Reactive Palladium–Ligand Complexes for ¹¹C-Carbonylation at Ambient Pressure: A Breakthrough in Carbon-11 Chemistry
The Skin and Natural Cannabinoids–Topical and Transdermal Applications
Cutaneous Polymeric-Micelles-Based Hydrogel Containing Origanum vulgare L. Essential Oil: In Vitro Release and Permeation, Angiogenesis, and Safety Profile In Ovo

Journal Description

Pharmaceuticals

Pharmaceuticals is a peer-reviewed, open access journal of medicinal chemistry and related drug sciences, published monthly online by MDPI. The Academy of Pharmaceutical Sciences (APS) is partners of Pharmaceuticals and their members receive a discount on the article processing charge.

Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q2 (Pharmacology & Pharmacy) / CiteScore - Q2 (Pharmaceutical Science)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 15.7 days after submission; acceptance to publication is undertaken in 3.6 days (median values for papers published in this journal in the first half of 2023).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Testimonials: See what our editors and authors say about Pharmaceuticals.
International Electronic Conference on Medicinal Chemistry (https://sciforum.net/series/ecmc/latest)
Companion journals for Pharmaceuticals include: Pharmacoepidemiology, Psychoactives and Drugs and Drug Candidates.

Impact Factor: 4.6 (2022); 5-Year Impact Factor: 4.9 (2022)

Imprint Information Journal Flyer Open Access ISSN: 1424-8247

Latest Articles

23 pages, 2366 KiB

Open AccessArticle

In Vitro Anti-Diabetic, Anti-Inflammatory, Antioxidant Activities and Toxicological Study of Optimized Psychotria malayana Jack Leaves Extract

Sharifah Nurul Akilah Syed Mohamad

Alfi Khatib

Siti Zaiton Mat So’ad

Qamar Uddin Ahmed

Zalikha Ibrahim

Tanzina Sharmin Nipun

Humaryanto Humaryanto

Mohamed F. AlAjmi

Shaden A. M. Khalifa

and

Hesham R. El-Seedi

Pharmaceuticals 2023, 16(12), 1692; https://doi.org/10.3390/ph16121692 - 05 Dec 2023

Abstract

Psychotria malayana Jack (Family: Rubiaceae, local name: Salung) is a traditional herb used to treat diabetes. A previous study by our research group demonstrated that P. malayana methanolic and water extract exhibits significant potential as an effective agent for managing diabetes. Further research has been performed on the extraction optimization of this plant to enhance its inhibitory activity against α-glucosidase, a key enzyme associated with diabetes, and to reduce its toxicity. The objectives of this study are to evaluate the anti-diabetic, anti-inflammatory, and antioxidant properties of the optimized P. malayana leaf extract (OE), to evaluate its toxicity using a zebrafish embryo/larvae model, and to analyze its metabolites. The anti-diabetic effects were assessed by investigating α-glucosidase inhibition (AGI), while the inflammation inhibitory activity was performed using the soybean lipoxygenase inhibitory (SLOXI) test. The assessment of antioxidant activity was performed utilizing FRAP and DPPH assays. The toxicology study was conducted using the zebrafish embryo/larvae (Danio rerio) model. The metabolites present in the extracts were analyzed using GC-MS and LC-MS. OE demonstrated significant AGI and SLOXI activities, represented as 2.02 and 4.92 µg/mL for IC₅₀ values, respectively. It exhibited potent antioxidant activities as determined by IC₅₀ values of 13.08 µg/mL (using the DPPH assay) and 95.44 mmol TE/mg DW (using the FRAP assay), and also demonstrated an LC₅₀ value of 224.29 µg/mL, which surpasses its therapeutic index of 111.03. OE exhibited a higher therapeutic index compared to that of the methanol extract (13.84) stated in the previous state of the art. This suggests that OE exhibits a lower level of toxicity, making it safer for use, and has the potential to be highly effective in its anti-diabetic activity. Liquid chromatography–mass spectrometry (LC-MS) and gas chromatography–mass spectrometry (GC-MS) demonstrated the presence of several constituents in this extract. Among them, several compounds, such as propanoic acid, succinic acid, D-tagatose, myo-inositol, isorhamnetin, moracin M-3′-O-β-D-glucopyranoside, procyanidin B3, and leucopelargonidin, have been reported as possessing anti-diabetic and antioxidant activities. This finding offers great potential for future research in diabetes treatment. Full article

(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2023)

