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Pharmaceuticals, Volume 17, Issue 10 (October 2024) – 157 articles

Cover Story (view full-size image): Conventional chemotherapy for colorectal cancer (CRC) often causes severe side effects. Recently, chitosan (CS), a mucoadhesive polymer, has gained attention as a drug delivery system (DDS) for enhancing drug efficacy. This review highlights research on CS-based smart hydrogels for CRC treatment, focusing on two types: stimuli-responsive injectable hydrogels with sol–gel transitions and CS-based hydrogels that release drugs in response to one, two, or multiple triggers. It also explores CS's structural features, hydrogel preparation methods, and recent advancements in smart CS-based hydrogels for CRC therapy. View this paper
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20 pages, 3330 KiB  
Article
Extraction, Purification, Characterization, and Wound Healing Effects of Novel Prickly Pear (Opuntiaficus-indica (L.) Mill.) Heteropolysaccharides
by Naourez Ktari, Wafa Gargouri, Lobna Jlaiel, Imen Trabelsi, Sirine Ben Slima, Sana Bardaa, Farida Bendali and Riadh Ben Salah
Pharmaceuticals 2024, 17(10), 1410; https://doi.org/10.3390/ph17101410 - 21 Oct 2024
Viewed by 541
Abstract
Background: The present study undertakes the purification of a novel polysaccharide from Tunisian prickly pear (Opuntiaficus-indica (L.) Mill.) rackets (PPPRs) and the determination of its physicochemical properties, structure, antibacterial and antioxidant properties, as well as its in vitro and in vivo wound healing [...] Read more.
Background: The present study undertakes the purification of a novel polysaccharide from Tunisian prickly pear (Opuntiaficus-indica (L.) Mill.) rackets (PPPRs) and the determination of its physicochemical properties, structure, antibacterial and antioxidant properties, as well as its in vitro and in vivo wound healing potential. Methods: The PPPR was structurally analyzed by Fourier Transform Infrared Spectroscopy (FTIR) and UV/Visible Spectroscopy, revealing characteristic bands of polysaccharides. According to thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and Gas Chromatography–Mass Spectrometry (GC–MS) analyses. Results: The crude PPPR is an heteropolysaccharide composed of glucose (62.4%), galactose (19.37%), mannose (10.24%), and rhamnose (7.98%), with an average molecular weight of 90.94 kDa. This novel polysaccharide exhibited notable antioxidant potential assessed by four different in vitro assays: the 2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay, ferric reducing power, ferrous chelating activity, and scavenging activity against 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS). In addition, the PPPR displayed high antibacterial activities with a MIC of 2.5 mg/mL against Salmonella Typhimurium and Pseudomonas aeruginosa, cytocompatibility properties, and non-cytotoxicity. Subsequently, the effect of the PPPR on skin wound healing was studied in a diabetic rat model induced by alloxan, revealing a significant acceleration in the wound healing process. This acceleration was evidenced by the expedited recovery of the dermis, increased formation of blood vessels, and enhanced tissue granulation. Conclusion: Therefore, the findings offer fresh perspectives on the creation of a potentially efficient and promising racket polysaccharide-based therapy for the treatment of persistent diabetic wounds. Full article
(This article belongs to the Section Natural Products)
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17 pages, 2709 KiB  
Article
Antidepressant-like Effects of Cannabis sativa L. Extract in an Lipopolysaccharide Model: Modulation of Mast Cell Activation in Deep Cervical Lymph Nodes and Dura Mater
by Joonyoung Shin, Dong-Uk Kim, Gi-Sang Bae, Ji-Ye Han, Do-Won Lim, Young-Mi Lee, Eunjae Kim, Eunjeong Kwon, Dongwoon Han and Sungchul Kim
Pharmaceuticals 2024, 17(10), 1409; https://doi.org/10.3390/ph17101409 - 21 Oct 2024
Viewed by 1010
Abstract
Background: Lipopolysaccharide (LPS)-induced neuroinflammation is a well-established model for studying depression-like behavior, driven by pro-inflammatory cytokines such as TNF-α and IL-1β. Mast cells (MCs) contribute to neuroinflammation by releasing mediators that exacerbate depressive-like symptoms. This study evaluates the antidepressant-like and anti-inflammatory effects of [...] Read more.
Background: Lipopolysaccharide (LPS)-induced neuroinflammation is a well-established model for studying depression-like behavior, driven by pro-inflammatory cytokines such as TNF-α and IL-1β. Mast cells (MCs) contribute to neuroinflammation by releasing mediators that exacerbate depressive-like symptoms. This study evaluates the antidepressant-like and anti-inflammatory effects of Cannabis sativa L. inflorescence extract (CSL) in an LPS-induced neuroinflammation model. Methods: Male C57BL/6 mice were intraperitoneally injected with CSL at doses of 10, 20, and 30 mg/kg, 30 min prior to LPS (0.83 mg/kg) administration. Depressive behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). The neutrophil-to-lymphocyte ratio (NLR) was measured to assess systemic inflammation. Cytokine levels in the prefrontal cortex (PFC) were measured, and mast cell degranulation in the lymph nodes and dura mater was analyzed histologically (approval number: WKU24-64). Results: CSL significantly improved depressive-like behaviors and decreased the NLR, indicating reduced systemic inflammation. CSL also significantly reduced TNF-α and IL-1β levels in the PFC. Furthermore, CSL inhibited MC degranulation in the deep cervical lymph nodes and dura mater, with the strongest effects observed at 30 mg/kg. Conclusions: CSL demonstrated antidepressant-like and anti-inflammatory effects in an LPS-induced neuroinflammation model, likely through the modulation of cytokine expression and mast cell activity. These results suggest the potential of CSL as a therapeutic option for treating inflammation-related depression. Full article
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12 pages, 1730 KiB  
Article
Glutathione Modulates Hydrogen Sulfide Release and the Ocular Hypotensive Action of Diallyl Polysulfide Compounds
by Susmit Mhatre, Rai Anjali, Pulkit Sahai, John Auden, Somnath Singh, Ya Fatou Njie Mbye, Sunny E. Ohia and Catherine A. Opere
Pharmaceuticals 2024, 17(10), 1408; https://doi.org/10.3390/ph17101408 - 21 Oct 2024
Viewed by 471
Abstract
Background: Hydrogen sulfide (H2S) is an endogenous transmitter with the potential to regulate aqueous humor dynamics and protect retinal neurons from degeneration. The aim of the present study was two-fold: (a) to evaluate the release of H2S from two [...] Read more.
Background: Hydrogen sulfide (H2S) is an endogenous transmitter with the potential to regulate aqueous humor dynamics and protect retinal neurons from degeneration. The aim of the present study was two-fold: (a) to evaluate the release of H2S from two polysulfides, diallyl disulfide (DADS), and diallyl trisulfide (DATS); and (b) to investigate their ocular hypotensive actions in normotensive male and female rabbits in the presence and absence of GSH. Materials and Methods: H2S was quantified hourly for up to 6 h using a H2S-Biosensor (World Precision Instruments, Sarasota, Fl). Intraocular pressure (IOP) was assessed in normotensive New Zealand Albino rabbits using a pneumotonometer (model 30 classic; Reichert Ophthalmic Instruments, Depew, NY, USA). Results: In the presence of GSH, there was an increase in the in vitro release of H2S produced by DADS and DATS. Both DADS and DATS also caused a dose-dependent reduction in IOP in male and female rabbits, in both treated and untreated eyes. For instance, in male animals, the presence of GSH (3% and 5%) significantly (p < 0.05, n = 5) enhanced the ocular hypotensive action of DADS (2%) and DATS (2%) from 14.02 ± 2.89% to 18.67 ± 5.6% and from 16.22 ± 3.48 to 23.62 ± 5.79%, respectively. Conclusions: GSH enhanced both H2S release and ocular hypotensive action of the polysulfides in a manner that was dependent on the number of sulfur atoms present in each polysulfide. Furthermore, female animals were less sensitive to the IOP-lowering action of the polysulfides, when compared to their male counterparts. Full article
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28 pages, 6755 KiB  
Article
Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors Based on the Pyridyl–Pyridazine Moiety for the Potential Treatment of Alzheimer’s Disease
by Mohamed Elsawalhy, Adel A-H Abdel-Rahman, Ebtesam A. Basiony, Salma A. Ellithy, Allam A. Hassan, Eman S. Abou-Amra, Abdelhamid Ismail, Abdulrahman A. Almehizia, Mohamed A. Al-Omar, Ahmed M. Naglah and Nasser A. Hassan
Pharmaceuticals 2024, 17(10), 1407; https://doi.org/10.3390/ph17101407 - 21 Oct 2024
Viewed by 784
Abstract
Background: Alzheimer’s disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel [...] Read more.
