Pharmaceuticals

20 pages, 2396 KiB

Open AccessArticle

Modelling of Cetylpyridinium Chloride Availability in Complex Mixtures for the Prediction of Anti-Microbial Activity Using Diffusion Ordered Spectroscopy, Saturation Transfer Difference and 1D NMR

by Cameron Robertson, Sayoni Batabyal, Darren Whitworth, Tomris Coban, Angharad Smith, Alessandra Montesanto, Robert Lucas and Adam Le Gresley

Pharmaceuticals 2024, 17(12), 1570; https://doi.org/10.3390/ph17121570 - 22 Nov 2024

Abstract

Background/Objectives: A range of NMR techniques, including diffusion ordered spectroscopy (DOSY) were used to characterise complex micelles formed by the anti-microbial cationic surfactant cetylpyridium chloride and to quantify the degree of interaction between cetylpyridium chloride and hydroxyethyl cellulose in a variety of commercially [...] Read more.

Background/Objectives: A range of NMR techniques, including diffusion ordered spectroscopy (DOSY) were used to characterise complex micelles formed by the anti-microbial cationic surfactant cetylpyridium chloride and to quantify the degree of interaction between cetylpyridium chloride and hydroxyethyl cellulose in a variety of commercially relevant formulations as a model for the disk retention assay. Methods: This NMR-derived binding information was then compared with the results of formulation analysis by traditional disk retention assay (DRA) and anti-microbial activity assays to assess the suitability of these NMR techniques for the rapid identification of formulation components that could augment or retard antimicrobial activity DRA. Results: NMR showed a strong ability to predict anti-microbial activity for a diverse range of formulations containing cetylpyridinium chloride (CPC). Conclusions: This demonstrates the value of this NMR-based approach as a rapid, relatively non-destructive method for screening commercial experimental anti-microbial formulations for efficacy and further helps to understand the interplay of excipients and active ingredients. Full article

(This article belongs to the Special Issue Pharmaceutical Formulation Characterization Design)

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18 pages, 5582 KiB

Open AccessArticle

Comparison of Two Chelator Scaffolds as Basis for Cholecystokinin-2 Receptor Targeting Bimodal Imaging Probes

by Giacomo Gariglio, Katerina Bendova, Martin Hermann, Asta Olafsdottir, Jane K. Sosabowski, Milos Petrik, Elisabeth von Guggenberg and Clemens Decristoforo

Pharmaceuticals 2024, 17(12), 1569; https://doi.org/10.3390/ph17121569 - 22 Nov 2024

Abstract

Background/Objectives: Dual-modality probes, combining positron emission tomography (PET) with fluorescence imaging (FI) capabilities in a single molecule, are of high relevance for the accurate staging and guided resection of tumours. We herein present a pair of candidates targeting the cholecystokinin-2 receptor (CCK2R), [...] Read more.

Background/Objectives: Dual-modality probes, combining positron emission tomography (PET) with fluorescence imaging (FI) capabilities in a single molecule, are of high relevance for the accurate staging and guided resection of tumours. We herein present a pair of candidates targeting the cholecystokinin-2 receptor (CCK2R), namely [⁶⁸Ga]Ga-CyTMG and [⁶⁸Ga]Ga-CyFMG. In these probes, the SulfoCy5.5 fluorophore and two units of a CCK2R-binding motif are coupled to the chelator acting as a core scaffold, triazacyclononane-phosphinic acid (TRAP), and Fusarinine C (FSC), respectively. Using this approach, we investigated the influence of these chelators on the final properties. Methods: The synthetic strategy to both precursors was based on the stoichiometric conjugation of the components via click chemistry. The characterization in vitro included the evaluation of the CCK2R affinity and internalization in A431-CCK2R cells. Ex vivo biodistribution as well as PET and FI studies were performed in xenografted mice. Results: ⁶⁸Ga labelling was accomplished with high radiochemical yield and purity for both precursors. A CCK2R affinity in the subnanomolar range of the conjugates and a receptor-specific uptake of the radioligands in cells were observed. In A431-CCK2R/A431-mock xenografted mice, the investigated compounds showed specific accumulation in the tumours and reduced off-target uptake compared to a previously developed compound. Higher accumulation and prolonged retention in the kidneys were observed for [⁶⁸Ga]Ga-CyTMG when compared to [⁶⁸Ga]Ga-CyFMG. Conclusions: Despite the promising targeting properties observed, further probe optimization is required to achieve enhanced imaging contrast at early timepoints. Additionally, the results indicate a distinct influence of the chelators in terms of renal accumulation and retention. Full article

(This article belongs to the Special Issue Development of Novel Radiopharmaceuticals for SPECT and PET Imaging)

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21 pages, 2308 KiB

Open AccessArticle

Pyroptosis in Endothelial Cells and Extracellular Vesicle Release in Atherosclerosis via NF-κB-Caspase-4/5-GSDM-D Pathway

by Salman Shamas, Razia Rashid Rahil, Laveena Kaushal, Vinod Kumar Sharma, Nissar Ahmad Wani, Shabir H. Qureshi, Sheikh F. Ahmad, Sabry M. Attia, Mohammad Afzal Zargar, Abid Hamid and Owais Mohmad Bhat

Pharmaceuticals 2024, 17(12), 1568; https://doi.org/10.3390/ph17121568 - 22 Nov 2024

Abstract

Background: Pyroptosis, an inflammatory cell death, is involved in the progression of atherosclerosis. Pyroptosis in endothelial cells (ECs) and its underlying mechanisms in atherosclerosis are poorly understood. Here, we investigated the role of a caspase-4/5-NF-κB pathway in pyroptosis in palmitic acid (PA)-stimulated [...] Read more.

