Pharmaceuticals

27 pages, 764 KiB

Open AccessArticle

Effects of Carnosine Supplementation on Cognitive Outcomes in Prediabetes and Well-Controlled Type 2 Diabetes: A Randomised Placebo-Controlled Clinical Trial

by Rohit Hariharan, Aya Mousa, Kirthi Menon, Jack Feehan, Barbara Ukropcová, Jozef Ukropec, Martin Schön, Arshad Majid, Giancarlo Aldini, Maximilian de Courten, James Cameron, Simon M. Bell and Barbora de Courten

Pharmaceuticals 2025, 18(5), 630; https://doi.org/10.3390/ph18050630 (registering DOI) - 26 Apr 2025

Abstract

Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human [...] Read more.

Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human studies for improving cognitive function, insulin resistance and T2DM, but its therapeutic effects on cognition remain unclear. The aim of this study is to assess the effects of carnosine on cognitive function in individuals with prediabetes or well-controlled T2DM. Methods: This is a secondary analysis of a double-blind randomised controlled trial (RCT), whereby 49 adults with prediabetes or early-stage well-controlled T2DM were randomised to receive 2 g of carnosine or identical placebo daily for 14 weeks. At baseline and follow-up, cognitive function was assessed as a secondary outcome using the Digit-Symbol Substitution Test, Stroop test, Trail Making Tests A & B, and the Cambridge Automated Neuropsychological Test Battery (CANTAB). Results: In total, 42 adults (23 males and 19 females) completed the trial. There were no differences in participant anthropometry or cognitive functioning between carnosine and placebo groups at baseline (all p > 0.1). After the 14-week supplementation period, there were no differences between carnosine and placebo groups in change and follow-up values for any cognitive measures including Stroop, Digit Symbol Substitution Sest, Trail Making A/B or CANTAB (all p > 0.05). Adjustments for baseline cognitive scores, diabetic status, level of education, age or interaction effects with participants’ sex did not change the results. Conclusions: Carnosine supplementation did not improve cognitive measures in individuals with prediabetes or T2DM in this study. While larger trials may provide further insights, alternative factors—such as the relatively young and healthy profile of our cohort—may have contributed to the lack of observed effect. Future research should examine individuals with existing cognitive impairment or those at higher risk of cognitive decline to better define the therapeutic potential of carnosine in this context. Full article

(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Internal Diseases)

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21 pages, 2427 KiB

Open AccessArticle

Neuroprotective Potential of Tetraselmis chuii Compounds: Insights into Blood–Brain Barrier Permeability and Intestinal Transport

by Melis Cokdinleyen, Alberto Valdés, Huseyin Kara, Elena Ibáñez and Alejandro Cifuentes

Pharmaceuticals 2025, 18(5), 629; https://doi.org/10.3390/ph18050629 (registering DOI) - 26 Apr 2025

Abstract

Background/Objectives: Alzheimer’s disease (AD) is the most common type of dementia, characterized by complex processes such as neuro-inflammation, oxidative damage, synaptic loss, and neuronal death. Carotenoids are among the potential therapeutic molecules that have attracted attention due to their neuroprotective properties, but their [...] Read more.

Background/Objectives: Alzheimer’s disease (AD) is the most common type of dementia, characterized by complex processes such as neuro-inflammation, oxidative damage, synaptic loss, and neuronal death. Carotenoids are among the potential therapeutic molecules that have attracted attention due to their neuroprotective properties, but their efficacy is limited mainly by their capacity to cross the blood–brain barrier (BBB). Results: The results showed that T. chuii extracts could protect neuronal cells from neurotoxic damage, especially against L-glutamate and H₂O₂. Moreover, the BBB permeability and the intestinal transport analyses revealed that fucoxanthinol, crocoxanthin, diatoxanthin, neoxanthin, violaxanthin, and prasinoxanthin have diverse permeabilities depending on the incubation time and the cell model used. Fucoxanthinol was the carotenoid with the highest and similar permeability in HBMEC cells (4.41%, 5.13%, and 18.94% at 2, 4, and 24 h, respectively) and Caco-2 cells (7.01%, 8.63%, and 18.36% at the same times), while crocoxanthin, diatoxanthin, and neoxanthin showed different kinetics. Methods: The neuroprotective potential of two extracts obtained from Tetraselmis chuii microalga were evaluated against Aβ1-42-, L-glutamate-, and H₂O₂-induced toxicities in SH-SY5Y cells. In addition, the BBB permeability and the intestinal transepithelial transport of the main carotenoids present in the extracts were evaluated and compared using two cell culture models, HBMEC and Caco-2 cells. For that aim, the transport of the bioactive molecules across the barriers was evaluated using UHPLC-q-TOF-MS after 2, 4, and 24 h of incubation. Conclusions: These findings indicate that T. chuii is a promising natural source of bioactive compounds to develop functional foods against neurodegenerative diseases. Full article

(This article belongs to the Special Issue Antioxidant and Anti-Inflammatory Effects of Natural Product Extracts)

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16 pages, 4770 KiB

Open AccessArticle

The Immunomodulatory Effects of Apigenin and Quercetin on Cytokine Secretion by the Human Gingival Fibroblast Cell Line and Their Potential Link to Alzheimer’s Disease

by Anna Kurek-Górecka, Małgorzata Kłósek, Radosław Balwierz, Grażyna Pietsz and Zenon P. Czuba

Pharmaceuticals 2025, 18(5), 628; https://doi.org/10.3390/ph18050628 (registering DOI) - 26 Apr 2025

Abstract

Background: The link between periodontal pathogens, inflammation, and neurodegenerative processes, including Alzheimer’s disease (AD), is evident. Porphyromonas gingivalis and Treponema denticola release lipopolysaccharide (LPS), constituting a virulence factor that takes part in the brain inflammatory process. Human gingival fibroblasts (HGF-1) are a source [...] Read more.

Background: The link between periodontal pathogens, inflammation, and neurodegenerative processes, including Alzheimer’s disease (AD), is evident. Porphyromonas gingivalis and Treponema denticola release lipopolysaccharide (LPS), constituting a virulence factor that takes part in the brain inflammatory process. Human gingival fibroblasts (HGF-1) are a source of pro-inflammatory cytokines released during periodontal diseases. Propolis is a rich source of quercetin and apigenin, which exhibit anti-inflammatory and immunomodulatory activities, influencing the concentration of pro-inflammatory cytokines. Considering this aspect, models with stimulated HGF-1, followed by LPS and/or interferon-α (IFN-α), were used. Aim: This study was designed to evaluate the concentrations of selected cytokines produced by HGF-1, which may influence brain inflammation. The immunomodulatory effects of apigenin and quercetin were investigated by measuring the concentration of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-15 (IL-15), and tumour necrosis factor (TNF-α). This study’s novelty is based on insights into the immunomodulatory effects of selected flavonoids by correlating the secretion of pro-inflammatory cytokines by gingival fibroblasts during periodontal disease with inflammatory processes in the brain. The cytotoxicity of apigenin and quercetin was estimated using the MTT assay. Fibroblasts were stimulated with LPS at 200 ng/mL and/or IFN-α at 100 U/mL concentration, followed by incubation with apigenin (25–50 µg/mL) and quercetin (25–50 µg/mL). Cytokine concentrations were measured using the xMAP technology. Results: The most pronounced and statistically significant reduction in cytokine levels, particularly IL-6 and IL-15, was observed for quercetin in both concentrations (25 µg/mL and 50 µg/mL), especially following LPS stimulation. Apigenin in both analysed concentrations also significantly decreased the level of IL-6. These results suggest that quercetin and apigenin may indirectly act as potential immunomodulators in preventing brain inflammation by inhibiting the inflammatory process in periodontitis; however, this should be confirmed in further studies. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

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11 pages, 664 KiB

Open AccessArticle

Auto-Induction in Oral Esketamine Treatment for Treatment-Resistant Depression: An Exploratory Study

by Jolien K. E. Veraart, Cornelis F. Vos, Nieko C. Punt, Dylan Visser, Mireille A. Wessels, Sanne Y. Smith-Apeldoorn, Jeanine Kamphuis, Robert A. Schoevers and Daan J. Touw

Pharmaceuticals 2025, 18(5), 627; https://doi.org/10.3390/ph18050627 (registering DOI) - 25 Apr 2025

Abstract

Background: Esketamine is a rapidly acting antidepressant with robust efficacy in treatment-resistant depression (TRD). Diminishing therapeutic effects and attenuated side effects have been reported after long-term use. This study aimed to investigate its long-term pharmacokinetics and factors that may contribute to reduced efficacy [...] Read more.