Background: Alzheimer’s disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, 1H NMR, and 13C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results: Compound 5 was the most potent inhibitor, with IC50 values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of −10.21 kcal/mol to AChE and −13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5, 8, and 9, with Compound 5 showing the best activity. Conclusions: Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer’s disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors. Full article
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38 pages, 2368 KiB  
Review
Lignin: An Adaptable Biodegradable Polymer Used in Different Formulation Processes
by Andreea Creteanu, Claudiu N. Lungu and Mirela Lungu
Pharmaceuticals 2024, 17(10), 1406; https://doi.org/10.3390/ph17101406 - 21 Oct 2024
Viewed by 740
Abstract
Introduction: LIG is a biopolymer found in vascular plant cell walls that is created by networks of hydroxylated and methoxylated phenylpropane that are randomly crosslinked. Plant cell walls contain LIG, a biopolymer with significant potential for usage in modern industrial and pharmaceutical applications. [...] Read more.
Introduction: LIG is a biopolymer found in vascular plant cell walls that is created by networks of hydroxylated and methoxylated phenylpropane that are randomly crosslinked. Plant cell walls contain LIG, a biopolymer with significant potential for usage in modern industrial and pharmaceutical applications. It is a renewable raw resource. The plant is mechanically protected by this substance, which may increase its durability. Because it has antibacterial and antioxidant qualities, LIG also shields plants from biological and chemical challenges from the outside world. Researchers have done a great deal of work to create new materials and substances based on LIG. Numerous applications, including those involving antibacterial agents, antioxidant additives, UV protection agents, hydrogel-forming molecules, nanoparticles, and solid dosage forms, have been made with this biopolymer. Methods: For this review, a consistent literature screening using the Pubmed database from 2019–2024 has been performed. Results: The results showed that there is an increase in interest in lignin as an adaptable biomolecule. The most recent studies are focused on the biosynthesis and antimicrobial properties of lignin-derived molecules. Also, the use of lignin in conjunction with nanostructures is actively explored. Conclusions: Overall, lignin is a versatile molecule with multiple uses in industry and medical science Full article
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26 pages, 5124 KiB  
Article
Evaluation of Mucoadhesive Nano-Bilosomal In Situ Gels Containing Anti-Psychotic Clozapine for Treatment of Schizophrenia: In Vitro and In Vivo Studies
by Marwa H. Abdallah, Mona M. Shahien, Hemat El-Sayed El-Horany, Enas Haridy Ahmed, Hanan M. El-Nahas, Nourhan A. Abdulla and Tarek M. Ibrahim
Pharmaceuticals 2024, 17(10), 1404; https://doi.org/10.3390/ph17101404 - 21 Oct 2024
Viewed by 581
Abstract
Background/Objectives: Patients with schizophrenia have significant challenges in adhering to and complying with oral medicines, resulting in adverse consequences such as symptom worsening and psychotic relapse. Methods: This study aimed to develop clove oil-based bilosomes using definitive screening design (DSD) to maximize the [...] Read more.
Background/Objectives: Patients with schizophrenia have significant challenges in adhering to and complying with oral medicines, resulting in adverse consequences such as symptom worsening and psychotic relapse. Methods: This study aimed to develop clove oil-based bilosomes using definitive screening design (DSD) to maximize the anti-schizophrenic action of clozapine and promote its nose-to-brain delivery. The target was to optimize the physicochemical properties of bilosomes and incorporate them into mucoadhesive intranasal in situ gels, searching for augmented ex vivo and in vivo clozapine delivery. Results: The bilosomes’ particle size was decreased by increasing the span, SDC, and clove oil amounts. In addition to using a high lipid amount, the aforementioned components also helped increase the entrapment efficiency values. Increased zeta potential was only observed by increasing surfactant amount and reducing clozapine concentration. After incorporation of optimized liquid clove oil-based bilosomes, which had a spherical nano-sized vesicular shape, into P 407-dependent gels, an HPMC (2% w/w)/P 407 (20% w/w)-containing formulation (G6) was selected as an optimized gel owing to its acceptable gelation time (13.28 s), gel strength (27.72 s), viscosity (12,766.67 cP), and mucoadhesive strength (4273.93 dyne/cm2). The optimized G6 exhibited higher Jss (50.86 μg/cm2·h−1) through the nasal mucosa compared to the control gel (23.03 μg/cm2·h−1). Compared to the control gel, G6 displayed higher relative bioavailability (491.37%) than a commercial tablet (264.46%). Following ELISA analysis, dopamine and serotonin were significantly reduced, while BDNF was remarkably increased after administration of optimized G6 into schizophrenic rats. Conclusion: Our study indicates the potential of intranasal bilosomal gels in upgrading the anti-schizophrenic and neuroprotective activity of clozapine. Full article
(This article belongs to the Section Pharmaceutical Technology)
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16 pages, 4879 KiB  
Review
Discovery and Development of Caffeic Acid Analogs as Versatile Therapeutic Agents
by Yi Mou, Shuai Wen, Hong-Kai Sha, Yao Zhao, Li-Juan Gui, Yan Wang and Zheng-Yu Jiang
Pharmaceuticals 2024, 17(10), 1403; https://doi.org/10.3390/ph17101403 - 20 Oct 2024
Viewed by 1079
Abstract
Caffeic acid (CA) is a polyphenolic acid compound widely distributed in plant seeds. As natural compounds with high research interest, caffeic acid and its derivatives show good activity in the treatment of tumors and inflammation and have antibacterial properties. In recent years, caffeic [...] Read more.
Caffeic acid (CA) is a polyphenolic acid compound widely distributed in plant seeds. As natural compounds with high research interest, caffeic acid and its derivatives show good activity in the treatment of tumors and inflammation and have antibacterial properties. In recent years, caffeic acid derivatives have been studied extensively, and these derivatives fall roughly into three categories: (1) caffeic acid ester derivatives, (2) caffeic acid amide derivatives, (3) caffeic acid hybrids. These caffeic acid analogues exert mainly antibacterial and antioxidant activities. Among the caffeic acid analogues summarized in this paper, compounds 1g and CAP10 have good activity against Candida albicans, and their MIC50 is 32 µg/mL and 13 μM, respectively. In a DPPH assay, compounds 3k, 5a, CS2, Phellinsin A and 8j showed strong antioxidant activity, and their IC50 values are 18.6 μM, 67.85 μM, 40.29 μM, 0.29 ± 0.004 mM, 4774.37 ± 137.20 μM, respectively. Overall, compound CAP10 had the best antibacterial activity and compound 3k had the best antioxidant activity. This paper mainly summarizes and discusses some representative caffeic acid analogs, hoping to provide better drug design strategies for the subsequent development of caffeic acid analogs. Full article
(This article belongs to the Section Natural Products)
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19 pages, 3873 KiB  
Article
Inhibitory Effect of Luteolin on Spike S1 Glycoprotein-Induced Inflammation in THP-1 Cells via the ER Stress-Inducing Calcium/CHOP/MAPK Pathway
by Sonthaya Umsumarng, Sivamoke Dissook, Punnida Arjsri, Kamonwan Srisawad, Pilaiporn Thippraphan, Apiwat Sangphukieo, Patcharawadee Thongkumkoon and Pornngarm Dejkriengkraikul
Pharmaceuticals 2024, 17(10), 1402; https://doi.org/10.3390/ph17101402 - 20 Oct 2024
Viewed by 1622
Abstract
Background/Objectives: The global SARS-CoV-2 outbreak has escalated into a critical public health emergency, with the spike glycoprotein S1 subunit of SARS-CoV-2 (spike-S1) linked to inflammation in lung tissue and immune cells. Luteolin, a flavone with anti-inflammatory properties, shows promise, but research on its [...] Read more.
