Pharmaceuticals

31 pages, 890 KiB

Open AccessReview

Critical Appraisal of Pharmaceutical Therapy in Diabetic Cardiomyopathy—Challenges and Prospectives

by Elina Khattab, Michaelia Kyriakou, Elena Leonidou, Stefanos Sokratous, Angeliki Mouzarou, Michael M. Myrianthefs and Nikolaos P. E. Kadoglou

Pharmaceuticals 2025, 18(1), 134; https://doi.org/10.3390/ph18010134 - 20 Jan 2025

Viewed by 722

Abstract

Diabetes mellitus (DM) is a multifaceted disorder with a pandemic spread and a remarkable burden of cardiovascular mortality and morbidity. Diabetic cardiomyopathy (DBCM) has been increasingly recognized as the development of cardiac dysfunction, which is accompanied by heart failure (HF) symptoms in the [...] Read more.

Diabetes mellitus (DM) is a multifaceted disorder with a pandemic spread and a remarkable burden of cardiovascular mortality and morbidity. Diabetic cardiomyopathy (DBCM) has been increasingly recognized as the development of cardiac dysfunction, which is accompanied by heart failure (HF) symptoms in the absence of obvious reasons like ischemic heart disease, hypertension, or valvulopathies. Several pathophysiological mechanisms have been proposed, including metabolic disorders (e.g., glycation products), oxidative stress, low-grade inflammation, mitochondrial dysfunction, etc., which should guide the development of new therapeutic strategies. Up to now, HF treatment has not differed between patients with and without diabetes, which limits the expected benefits despite the high cardiovascular risk in the former group. However, DBCM patients may require different management, which prioritize anti-diabetic medications or testing other novel therapies. This review aims to appraise the challenges and prospectives of the individualized pharmaceutical therapy for DBCM. Full article

(This article belongs to the Section Pharmacology)

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28 pages, 1517 KiB

Open AccessReview

Molecular Mechanisms Underlying Neuroinflammation Intervention with Medicinal Plants: A Critical and Narrative Review of the Current Literature

by Sandra Maria Barbalho, Beatriz Leme Boaro, Jéssica da Silva Camarinha Oliveira, Jiří Patočka, Caroline Barbalho Lamas, Masaru Tanaka and Lucas Fornari Laurindo

Pharmaceuticals 2025, 18(1), 133; https://doi.org/10.3390/ph18010133 - 20 Jan 2025

Viewed by 1067

Abstract

Neuroinflammation is a key factor in the progression of neurodegenerative diseases, driven by the dysregulation of molecular pathways and activation of the brain’s immune system, resulting in the release of pro-inflammatory and oxidative molecules. This chronic inflammation is exacerbated by peripheral leukocyte infiltration [...] Read more.

Neuroinflammation is a key factor in the progression of neurodegenerative diseases, driven by the dysregulation of molecular pathways and activation of the brain’s immune system, resulting in the release of pro-inflammatory and oxidative molecules. This chronic inflammation is exacerbated by peripheral leukocyte infiltration into the central nervous system. Medicinal plants, with their historical use in traditional medicine, have emerged as promising candidates to mitigate neuroinflammation and offer a sustainable alternative for addressing neurodegenerative conditions in a green healthcare framework. This review evaluates the effects of medicinal plants on neuroinflammation, emphasizing their mechanisms of action, effective dosages, and clinical implications, based on a systematic search of databases such as PubMed, SCOPUS, and Web of Science. The key findings highlight that plants like Cleistocalyx nervosum var. paniala, Curcuma longa, Cannabis sativa, and Dioscorea nipponica reduce pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), inhibit enzymes (COX-2 and iNOS), and activate antioxidant pathways, particularly Nrf2. NF-κB emerged as the primary pro-inflammatory pathway inhibited across studies. While the anti-inflammatory potential of these plants is significant, the variability in dosages and phytochemical compositions limits clinical translation. Here, we highlight that medicinal plants are effective modulators of neuroinflammation, underscoring their therapeutic potential. Future research should focus on animal models, standardized protocols, and safety assessments, integrating advanced methodologies, such as genetic studies and nanotechnology, to enhance their applicability in neurodegenerative disease management. Full article

(This article belongs to the Section Natural Products)

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13 pages, 887 KiB

Open AccessPerspective

Copper Imparts a New Therapeutic Property to Resveratrol by Generating ROS to Deactivate Cell-Free Chromatin

by Salooni Khanvilkar and Indraneel Mittra

Pharmaceuticals 2025, 18(1), 132; https://doi.org/10.3390/ph18010132 - 20 Jan 2025

Viewed by 555

Abstract

Resveratrol, a bioactive phytoalexin, has been extensively studied as a pharmaceutical and nutraceutical candidate for the treatment of various diseases. Although its therapeutic effects have been largely attributed to its anti-oxidant properties, its underlying mechanisms and dose dependency are not well understood. Recent [...] Read more.

Resveratrol, a bioactive phytoalexin, has been extensively studied as a pharmaceutical and nutraceutical candidate for the treatment of various diseases. Although its therapeutic effects have been largely attributed to its anti-oxidant properties, its underlying mechanisms and dose dependency are not well understood. Recent studies have shown that cell-free chromatin particles (cfChPs), which are released daily from billions of dying cells, can enter circulation and be internalized by healthy cells, wherein they trigger various damaging effects, including double-strand DNA breaks. Notably, deactivating cfChPs using a mixture of resveratrol and copper can neutralize their harmful effects. The addition of copper imparts a novel therapeutic property to resveratrol viz. the generation of reactive oxygen species (ROS), which are capable of deactivating cfChPs without damaging the genomic DNA. This perspective article discusses how the deactivation of cfChPs via the ROS generated by combining resveratrol with copper can have multiple therapeutic effects. Exploiting the damaging effects of ROS to deactivate cfChPs and ameliorate disease conditions may be a viable therapeutic approach. Full article

(This article belongs to the Section Medicinal Chemistry)

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20 pages, 5226 KiB

Open AccessArticle

p97 Inhibitors Possessing Antiviral Activity Against SARS-CoV-2 and Low Cytotoxicity

by Rui Ding, Tiffany C. Edwards, Prithwish Goswami, Daniel J. Wilson, Christine D. Dreis, Yihong Ye, Robert J. Geraghty and Liqiang Chen

Pharmaceuticals 2025, 18(1), 131; https://doi.org/10.3390/ph18010131 - 19 Jan 2025

Viewed by 851

Abstract

Background: p97 (also known as valosin-containing protein, VCP) is a member of the AAA+ ATPase family and is intimately associated with protein quality control and homeostasis regulation. Therefore, pharmaceutical inhibition of p97 has been actively pursued as an anticancer strategy. Recently, p97 has [...] Read more.

Background: p97 (also known as valosin-containing protein, VCP) is a member of the AAA+ ATPase family and is intimately associated with protein quality control and homeostasis regulation. Therefore, pharmaceutical inhibition of p97 has been actively pursued as an anticancer strategy. Recently, p97 has emerged as an important pro-viral host factor and p97 inhibitors are being evaluated as potential antiviral agents. Methods: We designed and synthesized novel p97 inhibitors based on the rearrangement of the central fused ring of our previously reported p97 inhibitors. These compounds were tested for inhibition of p97, cytotoxicity, and antiviral activity against SARS-CoV-2. Molecular docking was also performed on selected inhibitors to shed light on their binding modes. Results: Among these new p97 inhibitors, two compounds possess enhanced anti-p97 activity over their parent compounds. More significantly, these two inhibitors exhibit strong antiviral activity against SARS-CoV-2 at doses with no significant cytotoxicity. Molecular docking reveals no major change of the binding mode relative to that of their parent compounds, further supporting our design strategy. Conclusions: These compounds are structurally novel p97 inhibitors that display low toxicity and possess promising antiviral activity against SARS-CoV-2 and potentially other viruses. Further structural exploration is therefore justified and improved analogs will serve as useful tools for studying p97 as a promising host antiviral target. Full article

(This article belongs to the Special Issue Antiviral Agents, 2024)

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20 pages, 1194 KiB

Open AccessReview

Uncovering Psychedelics: From Neural Circuits to Therapeutic Applications

by Alice Melani, Marco Bonaso, Letizia Biso, Benedetta Zucchini, Ciro Conversano and Marco Scarselli

Pharmaceuticals 2025, 18(1), 130; https://doi.org/10.3390/ph18010130 - 19 Jan 2025

Viewed by 1550

Abstract

Psychedelics, historically celebrated for their cultural and spiritual significance, have emerged as potential breakthrough therapeutic agents due to their profound effects on consciousness, emotional processing, mood, and neural plasticity. This review explores the mechanisms underlying psychedelics’ effects, focusing on their ability to modulate [...] Read more.