Background: Esketamine is a rapidly acting antidepressant with robust efficacy in treatment-resistant depression (TRD). Diminishing therapeutic effects and attenuated side effects have been reported after long-term use. This study aimed to investigate its long-term pharmacokinetics and factors that may contribute to reduced efficacy over time in patients with TRD by evaluating the potential role of auto-induction. Methods: Pharmacokinetic data were collected from 18 patients receiving oral esketamine for six weeks. A pharmacokinetic model was developed to predict esketamine and noresketamine plasma concentrations. Observed esketamine and noresketamine plasma concentrations were compared to model-predicted concentrations to assess deviations suggestive of auto-induction. Results: On day 39, plasma concentrations of esketamine and noresketamine were 59% and 35% lower than predicted, respectively, indicative of auto-induction of CYP3A4 and CYP2B6. Conclusions: Auto-induction appears to occur in oral esketamine treatment, which may contribute to reduced therapeutic efficacy and side effects in long-term treatment. Identifying auto-induction as a mechanism of tolerance potentially has important clinical implications. Further studies are warranted to confirm these findings and evaluate strategies to maintain therapeutic efficacy. Full article

(This article belongs to the Topic Pharmacokinetic and Pharmacodynamic Modelling in Drug Discovery and Development)

9 pages, 571 KiB

Open AccessCase Report

Drug Incompatibilities and Complex Assemblies: Let Us Remain Vigilant!

by Cordélia Salomez-Ihl, Anthony Martin Mena, Marie-Carmen Molina, Romane Chapuis, Marjorie Durand, Sébastien Chanoine, Julien Leenhardt, Philippe Py, Marie-Dominique Brunet, Yung-Sing Wong, Marie Chevallier, Bertrand Décaudin, Pascal Odou, Pierrick Bedouch and Roseline Mazet

Pharmaceuticals 2025, 18(5), 626; https://doi.org/10.3390/ph18050626 - 25 Apr 2025

Abstract

Background/Objectives: Multi-lumen devices that limit physicochemical incompatibilities (PCIs) are frequently used in neonatal intensive care units where premature infants receive numerous infusions. The aim of the study was to investigate a PCI that occurred despite the use of a device of this [...] Read more.

Background/Objectives: Multi-lumen devices that limit physicochemical incompatibilities (PCIs) are frequently used in neonatal intensive care units where premature infants receive numerous infusions. The aim of the study was to investigate a PCI that occurred despite the use of a device of this type (EDELVAISS^® Multiline NEO, Doran International, Toussieu, France). Case Summary: A 7-week-old preterm infant received ganciclovir at therapeutic dosage for cytomegalovirus (CMV) infection. After the fifth administration of ganciclovir, a PCI occurred, leading to a white precipitate. The peripheral inserted central catheter (PICC) (PREMICATH^®2Fr, Vygon, Ecouen, France) had to be replaced. Laboratory reproduction of the administrations during 72 h, nuclear magnetic resonance (NMR) analysis and particle counting were carried out to analyse the occurrence of events leading to PCIs. The precipitate was linked to a PCI of parenteral nutrition associated with a dilution error of ganciclovir (omission of a 10-fold dilution step, resulting in ganciclovir being administered at 30 mg/L instead of 3 mg/L). Due to the presence of lipids in the parenteral nutrition, visual detection of the white precipitate was difficult. Conclusions: Multi-lumen infusion devices limit but do not prevent the occurrence of PCIs, particularly in the event of a preparation error. Despite the use of this type of device, great vigilance is still required, particularly with regard to prescription analysis and reconstitution procedures. Full article

(This article belongs to the Section Pharmaceutical Technology)

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21 pages, 1950 KiB

Open AccessArticle

Anti-Leukemic Profiling of Oxazole-Linked Oxadiazole Derivatives: A Computational and Kinetic Approach

by Manal M. Khowdiary, Shoaib Khan, Tayyiaba Iqbal, Wajid Rehman, Azam Hayat, Rafaqat Hussain, Nehad A. L. Shaaer and Hamdy Kashtoh

Pharmaceuticals 2025, 18(5), 625; https://doi.org/10.3390/ph18050625 - 25 Apr 2025

Abstract

Background/ Objectives: Leukemia is a common cancer that arises in both children and adults when bone marrow’s hematopoietic stem cells proliferate unrestrained because of anomalies in normal cell regulatory systems. The present study focused on biological evaluation of oxazole-based oxadiazole scaffolds to evaluate [...] Read more.

Background/ Objectives: Leukemia is a common cancer that arises in both children and adults when bone marrow’s hematopoietic stem cells proliferate unrestrained because of anomalies in normal cell regulatory systems. The present study focused on biological evaluation of oxazole-based oxadiazole scaffolds to evaluate the anti-proliferative effect on leukemic cancer cell lines. Methods: All novel oxazole-based oxadiazole scaffolds were synthesized and structurally characterized via ¹³C NMR, ¹H NMR, and HREI-MS. In order to identify an efficient anti-leukemia agent, the biological profiles of each compound were evaluated in comparison to the reference drug, Etoposide (IC₅₀= 10.50 and 15.20 μM). Results: Analog 6 substituted with p-CF₃ at phenyl ring was identified with excellent inhibition against the HL-60 and PLB-985 cancer cell lines, with IC₅₀ of 8.50 and 12.50 μM. Through hydrogen bond formation, the trifluoromethyl moiety of analog 6 interacts with target tyrosine kinase enzyme (PDB-ID:4CSV). The interactive character of active ligands with target enzyme was demonstrated by molecular docking. The rate of inhibition in contrast with the drug concentration was also tested to check the inhibition percentage and inhibitor type via enzyme kinetics. Furthermore, the enzyme–ligand complex was also investigated via MD simulation along with pharmacophore modeling. DFT calculations were used to estimate the lead compounds’ relative stability and reactivity. According to ADMET investigation, there is safe toxicological profile for these compounds. Conclusion: The current study suggests that the potent compounds have significant anti-proliferative potential, and with further in vivo validation, hold promise for future optimization as potential leukemia treatments. Full article

(This article belongs to the Section Medicinal Chemistry)

13 pages, 902 KiB

Open AccessBrief Report

Anxiolytic-like Effect Characterization of Essential Oil from Local Lavender Cultivation

by Sol Micaela Angulo, Victoria Belén Occhieppo, Cristian Moya, Rosana Crespo and Claudia Bregonzio

Pharmaceuticals 2025, 18(5), 624; https://doi.org/10.3390/ph18050624 - 25 Apr 2025

Abstract

Background: Anxiety disorders have a 7.3% worldwide prevalence and, considering the long period of treatment, developing new efficient and safer pharmacological tools is critical. Essential oils consist of highly concentrated lipophilic compounds from plants with therapeutic potential effects, such as Lavandula burnatii, [...] Read more.

Background: Anxiety disorders have a 7.3% worldwide prevalence and, considering the long period of treatment, developing new efficient and safer pharmacological tools is critical. Essential oils consist of highly concentrated lipophilic compounds from plants with therapeutic potential effects, such as Lavandula burnatii, produced in Córdoba, Argentine, with high levels of active pharmaceutical ingredients in its essential oil (linalyl acetate and linalool). The evidence indicates that lavender essential oil could induce anxiolytic effects; however, more systematic studies are needed. Methods: To test the anxiolytic attributes of Lavandula burnatii, male Wistar rats (200–260 g) were injected intraperitoneally with two different doses of essential oil (30/80 mg/kg) or vehicle (Myritol 318, a high-purity vegetable oil), once (acute) or for 7 days. One hour after the last administration, the anxiolytic effects were evaluated using the following behavioral tests: the dark–light test and the elevated plus maze test. The open-field test was used to assess locomotor activity. Results: Our results showed that the lower dose of lavender essential oil induces anxiolytic effects since it increases the time spent in the aversive compartment in each evaluation. The acute administration has no impact on the behaviors evaluated. The higher dose is comparable with the control group and does not show significant differences. Conclusions: More studies are needed to better characterize the beneficial effects of this essential oil for anxiety disorders and to establish an adequate dosage range. Full article

(This article belongs to the Special Issue Plant-Based Bioactive Products for Pharmaceutical Applications)

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20 pages, 718 KiB

Open AccessSystematic Review

The Relevance of Pharmacokinetic Biomarkers in Response to Methadone Treatment: A Systematic Review

by Sheila Recarey-Rama, Jesús Gómez-Trigo, Almudena Gil-Rodriguez, Eduardo Dominguez, Inés Sánchez-Martínez, Ángela Riveiro-Recimil, Alba Barral-Raña, Jose de Leon, Ana Rodriguez-Viyuela, Manuel Arrojo, Angel Carracedo and Olalla Maroñas

Pharmaceuticals 2025, 18(5), 623; https://doi.org/10.3390/ph18050623 - 25 Apr 2025

Abstract

Background/Objectives: Methadone maintenance treatment (MMT) is widely used in opioid use disorder (OUD). Its efficacy is influenced by its metabolism, primarily mediated by Cytochrome P450 (CYP450) enzymes in the liver. Genetic polymorphisms in CYP450 genes and other factors, such as age, sex, [...] Read more.

