Pharmaceuticals

28 pages, 4479 KB

Open AccessArticle

Integrated Network Pharmacology and Molecular Dynamics Reveal Multi-Target Anticancer Mechanisms of Myrtus communis Essential Oils

by Ahmed Bayoudh, Nidhal Tarhouni, Riadh Ben Mansour, Saoussen Mekrazi, Raoudha Sadraoui, Karim Kriaa, Zakarya Ahmed, Ahlem Soussi, Imen Kallel and Bilel Hadrich

Pharmaceuticals 2025, 18(10), 1542; https://doi.org/10.3390/ph18101542 (registering DOI) - 13 Oct 2025

Abstract

Background: Cancer’s multifactorial complexity demands innovative polypharmacological strategies that can simultaneously target multiple oncogenic pathways. Natural products, with their inherent chemical diversity, offer promising multi-target therapeutic potential. This study comprehensively investigates the anticancer mechanisms of Tunisian Myrtus communis essential oils (McEOs) using an [...] Read more.

Background: Cancer’s multifactorial complexity demands innovative polypharmacological strategies that can simultaneously target multiple oncogenic pathways. Natural products, with their inherent chemical diversity, offer promising multi-target therapeutic potential. This study comprehensively investigates the anticancer mechanisms of Tunisian Myrtus communis essential oils (McEOs) using an integrated computational-experimental framework to elucidate their polypharmacological basis and therapeutic potential. Methods: McEO composition was characterized via GC-MS analysis. Antiproliferative activity was evaluated against HeLa (cervical), MCF-7 (breast), and Raji (lymphoma) cancer cell lines using MTT assays. A multi-scale computational pipeline integrated network pharmacology, molecular docking against eight key oncoproteins, and 100 ns all-atom molecular dynamics simulations to elucidate molecular mechanisms and target interactions. Results: GC-MS revealed a 1,8-cineole-rich chemotype (38.94%) containing significant sesquiterpenes. McEO demonstrated potent differential cytotoxicity: HeLa (IC₅₀ = 8.12 μg/mL) > MCF-7 (IC₅₀ = 19.59 μg/mL) > Raji cells (IC₅₀ = 27.32 μg/mL). Network pharmacology quantitatively explained this differential sensitivity through target overlap analysis, showing higher associations with breast (23%) and cervical (18.3%) versus lymphoma (5.5%) cancer pathways. Molecular docking identified spathulenol as a high-affinity Androgen Receptor (AR) antagonist (XP GScore: −9.650 kcal/mol). Molecular dynamics simulations confirmed exceptional spathulenol-AR complex stability, maintaining critical hydrogen bonding with Asn705 for 96% of simulation time. Conclusions: McEO exerts sophisticated multi-target anticancer effects through synergistic constituent interactions, notably spathulenol’s potent AR antagonism. This integrated computational-experimental approach validates McEO’s polypharmacological basis and supports its therapeutic potential, particularly for hormone-dependent malignancies, while establishing a robust framework for natural product bioactivity deconvolution. Full article

(This article belongs to the Section Natural Products)

► Show Figures

Graphical abstract

30 pages, 24475 KB

Open AccessArticle

Integration of Network Pharmacology, Molecular Docking, and In Vitro Nitric Oxide Inhibition Assay to Explore the Mechanism of Action of Thai Traditional Polyherbal Remedy, Mo-Ha-Rak, in the Treatment of Prolonged Fever

by Chinnaphat Chaloemram, Ruchilak Rattarom, Anake Kijjoa and Somsak Nualkaew

Pharmaceuticals 2025, 18(10), 1541; https://doi.org/10.3390/ph18101541 - 13 Oct 2025

Abstract

Background: Prolonged fever (PF) is one of the most challenging clinical conditions due to its complex molecular mechanisms and limited effective treatments. Objective: The current study aimed to explore the mechanism of action of Mo-Ha-Rak (MHR), a Thai traditional polyherbal remedy, in PF [...] Read more.

Background: Prolonged fever (PF) is one of the most challenging clinical conditions due to its complex molecular mechanisms and limited effective treatments. Objective: The current study aimed to explore the mechanism of action of Mo-Ha-Rak (MHR), a Thai traditional polyherbal remedy, in PF treatment. Methods: Integration of network pharmacology, molecular docking, and inhibition of nitric oxide (NO) production in LPS-induced RAW264.7 macrophages approaches were used. Results: The study identified 86 potential active compounds, 131 potential therapeutic targets, and 9 hub genes for MHR. Key targets with the highest degree of connectivity in PF, including TNF, IL6, IL1B, PTGS2, STAT3, and NFKB1, are closely associated with arachidonic acid metabolism pathways, which play critical roles in infections, inflammation, cell proliferation, and apoptosis in the PF microenvironment. Molecular docking analysis suggested that core compounds exhibited strong binding affinities for four key targets, viz. TNF, IL6, IL1B, and PTGS2, with binding energies ranging from −4.1 to −9.8 kJ/mol. MHR exhibited dose-dependent reduction of NO production at concentrations of 10–100 µg/mL. Among the biomarkers of MHR tested, ellagic acid, loureirin A, resveratrol, and rhein showed potential to inhibit NO production. Conclusions: This study demonstrates that MHR exerts its therapeutic effects on PF through a complex network of multiple compounds, targets, and pathways. These findings highlight the mechanisms of PF and the role of MHR in modulating the arachidonic acid metabolism pathway, which underlies the development of fever. Full article

