive and chemotherapeutic health benefits/regimen, or as alternative therapeutic remedy for several human diseases. Nevertheless, the therapeutic potential of most of the plants in the genus have not been exhaustively explored with regard to phytochemistry and pharmacology, but mostly complementary approaches lacking rigorous, scientific research-based knowledge. Therefore, the therapeutic potentials of the Dacryodes genus remain largely untapped, and comprehensive research is necessary to fully harness their medicinal properties. Full article
(This article belongs to the Special Issue Feature Reviews in Natural Products)
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13 pages, 4362 KiB  
Article
Rutin Gel with Bone Graft Accelerates Bone Formation in a Rabbit Model by Inhibiting MMPs and Enhancing Collagen Activities
by Fahad F. Albaqami, Hassan N. Althurwi, Khalid M. Alharthy, Abubaker M. Hamad and Fatin A. Awartani
Pharmaceuticals 2023, 16(5), 774; https://doi.org/10.3390/ph16050774 - 22 May 2023
Viewed by 1678
Abstract
Bone graft techniques are used to compensate for bone loss in areas with deficient regeneration. However, matrix metalloproteases (MMPs) can limit bone formation by degrading extracellular matrices, which are required for bone regrowth. Noteworthily, rutin is a natural flavonoid compound that inhibits the [...] Read more.
Bone graft techniques are used to compensate for bone loss in areas with deficient regeneration. However, matrix metalloproteases (MMPs) can limit bone formation by degrading extracellular matrices, which are required for bone regrowth. Noteworthily, rutin is a natural flavonoid compound that inhibits the genetic expression of various MMPs. Therefore, rutin may serve as an inexpensive and stable alternative to the growth factors used to accelerate dental bone graft healing. This study aimed to evaluate the potential of mixing rutin gel with allograft bone to accelerate the healing of bone defects in an in vivo rabbit model. Bone defects were surgically induced in New Zealand rabbits (n = 3 per group) and subsequently treated with bone grafts along with rutin or control gel. Overall, treatment with rutin significantly prevented the expression of several MMPs and increased type III collagen in the gingiva around the surgical site. Additionally, rutin-treated animals showed enhanced bone formation with higher bone marrow content in the jawbone defect area compared with the control group. Taken together, these findings demonstrate that rutin gel, when added to bone grafts, quickly enhances bone formation and may serve as a suitable alternative to expensive growth factors for the same purpose. Full article
(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Its Analogues)
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45 pages, 3569 KiB  
Article
Comparative Study on the Effect of Phenolics and Their Antioxidant Potential of Freeze-Dried Australian Beach-Cast Seaweed Species upon Different Extraction Methodologies
by Vigasini Subbiah, Faezeh Ebrahimi, Osman T. Agar, Frank R. Dunshea, Colin J. Barrow and Hafiz A. R. Suleria
Pharmaceuticals 2023, 16(5), 773; https://doi.org/10.3390/ph16050773 - 22 May 2023
Cited by 8 | Viewed by 3029
Abstract
Brown seaweed is rich in phenolic compounds and has established health benefits. However, the phenolics present in Australian beach-cast seaweed are still unclear. This study investigated the effect of ultrasonication and conventional methodologies using four different solvents on free and bound phenolics of [...] Read more.
Brown seaweed is rich in phenolic compounds and has established health benefits. However, the phenolics present in Australian beach-cast seaweed are still unclear. This study investigated the effect of ultrasonication and conventional methodologies using four different solvents on free and bound phenolics of freeze-dried brown seaweed species obtained from the southeast Australian shoreline. The phenolic content and their antioxidant potential were determined using in vitro assays followed by identification and characterization by LC-ESI-QTOF-MS/MS and quantified by HPLC-PDA. The Cystophora sp. displayed high total phenolic content (TPC) and phlorotannin content (FDA) when extracted using 70% ethanol (ultrasonication method). Cystophora sp., also exhibited strong antioxidant potential in various assays, such as DPPH, ABTS, and FRAP in 70% acetone through ultrasonication. TAC is highly correlated to FRAP, ABTS, and RPA (p < 0.05) in both extraction methodologies. LC-ESI-QTOF-MS/MS analysis identified 94 and 104 compounds in ultrasound and conventional methodologies, respectively. HPLC-PDA quantification showed phenolic acids to be higher for samples extracted using the ultrasonication methodology. Our findings could facilitate the development of nutraceuticals, pharmaceuticals, and functional foods from beach-cast seaweed. Full article
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14 pages, 1673 KiB  
Article
Prescribed Drugs and Self-Directed Violence: A Descriptive Study in the Spanish Pharmacovigilance Database
by Ana Avedillo-Salas, Javier Pueyo-Val, Ana Fanlo-Villacampa, Cristina Navarro-Pemán, Francisco Javier Lanuza-Giménez, Ignatios Ioakeim-Skoufa and Jorge Vicente-Romero
Pharmaceuticals 2023, 16(5), 772; https://doi.org/10.3390/ph16050772 - 22 May 2023
Cited by 3 | Viewed by 1995
Abstract
Self-inflicted violence is a major and growing public health problem and its prediction and prevention is challenging for healthcare systems worldwide. Our aim was to identify prescribed drugs associated with self-directed violent behaviors in Spain. A descriptive, longitudinal and retrospective study of spontaneous [...] Read more.
Self-inflicted violence is a major and growing public health problem and its prediction and prevention is challenging for healthcare systems worldwide. Our aim was to identify prescribed drugs associated with self-directed violent behaviors in Spain. A descriptive, longitudinal and retrospective study of spontaneous reports of adverse drug reactions corresponding to self-directed violence was recorded in the Spanish Pharmacovigilance Database (FEDRA®) from 1984 to 31 March 2021. A total of 710 cases were reported in the study period. The mean age was 45.52 years (range 1–94). There were no gender differences except in children, where most reports were of male children. The main therapeutic groups that were involved included drugs for the nervous system (64.5%) and anti-infectives for systemic use (13.2%). The most commonly reported drugs were varenicline, fluoxetine, lorazepam, escitalopram, venlafaxine, veralipride, pregabalin, roflumilast and bupropion. There were reports of montelukast, hydroxychloroquine, isotretinoin, methylphenidate, infliximab, natalizumab, ribavirin and efavirenz, which were less known to be involved in self-directed violence. This study shows that self-directed violence is a rare adverse drug reaction, and can be related to the use of some medicines. It is important for healthcare professionals to consider this risk in their clinical praxis, implementing person-centred approaches. Further studies are needed, considering comorbidities and potential interactions. Full article
(This article belongs to the Section Pharmacology)
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18 pages, 3401 KiB  
Article
A Three-Step Process to Isolate Large Quantities of Bioactive Sesquiterpene Lactones from Cichorium intybus L. Roots and Semisynthesis of Chicory STLs Standards
by Francesca Ruggieri, Philippe Hance, Bruna Gioia, Alexandre Biela, Pascal Roussel, Jean-Louis Hilbert and Nicolas Willand
Pharmaceuticals 2023, 16(5), 771; https://doi.org/10.3390/ph16050771 - 22 May 2023
Cited by 3 | Viewed by 1821
Abstract
Sesquiterpene lactones (STLs) are a large group of terpenoids most commonly found in plants of the Asteraceae family, e.g., in chicory plants, displaying a wide range of interesting biological activities. However, further studies on the biological potential of chicory-derived STLs and analogues are [...] Read more.