Background: Pyroptosis, an inflammatory cell death, is involved in the progression of atherosclerosis. Pyroptosis in endothelial cells (ECs) and its underlying mechanisms in atherosclerosis are poorly understood. Here, we investigated the role of a caspase-4/5-NF-κB pathway in pyroptosis in palmitic acid (PA)-stimulated ECs and EVs as players in pyroptosis. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured in an endothelial cell medium, treated with Ox-LDL, PA, caspase-4/5 inhibitor, NF-κB inhibitor, and sEV release inhibitor for 24 h, respectively. The cytotoxicity of PA was determined using an MTT assay, cell migration using a scratch-wound-healing assay, cell morphology using bright field microscopy, and lipid deposition using oil red O staining. The mRNA and protein expression of GSDM-D, CASP4, CASP5, NF-κB, NLRP3, IL-1β, and IL-18 were determined with RT-PCR and Western blot. Immunofluorescence was used to determine NLRP3 and ICAM-1 expressions. Extracellular vesicles (EVs) were isolated using an exosome isolation kit and were characterized by Western blot and scanning electron microscopy. Results: PA stimulation significantly changed the morphology of the HUVECs characterized by cell swelling, plasma membrane rupture, and increased LDH release, which are features of pyroptosis. PA significantly increased lipid accumulation and reduced cell migration. PA also triggered inflammation and endothelial dysfunction, as evidenced by NLRP3 activation, upregulation of ICAM-1 (endothelial activation marker), and pyroptotic markers (NLRP3, GSDM-D, IL-1β, IL-18). Inhibition of caspase-4/5 (Ac-FLTD-CMK) and NF-κB (trifluoroacetate salt (TFA)) resulted in a significant reduction in LDH release and expression of caspase-4/5, NF-κB, and gasdermin D (GSDM-D) in PA-treated HUVECs. Furthermore, GW4869, an exosome release inhibitor, markedly reduced LDH release in PA-stimulated HUVECs. EVs derived from PA-treated HUVECs exacerbated pyroptosis, as indicated by significantly increased LDH release and augmented expression of GSDM-D, NF-κB. Conclusions: The present study revealed that inflammatory, non-canonical caspase-4/5-NF-κB signaling may be one of the crucial mechanistic pathways associated with pyroptosis in ECs, and pyroptotic EVs facilitated pyroptosis in normal ECs during atherosclerosis. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery and Development of Drugs for Civilization Diseases)

25 pages, 13480 KiB

Open AccessArticle

Comparison of Drug Delivery Systems with Different Types of Nanoparticles in Terms of Cellular Uptake and Responses in Human Endothelial Cells, Pericytes, and Astrocytes

by Hakan Sahin, Oguz Yucel, Paul Holloway, Eren Yildirim, Serkan Emik, Gulten Gurdag, Gamze Tanriverdi and Gozde Erkanli Senturk

Pharmaceuticals 2024, 17(12), 1567; https://doi.org/10.3390/ph17121567 - 22 Nov 2024

Abstract

Background/Objectives: The key components of the blood–brain barrier (BBB) are endothelial cells, pericytes, astrocytes, and the capillary basement membrane. The BBB serves as the main barrier for drug delivery to the brain and is the most restrictive endothelial barrier in the body. [...] Read more.

Background/Objectives: The key components of the blood–brain barrier (BBB) are endothelial cells, pericytes, astrocytes, and the capillary basement membrane. The BBB serves as the main barrier for drug delivery to the brain and is the most restrictive endothelial barrier in the body. Nearly all large therapeutic molecules and over 90% of small-molecule drugs cannot cross the BBB. To overcome this challenge, nanotechnology, particularly drug delivery systems such as nanoparticles (NPs), have gained significant attention. Methods: Poly(lactide-co-glycolide) (PLGA) and albumin-based NPs (bovine/human), with or without transferrin (Tf) ligands (BSA, HSA, BSA-Tf, HSA-Tf), and nanolipid carriers (NLC) were synthesized. The interactions of these NPs with human brain microvascular endothelial cells (hBMECs), human brain vascular pericytes (hBVPs), and human astrocytes (hASTROs) were analyzed. Results: At doses of 15.62 µg/mL, 31.25 µg/mL, and 62.5 µg/mL, none of the NPs caused toxic effects on hBMECs, hBVPs, or hASTROs after 3 h of incubation. All NPs were internalized by the cells, but BSA-Tf and HSA-Tf showed significantly higher uptake in hBMECs in a dose-dependent manner. Ultrastructural analysis revealed notable differences between NP formulation and cell type. Conclusions: Our findings underscore the potential of ligand-targeted NPs to selectively interact with BBB endothelial cells. Ultrastructural analysis reveals distinct cellular processing pathways for various NP formulations across BBB-associated cell types, with autophagy emerging as a crucial mechanism for NP handling in pericytes and astrocytes. Changes in NP chemical properties upon biological exposure present significant challenges for nanomedicine design, emphasizing the need for further investigation into NP interactions at the cellular and subcellular levels. Full article

(This article belongs to the Special Issue Drug Delivery across the Blood–Brain Barrier)

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18 pages, 3119 KiB

Open AccessReview

Synthesis of Diazacyclic and Triazacyclic Small-Molecule Libraries Using Vicinal Chiral Diamines Generated from Modified Short Peptides and Their Application for Drug Discovery

by Mukund P. Tantak, Ramanjaneyulu Rayala, Prakash Chaudhari, Chhanda C. Danta and Adel Nefzi

Pharmaceuticals 2024, 17(12), 1566; https://doi.org/10.3390/ph17121566 - 22 Nov 2024

Abstract

Small-molecule probes are powerful tools for studying biological systems and can serve as lead compounds for developing new therapeutics. Especially, nitrogen heterocycles are of considerable importance in the pharmaceutical field. These compounds are found in numerous bioactive structures. Their synthesis often requires several [...] Read more.