(This article belongs to the Section Natural Products)

► Show Figures

Graphical abstract

28 pages, 1626 KB

Open AccessReview

Iteration of Tumor Organoids in Drug Development: Simplification and Integration

by Rui Zhao, Qiushi Feng, Yangyang Xia, Lingzi Liao and Shang Xie

Pharmaceuticals 2025, 18(10), 1540; https://doi.org/10.3390/ph18101540 - 13 Oct 2025

Abstract

The inherent complexity and heterogeneity of tumors pose substantial challenges for the development of effective oncology therapeutics. Organoids, three-dimensional (3D) in vitro models, have become essential tools for predicting therapeutic responses and advancing precision oncology, with established correlations to clinical outcomes in patient-derived [...] Read more.

The inherent complexity and heterogeneity of tumors pose substantial challenges for the development of effective oncology therapeutics. Organoids, three-dimensional (3D) in vitro models, have become essential tools for predicting therapeutic responses and advancing precision oncology, with established correlations to clinical outcomes in patient-derived models. These systems have transformed preclinical drug screening by bridging the gap between conventional two-dimensional (2D) cultures and in vivo models, preserving tumor histopathology, cellular heterogeneity, and patient-specific molecular profiles. Despite their potential, limitations in tumor organoid biology, including inter-batch variability and microenvironmental simplification, can undermine their reliability and scalability in large-scale drug screening. To overcome these challenges, the integration of advanced technologies such as artificial intelligence (AI), automated biomanufacturing, multi-omics analytics, and vascularization strategies has been explored. This review highlights the “Organoid plus and minus” framework, which combines technological augmentation with culture system refinement to improve screening accuracy, throughput, and physiological relevance. We are convinced that the future of drug development hinges on the convergence of these multidisciplinary technologies with standardized biobanking and co-clinical validation frameworks. This integration will position organoids as a cornerstone for personalized drug discovery and therapeutic optimization, ultimately advancing the development of efficacy in oncology. Full article

(This article belongs to the Special Issue New Targets and Experimental Therapeutic Approaches for Cancers)

► Show Figures

Figure 1

12 pages, 1479 KB

Open AccessArticle

Structure-Guided In-Use Stability Assessment of Monoclonal Antibody Tislelizumab

by David Andre Rudd and Ghizal Siddiqui

Pharmaceuticals 2025, 18(10), 1539; https://doi.org/10.3390/ph18101539 (registering DOI) - 13 Oct 2025

Abstract

Background/Objectives: Monoclonal antibody (mAb) stability is critical not only during manufacturing but also at the point of clinical administration. For therapies like tislelizumab (Tevimbra), a programmed death-1 (PD-1) targeting IgG mAb, delays in dosing often result in prepared infusions being discarded, contributing [...] Read more.

Background/Objectives: Monoclonal antibody (mAb) stability is critical not only during manufacturing but also at the point of clinical administration. For therapies like tislelizumab (Tevimbra), a programmed death-1 (PD-1) targeting IgG mAb, delays in dosing often result in prepared infusions being discarded, contributing to substantial drug waste despite being engineered for improved stability. Methods: To evaluate the physicochemical in-use stability of tislelizumab in a ready-to-administer format, we mapped degradation pathways, including post-translational modifications (PTMs); peptide alterations; pH and solution characteristics—under 12-month storage (ultra-long), under 1-month storage (0, 7, 14, 21, 28 and 31 days), and under exposure-related forced degradation conditions including room temperature, elevated temperature, pH (acidic/basic), oxidation and UV exposure. Structural analysis was contextualised to the known PD-1 binding site, making stability assessment relevant to tislelizumab’s mechanism-of-action in blocking PD-1. To assess solution stability, a validated size-exclusion chromatography (SEC) assay was applied to all conditions. Results: Aggregation was identified as the primary degradation pathway during ultra-long-term storage. SEC and chemical assessment revealed no measurable changes in protein quantity, aggregation, peptide integrity, or PTM profile over 31 days at 2–8 °C in polyolefin intravenous bags (1.6 mg/mL). Conclusions: These results support the structural and physicochemical stability of tislelizumab under refrigerated conditions. Full article