Sesquiterpene lactones (STLs) are a large group of terpenoids most commonly found in plants of the Asteraceae family, e.g., in chicory plants, displaying a wide range of interesting biological activities. However, further studies on the biological potential of chicory-derived STLs and analogues are challenging as only four of these molecules are commercially available (as analytical standards), and to date, there are no published or patented simple extraction–purification processes capable of large-scale STLs isolation. In this work, we describe a novel three-step large-scale extraction and purification method for the simultaneous purification of 11,13-dihydrolactucin (DHLc) and lactucin (Lc) starting from a chicory genotype rich in these STLs and the corresponding glucosyl and oxalyl conjugated forms. After a small-scale screening on 100 mg of freeze-dried chicory root powder, the best results were achieved with a 17 h water maceration at 30 °C. With these conditions, we managed to increase the content of DHLc and Lc, at the same time favoring the hydrolysis of their conjugated forms. On a larger scale, the extraction of 750 g of freeze-dried chicory root powder, followed by a liquid–liquid extraction step and a reversed-phase chromatography, allowed the recovery of 642.3 ± 76.3 mg of DHLc and 175.3 ± 32.9 mg of Lc. The two pure STLs were subsequently used in the context of semisynthesis to generate analogues for biological evaluation as antibacterial agents. In addition, other described chicory STLs that are not commercially available were also synthesized or extracted to serve as analytical standards for the study. In particular, lactucin-oxalate and 11,13-dihydrolactucin-oxalate were synthesized in two steps starting from Lc and DHLc, respectively. On the other hand, 11β,13-dihydrolactucin-glucoside was obtained after a MeOH/H2O (70/30) extraction, followed by a liquid–liquid extraction step and a reversed-phase chromatography. Together, this work will help facilitate the evaluation of the biological potential of chicory-derived STLs and their semisynthetic analogues. Full article
(This article belongs to the Topic Compounds with Medicinal Value (2nd Volume))
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13 pages, 457 KiB  
Review
Monoclonal Antibodies in Pregnancy and Breastfeeding in Patients with Multiple Sclerosis: A Review and an Updated Clinical Guide
by Panagiotis Gklinos and Ruth Dobson
Pharmaceuticals 2023, 16(5), 770; https://doi.org/10.3390/ph16050770 - 21 May 2023
Cited by 3 | Viewed by 4285
Abstract
The use of high-efficacy disease-modifying therapies (DMTs) early in the course of multiple sclerosis (MS) has been shown to improve clinical outcomes and is becoming an increasingly popular treatment strategy. As a result, monoclonal antibodies, including natalizumab, alemtuzumab, ocrelizumab, ofatumumab, and ublituximab, are [...] Read more.
The use of high-efficacy disease-modifying therapies (DMTs) early in the course of multiple sclerosis (MS) has been shown to improve clinical outcomes and is becoming an increasingly popular treatment strategy. As a result, monoclonal antibodies, including natalizumab, alemtuzumab, ocrelizumab, ofatumumab, and ublituximab, are frequently used for the treatment of MS in women of childbearing age. To date, only limited evidence is available on the use of these DMTs in pregnancy. We aim to provide an updated overview of the mechanisms of action, risks of exposure and treatment withdrawal, and pre-conception counseling and management during pregnancy and post-partum of monoclonal antibodies in women with MS. Discussing treatment options and family planning with women of childbearing age is essential before commencing a DMT in order to make the most suitable choice for each individual patient. Full article
(This article belongs to the Section Biopharmaceuticals)
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18 pages, 3559 KiB  
Article
Canagliflozin Ameliorates Oxidative Stress and Autistic-like Features in Valproic-Acid-Induced Autism in Rats: Comparison with Aripiprazole Action
by Mohammed Moutaz Nakhal, Petrilla Jayaprakash, Salahdein Aburuz, Bassem Sadek and Amal Akour
Pharmaceuticals 2023, 16(5), 769; https://doi.org/10.3390/ph16050769 - 19 May 2023
Cited by 4 | Viewed by 1825
Abstract
Based on their proven anti-inflammatory and antioxidant effects, recent studies have examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in neurodevelopmental disorders such as autism spectrum disorder (ASD). Therefore, the aim of this study is to assess the effects of [...] Read more.
Based on their proven anti-inflammatory and antioxidant effects, recent studies have examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in neurodevelopmental disorders such as autism spectrum disorder (ASD). Therefore, the aim of this study is to assess the effects of subchronic systemic treatment with intraperitoneal (i.p.) canagliflozin (20, 50, and 100 mg/kg) compared to aripiprazole (ARP) (3 mg/g, i.p.) in a valproic acid (VPA)-induced rat model of autism. The behavioral characteristics of ASD, oxidative stress, and acetylcholinesterase (AChE) activity in rats with ASD-like behaviors, which were induced by prenatal exposure to VPA, were evaluated. The behavioral assessment methods used for this study were the open field test (OFT), the marble-burying test (MBT), and the nestlet-shredding test (NST) to examine their exploratory, anxiety, and compulsiveness-like actions, while the biochemical assessment used for this study was an ELISA colorimetric assay to measure ASD biomarker activity in the hippocampus, prefrontal cortex, and cerebellum. Rats that were pretreated with 100 mg/kg of canagliflozin displayed a significantly lower percentage of shredding (1.12 ± 0.6%, p < 0.01) compared to the ARP group (3.52 ± 1.6%). Pretreatment with (20 mg/kg, 50 mg/kg, and 100 mg/kg) canagliflozin reversed anxiety levels and hyperactivity and reduced hyper-locomotor activity significantly (161 ± 34.9 s, p < 0.05; 154 ± 44.7 s, p < 0.05; 147 ± 33.6 s, p < 0.05) when compared with the VPA group (303 ± 140 s). Moreover, canagliflozin and ARP mitigated oxidative stress status by restoring levels of glutathione (GSH) and catalase (CAT) and increasing the levels of malondialdehyde (MDA) in all tested brain regions. The observed results propose repurposing of canagliflozin in the therapeutic management of ASD. However, further investigations are still required to verify the clinical relevance of canagliflozin in ASD. Full article
(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders, 3rd Edition)
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13 pages, 5686 KiB  
Article
Effect of the Composition of Leuzea and Cranberry Meal Extracts on Metabolic Processes in Norm and Pathology
by Daria Khalikova, Sergey An’kov, Nataliya Zhukova, Tatyana Tolstikova, Sergey Popov and Anastasia Saiko
Pharmaceuticals 2023, 16(5), 768; https://doi.org/10.3390/ph16050768 - 19 May 2023
Cited by 1 | Viewed by 1415
Abstract
This study was conducted to evaluate the effects of long-term administration of a new herbal composition of leuzea and cranberry meal extracts at a dose of 70:500 mg/kg in healthy and pathological mice. After 4 weeks of daily composition administration to healthy CD-1 [...] Read more.
This study was conducted to evaluate the effects of long-term administration of a new herbal composition of leuzea and cranberry meal extracts at a dose of 70:500 mg/kg in healthy and pathological mice. After 4 weeks of daily composition administration to healthy CD-1 mice and C57BL/6 mice with diet-induced metabolic syndrome, oral glucose tolerance test (OGTT), serum biochemical examination and histology of internal organs were performed. Additionally, histological examination of white and brown adipose tissue was performed to evaluate the ability of the composition to prevent abdominal obesity in C57BL/6Ay (agouti yellow) mice. The results showed that the composition increased tissue sensitivity to glucose in healthy CD-1 mice; at the same time, it did not worsen the course of pathological processes in pathological mice. In both cases, the application of the developed composition was safe and contributed to the restoration of metabolic parameters. Full article
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19 pages, 7801 KiB  
Article
Natural Product-Based Screening for Lead Compounds Targeting SARS CoV-2 Mpro
by Jie Chen, Xiang Zhou, Lifeng Fu and Haiyu Xu
Pharmaceuticals 2023, 16(5), 767; https://doi.org/10.3390/ph16050767 - 19 May 2023
Cited by 4 | Viewed by 2087
Abstract
Drugs that cure COVID-19 have been marketed; however, this disease continues to ravage the world without becoming extinct, and thus, drug discoveries are still relevant. Since Mpro has known advantages as a drug target, such as the conserved nature of the active [...] Read more.