Background/Objectives: The global SARS-CoV-2 outbreak has escalated into a critical public health emergency, with the spike glycoprotein S1 subunit of SARS-CoV-2 (spike-S1) linked to inflammation in lung tissue and immune cells. Luteolin, a flavone with anti-inflammatory properties, shows promise, but research on its effectiveness against long-COVID-related inflammation and spike protein-induced responses remains limited. This study aims to elucidate the underlying mechanisms of inflammation in THP-1 cells induced by the spike-S1. Additionally, it seeks to assess the potential of luteolin in mitigating inflammatory responses induced by the spike-S1 in a THP-1 macrophage model. Methods: The gene expression profiles of spike-S1 in THP-1 cells were analyzed by transcriptome sequencing. The inhibitory effect of luteolin on ER stress and inflammation in spike-S1-induced THP-1 cells was investigated using Western blotting, RT-PCR, and ELISA. Results: The candidate genes (CAMK2A, SIGLEC7, PPARGC1B, SEC22B, USP28, IER2, and TIRAP) were upregulated in the spike-S1-induced THP-1 group compared to the control group. Among these, calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) was identified as the most promising molecule in spike-S1-induced THP-1 cells. Our results indicate that the spike S1 significantly increased the expression of ER-stress markers at both gene and protein levels. Luteolin significantly reduced ER stress by decreasing the expression of ER-stress marker genes and ER-stress marker proteins (p < 0.01). Additionally, luteolin exhibited anti-inflammatory properties upon spike S1-induction in THP-1 cells by significantly suppressing IL-6, IL-8, and IL-1β cytokine secretion in a dose-dependent manner (p < 0.05). Furthermore, our results revealed that luteolin exhibited the downregulation of the MAPK pathway, as evidenced by modulating the phosphorylation of p-ERK1/2, p-JNK and p-p38 proteins (p < 0.05). Conclusions: The results from this study elucidate the mechanisms by which the spike S1 induces inflammation in THP-1 cells and supports the use of naturally occurring bioactive compounds, like luteolin, against inflammation-related SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Bioactive Substances, Oxidative Stress, and Inflammation)
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16 pages, 5977 KiB  
Article
Novel Deep Sea Isoindole Alkaloid FGFC1 Exhibits Its Fibrinolytic Effects by Inhibiting Thrombin-Activatable Fibrinolysis Inhibitor
by Haixing Zhang, Xiaozhen Diao, Tingting Jiang, Mingjun Wei, Yue Su, Jingjing Shen, Chunlin Bao and Wenhui Wu
Pharmaceuticals 2024, 17(10), 1401; https://doi.org/10.3390/ph17101401 - 20 Oct 2024
Viewed by 570
Abstract
Background: The thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator in the balance between blood clot formation (coagulation) and dissolution (fibrinolysis), which is mainly activated by thrombin bonded with thrombomodulin (TM). Methods: In this study, the investigation focused on the unique target TAFI [...] Read more.
Background: The thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator in the balance between blood clot formation (coagulation) and dissolution (fibrinolysis), which is mainly activated by thrombin bonded with thrombomodulin (TM). Methods: In this study, the investigation focused on the unique target TAFI of fungi fibrinolytic compound 1 (FGFC1), a novel fibrinolytic compound sourced from the deep sea. In this sense, the regulation of TAFI by FGFC1, in comparison to established TAFI inhibitors such as DS-1040 and PCTI in hPPP, was investigated, which was validated through the molecular docking of FGFC1 to TAFI. The inhibitory effect of FGFC1 on TAFI-mediating coagulation (ex vivo and in vitro) and its fibrinolytic effect (ex vivo) were investigated in hPPP and hCMEC/D3 cells, respectively, followed by SEM. Results: FGFC1 solutions ranging from 0.023 to 0.736 mM effectively inhibited TAFI activation. Notably, the 0.023 mM concentration demonstrated significant suppression, comparable to DS-1040 and PCTI. These inhibitory effects of FGFC1 (0.023–0.368 mM) were further validated through the enhancement in TAFI (TAFIa) activation by fibrins in the coagulum prior to proteolysis, resulting in the cleavage of TAFIa from 33 kDa to 28 kDa. Furthermore, these regulatory effects of FGFC1 on TAFI were demonstrated to have minimal association with TM-mediated control, as confirmed through a molecular docking analysis. FGFC1 (0.023–0.092 mM) was suggested to have obstructive effects on TAFI-mediated coagulation in the hPPP, which was demonstrated by the inhibition of clot aggregation, protein crystallization, and platelet anchoring, as observed through SEM. Simultaneously, FGFC1 (0.023 to 0.368 mM) significantly enhanced TAFI-mediated fibrinolysis, which was also supported by increased levels of t-PA, u-PA, and plasmin. Conclusions: From the above findings, FGFC1 is identified as a novel dual-target bioactive compound participating in blood formation/dissolution that demonstrates anti-coagulation and fibrinolytic effects by regulating TAFI activation, inhibiting TAFIa–fibrin combination, and initiating proteolysis. It also provided convincing evidence that TAFI plays a critical role in thrombolysis as a molecular link between coagulation and fibrinolysis. Furthermore, the application of FGFC1 was indicated as a potential therapeutic strategy in thromboembolic and hemorrhagic diseases. Full article
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25 pages, 6428 KiB  
Article
Hydrogel Containing Propolis: Physical Characterization and Evaluation of Biological Activities for Potential Use in the Treatment of Skin Lesions
by Lindalva Maria de Meneses Costa Ferreira, Naila Ferreira da Cruz, Desireé Gyles Lynch, Patrícia Fagundes da Costa, Claudio Guedes Salgado, José Otávio Carréra Silva-Júnior, Alessandra Rossi and Roseane Maria Ribeiro-Costa
Pharmaceuticals 2024, 17(10), 1400; https://doi.org/10.3390/ph17101400 - 20 Oct 2024
Viewed by 848
Abstract
Background: Skin injury affects the integrity of the skin structure and induces the wound healing process, which is defined by a well-coordinated series of cellular and molecular reactions that aim to recover or replace the injured tissue. Hydrogels are a group of promising [...] Read more.
Background: Skin injury affects the integrity of the skin structure and induces the wound healing process, which is defined by a well-coordinated series of cellular and molecular reactions that aim to recover or replace the injured tissue. Hydrogels are a group of promising biomaterials that are able to incorporate active ingredients for use as dressings. This study aimed to synthesize hydrogels with and without propolis extract and evaluate their physical characteristics and biological activities in vitro for potential use as active dressings in the treatment of skin lesions. Methods: The antifungal [Candida albicans (C. albicans) and Candida tropicalis (C. tropicalis)] and antibacterial [Staphylococcus aureus (S. aureus), Pseudomonas aeruginosas (P. aeruginosas) and Escherichia coli (E. coli)] activity was assessed by the microdilution method in plates and antioxidant potential by the reduction of the phosphomolybdate complex. Results: The hydrogels showed good water absorption capacity, high solubility, and high gel fraction, as well as good porosity, water retention, and vapor transmission rates. They revealed a totally amorphous structure. The extract and the hydrogels containing the propolis extract (1.0% and 2.5%) did not inhibit fungal growth. However, they showed antibacterial activity against strains of S. aureus and P. aeruginosas. Regarding the E. coli strain, only the extract inhibited its growth. It showed good antioxidant activity by the evaluation method used. Conclusions: Therefore, the hydrogels containing propolis extract can be a promising alternative with antibacterial and antioxidant action for use as dressings for the treatment of skin lesions. Full article
(This article belongs to the Section Medicinal Chemistry)
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35 pages, 4039 KiB  
Review
Jatropha Diterpenes: An Updated Review Concerning Their Structural Diversity, Therapeutic Performance, and Future Pharmaceutical Applications
by Thalisson A. de Souza, Luiz H. A. Pereira, Alan F. Alves, Douglas Dourado, Jociano da S. Lins, Marcus T. Scotti, Luciana Scotti, Lucas S. Abreu, Josean F. Tavares and Marcelo S. Silva
Pharmaceuticals 2024, 17(10), 1399; https://doi.org/10.3390/ph17101399 - 19 Oct 2024
Viewed by 1022
Abstract
The Euphorbiaceae family is a rich source of bioactive terpenoids. Among its genera, Jatropha is a conspicuous producer of diterpenes and includes approximately 175 species, many of which have medicinal uses. To date, 140 diterpenes from Jatropha (JTDs) have been reported. Given their [...] Read more.
The Euphorbiaceae family is a rich source of bioactive terpenoids. Among its genera, Jatropha is a conspicuous producer of diterpenes and includes approximately 175 species, many of which have medicinal uses. To date, 140 diterpenes from Jatropha (JTDs) have been reported. Given their structural diversity and notable biological activities, this work aims to highlight the pharmaceutical potential of JTDs. To achieve this goal, an extensive literature review was conducted, encompassing studies on structural elucidation through NMR and pharmacological assays, both in vitro and in vivo. Based on 132 selected papers, a thorough discussion is presented on the biosynthesis, extraction, isolation, and structural characterization of JTDs, including a compilation of their 13C NMR chemical shifts. The review also covers their synthetic production and biological effects. Additionally, an in silico analysis predicting the drug-likeness of 141 JTDs was carried out. Notably, the occurrence of macrocyclic diterpenes has doubled in the past decade, and the summary of their NMR data provides a useful resource for future research. Furthermore, 21 distinct pharmacological activities were identified, with potent cytotoxic effects targeting new molecular pathways being particularly significant. Recent advances highlight the contributions of modern approaches in organic synthesis and the pharmacological evaluation of natural products. The drug-likeness analysis identified JTD classes and compounds with favorable physicochemical and ADMET features for pharmaceutical development. In light of these findings, the use of nanotechnology is proposed as a future direction for continued research on JTDs, a fascinating class of natural compounds. This work opens up new avenues for the study of Euphorbiaceae species, particularly the Jatropha genus and its bioactive compounds. Full article
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18 pages, 2961 KiB  
Article
Protective Capacity of Helichrysum italicum Infusion Against Intestinal Barrier Disruption and Translocation of Salmonella Infantis
by Katja Kramberger, Katja Bezek Kranjc, Zala Jenko Pražnikar, Darja Barlič-Maganja and Saša Kenig
Pharmaceuticals 2024, 17(10), 1398; https://doi.org/10.3390/ph17101398 - 19 Oct 2024
Viewed by 931
Abstract
Background: Helichrysum italicum is a Mediterranean plant with well-known anti-inflammatory activity, but our previous whole transcriptome analysis has found that H. italicum infusion (HII) can also affect cytoskeletal rearrangement and tight junctions. The goal of the present study was to determine if HII [...] Read more.
