Pharmaceuticals

10 pages, 891 KiB

Open AccessArticle

Ginsenoside Re as a Probe for Evaluating the Catalytic Potential of Microcrystalline Cellulose for the Degradation of Active Pharmaceutical Ingredients

by Xinyu Gao and Shengyuan Xiao

Pharmaceuticals 2025, 18(6), 869; https://doi.org/10.3390/ph18060869 - 11 Jun 2025

Abstract

Background/Objectives: Microcrystalline cellulose (MCC) is a commonly used pharmaceutical excipient. At present, the catalytic potential of MCCs for the degradation of active pharmaceutical ingredients (APIs) has not been paid adequate attention. This study aims to investigate the representativeness of the pH value of [...] Read more.

Background/Objectives: Microcrystalline cellulose (MCC) is a commonly used pharmaceutical excipient. At present, the catalytic potential of MCCs for the degradation of active pharmaceutical ingredients (APIs) has not been paid adequate attention. This study aims to investigate the representativeness of the pH value of an MCC determined in accordance with the pharmacopeia method to the acidity on its surface. Methods: We tested the differences between the catalytic activities of different MCCs and their supernatant prepared in accordance with the pharmacopeia method for the hydrolysis of ginsenoside Re, which is relatively stable in neutral or weak alkaline aqueous solutions but sensitive to acid. The sulfur content of the sulfuric acid-prepared MCC was measured using an ICP-OES. Results: All of the five tested commercially available and two self-prepared MCCs have been found to significantly promote the hydrolysis of ginsenoside Re. But their supernatants were neutral and chemically inert to Re. The sulfur content of the MCC prepared in this experiment using sulfuric acid hydrolysis was determined to be 109.60 µg/g, which is equivalent to 186 to 465 µM of sulfuric acid on the surface. Conclusions: The pH value of an MCC determined in accordance with the pharmacopeia method is not representative of the acidity on its surface. The primary reason should be that there is immobilized acid that is not so easily dissociated into the media. Ginsenoside Re is sensitive and applicable as a probe for the evaluation of the catalytic potential of pharmaceutically used MCCs. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 1541 KiB

Open AccessArticle

Impact of Antiglaucoma Drug Number and Class on Corneal Epithelial Thickness Measured by OCT

by Piotr Miklaszewski, Anna Maria Gadamer, Dominika Janiszewska-Bil, Anita Lyssek-Boroń, Dariusz Dobrowolski, Edward Wylęgała, Beniamin Oskar Grabarek, Michael Janusz Koss and Katarzyna Krysik

Pharmaceuticals 2025, 18(6), 868; https://doi.org/10.3390/ph18060868 - 11 Jun 2025

Abstract

Background/Objectives: The corneal epithelium plays a vital role in maintaining corneal transparency and ocular surface integrity. Chronic topical use of antiglaucoma medications may induce epithelial changes, especially with the concurrent use of multiple agents. This study aimed to evaluate the association between the [...] Read more.

Background/Objectives: The corneal epithelium plays a vital role in maintaining corneal transparency and ocular surface integrity. Chronic topical use of antiglaucoma medications may induce epithelial changes, especially with the concurrent use of multiple agents. This study aimed to evaluate the association between the number and class of antiglaucoma medications and central corneal epithelial thickness (CET), measured using a spectral-domain optical coherence tomography (SD-OCT) device. Methods: This cross-sectional study included 456 eyes from 242 adults (median age 72 years), grouped by the number of antiglaucoma agents used (0–4 medications). All pharmacologically treated participants had received the same regimen for ≥6 months. CET was measured using SD-OCT (SOLIX, Optovue). Generalized estimating equations (GEEs) accounted for inter-eye correlation. Two models were constructed: one evaluating specific medication effects and another assessing CET reduction per additional drug used. Age and sex were included as covariates. Results: CET progressively decreased with the number of medications, ranging from 53 µm in controls to 48 µm with quadruple therapy. Multivariable GEE analysis confirmed a cumulative thinning effect, with each additional medication associated with further CET reduction (β = −2.83 to −9.17 µm, p < 0.001). Latanoprost exerted the most pronounced single-drug effect (β = −3.01 µm, p < 0.001). Age was a modest negative predictor, while sex showed no significant effect. Conclusions: The cumulative number and specific class of antiglaucoma medications have a significant impact on corneal epithelial thickness. These results emphasize the need for vigilant ocular surface evaluation in patients on multi-drug regimens and propose CET as a surrogate marker for the burden of topical therapy. Full article

(This article belongs to the Special Issue Recent Advances in Ocular Pharmacology)

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37 pages, 1218 KiB

Open AccessSystematic Review

Unveiling the Anti-Inflammatory Effects of Antidepressants: A Systematic Review of Human Studies over the Last Decade

by Layla Bleibel, Paulina Sokołowska, Gabriela Henrykowska, Jacek Owczarek and Anna Wiktorowska-Owczarek

Pharmaceuticals 2025, 18(6), 867; https://doi.org/10.3390/ph18060867 - 10 Jun 2025

Abstract

Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, [...] Read more.