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24 pages, 2576 KiB

Open AccessArticle

Procognitive, Anxiolytic, and Antidepressant-like Properties of Hyperoside and Protocatechuic Acid Corresponding with the Increase in Serum Serotonin Level after Prolonged Treatment in Mice

Jolanta Orzelska-Górka

Katarzyna Dos Santos Szewczyk

Monika Gawrońska-Grzywacz

Mariola Herbet

Anna Lesniak

Anna Bielenica

Magdalena Bujalska-Zadrożny

and

Grażyna Biała

Pharmaceuticals 2023, 16(12), 1691; https://doi.org/10.3390/ph16121691 - 05 Dec 2023

Abstract

Two polyphenols–hyperoside (HYP) and protocatechuic acid (PCA) were reported to exert antidepressant activity in rodents after acute treatment. Our previous study also showed that this activity might have been influenced by the monoaminergic system and the upregulation of the brain-derived neurotropic factor (BDNF) level. A very long-term pharmacological therapy is required for the treatment of a patient with depression. The repetitive use of antidepressants is recognized to impact the brain structures responsible for regulating both emotional and cognitive behaviors. Thus, we investigated the antidepressant, anxiolytic, and procognitive effects of HYP and PCA in mice after acute and prolonged treatment (14 days). Both polyphenols induced an anxiogenic-like effect after acute treatment, whereas an anxiolytic effect occurred after repetitive administration. PCA and HYP showed procognitive effects when they were administered acutely and chronically, but it seems that their influence on long-term memory was stronger than on short-term memory. In addition, the preset study showed that the dose of 7.5 mg/kg of PCA and HYP was effective in counteracting the effects of co-administered scopolamine in the long-term memory impairment model induced by scopolamine. Our experiments revealed the compounds have no affinity for 5-HT_1A and 5-HT_2A receptors, whereas a significant increase in serum serotonin level after prolonged administration of PCA and HYP at a dose of 3.75 mg/kg was observed. Thus, it supports the involvement of the serotonergic system in the polyphenol mechanisms. These findings led us to hypothesize that the polyphenols isolated from Impatiens glandulifera can hold promise in treating mental disorders with cognitive dysfunction. Consequently, extended studies are necessary to delve into their pharmacological profile. Full article

(This article belongs to the Section Pharmacology)

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4 pages, 186 KiB

Open AccessEditorial

Special Issue: Evaluation of the Antitumor Mechanism of Armed Antibodies

Yoshikatsu Koga

Hiroki Takashima

and

Shigehiro Koganemaru

Pharmaceuticals 2023, 16(12), 1690; https://doi.org/10.3390/ph16121690 - 05 Dec 2023

Abstract

This Special Issue focuses on the use of therapeutic antibodies in vitro, in vivo, and in clinical studies [...] Full article

(This article belongs to the Special Issue Evaluation of the Antitumor Mechanism of Armed Antibodies)

4 pages, 203 KiB

Open AccessEditorial

Drug Safety and Relevant Issues in the Real-World

Maria Antonietta Barbieri

Natasha Irrera

and

Irma Convertino

Pharmaceuticals 2023, 16(12), 1689; https://doi.org/10.3390/ph16121689 - 05 Dec 2023

Abstract

The global impact of the COVID-19 pandemic has underscored the pivotal role of drug safety and effective communication within the realm of pharmacovigilance, particularly in times of unprecedented public health emergencies [...] Full article

(This article belongs to the Special Issue Drug Safety and Relevant Issues in the Real-World)

34 pages, 30095 KiB

Open AccessArticle

A Computational Method for the Binding Mode Prediction of COX-1 and COX-2 Inhibitors: Analyzing the Union of Coxibs, Oxicams, Propionic and Acetic Acids

Estefany Bello-Vargas

Mario Alberto Leyva-Peralta

Zeferino Gómez-Sandoval

Mario Ordóñez

and

Rodrigo Said Razo-Hernández

Pharmaceuticals 2023, 16(12), 1688; https://doi.org/10.3390/ph16121688 - 04 Dec 2023