(This article belongs to the Topic Optimization of Drug Utilization and Medication Adherence)

► Show Figures

Graphical abstract

15 pages, 1948 KB

Open AccessArticle

Characterization of O-Glycosylation and N-Glycosylation in Bispecific Antibodies and Its Importance in Therapeutic Antibody Development

by Maoqin Duan, Luyun Guo, Zhen Long, Yongbo Ni, Yalan Yang, Jialiang Du, Meng Li, Jialing Zhang, Tao Tang, Chuanfei Yu and Lan Wang

Pharmaceuticals 2025, 18(10), 1538; https://doi.org/10.3390/ph18101538 - 13 Oct 2025

Abstract

Background/Objectives: This study comprehensively characterized the O- and N-glycosylation profiles of bispecific antibodies (BsAbs) via advanced analytical techniques to evaluate their structural and functional implications. Methods: High-resolution MS revealed O-xylosylation at Ser468 within the (G4S)4 linker peptide, which [...] Read more.

Background/Objectives: This study comprehensively characterized the O- and N-glycosylation profiles of bispecific antibodies (BsAbs) via advanced analytical techniques to evaluate their structural and functional implications. Methods: High-resolution MS revealed O-xylosylation at Ser468 within the (G4S)4 linker peptide, which was identified as xylose with a molecular weight of 132.042 Da. HILIC-HPLC analysis of N-glycosylation revealed glycan species engineered to eliminate Fc effector functions. O-glycosylation analysis via β-elimination followed by high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) identified xylose as the predominant glycan. Results: O-xylosylation does not affect the binding of BsAbs to either antigen Programmed Death-1 (PD-1) or Vascular Endothelial Growth Factor (VEGF). Notably, O-xylosylation interactions with mannose receptor represent the first discovery highlighting potential immunomodulatory roles. Conclusions: This study highlights the critical importance of monitoring comprehensive glycosylation characterization during the development of BsAb with (G4S)n linkers to ensure optimal therapeutic efficacy, safety, and reduced immunogenic potential. Full article

(This article belongs to the Section Biopharmaceuticals)

► Show Figures

Figure 1

6 pages, 171 KB

Open AccessEditorial

Metal Nanoparticles’ Biological Activity and Pharmaceutical Applications

by Elitsa L. Pavlova and Debbie C. Crans

Pharmaceuticals 2025, 18(10), 1537; https://doi.org/10.3390/ph18101537 - 13 Oct 2025

Abstract

Because of their variable physicochemical characteristics, metal nanoparticles are suitable and highly favorable for introduction to, and use in, living systems [...] Full article

(This article belongs to the Special Issue Metal Nanoparticles’ Biological Activity and Pharmaceutical Applications)

36 pages, 1531 KB

Open AccessReview

From AI-Assisted In Silico Computational Design to Preclinical In Vivo Models: A Multi-Platform Approach to Small Molecule Anti-IBD Drug Discovery

by Joya Datta Ripa, Sarfaraz Ali, Matt Field, John Smithson and Phurpa Wangchuk

Pharmaceuticals 2025, 18(10), 1536; https://doi.org/10.3390/ph18101536 - 13 Oct 2025

Abstract

Background: Inflammatory Bowel Disease (IBD), including Ulcerative Colitis and Crohn’s Disease, is a multifactorial inflammatory condition of the intestinal tract driven by a complex interplay of genetic factors, immune system dysfunction, and gut microbiota alterations. This review aims to synthesize current advancements [...] Read more.

Background: Inflammatory Bowel Disease (IBD), including Ulcerative Colitis and Crohn’s Disease, is a multifactorial inflammatory condition of the intestinal tract driven by a complex interplay of genetic factors, immune system dysfunction, and gut microbiota alterations. This review aims to synthesize current advancements in modern drug development strategies for IBD. It emphasizes the integration of computational modelling, cell-based experiments, and animal model studies to enhance translational outcomes. Methods: To compile this review, an extensive literature search was performed utilizing PubMed, Scopus, and Google Scholar databases for English-language research and review articles published between 2000 and 2025 using keywords such as “IBD,” “molecular docking,” “bioinformatics,” “organoids,” “animal models,” and “network pharmacology,” among others. A total of 199 peer-reviewed studies were identified for inclusion based on relevance, transparency, and methodological robustness. Results: The review outlines a range of cutting-edge approaches to IBD drug discovery. These include computer modelling, molecular docking, and network analysis to accelerate early-stage target prediction and drug screening. The review further highlights the critical importance of utilizing 2D and 3D cell culture systems in parallel with advanced animal models. It emphasizes the critical integration of computational predictions with biologically relevant in vitro and in vivo validations to improve the reliability and efficiency of drug development. Conclusions: The integration of computer modelling, cell culture systems, and animal studies provides a revolutionary paradigm for accelerating drug discovery to IBD and other diseases enabling personalized and more effective treatment approaches. Full article