Background: Helichrysum italicum is a Mediterranean plant with well-known anti-inflammatory activity, but our previous whole transcriptome analysis has found that H. italicum infusion (HII) can also affect cytoskeletal rearrangement and tight junctions. The goal of the present study was to determine if HII improves the intestinal barrier (IB) dysfunction and by what mechanism. Methods: Caco-2 cells on Transwell inserts were used as a model of IB permeability. Heat-killed (HKB) or live Salmonella Infantis bacteria were used to induce IB integrity disruption upon three different testing conditions: pre-, co-, and post-treatment with 0.2 v/v% HII. Transepithelial electrical resistance values were used as an indicator of monolayer integrity before and after all treatments, and RT-PCR was used to assess the expression of tight junction proteins (TJPs) and inflammatory cytokines known to regulate intestinal permeability. Results: We found that all three treatments with HII improved the HKB-induced integrity disruption and decreased the down-regulation of TJP1, OCLN, and CLDN1, with the greatest effect observed in the pre-treated cells. Treatment with HII also decreased the up-regulation of CLDN2, TNF-α, IL-1β, and IL-6. In addition, pre-treatment of Caco-2 cells with HII prevented translocation of S. Infantis but did not prevent adhesion and invasion. Conclusion: This study showed that HII can improve inflammation-disrupted IB function by indirect modulation of mRNA expression of TJPs, especially in a preventive manner. Full article
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30 pages, 9304 KiB  
Article
Effects of Free and Nanoencapsulated Benznidazole in Acute Trypanosoma cruzi Infection: Role of Cholinergic Pathway and Redox Status
by Aniélen D. da Silva, Mateus Fracasso, Nathieli B. Bottari, Taís V. Palma, Ana M. Engelmann, Milagros F. V. Castro, Charles E. Assmann, Vitor Mostardeiro, Karine P. Reichert, Jelson Nauderer, Marcelo L. da Veiga, Maria Izabel U. M. da Rocha, Luiz Claudio Milleti, Gabriella B. das Neves, Samanta Gundel, Aline F. Ourique, Silvia G. Monteiro, Vera M. Morsch, Maria Rosa Chitolina and Aleksandro S. Da Silva
Pharmaceuticals 2024, 17(10), 1397; https://doi.org/10.3390/ph17101397 - 19 Oct 2024
Viewed by 781
Abstract
Background/Objectives: The Trypanosoma cruzi infection promotes an intense inflammatory process that affects several tissues. The cholinergic system may exert a regulatory immune response and control the inflammatory process. This study aimed to evaluate the comparative effect of free and nanoencapsulated benznidazole in [...] Read more.
Background/Objectives: The Trypanosoma cruzi infection promotes an intense inflammatory process that affects several tissues. The cholinergic system may exert a regulatory immune response and control the inflammatory process. This study aimed to evaluate the comparative effect of free and nanoencapsulated benznidazole in acute T. cruzi infection to assess hematological, biochemical, and oxidative status triggered by the cholinergic system. Methods: For this, fifty female Swiss mice were distributed in eight groups, i.e., uninfected and infected animals under four treatment protocols: untreated (control—CT); vehicle treatment (Eudragit L 100—EL-100); benznidazole treatment (BNZ); and nanoencapsulated benznidazole treatment (NBNZ). After eight treatment days, the animals were euthanized for sample collection. Results: The peak of parasitemia was at day 7 p.i., and the BNZ and NBNZ controlled and reduced the parasite rate but showed no efficacy in terms of total elimination of parasites analyzed by RT-PCR in both infected groups. The infection promotes significant anemia, leukopenia, and thrombocytopenia, which the BNZ improves. There was an increase in AChE activity during infection, leading to a pro-inflammatory response and an increase in M1 and M2 mACh receptors in the BNZ group, showing that the treatment interacted with the cholinergic pathway. In addition, a pro-oxidative response was characterized in the infection and mainly in the infected BNZ and NBNZ groups. The histopathological analysis showed significative splenomegaly and inflammatory infiltrate in the heart, liver, and spleen. Conclusions: The administration of the BNZ or NBNZ reverses hematological, hepatic, and renal alterations through cholinergic signaling and stimulates a pro-inflammatory response during acute T. cruzi infection. Full article
(This article belongs to the Special Issue Drug Discovery of Antiprotozoal Agents 2024)
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12 pages, 1631 KiB  
Review
The Impact of Pdcd4, a Translation Inhibitor, on Drug Resistance
by Qing Wang and Hsin-Sheng Yang
Pharmaceuticals 2024, 17(10), 1396; https://doi.org/10.3390/ph17101396 - 19 Oct 2024
Viewed by 556
Abstract
Programmed cell death 4 (Pdcd4) is a tumor suppressor, which has been demonstrated to efficiently suppress tumorigenesis. Biochemically, Pdcd4 binds with translation initiation factor 4A and represses protein translation. Beyond its role in tumor suppression, growing evidence suggests that Pdcd4 enhances the chemosensitivity [...] Read more.
Programmed cell death 4 (Pdcd4) is a tumor suppressor, which has been demonstrated to efficiently suppress tumorigenesis. Biochemically, Pdcd4 binds with translation initiation factor 4A and represses protein translation. Beyond its role in tumor suppression, growing evidence suggests that Pdcd4 enhances the chemosensitivity of several anticancer drugs. To date, numerous translational targets of Pdcd4 have been identified. These targets govern important signal transduction pathways, and their attenuation may improve chemosensitivity or overcome drug resistance. This review will discuss the signal transduction pathways regulated by Pdcd4 and the potential mechanisms through which Pdcd4 enhances chemosensitivity or counteracts drug resistance. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 3709 KiB  
Article
Oral Active Carbon Quantum Dots for Diabetes
by Gamze Camlik, Besa Bilakaya, Esra Küpeli Akkol, Adrian Joshua Velaro, Siddhanshu Wasnik, Adi Muradi Muhar, Ismail Tuncer Degim and Eduardo Sobarzo-Sánchez
Pharmaceuticals 2024, 17(10), 1395; https://doi.org/10.3390/ph17101395 - 19 Oct 2024
Viewed by 603
Abstract
Background/Objectives: Metformin (Met), an oral drug used to treat type II diabetes, is known to control blood glucose levels. Metformin carbon quantum dots (MetCQDs) were prepared to enhance the bioavailability and effectiveness of metformin. Several studies have shown that carbon quantum dots (CQDs) [...] Read more.
Background/Objectives: Metformin (Met), an oral drug used to treat type II diabetes, is known to control blood glucose levels. Metformin carbon quantum dots (MetCQDs) were prepared to enhance the bioavailability and effectiveness of metformin. Several studies have shown that carbon quantum dots (CQDs) have attractive properties like small particle size, high penetrability, low cytotoxicity, and ease of synthesis. CQDs are made from a carbon source, namely, citric acid, and a heteroatom, such as nitrogen. The active molecule can be a carbon source or a heteroatom, as reported here. Methods: This study aims to produce MetCQDs from an active molecule. MetCQDs were successfully produced by microwave-based production methods and characterized. The effect of the MetCQDs was tested in Wistar albino rats following a Streptozocin-induced diabetic model. Results: The results show that the products have a particle size of 9.02 ± 0.04 nm, a zeta potential of −10.4 ± 0.214 mV, and a quantum yield of 15.1 ± 0.045%. Stability studies and spectrophotometric analyses were carried out and the effectiveness of MetCQDs evaluated in diabetic rats. The results show a significant reduction in blood sugar levels (34.1–51.1%) compared to the group receiving only metformin (37.1–55.3%) over a period of 30 to 360 min. Histopathological examinations of the liver tissue indicate improvement in the liver health indicators of the group treated with MetCQDs. Conclusions: Based on these results, the products have potential therapeutic advantages in diabetes management through their increased efficacy and may have reduced side effects compared to the control group. Full article
(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy)
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17 pages, 11924 KiB  
Article
Auranofin as a Novel Anticancer Drug for Anaplastic Thyroid Cancer
by Seung-Chan An, Hak Hoon Jun, Kyeong Mi Kim, Issac Kim, Sujin Choi, Hyunjeong Yeo, Soonchul Lee and Hyun-Ju An
Pharmaceuticals 2024, 17(10), 1394; https://doi.org/10.3390/ph17101394 - 18 Oct 2024
Viewed by 759
Abstract
Background/Objectives: Anaplastic thyroid cancer (ATC) is an aggressive and rare cancer with a poor prognosis, and traditional therapies have limited efficacy. This study investigates drug repositioning, focusing on auranofin, a gold-based drug originally used for rheumatoid arthritis, as a potential treatment for ATC. [...] Read more.