Background/Objectives: Methadone maintenance treatment (MMT) is widely used in opioid use disorder (OUD). Its efficacy is influenced by its metabolism, primarily mediated by Cytochrome P450 (CYP450) enzymes in the liver. Genetic polymorphisms in CYP450 genes and other factors, such as age, sex, and concomitant treatments, contribute to interindividual variability in methadone response. This article addresses the relevance of pharmacokinetic biomarkers in methadone metabolism and its impact on treatment outcomes in European populations over the past 25 years. Methods: A systematic review was conducted using four databases (PsycINFO, PubMed, Scopus, and Web of Science) for studies published between 2000 and 2024 following the PRISMA 2020 guidelines (CRD42025641373 in PROSPERO). Two independent reviewers screened and assessed the study quality using NHLBI tools. Discrepancies were solved through consensus. Relevant data including sample size, genetic biomarkers, and key findings were extracted for each study. Data were synthesized and described in detail. Results: Fourteen studies on pharmacogenetic biomarkers influencing methadone metabolism in European populations were analyzed, encompassing a total of 3180 subjects. CYP2B6*6 was identified as a key variant associated with increased (S)-methadone plasma levels, potentially leading to cardiac complications, while the role of other pharmacokinetic genes, including ABCB1 and CYP2D6, was inconclusive. Conclusions: Genetic polymorphisms significantly influence methadone metabolism, with the CYP2B6*6 allele playing a key role in (S)-methadone metabolism and associated with cardiac risks. Pharmacogenetic studies integrating co-mediation—the principal cause of phenoconversion—as a potential variable alongside gender differences and encompassing adequate sample sizes could improve outcomes and establish the basis for personalized medicine of MMT. Full article

(This article belongs to the Section Pharmacology)

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16 pages, 862 KiB

Open AccessArticle

Miraculin Can Contribute to a Reduction in Inflammatory Biomarkers and Cachexia in Malnourished Patients with Cancer and Taste Disorders

by Ana Isabel Álvarez-Mercado, Bricia López-Plaza, Julio Plaza-Diaz, Lucía Arcos-Castellanos, Francisco Javier Ruiz-Ojeda, Marco Brandimonte-Hernández, Jaime Feliú-Batlle, Thomas Hummel, Samara Palma-Milla and Ángel Gil

Pharmaceuticals 2025, 18(5), 622; https://doi.org/10.3390/ph18050622 - 25 Apr 2025

Abstract

Background: In 2022, there were an estimated 20 million new cancer cases and 9.7 million deaths. The number of new cancer cases is expected to rise to over 35 million by 2050, marking a 75% increase from 2022 levels. Twenty to eighty-six percent [...] Read more.

Background: In 2022, there were an estimated 20 million new cancer cases and 9.7 million deaths. The number of new cancer cases is expected to rise to over 35 million by 2050, marking a 75% increase from 2022 levels. Twenty to eighty-six percent of cancer patients suffer from taste disorders (TD), which are associated with an increased risk of malnutrition. Cachectic syndrome is linked to the presence and growth of tumors and leads to systemic inflammation. Synsepalum dulcificum is a plant whose berries contain miraculin, a glycoprotein that transforms sour tastes into sweet and can ameliorate TD. Objectives: To evaluate the effect of the regular intake of dried miracle berries (DMBs), a novel food containing miraculin, on biomarkers of inflammation and cachexia in malnourished patients with cancer and TD receiving systemic antineoplastic therapy. Methods: we conducted a triple-blind, randomized, placebo-controlled pilot clinical trial. Thirty-one patients with cancer of various etiologies who received chemotherapy were enrolled in this pilot study and divided into three groups. The first group received a tablet containing 150 mg of DMB (standard dose), the high-dose group received a tablet of 300 mg of DMB, and the third group received a tablet with 300 mg of the placebo for three months before each main meal. The plasma levels of several molecules associated with inflammation and cancer cachexia were measured using the X-MAP Luminex multiplexing platform. Results: We found decreased plasma levels of IFN-γ in the standard-dose group. In addition, our results suggest a downtrend of IL-1β levels in the three groups after three months of intervention (p = 0.093). Moreover, the three groups showed a reduction in tumor-derived molecule proteolysis-inducing factor/dermcidin (p = 0.021). It is important to highlight the positive correlation between IL-6 and IL-10 in the standard group, which suggests a better balance between proinflammatory and anti-inflammatory cytokines. Regardless of DMB consumption, soluble TNF receptor type II tended to decrease with treatment in patients who responded well to the antineoplastic treatment (p = 0.011). We did not find significant correlations between cytokines and sensory variables or dietary and nutritional status. Conclusions: Our results suggest that the regular consumption of a standard dose of DMB along with a systemic antineoplastic treatment could contribute to reducing inflammation and cachexia biomarkers in malnourished patients with cancer exhibiting TD. In this sense, nutritional support is crucial in the treatment of cancer cachexia. In our view, it should be considered a coadjuvant of therapeutics. Future studies on the molecular signaling pathways and specific mechanisms of action of bioactive compounds within food supplements, such as miraculin, will allow them to be used to target pathogenic mechanisms of cancer cachexia and malnutrition: NCT05486260. Full article

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17 pages, 3974 KiB

Open AccessArticle

Development of a Population Pharmacokinetic Model of Levofloxacin in Healthy Adults and Identification of Optimal Dosing Regimens

by Yun-Jung Lee, Gaeun Kang, Dae-Young Zang and Dong-Hwan Lee

Pharmaceuticals 2025, 18(5), 621; https://doi.org/10.3390/ph18050621 - 25 Apr 2025

Abstract

Background/Objectives: Levofloxacin dosing guidelines recommend adjustments only when the creatinine clearance (CrCl) is <50 mL/min. We hypothesized that further dose stratification based on CrCl could improve therapeutic outcomes, even when the CrCl ≥ 50 mL/min. This study aimed to develop a population [...] Read more.

Background/Objectives: Levofloxacin dosing guidelines recommend adjustments only when the creatinine clearance (CrCl) is <50 mL/min. We hypothesized that further dose stratification based on CrCl could improve therapeutic outcomes, even when the CrCl ≥ 50 mL/min. This study aimed to develop a population pharmacokinetic (PK) model of levofloxacin in healthy adults and identify optimal dosing regimens. Methods: In this prospective, open-label study, 12 healthy adults received a single dose of levofloxacin. Plasma concentrations were measured using liquid chromatography–tandem mass spectrometry. A population PK model was developed with nonlinear mixed-effects modeling, and Monte Carlo simulations were performed to identify optimal dosing regimens. Results: A two-compartment model with first-order kinetics best described the levofloxacin PK profiles. The CrCl was associated with a variation in clearance and lean body mass, with a variation in peripheral volume of distribution. Simulations identified optimal regimens, defined as those achieving a probability of target attainment of at least 90% for the target unbound 24-hour area under the curve at steady state to minimum inhibitory concentration ratio (fAUC/MIC), which differed by pathogen (≥30 for Gram-positive bacteria; ≥100 for Gram-negative bacteria). For the ratio fAUC/MIC ≥ 30 and an MIC of 0.5 mg/L, 500 mg daily was optimal for patients with a CrCl of 50–89 mL/min. For the ratio fAUC/MIC ≥ 100, 1000 mg daily was required in the same CrCl range and MIC value. Conclusions: The population PK model incorporating CrCl and lean body mass improved the prediction of levofloxacin PKs. Refining current dosing recommendations by incorporating stratified CrCl and MIC values could optimize therapeutic outcomes, particularly for patients with a CrCl ≥ 50 mL/min. Full article

(This article belongs to the Special Issue Population Pharmacokinetics and Pharmacogenetics)

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21 pages, 3108 KiB

Open AccessArticle

2-Amino-3-Chlorobenzoic Acid from Streptomyces coelicolor: A Cancer Antagonist Targeting PI3K/AKT Markers via miRNA Modulation

by Ashraf Khalifa, Joseph D. Balthazar, Pandurangan Subash-Babu, Mohamed Y. Zaky, Zeinab A. El-Moaty and Hairul Islam M. Ibrahim

Pharmaceuticals 2025, 18(5), 620; https://doi.org/10.3390/ph18050620 - 24 Apr 2025

Abstract

Background/Objectives: Actinomycetes, particularly species within the Streptomyces genus, are renowned for their ability to produce a wide array of bioactive molecules with therapeutic potential. This study aimed to comprehensively investigate the antimicrobial and anticancer properties of Streptomyces coelicolor ERI-15, with a particular focus [...] Read more.