(This article belongs to the Collection Feature Review Collection in Medicinal Chemistry)

► Show Figures

Graphical abstract

31 pages, 25829 KB

Open AccessArticle

The Hepatoprotective Properties of the Revised Formulation of Dahuang Xiaoshi Tang, an Ancient Chinese Herbal Decoction, Are Probed by Integrated Metabolomics and Network Pharmacology

by Xiangpeng Kong, Xiaoyang Wang, Haiqin Ren, Yajun Yao, Hui Zhang, Huifeng Li, Huifang Li, Yangang Cheng, Zhuqing Song, Miaorong Pei and Karl Wah Keung Tsim

Pharmaceuticals 2025, 18(10), 1534; https://doi.org/10.3390/ph18101534 - 13 Oct 2025

Abstract

Background: Dahuang Xiaoshi Tang (DXT), an ancient Chinese herbal remedy dating back to 220 AD, as documented initially in “Treatise on Febrile and Miscellaneous Diseases,” is used to treat damp-heat jaundice with interior sthenia syndrome. In DXT, anthraquinones and alkaloids form insoluble [...] Read more.

Background: Dahuang Xiaoshi Tang (DXT), an ancient Chinese herbal remedy dating back to 220 AD, as documented initially in “Treatise on Febrile and Miscellaneous Diseases,” is used to treat damp-heat jaundice with interior sthenia syndrome. In DXT, anthraquinones and alkaloids form insoluble complexes, reducing its effectiveness. A revised herbal extract, DXT-M, was developed, and its hepatoprotective properties were demonstrated in animal models using pharmacodynamic, metabolomic, network pharmacological, and toxicological approaches. Methods: The α-naphthalene isothiocyanate was utilised to establish the acute liver injury rat model. The assays of glutamate pyruvate transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, bilirubin, total bile acid, complement 3 (C3) and C4, interleukin-2 (IL-2) and IL-6, tumour necrosis factor α (TNF-α), and pathological morphology were used to evaluate the hepatoprotection of DXT in comparison to DXT-M. The ¹H-NMR-based serum and urine metabolomics were performed to identify potential biomarkers and metabolic pathways of DXT-M in treating hepatitis. The intrinsic regulatory mechanisms of DXT in liver protection, as well as the combination of network toxicology, were elucidated. Statistical analyses included RM two-way ANOVA with Geisser–Greenhouse correction and Dunnett’s post hoc test for longitudinal data, and one-way ANOVA with Dunnett’s post hoc test for group comparisons. Data were shown as mean ± SD. Results: Liver-injured animals exhibited weight loss, ruffled fur, and liver damage, accompanied by elevated liver function indicators. DXT-M effectively improved these symptoms, repaired liver damage, restored liver function, and regulated immune status by modulating complement 3. Metabonomics and other analyses indicated the CYP/GST-ROS axis is key to its hepatoprotective effects. DXT-M outperformed DXT in efficacy. Conclusions: DXT-M demonstrated significant effectiveness in restoring liver pathological damage, correcting abnormal biochemical indicators of liver function, and regulating complement factors. The pathway of CYP/GST-ROS served as the shared regulatory axis and transformation site for DXT-M’s liver protective effects. These findings suggest that DXT-M has potential as a treatment for acute liver injury, highlighting the need for further research into its underlying molecular mechanisms as well as its complete material basis. This study’s main limitation is its focus on acute models; future research should include other liver diseases and clinical observation to evaluate its full potential. Full article

(This article belongs to the Special Issue Network Pharmacology of Natural Products, 2nd Edition)

► Show Figures

Graphical abstract

26 pages, 3041 KB

Open AccessSystematic Review

Impact of the COVID-19 Pandemic on Drug-Resistant Tuberculosis in Europe: A Meta-Analysis of Epidemiological Trends

by Christina Zouganeli, Dimitra K. Toubanaki, Ourania Karaoulani, Georgia Vrioni, Evdokia Karagouni and Antonia Efstathiou

Pharmaceuticals 2025, 18(10), 1535; https://doi.org/10.3390/ph18101535 - 12 Oct 2025

Abstract

Background/Objectives: The COVID-19 pandemic has significantly intensified global concerns surrounding antimicrobial resistance (AMR), particularly in relation to tuberculosis (TB). In the European Union (EU), the reallocation of healthcare resources towards managing COVID-19 led to a de-prioritization of TB surveillance and control. This [...] Read more.