Background/Objectives: Depression ranks among the most prevalent mental health conditions globally, marked by a variety of symptoms that frequently cause significant emotional distress and impairment in individuals, alongside a high recurrence rate. The predominant approach to treating depression revolves around monoamine theory, utilizing SSRIs and SNRIs, with Esketamine emerging as a supplementary option in recent times. Nevertheless, there is a growing focus on exploring the relationship between inflammation and depression, revealing a strong correlation between the two. This insight prompts consideration of the anti-inflammatory properties of current antidepressants in their therapeutic application. Methods: A systematic literature search was conducted using the PubMed database to identify randomized controlled trials (RCTs) and clinical trials (CTs) that assessed the in vivo anti-inflammatory effects of SSRIs (fluoxetine, escitalopram, sertraline, and paroxetine), the SNRI venlafaxine, and esketamine/ketamine in human subjects undergoing treatment for depression. The included studies were evaluated based on changes in levels of pro-inflammatory and anti-inflammatory markers in response to the antidepressant treatments. Results: SSRIs, SNRIs, esketamine, and ketamine (a racemic mixture of S- and R-ketamine not formally approved for the treatment of depression) exhibit anti-inflammatory effects through diverse mechanisms, such as reducing pro-inflammatory cytokines or enhancing anti-inflammatory cytokines in serum or within specific brain regions like the hippocampus and prefrontal cortex. These actions are mediated through various inflammatory pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the brain Nod-like receptor pyrin-containing 3 (NLRP3) inflammasome, the glutamatergic system, the gut–brain axis, the hypothalamic–pituitary axis, impaired neuroplasticity, and the kynurenine pathway. Conclusions: In summary, SSRIs, SNRIs, esketamine, and ketamine exert an anti-inflammatory role alongside their antidepressant effects via these intricate mechanisms. Full article

(This article belongs to the Special Issue Pharmacology of Antidepressants: Recent Advances)

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33 pages, 2003 KiB

Open AccessReview

Acute Compartment Syndrome and Intra-Abdominal Hypertension, Decompression, Current Pharmacotherapy, and Stable Gastric Pentadecapeptide BPC 157 Solution

by Predrag Sikiric, Sven Seiwerth, Anita Skrtic, Mario Staresinic, Sanja Strbe, Antonia Vuksic, Suncana Sikiric, Dinko Bekic, Toni Penovic, Dominik Drazenovic, Tomislav Becejac, Marijan Tepes, Zrinko Madzar, Luka Novosel, Lidija Beketic Oreskovic, Ivana Oreskovic, Mirjana Stupnisek, Alenka Boban Blagaic and Ivan Dobric

Pharmaceuticals 2025, 18(6), 866; https://doi.org/10.3390/ph18060866 - 10 Jun 2025

Abstract

In this study, pharmacotherapies of abdominal compartment syndrome (ACS) and intra-abdominal hypertension (IAH) in animal studies were reviewed from the perspective of ACS/IAH as failed cytoprotection issues, as non-specific injuries, and from the point of view of the cytoprotection concept as resolution. Therefore, [...] Read more.

In this study, pharmacotherapies of abdominal compartment syndrome (ACS) and intra-abdominal hypertension (IAH) in animal studies were reviewed from the perspective of ACS/IAH as failed cytoprotection issues, as non-specific injuries, and from the point of view of the cytoprotection concept as resolution. Therefore, this review challenges the unresolved theoretical and practical issues of severe multiorgan failure, acknowledged significance in clinics, and resolving outcomes (i.e., open abdomen). Generally, the reported agents not aligned with cytoprotection align with current pharmacotherapy limitations and have (non-)confirmed effectiveness, mostly in only one organ, mild/moderate IAH, prophylactic application, and provide only a tentative resolution. Contrarily, stable gastric pentadecapeptide BPC 157 therapy, as a novel and relevant cytoprotective mediator having pleiotropic beneficial effects, simultaneously resolves many targets, resolving established disturbances, specifically compression/ischemia (grade III and grade IV), and decompression/advanced reperfusion. BPC 157 therapy rapidly activates collateral bypassing pathways, and, in ACS and IAH, and later, in reperfusion, there is a “bypassing key” (i.e., azygos vein direct blood flow delivery). This serves to counteract multiorgan and vessel failure, including lesions and hemorrhages in the brain, heart, lung, liver, kidney and gastrointestinal tract, thrombosis, peripherally and centrally, intracranial (superior sagittal sinus), portal and caval hypertension and aortal hypotension, occlusion/occlusion-like syndrome, advanced Virchow triad circumstances, and free radical formation acting as a membrane stabilizer and free radical scavenger. Likewise, not only in ACS/IAH resolving, but also in other occlusion/occlusion-like syndromes, this “bypassing key” could be an effect of the essential endothelial cytoprotective capacity of BPC 157 and a particular modulatory effect on the NO-system, and a rescuing impact on vasomotor tone. Full article

(This article belongs to the Section Pharmacology)

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15 pages, 717 KiB

Open AccessArticle

Pharmacokinetic Equations Applied to Obtain New Topological Models in the Search of Antibacterial Compounds

by Jose I. Bueso-Bordils, Gerardo M. Antón-Fos, Rafael Martín-Algarra and Pedro A. Alemán-López

Pharmaceuticals 2025, 18(6), 865; https://doi.org/10.3390/ph18060865 - 10 Jun 2025

Abstract

Background: QSAR (Quantitative Structure–Activity Relationships) methods have been the basis for the design of new molecules with a certain activity. The great advantage of QSAR methods is that they can predict the pharmacological activity of compounds without the need to obtain or synthesize [...] Read more.