Abstract

Among the biological targets extensively investigated to improve inflammation and chronic inflammatory conditions, cyclooxygenase enzymes (COXs) occupy a prominent position. The inhibition of these enzymes, essential for mitigating inflammatory processes, is chiefly achieved through Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). In this work, we introduce a novel method—based on computational molecular docking—that could aid in the structure-based design of new compounds or the description of the anti-inflammatory activity of already-tested compounds. For this, we used eight crystal complexes (four COX-1 and COX-2 each), and each pair had a specific NSAID: Celecoxib, Meloxicam, Ibuprofen, and Indomethacin. This selection was based on the ligand selectivity towards COX-1 or COX-2 and their binding mode. An interaction profile of each NSAID was compiled to detect the residues that are key for their binding mode, highlighting the interaction made by the Me group. Furthermore, we rigorously validated our models based on structural accuracy (RMSD < 1) and (R² > 70) using eight NSAIDs and thirteen compounds with IC₅₀ values for each enzyme. Therefore, this model can be used for the binding mode prediction of small and structurally rigid compounds that work as COX inhibitors or the prediction of new compounds that are designed by means of a structure-based approach. Full article

(This article belongs to the Special Issue Methyl-Containing Pharmaceuticals)

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18 pages, 11400 KiB

Open AccessArticle

Lysicamine Reduces Protein Kinase B (AKT) Activation and Promotes Necrosis in Anaplastic Thyroid Cancer

Mariana Teixeira Rodrigues

Ana Paula Picaro Michelli

Gustavo Felisola Caso

Paloma Ramos de Oliveira

Dorival Mendes Rodrigues-Junior

Mirian Galliote Morale

Joel Machado Júnior

Karina Ramalho Bortoluci

Rodrigo Esaki Tamura

Tamiris Reissa Cipriano da Silva

Cristiano Raminelli

Eric Chau

Biana Godin

Jamile Calil-Silveira

and

Ileana G. Sanchez Rubio

Pharmaceuticals 2023, 16(12), 1687; https://doi.org/10.3390/ph16121687 - 04 Dec 2023

Abstract

Anaplastic thyroid cancer (ATC) is an aggressive form of thyroid cancer (TC), accounting for 50% of total TC-related deaths. Although therapeutic approaches against TC have improved in recent years, the survival rate remains low, and severe adverse effects are commonly reported. However, unexplored alternatives based on natural compounds, such as lysicamine, an alkaloid found in plants with established cytotoxicity against breast and liver cancers, offer promise. Therefore, this study aimed to explore the antineoplastic effects of lysicamine in papillary TC (BCPAP) and ATC (HTH83 and KTC-2) cells. Lysicamine treatment reduced cell viability, motility, colony formation, and AKT activation while increasing the percentage of necrotic cells. The absence of caspase activity confirmed apoptosis-independent cell death. Necrostatin-1 (NEC-1)-mediated necrosome inhibition reduced lysicamine-induced necrosis in KTC-2, suggesting necroptosis induction via a reactive oxygen species (ROS)-independent mechanism. Additionally, in silico analysis predicted lysicamine target proteins, particularly those related to MAPK and TGF-β signaling. Our study demonstrated lysicamine’s potential as an antineoplastic compound in ATC cells with a proposed mechanism related to inhibiting AKT activation and inducing cell death. Full article

(This article belongs to the Special Issue Targeting Thyroid Cancer: From Biology to Therapeutic Strategies)

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14 pages, 5215 KiB

Open AccessArticle

Preliminary Evidence of Efficacy, Safety, and Treatment Satisfaction with Tirbanibulin 1% Ointment: A Clinical Perspective on Actinic Keratoses

and

Pharmaceuticals 2023, 16(12), 1686; https://doi.org/10.3390/ph16121686 - 04 Dec 2023

Abstract

Background: Actinic keratosis is a common precancerous skin lesion that can progress into invasive squamous cell carcinomas. Many topical treatments for actinic keratoses often have poor tolerability and prolonged duration. Tirbanibulin is a novel synthetic drug with potent antitumor and antiproliferative activities. Methods: We conducted a single-center, prospective and observational study using tirbanibulin ointment on a 25 cm² area for 5 consecutive days on 30 participants with AKs on the face or scalp. They were followed for at least 57 days to assess the safety profile and efficacy of the drug as well as treatment satisfaction. We evaluated six signs of local skin reaction (LSR): erythema, scaling, crusting, swelling, blisters/pustules, and erosions/ulcerations, grading the severity as mild, moderate, or severe. The effectiveness was evaluated both clinically and dermoscopically. The treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4). Results: On day 57, 70% of the patients showed a complete clinical and dermoscopic response. The highest scores obtained from the TSQM 1.4 were more evident in the convenience and side effects domains. Most LSRs, including erythema (83.3%), scaling (30%), and swelling (3.3%), occurred on day 8 but resolved spontaneously. Conclusion: Tirbanibulin is a viable therapeutic option with a short regimen treatment and good tolerability, which favors therapy adherence. Full article