Background/Objectives: Actinomycetes, particularly species within the Streptomyces genus, are renowned for their ability to produce a wide array of bioactive molecules with therapeutic potential. This study aimed to comprehensively investigate the antimicrobial and anticancer properties of Streptomyces coelicolor ERI-15, with a particular focus on a purified compound, 2-amino-3-chlorobenzoic acid (2A3CB), and its efficacy against microbial pathogens and breast cancer cell lines. Methods: Antimicrobial compounds were produced through fermentation techniques and isolated via column chromatography. Bioassay-guided fractionation was conducted against Staphylococcus aureus (ATCC 25923), methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (ATCC 25922), and Bacillus subtilis (ATCC 441). Major fractions were further purified using preparative thin-layer chromatography (TLC). The structures of active compounds were elucidated using spectral analyses including IR, mass spectrometry, and ¹H/¹³C NMR. The compound 2A3CB (m/z 171) was tested against MDA-MB-231 and 3T3 cell lines. Cytotoxicity was assessed by the MTT assay, and apoptotic mechanisms were explored via cell proliferation assays, dual fluorescent staining, migration and invasion assays, and analysis of apoptotic markers at mRNA and protein levels. Results: 2A3CB exhibited strong cytotoxic effects on MDA-MB-231 cells, with IC₅₀ values of 26 µM, 5 µM, and 7.2 µM at 24, 48, and 72 h, respectively. It significantly inhibited cell proliferation and migration, and induced apoptosis via caspase-mediated pathways. Expression levels of PTEN, PCNA, BAX, and STAT3 were downregulated, suggesting inhibition of metastasis through the suppression of invasion and migration. Conclusions: The results demonstrate that 2A3CB, derived from S. coelicolor ERI-15, possesses potent antimicrobial and anticancer properties. Its ability to inhibit growth and induce apoptosis in MDA-MB-231 breast cancer cells highlights its potential as a natural therapeutic candidate for targeted cancer treatment, particularly in breast cancer progression. Full article

(This article belongs to the Special Issue Therapeutic Effects of Natural Products and Their Clinical Research)

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24 pages, 4123 KiB

Open AccessArticle

Developing a Chromatographic Method for Quantifying Latanoprost and Related Substances in Glaucoma Treatments

by Katarzyna Asendrych-Wicik, Katarzyna Malik and Magdalena Markowicz-Piasecka

Pharmaceuticals 2025, 18(5), 619; https://doi.org/10.3390/ph18050619 - 24 Apr 2025

Abstract

Background/Objectives: Latanoprost is a leading active pharmaceutical ingredient belonging to the synthetic prostaglandin F2α analogs, widely used as a first-line treatment for open-angle glaucoma and increased intraocular pressure. This study addresses the critical need for an accurate and precise chromatographic method that [...] Read more.

Background/Objectives: Latanoprost is a leading active pharmaceutical ingredient belonging to the synthetic prostaglandin F2α analogs, widely used as a first-line treatment for open-angle glaucoma and increased intraocular pressure. This study addresses the critical need for an accurate and precise chromatographic method that is capable of simultaneously quantifying latanoprost and six latanoprost-related substances in antiglaucoma eye drops. This will be crucial for patient safety and treatment efficacy. This method enables the separation of latanoprost isomers, (15S)-latanoprost, latanoprost enantiomer, and 5,6-trans latanoprost from latanoprost signal. Furthermore, it is specific for the well-known latanoprost degradants—the major latanoprost acid and the minor 15-ketolatanoprost—as well as synthetic derivatives, such as triphenylphosphine oxide (TPPO) and propan-2-yl 5-(diphenylphosphoryl)pentanoate (IDPP). Using forced degradation studies using high temperatures, UV light, alkalis, acids, and oxidizing agents, the degradation profiles of the drugs were characterized and the method’s stability-indicating power was confirmed. Methods: Separation was achieved on a stationary combined system comprising chiral and cyano columns. Reverse-phase gradient elution and UV 210 nm detection were employed. The novel method was validated according to the European Medicines Agency International Council for Harmonisation Q2 Validation of analytical procedures—Scientific guideline. Results: The method was shown to be linear in the range of 40–60 µg/mL for latanoprost and 0.05–2.77 µg/mL for related substances, confirmed by a correlation coefficient of r = 0.999. Recoveries for latanoprost were obtained within the range of 98.0–102.0% for assays and 90.0–110.0% for impurities. The detection and quantification limits for latanoprost were 0.025 µg/mL and 0.35 µg/mL, respectively. Conclusions: The analytical procedure developed is adequately sensitive, precise, and accurate compared to existing methods. The method can be reliably used to control the critical quality attributes of low-dose latanoprost products, ensuring their required high pharmaceutical quality, which translates into improvements in patient care. This advancement holds significant implications for enhancing the therapeutic management of glaucoma, ensuring drug safety and efficacy. Full article

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

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22 pages, 19376 KiB

Open AccessArticle

Exploring Therapeutic Potential of Bi-Qi Capsules in Treatment of Gout by Discovering Crucial Drug Targets

by Jing Xie, Yu Zhang, Rong Ren, Ruizhen Bu, Liying Chen, Juezhuo Hou, Dandan Shang, Yadong Liu, Dan Wang, Tao Wang and Hong Zhou

Pharmaceuticals 2025, 18(5), 618; https://doi.org/10.3390/ph18050618 - 24 Apr 2025

Abstract

Objectives: This research aims to explore the therapeutic potential of Bi-Qi capsules in the treatment of gout by identifying crucial drug targets through a multidimensional data analysis strategy. Methods: Bi-Qi capsule drug targets and differentially expressed genes (DEGs) of gout were [...] Read more.

Objectives: This research aims to explore the therapeutic potential of Bi-Qi capsules in the treatment of gout by identifying crucial drug targets through a multidimensional data analysis strategy. Methods: Bi-Qi capsule drug targets and differentially expressed genes (DEGs) of gout were derived from public databases, such as Swiss Target Prediction, STITCH, and the GEO database. Subsequently, the overlapped targets were analyzed to elucidate the potential therapeutic mechanism and to identify candidate targets of Bi-Qi capsules against gout. Next, Mendelian randomization (MR) analysis was employed to screen and explore the causal relationship between candidate targets and gout. Finally, single-cell RNA sequencing (scRNA-seq), gene set enrichment analysis (GSEA), transcription factor and ceRNA regulatory networks, and molecular docking were performed to validate the role of the crucial targets of Bi-Qi capsules in the treatment of gout. Results: A total of 46 candidate targets were identified, in which KCNA5, PTGS2, and TNF exhibited significant causal relationships with gout (p < 0.05) and were regarded as the crucial targets. Through scRNA-seq and gene labeling, crucial targets were found to be expressed in eighteen cell clusters and eight cell types, which are closely associated with carbohydrate metabolism, nerve conduction, and the innate immunity process. Bi-Qi capsule active compounds such as tanshinone IIA, strychnine, tanshinaldehyde, cryptotanshinone, tumulosic acid, and glycyrrhetic acid exhibit a better binding ability to crucial targets. Conclusions: The results not only elucidate the anti-gout mechanism of Bi-Qi capsules but also provide an insight into multi-target natural medication for metabolic disease treatment, which contributes to guiding the clinical application of Bi-Qi capsules in the future. Full article

(This article belongs to the Section Pharmacology)

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23 pages, 8189 KiB

Open AccessReview

Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery

by Taegwan Kim, Eunbee Baek and Jonghoon Kim

Pharmaceuticals 2025, 18(5), 617; https://doi.org/10.3390/ph18050617 - 24 Apr 2025

Abstract

Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein interfaces. However, despite their potential, the synthesis [...] Read more.