Background/Objectives: Anaplastic thyroid cancer (ATC) is an aggressive and rare cancer with a poor prognosis, and traditional therapies have limited efficacy. This study investigates drug repositioning, focusing on auranofin, a gold-based drug originally used for rheumatoid arthritis, as a potential treatment for ATC. Methods: Auranofin was identified from an FDA-approved drug library and tested on two thyroid cancer cell lines, 8505C and FRO. Antitumor efficacy was evaluated through gene and protein expression analysis using Western blot, FACS, and mRNA sequencing. In vivo experiments were conducted using subcutaneous injections in nude mice to confirm the anticancer effects of auranofin. Results: Auranofin induced reactive oxygen species (ROS) production and apoptosis, leading to a dose-dependent reduction in cell viability, G1/S phase cell cycle arrest, and altered expression of regulatory proteins. It also inhibited cancer stem cell activity and suppressed epithelial–mesenchymal transition. mRNA sequencing revealed significant changes in the extracellular matrix–receptor interaction pathway, supported by Western blot results. In vivo xenograft models demonstrated strong antitumor activity. Conclusions: Auranofin shows promise as a repurposed therapeutic agent for ATC, effectively inhibiting cell proliferation, reducing metastasis, and promoting apoptosis. These findings suggest that auranofin could play a key role in future ATC treatment strategies. Full article
(This article belongs to the Special Issue Advances in Drug Analysis and Drug Development)
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11 pages, 1350 KiB  
Article
Protective Effects of Annona Atemoya Extracts on Inflammation, Oxidative Stress, and Renal Function in Cadmium-Induced Nephrotoxicity in Wistar Rats
by Alexandre Coelho Serquiz, Joana de Angelis da Costa Barros Gomes, Naisandra Bezerra da Silva Farias, Denise Mafra, Pietra Maria Pereira de Lima, Daniella de Oliveira Coutinho, Fernanda Priscila Barbosa Ribeiro, Hugo Alexandre de Oliveira Rocha and José Luiz de Brito Alves
Pharmaceuticals 2024, 17(10), 1393; https://doi.org/10.3390/ph17101393 - 18 Oct 2024
Viewed by 443
Abstract
Background: Cadmium (Cd), a highly toxic heavy metal from agricultural activities, and its exposure can lead to impaired renal function by increasing reactive oxygen species. The atemoya fruit is known for its high phenolic and antioxidant compounds. This study aimed to evaluate the [...] Read more.
Background: Cadmium (Cd), a highly toxic heavy metal from agricultural activities, and its exposure can lead to impaired renal function by increasing reactive oxygen species. The atemoya fruit is known for its high phenolic and antioxidant compounds. This study aimed to evaluate the effects of atemoya extracts on renal function, oxidative stress parameters, and inflammatory biomarkers in a cadmium-induced nephrotoxicity model. Methods: Three aqueous extracts were prepared from different parts of the atemoya fruit: seeds, peel, and pulp. Twenty-five male Wistar rats were allocated into four groups: control, seed, peel, and pulp extracts at 2 g/kg for 25 days. All treatment groups administered intraperitoneal injections of cadmium chloride (CdCl2) (2 mg/kg) to induce renal damage. Results: The cadmium-treated groups showed decreased creatinine clearance, SOD, CAT, and GPx activities (p < 0.05) and increased serum levels of TNF-α and IL-6 compared to the control group (p < 0.05). The treatment with seed, peel, and pulp extracts increased creatinine clearance (p < 0.05), increased SOD, CAT, and GPx activities (p < 0.05), and reduced serum levels of TNF-α and IL-6 compared to the Cd group (p < 0.05). Conclusions: This study supports the use of atemoya as a promising candidate for mitigating nephrotoxicity and highlights the importance of its antioxidant and anti-inflammatory properties in renal health. Full article
(This article belongs to the Special Issue Bioactive Substances, Oxidative Stress, and Inflammation)
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16 pages, 1702 KiB  
Article
Assessing the Neurodevelopmental Impact of Fluoxetine, Citalopram, and Paroxetine on Neural Stem Cell-Derived Neurons
by Kimia Hosseini, Andrea Cediel-Ulloa, Mohamed H. AL-Sabri, Anna Forsby and Robert Fredriksson
Pharmaceuticals 2024, 17(10), 1392; https://doi.org/10.3390/ph17101392 - 18 Oct 2024
Viewed by 564
Abstract
Background/Objectives: Many pregnant women globally suffer from depression and are routinely prescribed selective serotonin reuptake inhibitors (SSRIs). These drugs function by blocking the re-uptake of serotonin by the serotonin transporter (SERT) into neurons, resulting in its accumulation in the presynaptic cleft. Despite a [...] Read more.
Background/Objectives: Many pregnant women globally suffer from depression and are routinely prescribed selective serotonin reuptake inhibitors (SSRIs). These drugs function by blocking the re-uptake of serotonin by the serotonin transporter (SERT) into neurons, resulting in its accumulation in the presynaptic cleft. Despite a large amount of research suggesting a potential link to neurodevelopmental disorders in children whose mothers took these drugs during pregnancy, their possible adverse effects are still debated, and results are contradictory. On the other hand, there is an immediate need for improved cell-based models for developmental neurotoxicity studies (DNT) to minimize the use of animals in research. Methods: In this study, we aimed to assess the effects of clinically relevant concentrations of paroxetine (PAR), fluoxetine (FLX), and citalopram (CIT)—on maturing neurons derived from human neural stem cells using multiple endpoints. Results: Although none of the tested concentrations of FLX, CIT, or PAR significantly affected cell viability, FLX (10 µM) exhibited the highest reduction in viability compared to the other drugs. Regarding neurite outgrowth, CIT did not have a significant effect. However, FLX (10 µM) significantly reduced both mean neurite outgrowth and mean processes, PAR significantly reduced mean processes, and showed a trend of dysregulation of multiple genes associated with neuronal development at therapeutic-relevant serum concentrations. Conclusions: Transcriptomic data and uptake experiments found no SERT activity in the system, suggesting that the adverse effects of FLX and PAR are independent of SERT. Full article
(This article belongs to the Section Pharmacology)
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21 pages, 1019 KiB  
Review
Amyotrophic Lateral Sclerosis: Insights and New Prospects in Disease Pathophysiology, Biomarkers and Therapies
by Jameel M. Al-Khayri, Mamtha Ravindran, Akshatha Banadka, Chendanda Devaiah Vandana, Kushalva Priya, Praveen Nagella and Kowshik Kukkemane
Pharmaceuticals 2024, 17(10), 1391; https://doi.org/10.3390/ph17101391 - 18 Oct 2024
Viewed by 1331
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease’s [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disorder marked by the gradual loss of motor neurons, leading to significant disability and eventual death. Despite ongoing research, there are still limited treatment options, underscoring the need for a deeper understanding of the disease’s complex mechanisms and the identification of new therapeutic targets. This review provides a thorough examination of ALS, covering its epidemiology, pathology, and clinical features. It investigates the key molecular mechanisms, such as protein aggregation, neuroinflammation, oxidative stress, and excitotoxicity that contribute to motor neuron degeneration. The role of biomarkers is highlighted for their importance in early diagnosis and disease monitoring. Additionally, the review explores emerging therapeutic approaches, including inhibitors of protein aggregation, neuroinflammation modulators, antioxidant therapies, gene therapy, and stem cell-based treatments. The advantages and challenges of these strategies are discussed, with an emphasis on the potential for precision medicine to tailor treatments to individual patient needs. Overall, this review aims to provide a comprehensive overview of the current state of ALS research and suggest future directions for developing effective therapies. Full article
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16 pages, 4745 KiB  
Article
New Quinazolin-4(3H)-One Derivatives Incorporating Isoxazole Moiety as Antioxidant Agents: Synthesis, Structural Characterization, and Theoretical DFT Mechanistic Study
by Yassine Rhazi, Riham Sghyar, Noemi Deak, Bouchra Es-Sounni, Bouchra Rossafi, Albert Soran, Mustapha Laghmari, Azize Arzine, Asmae Nakkabi, Khalil Hammani, Samir Chtita, Mohammed M. Alanazi, Gabriela Nemes and Mohamed El. Yazidi
Pharmaceuticals 2024, 17(10), 1390; https://doi.org/10.3390/ph17101390 - 18 Oct 2024
Viewed by 508
Abstract
Background: This research centers on the development and spectroscopic characterization of new quinazolin-4(3H)-one-isoxazole derivatives (5a–e). The aim was to investigate the regioselectivity of the 1,3-dipolar cycloaddition involving arylnitriloxides and N-propargylquinazolin-4(3H)-one, and to assess the antioxidant properties of the synthesized compounds. [...] Read more.