Drugs that cure COVID-19 have been marketed; however, this disease continues to ravage the world without becoming extinct, and thus, drug discoveries are still relevant. Since Mpro has known advantages as a drug target, such as the conserved nature of the active site and the absence of homologous proteins in the body, it receives the attention of many researchers. Meanwhile, the role of traditional Chinese medicine (TCM) in the control of epidemics in China has also led to a focus on natural products, with the hope of finding some promising lead molecules through screening. In this study, we selected a commercial library of 2526 natural products from plants, animals and microorganisms with known biological activity for drug discovery, which had previously been reported for compound screening of the SARS CoV-2 S protein, but had not been tested on Mpro. This library contains compounds from a variety of Chinese herbs, including Lonicerae Japonicae Flos, Forsythiae Fructus and Scutellariae Radix, which are derived from traditional Chinese medicine prescriptions that have been shown to be effective against COVID-19. We used the conventional FRET method for the initial screening. After two rounds of selection, the remaining 86 compounds were divided into flavonoids, lipids, phenylpropanoids, phenols, quinones, alkaloids, terpenoids and steroids according to the skeleton structures, with inhibition rates greater than 70%. The top compounds in each group were selected to test the effective concentration ranges; the IC50 values were as follows: (−)–gallocatechin gallate (1.522 ± 0.126 μM), ginkgolic acid C15:1 (9.352 ± 0.531 μM), hematoxylin (1.025 ± 0.042 μM), fraxetin (2.486 ± 0.178 μM), wedelolactone (1.003 ± 0.238 μM), hydroxytyrosol acetate (3.850 ± 0.576 μM), vanitiolide (2.837 ± 0.225 μM), β,β–dimethylacrylalkannin (2.731 ± 0.308 μM), melanin (7.373 ± 0.368 μM) and cholesteryl sodium sulfate (2.741 ± 0.234μM). In the next step, we employed two biophysical techniques, SPR and nanoDSF, to obtain KD/Kobs values: hematoxylin (0.7 μM), (−)–gallocatechin gallate (126 μM), ginkgolic acid C15:1 (227 μM), wedelolactone (0.9770 μM), β,β–dimethylacrylalkannin (1.9004 μM,), cholesteryl sodium sulfate (7.5950 μM) and melanin (11.5667 μM), which allowed better assessments of the binding levels. Here, seven compounds were the winners. Then, molecular docking experiments were specially performed by AutoDock Vina to analyze the mode of interactions within Mpro and ligands. We finally formulated the present in silico study to predict pharmacokinetic parameters as well as drug-like properties, which is presumably the step that tells humans whether the compounds are drug-like or not. Moreover, hematoxylin, melanin, wedelolactone, β,β–dimethylacrylalkannin and cholesteryl sodium sulfate are in full compliance with the “Lipinski” principle and possess reasonable ADME/T properties, they have a greater potential of being lead compounds. The proposed five compounds are also the first to be found to have potential inhibitory effects on SARS CoV-2 Mpro. We hope that the results in this manuscript may serve as benchmarks for the above potentials. Full article
(This article belongs to the Special Issue Protease-Based Drug Discovery)
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19 pages, 3281 KiB  
Review
Tris(aminomethyl)phosphines and Their Copper(I) (Pseudo)halide Complexes with Aromatic Diimines—A Critical Retrospection
by Radosław Starosta
Pharmaceuticals 2023, 16(5), 766; https://doi.org/10.3390/ph16050766 - 19 May 2023
Cited by 3 | Viewed by 1947
Abstract
Metal complexes feature a wide range of available geometries, diversified lability, controllable hydrolytic stability, and easily available rich redox activity. These characteristics, combined with the specific properties of coordinated organic molecules, result in many different mechanisms of biological action, making each of the [...] Read more.
Metal complexes feature a wide range of available geometries, diversified lability, controllable hydrolytic stability, and easily available rich redox activity. These characteristics, combined with the specific properties of coordinated organic molecules, result in many different mechanisms of biological action, making each of the myriads of the classes of metal coordination compounds unique. This focused review presents combined and systematized results of the studies of a group of copper(I) (pseudo)halide complexes with aromatic diimines and tris(aminomethyl)phosphines of a general formula [CuX(NN)PR3], where X = I or NCS, NN = 2,2′-bipyridyl, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline or 2,2′-biquinoline, and PR3 = air-stable tris(aminomethyl)phosphines. The structural and electronic properties of the phosphine ligands and luminescent complexes are discussed. The complexes with 2,9-dimethyl-1,10-phenanthroline, apart from being air- and water-stable, exhibit a very high in vitro antimicrobial activity against the Staphylococcus aureus and Candida albicans. Moreover, some of these complexes also show a strong in vitro antitumor activity against human ovarian carcinoma cell lines: MDAH 2774 and SCOV 3, CT26 (mouse colon carcinoma), and A549 (human lung adenocarcinoma) cell lines. The tested complexes are moderately able to induce DNA lesions through free radical processes, however the trends do not reflect observed differences in biological activity. Full article
(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)
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17 pages, 3228 KiB  
Article
Alkaloid from Geissospermum sericeum Benth. & Hook.f. ex Miers (Apocynaceae) Induce Apoptosis by Caspase Pathway in Human Gastric Cancer Cells
by Mirian Letícia Carmo Bastos, João Victor Silva-Silva, Jorddy Neves Cruz, Amanda Roberta Palheta da Silva, Alexandre Augusto Bentaberry-Rosa, Gisele da Costa Ramos, José Edson de Sousa Siqueira, Márlia Regina Coelho-Ferreira, Sandro Percário, Patrícia Santana Barbosa Marinho, Andrey Moacir do Rosario Marinho, Marcelo de Oliveira Bahia and Maria Fâni Dolabela
Pharmaceuticals 2023, 16(5), 765; https://doi.org/10.3390/ph16050765 - 18 May 2023
Cited by 11 | Viewed by 2087
Abstract
Gastric cancer is among the major causes of death from neoplasia leading causes of death worldwide, with high incidence rates and problems related to its treatment. Here, we outline how Geissospermum sericeum exerts antitumor activity on the ACP02 cell line (human gastric adenocarcinoma) [...] Read more.
Gastric cancer is among the major causes of death from neoplasia leading causes of death worldwide, with high incidence rates and problems related to its treatment. Here, we outline how Geissospermum sericeum exerts antitumor activity on the ACP02 cell line (human gastric adenocarcinoma) and the mechanism of cell death. The ethanol extract and fractions, neutral fraction and alkaloid fraction, were characterized by thin-layer chromatography and HPLC-DAD, yielding an alkaloid (geissoschizoline N4-methylchlorine) identified by NMR. The cytotoxicity activity of the samples (ethanol extract, neutral fraction, alkaloid fraction, and geissoschizoline N4-methylchlorine) in HepG2 and VERO cells was determined by MTT. The ACP02 cell line was used to assess the anticancer potential. Cell death was quantified with the fluorescent dyes Hoechst 33342, propidium iodide, and fluorescein diacetate. The geissoschizoline N4-methylchlorine was evaluated in silico against caspase 3 and 8. In the antitumor evaluation, there was observed a more significant inhibitory effect of the alkaloid fraction (IC50 18.29 µg/mL) and the geissoschizoline N4-methylchlorine (IC50 12.06 µg/mL). However, geissoschizoline N4-methylchlorine showed lower cytotoxicity in the VERO (CC50 476.0 µg/mL) and HepG2 (CC50 503.5 µg/mL) cell lines, with high selectivity against ACP02 cells (SI 39.47 and 41.75, respectively). The alkaloid fraction showed more significant apoptosis and necrosis in 24 h and 48 h, with increased necrosis in higher concentrations and increased exposure time. For the alkaloid, apoptosis and necrosis were concentration- and time-dependent, with a lower necrosis rate. Molecular modeling studies demonstrated that geissoschizoline N4-methylchlorine could occupy the active site of caspases 3 and 8 energetically favorably. The results showed that fractionation contributed to the activity with pronounced selectivity for ACP02 cells, and geissoschizoline N4-methylchlor is a promising candidate for caspase inhibitors of apoptosis in gastric cancer. Thus, this study provides a scientific basis for the biological functions of Geissospermum sericeum, as well as demonstrates the potential of the geissoschizoline N4-methylchlorine in the treatment of gastric cancer. Full article
(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)
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16 pages, 2684 KiB  
Article
Identification of the Hepatic Metabolites of Flumazenil and their Kinetic Application in Neuroimaging
by Wei-Hsi Chen, Chuang-Hsin Chiu, Shiou-Shiow Farn, Kai-Hung Cheng, Yuan-Ruei Huang, Shih-Ying Lee, Yao-Ching Fang, Yu-Hua Lin and Kang-Wei Chang
Pharmaceuticals 2023, 16(5), 764; https://doi.org/10.3390/ph16050764 - 18 May 2023
Cited by 1 | Viewed by 1816
Abstract
Studies of the neurobiological causes of anxiety disorders have suggested that the γ-aminobutyric acid (GABA) system increases synaptic concentrations and enhances the affinity of GABAA (type A) receptors for benzodiazepine ligands. Flumazenil antagonizes the benzodiazepine-binding site of the GABA/benzodiazepine receptor (BZR) complex [...] Read more.