Macrocycles have emerged as significant therapeutic candidates in drug discovery due to their unique capacity to target complex and traditionally inaccessible biological interfaces. Their structurally constrained three-dimensional configurations facilitate high-affinity interactions with challenging targets, notably protein–protein interfaces. However, despite their potential, the synthesis and optimization of macrocyclic compounds present considerable challenges related to structural complexity, synthetic accessibility, and the attainment of favorable drug-like properties, particularly cell permeability and oral bioavailability. Recent advancements in synthetic methodologies have expanded the chemical space accessible to macrocycles, enabling the creation of structurally diverse and pharmacologically active compounds. Concurrent developments in computational strategies have further enhanced macrocycle design, providing valuable insights into structural optimization and predicting molecular properties essential for therapeutic efficacy. Additionally, a deeper understanding of macrocycles’ conformational adaptability, especially their ability to internally shield polar functionalities to improve membrane permeability, has significantly informed their rational design. This review discusses recent innovations in synthetic and computational methodologies that have advanced macrocycle drug discovery over the past five years. It emphasizes the importance of integrating these strategies to overcome existing challenges, illustrating how their synergy expands the therapeutic potential and chemical diversity of macrocycles. Selected case studies underscore the practical impact of these integrated approaches, highlighting promising therapeutic applications across diverse biomedical targets. Full article

(This article belongs to the Special Issue Advances in the Synthesis and Application of Heterocyclic Compounds)

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25 pages, 6242 KiB

Open AccessArticle

Development and Characterization of an Injectable Alginate/Chitosan Composite Hydrogel Reinforced with Cyclic-RGD Functionalized Graphene Oxide for Potential Tissue Regeneration Applications

by Mildred A. Sauce-Guevara, Sergio D. García-Schejtman, Emilio I. Alarcon, Sergio A. Bernal-Chavez and Miguel A. Mendez-Rojas

Pharmaceuticals 2025, 18(5), 616; https://doi.org/10.3390/ph18050616 - 23 Apr 2025

Abstract

Background: In tissue engineering, developing injectable hydrogels with tailored mechanical and bioactive properties remains a challenge. This study introduces an injectable hydrogel composite for soft tissue regeneration, composed of oxidized alginate (OA) and N-succinyl chitosan (NSC) cross-linked via Schiff base reaction, reinforced with [...] Read more.

Background: In tissue engineering, developing injectable hydrogels with tailored mechanical and bioactive properties remains a challenge. This study introduces an injectable hydrogel composite for soft tissue regeneration, composed of oxidized alginate (OA) and N-succinyl chitosan (NSC) cross-linked via Schiff base reaction, reinforced with graphene oxide (GOx) and cyclic arginylglycylaspartic acid (c-RGD). The objective was to create a multifunctional platform combining injectability, bioactivity, and structural stability. Methods: The OA/NSC/GOx-cRGD hydrogel was synthesized through Schiff base cross-linking (aldehyde-amine reaction). Characterization included FTIR (C=N bond at 1650 cm⁻¹), Raman spectroscopy (D/G bands at 1338/1567 cm⁻¹), SEM (porous microstructure), and rheological analysis (shear-thinning behavior). In vitro assays assessed fibroblast viability (MTT) and macrophage TNF-α secretion (ELISA), while ex-vivo injectability and retention were evaluated using chicken cardiac tissue. Results: The hydrogel exhibited shear-thinning behavior (viscosity: 10 to <1 Pa·s) and elastic-dominated mechanics (G′ > G″), ensuring injectability. SEM revealed an interconnected porous structure mimicking native extracellular matrix. Fibroblast viability remained ≥95%, and TNF-α secretion in macrophages decreased by 80% (30 vs. 150 pg/μL in controls), demonstrating biocompatibility and anti-inflammatory effects. The hydrogel adhered stably to cardiac tissue without leakage. Conclusions: The OA/NSC/GOx-cRGD composite integrates injectability, bioactivity, and structural stability, offering a promising scaffold for tissue regeneration. Its modular design allows further functionalization with peptides or growth factors. Future work will focus on translational applications, including scalability and optimization for dynamic biological environments. Full article

(This article belongs to the Section Biopharmaceuticals)

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29 pages, 1005 KiB

Open AccessReview

Advancements in Nanocarrier Systems for Nose-to-Brain Drug Delivery

by Thi-Thao-Linh Nguyen and Van-An Duong

Pharmaceuticals 2025, 18(5), 615; https://doi.org/10.3390/ph18050615 - 23 Apr 2025

Abstract

In recent decades, nose-to-brain drug delivery has shown effectiveness in treating many central nervous system diseases. Intranasally administered drugs can be delivered to the brain through the olfactory and trigeminal pathways that bypass the blood–brain barrier. However, nose-to-brain drug delivery is challenging due [...] Read more.

In recent decades, nose-to-brain drug delivery has shown effectiveness in treating many central nervous system diseases. Intranasally administered drugs can be delivered to the brain through the olfactory and trigeminal pathways that bypass the blood–brain barrier. However, nose-to-brain drug delivery is challenging due to the inadequate nasal mucosa absorption of drugs and the short retention time of the intranasal formulations. These problems can be minimized through the use of nano-drug delivery systems, such as micelles, polymeric nanoparticles, nanoemulsions, liposomes, solid lipid nanoparticles, and nanostructured lipid carriers. They can enhance the drug’s bioavailability in the brain via increases in drug solubility, permeation, and stability. Nose-to-brain nano-drug delivery systems have been evaluated in vivo by a number of research groups. This review aims to provide an overview of nose-to-brain delivery and recent advances in the development of nano-drug delivery systems for delivering drugs from the nose to the brain to improve the treatment of some central nervous system diseases. Full article

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

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40 pages, 1048 KiB

Open AccessReview

Antidiabetic GLP-1 Receptor Agonists Have Neuroprotective Properties in Experimental Animal Models of Alzheimer’s Disease

by Melinda Urkon, Elek Ferencz, József Attila Szász, Monica Iudita Maria Szabo, Károly Orbán-Kis, Szabolcs Szatmári and Előd Ernő Nagy

Pharmaceuticals 2025, 18(5), 614; https://doi.org/10.3390/ph18050614 - 23 Apr 2025

Abstract

In addition to the classically accepted pathophysiological features of Alzheimer’s disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The [...] Read more.

In addition to the classically accepted pathophysiological features of Alzheimer’s disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The present review aims to offer a comprehensive overview of the neuroprotective properties of GLP-1R agonists (GLP-1RAs), with a particular focus on experimental animal models of AD. Ameliorated amyloid-β plaque and neurofibrillary tangle formation and deposition following exenatide, liraglutide, and lixisenatide treatment was confirmed in several models. The GLP-1RAs studied alleviated central insulin resistance, as evidenced by the decreased serine phosphorylation of insulin receptor substrate 1 (IRS-1) and restored downstream phosphoinositide 3-kinase/RAC serine/threonine–protein kinase (PI3K/Akt) signaling. Furthermore, the GLP-1RAs influenced multiple mitogen-activated protein kinases (extracellular signal-regulated kinase: ERK; c-Jun N-terminal kinase: JNK, p38) positively and suppressed glycogen synthase kinase 3 (GSK-3β) hyperactivation. A lower proportion of reactive microglia and astrocytes was associated with better neuronal preservation following their administration. Finally, restoration of cognitive functions, particularly spatial memory, was also observed for semaglutide and dulaglutide. GLP-1RAs, therefore, hold promising disease-modifying potential in the management of AD. Full article

(This article belongs to the Special Issue Neurodegenerative Disorders: Computer – Aided Drug Design, Еxperimental Аpproaches and Mechanisms)

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28 pages, 16481 KiB

Open AccessArticle

Systems Biology-Driven Discovery of Host-Targeted Therapeutics for Oropouche Virus: Integrating Network Pharmacology, Molecular Docking, and Drug Repurposing

by Pranab Dev Sharma, Abdulrahman Mohammed Alhudhaibi, Abdullah Al Noman, Emad M. Abdallah, Tarek H. Taha and Himanshu Sharma

Pharmaceuticals 2025, 18(5), 613; https://doi.org/10.3390/ph18050613 - 23 Apr 2025

Abstract

Background: Oropouche virus (OROV), part of the Peribunyaviridae family, is an emerging pathogen causing Oropouche fever, a febrile illness endemic in South and Central America. Transmitted primarily through midge bites (Culicoides paraensis), OROV has no specific antiviral treatment or vaccine. This [...] Read more.