Background: This research centers on the development and spectroscopic characterization of new quinazolin-4(3H)-one-isoxazole derivatives (5a–e). The aim was to investigate the regioselectivity of the 1,3-dipolar cycloaddition involving arylnitriloxides and N-propargylquinazolin-4(3H)-one, and to assess the antioxidant properties of the synthesized compounds. The synthetic approach started with the alkylation of quinazolin-4(3H)-one using propargyl bromide, followed by a 1,3-dipolar cycloaddition reaction. Methods: The structural identification of the products was performed using various spectroscopic methods, such as IR, 1H, 13C, and HMBC NMR, HRMS, and single-crystal X-ray diffraction. To further examine the regioselectivity of the cycloaddition, Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d) level were employed. Additionally, the antioxidant potential of the compounds was tested in vitro using DPPH (2,2-Diphenyl-1-picrylhydrazyl)radical scavenging assays. The reaction selectively produced 3,5-disubstituted isoxazoles, with the regiochemical outcome being independent of the substituents on the phenyl ring. Results: Theoretical calculations using DFT were in agreement with the experimental results, revealing activation energies of −81.15 kcal/mol for P-1 and −77.32 kcal/mol for P-2, favoring the formation of P-1. An analysis of the Intrinsic Reaction Coordinate (IRC) confirmed that the reaction proceeded via a concerted but asynchronous mechanism. The antioxidant tests demonstrated that the synthesized compounds exhibited significant radical scavenging activity, as shown in the DPPH assay. The 1,3-dipolar cycloaddition of arylnitriloxides with N-propargylquinazolin-4(3H)-one successfully resulted in novel 3,5-disubstituted isoxazoles. Conclusions: The experimental findings were well-supported by theoretical predictions, and the antioxidant assays revealed strong activity, indicating the potential for future biological applications of these compounds. Full article
(This article belongs to the Section Medicinal Chemistry)
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23 pages, 2007 KiB  
Review
Targeting Tumor Hypoxia with Nanoparticle-Based Therapies: Challenges, Opportunities, and Clinical Implications
by Sujit Kumar Debnath, Monalisha Debnath, Arnab Ghosh, Rohit Srivastava and Abdelwahab Omri
Pharmaceuticals 2024, 17(10), 1389; https://doi.org/10.3390/ph17101389 - 18 Oct 2024
Viewed by 845
Abstract
Hypoxia is a crucial factor in tumor biology, affecting various solid tumors to different extents. Its influence spans both early and advanced stages of cancer, altering cellular functions and promoting resistance to therapy. Hypoxia reduces the effectiveness of radiotherapy, chemotherapy, and immunotherapy, making [...] Read more.
Hypoxia is a crucial factor in tumor biology, affecting various solid tumors to different extents. Its influence spans both early and advanced stages of cancer, altering cellular functions and promoting resistance to therapy. Hypoxia reduces the effectiveness of radiotherapy, chemotherapy, and immunotherapy, making it a target for improving therapeutic outcomes. Despite extensive research, gaps persist, necessitating the exploration of new chemical and pharmacological interventions to modulate hypoxia-related pathways. This review discusses the complex pathways involved in hypoxia and the associated pharmacotherapies, highlighting the limitations of current treatments. It emphasizes the potential of nanoparticle-based platforms for delivering anti-hypoxic agents, particularly oxygen (O2), to the tumor microenvironment. Combining anti-hypoxic drugs with conventional cancer therapies shows promise in enhancing remission rates. The intricate relationship between hypoxia and tumor progression necessitates novel therapeutic strategies. Nanoparticle-based delivery systems can significantly improve cancer treatment efficacy by targeting hypoxia-associated pathways. The synergistic effects of combined therapies underscore the importance of multimodal approaches in overcoming hypoxia-mediated resistance. Continued research and innovation in this area hold great potential for advancing cancer therapy and improving patient outcomes. Full article
(This article belongs to the Special Issue Tumor Therapy and Drug Delivery)
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21 pages, 3907 KiB  
Article
Synthesis and Bioevaluation of New Stable Derivatives of Chrysin-8-C-Glucoside That Modulate the Antioxidant Keap1/Nrf2/HO-1 Pathway in Human Macrophages
by Javier Ávila-Román, Lirenny Quevedo-Tinoco, Antonio J. Oliveros-Ortiz, Sara García-Gil, Gabriela Rodríguez-García, Virginia Motilva, Mario A. Gómez-Hurtado and Elena Talero
Pharmaceuticals 2024, 17(10), 1388; https://doi.org/10.3390/ph17101388 - 17 Oct 2024
Viewed by 516
Abstract
Background/Objectives: The beneficial effects of the flavonoid chrysin can be reduced by its poor oral bioavailability. It has been shown that chrysin-8-C-glucoside (1) has a better absorption capability. The aim of this study was to evaluate the antioxidant and anti-inflammatory [...] Read more.
Background/Objectives: The beneficial effects of the flavonoid chrysin can be reduced by its poor oral bioavailability. It has been shown that chrysin-8-C-glucoside (1) has a better absorption capability. The aim of this study was to evaluate the antioxidant and anti-inflammatory activity of this glucoside, as well as the respective hexa-acetate derivative 1a and the hexa-ethyl carbonate derivative 1b since the inclusion of moieties in bioactive molecules may increase or modify their biological effects. Methods: THP-1 macrophages were used to determine the viability in the presence of chrysin derivatives, and non-cytotoxic concentrations were selected. Subsequently, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) production and inflammatory mediators were examined. The involvement of chrysin derivatives with the Keap1 and Nrf2 antioxidant system was determined by docking and Western blotting studies. Results: Our data demonstrated, for the first time, that pretreatment with the three compounds caused a significant reduction in LPS-induced reactive oxygen species (ROS) production and pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) levels, as well as in cyclooxygenase 2 (COX-2) expression. The mechanisms underlying these protective effects were related, at least in part, to the competitive molecular interactions of these phenolic compounds with Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2), which would allow the dissociation of Nrf2 and its translocation into the nucleus and the subsequent up-regulation of hemo-oxygenase 1 (HO-1) expression. Conclusions: Compared to the 8-C-glucoside parent chrysin, compound 1a exhibited the strongest antioxidant and anti-inflammatory activity. We hypothesized that the incorporation of an acetate group (1a) may reduce its polarity and, thus, increase membrane permeability, leading to better pharmacological activity. These findings support the potential use of these phenolic compounds as Nrf2 activators against oxidative-stress-related inflammatory diseases. Full article
(This article belongs to the Section Pharmacology)
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13 pages, 271 KiB  
Article
Club Drugs and Psychiatric Outcomes: A Descriptive Case Series from Spain
by Chiara Montemitro, Alessio Mosca, Stefania Chiappini, Andrea Miuli, Fabrizio Schifano, Maria Josè Gordillo Montano, Cristina Merino del Villar, Rita Allegretti, Carlotta Marrangone, Gilberto Di Petta, Domenico De Berardis, Mauro Pettorruso and Giovanni Martinotti
Pharmaceuticals 2024, 17(10), 1387; https://doi.org/10.3390/ph17101387 - 17 Oct 2024
Viewed by 525
Abstract
Background: illegal drugs significantly contribute to global health issues, with health complications often occurring not only in regular users with Substance Use Disorders (SUDs) but also in first-time and occasional users. Methods: this study examines five clinical cases from a public hospital in [...] Read more.
Background: illegal drugs significantly contribute to global health issues, with health complications often occurring not only in regular users with Substance Use Disorders (SUDs) but also in first-time and occasional users. Methods: this study examines five clinical cases from a public hospital in Ibiza, Spain, where patients presented with acute psychiatric symptoms due to recreational drug use. Results: Contrary to previous studies on SUDs, our patients typically had higher education levels and stable employment. Most of them used multiple substances, with cannabis, cocaine, and alcohol being the most frequently used. There was also a common occurrence of consuming drugs with uncertain contents. Upon admission, typical symptoms included aggression, hallucinations, mood swings, and disorientation in time and space. Conclusions: Our findings underscore the significant mental health risks posed by illicit drugs, even for individuals with no prior psychiatric history. Factors like the drug’s potency, frequency and amount of use, past mental health issues, personality traits, and previous traumatic experiences might influence the onset of these symptoms. Full article
12 pages, 870 KiB  
Article
Hydroxyurea Pharmacokinetic Evaluation in Patients with Sickle Cell Disease
by Daniela Di Grazia, Cristina Mirabella, Francesco Chiara, Maura Caudana, Francesco Maximillian Anthony Shelton Agar, Marina Zanatta, Sarah Allegra, Jenni Bertello, Vincenzo Voi, Giovanni Battista Ferrero, Giuliana Abbadessa and Silvia De Francia
Pharmaceuticals 2024, 17(10), 1386; https://doi.org/10.3390/ph17101386 - 17 Oct 2024
Viewed by 632
Abstract
Background: Hydroxyurea (HU), also known as hydroxycarbamide, is an oral ribonucleotide reductase inhibitor. In 1999, the United States Food and Drug Administration (FDA) approved HU for the treatment of sickle cell disease (SCD). Since then, it has become the cornerstone in the management [...] Read more.