Background/Objectives: The COVID-19 pandemic has significantly intensified global concerns surrounding antimicrobial resistance (AMR), particularly in relation to tuberculosis (TB). In the European Union (EU), the reallocation of healthcare resources towards managing COVID-19 led to a de-prioritization of TB surveillance and control. This shift contributed to delays in TB diagnosis and treatment, creating conditions favorable for the emergence and spread of drug-resistant TB strains. This meta-analysis aims to assess epidemiological trends of drug-resistant TB across EU countries before, during, and after the pandemic and quantify the impact of COVID-19 on Mycobacterium tuberculosis resistance patterns. Methods: Data were obtained from the European Centre for Disease Prevention and Control (ECDC) covering 2015 to 2022. Following the TB incidence, the multidrug-resistant TB (MDR-TB) and rifampicin-resistant/MDR-TB (RR/MDR-TB) cases, as well as treatment success rates over 12- and 24-month periods, were analyzed. The analysis included 31 EU countries across three-time frames: pre-pandemic (2015–2019), pandemic onset (2020), and post-pandemic transition (2020–2022). Results: The pandemic was associated with a decrease in reported TB cases but a simultaneous increase in the proportion of MDR and RR/MDR cases. Treatment success rates showed a modest rise for 24-month regimens, while outcomes declined for 12-month therapies. Conclusions: These findings underscore the pandemic’s disruptive impact on TB control and highlight the need for renewed investment in diagnostic capacity, treatment access, and antimicrobial stewardship, in order to reduce antimicrobial resistance occurrence. Continued monitoring beyond 2022 is essential to fully understand long-term effects and inform future public health strategies. Full article

(This article belongs to the Special Issue New Approaches to Fighting Infectious Diseases: Overcoming the Antimicrobial Resistance in Current Treatments)

► Show Figures

Graphical abstract

31 pages, 4944 KB

Open AccessArticle

Synthesis, Spectroscopic Characterization, and Biological Evaluation of a Novel Acyclic Heterocyclic Compound: Anticancer, Antioxidant, Antifungal, and Molecular Docking Studies

by Mohammad Alhilal, Suzan Alhilal, Ilhan Sabancilar, Sobhi M. Gomha, Ahmed A. Elhenawy and Salama A. Ouf

Pharmaceuticals 2025, 18(10), 1533; https://doi.org/10.3390/ph18101533 - 12 Oct 2025

Abstract

Background/Objectives: This study aimed to synthesize a novel, high-molecular-weight acyclic heterocyclic compound, compound 5, via a one-pot reaction between Trichloroisocyanuric acid (TCCA) and ethanolamine, and evaluate its anticancer, antioxidant, and antifungal activities. Methods: Its complex tetrameric structure, assembled through N-N linkages, [...] Read more.

Background/Objectives: This study aimed to synthesize a novel, high-molecular-weight acyclic heterocyclic compound, compound 5, via a one-pot reaction between Trichloroisocyanuric acid (TCCA) and ethanolamine, and evaluate its anticancer, antioxidant, and antifungal activities. Methods: Its complex tetrameric structure, assembled through N-N linkages, was unequivocally confirmed by a full suite of spectroscopic techniques including IR, ¹H & ¹³C NMR, ²D-NMR, and high-resolution mass spectrometry (LC/Q-TOF/MS). The MTT assay was used to assess the anticancer activity of compound 5 against four different human cancer cell lines. Results: The findings indicate that human colon (HT29) and ovarian (OVCAR3) cancer cells were sensitive to the treatment, whereas brain (glioblastoma) (T98G) cancer cells were resistant. The most pronounced cytotoxic effect was observed in pancreatic (MiaPaCa2) cancer cells. Notably, compound 5 exhibited potent antifungal properties, achieving 100% inhibition of the pathogenic water mould Saprolegnia parasitica zoospores at 100 µM after 10 min. Molecular docking studies corroborated the biological data, revealing a high binding affinity for key cancer and fungal targets (Thymidylate Synthase and CYP51), providing a strong mechanistic basis for its observed activities. Conclusions: These findings establish compound 5 as a promising dual-action agent with significant potential as both a targeted anticancer lead and an eco-friendly antifungal for applications in aquaculture. Full article

(This article belongs to the Special Issue Heterocyclic Chemistry in Modern Drug Development)

► Show Figures

Figure 1

24 pages, 2016 KB

Open AccessArticle

New-Onset Diabetes After Transplantation in Renal Recipients: A Pilot Comparative Study of Immediate vs. Extended-Release Tacrolimus Formulation

by Ioana Adela Ratiu, Florin Bănică, Corina Moisa, Bianca Pașca, Daniela Gîtea, Iulia Dana Grosu, Gabriel Cristian Bako, Oliviu Voștinaru, Wael Abu Dayyih and Lorena Filip

Pharmaceuticals 2025, 18(10), 1532; https://doi.org/10.3390/ph18101532 - 12 Oct 2025

Abstract

Tacrolimus is frequently used in immunosuppressive therapy in renal transplant patients and is characterized by high toxicity, a low therapeutic index, and great individual variability. For these reasons, correct dosing is important to ensure patient safety by reducing the incidence of adverse effects [...] Read more.