Background: Oropouche virus (OROV), part of the Peribunyaviridae family, is an emerging pathogen causing Oropouche fever, a febrile illness endemic in South and Central America. Transmitted primarily through midge bites (Culicoides paraensis), OROV has no specific antiviral treatment or vaccine. This study aims to identify host-targeted therapeutics against OROV using computational approaches, offering a potential strategy for sustainable antiviral drug discovery. Methods: Virus-associated host targets were identified using the OMIM and GeneCards databases. The Enrichr and DSigDB platforms were used for drug prediction, filtering compounds based on Lipinski’s rule for drug likeness. A protein–protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape 3.10.3 software. Four key host targets—IL10, FASLG, PTPRC, and FCGR3A—were prioritized based on their roles in immune modulation and OROV pathogenesis. Molecular docking simulations were performed using the PyRx software to evaluate the binding affinities of selected small-molecule inhibitors—Acetohexamide, Deptropine, Methotrexate, Retinoic Acid, and 3-Azido-3-deoxythymidine—against the identified targets. Results: The PPI network analysis highlighted immune-mediated pathways such as Fc-gamma receptor signaling, cytokine control, and T-cell receptor signaling as critical intervention points. Molecular docking revealed strong binding affinities between the selected compounds and the prioritized targets, suggesting their potential efficacy as host-targeting antiviral candidates. Acetohexamide and Deptropine showed strong binding to multiple targets, indicating broad-spectrum antiviral potential. Further in vitro and in vivo validations are needed to confirm these findings and translate them into clinically relevant treatments. Conclusions: This study highlights the potential of using computational approaches to identify host-targeted therapeutics for Oropouche virus (OROV). By targeting key host proteins involved in immune modulation—IL10, FASLG, PTPRC, and FCGR3A—the selected compounds, Acetohexamide and Deptropine, demonstrate strong binding affinities, suggesting their potential as broad-spectrum antiviral candidates. Further experimental validation is needed to confirm their efficacy and potential for clinical application, offering a promising strategy for sustainable antiviral drug discovery. Full article

(This article belongs to the Special Issue Computational Methods in Drug Development)

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26 pages, 4056 KiB

Open AccessArticle

Epigallocatechin Gallate in Camellia sinensis Ameliorates Skin Aging by Reducing Mitochondrial ROS Production

by Ji Ho Park, Eun Young Jeong, Ye Hyang Kim, So Yoon Cha, Ha Yeon Kim, Yeon Kyung Nam, Jin Seong Park, So Yeon Kim, Yoo Jin Lee, Jee Hee Yoon, Byeonghyeon So, Duyeol Kim, Minseon Kim, Youngjoo Byun, Yun Haeng Lee, Song Seok Shin and Joon Tae Park

Pharmaceuticals 2025, 18(5), 612; https://doi.org/10.3390/ph18050612 - 23 Apr 2025

Abstract

Background: Reactive oxygen species (ROS) generated by mitochondrial dysfunction damage cellular organelles and contribute to skin aging. Therefore, strategies to reduce mitochondrial ROS production are considered important for alleviating skin aging, but no effective methods have been identified. Methods: In this study, we [...] Read more.

Background: Reactive oxygen species (ROS) generated by mitochondrial dysfunction damage cellular organelles and contribute to skin aging. Therefore, strategies to reduce mitochondrial ROS production are considered important for alleviating skin aging, but no effective methods have been identified. Methods: In this study, we evaluated substances utilized as cosmetic ingredients and discovered Camellia sinensis (C. sinensis) as a substance that reduces mitochondrial ROS levels. Results: C. sinensis extracts were found to act as senolytics that selectively kill senescent fibroblasts containing dysfunctional mitochondria. In addition, C. sinensis extracts facilitated efficient electron transport in the mitochondrial electron transport chain (ETC) by increasing the efficiency of oxidative phosphorylation (OXPHOS), thereby reducing mitochondrial ROS production, a byproduct of the inefficient ETC. This novel mechanism of C. sinensis extracts led to the restoration of skin aging and the skin barrier. Furthermore, epigallocatechin gallate (EGCG) was identified as an active ingredient that plays a key role in C. sinensis extract-mediated skin aging recovery. Indeed, similar to C. sinensis extracts, EGCG reduced ROS and improved skin aging in an artificial skin model. Conclusions: Our data uncovered a novel mechanism by which C. sinensis extract reverses skin aging by reducing mitochondrial ROS production via selective senescent cell death/increased OXPHOS efficiency. Our results suggest that C. sinensis extract or EGCG may be used as a therapeutic agent to reverse skin aging in clinical and cosmetic applications. Full article

(This article belongs to the Special Issue Antioxidants in the Processes of Retarding Ageing)

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20 pages, 2428 KiB

Open AccessArticle

A Short-Chain Analogue of Seminolipid: Synthesis and Inhibitory Effect on Mouse Fertilization

by Seung Gee Lee, Leila Vahdati, Laura Morelli, Luigi Panza, Federica Compostella and Nongnuj Tanphaichitr

Pharmaceuticals 2025, 18(5), 611; https://doi.org/10.3390/ph18050611 - 23 Apr 2025

Abstract

Background/Objectives: Seminolipid (sulfogalactosylglycerolipid (SGG)) is abundantly present on the sperm surface and its roles in sperm–egg interaction are well-documented. SGG liposomes have direct affinity for the zona pellucida (ZP), the egg extracellular matrix. SGG is also integral to the formation of sperm lipid [...] Read more.

Background/Objectives: Seminolipid (sulfogalactosylglycerolipid (SGG)) is abundantly present on the sperm surface and its roles in sperm–egg interaction are well-documented. SGG liposomes have direct affinity for the zona pellucida (ZP), the egg extracellular matrix. SGG is also integral to the formation of sperm lipid rafts, which are platforms on the sperm surface for ZP binding. Our objective was to chemically synthesize a short-chain analog of SGG (SC-SGG with a C6 acyl chain instead of C16 in the natural lipid), which is solubilized in an aqueous environment, and to determine the inhibitory effects of SC-SGG in mouse sperm–egg interaction, and thus fertilization. Methods: SC-SGG was synthesized from a 3-O-galactopyranosyl-sn-glycerol intermediate protected on the sugar moiety through the acylation of glycerol with caproic acid, deprotection and regioselective 3-O-sulfation of the galactose residue. SC-SGG solubilized in a medium was used to treat sperm–egg co-incubates or to pretreat sperm or eggs before co-incubating sperm with eggs or vice versa. Sperm–ZP binding and fertilization (scoring eggs with two pronuclei) were microscopically assessed. Results: SC-SGG was efficiently synthesized with a 78% overall yield. SC-SGG inhibited sperm–ZP binding and fertilization of mouse gametes in a concentration-dependent manner, and at 6 µM SC-SGG, the mouse fertilization was zero. SC-SGG inhibited the fertilizing ability of both sperm and eggs, as shown in the pretreatment experiments. Conclusions: SC-SGG was an effective inhibitor of mouse fertilization in vitro. It warrants development to be a non-hormonal contraceptive. Full article

(This article belongs to the Section Pharmacology)

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22 pages, 5127 KiB

Open AccessArticle

Antipyretic Mechanism of Bai Hu Tang on LPS-Induced Fever in Rat: A Network Pharmacology and Metabolomics Analysis

by Ke Pei, Yuchen Wang, Wentao Guo, He Lin, Zhe Lin and Guangfu Lv

Pharmaceuticals 2025, 18(5), 610; https://doi.org/10.3390/ph18050610 - 23 Apr 2025

Abstract

Background: Bai Hu Tang (BHT) is a classic antipyretic in traditional Chinese medicine, however, there is little scientific evidence on the mechanism and material basis of its antipyretic effect. Methods: In LPS-induced febrile rats, after administration of BHT at 42 g/kg [...] Read more.