(This article belongs to the Special Issue Novel Therapies for the Treatment of Skin Diseases)

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2 pages, 199 KiB

Open AccessCorrection

Correction: Vassallo et al. Hyaluronic Acid-Based Injective Medical Devices: In Vitro Characterization of Novel Formulations Containing Biofermentative Unsulfated Chondroitin or Extractive Sulfated One with Cyclodextrins. Pharmaceuticals 2023, 16, 1429

and

Pharmaceuticals 2023, 16(12), 1685; https://doi.org/10.3390/ph16121685 - 04 Dec 2023

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Hydrogels for Pharmaceutical and Biomedical Applications)

21 pages, 1275 KiB

Open AccessReview

A Critical Interpretive Synthesis of the Role of Arecoline in Oral Carcinogenesis: Is the Local Cholinergic Axis a Missing Link in Disease Pathophysiology?

and

Pharmaceuticals 2023, 16(12), 1684; https://doi.org/10.3390/ph16121684 - 04 Dec 2023

Abstract

Arecoline is the primary active carcinogen found in areca nut and has been implicated in the pathogenesis of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF). For this study, we conducted a stepwise review process by combining iterative scoping reviews with a post hoc search, with the aim of identifying the specific mechanisms by which arecoline initiates and promotes oral carcinogenesis. Our initial search allowed us to define the current trends and patterns in the pathophysiology of arecoline-induced OSF and OSCC, which include the induction of cell proliferation, facilitation of invasion, adhesion, and migration, increased collagen deposition and fibrosis, imbalance in immune and inflammatory mechanisms, and genotoxicity. Key molecular pathways comprise the activation of NOTCH1, MYC, PRDX2, WNT, CYR61, EGFR/Pl3K, DDR1 signaling, and cytokine upregulation. Despite providing a comprehensive overview of potential pathogenic mechanisms of OSF, the involvement of molecules functioning as areca alkaloid receptors, namely, the muscarinic and nicotinic acetylcholine receptors (AChRs), was not elucidated with this approach. Accordingly, our search strategy was refined to reflect these evidence gaps. The results of the second round of reviews with the post hoc search highlighted that arecoline binds preferentially to muscarinic AChRs, which have been implicated in cancer. Consistently, AChRs activate the signaling pathways that partially overlap with those described in the context of arecoline-induced carcinogenesis. In summary, we used a theory-driven interpretive review methodology to inform, extend, and supplement the conventional systematic literature assessment workflow. On the one hand, the results of this critical interpretive synthesis highlighted the prevailing trends and enabled the consolidation of data pertaining to the molecular mechanisms involved in arecoline-induced carcinogenesis, and, on the other, brought up knowledge gaps related to the role of the local cholinergic axis in oral carcinogenesis, thus suggesting areas for further investigation. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 6100 KiB

Open AccessArticle

Pharmacological Nature of the Purinergic P2Y Receptor Subtypes That Participate in the Blood Pressure Changes Produced by ADPβS in Rats

Roberto C. Silva-Velasco

Belinda Villanueva-Castillo

Kristian A. Haanes

Antoinette MaassenVanDenBrink

and

Carlos M. Villalón

Pharmaceuticals 2023, 16(12), 1683; https://doi.org/10.3390/ph16121683 - 03 Dec 2023

Abstract

Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example, adenosine-5′-(β-thio)-diphosphate (ADPβS; a stable synthetic analogue of ADP) can induce vasodilatation/vasodepressor responses by endothelium-dependent and independent mechanisms involving purinergic P2Y receptors; however, the specific subtypes participating in these responses remain unknown. Therefore, this study investigated the receptor subtypes mediating the blood pressure changes induced by intravenous bolus of ADPβS in male Wistar rats in the absence and presence of central mechanisms with the antagonists MRS2500 (P2Y₁), PSB0739 (P2Y₁₂), and MRS2211 (P2Y₁₃). For this purpose, 120 rats were divided into 60 anaesthetised rats and 60 pithed rats, and further subdivided into four groups (n = 30 each), namely: (a) anaesthetised rats, (b) anaesthetised rats with bilateral vagotomy, (c) pithed rats, and (d) pithed rats continuously infused (intravenously) with methoxamine (an α₁-adrenergic agonist that restores systemic vascular tone). We observed, in all four groups, that the immediate decreases in diastolic blood pressure produced by ADPβS were exclusively mediated by peripheral activation of P2Y₁ receptors. Nevertheless, the subsequent increases in systolic blood pressure elicited by ADPβS in pithed rats infused with methoxamine probably involved peripheral activation of P2Y₁, P2Y₁₂, and P2Y₁₃ receptors. Full article