Studies of the neurobiological causes of anxiety disorders have suggested that the γ-aminobutyric acid (GABA) system increases synaptic concentrations and enhances the affinity of GABAA (type A) receptors for benzodiazepine ligands. Flumazenil antagonizes the benzodiazepine-binding site of the GABA/benzodiazepine receptor (BZR) complex in the central nervous system (CNS). The investigation of flumazenil metabolites using liquid chromatography (LC)-tandem mass spectrometry will provide a complete understanding of the in vivo metabolism of flumazenil and accelerate radiopharmaceutical inspection and registration. The main goal of this study was to investigate the use of reversed-phase high performance liquid chromatography (PR-HPLC), coupled with electrospray ionization triple-quadrupole tandem mass spectrometry (ESI-QqQ MS), to identify flumazenil and its metabolites in the hepatic matrix. Carrier-free nucleophilic fluorination with an automatic synthesizer for [18F]flumazenil, combined with nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging, was used to predict the biodistribution in normal rats. The study showed that 50% of the flumazenil was biotransformed by the rat liver homogenate in 60 min, whereas one metabolite (M1) was a methyl transesterification product of flumazenil. In the rat liver microsomal system, two metabolites were identified (M2 and M3), as their carboxylic acid and hydroxylated ethyl ester forms between 10 and 120 min, respectively. A total of 10–30 min post-injection of [18F]flumazenil showed an immediate decreased in the distribution ratio observed in the plasma. Nevertheless, a higher ratio of the complete [18F]flumazenil compound could be used for subsequent animal studies. [18F] According to in vivo nanoPET/CT imaging and ex vivo biodistribution assays, flumazenil also showed significant effects on GABAA receptor availability in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, indicating the formation of metabolites. We reported the completion of the biotransformation of flumazenil by the hepatic system, as well as [18F]flumazenil’s potential as an ideal ligand and PET agent for the determination of the GABAA/BZR complex for multiplex neurological syndromes at the clinical stage. Full article
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12 pages, 1856 KiB  
Article
Triple-Therapy of Peritoneal Metastasis—Partial-Dehydration under Hyperthermic Condition Combined with Chemotherapy: The First Preliminary In-Vitro Results
by Carolina Khosrawipour, Agata Diakun, Shiri Li, Hien Lau, Joanna Kulas, Veria Khosrawipour, Wojciech Kielan and Agata Mikolajczyk-Martinez
Pharmaceuticals 2023, 16(5), 763; https://doi.org/10.3390/ph16050763 - 18 May 2023
Cited by 1 | Viewed by 1728
Abstract
A newly introduced combination of intraperitoneal dehydration and hyperthermia has recently been shown to be feasible and cytotoxic for colon cancer cells in vivo. For the first time, our study now aims to evaluate dehydration under hyperthermic conditions combined with chemotherapy for potential [...] Read more.
A newly introduced combination of intraperitoneal dehydration and hyperthermia has recently been shown to be feasible and cytotoxic for colon cancer cells in vivo. For the first time, our study now aims to evaluate dehydration under hyperthermic conditions combined with chemotherapy for potential use in the clinical setting. In this study, in vitro colon cancer cells (HT-29) were subjected to single or several cycles of partial dehydration under hyperthermic conditions (45 °C), followed by chemotherapy (triple exposure) with oxaliplatin or doxorubicin in various configurations. The viability, cytotoxicity, and proliferation of cells after the proposed protocols were assessed. Intracellular doxorubicin uptake was measured via flow cytometry. After one cycle of triple exposure, the viability of HT-29 cells was significantly reduced versus the untreated control (65.11 ± 5%, p < 0.0001) and versus only chemotherapy (61.2 ± 7%, p < 0.0001). An increased chemotherapeutic inflow into the cells after triple exposure was detected (53.4 ± 11%) when compared to cells treated with chemotherapy alone (34.23 ± 10%) (p < 0.001). Partial dehydration in a hyperthermic condition combined with chemotherapy increases the overall cytotoxicity of colon cancer cells significantly compared to chemotherapy alone. This could possibly be related to enhanced intracellular uptake of chemotherapeutic agents after partial dehydration. Further studies are required for the further evaluation of this new concept. Full article
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13 pages, 3039 KiB  
Review
Honey-Related Treatment Strategies in Dry Eye Disease
by Julia Prinz, Nicola Maffulli, Matthias Fuest, Peter Walter, Frank Hildebrand and Filippo Migliorini
Pharmaceuticals 2023, 16(5), 762; https://doi.org/10.3390/ph16050762 - 18 May 2023
Cited by 4 | Viewed by 2447
Abstract
This systematic review and meta-analysis investigated whether honey-related treatment strategies improve the signs and symptoms of patients with dry eye disease (DED). In March 2023, the following databases were accessed for clinical trials investigating the efficacy of honey-related treatment strategies in DED: PubMed, [...] Read more.
This systematic review and meta-analysis investigated whether honey-related treatment strategies improve the signs and symptoms of patients with dry eye disease (DED). In March 2023, the following databases were accessed for clinical trials investigating the efficacy of honey-related treatment strategies in DED: PubMed, Web of Science, Google Scholar, and EMBASE. The following data were extracted at baseline and at the last follow-up: Ocular Surface Disease Index, tear breakup time, Schirmer I test, and corneal staining. Data from 323 patients were retrieved (53.3% female, mean age 40.6 ± 18.1 years). The mean follow-up was 7.0 ± 4.2 weeks. All the endpoints of interest significantly improved from baseline to the last follow-up: tear breakup time (p = 0.01), Ocular Surface Disease Index (p < 0.0001), Schirmer I test (p = 0.0001), and corneal staining (p < 0.0001). No difference was found in tear breakup time (p = 0.3), Ocular Surface Disease Index (p = 0.4), Schirmer I test (p = 0.3), and corneal staining (p = 0.3) between the honey-related treatment strategies and the control groups. According to our main results, honey-related treatment strategies are effective and feasible to improve symptoms and signs of DED. Full article
(This article belongs to the Topic New Challenges in Ocular Drug Delivery)
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12 pages, 2413 KiB  
Article
SIRT1 Signaling Is Involved in the Vascular Improvement Induced by Moringa Oleifera Seeds during Aging
by Valeria Conti, Joseph Iharinjaka Randriamboavonjy, Herintsoa Rafatro, Valentina Manzo, Jessica Dal Col, Amelia Filippelli, Graziamaria Corbi and Angela Tesse
Pharmaceuticals 2023, 16(5), 761; https://doi.org/10.3390/ph16050761 - 18 May 2023
Cited by 1 | Viewed by 1639
Abstract
Vascular aging is linked to reduce NO bioavailability, endothelial dysfunction, oxidative stress, and inflammation. We previously showed that a 4-week treatment of middle-aged Wistar rats (MAWRs, 46 weeks old) with Moringa oleifera seed powder (MOI, 750 mg/kg/day) improved vascular function. Here, we investigated [...] Read more.