Background: QSAR (Quantitative Structure–Activity Relationships) methods have been the basis for the design of new molecules with a certain activity. The great advantage of QSAR methods is that they can predict the pharmacological activity of compounds without the need to obtain or synthesize them previously. Currently, the development of antibiotic resistance by microorganisms is the most important issue in the treatment of infectious diseases. This elevated resistance is associated with expanded morbidity and mortality, as well as an increase in healthcare costs. The development of new molecules with antibacterial activity is therefore urgently needed. Methods: By means of molecular topology, we developed discriminant functions (DF1 and DF2) capable of predicting antibacterial activity. When applied to a database with 6373 chemicals, they selected 266 molecules as candidates, from which 41% have this activity, according to the bibliography. Regression equations determining pharmacokinetic properties such as mean residence time (MRT), volume of distribution (V_D), and clearance (CL) were applied to the selected molecules. Results: We have observed that most antibacterial compounds have pharmacokinetic theoretical values in the intervals 20 > MRT > 0, 3 > V_D > 0, and 500 > CL > 0. We have applied these intervals to our antibacterial model with the objective of finding new antibacterials with a good pharmacokinetic profile. We show that they are an effective tool for discriminating antibacterial compounds, increasing the bibliographic success rate to 50.8, 59, and 61.5%, respectively. When drug-like filters are applied to these new models, the vast majority (89.9–100%) of the selected molecules present antibacterial activity. Conclusions: Considering these results, these new models could avoid the application of drug-likeness filters when searching for new potential antibacterials. All of this proves the usefulness of these mathematical–topological models. Full article

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

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31 pages, 12094 KiB

Open AccessArticle

Engineering Lipid–Polymer Nanoparticles for siRNA Delivery to Cancer Cells

by Arthur Manda, Abdulelah Alhazza, Hasan Uludağ and Hamidreza Montazeri Aliabadi

Pharmaceuticals 2025, 18(6), 864; https://doi.org/10.3390/ph18060864 - 10 Jun 2025

Abstract

Background: RNA interference (RNAi) is a powerful tool that can target many proteins without the expensive and time-consuming drug development studies. However, due to the challenges in delivering RNA molecules, the potential impact of RNAi approaches is yet to be fully realized [...] Read more.

Background: RNA interference (RNAi) is a powerful tool that can target many proteins without the expensive and time-consuming drug development studies. However, due to the challenges in delivering RNA molecules, the potential impact of RNAi approaches is yet to be fully realized in clinical settings. Lipid nanoparticles (LNPs) have been the most successful delivery system for nucleic acids, but targeted delivery to a solid tumor still eludes the developed LNPs. We hypothesized that specially designed low-molecular-weight PEIs can partially or completely replace the ionizable lipids for more accommodating vehicles due to the structural flexibility offered by polymers, which could lead to safer and more efficient nucleic acid delivery. Methods: To achieve this, we first optimized the LNP formulations as a point of reference for three outcomes: cellular uptake, cytotoxicity, and silencing efficiency. Using a response surface methodology (Design Expert), we optimized siRNA delivery by varying mole fractions of lipid components. Leveraging the optimal LNP formulation, we integrated specifically designed cationic polymers as partial or complete replacements for the ionizable lipid. This methodological approach, incorporating optimal combined designs and response surface methodologies, refined the LPNPs to an optimal efficiency. Results: Our data revealed that DOPE and Dlin-MC3-DMA contributed to higher efficiency in selected breast cancer cells over DSPC and ALC-0315 as neutral and ionizable lipids, respectively, based on the software analysis and direct comparative experiments. Incorporation of selected polymers enhanced the cellular internalization significantly, which in some formulations resulted in higher efficiency. Conclusions: These findings offer a framework for the rational design of LPNPs, that could enhance the passive targeting and silencing efficiency in cancer treatment and broader applications for RNAi-based strategies. Full article

(This article belongs to the Topic Applications of Polymers and Polymer Nanomaterials in Drug Delivery and Nanomedicine)

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21 pages, 2171 KiB

Open AccessArticle

Commiphora leptophloeos Bark Decoction: Phytochemical Composition, Antioxidant Capacity, and Non-Genotoxic Safety Profile

by José Rafael da Silva Araujo, Rafael de Felício, Camila Marinho da Silva, Palloma Lima de Oliveira, Silvany de Sousa Araújo, Laís Roberta Deroldo Sommaggio, Adriana Fabiana Corrêa da Silva, Paulo Henrique Valença Nunes, Bruno Oliveira de Veras, Erwelly Barros de Oliveira, Jaciana dos Santos Aguiar, Maria Aparecida Marin-Morales, Daniela Barretto Barbosa Trivella, Ana Maria Benko-Iseppon, Márcia Vanusa da Silva and Ana Christina Brasileiro-Vidal

Pharmaceuticals 2025, 18(6), 863; https://doi.org/10.3390/ph18060863 - 10 Jun 2025

Abstract

Background: Commiphora leptophloeos has long been used in Latin American folk medicine for the treatment of respiratory and gastrointestinal disorders. Therefore, toxicological and phytochemical investigations are required to assess the safety and support the evidence-based use of its bark in medicinal applications. [...] Read more.

Background: Commiphora leptophloeos has long been used in Latin American folk medicine for the treatment of respiratory and gastrointestinal disorders. Therefore, toxicological and phytochemical investigations are required to assess the safety and support the evidence-based use of its bark in medicinal applications. This study aimed to evaluate the aqueous bark extract of C. leptophloeos, focusing on its chemical composition and its antioxidant, cytotoxic, and genotoxic properties. Methods: The aqueous extract was obtained by decoction of dried bark samples. Phytochemical characterization was conducted using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS), and data were processed using the NP³ MS Workflow 1.1.4 software, allowing for the annotation of key secondary metabolites. Antioxidant activity was assessed through multiple in vitro assays, including DPPH, ABTS, phosphomolybdenum, and reducing power tests. Cytotoxicity was evaluated using the MTT assay, while genotoxicity was investigated through the Ames test and micronucleus assay. Results: Phytochemical analysis revealed several flavonoids, with procyanidin B2 annotated as a major compound. The extract exhibited strong antioxidant activity, with EC₅₀ values of 5.43 μg/mL (DPPH), 12.40 μg/mL (ABTS), 35.20 μg/mL (phosphomolybdenum), and 31.27 μg/mL (reducing power). The MTT assay showed no cytotoxic effects at concentrations up to 6400 μg/mL. Furthermore, both the Ames and micronucleus assays showed the absence of genotoxic effects at concentrations up to 1600 μg/plate and 400 μg/mL, respectively. Conclusions: The aqueous bark extract of C. leptophloeos demonstrates strong antioxidant potential and a favorable safety profile, with no detectable cytotoxicity or genotoxicity at concentrations effective in antioxidant assays. Further studies are recommended to confirm and validate its traditional medicinal properties using appropriate in vivo models, followed by pre-clinical evaluations. Full article