Small-molecule probes are powerful tools for studying biological systems and can serve as lead compounds for developing new therapeutics. Especially, nitrogen heterocycles are of considerable importance in the pharmaceutical field. These compounds are found in numerous bioactive structures. Their synthesis often requires several steps or the use of functionalized starting materials. This review describes the use of vicinal diamines generated from modified short peptides to access substituted diaza- and triazacyclic compounds. Small-molecule diaza- and triazacyclic compounds with different substitution patterns and embedded in various molecular frameworks constitute important structure classes in the search for bioactivity. The compounds are designed to follow known drug likeness rules, including “Lipinski’s Rule of Five”. The screening of diazacyclic and traizacyclic libraries has shown the utility of these classes of compounds for the de novo identification of highly active compounds, including antimalarials, antimicrobial compounds, antifibrotic compounds, potent analgesics, and antitumor agents. Examples of the synthesis of diazacyclic and triazacyclic small-molecule libraries from vicinal chiral polyamines generated from modified short peptides and their application for the identification of highly active compounds are described. Full article

(This article belongs to the Special Issue Nitrogen Containing Scaffolds in Medicinal Chemistry 2023)

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16 pages, 2608 KiB

Open AccessArticle

Microparticles Loaded with Bursera microphylla A. Gray Fruit Extract with Anti-Inflammatory and Antimicrobial Activity

by Víctor Alonso Reyna-Urrutia, Ramón Enrique Robles-Zepeda, Miriam Estevez, Marlen Alexis Gonzalez-Reyna, Grecia Vianney Alonso-Martínez, Juan Ramón Cáñez-Orozco, Julio César López-Romero and Heriberto Torres-Moreno

Pharmaceuticals 2024, 17(12), 1565; https://doi.org/10.3390/ph17121565 - 21 Nov 2024

Abstract

Background: Bursera microphylla (B) A. Gray, a plant native to northwest Mexico, has long been utilized in traditional medicine for its anti-inflammatory effects. Previous studies have highlighted the bioactivity of B. microphylla fruit extract. Chitosan (Cs), a biopolymer known for its favorable [...] Read more.

Background: Bursera microphylla (B) A. Gray, a plant native to northwest Mexico, has long been utilized in traditional medicine for its anti-inflammatory effects. Previous studies have highlighted the bioactivity of B. microphylla fruit extract. Chitosan (Cs), a biopolymer known for its favorable physicochemical properties, has proven effective in encapsulating bioactive compounds. This study aimed to synthesize and characterize Cs-based microparticles containing B. microphylla fruit extract and evaluate their in vitro anti-inflammatory activity. Methods: Cs-based three-dimensional hydrogels were synthesized using physical cross-linking with ammonium hydroxide, incorporating B. microphylla fruit extract. The hydrogels were freeze-dried and mechanically ground into microparticles. The physicochemical properties of the microencapsulates were analyzed through scanning electron microscopy (SEM), optical microscopy (OM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and moisture absorption tests. Anti-inflammatory activity was assessed by measuring nitric oxide (NO) reduction in LPS-activated RAW 264.7 cells. Antimicrobial activity was evaluated against Staphylococcus aureus. Results: SEM and OM analyses revealed irregular morphologies with rounded protuberances, with particle sizes ranging from 135 to 180 µm. FTIR spectra indicated that no new chemical bonds were formed, preserving the integrity of the original compounds. TGA confirmed that the encapsulated extract was heat-protected. The moisture absorption test indicated the microparticles’ hydrophilic nature. In vitro, the microencapsulated extract reduced NO production by 46%, compared to 32% for the non-encapsulated extract. The microencapsulated extract was effective in reducing the microbial load of S. aureus between 15–24%. Conclusions: Cs-based microencapsulates containing B. microphylla fruit extract exhibited no chemical interactions during synthesis and demonstrated significant anti-inflammatory and antimicrobial activity. These results suggest that the Cs-based system is a promising candidate for managing inflammatory conditions. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals — Multi-Targeted Natural Products as Therapeutics)

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20 pages, 10426 KiB

Open AccessArticle

Sparstolonin B Reduces Estrogen-Dependent Proliferation in Cancer Cells: Possible Role of Ceramide and PI3K/AKT/mTOR Inhibition

by Yağmur Dilber, Hanife Tuğçe Çeker, Aleyna Öztüzün, Bürke Çırçırlı, Esma Kırımlıoğlu, Zerrin Barut and Mutay Aslan

Pharmaceuticals 2024, 17(12), 1564; https://doi.org/10.3390/ph17121564 - 21 Nov 2024

Abstract

Background: The aim of this study was to determine the effect of Sparstolonin B (SsnB) on cell proliferation and apoptosis in human breast cancer (MCF-7) and human ovarian epithelial cancer (OVCAR-3) cell lines in the presence and absence of estradiol hemihydrate (ES). Phosphoinositol-3 [...] Read more.

Background: The aim of this study was to determine the effect of Sparstolonin B (SsnB) on cell proliferation and apoptosis in human breast cancer (MCF-7) and human ovarian epithelial cancer (OVCAR-3) cell lines in the presence and absence of estradiol hemihydrate (ES). Phosphoinositol-3 kinase (PI3K), phosphorylated protein kinase B alpha (p-AKT), phosphorylated mTOR (mechanistic target of rapamycin) signaling proteins, and sphingomyelin/ceramide metabolites were also measured within the scope of the study. Methods: The anti-proliferative effects of SsnB therapy were evaluated over a range of times and concentrations. Cell proliferation was determined by measuring the Proliferating Cell Nuclear Antigen (PCNA). PCNA was quantified by ELISA and cell distribution was assessed by immunofluorescence microscopy. MTT analysis was used to test the vitality of the cells, while LC-MS/MS was used to analyze the amounts of ceramides (CERs), sphingosine-1-phosphate (S1P), and sphingomyelins (SMs). TUNEL labeling was used to assess apoptosis, while immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA) were used to measure the levels of PI3K, p-AKT, and p-mTOR proteins. Results: Sparstolonin B administration significantly decreased cell viability in MCF-7 and OVCAR-3 cells both in the presence and absence of ES, while it did not cause toxicity in healthy human fibroblasts. In comparison to controls, cancer cells treated with SsnB showed a significant drop in the levels of S1P, PI3K, p-AKT, and p-mTOR. In cancer cells cultured with SsnB, a significant increase in intracellular concentrations of C16-C24 CERs and apoptosis was observed. Conclusions: SsnB downregulated the levels of S1P, PI3K, p-AKT, and p-mTOR while reducing cell proliferation and promoting ceramide buildup and apoptosis. Full article