Vascular aging is linked to reduce NO bioavailability, endothelial dysfunction, oxidative stress, and inflammation. We previously showed that a 4-week treatment of middle-aged Wistar rats (MAWRs, 46 weeks old) with Moringa oleifera seed powder (MOI, 750 mg/kg/day) improved vascular function. Here, we investigated the involvement of SIRT1 in MOI-induced vascular improvement. MAWRs were treated with a standard or MOI-containing diet. Young rats (YWR, 16 weeks old) were the controls and received a standard diet. The hearts and aortas were harvested to evaluate SIRT1 and FOXO1 expression via Western blot and/or immunostaining, SIRT1 activity via a fluorometric assay, and oxidative stress using the DHE fluorescent probe. In the hearts and aortas, SIRT1 expression, reduced in MAWRs compared to YWRs, was enhanced in MOI MAWRs. In the hearts, SIRT1 activity did not differ between YWRs and MAWRs, whereas it was increased in MOI MAWRs compared with them. In the aortas, SIRT1 activity decreased in MAWRs, and it was similar in the MOI MAWRs and YWRs. FOXO1 expression increased in the nuclei of MAWR aortas compared to YWR and was reversed in MOI MAWRs. Interestingly, MOI treatment normalized oxidative stress enhanced in MAWRs, in both the heart and aorta. These results demonstrate the protective role of MOI against cardiovascular dysfunction due to aging via enhanced SIRT1 function and subsequently reduced oxidative stress. Full article
(This article belongs to the Special Issue Antioxidants in the Processes of Retarding Ageing)
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10 pages, 511 KiB  
Review
Insulin-like Growth Factor-1 (IGF-1) Related Drugs in Pain Management
by Seokhyun Jin and Jianguo Cheng
Pharmaceuticals 2023, 16(5), 760; https://doi.org/10.3390/ph16050760 - 18 May 2023
Viewed by 2539
Abstract
Objective. The aim of this review is to explore the role of IGF-1 and IGF-1R inhibitors in pain-related conditions and assess the effectiveness of IGF-1-related drugs in pain management. Specifically, this paper investigates the potential involvement of IGF-1 in nociception, nerve regeneration, [...] Read more.
Objective. The aim of this review is to explore the role of IGF-1 and IGF-1R inhibitors in pain-related conditions and assess the effectiveness of IGF-1-related drugs in pain management. Specifically, this paper investigates the potential involvement of IGF-1 in nociception, nerve regeneration, and the development of neuropathic pain. Methods. We conducted a search of the PUBMED/MEDLINE database, Scopus, and the Cochrane Library for all reports published in English on IGF-1 in pain management from origination through November 2022. The resulting 545 articles were screened, and 18 articles were found to be relevant after reading abstracts. After further examination of the full text of these articles, ten were included in the analysis and discussion. The levels of clinical evidence and implications for recommendations of all the included human studies were graded. Results. The search yielded 545 articles, of which 316 articles were deemed irrelevant by reading the titles. There were 18 articles deemed relevant after reading abstracts, of which 8 of the reports were excluded due to lack of IGF-1-related drug treatment after reviewing the full text of the articles. All ten articles were retrieved for analysis and discussion. We found that IGF-1 may have several positive effects on pain management, including promoting the resolution of hyperalgesia, preventing chemotherapy-induced neuropathy, reversing neuronal hyperactivity, and elevating the nociceptive threshold. On the other hand, IGF-1R inhibitors may alleviate pain in mice with injury of the sciatic nerve, bone cancer pain, and endometriosis-induced hyperalgesia. While one study showed marked improvement in thyroid-associated ophthalmopathy in humans treated with IGF-1R inhibitor, two other studies did not find any benefits from IGF-1 treatment. Conclusions. This review highlights the potential of IGF-1 and IGF-1R inhibitors in pain management, but further research is needed to fully understand their efficacy and potential side effects. Full article
(This article belongs to the Special Issue Insulin-Like Growth Factor-1 (IGF-1) Receptor as Drug Targets)
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13 pages, 1320 KiB  
Article
The Relationship between Character Traits and In Vivo Cerebral Serotonin Transporter Availability in Healthy Subjects: A High-Resolution PET Study with C-11 DASB
by Jeong-Hee Kim, Hang-Keun Kim, Sang-Wha Lee, Young-Don Son and Jong-Hoon Kim
Pharmaceuticals 2023, 16(5), 759; https://doi.org/10.3390/ph16050759 - 18 May 2023
Viewed by 1223
Abstract
To elucidate the potential roles of serotonergic activity in human character traits (i.e., self-directedness, cooperativeness, and self-transcendence), we investigated the relationship between these character traits and serotonin transporter (5-HTT) in healthy subjects. Twenty-four participants underwent High-Resolution Research Tomograph–positron emission tomography scans with [ [...] Read more.
To elucidate the potential roles of serotonergic activity in human character traits (i.e., self-directedness, cooperativeness, and self-transcendence), we investigated the relationship between these character traits and serotonin transporter (5-HTT) in healthy subjects. Twenty-four participants underwent High-Resolution Research Tomograph–positron emission tomography scans with [11C]DASB. To quantify 5-HTT availability, binding potential (BPND) of [11C]DASB was obtained using the simplified reference tissue model. The Temperament and Character Inventory was used to assess subjects’ levels of three character traits. There were no significant correlations between the three character traits. Self-directedness was significantly positively correlated with [11C]DASB BPND in the left hippocampus, left middle occipital gyrus, bilateral superior parietal gyrus, left inferior parietal gyrus, left middle temporal gyrus (MTG), and left inferior temporal gyrus (ITG). Cooperativeness was significantly negatively correlated with [11C]DASB BPND in the median raphe nucleus. Self-transcendence was significantly negatively correlated with [11C]DASB BPND in the right MTG and right ITG. Our results show significant correlations between the three character traits and 5-HTT availability in specific brain regions. In particular, self-directedness was significantly positively correlated with 5-HTT availability, suggesting that a goal-oriented, self-confident, and resourceful character may be related to higher serotonergic neurotransmission. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Serotonin and Its Receptors)
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26 pages, 3952 KiB  
Article
Structure Optimization of 12β-O-γ-Glutamyl Oleanolic Acid Derivatives Resulting in Potent FXR Antagonist/Modulator for NASH Therapy
by Hao Ma, Yunyang Bao, Shuaishuai Niu, Shaorong Wang, Yiming Li, Hongwei He, Na Zhang and Weishuo Fang
Pharmaceuticals 2023, 16(5), 758; https://doi.org/10.3390/ph16050758 - 17 May 2023
Cited by 4 | Viewed by 1901
Abstract
The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense [...] Read more.
The farnesoid X receptor (FXR) plays a crucial role in regulating the metabolism of bile acids, lipids, and sugars. Consequently, it is implicated in the treatment of various diseases, including cholestasis, diabetes, hyperlipidemia, and cancer. The advancement of novel FXR modulators holds immense importance, especially in managing metabolic disorders. In this study, a series of oleanolic acid (OA) derivatives bearing 12β-O-(γ-glutamyl) groups were designed and synthesized. Using a yeast one-hybrid assay, we established a preliminary structure–activity relationship (SAR) and identified the most potent compound, 10b, which selectively antagonizes FXR over other nuclear receptors. Compound 10b can differentially modulate the downstream genes of FXR, including with the upregulation of the CYP7A1 gene. In vivo testing revealed that 10b (100 mg·Kg−1) not only effectively inhibits lipid accumulation in the liver but also prevents liver fibrosis in both BDL rats and HFD mice. Molecular modeling indicated that the branched substitution of 10b extends into the H11–H12 region of FXR-LBD, possibly accounting for its CYP7A1 upregulation, which is different from a known OA 12β-alkonate. These findings suggest that 12-glutamyl OA derivative 10b represents a promising candidate for the treatment of nonalcoholic steatohepatitis (NASH). Full article
(This article belongs to the Section Medicinal Chemistry)
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16 pages, 3084 KiB  
Article
MKX-AS1 Gene Expression Associated with Variation in Drug Response to Oxaliplatin and Clinical Outcomes in Colorectal Cancer Patients
by Ricardo D. Gonzalez, George W. Small, Adrian J. Green, Farida S. Akhtari, Alison A. Motsinger-Reif, Julia C. F. Quintanilha, Tammy M. Havener, David M. Reif, Howard L. McLeod and Tim Wiltshire
Pharmaceuticals 2023, 16(5), 757; https://doi.org/10.3390/ph16050757 - 17 May 2023
Cited by 1 | Viewed by 1833
Abstract
Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene MKX-AS1 and partnered sense gene MKX could impact the response of genetically varied cell [...] Read more.
Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene MKX-AS1 and partnered sense gene MKX could impact the response of genetically varied cell lines to OXAL treatment. This study found that the expression levels of MKX-AS1 and MKX in lymphocytes (LCLs) and CRC cell lines differed between the rs11006706 genotypes, indicating that this gene pair could play a role in OXAL response. Further analysis of patient survival data from the Cancer Genome Atlas (TCGA) and other sources showed that patients with high MKX-AS1 expression status had significantly worse overall survival (HR = 3.2; 95%CI = (1.17–9); p = 0.024) compared to cases with low MKX-AS1 expression status. Alternatively, high MKX expression status had significantly better overall survival (HR = 0.22; 95%CI = (0.07–0.7); p = 0.01) compared to cases with low MKX expression status. These results suggest an association between MKX-AS1 and MKX expression status that could be useful as a prognostic marker of response to OXAL and potential patient outcomes in CRC. Full article
(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)
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20 pages, 7315 KiB  
Article
Screening and Elucidation of Chemical Structures of Novel Mammalian α-Glucosidase Inhibitors Targeting Anti-Diabetes Drug from Herbals Used by E De Ethnic Tribe in Vietnam
by Van Bon Nguyen, San-Lang Wang, Tu Quy Phan, Thi Huyen Thoa Pham, Hung-Tse Huang, Chia-Ching Liaw and Anh Dzung Nguyen
Pharmaceuticals 2023, 16(5), 756; https://doi.org/10.3390/ph16050756 - 17 May 2023
Cited by 3 | Viewed by 1565
Abstract
Among ten extracts of indigenous medicinal plants, the MeOH extract of Terminalia triptera Stapf. (TTS) showed the most efficient mammalian α-glucosidase inhibition for the first time. The data of screening bioactive parts used indicated that the TTS trunk bark and leaves extracts demonstrated [...] Read more.
Among ten extracts of indigenous medicinal plants, the MeOH extract of Terminalia triptera Stapf. (TTS) showed the most efficient mammalian α-glucosidase inhibition for the first time. The data of screening bioactive parts used indicated that the TTS trunk bark and leaves extracts demonstrated comparable and higher effects compared to acarbose, a commercial anti-diabetic drug, with half-maximal inhibitory concentration (IC50) values of 181, 331, and 309 µg/mL, respectively. Further bioassay-guided purification led to the isolation of three active compounds from the TTS trunk bark extract and identified as (−)-epicatechin (1), eschweilenol C (2), and gallic acid (3). Of these, compounds 1 and 2 were determined as novel and potent mammalian α-glucosidase inhibitors. The virtual study indicated that these compounds bind to α-glucosidase (Q6P7A9) with acceptable RMSD values (1.16–1.56 Å) and good binding energy (DS values in the range of −11.4 to −12.8 kcal/mol) by interacting with various prominent amino acids to generate five and six linkages, respectively. The data of Lipinski’s rule of five and absorption, distribution, metabolism, excretion and toxicity (ADMET)-based pharmacokinetics and pharmacology revealed that these purified compounds possess anti-diabetic drug properties, and the compounds are almost not toxic for human use. Thus, the findings of this work suggested that (−)-epicatechin and eschweilenol C are novel potential mammalian α-glucosidase inhibitor candidates for type 2 diabetes treatment. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
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18 pages, 11544 KiB  
Article
Resveratrol Enhances Cytotoxic Effects of Cisplatin by Inducing Cell Cycle Arrest and Apoptosis in Ovarian Adenocarcinoma SKOV-3 Cells through Activating the p38 MAPK and Suppressing AKT
by Phateep Hankittichai, Phatarawat Thaklaewphan, Nitwara Wikan, Jirapak Ruttanapattanakul, Saranyapin Potikanond, Duncan R. Smith and Wutigri Nimlamool
Pharmaceuticals 2023, 16(5), 755; https://doi.org/10.3390/ph16050755 - 17 May 2023
Cited by 4 | Viewed by 2367
Abstract
In the current study, we identified a mechanism of resveratrol (RES) underlying its anti-cancer properties against human ovarian adenocarcinoma SKOV-3 cells. We investigated its anti-proliferative and apoptosis-inducing effects in combination with cisplatin, using cell viability assay, flow cytometry, immunofluorescence study and Western blot [...] Read more.
In the current study, we identified a mechanism of resveratrol (RES) underlying its anti-cancer properties against human ovarian adenocarcinoma SKOV-3 cells. We investigated its anti-proliferative and apoptosis-inducing effects in combination with cisplatin, using cell viability assay, flow cytometry, immunofluorescence study and Western blot analysis. We discovered that RES suppressed cancer cell proliferation and stimulated apoptosis, especially when combined with cisplatin. This compound also inhibited SKOV-3 cell survival, which may partly be due to its potential to inhibit protein kinase B (AKT) phosphorylation and induce the S-phase cell cycle arrest. RES in combination with cisplatin strongly induced cancer cell apoptosis through activating the caspase-dependent cascade, which was associated with its ability to stimulate nuclear phosphorylation of p38 mitogen-activated protein kinase (MAPK), well recognized to be involved in transducing environmental stress signals. RES-induced p38 phosphorylation was very specific, and the activation status of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) was not mainly affected. Taken together, our study provides accumulated evidence that RES represses proliferation and promotes apoptosis in SKOV-3 ovarian cancer cells through activating the p38 MAPK pathway. It is interesting that this active compound may be used as an effective agent to sensitize ovarian cancer to apoptosis induced by standard chemotherapies. Full article
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12 pages, 1128 KiB  
Review
RadioLigand Therapy with [177Lu]Lu-PSMA-617 for Salivary Gland Cancers: Literature Review and First Compassionate Use in France
by Marie Terroir, Chloé Lamesa, Mehdi Krim, Lavinia Vija, Jean-Sébastien Texier, Thibaut Cassou-Mounat, Jean-Pierre Delord, Delphine Vallot and Frédéric Courbon
Pharmaceuticals 2023, 16(5), 754; https://doi.org/10.3390/ph16050754 - 16 May 2023
Cited by 3 | Viewed by 1829
Abstract
Salivary gland cancers are rare tumors comprising a large group of heterogeneous tumors with variable prognosis. Their therapeutic management at a metastatic stage is challenging due to the lack of therapeutic lines and the toxicity of treatments. [177Lu]Lu-PSMA-617 (prostate-specific membrane antigen) [...] Read more.