(This article belongs to the Special Issue Adenosine Metabolism-Key Targets in Cardiovascular Pharmacology)

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22 pages, 7019 KiB

Open AccessArticle

Structure-Based Optimization of 1,2,4-Triazole-3-Thione Derivatives: Improving Inhibition of NDM-/VIM-Type Metallo-β-Lactamases and Synergistic Activity on Resistant Bacteria

and

Pharmaceuticals 2023, 16(12), 1682; https://doi.org/10.3390/ph16121682 - 02 Dec 2023

Abstract

The worldwide emergence and dissemination of Gram-negative bacteria expressing metallo-β-lactamases (MBLs) menace the efficacy of all β-lactam antibiotics, including carbapenems, a last-line treatment usually restricted to severe pneumonia and urinary tract infections. Nonetheless, no MBL inhibitor is yet available in therapy. We previously identified a series of 1,2,4-triazole-3-thione derivatives acting as micromolar inhibitors of MBLs in vitro, but devoid of synergistic activity in microbiological assays. Here, via a multidisciplinary approach, including molecular modelling, synthesis, enzymology, microbiology, and X-ray crystallography, we optimized this series of compounds and identified low micromolar inhibitors active against clinically relevant MBLs (NDM-1- and VIM-type). The best inhibitors increased, to a certain extent, the susceptibility of NDM-1- and VIM-4-producing clinical isolates to meropenem. X-ray structures of three selected inhibitors in complex with NDM-1 elucidated molecular recognition at the base of potency improvement, confirmed in silico predicted orientation, and will guide further development steps. Full article

(This article belongs to the Special Issue Antibiotic Resistance in Gram-Negative Bacteria: The Threat from the Pink Corner)

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14 pages, 3217 KiB

Open AccessArticle

Eriocitrin Disrupts Erythrocyte Membrane Asymmetry through Oxidative Stress and Calcium Signaling and the Activation of Casein Kinase 1α and Rac1 GTPase

Sumiah A. Alghareeb

Jawaher Alsughayyir

and

Mohammad A. Alfhili

Pharmaceuticals 2023, 16(12), 1681; https://doi.org/10.3390/ph16121681 - 02 Dec 2023

Abstract

Background: Hemolysis and eryptosis result in the premature elimination of circulating erythrocytes and thus contribute to chemotherapy-related anemia, which is extremely prevalent in cancer patients. Eriocitrin (ERN), a flavanone glycoside in citrus fruits, has shown great promise as an anticancer agent, but the potential toxicity of ERN to human erythrocytes remains unstudied. Methods: Erythrocytes were exposed to anticancer concentrations of ERN (10–100 μM) for 24 h at 37 °C, and hemolysis and associated markers were quantified using colorimetric assays. Eryptosis was assessed by flow cytometric analysis to detect phosphatidylserine (PS) exposure by annexin-V-FITC, intracellular Ca²⁺ using Fluo4/AM, and oxidative stress with 2-,7-dichlorodihydrofluorescin diacetate (H₂DCFDA). ERN was also tested against specific signaling inhibitors and anti-hemolytic agents. Results: ERN caused significant, concentration-dependent hemolysis at 20–100 μM. ERN also significantly increased the percentage of eryptotic cells characterized by Ca²⁺ elevation and oxidative stress. Furthermore, the hemolytic activity of ERN was significantly ameliorated in the presence of D4476, NSC23766, isosmotic urea and sucrose, and polyethylene glycol 8000 (PEG). In whole blood, ERN significantly elevated MCV and ESR, with no appreciable effects on other peripheral blood cells. Conclusions: ERN promotes premature erythrocyte death through hemolysis and eryptosis characterized by PS externalization, Ca²⁺ accumulation, membrane blebbing, loss of cellular volume, and oxidative stress. These toxic effects, mediated through casein kinase 1α and Rac1 GTPase, can be ameliorated by urea, sucrose, and PEG. Altogether, these novel findings are relevant to the further development of ERN as an anticancer therapeutic. Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods with Pharmaceutical Interest 2023)