(This article belongs to the Section Pharmacology)

26 pages, 1339 KiB

Open AccessReview

Iodine-123 Metaiodobenzylguanidine (I-123 MIBG) in Clinical Applications: A Comprehensive Review

by Ming-Cheng Chang, Cheng-Liang Peng, Chun-Tang Chen, Ying-Hsia Shih, Jyun-Hong Chen, Yi-Jou Tai and Ying-Cheng Chiang

Pharmaceuticals 2024, 17(12), 1563; https://doi.org/10.3390/ph17121563 - 21 Nov 2024

Abstract

Iodine-123 metaiodobenzylguanidine (I-123 MIBG) is a crucial radiopharmaceutical widely used in nuclear medicine for its diagnostic capabilities in both cardiology and oncology. This review aims to present a comprehensive evaluation of the clinical applications of I-123 MIBG, focusing on its use in diagnosing [...] Read more.

Iodine-123 metaiodobenzylguanidine (I-123 MIBG) is a crucial radiopharmaceutical widely used in nuclear medicine for its diagnostic capabilities in both cardiology and oncology. This review aims to present a comprehensive evaluation of the clinical applications of I-123 MIBG, focusing on its use in diagnosing and managing various diseases. In cardiology, I-123 MIBG has proven invaluable in assessing cardiac sympathetic innervation, particularly in patients with heart failure, where it provides prognostic information that guides treatment strategies. In oncology, I-123 MIBG is primarily utilized for imaging neuroendocrine tumors, such as neuroblastoma and pheochromocytoma, where it offers high specificity and sensitivity in the detection of adrenergic tissue. Additionally, its role in neurology, specifically in differentiating between Parkinson’s disease, dementia, and Lewy body dementia, has become increasingly significant due to its ability to identify postganglionic sympathetic dysfunction. Despite its established clinical utility, the use of I-123 MIBG is not without limitations, including variability in imaging protocols and interpretation challenges. This review will explore these issues and discuss emerging alternatives, while also highlighting areas where I-123 MIBG continues to be a gold standard. By synthesizing the current research, this article aims to provide a clear understanding of the strengths, limitations, and prospects of I-123 MIBG in clinical practice. Full article

(This article belongs to the Special Issue Past, Present and Future Radiotracer Techniques: Radiopharmaceuticals in Cancer Theranostics)

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18 pages, 5959 KiB

Open AccessArticle

mTOR Pathway Inhibition, Anticancer Activity and In Silico Calculations of Novel Hydrazone Derivatives in Two- and Three-Dimensional Cultured Type 1 Endometrial Cancer Cells

by Muhammet Volkan Bulbul, Arif Mermer, Bircan Kolbasi, Fatih Kocabas, Semiha Mervenur Kalender, Kiymet Asli Kirectepe Aydin, Turan Demircan and İlknur Keskin

Pharmaceuticals 2024, 17(12), 1562; https://doi.org/10.3390/ph17121562 - 21 Nov 2024

Abstract

Background: Endometrial cancer remains a significant health concern, with type 1 endometrial cancer characterized by aberrant expression of estrogen-dependent and mTOR pathway proteins. In this study, we evaluated the effects of two novel hydrazone derivatives against the Ishikawa cell line, a model for [...] Read more.

Background: Endometrial cancer remains a significant health concern, with type 1 endometrial cancer characterized by aberrant expression of estrogen-dependent and mTOR pathway proteins. In this study, we evaluated the effects of two novel hydrazone derivatives against the Ishikawa cell line, a model for endometrial cancer. Methods: Two novel hydrazone derivatives, MVB1 and MVB2, were synthesized and characterized. The anticancer activity of the compounds in both two- and three-dimensional cultured Ishikawa cells was evaluated by MTT assay. The interaction of the compounds with proteins in the PI3K/AKT/mTOR pathway was evaluated by molecular docking studies and in vitro western blot analyses were performed. Additionally, ADME/T calculations were performed to evaluate the drug-like properties of the compounds. Results: MVB1 and MVB2 showed promising anticancer activity with IC₅₀ values of 8.3 ± 0.5 µM and 9.0 ± 1.2 µM in 2D cultures, respectively, and 49.9 ± 2 µM and 20.6 ± 1.9 µM in 3D cultures, respectively. Molecular docking studies revealed significant interactions between these compounds and key proteins in the PI3K/AKT/mTOR pathway, with MVB1 exhibiting the highest mean binding score (−10.5 kcal/mol) among PI3K, AKT1, and mTOR proteins. In vitro studies confirmed that MVB1 effectively suppressed PI3K protein expression in both 2D and 3D cultures (p ≤ 0.0001). Conclusions: The findings suggest that MVB1 and MVB2, especially MVB1, are promising candidates for further development as potential therapeutics for endometrial cancer by targeting the PI3K/AKT/mTOR pathway. Full article

(This article belongs to the Section Medicinal Chemistry)

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18 pages, 3893 KiB

Open AccessArticle

Modulatory Effect of Cucurbitacin D from Elaeocarpus hainanensis on ZNF217 Oncogene Expression in NPM-Mutated Acute Myeloid Leukemia

by Sabrina Adorisio, Alessandra Fierabracci, Ba Thi Cham, Vu Dinh Hoang, Nguyen Thi Thuy Linh, Le Thi Hong Nhung, Maria Paola Martelli, Emira Ayroldi, Simona Ronchetti, Lucrezia Rosati, Silvia Di Giacomo, Trinh Thi Thuy and Domenico Vittorio Delfino

Pharmaceuticals 2024, 17(12), 1561; https://doi.org/10.3390/ph17121561 - 21 Nov 2024

Abstract

Background/Objectives: The expression of oncogene zinc-finger protein 217 (ZNF217) has been reported to play a central role in cancer development, resistance, and recurrence. Therefore, targeting ZNF217 has been proposed as a possible strategy to fight cancer, and there has been much research on [...] Read more.