Psychedelics, historically celebrated for their cultural and spiritual significance, have emerged as potential breakthrough therapeutic agents due to their profound effects on consciousness, emotional processing, mood, and neural plasticity. This review explores the mechanisms underlying psychedelics’ effects, focusing on their ability to modulate brain connectivity and neural circuit activity, including the default mode network (DMN), cortico-striatal thalamo-cortical (CSTC) loops, and the relaxed beliefs under psychedelics (REBUS) model. Advanced neuroimaging techniques reveal psychedelics’ capacity to enhance functional connectivity between sensory cerebral areas while reducing the connections between associative brain areas, decreasing the rigidity and rendering the brain more plastic and susceptible to external changings, offering insights into their therapeutic outcome. The most relevant clinical trials of 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and lysergic acid diethylamide (LSD) demonstrate significant efficacy in treating treatment-resistant psychiatric conditions such as post-traumatic stress disorder (PTSD), depression, and anxiety, with favorable safety profiles. Despite these advancements, critical gaps remain in linking psychedelics’ molecular actions to their clinical efficacy. This review highlights the need for further research to integrate mechanistic insights and optimize psychedelics as tools for both therapy and understanding human cognition. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 1160 KiB

Open AccessArticle

The Effects of Oral Semaglutide on Hepatic Fibrosis in Subjects with Type 2 Diabetes in Real-World Clinical Practice: A Post Hoc Analysis of the Sapporo-Oral SEMA Study

by Hiroya Kitsunai, Yuka Shinozaki, Sho Furusawa, Naoyuki Kitao, Miki Ito, Hiroyoshi Kurihara, Chiho Oba-Yamamoto, Jun Takeuchi, Akinobu Nakamura, Yumi Takiyama and Hiroshi Nomoto

Pharmaceuticals 2025, 18(1), 129; https://doi.org/10.3390/ph18010129 - 19 Jan 2025

Viewed by 647

Abstract

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important common comorbidity in subjects with type 2 diabetes, and liver fibrosis is a factor directly related to its prognosis. Glucagon-like peptide-1 receptor agonists are useful treatment options for MASLD; however, the efficacy of [...] Read more.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important common comorbidity in subjects with type 2 diabetes, and liver fibrosis is a factor directly related to its prognosis. Glucagon-like peptide-1 receptor agonists are useful treatment options for MASLD; however, the efficacy of oral semaglutide in treating liver steatosis/fibrosis has not been fully elucidated. Methods: A secondary analysis of a multicenter, retrospective, observational study investigating the efficacy and safety of oral semaglutide in Japanese subjects with type 2 diabetes in a real-world clinical setting (the Sapporo-Oral SEMA study) was conducted. Subjects in the original cohort were divided into groups as follows: subjects with suspected MASLD (alanine aminotransferase > 30 U/L) were placed in an overall group; a subpopulation from an overall group at high risk for hepatic fibrosis (fibrosis-4 (FIB-4) index ≥ 1.3 or platelet count < 200,000/µL) was placed in a high-risk group; and the remaining subjects were placed in a low-risk group. Changes in the hepatic steatosis index and FIB-4 index after oral semaglutide induction were explored using a paired t-test or the Wilcoxon signed-rank test. Results: Overall, 169 subjects (including 131 that switched from other medications) were analyzed, and 67 and 102 subjects were selected for the high-risk and low-risk groups, respectively. Oral semaglutide significantly improved the hepatic steatosis index (from 46.1 to 44.6, p < 0.001) and FIB-4 index (from 1.04 to 0.96, p < 0.001) as well as several metabolic parameters in all cohorts. The efficacy of semaglutide in treating liver fibrosis was confirmed by the addition of, and switching from, existing agent groups. Furthermore, improvement in the FIB-4 index was significantly negatively correlated with the baseline FIB-4 index. Conclusions: The induction of oral semaglutide might be a useful treatment option for subjects with type 2 diabetes at high risk for liver fibrosis, even when switching from conventional medications for diabetes. Full article

(This article belongs to the Special Issue Pharmacotherapy of Liver Fibrosis and Hepatitis: Recent Advances)

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13 pages, 581 KiB

Open AccessArticle

Impact of Oseltamivir and Diabetes Development

by Bor-Show Tzang, Chih-Chen Tzang, Pei-Hua Chuang, I-Ying Kuo, Yu-Chun Pan, Pei-Hsun Wu and Tsai-Ching Hsu

Pharmaceuticals 2025, 18(1), 128; https://doi.org/10.3390/ph18010128 - 18 Jan 2025

Viewed by 845

Abstract

Background/Objectives: Influenza is a major global health challenge, causing thousands of deaths annually. Antiviral drugs, particularly oseltamivir, a neuraminidase inhibitor, have become essential therapeutic options due to their oral bioavailability and efficacy. Previous studies suggest a potential association between oseltamivir use and [...] Read more.

Background/Objectives: Influenza is a major global health challenge, causing thousands of deaths annually. Antiviral drugs, particularly oseltamivir, a neuraminidase inhibitor, have become essential therapeutic options due to their oral bioavailability and efficacy. Previous studies suggest a potential association between oseltamivir use and the onset of diabetes mellitus. However, further investigation is needed to establish a definitive link. Methods: This retrospective cohort study utilized data from the Taiwan National Health Insurance Research Database (NHIRD), including 1,631,968 patients (815,984 oseltamivir users) between 1 January 2009 and 28 December 2018. All statistical analyses were performed using SAS 9.4M8 software (SAS Institute Inc., Cary, NC, USA). Results: Cox proportional hazards regression and multivariate analyses revealed a statistically significant association between oseltamivir use and overall diabetes risk (HR = 1.027, p = 0.0186). While no significant association was observed for Type 1 diabetes (HR = 1.021; p = 0.06795), oseltamivir users showed a higher incidence of Type 2 diabetes (HR = 1.024; p < 0.05). Oseltamivir was also linked to increased risks of comorbidities, including dyslipidemia (HR = 1.295, p < 0.0001), chronic liver disease (HR = 1.446, p < 0.0001), hypertension (HR = 1.586, p < 0.0001), and obesity (HR = 2.949, p < 0.0001). Conclusions: Oseltamivir is associated with an increased risk of Type 2 diabetes but not Type 1, and related comorbidities. Full article

(This article belongs to the Section Pharmacology)

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38 pages, 4414 KiB

Open AccessReview

Recent Advances in Peptide-Loaded PLGA Nanocarriers for Drug Delivery and Regenerative Medicine

by Hossein Omidian, Renae L. Wilson and Ana M. Castejon

Pharmaceuticals 2025, 18(1), 127; https://doi.org/10.3390/ph18010127 - 18 Jan 2025

Viewed by 613

Abstract

Peptide-loaded poly(lactide-co-glycolide) (PLGA) nanocarriers represent a transformative approach to addressing the challenges of peptide-based therapies. These systems offer solutions to peptide instability, enzymatic degradation, and limited bioavailability by providing controlled release, targeted delivery, and improved stability. The versatility of PLGA nanocarriers extends across [...] Read more.

Peptide-loaded poly(lactide-co-glycolide) (PLGA) nanocarriers represent a transformative approach to addressing the challenges of peptide-based therapies. These systems offer solutions to peptide instability, enzymatic degradation, and limited bioavailability by providing controlled release, targeted delivery, and improved stability. The versatility of PLGA nanocarriers extends across therapeutic domains, including cancer therapy, neurodegenerative diseases, vaccine development, and regenerative medicine. Innovations in polymer chemistry, surface functionalization, and advanced manufacturing techniques, such as microfluidics and electrospraying, have further enhanced the efficacy and scalability of these systems. This review highlights the key physicochemical properties, preparation strategies, and proven benefits of peptide-loaded PLGA systems, emphasizing their role in sustained drug release, immune activation, and tissue regeneration. Despite remarkable progress, challenges such as production scalability, cost, and regulatory hurdles remain. Full article

(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)

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30 pages, 8378 KiB

Open AccessArticle

Examining Prenylated Xanthones as Potential Inhibitors Against Ketohexokinase C Isoform for the Treatment of Fructose-Driven Metabolic Disorders: An Integrated Computational Approach

by Tilal Elsaman and Magdi Awadalla Mohamed

Pharmaceuticals 2025, 18(1), 126; https://doi.org/10.3390/ph18010126 - 18 Jan 2025

Viewed by 722

Abstract

Background/Objectives: Fructose-driven metabolic disorders, such as obesity, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes, are significant global health challenges. Ketohexokinase C (KHK-C), a key enzyme in fructose metabolism, is a promising therapeutic target. α-Mangostin, a naturally occurring prenylated xanthone, has [...] Read more.