Salivary gland cancers are rare tumors comprising a large group of heterogeneous tumors with variable prognosis. Their therapeutic management at a metastatic stage is challenging due to the lack of therapeutic lines and the toxicity of treatments. [177Lu]Lu-PSMA-617 (prostate-specific membrane antigen) is a vectored radioligand therapy (RLT) initially developed to treat castration-resistant metastatic prostate cancer with encouraging results in terms of efficacy and toxicity. Many malignant cells could be treated with [177Lu]Lu-PSMA-617 as long as they express PSMA as a consequence of androgenic pathway activation. RLT may be used when anti-androgen hormonal treatment has failed, particularly in prostate cancer. [177Lu]Lu-PSMA-617 has been proposed in certain salivary gland cancers, though the expression of PSMA is demonstrated by a significant uptake using [68Ga]Ga-PSMA-11 PET scan. This theranostic approach could be a new therapeutic option, warranting prospective investigation in a larger cohort. We review the literature on this subject and offer a clinical illustration of compassionate use in France as a perspective for administering [177Lu]Lu-PSMA-617 in salivary gland cancer. Full article
(This article belongs to the Special Issue PSMA Targeted Imaging and Radiation Therapy)
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21 pages, 3138 KiB  
Article
Dapagliflozin Ameliorates Cognitive Impairment in Aluminum-Chloride-Induced Alzheimer’s Disease via Modulation of AMPK/mTOR, Oxidative Stress and Glucose Metabolism
by Waad A. Samman, Salma M. Selim, Hassan M. El Fayoumi, Norhan M. El-Sayed, Eman T. Mehanna and Reem M. Hazem
Pharmaceuticals 2023, 16(5), 753; https://doi.org/10.3390/ph16050753 - 16 May 2023
Cited by 9 | Viewed by 2914
Abstract
Alzheimer’s disease (AD) is a progressive neurological illness characterized by memory loss and cognitive deterioration. Dapagliflozin was suggested to attenuate the memory impairment associated with AD; however, its mechanisms were not fully elucidated. This study aims to examine the possible mechanisms of the [...] Read more.
Alzheimer’s disease (AD) is a progressive neurological illness characterized by memory loss and cognitive deterioration. Dapagliflozin was suggested to attenuate the memory impairment associated with AD; however, its mechanisms were not fully elucidated. This study aims to examine the possible mechanisms of the neuroprotective effects of dapagliflozin against aluminum chloride (AlCl3)-induced AD. Rats were distributed into four groups: group 1 received saline, group 2 received AlCl3 (70 mg/kg) daily for 9 weeks, and groups 3 and 4 were administered AlCl3 (70 mg/kg) daily for 5 weeks. Dapagliflozin (1 mg/kg) and dapagliflozin (5 mg/kg) were then given daily with AlCl3 for another 4 weeks. Two behavioral experiments were performed: the Morris Water Maze (MWM) and the Y-maze spontaneous alternation (Y-maze) task. Histopathological alterations in the brain, as well as changes in acetylcholinesterase (AChE) and amyloid β (Aβ) peptide activities and oxidative stress (OS) markers, were all evaluated. A western blot analysis was used for the detection of phosphorylated 5’ AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of Rapamycin (p-mTOR) and heme oxygenase-1 (HO-1). Tissue samples were collected for the isolation of glucose transporters (GLUTs) and glycolytic enzymes using PCR analysis, and brain glucose levels were also measured. The current data demonstrate that dapagliflozin represents a possible approach to combat AlCl3-induced AD in rats through inhibiting oxidative stress, enhancing glucose metabolism and activating AMPK signaling. Full article
(This article belongs to the Special Issue New Perspective in Alzheimer's Disease Treatment)
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14 pages, 3172 KiB  
Article
Network Biology-Inspired Machine Learning Features Predict Cancer Gene Targets and Reveal Target Coordinating Mechanisms
by Taylor M. Weiskittel, Andrew Cao, Kevin Meng-Lin, Zachary Lehmann, Benjamin Feng, Cristina Correia, Cheng Zhang, Philip Wisniewski, Shizhen Zhu, Choong Yong Ung and Hu Li
Pharmaceuticals 2023, 16(5), 752; https://doi.org/10.3390/ph16050752 - 16 May 2023
Cited by 1 | Viewed by 1894
Abstract
Anticipating and understanding cancers’ need for specific gene activities is key for novel therapeutic development. Here we utilized DepMap, a cancer gene dependency screen, to demonstrate that machine learning combined with network biology can produce robust algorithms that both predict what genes a [...] Read more.
Anticipating and understanding cancers’ need for specific gene activities is key for novel therapeutic development. Here we utilized DepMap, a cancer gene dependency screen, to demonstrate that machine learning combined with network biology can produce robust algorithms that both predict what genes a cancer is dependent on and what network features coordinate such gene dependencies. Using network topology and biological annotations, we constructed four groups of novel engineered machine learning features that produced high accuracies when predicting binary gene dependencies. We found that in all examined cancer types, F1 scores were greater than 0.90, and model accuracy remained robust under multiple hyperparameter tests. We then deconstructed these models to identify tumor type-specific coordinators of gene dependency and identified that in certain cancers, such as thyroid and kidney, tumors’ dependencies are highly predicted by gene connectivity. In contrast, other histologies relied on pathway-based features such as lung, where gene dependencies were highly predictive by associations with cell death pathway genes. In sum, we show that biologically informed network features can be a valuable and robust addition to predictive pharmacology models while simultaneously providing mechanistic insights. Full article
(This article belongs to the Section Pharmacology)
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19 pages, 3232 KiB  
Article
Assessment of Aptamer as a Potential Drug Targeted Delivery for Retinal Angiogenesis Inhibition
by David Moreira, Jéssica Lopes-Nunes, Fátima Milhano Santos, Maria Paula Cabral Campello, Maria Cristina Oliveira, António Paulo, Cândida Tomaz and Carla Cruz
Pharmaceuticals 2023, 16(5), 751; https://doi.org/10.3390/ph16050751 - 16 May 2023
Cited by 3 | Viewed by 2173
Abstract
AT11-L0 is an aptamer derivative of AS1411 composed of G-rich sequences that can adopt a G-quadruplex (G4) structure and target nucleolin (NCL), a protein that acts as a co-receptor for several growth factors. Hence, this study aimed to characterize the AT11-L0 G4 structure [...] Read more.
AT11-L0 is an aptamer derivative of AS1411 composed of G-rich sequences that can adopt a G-quadruplex (G4) structure and target nucleolin (NCL), a protein that acts as a co-receptor for several growth factors. Hence, this study aimed to characterize the AT11-L0 G4 structure and its interaction with several ligands for NCL targeting and to evaluate their capacity to inhibit angiogenesis using an in vitro model. The AT11-L0 aptamer was then used to functionalize drug-associated liposomes to increase the bioavailability of the aptamer-based drug in the formulation. Biophysical studies, such as nuclear magnetic resonance, circular dichroism, and fluorescence titrations, were performed to characterize the liposomes functionalized with the AT11-L0 aptamer. Finally, these liposome formulations with the encapsulated drugs were tested on the human umbilical vein endothelial cell (HUVEC) model to assess their antiangiogenic capacity. The results showed that the AT11-L0 aptamer–ligand complexes are highly stable, presenting melting temperatures from 45 °C to 60 °C, allowing for efficient targeting of NCL with a KD in the order of nM. The aptamer-functionalized liposomes loaded with ligands C8 and dexamethasone did not show cytotoxic effects in HUVEC cells compared with the free ligands and AT11-L0, as assessed by cell viability assays. AT11-L0 aptamer-functionalized liposomes encapsulating C8 and dexamethasone did not present a significant reduction in the angiogenic process when compared with the free ligands. In addition, AT11-L0 did not show anti-angiogenic effects at the concentrations tested. However, C8 shows potential as an angiogenesis inhibitor, which should be further developed and optimized in future experiments. Full article
(This article belongs to the Special Issue Potential of the Aptamers to Fill Therapeutic and Diagnostic Gaps)
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16 pages, 1376 KiB  
Review
Effects of Lipid-Modifying and Other Drugs on Lipoprotein(a) Levels—Potent Clinical Implications
by Amalia Despoina Koutsogianni, George Liamis, Evangelos Liberopoulos, Petros Spyridonas Adamidis and Matilda Florentin
Pharmaceuticals 2023, 16(5), 750; https://doi.org/10.3390/ph16050750 - 16 May 2023
Cited by 6 | Viewed by 3092
Abstract
The past few years have shown an ongoing interest in lipoprotein(a) (Lp(a)), a lipid molecule that has been proven to have atherogenic, thrombogenic, and inflammatory properties. Several lines of evidence, indeed, have demonstrated an increased risk of cardiovascular disease as well as calcific [...] Read more.