Tacrolimus is frequently used in immunosuppressive therapy in renal transplant patients and is characterized by high toxicity, a low therapeutic index, and great individual variability. For these reasons, correct dosing is important to ensure patient safety by reducing the incidence of adverse effects while maintaining an optimal blood level that prevents graft loss. New-onset diabetes after transplantation (NODAT) affects 15–30% of patients treated with tacrolimus, with potential differences between immediate-release (IR) and extended-release (ER) formulations. Objective: This study seeks to compare the incidence of NODAT between IR tacrolimus and ER tacrolimus formulations in renal transplant patients and correlate it with in vitro release characteristics. Methods: This is a retrospective pilot study including 66 renal transplant patients (33 IR tacrolimus, 33 ER tacrolimus) followed for 5 years. NODAT was defined according to standard criteria. In vitro dissolution testing was performed at pH values of 1.2, 4.5, and 6.8, with sampling at 15, 30, 60, 90, 120, and 360 min. Results: The obtained results do not indicate differences regarding the incidence of diabetes mellitus in patients treated with the two forms of tacrolimus. The determined NODAT incidence was 42.4% (ER tacrolimus) vs. 39.4% (IR tacrolimus), p = 0.802, and ER tacrolimus showed slower release without significant pH-dependent variations. Conclusions: No significant differences in NODAT incidence were identified between formulations. The release–clinical outcome correlation requires validation in larger multicenter studies. These results contribute to the evidence base for tacrolimus formulation selection in renal transplant patients and other associated pathologies. Full article

(This article belongs to the Special Issue New Development in Pharmacotherapy of Kidney Diseases)

► Show Figures

Graphical abstract

12 pages, 1376 KB

Open AccessArticle

Resensitizing the Untreatable: Zidovudine and Polymyxin Combinations to Combat Pan-Drug-Resistant Klebsiella pneumoniae

by Jan Naseer Kaur, Jack F. Klem, Gebremedhin S. Hailu, Nader N. Nasief, Yang Liu, Allison Hanna, Albert Chen, Patricia Holden, Shivali Kapoor, Nicholas M. Smith, Mark Sutton, Jian Li and Brian T. Tsuji

Pharmaceuticals 2025, 18(10), 1531; https://doi.org/10.3390/ph18101531 - 11 Oct 2025

Abstract

Background: The emergence of pan-drug-resistant (PDR) Klebsiella pneumoniae has compromised the efficacy of last-line agents, leaving few therapeutic options. Repurposing zidovudine, an FDA-approved thymidine analog with antibacterial activity, may enhance existing therapies, but pharmacodynamic data under clinically relevant conditions are scarce. This study [...] Read more.

Background: The emergence of pan-drug-resistant (PDR) Klebsiella pneumoniae has compromised the efficacy of last-line agents, leaving few therapeutic options. Repurposing zidovudine, an FDA-approved thymidine analog with antibacterial activity, may enhance existing therapies, but pharmacodynamic data under clinically relevant conditions are scarce. This study addresses this gap using static and dynamic in vitro models. Materials/methods: A PDR strain of Klebsiella pneumoniae harboring bla_NDM-1, bla_CMY-6, bla_CTX-M-15, bla_SHV-2, and disrupted mgrB was used in this study. Minimum inhibitory concentrations (MICs) followed by static time-kills were performed to investigate the synergistic interplay between zidovudine and last-line antibiotics (ceftazidime/avibactam, polymyxin B). To simulate human pharmacokinetics, a hollow-fiber infection model (HFIM) was employed using steady-state concentrations of zidovudine (4 mg/L), polymyxin B (4 mg/L), and avibactam (22 mg/L). Structural and morphological effects on bacterial cells were examined via fluorescence microscopy following glutaraldehyde fixation. Results: In this study, the PDR K. pneumoniae showed a ~5-fold reduction in polymyxin MIC when combined with zidovudine (from >4 µg/mL to 0.25 µg/mL). Time-kill assays demonstrated ≥2.5 log₁₀ CFU/mL bacterial reduction with zidovudine-based combinations, whereas monotherapies failed to inhibit bacterial growth. In the HFIM, the triple combination achieved rapid bactericidal activity (>3 log₁₀ CFU/mL reduction within 4 h) and sustained killing (>5–6 log₁₀ reduction maintained through 216 h), with bacterial counts remaining below 1 CFU/mL. In contrast, dual combinations initially reduced bacterial burden (1–3 log₁₀ reduction) but failed to maintain suppression, with significant regrowth (>10¹⁰ CFU/mL) observed by 168 h. Microscopy corroborated these findings, revealing extensive cellular damage in the zidovudine-containing treatment arms. These HFIM results underscore the potential of zidovudine-based triple therapy in overcoming resistance to last-line antibiotics in K. pneumoniae. Conclusions: Our results provide promising unprecedented insight into novel zidovudine-based combination therapies against difficult-to-treat MBL Gram-negatives. The observed synergy in MIC reduction, rapid killing in time-kill assays, and near-complete eradication in the HFIM underscore the therapeutic potential of this triple combination. Future studies will focus on broadening the application of these novel combinations to other ‘superbugs’, such as highly resistant strains of Acinetobacter baumannii and Pseudomonas aeruginosa. Full article