Background/Objectives: Fructose-driven metabolic disorders, such as obesity, non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and type 2 diabetes, are significant global health challenges. Ketohexokinase C (KHK-C), a key enzyme in fructose metabolism, is a promising therapeutic target. α-Mangostin, a naturally occurring prenylated xanthone, has been identified as an effective KHK-C inhibitor, prompting exploration of its analogs for enhanced efficacy. This study aimed to identify α-Mangostin analogs with improved inhibitory properties against KHK-C to address these disorders. Methods: A library of 1383 analogs was compiled from chemical databases and the literature. Molecular docking, binding free energy calculations, pharmacokinetic assessments, molecular dynamics simulations, and quantum mechani–cal analyses were used to screen and evaluate the compounds. α-Mangostin’s binding affinity (37.34 kcal/mol) served as the benchmark. Results: Sixteen analogs demonstrated binding affinities superior to α-Mangostin (from −45.51 to −61.3 kcal/mol), LY-3522348 (−45.36 kcal/mol), and reported marine-derived inhibitors (from −22.74 to −51.83 kcal/mol). Hits 7, 8, 9, 13, and 15 not only surpassed these benchmarks in binding affinity, but also exhibited superior pharmacokinetic properties compared to α-Mangostin, LY-3522348, and marine-derived inhibitors, indicating strong in vivo potential. Among these, hit 8 emerged as the best performer, achieving a binding free energy of −61.30 kcal/mol, 100% predicted oral absorption, enhanced metabolic stability, and stable molecular dynamics. Conclusions: Hit 8 emerged as the most promising candidate due to its superior binding affinity, favorable pharmacokinetics, and stable interactions with KHK-C. These findings highlight its potential for treating fructose-driven metabolic disorders, warranting further experimental validation. Full article

(This article belongs to the Special Issue Structural and Computationally Driven Molecule Design in Drug Discovery: 2nd Edition)

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21 pages, 8490 KiB

Open AccessArticle

2-Aminothiophene Derivatives—New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity

by Rodrigo Santos Aquino de Araújo, Vitória Gaspar Bernardo, Robert da Silva Tibúrcio, Danilo Cesar Galindo Bedor, Michel Leandro de Campos, Roberto Pontarolo, Julyanne Maria Saraiva de Sousa, Klinger Antonio da Franca Rodrigues, Marcus Tullius Scotti, Anuraj Nayarisseri, Pascal Marchand and Francisco Jaime Bezerra Mendonça-Junior

Pharmaceuticals 2025, 18(1), 125; https://doi.org/10.3390/ph18010125 - 17 Jan 2025

Viewed by 748

Abstract

Background/Objectives: Leishmaniasis is one of the 20 Neglected Tropical Diseases according to the WHO, affecting approximately 12 million people in four continents, generating serious public health problems. The lack of therapeutic options, associated with toxicity and the emergence of resistance to the [...] Read more.

Background/Objectives: Leishmaniasis is one of the 20 Neglected Tropical Diseases according to the WHO, affecting approximately 12 million people in four continents, generating serious public health problems. The lack of therapeutic options, associated with toxicity and the emergence of resistance to the few available drugs, makes it urgent to develop new drug options. In this context, the aims of this work are to expand the knowledge about the pharmacophore group responsible for the antileishmanial potential of 2-aminothiophene derivatives. Thus, new compounds were synthesized containing chemical modifications at the C-3, C-4, and C-5 positions of the 2-aminothiophene ring, in addition to the S-Se bioisosterism. Methods: Dozens of 2-AT and 2-aminoselenophen (2-AS) derivatives were sequentially synthesized through applications of the Gewald reaction and were then evaluated in vitro for their activities against L. amazonensis and for cytotoxicity against macrophages. Results: Several series of compounds were synthesized, and it was possible to identify some substitution patterns favorable to the activity generating compounds with IC₅₀ values below 10 µM, such as the non-essentiality of the presence of a carbonitrile group at C-3; the importance of the presence and size of cycloalkyl/piperidinyl chains at C-4 and C-5 in modulating the activity; and the increase in activity without affecting the safety of the S/Se bioisosteric substitution. Conclusions: Taken together, these findings reaffirm the great potential of 2-aminothiophenes to generate antileishmanial drug candidates and offers contributions to the drug design of compounds with an even more promising profile for the problem of leishmaniasis. Full article

(This article belongs to the Special Issue Drug Discovery of Antiprotozoal Agents 2024)

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18 pages, 3812 KiB

Open AccessArticle

The Stability-Indicating Ultra High-Performance Liquid Chromatography with Diode Array Detector and Tandem Mass Spectrometry Method Applied for the Forced Degradation Study of Ritlecitinib: An Appraisal of Green and Blue Metrics

by Jelena Kovačić, Daniela Amidžić Klarić, Nikša Turk, Željko Krznarić, Emma Riordan and Ana Mornar

Pharmaceuticals 2025, 18(1), 124; https://doi.org/10.3390/ph18010124 - 17 Jan 2025

Viewed by 723

Abstract

Background/Objectives: Janus kinase inhibitors open new horizons for small-molecule drugs in treating inflammatory bowel disease, with ritlecitinib demonstrating significant efficacy in clinical trials for ulcerative colitis and Crohn’s disease. Ritlecitinib, a second-generation JAK3 inhibitor, is a novel therapeutic agent for alopecia areata and [...] Read more.

Background/Objectives: Janus kinase inhibitors open new horizons for small-molecule drugs in treating inflammatory bowel disease, with ritlecitinib demonstrating significant efficacy in clinical trials for ulcerative colitis and Crohn’s disease. Ritlecitinib, a second-generation JAK3 inhibitor, is a novel therapeutic agent for alopecia areata and other autoimmune conditions. Methods: A new stability-indicating UHPLC-DAD-MS/MS method was developed, validated, and applied for a forced degradation study of ritlecitinib under ICH guidelines. Results: The method demonstrated high specificity, sensitivity (LOD: 0.04 µg/mL; LOQ: 0.14 µg/mL), precision (RSD ≤ 0.15%), and accuracy (99.9–100.3%). Forced degradation studies under acidic, basic, oxidative, thermal, and photolytic conditions revealed four novel degradation products. Basic degradation followed second-order kinetics, while oxidative degradation followed zero-order kinetics. Conclusions: The validated method reliably characterized ritlecitinib’s stability and degradation products, providing essential data for optimizing formulation, determining proper storage conditions, anticipating drug–excipient interactions, and ensuring quality control. The eco-friendliness and applicability of the developed forced degradation procedure were evaluated using various green and blue metric tools. Incorporating green analytical principles underscores its potential for sustainable pharmaceutical analysis. Full article

(This article belongs to the Special Issue Advances in Drug Analysis and Drug Development)

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14 pages, 11171 KiB

Open AccessArticle

Quinazolinone Derivative MR2938 Protects DSS-Induced Barrier Dysfunction in Mice Through Regulating Gut Microbiota

by Ling Lv, Mireguli Maimaitiming, Jichen Yang, Shuli Xia, Xin Li, Pingyuan Wang, Zhiqing Liu and Chang-Yun Wang

Pharmaceuticals 2025, 18(1), 123; https://doi.org/10.3390/ph18010123 - 17 Jan 2025

Viewed by 547

Abstract

Background/Objectives: Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by colorectal immune infiltration and significant microbiota compositional changes. Gut microbiota homeostasis is necessary to maintain the healthy state of humans. MR2938, a quinazolin-4(3H)-one derivative derived from the marine natural [...] Read more.