Background: Bai Hu Tang (BHT) is a classic antipyretic in traditional Chinese medicine, however, there is little scientific evidence on the mechanism and material basis of its antipyretic effect. Methods: In LPS-induced febrile rats, after administration of BHT at 42 g/kg for half an hour, body temperature was measured at hourly intervals for 9 consecutive hours. Then, serum levels of TNF-α, IL-1β, and IL-6, and serum and cerebrospinal fluid (CSF) levels of AVP, cAMP, PGE2, Ca and CRH, and the remaining sera were used for metabolomics. These were then combined with network pharmacology methodology to further analyse the antipyretic effect of BHT and then dock key targets with differential components. Results: Administration of BHT to LPS-induced febrile rats significantly reduced elevated body temperature, TNF-α, IL-1β and IL-6 levels, but serum and CSF levels of AVP, cAMP, PGE2, Ca²⁺ and CRH were significantly elevated compared to the control group. Network pharmacological analyses indicated that the putative functional targets of BHT were regulation of immune responses, associated protein binding and inflammatory responses, and fine-tuning of phosphatase binding and activation of signalling pathways such as MAPK, PI3K, AKT, NF-kB, cAMP and inflammatory pathways. Metabolomic analysis showed that the antipyretic effect of BHT and its mechanism are likely to be involved in fatty acid metabolism, bile acid metabolism and amino acid metabolism in the organism, with L-arginine, glycyrrhetinic acid and N-acetylpentraxine as the main differential metabolites that play a significant role in heat recovery. The results also showed better docking of glycyrrhetinic acid with TNF-α, IL-6R, PTGS2. Conclusions: BHT provides a valuable adjunct to traditional clinical antipyretics by improving body temperature and metabolism and reducing inflammation. Full article

(This article belongs to the Section Pharmacology)

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13 pages, 424 KiB

Open AccessArticle

Impact of Co-Occurring Psychiatric Comorbidities and Substance Use Disorders on Outcomes in Adolescents and Young Adults with Opioid Use Disorder: A Retrospective Cohort Study

by Ligang Liu, Erin R. McKnight, Andrea E. Bonny, Heqing Tao, Pujing Zhao and Milap C. Nahata

Pharmaceuticals 2025, 18(5), 609; https://doi.org/10.3390/ph18050609 - 23 Apr 2025

Abstract

Background/Objectives: Adolescents and young adults (AYAs) with opioid use disorder (OUD) frequently have co-occurring psychiatric conditions and substance use disorders (SUDs). This study evaluated the association of psychiatric comorbidities and other SUDs with treatment retention and urine drug test (UDT) results in AYAs [...] Read more.

Background/Objectives: Adolescents and young adults (AYAs) with opioid use disorder (OUD) frequently have co-occurring psychiatric conditions and substance use disorders (SUDs). This study evaluated the association of psychiatric comorbidities and other SUDs with treatment retention and urine drug test (UDT) results in AYAs with OUD. Methods: This retrospective cohort study included AYAs enrolled in the Substance Use Treatment and Recovery clinic from 2009 to 2022. Participants were categorized into four groups: no comorbidities, only mental health disorders, only other SUDs, and both disorders. Treatment outcomes included retention time and UDT results for medication for OUD (MOUD) and illicit substances, including tetrahydrocannabinol (THC). Kruskal–Wallis tests were used to evaluate differences across groups, and regression models identified variables associated with outcomes. Statistical significance was set at p < 0.05. Results: Among 157 patients, the median retention time was 300 days. Depression (p = 0.04), post-traumatic stress disorder (p = 0.002), and alcohol use disorder (p = 0.04) were associated with prolonged retention, whereas cannabis use disorder predicted shorter retention (p = 0.02). The median proportion of positive UDTs was 0.9 for MOUD, 0.1 for illicit substances, and 0.0 for THC. Older age (p = 0.02) and the use of antidepressants and anxiolytics were associated with greater adherence to MOUD. Cannabis use disorder (p = 0.02) and male sex (p = 0.04) predicted positive UDTs for THC, while MOUD use was linked to lower THC positivity (p = 0.02). The main limitations of this study were related to its retrospective study design and single-center setting. Conclusions: Psychiatric and substance use comorbidities significantly influence retention and treatment adherence in AYAs with OUD. Integrated treatment may improve engagement and outcomes. Further research is needed to tailor interventions for AYAs with co-occurring disorders. Full article

(This article belongs to the Special Issue Drug Safety and Risk Management in Clinical Practice)

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24 pages, 3012 KiB

Open AccessArticle

Structural Activity Relationship Analysis of New Diphenyl PFI-3 Analogues Targeting for the Treatment of Glioblastoma

by Dong-Jin Hwang, Chuanhe Yang, Yinan Wang, Hannah Kelso, Satyanarayana Pochampally, Lawrence M. Pfeffer and Duane D. Miller

Pharmaceuticals 2025, 18(5), 608; https://doi.org/10.3390/ph18050608 - 23 Apr 2025

Abstract

Background/Objectives: Human glioblastoma (GBM) is the most aggressive brain cancer in adults and a highly treatment-refractory malignancy. The overall prognosis for the GBM is extremely poor, with a median survival of 12–14 months after initial diagnosis. Many GBM patients initially respond to [...] Read more.

Background/Objectives: Human glioblastoma (GBM) is the most aggressive brain cancer in adults and a highly treatment-refractory malignancy. The overall prognosis for the GBM is extremely poor, with a median survival of 12–14 months after initial diagnosis. Many GBM patients initially respond to the DNA alkylating agent temozolomide (TMZ), but patients often become therapy-resistant, and tumors recur. We previously reported that treatment with PFI-3, which is a small molecule inhibitor of the bromodomain of the BRG1 subunit of the SW1/SNF chromatin remodeling complex, enhanced the sensitivity of GBM cells to TMZ in vitro and in vivo GBM animal models. Our general objective was to perform an SAR study of new diphenyl PFI-3 analogs. Methods: New structural analogs of PFI-3 were developed, synthesized, and tested for their ability to enhance TMZ-induced GBM cell death by ELISA. Results: Following on the enhanced activity of compounds 2a and 2b, new diphenyl PFI-3 analogs with specific structural adjustments were made to better understand the structural requirements to optimize function. Additionally, several new structurally different candidates (e.g., 4a, 4b, and 5) showed much better efficacy in sensitizing GBM cells to TMZ-induced GBM cell death. Conclusions: Four series of PFI-3 analogs (2, 3, 4, and 5) were designed, synthesized, and tested for the ability to sensitize GBM cells to TMZ-induced cell death. Series 2 optimized the A-ring and R-isomer chirality. Series 3 used a 5-membered linker with weak activity. Series 4’s di-phenyl urea compounds showed better bromodomain inhibition. Series 5’s methoxyphenyl-B-ring analogs were exceptionally strong inhibitors. Full article

(This article belongs to the Section Medicinal Chemistry)

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50 pages, 5274 KiB

Open AccessReview

Quinoline Quest: Kynurenic Acid Strategies for Next-Generation Therapeutics via Rational Drug Design

by Masaru Tanaka, István Szatmári and László Vécsei

Pharmaceuticals 2025, 18(5), 607; https://doi.org/10.3390/ph18050607 - 22 Apr 2025

Abstract

Background: Quinoline-derived metabolites exhibit notable chemical complexity. What causes minor structural alterations to induce significant changes in disease outcomes? Historically, eclipsed by more straightforward scaffolds, these chemicals serve as a dynamic hub in tryptophan metabolism, linking immunomodulation, excitotoxicity, and cancer. However, many of [...] Read more.

Background: Quinoline-derived metabolites exhibit notable chemical complexity. What causes minor structural alterations to induce significant changes in disease outcomes? Historically, eclipsed by more straightforward scaffolds, these chemicals serve as a dynamic hub in tryptophan metabolism, linking immunomodulation, excitotoxicity, and cancer. However, many of these compounds struggle to cross the blood–brain barrier, and we still do not fully understand how certain structural changes affect their bioavailability or off-target effects. Thus, contemporary research highlights halogenation, esterification, and computational modeling to enhance structure–activity relationships. Summary: This narrative review emphasizes the integration of rational drug design, multi-target ligands, and prodrug methods in enhancing quinoline scaffolds. We explore each molecule’s therapeutic promise, refine each scaffold’s design, and develop each derivative to maximize clinical utility. Translating these laboratory findings into clinical practice, however, remains a formidable challenge. Conclusions: Through the synthesis of findings regarding NMDA receptor antagonism, improved oral bioavailability, and reduced metabolic instability, we demonstrate how single-site changes might modulate excitotoxicity and immunological signaling. Advancing quinoline-based medicines will yield significant advancements in neurology, psychiatry, and oncology. This enlarged framework fosters collaborative discovery, engages various audiences, and advances the field towards next-generation disease-modifying therapies. Robust preclinical validation, patient classification, and comprehensive toxicity evaluations are crucial stages for achieving these extensive endeavors and fostering future therapeutic discoveries globally. Full article