Background/Objectives: The expression of oncogene zinc-finger protein 217 (ZNF217) has been reported to play a central role in cancer development, resistance, and recurrence. Therefore, targeting ZNF217 has been proposed as a possible strategy to fight cancer, and there has been much research on compounds that can target ZNF217. The present work investigates the chemo-preventive properties of cucurbitacin D, a compound with a broad range of anticancer effects, in hematological cancer cells, specifically with regard to its ability to modulate ZNF217 expression. Methods: Different cucurbitacins were isolated from the Vietnamese plant Elaeocarpus hainanensis. The purified compounds were tested on nucleophosmin-mutated acute myeloid leukemia and other hematological cancer cell lines to assess their effects on the cell cycle, cell viability and apoptosis, and the expression of ZNF217. Results: Cucurbitacin D resulted in a reduction in the number of acute myeloid leukemia cells by inducing an increase in apoptosis and blocking cell cycle progression. It also led to a significant decrease in ZNF217 expression in the nucleophosmin-mutated acute myeloid leukemia cell line but not in the other hematologic cancer cell lines. The reduction in ZNF217 expression contributed significantly to the blocking of cell cycle progression but did not affect apoptosis. Conclusions: The obtained results suggest that cucurbitacin D is a promising molecule for targeting mutated nucleophosmin or its pathway in acute myeloid leukemia cells, although further studies are needed for in-depth investigations into its specific mechanisms. Full article

(This article belongs to the Special Issue Medicinal Plants: A Natural Approach to Inflammatory Diseases and Conditions Related to Oxidative Stress)

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20 pages, 4255 KiB

Open AccessArticle

Exploring the Antimycobacterial Potential of Podocarpusflavone A from Kielmeyera membranacea: In Vitro and In Vivo Insights

by Marlon Heggdorne de Araujo, Salomé Muñoz Sánchez, Thatiana Lopes Biá Ventura Simão, Natalia Nowik, Stella Schuenck Antunes, Shaft Corrêa Pinto, Davide Sorze, Francesca Boldrin, Riccardo Manganelli, Nelilma Correia Romeiro, Elena B. Lasunskaia, Fons J. Verbeek, Herman P. Spaink and Michelle Frazão Muzitano

Pharmaceuticals 2024, 17(12), 1560; https://doi.org/10.3390/ph17121560 - 21 Nov 2024

Abstract

Background/Objectives: Tuberculosis (TB) is one of the leading infectious causes of death worldwide, highlighting the importance of identifying new anti-TB agents. In previous research, our team identified antimycobacterial activity in Kielmeyera membranacea leaf extract; therefore, this study aims to conduct further exploration [...] Read more.

Background/Objectives: Tuberculosis (TB) is one of the leading infectious causes of death worldwide, highlighting the importance of identifying new anti-TB agents. In previous research, our team identified antimycobacterial activity in Kielmeyera membranacea leaf extract; therefore, this study aims to conduct further exploration of its potential. Methods: Classical chromatography was applied for fractionation and spectrometric techniques were utilized for chemical characterization. For in vitro tests, samples were assessed against Mycobacterium tuberculosis and Mycobacterium marinum. The toxicity and efficacy of active samples were evaluated in vivo using different zebrafish models. Chemogenomics studies were applied to predict the isolated active compound’s potential mode of action. Results: We performed fractionation of K. membranacea ethanolic extract (EE) and then its dichloromethane fraction (DCM), and the biflavonoid podocarpusflavone A (PCFA) was isolated and identified as a promising active compound. The EE and PCFA were found to be non-toxic to zebrafish larvae and were able to inhibit M. tuberculosis growth extracellularly. Additionally, PCFA demonstrated antimycobacterial activity within infected macrophages, especially when combined with isoniazid. In addition, the EE, DCM, and PCFA have shown the ability to inhibit M. marinum’s growth during in vivo zebrafish larvae yolk infection. Notably, PCFA also effectively countered systemic infection established through the caudal vein, showing a similar inhibitory activity profile to rifampicin, both at 32 µM. A reduction in the transcriptional levels of pro-inflammatory cytokines confirmed the infection resolution. The protein tyrosine phosphatase B (PtpB) of M. tuberculosis, which inhibits the macrophage immune response, was predicted as a theoretical target of PCFA. This finding is in agreement with the higher activity observed for PCFA intracellularly and in vivo on zebrafish, compared with the direct action in M. tuberculosis. Conclusions: Here, we describe the discovery of PCFA as an intracellular inhibitor of M. tuberculosis and provide evidence of its in vivo efficacy and safety, encouraging its further development as a combination drug in novel therapeutic regimens for TB. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals — Multi-Targeted Natural Products as Therapeutics)

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13 pages, 1574 KiB

Open AccessArticle

Pharmacological Evaluation of the Traditional Brazilian Medicinal Plant Monteverdia ilicifolia in Gastroesophageal Reflux Disease: Preliminary Results of a Randomized Double-Blind Controlled Clinical Trial

by Maitê Scherer da Silva, Rebeca Vargas Antunes Schunck, Maicon Pereira Moraes, Giana Blume Corssac, Gabriela Meirelles, Sara Elis Bianchi, Leonardo Vieira Targa, Valquiria Bassani, Marcelo Rodrigues Gonçalves, Caroline Dani and Ionara Rodrigues Siqueira

Pharmaceuticals 2024, 17(11), 1559; https://doi.org/10.3390/ph17111559 - 20 Nov 2024

Abstract

Background/Objectives: The present work aimed to compare the effects of the standardized dry extract from the leaves of Monteverdia ilicifolia, popularly known as “espinheira-santa”, with omeprazole in the management of dyspepsia related to gastroesophageal reflux disease (GERD). Methods: A double-blind, randomized, non-inferiority [...] Read more.