Background: Hydroxyurea (HU), also known as hydroxycarbamide, is an oral ribonucleotide reductase inhibitor. In 1999, the United States Food and Drug Administration (FDA) approved HU for the treatment of sickle cell disease (SCD). Since then, it has become the cornerstone in the management of SCD patients, helping to reduce vaso-occlusive crises, acute chest syndrome, the need for blood transfusions, hospitalizations and mortality. There is considerable variability among individuals in HU pharmacokinetic (Pk) parameters that can influence treatment efficacy and toxicity. The objective of this work is part of a clinical study aimed at investigating HU Pk and determining the optimal sampling time to estimate the Area Under the Curve (AUC) in SCD patients. Methods: HU plasma concentration in 80 patients at various time points (2, 4, 6, 24 h) following a 48-h drug washout was quantified using High-Pressure Liquid Chromatography (HPLC) coupled with an ultraviolet (UV) detection method previously described in the literature and adapted to new conditions with partial modifications. Results: The mean HU administered dose was 19.5 ± 5.1 mg/kg (range: 7.7–37.5 mg/kg). The median AUC quantified in plasma patients was 101.3 mg/L/h (Interquartile Range (IQR): 72.5–355.9) and it was not influenced by the weight-based dose. However, there was a strong positive correlation between AUC and Body Mass Index (BMI) as well as dose per Body Surface Area (BSA). Along with a three-point approach for AUC determination present in the literature, we show results obtained from a four-point sampling strategy, which is more useful and effective for better optimizing dose escalation to the maximum tolerated dose (MTD). Moreover, we observed that most patients achieved the maximum HU plasma concentration two hours after drug administration, regardless of age differences. Conclusions: HU treatment, which represents a milestone in the treatment of SCD due to its ability to reduce disease complications and improve patients’ quality of life, requires careful monitoring to optimize the individual dose for saving potential side effects and/or adverse events. Full article
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13 pages, 1631 KiB  
Article
Exome Sequence Data of Eight SLC Transporters Reveal That SLC22A1 and SLC22A3 Variants Alter Metformin Pharmacokinetics and Glycemic Control
by Monserrat I. Morales-Rivera, Radamés Alemón-Medina, Angélica Martínez-Hernández, Cecilia Contreras-Cubas, Nelly F. Altamirano-Bustamante, Josefina Gómez-Garduño, Elvia C. Mendoza-Caamal, J. Orlando Nuñez-González, Raquel García-Álvarez, Cristina Revilla-Monsalve, José Antonio Valcarcel-Gamiño, José Rafael Villafan-Bernal, Federico Centeno-Cruz, Humberto García-Ortiz, Francisco Barajas-Olmos and Lorena Orozco
Pharmaceuticals 2024, 17(10), 1385; https://doi.org/10.3390/ph17101385 - 17 Oct 2024
Viewed by 619
Abstract
Background: Type 2 diabetes (T2D) is one of the leading causes of mortality and is a public health challenge worldwide. Metformin is the first-choice treatment for T2D; its pharmacokinetics (PK) is facilitated by members of the solute carrier (SLC) superfamily of transporters, [...] Read more.
Background: Type 2 diabetes (T2D) is one of the leading causes of mortality and is a public health challenge worldwide. Metformin is the first-choice treatment for T2D; its pharmacokinetics (PK) is facilitated by members of the solute carrier (SLC) superfamily of transporters, it is not metabolized, and it is excreted by the kidney. Although interindividual variability in metformin pharmacokinetics is documented in the Mexican population, its pharmacogenomics is still underexplored. We aimed to identify variants in metformin SLC transporter genes associated with metformin PK and response in Mexican patients. Methods: Using exome data from 2217 Mexican adults, we identified 86 biallelic SNVs in the eight known genes encoding SLC transporters, with a minor allele frequency ≥ 1%, which were analyzed in an inadequate glycemic control (IGC) association study in T2D metformin treated patients. Metformin PK was evaluated in a pediatric cohort and the effect of associated SNVs was correlated. Results: Functional annotation classified two SNVs as pathogenic. The association study revealed two blocks associated with IGC. These haplotypes comprise rs622591, rs4646272, rs4646273, and rs4646276 in SLC22A1; and rs1810126 and rs668871 in SLC22A3. PK profiles revealed that homozygotes of the SLC22A1 haplotype reached lower plasma metformin concentrations 2 h post administration than the other groups. Conclusions: Our findings highlight the potential of pharmacogenomics studies to enhance precision medicine, which may involve dosage adjustments or the exploration of alternative therapeutic options. These hold significant implications for public health, particularly in populations with a high susceptibility to develop metabolic diseases, such as Latin Americans. Full article
(This article belongs to the Special Issue Pharmacogenomics for Precision Medicine)
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22 pages, 8453 KiB  
Article
Efficacy of Quercetin and Quercetin Loaded Chitosan Nanoparticles Against Cisplatin-Induced Renal and Testicular Toxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis
by Alaa F. Bakr, Riham A. El-Shiekh, Mohamed Y. Mahmoud, Heba M. A. Khalil, Mohammad H. Alyami, Hamad S. Alyami, Omneya Galal and Dina F. Mansour
Pharmaceuticals 2024, 17(10), 1384; https://doi.org/10.3390/ph17101384 - 17 Oct 2024
Viewed by 734
Abstract
Background/Objectives: Flavonoids, including quercetin, have attracted much attention due to their potential health-promoting effects. Methods: The current experiment aims to see whether quercetin (QUE) in nanoparticle form could mitigate testicular and renal toxicity caused by cisplatin (CIS) more effectively than normally formulated QUE. [...] Read more.
Background/Objectives: Flavonoids, including quercetin, have attracted much attention due to their potential health-promoting effects. Methods: The current experiment aims to see whether quercetin (QUE) in nanoparticle form could mitigate testicular and renal toxicity caused by cisplatin (CIS) more effectively than normally formulated QUE. Rats were randomly treated with CIS alone or in combination with QUE or QUE.NPs (Quercetin-loaded chitosan nanoparticles) for 4 weeks. QUE and QUE.NPs were given orally (10 mg/kg, three times a week), while CIS was given intraperitoneally (2 mg/kg, twice a week). Results: Compared to QUE- and CIS + QUE.NP-treated rats, CIS exposure induced anxiety and emotional stress as well as promoted oxidative stress in both testicular and renal tissues. Moreover, CIS reduced serum testosterone levels and diminished testicular IL-10, as well as CIS-induced renal failure, as indicated by hypokalemia, and increased levels of creatinine, urea, sodium, IL-18, and KIM-1. Further, severe histological changes were observed in the testis and kidney of CIS-intoxicated rats. Regarding immunohistochemical staining, CIS significantly upregulated Bax, downregulated Bcl-2, and moderately enhanced PCNA expression. Conclusions: Our findings suggest that both QUE and QUE.NPs modulated emotional disturbance and improved testicular and renal functions via modulation of oxidation, inflammation, and apoptosis. However, QUE.NPs performed better than QUE-treated rats. Full article
(This article belongs to the Section Pharmacology)
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18 pages, 2773 KiB  
Article
Probiotic and Postbiotic Potentials of Enterococcus faecalis EF-2001: A Safety Assessment
by Kwon Il Han, Hyun-Dong Shin, Yura Lee, Sunhwa Baek, Eunjung Moon, Youn Bum Park, Junhui Cho, Jin-Ho Lee, Tack-Joong Kim and Ranjith Kumar Manoharan
Pharmaceuticals 2024, 17(10), 1383; https://doi.org/10.3390/ph17101383 - 17 Oct 2024
Viewed by 706
Abstract
Background: Probiotics, which are live microorganisms that, when given in sufficient quantities, promote the host’s health, have drawn a lot of interest for their ability to enhance gut health. Enterococcus faecalis, a member of the human gut microbiota, has shown promise as [...] Read more.