(This article belongs to the Special Issue Pharmacologically Active Compounds from Plants)

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18 pages, 1139 KiB

Open AccessArticle

Designing Novel Antimicrobial Agents from the Synthetic Antimicrobial Peptide (Pep-38) to Combat Antibiotic Resistance

by Yara Al Tall, Yasmeen Alkurdi, Nid’A Alshraiedeh and Salsabeel H. Sabi

Pharmaceuticals 2025, 18(6), 862; https://doi.org/10.3390/ph18060862 - 10 Jun 2025

Abstract

Background/Objectives: The rise of antibiotic-resistant bacteria presents a major global health challenge, highlighting the need for novel antimicrobial agents such as antimicrobial peptides (AMPs). AMPs are promising due to their broad-spectrum activity, membrane-disruptive mechanisms, and low development of resistance. This study aimed to [...] Read more.

Background/Objectives: The rise of antibiotic-resistant bacteria presents a major global health challenge, highlighting the need for novel antimicrobial agents such as antimicrobial peptides (AMPs). AMPs are promising due to their broad-spectrum activity, membrane-disruptive mechanisms, and low development of resistance. This study aimed to design and evaluate novel AMPs derived from a synthetic parent peptide (PEP-38). Methods: Novel peptides were designed using bioinformatics tools, including CAMP_R3 and Peptide Ranker. Their antimicrobial potential was validated through in vitro assays, including bacterial susceptibility, antibiofilm activity, cytotoxicity, hemolysis, and time–kill kinetics. Results: Among the designed peptides, Hel-4K-12K showed potent activity against both Gram-positive and Gram-negative bacteria, with MICs ranging from 3.125 to 6.25 µM. It also effectively eradicated biofilms of resistant Staphylococcus aureus at an MBEC of 6.25 µM. Time–kill assays confirmed rapid bactericidal action, achieving complete bacterial elimination within one hour at its MIC. Moreover, Hel-4K-12K exhibited low toxicity toward mammalian MDCK cells (>82% viability at MIC) and minimal hemolytic activity on human erythrocytes. Conclusions: Hel-4K-12K demonstrates strong antibacterial and antibiofilm activities with a favorable safety profile, indicating its potential as a therapeutic candidate for treating infections caused by resistant bacteria. These findings support further development of this peptide as a basis for new antimicrobial drug strategies. In addition to its promising in vitro profile, future studies will investigate Hel-4K-12K in animal models and evaluate strategies for attaining stable formulations, such as peptide encapsulation or PEGylation. These steps are critical to ensure its therapeutic viability in systemic applications. Full article

(This article belongs to the Section Biopharmaceuticals)

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16 pages, 3198 KiB

Open AccessArticle

Validation of a Traditional Medicine, Achyrocline satureioides Infusion, for the Improvement of Mild Respiratory Infection Symptoms: A Randomized, Placebo-Controlled and Open-Label Clinical Trial

by Catherina Isdra Moszkowicz Bastos, Caroline Dani, Laura Reck Cechinel, Arthur Hipolito da Silva Neves, Fabiana Briato Rasia, Marcelo Lazzaron Lamers, Sara Elis Bianchi, Gabriela Meirelles, Paulo Valdeci Worm, Valquiria Linck Bassani and Ionara Rodrigues Siqueira

Pharmaceuticals 2025, 18(6), 861; https://doi.org/10.3390/ph18060861 - 9 Jun 2025

Abstract

Background/Objectives: The need for the scientific validation of traditional and folk medicine knowledge has emerged lately. Achyrocline satureioides inflorescences have been widely used for the management of mild viral respiratory infection symptoms in South Brazil, Uruguay and Argentina. We intended to assess the [...] Read more.

Background/Objectives: The need for the scientific validation of traditional and folk medicine knowledge has emerged lately. Achyrocline satureioides inflorescences have been widely used for the management of mild viral respiratory infection symptoms in South Brazil, Uruguay and Argentina. We intended to assess the therapeutic efficacy of a 14-day course with A. satureioides for mild viral respiratory infection symptoms. Methods: We conducted a randomized, open-label, placebo-controlled trial. Before COVID-19 (SARS-CoV-2) diagnostic tests, participants were randomly assigned to one of two experimental groups: A. satureioides or Malus domestica infusions, with instructions to use the infusions twice a day for 14 days. Our primary endpoint was the recovery time for respiratory symptoms in the overall analysis; the secondary outcomes were the recovery time for non-respiratory symptoms and for stratified analysis, taking into account the vaccination status against SARS-CoV-2 and COVID-19 infection; and the rate of symptom recovery was also evaluated. Results: The A. satureioides infusion significantly accelerated the resolution of sore throat and sneezing compared with the control group. The participants with COVID-19 who had not been vaccinated and received A. satureioides infusion recovered faster from sore throat, body ache, fever and cough, and showed a shorter median survival time for symptom resolution. The SARS-CoV-2-negative group that received A. satureioides had a faster improvement in the survival analysis of sore throat, earache and loss of appetite. Conclusions: Our findings support the hypothesis that Achyrocline satureioides inflorescence infusions may offer therapeutic benefits in the management of mild viral respiratory infections, as its administration was associated with a significantly accelerated resolution of clinical symptoms. This study was registered in the Brazilian Registry of Clinical Trials (ReBEC; registration number RBR-8g6f2rv) on 27 January 2022. Full article