Background/Objectives: The present work aimed to compare the effects of the standardized dry extract from the leaves of Monteverdia ilicifolia, popularly known as “espinheira-santa”, with omeprazole in the management of dyspepsia related to gastroesophageal reflux disease (GERD). Methods: A double-blind, randomized, non-inferiority and double-dummy clinical trial was conducted. In total, 86 patients with GERD symptoms were randomized into three groups: Omeprazol (20 mg), M. ilicifolia (400 mg), or M. ilicifolia (860 mg). Capsules were provided by SUSTENTEC^®, Pato Bragato, Brazil. It was requested that the participants take three capsules before breakfast and dinner for 4 weeks. Clinical outcomes were obtained at the beginning and end of the study, with GERD symptoms (QS-GERD), the impact of heartburn symptoms on quality of life (HBQOL), and medical records. Results: Overall, 75.6% of the participants showed adherence without any differences among the experimental groups. All groups had significant reductions in both QS-GERD and HBQOL scores. Omeprazole and 400 and 860 mg of M. ilicifolia decreased the QS-GERD total scores at the endpoint compared to the baseline (Chi-square = 129.808; p < 0.0001), as well as individual item scores, such as heartburn intensity (Chi-square = 93.568, p < 0.0001) and heartburn after meals (Chi-square = 126.426, p < 0.0001). There were no differences among the experimental groups after the intervention. Conclusions: Our results suggest that capsules with a standardized dry extract from the leaves of M. ilicifolia at a dosage of 400 or 860 mg are non-inferior to omeprazole, a proton pump inhibitor. Full article

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26 pages, 11276 KiB

Open AccessArticle

Network Pharmacology and Molecular Docking Reveal Anti-Asthmatic Potential of Zephyranthes rosea Lindl. in an Ovalbumin-Induced Asthma Model

by Amir Ali, Hafiz Majid Rasheed, Siddique Akber Ansari, Shoeb Anwar Ansari and Hamad M. Alkahtani

Pharmaceuticals 2024, 17(11), 1558; https://doi.org/10.3390/ph17111558 - 20 Nov 2024

Abstract

Background: This study aimed to evaluate the anti-inflammatory effects of a Zephyranthes rosea in an ovalbumin-induced asthma model. Methods: Allergic asthma was induced in mice via intraperitoneal injection, followed by intranasal ovalbumin challenge. Methanolic extract of Z. rosea bulb was orally administered to [...] Read more.

Background: This study aimed to evaluate the anti-inflammatory effects of a Zephyranthes rosea in an ovalbumin-induced asthma model. Methods: Allergic asthma was induced in mice via intraperitoneal injection, followed by intranasal ovalbumin challenge. Methanolic extract of Z. rosea bulb was orally administered to asthmatic mice for 14 days. Hematological parameters for bronchoalveolar lavage fluid (BALF) and blood were analyzed. The mRNA expression levels of interleukins and transforming growth factor beta (TGF-β1) in lung tissues were determined using reverse transcriptase–polymerase chain reaction (RT–PCR). Network pharmacology analysis was used to find possible Z. rosea targets. After building a protein–protein interaction network to find hub genes, GO and KEGG enrichment analyses were carried out to determine the potential mechanism. In silico analysis was performed by Molecular Operating Environment. Results: GC-MS analysis of Z. rosea extract detected major classes of phytochemicals. Hematological parameters in blood and BALF from Z. rosea extract-treated animals were significantly reduced in a dose-dependent fashion. Histopathology revealed that Z. rosea bulb had an ameliorative effect on lung tissues. Moreover, treatment with Z. rosea bulb extract significantly restored the normal levels of IL-4, IL-6, IL-1β, IL-10, IL-13, and TGF-β1 in allergic asthmatic mice compared to the diseased group. In silico analysis, particularly of the binding affinities of Z. rosea bulb phytoconstituents for IL6, AKT1, and Src, supported in vivo results. Conclusions: These findings indicated that Z. rosea bulb extract significantly ameliorates cellular and molecular biomarkers of bronchial inflammation and could be a potential candidate for treating allergic asthma. Full article

(This article belongs to the Section Natural Products)

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14 pages, 1263 KiB

Open AccessReview

Less Pain with Intra-Articular Hyaluronic Acid Injections for Knee Osteoarthritis Compared to Placebo: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

by Filippo Migliorini, Nicola Maffulli, Luise Schäfer, Joshua Kubach, Marcel Betsch and Mario Pasurka

Pharmaceuticals 2024, 17(11), 1557; https://doi.org/10.3390/ph17111557 - 20 Nov 2024

Abstract

The present meta-analysis investigated the efficacy of intra-articular hyaluronic acid (HA) injections for knee osteoarthritis. The outcomes of interest were the visual analogue scale (VAS) and Western Ontario McMaster Osteo-Arthritis Index (WOMAC) scores. This study was conducted according to the 2020 PRISMA statement. [...] Read more.