The past few years have shown an ongoing interest in lipoprotein(a) (Lp(a)), a lipid molecule that has been proven to have atherogenic, thrombogenic, and inflammatory properties. Several lines of evidence, indeed, have demonstrated an increased risk of cardiovascular disease as well as calcific aortic valve stenosis in patients with elevated Lp(a) levels. Statins, the mainstay of lipid-lowering therapy, slightly increase Lp(a) levels, while most other lipid-modifying agents do not significantly alter Lp(a) concentrations, except for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The latter have been shown to reduce Lp(a) levels; however, the clinical significance of this effect has not been clearly elucidated. Of note, the pharmaceutical lowering of Lp(a) may be achieved with novel treatments specifically designed for this purpose (i.e., antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)). Large clinical trials with cardiovascular outcomes with these agents are ongoing, and their results are eagerly awaited. Furthermore, several non-lipid-modifying drugs of various classes may influence Lp(a) concentrations. We have searched MEDLINE, EMBASE, and CENTRAL databases up to 28 January 2023 and summarized the effects of established and emerging lipid-modifying drugs and other medications on Lp(a) levels. We also discuss the potent clinical implications of these alterations. Full article
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21 pages, 6972 KiB  
Article
S-72, a Novel Orally Available Tubulin Inhibitor, Overcomes Paclitaxel Resistance via Inactivation of the STING Pathway in Breast Cancer
by Zhenyan Hou, Songwen Lin, Tingting Du, Mingjin Wang, Weida Wang, Shen You, Nina Xue, Yichen Liu, Ming Ji, Heng Xu and Xiaoguang Chen
Pharmaceuticals 2023, 16(5), 749; https://doi.org/10.3390/ph16050749 - 15 May 2023
Cited by 1 | Viewed by 2102
Abstract
Microtubule-targeting agents are widely used as active anticancer drugs. However, drug resistance always emerges after their long-term use, especially in the case of paclitaxel, which is the cornerstone of all subtypes of breast cancer treatment. Hence, the development of novel agents to overcome [...] Read more.
Microtubule-targeting agents are widely used as active anticancer drugs. However, drug resistance always emerges after their long-term use, especially in the case of paclitaxel, which is the cornerstone of all subtypes of breast cancer treatment. Hence, the development of novel agents to overcome this resistance is vital. This study reports on a novel, potent, and orally bioavailable tubulin inhibitor called S-72 and evaluated its preclinical efficacy in combating paclitaxel resistance in breast cancer and the molecular mechanisms behind it. We found that S-72 suppresses the proliferation, invasion and migration of paclitaxel-resistant breast cancer cells in vitro and displays desirable antitumor activities against xenografts in vivo. As a characterized tubulin inhibitor, S-72 typically inhibits tubulin polymerization and further triggers mitosis-phase cell cycle arrest and cell apoptosis, in addition to suppressing STAT3 signaling. Further studies showed that STING signaling is involved in paclitaxel resistance, and S-72 blocks STING activation in paclitaxel-resistant breast cancer cells. This effect further restores multipolar spindle formation and causes deadly chromosomal instability in cells. Our study offers a promising novel microtubule-destabilizing agent for paclitaxel-resistant breast cancer treatment as well as a potential strategy that can be used to improve paclitaxel sensitivity. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 1981 KiB  
Article
The Potential of Epigallocatechin-3-gallate (EGCG) as Complementary Medicine for the Treatment of Inflammatory Bowel Disease
by Sabrina Schnur, Fabian Hans, Annika Dehne, Janina Osti, Malte-Ole Schneemann, Marc Schneider and Marius Hittinger
Pharmaceuticals 2023, 16(5), 748; https://doi.org/10.3390/ph16050748 - 14 May 2023
Cited by 1 | Viewed by 2242
Abstract
Complementary and alternative medicine has the potential to enrich conventional therapy to improve the treatment of various diseases. Patients that suffer from inflammatory bowel disease, which requires a constant need for medication, have to deal with the adverse effects of repeated application. Natural [...] Read more.
Complementary and alternative medicine has the potential to enrich conventional therapy to improve the treatment of various diseases. Patients that suffer from inflammatory bowel disease, which requires a constant need for medication, have to deal with the adverse effects of repeated application. Natural products such as Epigallocatechin-3-gallate (EGCG) possess the potential to improve symptoms of inflammatory diseases. We investigated the efficacy of EGCG on an inflamed co-culture model simulating IBD and compared it to the efficacies of four commonly applied active pharmaceutical ingredients. EGCG (200 µg/mL) strongly stabilized the TEER value of the inflamed epithelial barrier to 165.7 ± 4.6% after 4 h. Moreover, the full barrier integrity was maintained even after 48 h. This corresponds to the immunosuppressant 6-Mercaptopurin and the biological drug Infliximab. The EGCG treatment significantly decreased the release of the pro-inflammatory cytokines IL-6 (to 0%) and IL-8 (to 14.2%), similar to the effect of the corticosteroid Prednisolone. Therefore, EGCG has a high potential to be deployed as complementary medicine in IBD. In future studies, the improvement of EGCG stability is a key factor in increasing the bioavailability in vivo and fully harnessing the health-improving effects of EGCG. Full article
(This article belongs to the Special Issue Bioactive Substances, Oxidative Stress, and Inflammation)
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25 pages, 6323 KiB  
Review
Neuropharmacological Potential of Diterpenoid Alkaloids
by Arash Salehi, Mustafa Ghanadian, Behzad Zolfaghari, Amir Reza Jassbi, Maryam Fattahian, Parham Reisi, Dezső Csupor, Ikhlas A. Khan and Zulfiqar Ali
Pharmaceuticals 2023, 16(5), 747; https://doi.org/10.3390/ph16050747 - 14 May 2023
Cited by 3 | Viewed by 2194
Abstract
This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of Aconitum and Delphinium (Ranunculaceae). DAs have long been a focus of research attention due to their numerous intricate structures and [...] Read more.
This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of Aconitum and Delphinium (Ranunculaceae). DAs have long been a focus of research attention due to their numerous intricate structures and diverse biological activities, especially in the central nervous system (CNS). These alkaloids originate through the amination reaction of tetra or pentacyclic diterpenoids, which are classified into three categories and 46 types based on the number of carbon atoms in the backbone structure and structural differences. The main chemical characteristics of DAs are their heterocyclic systems containing β-aminoethanol, methylamine, or ethylamine functionality. Although the role of tertiary nitrogen in ring A and the polycyclic complex structure are of great importance in drug-receptor affinity, in silico studies have emphasized the role of certain sidechains in C13, C14, and C8. DAs showed antiepileptic effects in preclinical studies mostly through Na+ channels. Aconitine (1) and 3-acetyl aconitine (2) can desensitize Na+ channels after persistent activation. Lappaconitine (3), N-deacetyllapaconitine (4), 6-benzoylheteratisine (5), and 1-benzoylnapelline (6) deactivate these channels. Methyllycaconitine (16), mainly found in Delphinium species, possesses an extreme affinity for the binding sites of α7 nicotinic acetylcholine receptors (nAChR) and contributes to a wide range of neurologic functions and the release of neurotransmitters. Several DAs such as bulleyaconitine A (17), (3), and mesaconitine (8) from Aconitum species have a drastic analgesic effect. Among them, compound 17 has been used in China for decades. Their effect is explained by increasing the release of dynorphin A, activating the inhibitory noradrenergic neurons in the β-adrenergic system, and preventing the transmission of pain messages by inactivating the Na+ channels that have been stressed. Acetylcholinesterase inhibitory, neuroprotective, antidepressant, and anxiolytic activities are other CNS effects that have been investigated for certain DAs. However, despite various CNS effects, recent advances in developing new drugs from DAs were insignificant due to their neurotoxicity. Full article
(This article belongs to the Section Natural Products)
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