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24 pages, 7057 KiB

Open AccessArticle

Synergistic Effect of Banaba Leaf Extract and Policosanol (Raydel^®) Ameliorate High Cholesterol and High Galactose-Diet Induced Adverse Events in Zebrafish

by Kyung-Hyun Cho, Sang Hyuk Lee, Yunki Lee, Ashutosh Bahuguna, Ji-Eun Kim, Krismala Djayanti and Cheolmin Jeon

Pharmaceuticals 2025, 18(6), 860; https://doi.org/10.3390/ph18060860 - 9 Jun 2025

Abstract

Background: This study aimed to explore the therapeutic potential of a dietary regimen of banaba leaf extract (BNB), policosanol (PCO, Raydel^®), and their combination (BNB+PCO), to mitigate high cholesterol (HC) and high galactose (HG) diet-induced dyslipidemia, hyperglycemia, oxidative stress, senescence, [...] Read more.

Background: This study aimed to explore the therapeutic potential of a dietary regimen of banaba leaf extract (BNB), policosanol (PCO, Raydel^®), and their combination (BNB+PCO), to mitigate high cholesterol (HC) and high galactose (HG) diet-induced dyslipidemia, hyperglycemia, oxidative stress, senescence, and organ damage in zebrafish (Danio rerio). Methodology: Zebrafish (n = 28/group) were fed with HC (4% w/w)+HG (30% w/w) or HC+HG supplemented either with BNB (0.1% w/w) or PCO (0.1% w/w) or BNB+PCO (0.1% w/w each). Following 6 weeks of dietary intervention, biochemical and histopathological examinations across the groups were performed. Results: Post 6 weeks of consumption, the BNB+PCO group exhibited a significant 40% decrease in body weight (BW) relative to the BW of the HC+HG group, while the BNB or PCO groups displayed nonsignificant changes in BW. Both BNB and PCO reduced HC+HG-induced dyslipidemia and hyperglycemia; however, co-administration (BNB+PCO) demonstrated a significantly greater therapeutic effect in countering these conditions compared to either BNB or PCO alone. A similar effect of the BNB+PCO combination was observed on the elevation of plasma sulfhydryl content, paraoxonase (PON), and ferric ion reduction activity (FRA), with notably ~1.2-times (p < 0.01) higher levels compared to their corresponding values observed in the BNB or PCO groups. Significantly diminished plasma AST, ALT, hepatic interleukin 6 (IL-6) levels, and fatty liver changes were observed in response to BNB+PCO, compared to either BNB or PCO alone. Also, BNB+PCO displayed a higher curative effect against HC+HG-induced impairment of tissue regeneration than BNB or PCO alone. A notable effect of BNB+PCO was perceived in protecting kidneys, testis, and ovary damage. Consistently, BNB+PCO showed a profound impact on mitigating HC+HG elevated reactive oxygen species (ROS) generation, apoptosis, cellular senescence, and accumulation of brain-binding lipid proteins (BLBPs) and 4-hydroxynoneal (4-HNE) in the brain. Conclusions: The findings highlight the synergistic effects of the BNB and PCO combination to mitigate the adversity posed by the consumption of the HC+HG diet. Full article

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

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17 pages, 4283 KiB

Open AccessArticle

SPHK1-S1p Signaling Drives Fibrocyte-Mediated Pulmonary Fibrosis: Mechanistic Insights and Therapeutic Potential

by Fei Lu, Gaoming Wang, Xiangzhe Yang, Jing Luo, Haitao Ma, Liangbin Pan, Yu Yao and Kai Xie

Pharmaceuticals 2025, 18(6), 859; https://doi.org/10.3390/ph18060859 - 9 Jun 2025

Abstract

Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on [...] Read more.

Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on the SPHK1 pathway as a potential therapeutic target. Methods: We utilized Mendelian Randomization and phenome-wide association analyses on genes involved in sphingolipid metabolism to identify potential regulators of idiopathic pulmonary fibrosis (IPF). A bleomycin-induced mouse model was employed to examine the role of the SPHK1-S1P axis in fibrocyte recruitment, using SKI-349 to target SPHK1 and FTY720 to antagonize S1PR1. Results: Our analyses revealed SPHK1 as a significant genetic driver of IPF. Targeting SPHK1 and S1PR1 led to a marked reduction in fibrocyte accumulation, collagen deposition, and histopathological fibrosis. Additionally, PAXX and RBKS were identified as downstream effectors of SPHK1. Our protein–protein interaction mapping indicated potential therapeutic synergies with existing anti-fibrotic drug targets. Conclusions: Our findings establish the SPHK1-S1P-S1PR1 axis as a key regulator of fibrocyte-mediated pulmonary fibrosis and support SPHK1 as a promising therapeutic target. Full article

(This article belongs to the Special Issue Innovative Drug Strategies in Chronic Disease Management: Addressing Non-Adherence and Improving Therapeutic Outcomes)

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2 pages, 136 KiB

Open AccessCorrection

Correction: Sgherza et al. Efficacy and Safety of Isatuximab, Carfilzomib, and Dexamethasone (IsaKd) in Multiple Myeloma Patients at the First Relapse After Autologous Stem Cell Transplantation and Lenalidomide Maintenance: Results from the Multicenter, Real-Life AENEID Study. Pharmaceuticals 2025, 18, 595

by Nicola Sgherza, Olga Battisti, Paola Curci, Concetta Conticello, Salvatore Palmieri, Daniele Derudas, Candida Germano, Enrica Antonia Martino, Giuseppe Mele, Roberta Della Pepa, Francesca Fazio, Anna Mele, Bernardo Rossini, Giulia Palazzo, Daniela Roccotelli, Simona Rasola, Maria Teresa Petrucci, Domenico Pastore, Giuseppe Tarantini, Fabrizio Pane, Massimo Gentile, Francesco Di Raimondo, Emanuela Resta and Pellegrino Musto Show full author list Hide full author list