The present meta-analysis investigated the efficacy of intra-articular hyaluronic acid (HA) injections for knee osteoarthritis. The outcomes of interest were the visual analogue scale (VAS) and Western Ontario McMaster Osteo-Arthritis Index (WOMAC) scores. This study was conducted according to the 2020 PRISMA statement. All the randomised controlled trials (RCTs) comparing the efficacy of intra-articular HA injections versus placebo injections for knee osteoarthritis were accessed in September 2024. Data from 3851 patients were collected. In total, 64% (2467 of 3851 patients) were women, and the mean age of the patients was 63.5 ± 4.9 years. At baseline, good comparability was found for the mean age, BMI, percentage of women, and patient-reported outcome measures (PROMs). Studies which reported data from two to four weeks of follow-up evidenced a lower value of the subscales pain (p < 0.0001) and stiffness (p = 0.01) of the WOMAC score. No difference was observed in VAS at rest (p = 0.4), VAS at exercise (p = 0.1), and subscale function (p = 0.4) of the WOMAC score. Studies which reported data from five to eight weeks of follow-up evidenced lower VAS at rest in favour of the HA group (p = 0.01). No difference in the other PROMs of interest was observed: VAS at exercise (p = 0.1), and the subscales pain (p = 0.3), function (p = 0.4), and stiffness (p = 0.4) of the WOMAC score. The current level I of evidence suggests that intra-articular HA injections in the knee might reduce pain in the short term. Full article

(This article belongs to the Section Pharmacology)

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24 pages, 740 KiB

Open AccessReview

Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine–Glycine–Aspartate) Strategies

by Bojana Bogdanović, Daniel Fagret, Catherine Ghezzi and Christopher Montemagno

Pharmaceuticals 2024, 17(11), 1556; https://doi.org/10.3390/ph17111556 - 20 Nov 2024

Abstract

Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including [...] Read more.

Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including variable efficacy and unmet high expectations. Nevertheless, the consistent expression of integrins on tumor and stromal cells underscores their ongoing relevance and potential. Traditional RGD-based imaging and therapeutic agents have faced limitations, such as inconsistent target expression and rapid systemic clearance, which have reduced their effectiveness. To overcome these challenges, recent research has focused on advancing RGD-based strategies and exploring innovative solutions. This review offers a thorough analysis of the latest developments in the RGD–integrin field, with a particular focus on addressing previous limitations. It delves into new dual-targeting approaches and cutting-edge RGD-based agents designed to improve both tumor diagnosis and therapeutic outcomes. By examining these advancements, this review illuminates new pathways for enhancing the specificity and efficacy of integrin-targeted therapies, paving the way for more effective cancer diagnosis and treatment strategies. Full article

(This article belongs to the Special Issue Synthesis and Development of Novel Radiopharmaceuticals for Targeted Radiotherapy and Theranostics)

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30 pages, 4678 KiB

Open AccessReview

Antimicrobial Peptides: The Game-Changer in the Epic Battle Against Multidrug-Resistant Bacteria

by Helal F. Hetta, Nizar Sirag, Shumukh M. Alsharif, Ahmad A. Alharbi, Tala T. Alkindy, Alanoud Alkhamali, Abdullah S. Albalawi, Yasmin N. Ramadan, Zainab I. Rashed and Fawaz E. Alanazi

Pharmaceuticals 2024, 17(11), 1555; https://doi.org/10.3390/ph17111555 - 20 Nov 2024

Abstract

The rapid progress of antibiotic resistance among bacteria has prompted serious medical concerns regarding how to manage multidrug-resistant (MDR) bacterial infections. One emerging strategy to combat antibiotic resistance is the use of antimicrobial peptides (AMPs), which are amino acid chains that act as [...] Read more.

The rapid progress of antibiotic resistance among bacteria has prompted serious medical concerns regarding how to manage multidrug-resistant (MDR) bacterial infections. One emerging strategy to combat antibiotic resistance is the use of antimicrobial peptides (AMPs), which are amino acid chains that act as broad-spectrum antimicrobial molecules and are essential parts of the innate immune system in mammals, fungi, and plants. AMPs have unique antibacterial mechanisms that offer benefits over conventional antibiotics in combating drug-resistant bacterial infections. Currently, scientists have conducted multiple studies on AMPs for combating drug-resistant bacterial infections and found that AMPs are a promising alternative to conventional antibiotics. On the other hand, bacteria can develop several tactics to resist and bypass the effect of AMPs. Therefore, it is like a battle between the bacterial community and the AMPs, but who will win? This review provides thorough insights into the development of antibiotic resistance as well as detailed information about AMPs in terms of their history and classification. Furthermore, it addresses the unique antibacterial mechanisms of action of AMPs, how bacteria resist these mechanisms, and how to ensure AMPs win this battle. Finally, it provides updated information about FDA-approved AMPs and those that were still in clinical trials. This review provides vital information for researchers for the development and therapeutic application of novel AMPs for drug-resistant bacterial infections. Full article

(This article belongs to the Special Issue Naturally Occurring Peptides and Proteins and Related Drugs)

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19 pages, 3244 KiB

Open AccessArticle

Cilomilast Modulates Rhinovirus-Induced Airway Epithelial ICAM-1 Expression and IL-6, CXCL8 and CCL5 Production

by Jie Zhu, Michael R. Edwards, Simon D. Message, Luminita A. Stanciu, Sebastian L. Johnston and Peter K. Jeffery

Pharmaceuticals 2024, 17(11), 1554; https://doi.org/10.3390/ph17111554 - 20 Nov 2024

Abstract

Background: Cilomilast, a phosphodiesterase-4 (PDE4) selective inhibitor, has anti-inflammatory effects in vitro and in vivo and reduces COPD exacerbations. We tested the hypothesis that cilomilast inhibits virus-induced airway epithelial intercellular adhesion molecule-1 (ICAM-1) expression and inflammatory cytokine/chemoattractants, IL-6, CXCL8, and CCL5 production in [...] Read more.