Background: Probiotics, which are live microorganisms that, when given in sufficient quantities, promote the host’s health, have drawn a lot of interest for their ability to enhance gut health. Enterococcus faecalis, a member of the human gut microbiota, has shown promise as a probiotic candidate due to its functional attributes. However, safety concerns associated with certain strains warrant comprehensive evaluation before therapeutic application. Materials and Methods: In this study, E. faecalis EF-2001, originally isolated from fecal samples of a healthy human infant, was subjected to a multi-faceted assessment for its safety and probiotic potential. In silico analysis, CAZyme, biosynthetic, and stress-responsive proteins were identified. Results: The genome lacked biogenic amine genes but contained some essential amino acid and vitamin synthetic genes, and carbohydrate-related enzymes essential for probiotic properties. The negligible difference of 0.03% between the 1st and 25th generations indicates that the genetic information of the E. faecalis EF-2001 genome remained stable. The live E. faecalis EF-2001 (E. faecalis EF-2001L) demonstrated low or no virulence potential, minimal D-Lactate production, and susceptibility to most antibiotics except some aminoglycosides. No bile salt deconjugation or biogenic amine production was observed in an in vitro assay. Hemolytic activity assessment showed a β-hemolytic pattern, indicating no red blood cell lysis. Furthermore, the EF-2001L did not produce gelatinase and tolerated simulated gastric and intestinal fluids in an in vitro study. Similarly, heat-killed E. faecalis EF-2001 (E. faecalis EF-2001HK) exhibits tolerance in both acid and base conditions in vitro. Further, no cytotoxicity of postbiotic EF-2001HK was observed in human colorectal adenocarcinoma HT-29 cells. Conclusions: These potential properties suggest that probiotic and postbiotic E. faecalis EF-2001 could be considered safe and retain metabolic activity suitable for human consumption. Full article
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15 pages, 2047 KiB  
Article
High-CBD Extract (CBD-X) in Asthma Management: Reducing Th2-Driven Cytokine Secretion and Neutrophil/Eosinophil Activity
by Miran Aswad, Antonina Pechkovsky, Narmeen Ghanayiem, Haya Hamza, Yaniv Dotan and Igal Louria-Hayon
Pharmaceuticals 2024, 17(10), 1382; https://doi.org/10.3390/ph17101382 - 17 Oct 2024
Viewed by 610
Abstract
Background/Objectives: Asthma is a chronic inflammatory disorder of the airways affecting over 10% of the global population. It is characterized by airway inflammation, mucus hypersecretion, and bronchial hyperresponsiveness, driven predominantly by type 2 helper T cells (Th2) and type 2 innate lymphoid cells [...] Read more.
Background/Objectives: Asthma is a chronic inflammatory disorder of the airways affecting over 10% of the global population. It is characterized by airway inflammation, mucus hypersecretion, and bronchial hyperresponsiveness, driven predominantly by type 2 helper T cells (Th2) and type 2 innate lymphoid cells (ILC2s) in a subset of patients. However, a significant portion of asthmatic individuals present with “type 2-low” asthma that is often refractory to standard inhaled corticosteroid (ICS) therapy. Therefore, developing innovative therapeutic strategies has become essential. Recent studies have highlighted cannabidiol (CBD) as a promising anti-inflammatory agent capable of modulating immune responses. This study investigates the therapeutic potential of a high-CBD extract (CBD-X) in asthma. Methods: We evaluated the effects of CBD-X on cells involved in asthma pathogenesis using primary human Th2 cells, neutrophils, and asthma mouse model. Results: Our findings indicate that CBD-X extract inhibits Th2 differentiation and reduces the secretion of IL-5 and IL-13, which are crucial cytokines in asthma. Additionally, CBD-X significantly reduces pro-inflammatory cytokines IL-8 and IL-6 in neutrophils and impairs their migration, a critical step in airway inflammation. In a murine asthma model, CBD-X administration led to marked downregulation of IgE and pro-asthmatic cytokines, along with reduced leukocyte, eosinophil, and neutrophil infiltration in lung tissues. Conclusions: These results suggest that CBD-X extract could offer a novel and complementary approach to managing both type 2-high and type 2-low asthma by targeting key inflammatory pathways and modulating immune cell behavior. Full article
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13 pages, 2487 KiB  
Article
In Vivo Effects of a GHR Synthesis Inhibitor During Prolonged Treatment in Dogs
by Elpetra P. M. Timmermans, Joëlle Blankevoort, Guy C. M. Grinwis, Sietske J. Mesu, Ronette Gehring, Patric J. D. Delhanty, Peter E. M. Maas, Ger J. Strous and Jan A. Mol
Pharmaceuticals 2024, 17(10), 1381; https://doi.org/10.3390/ph17101381 - 16 Oct 2024
Viewed by 820
Abstract
Background: The activation of the growth hormone receptor (GHR) is a major determinant of body growth. Defective GHR signaling, as seen in human Laron dwarfism, resulted in low plasma IGF-1 concentrations and limited growth, but also marked absence in the development of breast [...] Read more.
Background: The activation of the growth hormone receptor (GHR) is a major determinant of body growth. Defective GHR signaling, as seen in human Laron dwarfism, resulted in low plasma IGF-1 concentrations and limited growth, but also marked absence in the development of breast cancer and type 2 diabetes. In vitro, we identified a small molecule (C#1) that inhibits the translation of GHR mRNA to receptor protein. Methods: Before its application in humans as a potential anticancer drug, C#1 was tested in animals to evaluate whether it could be administered to achieve a plasma concentration in vivo that inhibits cell proliferation in vitro without causing unwanted toxicity. To evaluate the efficacy and toxicity of C#1, a group of six intact female Beagle dogs was treated daily each morning for 90 days with an oral solution of C#1 in Soiae oleum emulgatum at a dose of 0.1 mg/kg body weight. During treatment, dogs were closely monitored clinically, and blood samples were taken to measure plasma C#1 concentrations, complete blood counts (CBC), clinical chemistry, and endocrinology. At the end of the treatment, dogs were euthanized for gross and histopathological analysis. An additional group of six female Beagle dogs was included for statistical reasons and only evaluated for efficacy during treatment for 30 days. Results: Daily administration of C#1 resulted in a constant mean plasma concentration of approximately 50 nmol/L. In both groups, two out of six dogs developed decreased appetite and food refusal after 4–5 weeks, and occasionally diarrhea. No significant effects in CBC or routine clinical chemistry were seen. Plasma IGF-1 concentrations, used as biomarkers for defective GHR signaling, significantly decreased by 31% over time. As plasma growth hormone (GH) concentrations decreased by 51% as well, no proof of GHR dysfunction could be established. The measured 43% decrease in plasma acylated/non-acylated ghrelin ratios will also lower plasma GH concentrations by reducing activation of the GH secretagogue receptor (GHSR). C#1 did not directly inhibit the GHSR in vivo, as shown in vitro. There were no significant effects on glucose, lipid, or folate/homocysteine metabolism. Conclusions: It is concluded that with daily dosing of 0.1 mg C#1/kg body weight, the induction of toxic effects prevented further increases in dosage. Due to the concomitant decrease in both IGF-1 and GH, in vivo inhibition of GHR could not be confirmed. Since the concept of specific inhibition of GHR synthesis by small molecules remains a promising strategy, searching for compounds similar to C#1 with lower toxicity should be worthwhile. Full article
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20 pages, 6974 KiB  
Article
Targeting Ferroptosis with Small Molecule Atranorin (ATR) as a Novel Therapeutic Strategy and Providing New Insight into the Treatment of Breast Cancer
by Mine Ensoy and Demet Cansaran-Duman
Pharmaceuticals 2024, 17(10), 1380; https://doi.org/10.3390/ph17101380 - 16 Oct 2024
Viewed by 644
Abstract
Background/Objectives: Ferroptosis results from the accumulation of iron-dependent lipid peroxides and reactive oxygen species (ROS). Previous research has determined the effect of atranorin (ATR) on other cell death mechanisms, but its potential for a ferroptotic effect depending on ROS levels is unclear. This [...] Read more.
Background/Objectives: Ferroptosis results from the accumulation of iron-dependent lipid peroxides and reactive oxygen species (ROS). Previous research has determined the effect of atranorin (ATR) on other cell death mechanisms, but its potential for a ferroptotic effect depending on ROS levels is unclear. This study details the therapeutic role of small-molecule ATR through ferroptosis by suppressing MDA-MB-231, MCF-7, BT-474, and SK-BR-3 breast cancer cells. Methods: The anti-proliferative effect of ATR on cells was evaluated by xCELLigence analysis, and ferroptotic activity was evaluated by enzymatic assay kits. The changes in gene and protein expression levels of ATR were investigated by the qRT-PCR and western blot. In addition, mitochondrial changes were examined by transmission electron microscopy. Results: ATR was found to reduce cell viability in cancer cells in a dose- and time-dependent manner without showing cytotoxic effects on normal breast cells. In BT-474 and MDA-MB-231 cells, ATR, which had a higher anti-proliferative effect, increased iron, lipid peroxidation, and ROS levels in cells and decreased the T-GSH/GSSG ratio. The results revealed for the first time that small-molecule ATR exhibited anti-cancer activity by inducing the glutathione pathway and ferroptosis. Conclusions: This study highlights the potential of ATR as a drug candidate molecule that can be used in the development of new therapeutic strategies for the treatment of triple-negative and luminal-B breast cancer subtypes. Full article
(This article belongs to the Section Biopharmaceuticals)
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