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14 pages, 2153 KiB

Open AccessArticle

Span 60/Cholesterol Niosomal Formulation as a Suitable Vehicle for Gallic Acid Delivery with Potent In Vitro Antibacterial, Antimelanoma, and Anti-Tyrosinase Activity

and

Pharmaceuticals 2023, 16(12), 1680; https://doi.org/10.3390/ph16121680 - 02 Dec 2023

Abstract

Natural compounds such as gallic acid (GA) have attracted more attention in cosmetic and pharmaceutical skin care products. However, the low solubility and poor stability of GA have limited its application. This study aimed to synthesize and characterize the GA niosomal dispersion (GAN) and investigate the potential of an optimal formulation as a skin drug delivery system for GA. For this purpose, GAN formulations were synthesized using the thin layer evaporation method with different molar ratios of Tween 60/Span 60, along with a constant molar ratio of polyethylene glycol 4000 (PEG-4000) and cholesterol in a methanol and chloroform solvent (1:4 v/v). The physicochemical properties of nanosystems in terms of size, zeta potential, drug entrapment, drug release, morphology, and system–drug interaction were characterized using different methods. In addition, in vitro cytotoxicity, anti-tyrosinase activity, and antibacterial activity were evaluated by MTT assay, the spectrophotometric method, and micro-well dilution assay. All formulations revealed a size of 80–276 nm, polydispersity index (PDI) values below 0.35, and zeta potential values below—9.7 mV. F2 was selected as the optimal formulation due to its smaller size and high stability. The optimal formulation of GAN (F2) was as follows: a 1:1 molar ratio of Span 60 to cholesterol and 1.5 mM GA. The release of the F2 drug showed a biphasic pattern, which was fast in the first 12 h until 58% was released. Our results showed the high antibacterial activity of GAN against Escherichia coli and Pseudomonas aeruginosa. The MTT assay showed that GA encapsulation increased its effect on B6F10 cancer cells. The F2 formulation exhibited potent anti-tyrosinase activity and inhibited melanin synthesis. These findings suggest that it can be used in dermatological skin care products in the cosmetic and pharmaceutical industries due to its significant antibacterial, anti-melanoma, and anti-tyrosinase activity. Full article

(This article belongs to the Special Issue Recent Advances in Skin Drug Delivery)

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20 pages, 1299 KiB

Open AccessReview

Targeted Alpha Therapy: All We Need to Know about ²²⁵Ac’s Physical Characteristics and Production as a Potential Theranostic Radionuclide

Wael Jalloul

Vlad Ghizdovat

Cati Raluca Stolniceanu

Teodor Ionescu

Irena Cristina Grierosu

Ioana Pavaleanu

Mihaela Moscalu

and

Cipriana Stefanescu

Pharmaceuticals 2023, 16(12), 1679; https://doi.org/10.3390/ph16121679 - 02 Dec 2023

Abstract

The high energy of α emitters, and the strong linear energy transfer that goes along with it, lead to very efficient cell killing through DNA damage. Moreover, the degree of oxygenation and the cell cycle state have no impact on these effects. Therefore, α radioisotopes can offer a treatment choice to individuals who are not responding to β− or gamma-radiation therapy or chemotherapy drugs. Only a few α-particle emitters are suitable for targeted alpha therapy (TAT) and clinical applications. The majority of available clinical research involves ²²⁵Ac and its daughter nuclide ²¹³Bi. Additionally, the ²²⁵Ac disintegration cascade generates γ decays that can be used in single-photon emission computed tomography (SPECT) imaging, expanding the potential theranostic applications in nuclear medicine. Despite the growing interest in applying ²²⁵Ac, the restricted global accessibility of this radioisotope makes it difficult to conduct extensive clinical trials for many radiopharmaceutical candidates. To boost the availability of ²²⁵Ac, along with its clinical and potential theranostic applications, this review attempts to highlight the fundamental physical properties of this α-particle-emitting isotope, as well as its existing and possible production methods. Full article

(This article belongs to the Special Issue Therapeutic Radionuclides in Nuclear Medicine)

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14 pages, 5369 KiB

Open AccessArticle

Computational and Experimental Drug Repurposing of FDA-Approved Compounds Targeting the Cannabinoid Receptor CB1

Emanuele Criscuolo

Maria Laura De Sciscio

and

Pharmaceuticals 2023, 16(12), 1678; https://doi.org/10.3390/ph16121678 - 02 Dec 2023