Background: Cilomilast, a phosphodiesterase-4 (PDE4) selective inhibitor, has anti-inflammatory effects in vitro and in vivo and reduces COPD exacerbations. We tested the hypothesis that cilomilast inhibits virus-induced airway epithelial intercellular adhesion molecule-1 (ICAM-1) expression and inflammatory cytokine/chemoattractants, IL-6, CXCL8, and CCL5 production in vitro. Methods: BEAS-2B bronchial epithelial cells were incubated with 0.5–2 MOI (multiplicity of infection–infectious units/cell) of rhinovirus 16 (RV16). Then, 0.1–10 μM cilomilast or 10 nM dexamethasone, as inhibition control, were added pre- or post-1 h RV16 infection. Supernatant and cells were sampled at 8, 24, 48, and 72 h after infection. Cell surface ICAM-1 expression was detected by immunogold labelling and visualised by high-resolution scanning electron microscopy (HR-SEM), while IL-6, CXCL8, and CCL5 protein release and mRNA expression were measured using an ELISA and RT-PCR. Results: Cilomilast significantly decreased RV16-induced ICAM-1 expression to approximately 45% (p < 0.01). CXCL8 protein/mRNA production was reduced by about 41% (p < 0.05), whereas IL-6 protein/mRNA production was increased to between 41–81% (p < 0.001). There was a trend to reduction by cilomilast of RV16-induced CCL5. Conclusions: Cilomilast has differential effects on RV16-induced ICAM-1 and interleukins, inhibiting virus-induced ICAM-1 expression and CXCL8 while increasing IL-6 production. These in vitro effects may help to explain the beneficial actions of this PDE4 inhibitor in vivo. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 4389 KiB

Open AccessArticle

Evolving Clinical Features of Diabetic Ketoacidosis: The Impact of SGLT2 Inhibitors

by Selin Genc, Bahri Evren, Onur Selcuk Yigit, Ibrahim Sahin, Ramazan Dayanan, Aleksandra Klisic, Ayse Erturk and Filiz Mercantepe

Pharmaceuticals 2024, 17(11), 1553; https://doi.org/10.3390/ph17111553 - 20 Nov 2024

Abstract

Background/Objectives: The antidiabetic effect of SGLT2 inhibitors (SGLT2-is) is based on their ability to increase glucose excretion through urine by inhibiting the kidney-resident SGLT2 protein. Euglycemic diabetic ketoacidosis (EuDKA) is an uncommon but potentially life-threatening adverse effect of these medications, which are [...] Read more.

Background/Objectives: The antidiabetic effect of SGLT2 inhibitors (SGLT2-is) is based on their ability to increase glucose excretion through urine by inhibiting the kidney-resident SGLT2 protein. Euglycemic diabetic ketoacidosis (EuDKA) is an uncommon but potentially life-threatening adverse effect of these medications, which are notable for their antidiabetic, cardiovascular, and renal protective properties. This study aimed to clarify the impact of SGLT2-is on demographic, clinical, and biochemical characteristics in patients with DKA. Methods: A total of 51 individuals with a diagnosis of DKA were included in the trial; 19 of these patients were treated with SGLT2-is, while 32 were not. Patients diagnosed with DKA and treated with SGLT2-is were compared to those not treated with the medication in terms of clinical, biochemical, and laboratory characteristics. Results: The age of patients utilizing SGLT2-is was statistically considerably greater than that of non-users (p < 0.001). EuDKA was exclusively noted in the SGLT2-is cohort (p = 0.005). Urinary tract infections, vulvovaginitis, and genitourinary infections were substantially more prevalent among SGLT2-i users compared with non-users among both women and the overall patient group (p = 0.036, p = 0.001, p = 0.005, p = 0.003, respectively). Plasma glucose concentrations were significantly higher in SGLT2-i non-users (p = 0.006). Chloride (Cl⁻) concentrations were elevated among SGLT2-i users (p = 0.036). Conclusions: The study findings indicate that SGLT2 inhibitors may substantially influence age, serum chloride, EuDKA, and the occurrence of genitourinary infections in individuals with DKA. Full article

(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy)

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Graphical abstract

21 pages, 5812 KiB

Open AccessArticle

GC–MS Characterization and Bioactivity Study of Eucalyptus globulus Labill. (Myrtaceae) Essential Oils and Their Fractions: Antibacterial and Antioxidant Properties and Molecular Docking Modeling

by Abdessamad Ait benlabchir, Kawtar Fikri-Benbrahim, Amina Moutawalli, Mohammed M. Alanazi, Asma Halmoune, Fatima Zahra Benkhouili, Asmaa Oubihi, Atul Kabra, Elbatoul Hanoune, Hamza Assila and Zineb Benziane Ouaritini

Pharmaceuticals 2024, 17(11), 1552; https://doi.org/10.3390/ph17111552 - 19 Nov 2024

Abstract

Background/Objectives: Eucalyptus globulus is a medicinal plant extensively used by the Moroccan population for treating a range of illnesses, especially respiratory conditions. Methods: This study aimed to assess the antioxidant and antibacterial properties of E. globulus essential oil and its individual fractions (F1, [...] Read more.

Background/Objectives: Eucalyptus globulus is a medicinal plant extensively used by the Moroccan population for treating a range of illnesses, especially respiratory conditions. Methods: This study aimed to assess the antioxidant and antibacterial properties of E. globulus essential oil and its individual fractions (F1, F2, and F3). Antioxidant activity was evaluated through iron-reducing power, 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. Antibacterial activity was tested using disk diffusion and dilution methods, supported by molecular docking studies. Furthermore, GC–MS analysis was conducted on the essential oil and its individual fractions. Results: GC–MS analysis identified the major compounds in the essential oil and its fractions as eucalyptol (62.32–42.60%), globulol (5.9–26.24%), o-cymene (6.89–24.35%), cryptone (7.10–15.95%), terpinen-4-ol (2.43–15.24%), and α-pinene (2.46–7.89%). Fraction F3 displayed the highest antioxidant activity in DPPH (IC₅₀ = 3.329 ± 0.054 mg/mL) and ABTS assays (IC₅₀ = 3.721 ± 0.027 mg/mL), while fraction F2 was most effective in the FRAP assay (IC₅₀ = 1.054 ± 0.008 mg/mL). The essential oil and its fractions also showed antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, and Acinetobacter baumannii. Molecular docking further corroborated these findings, supporting both antioxidant and antibacterial activities. Conclusions: The present findings demonstrate the antioxidant and antimicrobial properties of Eucalyptus globulus essential oil and its fractions, underscoring the need for further research to confirm their medicinal potential and explore pharmaceutical applications. Full article

(This article belongs to the Special Issue Advances in the Chemical-Biological Knowledge of Essential Oils)

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