Background/Objectives: Ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), is characterized by colorectal immune infiltration and significant microbiota compositional changes. Gut microbiota homeostasis is necessary to maintain the healthy state of humans. MR2938, a quinazolin-4(3H)-one derivative derived from the marine natural product penipanoid C, alleviated DSS-induced colitis in a dose-dependent manner. Herein, we aimed to investigate the impact of MR2938 on the gut microbiota in dextran sodium sulfate (DSS)-induced colitis in mice and to elucidate the role of the gut microbiota in the therapeutic mechanism of MR2938 for alleviating colitis. Methods: Acute colitis was induced with DSS in mice. Mice were administered with 100 mg/kg or 50 mg/kg of MR2938. Cecal content was also preserved in liquid nitrogen and subsequently analyzed following 16S RNA sequencing. Antibiotic cocktail-induced microbiome depletion was performed to further investigate the relationship between MR2938 and gut microbiota. The inflammatory factor levels were performed by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Alcian blue staining and immunofluorescence were used to estimate the intestinal barrier. Results: The 16S rRNA sequencing revealed microbiota modulation by MR2938. Compared with the model group, the 100 mg/kg MR2938 group was associated with higher abundances of Entercoccus and a lower abundance of Staphylococcus, while the 50 mg/kg MR2938 group was associated with higher abundances of Lactobacillus and a lower abundance of Staphylococcus. The antibiotic-mediated microbiota depletion experiments demonstrated that the gut microbiota primarily contributed to barrier function protection, with little impact on inflammatory factor levels during the MR2938 treatment. Conclusions: These findings suggest that intestinal flora play a crucial role in MR2938’s therapeutic mechanism for alleviating colitis. Full article

(This article belongs to the Special Issue Medications: Interactions with Diet, Herbs, Dietary Supplements and Probiotics)

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25 pages, 2882 KiB

Open AccessArticle

The Clinical Pharmacokinetics and Pharmacodynamics of Glimepiride—A Systematic Review and Meta-Analysis

by Mubara Azhar, Mohammed S. Alasmari, Ammara Zamir, Hamid Saeed, Faleh Alqahtani, Tanveer Ahmad and Muhammad Fawad Rasool

Pharmaceuticals 2025, 18(1), 122; https://doi.org/10.3390/ph18010122 - 17 Jan 2025

Viewed by 1088

Abstract

Background/Objectives: Glimepiride (GLM), a commonly used sulphonylurea drug for the management of type 2 diabetes mellitus (T2DM), has been the subject of numerous studies exploring its kinetic behaviors. However, a comprehensive evaluation that synthesizes all available pharmacokinetic (PK) data across diverse populations remains [...] Read more.

Background/Objectives: Glimepiride (GLM), a commonly used sulphonylurea drug for the management of type 2 diabetes mellitus (T2DM), has been the subject of numerous studies exploring its kinetic behaviors. However, a comprehensive evaluation that synthesizes all available pharmacokinetic (PK) data across diverse populations remains limited. This systematic review aims to provide detailed knowledge about the pharmacokinetics (PK), the associated pharmacodynamics (PD), and the drug interactions of GLM, which can be used to assess key parameters and identify factors influencing variability across diverse populations and clinical settings. Methods: A systematic search of the peer-reviewed literature was combined using major databases—Google Scholar, PubMed, Cochrane, and ScienceDirect, to identify studies reporting the PK of GLM. Following the data extraction, a meta-analysis using a random effect (RE) model was performed, where feasible, to quantitatively assess the variability of key PK parameters across different studies to create a more robust PK parameter estimate. Results: The final screening has yielded 40 articles. The area under the curve (AUC_0-∞) and the peak concentration (C_max) rise proportionately with increasing doses, depicting the linear kinetics of GLM. The subjects with genotype CYP2C9 *1/*3 depicted a 4-fold higher (AUC_0-∞) as compared to that of the CYP2C9 *1/*1 population. Preliminary meta-analysis results indicated significant variability in (AUC_0-∞) and C_max values among different studies. Heterogeneity across studies was high, warranting the use of RE models. Conclusions: The findings of this review would be helpful in the development and evaluation of PK models that may aid in suggesting individualized dosing. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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24 pages, 5476 KiB

Open AccessArticle

Sustainable Skincare Innovation: Cork Powder Extracts as Active Ingredients for Skin Aging

by Ana Silva, Cláudia Pinto, Sara Cravo, Sandra Mota, Liliana Rego, Smeera Ratanji, Clara Quintas, Joana Rocha e Silva, Carlos Afonso, Maria Elizabeth Tiritan, Honorina Cidade, Teresa Cruz and Isabel F. Almeida

Pharmaceuticals 2025, 18(1), 121; https://doi.org/10.3390/ph18010121 - 17 Jan 2025

Viewed by 959

Abstract

Background: An emerging practice within the concept of circular beauty involves the upcycling of agro-industrial by-products. Cork processing, for instance, yields by-products like cork powder, which presents an opportunity to create value-added cosmetic ingredients. Building upon our previous research, demonstrating the antioxidant [...] Read more.

Background: An emerging practice within the concept of circular beauty involves the upcycling of agro-industrial by-products. Cork processing, for instance, yields by-products like cork powder, which presents an opportunity to create value-added cosmetic ingredients. Building upon our previous research, demonstrating the antioxidant potential of hydroalcoholic extracts derived from two distinct cork powders (P0 and P1), in this work, aqueous extracts were prepared and analyzed. The safety and bioactivities of the newly obtained aqueous extracts, as well as the 30% ethanol extracts, previously reported to be the most promising for skin application, were also evaluated. Methods: Aqueous extracts were obtained from cork powders (P0 and P1) and the identification and quantification of some polyphenols was achieved by liquid chromatography (LC). Antioxidant potential was screened by DPPH method and the bioactivity and safety of extracts were further explored using cell-based assays. Results: All extracts exhibited a reduction in age-related markers, including senescence-associated beta-galactosidase (SA-β-gal) activity. Additionally, they demonstrated a pronounced anti-inflammatory effect by suppressing the production of several pro-inflammatory mediators in macrophages upon lipopolysaccharide stimulation. Moreover, the extracts upregulated genes and proteins associated with antioxidant activity, such as heme oxygenase 1. The aqueous extract from P1 powder was especially active in reducing pro-inflammatory mediators, namely the Nos2 gene, inducible nitric oxide protein levels, and nitric oxide production. Moreover, it did not induce skin irritation, as assessed by the EpiSkin test, in compliance with the OECD Test Guidelines. Conclusions: Overall, our findings underscore the potential of aqueous extracts derived from cork waste streams to mitigate various hallmarks of skin aging, including senescence and inflammaging, and their suitability for incorporation into cosmetics formulations. These results warrant further exploration for their application in the pharmaceutical and cosmetic industries and could foster a sustainable and circular bioeconomy. Full article

(This article belongs to the Special Issue Natural-Based Skincare Solutions)

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21 pages, 328 KiB

Open AccessReview

Opioid System and Epithelial–Mesenchymal Transition

by Marzena Łazarczyk, Dominik Skiba, Michel-Edwar Mickael, Kinga Jaskuła, Agata Nawrocka, Piotr Religa and Mariusz Sacharczuk

Pharmaceuticals 2025, 18(1), 120; https://doi.org/10.3390/ph18010120 - 17 Jan 2025

Viewed by 621

Abstract

Opioids are a challenging class of drugs due to their dual role. They alleviate pain, but also pose a risk of dependency, or trigger constipation, particularly in cancer patients, who require the more potent painkillers in more advanced stages of the disease, closely [...] Read more.

Opioids are a challenging class of drugs due to their dual role. They alleviate pain, but also pose a risk of dependency, or trigger constipation, particularly in cancer patients, who require the more potent painkillers in more advanced stages of the disease, closely linked to pain resulting from general inflammation, bone metastases, and primary or secondary tumour outgrowth-related nerve damage. Clinicians’ vigilance considering treatment with opioids is necessary, bearing in mind extensive data accumulated over decades that have reported the contribution of opioids to immunosuppression, tumour progression, or impaired tissue regeneration, either following opioid use during surgical tumour resection and post-surgical pain treatment, or as a result of other diseases like diabetes, where chronic wounds healing constitutes a challenge. During last few years, an increasing trend for seeking relationships between opioids and epithelial–mesenchymal transition (EMT) in cancer research can be observed. Transiently lasting EMT is desirable during wound healing, but in cancer, or vital organ fibrogenesis, EMT appears to be an obstacle to overcome, forcing to adjust treatment strategies that would reduce the risk for worsening of the disease outcome and patient prognosis. The same opioid may demonstrate promoting or inhibitory effect on EMT, dependently on various conditions in particular clinical cases. We have summarized current findings on this issue to uncover some rules that govern opioid-mediated EMT induction or repression; however, many aspects still remain to be elucidated. Full article

(This article belongs to the Special Issue Targeting Opioid Receptors for Innovative Therapies: Present and Emerging Concepts in Opioid Cure)

14 pages, 1950 KiB

Open AccessArticle

Fully Automated Production of (((S)-1-Carboxy-5-(6-([¹⁸F]fluoro)-2-methoxynicotinamido)pentyl)carbamoyl)-l-glutamic Acid ([¹⁸F]JK-PSMA-7)

by Philipp Krapf, Thomas Wicher, Boris D. Zlatopolskiy, Johannes Ermert and Bernd Neumaier

Pharmaceuticals 2025, 18(1), 119; https://doi.org/10.3390/ph18010119 - 17 Jan 2025

Viewed by 529

Abstract

Background: The radiotracer [¹⁸F]JK-PSMA-7, a prostate cancer imaging agent for positron emission tomography (PET), was previously synthesized by indirect radiofluorination using an ¹⁸F-labeled active ester as a prosthetic group, which had to be isolated and purified before it could be [...] Read more.