(This article belongs to the Special Issue Kynurenine Pathway: A Novel Therapeutic Opportunity)

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2 pages, 130 KiB

Open AccessEditorial

Advancing Neuropharmacology and Neurodegenerative Disease Therapy: Bridging Gaps and Paving New Pathways

by Manuela Leri and Marzia Vasarri

Pharmaceuticals 2025, 18(5), 606; https://doi.org/10.3390/ph18050606 - 22 Apr 2025

Abstract

The Special Issue of Pharmaceuticals, titled “Multi-target drug treatments for neurodegenerative disease”, highlighted recent advancements in neuropharmacology and the therapeutic landscape for neurodegenerative diseases, representing a significant stride forward in our understanding of these complex conditions [...] Full article

(This article belongs to the Special Issue Multi-target Drug Treatments for Neurodegenerative Disease)

19 pages, 13866 KiB

Open AccessArticle

Investigating the Effect and Mechanism of 3-Methyladenine Against Diabetic Encephalopathy by Network Pharmacology, Molecular Docking, and Experimental Validation

by Jiaxin Chu, Jianqiang Song, Zhuolin Fan, Ruijun Zhang, Qiwei Wang, Kexin Yi, Quan Gong and Benju Liu

Pharmaceuticals 2025, 18(5), 605; https://doi.org/10.3390/ph18050605 - 22 Apr 2025

Abstract

Background/Objectives: Diabetic encephalopathy (DE), a severe neurological complication of diabetes mellitus (DM), is characterized by cognitive dysfunction. 3-Methyladenine (3-MA), a methylated adenine derivative, acts as a biomarker for DNA methylation and exhibits hypoglycemic and neuroprotective properties. However, the pharmacological mechanisms underlying 3-MA’s therapeutic [...] Read more.

Background/Objectives: Diabetic encephalopathy (DE), a severe neurological complication of diabetes mellitus (DM), is characterized by cognitive dysfunction. 3-Methyladenine (3-MA), a methylated adenine derivative, acts as a biomarker for DNA methylation and exhibits hypoglycemic and neuroprotective properties. However, the pharmacological mechanisms underlying 3-MA’s therapeutic effects on diabetic microvascular complications remain incompletely understood, owing to the intricate and multifactorial pathogenesis of DE. Methods: This study employed network pharmacology and molecular docking techniques to predict potential targets and signaling pathways of 3-MA against DE, with subsequent validation through animal experiments to elucidate the molecular mechanisms of 3-MA in DE treatment. Results: Network pharmacological analysis identified two key targets of 3-MA in DE modulation: AKT and GSK3β. Molecular docking confirmed a strong binding affinity between 3-MA and AKT/GSK3β. In animal experiments, 3-MA significantly reduced blood glucose levels in diabetic mice, ameliorated learning and memory deficits, and preserved hippocampal neuronal integrity. Furthermore, we found that 3-MA inhibited apoptosis by regulating the expression of Bax and BCL-2. Notably, 3-MA also downregulated the expression of amyloid precursor protein (APP) and Tau while enhancing the expression of phosphorylated AKT and GSK-3β. Conclusions: Our findings may contribute to elucidating the therapeutic mechanisms of 3-MA in diabetic microangiopathy and provide potential therapeutic targets through activation of the AKT/GSK-3β pathway. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 1972 KiB

Open AccessArticle

Larvicidal Potential of Trattinnickia Burserifolia Mart. Essential Oil in Controlling the Malaria Vector in the Amazon

by Gisele Guimarães de Oliveira, Stherfany Mac Donald da Silva, Alessandro Pereira de Souza, Leticia Vieira Anchieta da Silva, Anauara Lima e Silva, Ana Cristina Gonçalves Reis de Melo, Rosemary Aparecida Roque, André Correa de Oliveira, Antonio Alves de Melo Filho and Andreimar Martins Soares

Pharmaceuticals 2025, 18(5), 604; https://doi.org/10.3390/ph18050604 - 22 Apr 2025

Abstract

Background: Among major public health problems, malaria stands out as a tropical disease caused by the Plasmodium protozoan, with mosquitoes of the Anopheles genus serving as its vectors. This disease affects a significant portion of the population, with the highest incidence in the [...] Read more.

Background: Among major public health problems, malaria stands out as a tropical disease caused by the Plasmodium protozoan, with mosquitoes of the Anopheles genus serving as its vectors. This disease affects a significant portion of the population, with the highest incidence in the Legal Amazon, a region responsible for 99% of cases. Although vector control strategies, such as the use of chemical insecticides, are commonly employed, mosquito resistance, environmental impacts, and risks to human health are driving the search for natural alternatives, including the application of essential oils. Objectives: This study investigates the larvicidal activity of Trattinnickia burserifolia Mart. essential oil against Anopheles darlingi. Methods: The essential oil was obtained through hydrodistillation, and its chemical composition was identified using gas chromatography–mass spectrometry. The larvicidal assay followed WHO protocols, testing oil concentrations ranging from 20 to 100 µg mL⁻¹. Results: Efficacy was evaluated after 24, 48, and 72 h to determine LC₅₀, LC₉₀, and other parameters. Chemical composition analysis revealed the presence of 40 compounds, primarily terpenes such as tricyclene, β-pinene, limonene, and α-pinene, which possess bioactive properties that contribute to vector control. The larvicidal activity test showed that LC₅₀ decreased with longer exposure times, indica ting increased efficacy over time. After 72 h, the LC₅₀ was 14.51 µg mL⁻¹, classifying the essential oil as highly effective. Conclusions: Therefore, T. burserifolia Mart. essential oil represents a promising natural alternative for malaria vector control. Full article

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

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21 pages, 5251 KiB

Open AccessArticle

Silkworm Cocoon—Derived Carbon Dots for Post-Trauma Hemostasis and Tissue Repair

by Xinru Wu, Miaomiao Yao, Xuan Qiao, Lintao Li, Zhiyun Meng, Shuchen Liu, Yunbo Sun, Hui Gan, Xiaoxia Zhu, Zhuona Wu, Ruolan Gu and Guifang Dou

Pharmaceuticals 2025, 18(5), 603; https://doi.org/10.3390/ph18050603 - 22 Apr 2025

Abstract

Background: Traumatic hemorrhage management is challenging due to the need to control severe bleeding and support tissue repair. An ideal material would possess both hemostatic and wound-healing properties. Methods: Silkworm cocoon-derived carbon dots (SC-CDs) were synthesized via a hydrothermal method. After physical and [...] Read more.

Background: Traumatic hemorrhage management is challenging due to the need to control severe bleeding and support tissue repair. An ideal material would possess both hemostatic and wound-healing properties. Methods: Silkworm cocoon-derived carbon dots (SC-CDs) were synthesized via a hydrothermal method. After physical and chemical characterization using techniques such as HR-TEM and XPS, their hemostatic efficacy was assessed in rat liver injury, tail transection, and mouse coagulation disorder models. Moreover, the effects of the SC-CDs on platelet aggregation and activation were evaluated. The potential of the SC-CDs to promote wound healing was investigated through cell scratch assays and a mouse full-thickness skin defect model. Results: The SC-CDs showed a high quantum yield (12.9% ± 0.42%), with low hemolytic activity and cytotoxicity. In the hemostasis models, the SC-CDs significantly reduced the bleeding time and volume. In the rat liver injury model, the bleeding time was shortened from 152.67 ± 4.16 s (Control) to 55.33 ± 9.50 s (p < 0.05). In the rat tail transection model, the bleeding volume was reduced from 1.71 ± 0.16 g (Control) to 0.4 ± 0.11 g (p < 0.05). In the mouse coagulation disorder model, an 8 mg/kg dose reduced the bleeding volume to 11.80% ± 0.39% of that of the Control (p < 0.05). Mechanistic studies suggested enhanced platelet activation and aggregation. In the wound healing experiments, the SC-CDs reduced the wound area (88.53 ± 11.78 mm² (Control) vs. 70.07 ± 6.71 mm² (SC-CDs), p < 0.05) and promoted fibroblast migration (24 h scratch width: 372.34 ± 9.06 μm (Control) vs. 259.49 ± 36.75 μm (SC-CDs), p < 0.05). Conclusions: SC-CDs show promise for hemorrhage management and tissue regeneration, with potential applications in cases of internal bleeding or coagulation disorders. Full article

(This article belongs to the Section Pharmaceutical Technology)

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Pharmaceuticals, Volume 18, Issue 5 (May 2025) – 28 articles

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