Pharmaceuticals 2025, 18(6), 858; https://doi.org/10.3390/ph18060858 - 9 Jun 2025

Abstract

In the original publication [...] Full article

28 pages, 727 KiB

Open AccessReview

Potential New Applications of Sodium–Glucose Cotransporter-2 Inhibitors Across the Continuum of Cancer-Related Cardiovascular Toxicity

by Agnieszka Maria Zebrowska and Anna Borowiec

Pharmaceuticals 2025, 18(6), 857; https://doi.org/10.3390/ph18060857 - 9 Jun 2025

Abstract

Sodium–glucose cotransporter-2 inhibitors (SGLT2i), initially developed for the management of type 2 diabetes mellitus, have demonstrated significant nephroprotective and cardioprotective effects. These benefits have led to their inclusion in heart failure (HF) management guidelines, irrespective of glycemic status and left ventricular ejection fraction [...] Read more.

Sodium–glucose cotransporter-2 inhibitors (SGLT2i), initially developed for the management of type 2 diabetes mellitus, have demonstrated significant nephroprotective and cardioprotective effects. These benefits have led to their inclusion in heart failure (HF) management guidelines, irrespective of glycemic status and left ventricular ejection fraction (LVEF). Various anticancer therapies, particularly anthracyclines, are associated with substantial cardiotoxicity risks, resulting in cancer therapy-related cardiovascular toxicity (CTR-CVT). Promising evidence from preclinical and observational studies indicates that SGLT2i may mitigate cardiotoxic effects of cancer therapy by alleviating LVEF decline, reducing HF incidence and hospitalizations, and lowering overall mortality. Moreover, improved survival has been reported in patients with various malignancies. The current review explores the potential applications of SGLT2i in the prevention of CTR-CVT, highlights their possible mechanisms of cardioprotection, discusses the published evidence, and emphasizes the need for the results from ongoing randomized controlled trials to establish SGLT2i efficacy and safety in cardio-oncology patients. Full article

(This article belongs to the Special Issue New Insights of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Biomedical Applications)

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12 pages, 630 KiB

Open AccessArticle

Real-World Analysis of Short-Term Effectiveness of Oral Semaglutide: Impact on Glycometabolic Control and Cardiovascular Risk

by Sara Palazzi, Federica Sentinelli, Antonella Zugaro, Sara Morgante, Livia Santarelli, Sandra Melanzi, Annamaria De Mutiis, Deamaria Piersanti, Barbara Macerola, Marco Iezzi, Pietro Mercuri, Alessandro Ferranti, Daniele Tienforti, Maria Gisella Cavallo, Arcangelo Barbonetti and Marco Giorgio Baroni

Pharmaceuticals 2025, 18(6), 856; https://doi.org/10.3390/ph18060856 - 8 Jun 2025

Abstract

Background: Oral semaglutide, a GLP1-receptor agonist (GLP1-RA), shows promise in efficacy and compliance, especially amid the global shortage of injectable GLP-1 RAs. Its short-term effectiveness remains unexplored. Objective: This real-world observational study assessed the short-term effectiveness of oral semaglutide after three [...] Read more.

Background: Oral semaglutide, a GLP1-receptor agonist (GLP1-RA), shows promise in efficacy and compliance, especially amid the global shortage of injectable GLP-1 RAs. Its short-term effectiveness remains unexplored. Objective: This real-world observational study assessed the short-term effectiveness of oral semaglutide after three months of therapy. Methods: Patients with type 2 diabetes from four Italian diabetes centers, who received an initial prescription of oral semaglutide, were reassessed after three months. Primary outcomes included glycated hemoglobin (HbA1c) and body weight reduction; secondary outcomes involved changes in lipid parameters and cardiovascular risk. Results: Among 167 participants (mean age 66.5 years, mostly obese, baseline HbA1c 8.4% ± 1.5), 83.2% received a 7 mg dose. After three months, HbA1c significantly declined (8.4% to 7.1%, −1.3%, p < 0.001), alongside body mass index (BMI) (30.9 kg/m² to 29.6 kg/m², p < 0.0001). The target HbA1c ≤ 7% was achieved by 54.5%, and 34.7% reached ≤6.5%. Patients losing >5% of their initial weight (30.5%) saw the largest HbA1c drop (−1.9%). Those with newly diagnosed diabetes or a duration < 5 years showed superior responses (p = 0.001), while no significant differences were found based on the timing of drug administration. Oral semaglutide replaced or supplemented prior therapies, allowing discontinuation of dipeptidyl peptidase 4 inhibitors (DPP4i), sulfonylureas, glinides, and acarbose, and deprescription of thiazolidinediones. A significant reduction in cardiovascular risk was observed (p = 0.04), together with a significant reduction in lipid parameters. Conclusions: Oral semaglutide showed significant short-term efficacy, reducing HbA1c, body weight, and cardiovascular risk in three months, making it a valuable therapeutic option. Full article

(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy, 2nd Edition)

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10 pages, 557 KiB

Open AccessArticle

Valproate-Enhanced Protocols for Alcohol Withdrawal Syndrome: A Brief Review and Retrospective Study of Efficacy and the Ability to Reduce Benzodiazepine Use

by Simone Pardossi, Alessandro Cuomo, Giacomo Gualtieri, Mario Pinzi, Giuditta Piumini and Andrea Fagiolini

Pharmaceuticals 2025, 18(6), 855; https://doi.org/10.3390/ph18060855 - 8 Jun 2025

Abstract

Background: Although benzodiazepines are the first-line treatment for alcohol withdrawal syndrome (AWS), their use may pose significant risks, including oversedation and the potential for misuse, particularly in vulnerable populations such as individuals with alcohol use disorder. Valproate has been investigated as a potential [...] Read more.