Background: The radiotracer [¹⁸F]JK-PSMA-7, a prostate cancer imaging agent for positron emission tomography (PET), was previously synthesized by indirect radiofluorination using an ¹⁸F-labeled active ester as a prosthetic group, which had to be isolated and purified before it could be linked to the pharmacologically active Lys-urea-Glu motif. Although this procedure could be automated on two-reactor modules like the GE TRACERLab FX2N (FXN) to afford the tracer in modest radiochemical yields (RCY) of 18–25%, it is unsuitable for cassette-based systems with a single reactor. Methods: To simplify implementation on an automated synthesis module, the radiosynthesis of [¹⁸F]JK-PSMA-7 was devised as a one-pot, two-step reaction. The new method is based on direct (“late-stage”) radiofluorination of an appropriate onium triflate precursor and subsequent deprotection with ortho-phosphoric acid. It was successfully established on the cassette-based Trasis AllInOne (AIO) module. Results: Overall, the new protocol enabled the production of [¹⁸F]JK-PSMA-7 in activity yields of 39 ± 4% (RCY = 58%) with an overall synthesis time of about 1 h. In a single production run with an initial activity of 36-43 GBq, 13-19 GBq of [¹⁸F]JK-PSMA-7 with a radiochemical purity of >99% was obtained. Conclusions: We have established a highly reliable, GMP-compliant process for the automated radiosynthesis of [¹⁸F]JK-PSMA-7 on the Trasis AllinOne (AIO) synthesizer, ensuring consistent and efficient production of this radioligand. Full article

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

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54 pages, 6031 KiB

Open AccessArticle

(E)-1-(3-(3-Hydroxy-4-Methoxyphenyl)-1-(3,4,5-Trimethoxyphenyl)allyl)-1H-1,2,4-Triazole and Related Compounds: Their Synthesis and Biological Evaluation as Novel Antimitotic Agents Targeting Breast Cancer

by Gloria Ana, Azizah M. Malebari, Sara Noorani, Darren Fayne, Niamh M. O’Boyle, Daniela M. Zisterer, Elisangela Flavia Pimentel, Denise Coutinho Endringer and Mary J. Meegan

Pharmaceuticals 2025, 18(1), 118; https://doi.org/10.3390/ph18010118 - 17 Jan 2025

Viewed by 711

Abstract

Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. Methods: A panel of [...] Read more.

Background/Objectives: The synthesis of (E)-1-(1,3-diphenylallyl)-1H-1,2,4-triazoles and related compounds as anti-mitotic agents with activity in breast cancer was investigated. These compounds were designed as hybrids of the microtubule-targeting chalcones, indanones, and the aromatase inhibitor letrozole. Methods: A panel of 29 compounds was synthesized and examined by a preliminary screening in estrogen receptor (ER) and progesterone receptor (PR)-positive MCF-7 breast cancer cells together with cell cycle analysis and tubulin polymerization inhibition. Results: (E)-5-(3-(1H-1,2,4-triazol-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)-2-methoxyphenol 22b was identified as a potent antiproliferative compound with an IC₅₀ value of 0.39 mM in MCF-7 breast cancer cells, 0.77 mM in triple-negative MDA-MB-231 breast cancer cells, and 0.37 mM in leukemia HL-60 cells. In addition, compound 22b demonstrated potent activity in the sub-micromolar range against the NCI 60 cancer cell line panel including prostate, melanoma, colon, leukemia, and non-small cell lung cancers. G₂/M phase cell cycle arrest and the induction of apoptosis in MCF-7 cells together with inhibition of tubulin polymerization were demonstrated. Immunofluorescence studies confirmed that compound 22b targeted tubulin in MCF-7 cells, while computational docking studies predicted binding conformations for 22b in the colchicine binding site of tubulin. Compound 22b also selectively inhibited aromatase. Conclusions: Based on the results obtained, these novel compounds are suitable candidates for further investigation as antiproliferative microtubule-targeting agents for breast cancer. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)

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11 pages, 1230 KiB

Open AccessArticle

Neuroprotective Actions of Cannabinoids in the Bovine Isolated Retina: Role of Hydrogen Sulfide

by Leah Bush, Anthonia Okolie, Jenaye Robinson, Fatima Muili, Catherine A. Opere, Sunny E. Ohia and Ya Fatou Njie Mbye

Pharmaceuticals 2025, 18(1), 117; https://doi.org/10.3390/ph18010117 - 17 Jan 2025

Viewed by 459

Abstract

Both hydrogen sulfide and endocannabinoids can protect the neural retina from toxic insults under in vitro and in vivo conditions. Purpose: The aim of the present study was two-fold: (a) to examine the neuroprotective action of cannabinoids [methanandamide and 2-arachidonyl glycerol (2-AG)] against [...] Read more.

Both hydrogen sulfide and endocannabinoids can protect the neural retina from toxic insults under in vitro and in vivo conditions. Purpose: The aim of the present study was two-fold: (a) to examine the neuroprotective action of cannabinoids [methanandamide and 2-arachidonyl glycerol (2-AG)] against hydrogen peroxide (H₂O₂)-induced oxidative damage in the isolated bovine retina and (b) to evaluate the role of endogenously biosynthesized hydrogen sulfide (H₂S) in the inhibitory actions of cannabinoids on the oxidative stress in the bovine retina. Methods: Isolated neural retinas from cows were exposed to oxidative damage using H₂O₂ (100 µM) for 10 min. When used, tissues were pretreated with methanandamide (1 nM–100 nM) and 2-AG (1–10 µM) for 30 min before a 10 min treatment with H₂O₂ (100 µM). In some experiments, retinas were pretreated with inhibitors of the biosynthesis of H₂S [cystathionine β-synthase/cystathionine γ-lyase (CBS/CSE), aminooxyacetic acid, AOAA 30 µM, or 3-mercaptopyruvate sulfurtransferase (3MST), α-keto-butyric acid, KBA 1 mM] and the CB1-receptor antagonist, AM251 (100 nM) for 30 min before treatment with methanandamide (1 nM–100 µM). Enzyme immunoassay measurement of 8-epi PGF2α (8-isoprostane) levels was performed to assess lipid peroxidation in retinal tissues. Results: In the presence of H₂O₂ (100 µM), methanandamide (1 nM–100 µM) and 2-AG (1–10 µM) significantly (p < 0.001) blocked the H₂O₂-induced elevation in 8-isoprostane levels in the isolated bovine retina. In the presence of the CB1 antagonist AM251 (100 nM), the effect of methanandamide (1 nM) on the H₂O₂-induced 8-isoprostane production was significantly (p < 0.001) attenuated. While AOAA (30 µM) had no significant (p > 0.05) effect on the inhibition of H₂O₂-induced oxidative stress elicited by methanandamide, KBA (1 mM) reversed the neuroprotective action of methanandamide. Conclusions: The cannabinoids, methanandamide and 2-AG can prevent H₂O₂-induced oxidative stress in the isolated bovine retina. The neuroprotective actions of cannabinoids are partially dependent upon the activation of the CB1 receptors and endogenous production of H₂S via the 3-MST/CAT pathway. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 8470 KiB

Open AccessArticle

Investigating the Effect and Potential Mechanism of Rhamnetin 3-O-α-Rhamnoside on Acute Liver Injury In Vivo and In Vitro

by Dandan Deng, Borong Zhao, Hong Yang, Songsong Wang, Ziying Geng, Jiangtao Zhou, Guane Yang and Liwen Han

Pharmaceuticals 2025, 18(1), 116; https://doi.org/10.3390/ph18010116 - 17 Jan 2025

Viewed by 408

Abstract

Background/Objectives: Rhamnetin 3-O-α-rhamnoside (ARR) is a major flavonoid of the herb Loranthus tanakae Franch. & Sav., which has been used for treating liver diseases in China. However, the protective effect of ARR on the liver has not been reported. Methods [...] Read more.