(This article belongs to the Section Pharmacology)

13 pages, 1501 KB

Open AccessArticle

Predictive Value of Baseline Left Ventricular Global Longitudinal Strain for Cardiac Dysfunction in Patients with Moderate to High Risk of Cancer Therapy-Related Cardiovascular Toxicity

by Anna Borowiec, Patrycja Ozdowska, Magdalena Rosinska, Agnieszka Maria Zebrowska, Slawomir Jasek, Beata Kotowicz, Hanna Kosela-Paterczyk, Elzbieta Lampka, Zbigniew Nowecki and Jan Walewski

Pharmaceuticals 2025, 18(10), 1530; https://doi.org/10.3390/ph18101530 - 11 Oct 2025

Abstract

Background: Anthracycline-based chemotherapy is associated with a risk of cancer therapy-related cardiac dysfunction (CTRCD), particularly in patients with moderate to high cardiovascular risk. Left ventricular global longitudinal strain (GLS) is a sensitive marker for early myocardial dysfunction, but the prognostic value of baseline [...] Read more.

Background: Anthracycline-based chemotherapy is associated with a risk of cancer therapy-related cardiac dysfunction (CTRCD), particularly in patients with moderate to high cardiovascular risk. Left ventricular global longitudinal strain (GLS) is a sensitive marker for early myocardial dysfunction, but the prognostic value of baseline GLS in this population remains unclear. Objective: We aimed to evaluate whether baseline GLS can predict CTRCD in moderate- to high-risk cancer patients undergoing anthracycline chemotherapy. Methods: In this prospective, single-center observational study, 80 anthracycline-naive cancer patients classified as moderate or high risk were enrolled. Baseline GLS was assessed via speckle-tracking echocardiography, with a threshold of ≥−18% considered decreased. Patients were followed for 12 months, and the primary endpoint was the development of CTRCD per ESC 2022 Cardio-oncology guidelines. Results: Of the 77 patients completing follow-up, 27.3% had decreased baseline GLS. CTRCD occurred in 62.4% of patients, with higher incidence among those with decreased GLS (76.7%) compared to those with normal GLS. In multivariable analysis, GLS ≥−18% was the only significant independent predictor of CTRCD (RR 12.0, 95% CI 2.0–71.9; p = 0.0065). All-cause mortality was also significantly higher in patients with decreased baseline GLS (19.1% vs. 1.8%, p = 0.018). Conclusions: Decreased baseline global longitudinal strain is an independent predictor of cancer therapy-related cardiac dysfunction and all-cause mortality in moderate- to high-risk patients receiving anthracycline therapy. These findings support the inclusion of baseline GLS in pre-treatment cardiovascular risk assessment, particularly in patients with an LVEF above 54%, to more effectively identify those who may benefit from early cardioprotective interventions. Full article

(This article belongs to the Special Issue Advances in Cancer Treatment and Toxicity)

► Show Figures

Figure 1

58 pages, 1997 KB

Open AccessReview

Immunomodulatory Activities of Emerging Rare Ginsenosides F1, Rg5, Rk1, Rh1, and Rg2: From Molecular Mechanisms to Therapeutic Applications

by Chang-Eui Hong and Su-Yun Lyu

Pharmaceuticals 2025, 18(10), 1529; https://doi.org/10.3390/ph18101529 - 11 Oct 2025

Abstract

Ginsenosides, the primary bioactive components of Panax ginseng, have demonstrated significant immunomodulatory potential. While major ginsenosides have been extensively studied, rare ginsenosides produced through deglycosylation, heating, and steaming show enhanced biological activities with improved bioavailability. This review aimed to comprehensively analyze the [...] Read more.