Background: Although benzodiazepines are the first-line treatment for alcohol withdrawal syndrome (AWS), their use may pose significant risks, including oversedation and the potential for misuse, particularly in vulnerable populations such as individuals with alcohol use disorder. Valproate has been investigated as a potential adjunctive treatment for AWS. We first conducted a brief narrative review of the existing literature on valproate in AWS, identifying only a few relevant studies. We then performed a retrospective study to evaluate the effectiveness of valproate, administered orally (PO) or intravenously (IV), in combination with benzodiazepines for the treatment of AWS and associated anxiety symptoms. Methods: We retrospectively analyzed 72 inpatients treated for AWS with valproate (IV or PO) combined with benzodiazepines. Dosages of valproate, the type and daily dose of benzodiazepine, and any adverse effects were recorded. Withdrawal symptoms were assessed using the Clinical Institute Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar) on days 1, 3, 5, and 7. Anxiety symptoms were evaluated using the Hamilton Anxiety Rating Scale (HAM-A) on days 1, 3, and 7. Results: The median daily benzodiazepine dose was 2.5 mg lorazepam-equivalents (IQR: 2.0–3.81 mg). Significant reductions in both CIWA-Ar and HAM-A scores were observed across all time points. Percentage reductions in both anxiety and withdrawal symptoms were significantly higher in the IV group. No serious adverse events occurred. Conclusions: Valproate appears to be an effective adjunctive treatment for AWS, providing symptom relief and enabling reduced benzodiazepine use. IV administration may offer more rapid clinical improvement. Larger prospective trials are warranted to confirm these findings. Full article

(This article belongs to the Special Issue Advances in Neuropharmacology of Drug Abuse)

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16 pages, 1346 KiB

Open AccessArticle

In Vitro Evaluation of Cytotoxic and Pro-Apoptotic Effects of Hesperidin Alone and in Combination with Cisplatin on Human Malignant Melanoma Cell Line (A431)

by Mehmet Uğur Karabat, Mehmet Cudi Tuncer and İlhan Özdemir

Pharmaceuticals 2025, 18(6), 854; https://doi.org/10.3390/ph18060854 - 7 Jun 2025

Abstract

Background/Objectives: Melanoma is an aggressive skin cancer with high metastatic potential and poor prognosis in advanced stages. Hesperidin, a natural flavonoid, has shown anticancer properties across various malignancies. This study aimed to evaluate the antiproliferative and pro-apoptotic effects of Hesperidin, alone and in [...] Read more.

Background/Objectives: Melanoma is an aggressive skin cancer with high metastatic potential and poor prognosis in advanced stages. Hesperidin, a natural flavonoid, has shown anticancer properties across various malignancies. This study aimed to evaluate the antiproliferative and pro-apoptotic effects of Hesperidin, alone and in combination with Cisplatin, on the human epidermoid carcinoma cell line A431. Materials and Methods: A431 cells were cultured under standard conditions and treated with different concentrations of Hesperidin and Cisplatin for 48 h. Cell viability was assessed using the MTT assay. Apoptosis was evaluated by Annexin V-FITC/PI staining and caspase-3/7 activity assays. Expression levels of Bax, caspase-3/7, and survivin were measured by RT-qPCR. Results: Hesperidin significantly reduced cell viability at both 24 and 48 h. Annexin V/PI staining revealed increased apoptosis, with the highest apoptotic ratio in the Hesperidin + Cisplatin group (p < 0.001). Caspase-3/7 activity was markedly elevated in Hesperidin-treated cells. RT-qPCR showed upregulation of Bax and caspase-3/7 and downregulation of survivin. Conclusions: Hesperidin demonstrated significant cytotoxic and pro-apoptotic effects in A431 cells. When combined with Cisplatin, a synergistic enhancement of apoptosis was observed. These findings support the potential of Hesperidin as a complementary agent in carcinoma therapy, pending further in vivo and clinical validation. Full article

(This article belongs to the Special Issue Adjuvant Therapies for Cancer Treatment: 2nd Edition)

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23 pages, 834 KiB

Open AccessReview

Metabolic Reprogramming in Melanoma: An Epigenetic Point of View

by Stefano Giuliani, Celeste Accetta, Simona di Martino, Claudia De Vitis, Elena Messina, Edoardo Pescarmona, Maurizio Fanciulli, Gennaro Ciliberto, Rita Mancini and Italia Falcone

Pharmaceuticals 2025, 18(6), 853; https://doi.org/10.3390/ph18060853 - 6 Jun 2025

Abstract

Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk [...] Read more.

Metabolic reprogramming and epigenetic alterations are fundamental hallmarks of cancer cells, contributing to adaptation, progression, and resistance. In melanoma, high metabolic-epigenetic plasticity enables the rapid modulation of cell states in response to environmental and therapeutic pressures. Recent studies have highlighted a bidirectional crosstalk between cellular metabolism and epigenetic regulation. Epigenetic modifications influence the transcriptional control of metabolic genes, thereby shaping metabolic phenotypes. Conversely, specific metabolites are essential cofactors or substrates for epigenetic enzymes, directly modulating the epigenome. Understanding the intricate mechanisms of this interaction offers opportunities for the development of innovative tumor management that combines epigenetic, metabolic, and therapy interventions. In this review, we summarize the latest evidence on the role of the metabolism–epigenetics axis in melanoma and discuss its potential clinical implications, aiming to provide a comprehensive overview of metabolic/epigenetic interconnections. Full article

(This article belongs to the Section Biopharmaceuticals)