Background/Objectives: Rhamnetin 3-O-α-rhamnoside (ARR) is a major flavonoid of the herb Loranthus tanakae Franch. & Sav., which has been used for treating liver diseases in China. However, the protective effect of ARR on the liver has not been reported. Methods: Zebrafish larvae were used as a visual animal model, and liver injury was induced by thioacetamide (TAA) for an acute liver injury (ALI) model. The hepatoprotective activity of ARR was evaluated by assessing liver morphology, liver function indices, oxidative stress, and the mRNA expression levels of inflammation-related genes in the zebrafish model. Additionally, the ROS level, inflammatory factors, and protein expression related to the IKKβ/NF-κB signaling pathway were measured to investigate a potential mechanism of ARR in HepG2 cells. Results: ARR ameliorated TAA-induced growth retardation, reduced liver injury phenotypes, and decreased oxidative stress in the zebrafish. ARR was also able to lower ROS levels in HepG2 cells, effectively inhibit the overactivation of the IKKβ/NF-κB signaling pathway in pathological conditions, inhibit NF-κB p65 translocation from the cytoplasm to the nucleus, and reduce the release of intracellular inflammatory factors. Conclusions: ARR showed significant protective activity against TAA-induced liver injury in in vivo and in vitro models, and its potential mechanism was closely related to the IKKβ/NF-κB signaling pathway. Full article

(This article belongs to the Section Pharmacology)

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21 pages, 6062 KiB

Open AccessArticle

Exploring Azithromycin’s Neuroprotective Role in Traumatic Brain Injury: Insights into Cognitive and Motor Recovery and Neuroinflammatory Modulation

by Mohannad A. Almikhlafi, Nehad A. Abdallah, Aakash Kumar, Tarun Sharma, Zuber Khan, Haifa A. Fadil, Sultan Althagfan, Ahmed K. B. Aljohani, Sara A. Almadani, Samar F. Miski, Tahani Saeedi, Rayan S. Alharbi, Abdulrahman M. Al-Harthe, Mohammed H. Alsubhi, Hanaa Wanas, Ahmed Aldhafiri, Sidharth Mehan and Hossein M. Elbadawy

Pharmaceuticals 2025, 18(1), 115; https://doi.org/10.3390/ph18010115 - 16 Jan 2025

Viewed by 705

Abstract

Background: Traumatic brain injury (TBI) is a leading cause of mortality worldwide and often results in substantial cognitive, motor, and psychological impairments, triggering oxidative stress, neuroinflammation, and neurodegeneration. This study examined the neuroprotective effects of azithromycin (AZI) in TBI. Methods: TBI was induced [...] Read more.

Background: Traumatic brain injury (TBI) is a leading cause of mortality worldwide and often results in substantial cognitive, motor, and psychological impairments, triggering oxidative stress, neuroinflammation, and neurodegeneration. This study examined the neuroprotective effects of azithromycin (AZI) in TBI. Methods: TBI was induced in rats using the weight-drop method. Subsequently, rats received a daily intraperitoneal (I.P.) dose of AZI (150 mg/kg) for 28 days. Behavioral tests (Morris water maze, rotarod, and open field tests) were performed to assess cognitive and motor functions. Neurochemical analyses included oxidative stress markers (GSH, SOD, MDA, catalase), inflammatory cytokines (TNF-α, IL-1β), apoptotic markers (caspase-3, Bax, Bcl-2), mitochondrial complexes (complex I, II, III, IV, and V), and the transforming growth factor- beta (TGF-β) as a neurofilament marker. Histological evaluations focused on neuronal integrity in the cortex, hippocampus, and striatum. Results: Treatment with AZI significantly facilitated motor and cognitive function recovery in TBI-affected rats. At the molecular level, AZI effectively reduced oxidative stress markers, ameliorated neuroinflammation by decreasing TNF-α, IL-1β, and neuronal apoptosis, and differentially modulated mitochondrial complexes. Histological assessments revealed enhanced neuronal integrity and fewer pathological changes in AZI-treated rats compared to untreated TBI controls. Conclusions: AZI was shown to interfere with several pathways involved in TBI’s pathophysiology. While preclinical results are promising, further studies are necessary to establish the long-term safety and efficacy of AZI in a clinical setting. This research supports the potential re-purposing of AZI as a novel treatment strategy for TBI and related neurodegenerative disorders. Full article

(This article belongs to the Special Issue Barrier Dynamics and Immune Interplay in Brain Aging and Injury)

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16 pages, 1061 KiB

Open AccessArticle

Post-Marketing Pharmacovigilance of Canakinumab from the FDA Adverse Event Reporting System (FAERS)

by Weidong Zhang, Yunzhou Chen, Zeyu Yao, Mengling Ouyang, Minghui Sun and Shupeng Zou

Pharmaceuticals 2025, 18(1), 114; https://doi.org/10.3390/ph18010114 - 16 Jan 2025

Viewed by 605

Abstract

Background: Canakinumab, a humanized anti-IL-1β monoclonal antibody, is known for its ability to suppress IL-1β-mediated inflammation. However, continuous monitoring of its safety remains essential. Thus, we comprehensively evaluated the safety signals of canakinumab by data mining from FAERS. Methods: We used a disproportionate [...] Read more.

Background: Canakinumab, a humanized anti-IL-1β monoclonal antibody, is known for its ability to suppress IL-1β-mediated inflammation. However, continuous monitoring of its safety remains essential. Thus, we comprehensively evaluated the safety signals of canakinumab by data mining from FAERS. Methods: We used a disproportionate analysis to quantify canakinumab-related adverse events (AEs) using four algorithms. Clinical prioritization of the detected signals was assessed with a semiquantitative score method. Serious and non-serious outcomes were compared by statistical methods. Additionally, a stratification analysis of serious infections was conducted at the system organ class (SOC) level. Results: A total of 28,496 canakinumab-related AEs were collected, and 71 suspicious signals detected. Among these, 19 preferred terms (PTs) were identified as unexpected signals, including deafness, appendicitis, brain oedema, cushingoid, cellulitis, and papilledema. Of the AEs, 16 were more likely reported as serious outcomes, such as pneumonia, abdominal pain, deafness, and infection. Based on clinical priority score, 44 PTs were classified as weak, 27 as moderate, and none as strong. Furthermore, 30 PTs demonstrated a high level of evidence, primarily derived from FDA prescribing information, randomized controlled trials, and systematic reviews. Stratification analysis of infections and infestations (serious outcomes) revealed a stronger association of severe infections with canakinumab in older or heavier individuals. All positive signals followed an early failure pattern, with the incidence of canakinumab-associated AEs decreasing over time. Conclusions: We found that most of the suspicious signals were associated with infections. More attention should be paid to serious infections, particularly in males, individuals aged ≥60 years, or those weighing >100 kg, who demonstrated the highest risk of serious infections. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Adverse Drug Reactions: 2nd Edition)

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27 pages, 1853 KiB

Open AccessReview

Two- and Three-Dimensional Culture Systems: Respiratory In Vitro Tissue Models for Chemical Screening and Risk-Based Decision Making

by Joanne Wallace, Mary C. McElroy, Mitchell Klausner, Richard Corley and Seyoum Ayehunie

Pharmaceuticals 2025, 18(1), 113; https://doi.org/10.3390/ph18010113 - 16 Jan 2025

Viewed by 726

Abstract

Risk of lung damage from inhaled chemicals or substances has long been assessed using animal models. However, New Approach Methodologies (NAMs) that replace, reduce, and/or refine the use of animals in safety testing such as 2D and 3D cultures are increasingly being used [...] Read more.

Risk of lung damage from inhaled chemicals or substances has long been assessed using animal models. However, New Approach Methodologies (NAMs) that replace, reduce, and/or refine the use of animals in safety testing such as 2D and 3D cultures are increasingly being used to understand human-relevant toxicity responses and for the assessment of hazard identification. Here we review 2D and 3D lung models in terms of their application for inhalation toxicity assessment. We highlight a key case study for the Organization for Economic Cooperation and Development (OECD), in which a 3D model was used to assess human toxicity and replace the requirement for a 90-day inhalation toxicity study in rats. Finally, we consider the regulatory guidelines for the application of NAMs and potential use of different lung models for aerosol toxicity studies depending on the regulatory requirement/context of use. Full article

(This article belongs to the Special Issue 2D and 3D Culture Systems: Current Trends and Biomedical Applications)

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20 pages, 1911 KiB

Open AccessReview

Dysregulation of Mitochondrial Homeostasis in Cardiovascular Diseases

by Ricky Patil, Hui Wang, Matthew Kazaleh, Gorav Ailawadi and Morgan Salmon

Pharmaceuticals 2025, 18(1), 112; https://doi.org/10.3390/ph18010112 - 16 Jan 2025

Viewed by 507

Abstract

Mitochondria dysfunction plays a central role in the development of vascular diseases as oxidative stress promotes alterations in mitochondrial morphology and function that contribute to disease progression. Redox imbalances can affect normal cellular processes including mitochondrial biogenesis, electrochemical equilibrium, and the regulation of [...] Read more.

