Pharmaceuticals

19 pages, 1521 KiB

Open AccessReview

CRRT Is More Than Just Continuous Renal Replacement Therapy

by Lóránd Erdélyi and Domonkos Trásy

Pharmaceuticals 2024, 17(12), 1571; https://doi.org/10.3390/ph17121571 - 22 Nov 2024

The physiology of the kidney has long been understood, and its mechanisms are well described. The pathology of renal failure is also a deeply researched area. It seems logical, therefore, to create devices that can replace the lost normal function of the kidney. [...] Read more.

The physiology of the kidney has long been understood, and its mechanisms are well described. The pathology of renal failure is also a deeply researched area. It seems logical, therefore, to create devices that can replace the lost normal function of the kidney. Using the physical processes that take place in the kidney, such as diffusion or convection across a membrane, various renal replacement therapies (RRT) have been created. There are those that are used intermittently and those that are used for longer periods. What they have in common is that all RRTs have the same purpose; to replace the excretory function of the kidney that has been lost. CRRT is an extracorporeal renal replacement therapy that effectively replicates the excretory function of the kidneys in cases of acute renal failure. However, it has become increasingly evident that this rapidly advancing treatment modality offers benefits beyond merely substituting kidney function, with its applications continuing to expand significantly with non-renal and other indications. The use of these devices has raised new questions, many of which are still not clearly answered. When should this start? Who should receive it? How long should it last? What indication should it be for? What modality should it be with? How does it change the pharmacokinetics of the medicines? To answer these questions, it is first worth understanding the mechanisms behind the processes and the factors that influence them. This should not only focus on the procedures used in RRT therapies, but also consider the patient’s condition and the physicochemical properties of the drugs. In this review, we aim to provide a literature summary to highlight the factors that may influence the success of RRT therapies. Full article

(This article belongs to the Special Issue Recent Advances in Drug Metabolism, Transport, and Pharmacokinetics)

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

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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

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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

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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

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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

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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

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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

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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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Pharmaceuticals, Volume 17, Issue 12 (December 2024) – 12 articles

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