Abstract

The cannabinoid receptor 1 (CB1R) plays a pivotal role in regulating various physiopathological processes, thus positioning itself as a promising and sought-after therapeutic target. However, the search for specific and effective CB1R ligands has been challenging, prompting the exploration of drug repurposing (DR) strategies. In this study, we present an innovative DR approach that combines computational screening and experimental validation to identify potential Food and Drug Administration (FDA)-approved compounds that can interact with the CB1R. Initially, a large-scale virtual screening was conducted using molecular docking simulations, where a library of FDA-approved drugs was screened against the CB1R’s three-dimensional structures. This in silico analysis allowed us to prioritize compounds based on their binding affinity through two different filters. Subsequently, the shortlisted compounds were subjected to in vitro assays using cellular and biochemical models to validate their interaction with the CB1R and determine their functional impact. Our results reveal FDA-approved compounds that exhibit promising interactions with the CB1R. These findings open up exciting opportunities for DR in various disorders where CB1R signaling is implicated. In conclusion, our integrated computational and experimental approach demonstrates the feasibility of DR for discovering CB1R modulators from existing FDA-approved compounds. By leveraging the wealth of existing pharmacological data, this strategy accelerates the identification of potential therapeutics while reducing development costs and timelines. The findings from this study hold the potential to advance novel treatments for a range of CB1R -associated diseases, presenting a significant step forward in drug discovery research. Full article

(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success)

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20 pages, 4586 KiB

Open AccessArticle

Green Synthesis and Characterization of Silver Nanoparticles Using Azadirachta indica Seeds Extract: In Vitro and In Vivo Evaluation of Anti-Diabetic Activity

Abdulwahed Fahad Alrefaei

Mikhlid H. Almutairi

Yong-Sun Moon

and

Sajid Ali

Pharmaceuticals 2023, 16(12), 1677; https://doi.org/10.3390/ph16121677 - 01 Dec 2023

Abstract

Background: Diabetes mellitus (DM) is a non-communicable, life-threatening syndrome that is present all over the world. The use of eco-friendly, cost-effective, and green-synthesised nanoparticles as a medicinal therapy in the treatment of DM is an attractive option. Objective: In the present study, silver nanoparticles (AI-AgNPs) were biosynthesized through the green synthesis method using Azadirachta indica seed extract to evaluate their anti-diabetic potentials. Methods: These nanoparticles were characterized by using UV-visible spectroscopy, Fourier transform infrared spectrophotometers (FTIR), scanning electron microscopy (SEM), DLS, and X-ray diffraction (XRD). The biosynthesized AI-AgNPs and crude extracts of Azadirachta indica seeds were evaluated for anti-diabetic potentials using glucose adsorption assays, glucose uptake by yeast cells assays, and alpha-amylase inhibitory assays. Results: Al-AgNPs showed the highest activity (75 ± 1.528%), while crude extract showed (63 ± 2.5%) glucose uptake by yeast at 80 µg/mL. In the glucose adsorption assay, the highest activity of Al-AgNPs was 10.65 ± 1.58%, while crude extract showed 8.32 ± 0.258% at 30 mM, whereas in the alpha-amylase assay, Al-AgNPs exhibited the maximum activity of 73.85 ± 1.114% and crude extract 65.85 ± 2.101% at 100 µg/mL. The assay results of AI-AgNPs and crude showed substantial dose-dependent activities. Further, anti-diabetic potentials were also investigated in streptozotocin-induced diabetic mice. Mice were administered with AI-AgNPs (10 to 40 mg/kg b.w) for 30 days. Conclusions: The results showed a considerable drop in blood sugar levels, including pancreatic and liver cell regeneration, demonstrating that AI-AgNPs have strong anti-diabetic potential. Full article

(This article belongs to the Special Issue Metal Nanoparticles’ Biological Activity and Pharmaceutical Applications)

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11 pages, 4342 KiB

Open AccessArticle

Efficacy of Selective Internal Radiation Therapy for Hepatocellular Carcinoma Post-Incomplete Response to Chemoembolization

Salma Binzaqr

Frederic Debordeaux

Jean-Frédéric Blanc

Panteleimon Papadopoulos

Elif Hindie

Bruno Lapouyade

and

Jean-Baptiste Pinaquy

Pharmaceuticals 2023, 16(12), 1676; https://doi.org/10.3390/ph16121676 - 01 Dec 2023