Mitochondria dysfunction plays a central role in the development of vascular diseases as oxidative stress promotes alterations in mitochondrial morphology and function that contribute to disease progression. Redox imbalances can affect normal cellular processes including mitochondrial biogenesis, electrochemical equilibrium, and the regulation of mitochondrial DNA. In this review, we will discuss these imbalances and, in particular, the potential role of mitochondrial fusion, fission, biogenesis, and mitophagy in the context of vascular diseases and how the dysregulation of normal function might contribute to disease progression. We will also discuss potential implications of targeting mitochondrial regulation as therapeutic targets to treat vascular disease formation. Full article

(This article belongs to the Special Issue Smooth Muscle and Endothelial Cells as Pharmacological Targets for Acute Oxidative Stress)

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2 pages, 711 KiB

Open AccessCorrection

Correction: Khavinson et al. Neuroprotective Effects of Tripeptides—Epigenetic Regulators in Mouse Model of Alzheimer’s Disease. Pharmaceuticals 2021, 14, 515

by Vladimir Khavinson, Anastasiia Ilina, Nina Kraskovskaya, Natalia Linkova, Nina Kolchina, Ekaterina Mironova, Alexander Erofeev and Michael Petukhov

Pharmaceuticals 2025, 18(1), 111; https://doi.org/10.3390/ph18010111 - 16 Jan 2025

Viewed by 323

Abstract

In the original publication [...] Full article

(This article belongs to the Section Medicinal Chemistry)

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16 pages, 3994 KiB

Open AccessArticle

Syringaldehyde Alleviates Cardiac Hypertrophy Induced by Hyperglycemia in H9c2 Cells Through GLP-1 Receptor Signals

by Yingxiao Li, Chao-Tien Hsu, Ting-Ting Yang and Kai-Chun Cheng

Pharmaceuticals 2025, 18(1), 110; https://doi.org/10.3390/ph18010110 - 16 Jan 2025

Viewed by 427

Abstract

Background: Cardiac hypertrophy is a significant complication of diabetes, often triggered by hyperglycemia. Glucagon-like peptide-1 (GLP-1) receptor agonists alleviate cardiac hypertrophy, but their efficacy diminishes under GLP-1 resistance. Syringaldehyde (SA), a natural phenolic compound, may activate GLP-1 receptors and mitigate hypertrophy. This study [...] Read more.

Background: Cardiac hypertrophy is a significant complication of diabetes, often triggered by hyperglycemia. Glucagon-like peptide-1 (GLP-1) receptor agonists alleviate cardiac hypertrophy, but their efficacy diminishes under GLP-1 resistance. Syringaldehyde (SA), a natural phenolic compound, may activate GLP-1 receptors and mitigate hypertrophy. This study explores SA’s therapeutic potential in hyperglycemia-induced cardiac hypertrophy in H9c2 cardiomyocytes. Methods: H9c2 cells were exposed to high glucose to induce hypertrophy. Cells were treated with varying SA concentrations, and hypertrophic biomarkers were analyzed using ELISA, qPCR, and Western blot. Results: SA reduced cell size and hypertrophic biomarkers in a dose-dependent manner while increasing GLP-1 receptor expression and cAMP levels. These effects were attenuated in GLP-1-resistant cells, highlighting the role of GLP-1 receptor activation. AMPK activation was essential, as its inhibition abolished SA’s effects. SA also decreased O-linked N-acetylglucosamine transferase (OGT) expression via AMPK activation, contributing to reduced hypertrophy. Conclusions: SA alleviates hyperglycemia-induced cardiac hypertrophy in H9c2 cells by activating the GLP-1 receptor and AMPK signaling pathway. Full article

(This article belongs to the Special Issue Natural Products in Diabetes Mellitus: 2nd Edition)

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24 pages, 8366 KiB

Open AccessArticle

Exploring the Underlying Mechanism of Weiling Decoction Alleviates Cold-Dampness Diarrhea Based on Network Pharmacology, Transcriptomics, Molecular Docking and Experimental Validation

by Yannan Zhang, Shuai Zhang, Yimeng Fan, Sijuan Huang, Shimin Wang, Zhihui Hao and Jianzhong Shen

Pharmaceuticals 2025, 18(1), 109; https://doi.org/10.3390/ph18010109 - 16 Jan 2025

Viewed by 456

Abstract

Background: Cold-dampness diarrhea (CDD) is a common gastrointestinal disorder in children, characterized by diarrhea and intestinal barrier dysfunction. Weiling decoction (WLD) is frequently used in clinical practice to treat CDD, a condition triggered by multiple factors. However, the molecular mechanisms underlying its [...] Read more.

Background: Cold-dampness diarrhea (CDD) is a common gastrointestinal disorder in children, characterized by diarrhea and intestinal barrier dysfunction. Weiling decoction (WLD) is frequently used in clinical practice to treat CDD, a condition triggered by multiple factors. However, the molecular mechanisms underlying its therapeutic effects remain poorly understood. Objectives: This study aimed to evaluate the efficacy of WLD in treating CDD and to elucidate its potential mechanisms. Methods: UPLC-HRMS/MS was employed to identify the chemical constituents of WLD and the absorption components in the plasma of WLD-treated rats. Additionally, a rat model of CDD was established to assess the therapeutic effects of WLD through a comprehensive approach. To elucidate the molecular mechanisms underlying these effects, network pharmacology and transcriptomic analyses were performed to identify potential signaling pathways associated with CDD alleviation. Molecular docking and flow cytometry assays were subsequently utilized to validate the identified signaling pathways. Results: A total of 223 chemical components were detected in WLD, and 49 absorption components were identified in the plasma of WLD-treated rats by UPLC-HRMS/MS. WLD treatment significantly alleviated the symptoms of CDD, reduced intestinal damage, and diminished the inflammatory response. Additionally, WLD influenced key genes in immune-related pathways. Molecular docking revealed strong binding affinities between the main components of WLD and key targets within these pathways. Flow cytometry, along with the analysis of inflammatory cytokines and transcription factors, demonstrated that WLD modulated the balance between Th1/Th2 and Th17/Treg cell populations. Conclusions: This study provides the first evidence that WLD alleviates CDD by regulating the balance between Th1/Th2 and Th17/Treg cell populations. These findings offer a theoretical basis for future investigations into the therapeutic potential of WLD in the treatment of CDD. Full article

(This article belongs to the Section Pharmacology)

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10 pages, 397 KiB

Open AccessArticle

Ceftazidime-Avibactam Versus Colistin for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: A Multicenter Cohort Study

by Thamer A. Almangour, Zakiyah Alkherb, Leen Ghonem, Mohammed Al Musawa, Abdullah Almohaizeie, Sara Almuhisen, Aminah Alharbi, Nader Damfu, Doaa Aljefri, Jeelan Alghaith, Awaly Alfozan, Ahlam Alghamdi, Ahmad Aljabri, Abdullah A. Alhifany, Mohammed Alessa and Yazed Saleh Alsowaida

Pharmaceuticals 2025, 18(1), 108; https://doi.org/10.3390/ph18010108 - 16 Jan 2025

Viewed by 588

Abstract

Purpose: To evaluate the real-world evidence of ceftazidime-avibactam (CAZ-AVI) compared to intravenous colistin for the treatment of multidrug-resistant (MDR) P. aeruginosa infections. Method: This is a multicenter, retrospective cohort study conducted in the period between 2017 and 2023 at five institutions for patients [...] Read more.