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17 pages, 5124 KiB

Open AccessArticle

Combination Treatment with Free Doxorubicin and Inductive Moderate Hyperthermia for Sarcoma Saos-2 Cells

by Valerii E. Orel, Anatolii G. Diedkov, Vasyl V. Ostafiichuk, Sergii A. Lyalkin, Igor O. Tkachenko, Denys L. Kolesnyk, Valerii B. Orel, Olga Yo. Dasyukevich, Oleksandr Yu. Rykhalskyi, Oleksii V. Movchan, Alexander Yu. Galkin and Anna B. Prosvietova

Pharmaceuticals 2025, 18(6), 852; https://doi.org/10.3390/ph18060852 - 6 Jun 2025

Abstract

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor. Doxorubicin (DOX) is extensively used in OS chemotherapy, yet improving patient outcomes remains challenging. This study investigated the effect of free DOX combined with inductive moderate hyperthermia (IMH) on Saos-2 human OS [...] Read more.

Background: Osteosarcoma (OS) is the most common primary malignant bone tumor. Doxorubicin (DOX) is extensively used in OS chemotherapy, yet improving patient outcomes remains challenging. This study investigated the effect of free DOX combined with inductive moderate hyperthermia (IMH) on Saos-2 human OS cells. Methods: Cell viability was assessed by trypan blue exclusion. Flow cytometry analyzed apoptosis, necrosis, and reactive oxygen species (ROS) in cells exposed to control (no treatment), IMH (42 MHz frequency, 500 μT magnetic field induction, 564 V/m electric field strength, 15 W output power, and 30 min duration) alone, DOX (0.06 μg/mL) alone, or DOX combined with IMH. The expression of p14^ARF tumor suppressor and epidermal growth factor receptor (EGFR) was evaluated by immunocytochemistry. Spatial autocorrelation analysis quantified the heterogeneity of p14^ARF and EGFR distributions in acquired images. Results: The half maximal inhibitory concentration (IC₅₀) of DOX in Saos-2 cells had minimal variation between 48 h (0.060 ± 0.01 μg/mL) and 72 h (0.055 ± 0.003 μg/mL). DOX + IMH resulted in a 15% increase in early apoptosis and a 20% elevation in ROS levels compared with DOX alone. Immunocytochemical analysis revealed a 37% increase in p14^ARF and a 32% reduction in EGFR expression following combined treatment in comparison to DOX alone. Image analysis showed that DOX + IMH treatment caused the highest Moran’s index values for p14^ARF and EGFR, reflecting less heterogeneous spatial distributions (p < 0.05). Conclusions: IMH enhanced DOX-induced cytotoxicity in Saos-2 cells by initiating ROS-mediated apoptosis and reducing heterogeneity of cellular responses. Full article

(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies, 2nd Edition)

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Graphical abstract

20 pages, 1823 KiB

Open AccessArticle

In Vitro and In Silico Assessments of Curcuminoids and Turmerones from Curcuma longa as Novel Inhibitors of Leishmania infantum Arginase

by Flora F. S. Spíndola, Anderson S. Pinheiro, Maria Athana Mpalantinos, Jefferson R. A. Silva, Walter S. M. F. Neto, Raissa A. Conceição, Eduarda M. Barreto, Barbara A. Abrahim-Vieira, Carlos R. Rodrigues, Alessandra M. T. Souza, Dirlei Nico, Ana Claudia F. Amaral, Andreza R. Garcia and Igor A. Rodrigues

Pharmaceuticals 2025, 18(6), 851; https://doi.org/10.3390/ph18060851 - 6 Jun 2025

Abstract

Background/Objectives: The anti-Leishmania potential of Curcuma longa and its derivatives, such as curcuminoids, is well-established, yet their mechanisms of action remain underexplored. This study investigates the inhibitory effects of C. longa extracts and curcumin on Leishmania infantum arginase, a key enzyme [...] Read more.

Background/Objectives: The anti-Leishmania potential of Curcuma longa and its derivatives, such as curcuminoids, is well-established, yet their mechanisms of action remain underexplored. This study investigates the inhibitory effects of C. longa extracts and curcumin on Leishmania infantum arginase, a key enzyme in polyamine and trypanothione biosynthesis, and evaluates their antiparasitic activity. Methods: Extracts were prepared via rhizome successive maceration with hexane (HEXCURC), dichloromethane (DCCURC), and ethanol (ETOHCURC) and chemically characterized by a combination of chromatographic and spectrometric methods. The inhibition of recombinant L. infantum arginase (LiARG) was assessed by urea quantification, while molecular docking explored interactions between the main compounds annotated in the extracts and the enzyme’s active site. Biological activity was tested against L. infantum promastigotes, intracellular amastigotes, and mammalian cells. Results: LC-MS and GC-MS revealed curcuminoids and turmerones as main compounds annotated in the extracts. DCCURC, HEXCURC, and curcumin showed the strongest LiARG inhibition (IC₅₀ = 10.04, 14.4, and 17.55 μg/mL, respectively). Docking analysis revealed that curcumin, demethoxycurcumin, and bisdemethoxycurcumin bind near the active site, with binding energies of –3.43, –4.14, and –3.99 kcal/mol, respectively. Curcumin demonstrated superior anti-promastigote activity (IC₅₀ = 15.01 μg/mL) and selectivity (SI = 12.7) compared to the extracts. It also significantly reduced amastigote burden in infected macrophages (IC₅₀ = 13.6 μg/mL). Conclusions: This is the first report demonstrating that C. longa extracts and curcumin inhibit LiARG. These findings support curcumin’s potential as a lead compound for developing multi-target therapies against leishmaniasis, combining enzyme inhibition with direct antiparasitic effects. Full article

(This article belongs to the Section Natural Products)

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