Abstract

Hepatocellular carcinoma (HCC) is one of the most common neoplasms worldwide and the third most common cause of cancer-related death. Several liver-targeted intra-arterial therapies are available for unresectable HCC, including selective internal radiation therapy (SIRT) and trans-arterial chemoembolization (TACE). Those two are the most used treatment modalities in localized non-operable HCC. TACE is the treatment option for patients with stage B, according to the BCLC staging system. In contrast, SIRT does not have an official role in the treatment algorithm, but recent studies showed promising outcomes in patients treated with SIRT. Although TACE is globally a safe procedure, it might provoke several vascular complications such as spasms, inflammatory constriction, and, in severe cases, occlusion, dissection, or collateralization. Hence, it is acclaimed that those complications could restrain the targeted response of the radio-embolization when we use it as second-line therapy post TACE. In this study, we will assess the efficacity of SIRT using Yttrium 90 Microspheres post incomplete or failure response to TACE. In our retrospective study, we had 23 patients who met the inclusion criteria. Furthermore, those patients have been followed radiologically and biologically. Then, we evaluated the therapeutic effect according to the mRECIST criteria, in addition to the personalized dose analysis. We found 8 patients were treated with TheraSphere^®, with a median tumor absorbed dose of 445 Gy, while 15 received SIR-Spheres^® treatment with a mean tumor dose of 268 Gy. After radiological analysis, 56.5% of the patients had a complete response, and 17.3% showed partial response, whereas 13% had stable disease and 13% had progressive disease. For patients treated with SIRT after an incomplete response or failure to TACE, we found an objective response rate of 73.8%. Despite the known vascular complications of TACE, SIRT can give a favorable response. Full article

(This article belongs to the Special Issue 20th Anniversary of Pharmaceuticals–Advances in Radiopharmaceutical Sciences and Nuclear Medicine)

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36 pages, 3585 KiB

Open AccessReview

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

and

Pharmaceuticals 2023, 16(12), 1675; https://doi.org/10.3390/ph16121675 - 01 Dec 2023

Abstract

The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Emerging Trends in Biopharmaceuticals)

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4 pages, 235 KiB

Open AccessEditorial

Recent Advances in Polymers as Matrices for Drug Delivery Applications

Zoilo González

Ana Ferrandez-Montero

and

Juan Domínguez-Robles

Pharmaceuticals 2023, 16(12), 1674; https://doi.org/10.3390/ph16121674 - 01 Dec 2023

Abstract

Polymeric-based drug delivery systems have become versatile and valuable candidates in sectors such as pharmaceuticals, health, medicine, etc [...] Full article

(This article belongs to the Special Issue Recent Advances in Polymers as Matrices for Drug Delivery Applications)

15 pages, 4089 KiB

Open AccessArticle

Fucosylated Chondroitin Sulfates with Rare Disaccharide Branches from the Sea Cucumbers Psolus peronii and Holothuria nobilis: Structures and Influence on Hematopoiesis

Nadezhda E. Ustyuzhanina

Maria I. Bilan

Natalia Yu. Anisimova

Mikhail V. Kiselevskiy

Anatolii I. Usov

and

Nikolay E. Nifantiev

Pharmaceuticals 2023, 16(12), 1673; https://doi.org/10.3390/ph16121673 - 30 Nov 2023

Abstract

Two fucosylated chondroitin sulfates were isolated from the sea cucumbers Psolus peronii and Holothuria nobilis using a conventional extraction procedure in the presence of papain, followed by anion-exchange chromatography on DEAE-Sephacel. Their composition was characterized in terms of quantitative monosaccharide and sulfate content, and structures were mainly elucidated using 1D- and 2D-NMR spectroscopy. As revealed by the data of the NMR spectra, both polysaccharides along with the usual fucosyl branches contained rare disaccharide branches α-D-GalNAc4S6R-(1→2)-α-L-Fuc3S4R → attached to O-3 of the GlcA of the backbone (R = H or SO₃⁻). The polysaccharides were studied as stimulators of hematopoiesis in vitro using mice bone marrow cells as the model. The studied polysaccharides were shown to be able to directly stimulate the proliferation of various progenitors of myelocytes and megakaryocytes as well as lymphocytes and mesenchymal cells in vitro. Therefore, the new fucosylated chondroitin sulfates can be regarded as prototype structures for the further design of GMP-compatible synthetic analogs for the development of new-generation hematopoiesis stimulators. Full article

(This article belongs to the Section Natural Products)

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