Purpose: To evaluate the real-world evidence of ceftazidime-avibactam (CAZ-AVI) compared to intravenous colistin for the treatment of multidrug-resistant (MDR) P. aeruginosa infections. Method: This is a multicenter, retrospective cohort study conducted in the period between 2017 and 2023 at five institutions for patients who received either CAZ-AVI or colistin-based regimens for treating MDR P. aeruginosa infections. Outcomes were compared using multivariate logistic regression analysis. Result: Among the screened patients, 203 patients were included: 89 in the CAZ-AVI group and 114 in the colistin group. A total of 57% presented with pneumonia, 21% with bacteremia, and 61% were in the intensive care unit. The rate of clinical cure was significantly higher among patients who received CAZ-AVI (67% vs. 50%; OR, 2.07; 95% CI, 1.16–3.68). The rate of in-hospital mortality was numerically lower among patients who received CAZ-AVI (40% vs. 49%; OR, 0.58; 95% CI, 0.33–1.03). The rate of AKI was significantly lower among patients who received CAZ-AVI (15% vs. 43%; OR, 0.23; 95% CI, 0.11–0.45). Conclusion: CAZ-AVI was more effective in treating MDR P. aeruginosa infections and showed a better safety profile compared to colistin. Thus, CAZ-AVI could be a better alternative for treating MDR P. aeruginosa infections. Full article

(This article belongs to the Special Issue Antibiotic Resistance in Gram-Negative Bacteria: The Threat From the Pink Corner, 2nd Edition)

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14 pages, 1613 KiB

Open AccessArticle

The Role of Endogenous Beta-Endorphin and Enkephalins in the Crosstalk Between Ethanol and Morphine

by Andy Tseng, Syed Muzzammil Ahmad, Abdul Hamid and Kabirullah Lutfy

Pharmaceuticals 2025, 18(1), 107; https://doi.org/10.3390/ph18010107 - 16 Jan 2025

Viewed by 432

Abstract

Background: There is clinical concern about the combined use of alcohol and opiates. Several lines of evidence support an interaction between alcohol and the endogenous opioid system. Thus, we hypothesized that ethanol, by causing the release of opioid peptides, may sensitize the system [...] Read more.

Background: There is clinical concern about the combined use of alcohol and opiates. Several lines of evidence support an interaction between alcohol and the endogenous opioid system. Thus, we hypothesized that ethanol, by causing the release of opioid peptides, may sensitize the system to the action of exogenous opioids such as morphine. Objectives: In this study, using the place conditioning paradigm, a model of reward, we determined whether a morphine challenge would alter the pre-established preference induced by ethanol conditioning in mice, and whether this response was mediated by the mu opioid receptor (MOP). Given that ethanol exposure stimulates the release of opioid peptides, we also assessed the role of beta-endorphin (β-END) and enkephalins (ENKs) in this response. Methods: Mice lacking MOPs, β-END, and/or ENKs, and their respective wild-type controls were tested for preconditioning place preference on day 1. Mice were then conditioned with ethanol (2 g/kg) versus saline on days 2 to 4 and then tested under a drug-free state for postconditioning place preference on day 5. On day 8, mice received a single injection of morphine (5 mg/kg) and were tested for place preference. On the test days, mice were placed in the central chamber and allowed to explore the chambers. The amount of time that mice spent in the drug-paired chamber was recorded. Results: We found that a challenge dose of morphine given on day 8 enhanced the conditioned place preference (CPP) response in mice previously conditioned with ethanol. This response was abolished in MOP-null mice, confirming the role of MOPs in this response. Although this enhanced response was not altered in mice lacking either β-END or ENKs compared to their wild-type littermates/controls, it was completely blunted in mice lacking both β-END and enkephalins. Conclusions: Together, these results suggest that these opioid peptides jointly mediate the crosstalk between the rewarding actions of morphine and ethanol. Full article

(This article belongs to the Special Issue Targeting Opioid Receptors for Innovative Therapies: Present and Emerging Concepts in Opioid Cure)

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23 pages, 3680 KiB

Open AccessArticle

Possibility of Using NO Modulators for Pharmacocorrection of Endothelial Dysfunction After Prenatal Hypoxia

by Igor Belenichev, Olena Popazova, Oleh Yadlovskyi, Nina Bukhtiyarova, Victor Ryzhenko, Sergii Pavlov, Valentyn Oksenych and Oleksandr Kamyshnyi

Pharmaceuticals 2025, 18(1), 106; https://doi.org/10.3390/ph18010106 - 16 Jan 2025

Viewed by 583

Abstract

Prenatal hypoxia (PH) is a key factor in the development of long-term cardiovascular disorders, which are caused by various mechanisms of endothelial dysfunction (ED), including those associated with NO deficiency. This emphasizes the potential of therapeutic agents with NO modulator properties, such as [...] Read more.

Prenatal hypoxia (PH) is a key factor in the development of long-term cardiovascular disorders, which are caused by various mechanisms of endothelial dysfunction (ED), including those associated with NO deficiency. This emphasizes the potential of therapeutic agents with NO modulator properties, such as Thiotriazoline, Angiolin, Mildronate, and L-arginine, in the treatment of PH. Methods: Pregnant female rats were given a daily intraperitoneal dose of 50 mg/kg of sodium nitrite starting on the 16th day of pregnancy. A control group of pregnant rats received saline instead. The resulting offspring were divided into the following groups: Group 1—intact rats; Group 2—rat pups subjected to prenatal hypoxia (PH) and treated daily with physiological saline; and Groups 3 to 6—rat pups exposed to prenatal hypoxia and treated daily from the 1st to the 30th day after birth. Levels of sEPCR, Tie2 tyrosine kinase, VEGF-B, SOD1/Cu-Zn SOD, GPX4, and GPX1 in the heart’s cytosolic homogenate were assessed using ELISA. The expression of VEGF and VEGF-B mRNA was analyzed via real-time polymerase chain reaction, and the nuclear area of myocardial microvessel endothelial cells was evaluated morphometrically. Results: We have shown that only two representatives of this group—Angiolin and Thiotriazoline—are able to exert full effect on the indices of endothelial dysfunction after PH to decrease sEPCR, increase Tie-2, VEGF-B and VEGF-B mRNA, Cu/ZnSOD, and GPX in myocardial cytosol, and increase the area of endotheliocyte nuclei in 1- and 2-month-old rats in comparison with the control. Conclusions: Our results experimentally substantiate the necessity of early postnatal cardio- and endothelioprotection using NO modulators, taking into account the role of NO-dependent mechanisms in the pathogenesis of cardiovascular system disorders in neonates after PH. Full article

(This article belongs to the Special Issue Therapeutic Methods Against Acute and Chronic Diseases and Oxidative Stress)

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16 pages, 1596 KiB

Open AccessSystematic Review

The Effect of the Concurrent Use of Angiotensin-Converting Enzyme Inhibitors or Receptor Blockers on Toxicity and Outcomes in Patients Treated with Radiotherapy: A Systematic Review and Meta-Analysis

by Wan-Chuen Liao, Hala Shokr, Corinne Faivre-Finn, Clare Dempsey, Kaye Janine Williams and Li-Chia Chen

Pharmaceuticals 2025, 18(1), 105; https://doi.org/10.3390/ph18010105 - 16 Jan 2025

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Abstract

Background/Objectives: ACEIs protect against radiation pneumonitis by reducing angiotensin II production, oxidative stress, and inflammation. This study highlights the significance of concurrent angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) use in radiotherapy by evaluating its impact on radiotherapy-related side effects [...] Read more.

Background/Objectives: ACEIs protect against radiation pneumonitis by reducing angiotensin II production, oxidative stress, and inflammation. This study highlights the significance of concurrent angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) use in radiotherapy by evaluating its impact on radiotherapy-related side effects and survival outcomes, addressing the gap in existing research and providing insights to guide clinical practice in oncology. Methods: The literature was retrieved from the MEDLINE, EMBASE, Web of Science, and Scopus databases from January 2000 to October 2024. Studies on adults (≥18 years) with histologically confirmed cancer, receiving ACEIs or ARBs during radiotherapy, were included. Radiotherapy-related side effects and clinical outcomes were analysed using odds ratios (ORs) and 95% confidence intervals (95%CIs), comparing ACEI/ARB users to non-users. Differences in the median survival time, recurrence, and death rates were also calculated. Results: Sixteen studies (14 cohort studies and two randomised trials) were included. ACEI users exhibited a 50% reduction in the risk of ≥grade 2 radiation pneumonitis (OR: 0.50, 95%CI: 0.32–0.77) in lung cancer and significant reductions in the odds of proctitis (80%, OR: 0.20, 95%CI: 0.12–0.33), haematuria (75%, OR: 0.25, 95%CI: 0.16–0.41), and rectal bleeding (61%, OR: 0.39, 95%CI: 0.30–0.51) in prostate cancer. ACEI/ARB users showed reduced symptomatic radiation necrosis in brain metastases and better 6-month functional independence in supratentorial glioblastoma. Among six studies reporting survival, ACEI/ARB users had longer median survival in early-stage non-small-cell lung cancer and glioblastoma but shorter survival in small cell lung cancer and brain metastases. ARB users had inconsistent survival rates for lung cancer. The varying survival outcomes suggest that ACEIs/ARBs have different effects depending on the cancer type and stage, potentially influenced by cancer-specific factors, treatment protocols, or disease progression. Conclusions: ACEI use is associated with a reduction in radiation pneumonitis, but evidence for other radiotherapy-related toxicity and survival outcomes remains inconsistent across cancer types and severities. Further research should carefully control for confounders. Full article

(This article belongs to the Section Pharmacology)

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