Ginsenosides, the primary bioactive components of Panax ginseng, have demonstrated significant immunomodulatory potential. While major ginsenosides have been extensively studied, rare ginsenosides produced through deglycosylation, heating, and steaming show enhanced biological activities with improved bioavailability. This review aimed to comprehensively analyze the immunomodulatory mechanisms, structure-activity relationships (SARs), therapeutic applications, and clinical translation strategies of five emerging rare ginsenosides: F1, Rg5, Rk1, Rh1, and Rg2. We conducted a comprehensive literature review examining the production methods, immunological effects, molecular mechanisms, pharmacokinetics, safety profiles, and clinical applications of these five compounds. Analysis focused on chemical structures, immune cell modulation, signaling pathways, disease model efficacy, and bioavailability enhancement strategies. Ginsenoside F1 uniquely demonstrated immunostimulatory effects, enhancing natural killer (NK) cell cytotoxicity and macrophage phagocytosis through mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) activation. Conversely, Rg5, Rk1, Rh1, and Rg2 exhibited anti-inflammatory properties via distinct mechanisms: Rg5 through Toll-like receptor 4 (TLR4)/NF-κB inhibition, Rk1 via triple pathway modulation (NF-κB, p38 MAPK, signal transducer and activator of transcription (STAT)), Rh1 by selective p38 MAPK and STAT1 inhibition, and Rg2 through modulation of both central nervous system (neuroinflammation) and peripheral organ systems. Structure-activity analysis revealed that sugar moiety positions critically determine immunological outcomes. Crucially, advanced delivery systems including nanostructured lipid carriers, self-microemulsifying systems, and specialized liposomes have overcome the major translational barrier of poor bioavailability, achieving up to 2.6-fold improvements and enabling clinical development. Safety assessments demonstrated favorable tolerability profiles across preclinical and clinical studies. These five rare ginsenosides represent promising immunomodulatory agents with distinct therapeutic applications. F1’s unique immunostimulatory properties position it for cancer immunotherapy, while the complementary anti-inflammatory mechanisms of Rg5, Rk1, Rh1, and Rg2 offer opportunities for precision medicine in inflammatory diseases. Advanced formulation technologies and optimized production methods now enable their significant clinical translation potential, providing promising therapeutic options for immune-related disorders pending further development. Full article

(This article belongs to the Special Issue Exploring the Anticancer and Immunomodulatory Mechanisms of Phytochemicals and Natural Bioactive Compounds)

► Show Figures

Graphical abstract

27 pages, 2236 KB

Open AccessReview

Potential and Mechanism of Nobiletin in Diabetes Mellitus and Associated Complications

by Chuyun Zhao, Wenjie Lai, Yu Li, Kinfong Hong and Youhua Xu

Pharmaceuticals 2025, 18(10), 1528; https://doi.org/10.3390/ph18101528 - 11 Oct 2025

Viewed by 43

Abstract

The incidence and mortality of diabetes have increased dramatically in recent decades. New strategies to treat diabetes and its complications with minimal side effects are urgently needed. New monomeric molecules extracted from herbs are an alternative medicine that is being explored as candidate [...] Read more.

The incidence and mortality of diabetes have increased dramatically in recent decades. New strategies to treat diabetes and its complications with minimal side effects are urgently needed. New monomeric molecules extracted from herbs are an alternative medicine that is being explored as candidate drugs for the treatment of diabetes and its complications. Nobiletin, a citrus flavonoid, has recently received increasing attention in scientific research due to its properties in combating diabetes and its complications, while existing research is scattered and unsystematic. This article summarizes recent studies and reviews the potential therapeutic role of nobiletin in preventing and alleviating diabetes and its complications, aiming to provide promising strategies for the clinical management of diabetes and its complications. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

37 pages, 1186 KB

Open AccessReview

Adipokines at the Metabolic–Brain Interface: Therapeutic Modulation by Antidiabetic Agents and Natural Compounds in Alzheimer’s Disease

by Paulina Ormazabal, Marianela Bastías-Pérez, Nibaldo C. Inestrosa and Pedro Cisternas

Pharmaceuticals 2025, 18(10), 1527; https://doi.org/10.3390/ph18101527 - 11 Oct 2025

Viewed by 36

Abstract

The parallel global increase in obesity and Alzheimer’s disease (AD) underscores an urgent public health challenge, with converging evidence indicating that metabolic dysfunction strongly contributes to neurodegeneration. Obesity is now recognized not only as a systemic metabolic condition but also as a modifiable [...] Read more.

The parallel global increase in obesity and Alzheimer’s disease (AD) underscores an urgent public health challenge, with converging evidence indicating that metabolic dysfunction strongly contributes to neurodegeneration. Obesity is now recognized not only as a systemic metabolic condition but also as a modifiable risk factor for AD, acting through mechanisms such as chronic low-grade inflammation, insulin resistance, and adipose tissue dysfunction. Among the molecular mediators at this interface, adipokines have emerged as pivotal regulators linking metabolic imbalance to cognitive decline. Adipokines are hormone-like proteins secreted by adipose tissue, including adiponectin, leptin, and resistin, that regulate metabolism, inflammation and can influence brain function. Resistin, frequently elevated in obesity, promotes neuroinflammation, disrupts insulin signaling, and accelerates β-amyloid (Aβ) deposition and tau pathology. Conversely, adiponectin enhances insulin sensitivity, suppresses oxidative stress, and supports mitochondrial and endothelial function, thereby exerting neuroprotective actions. The imbalance between resistin and adiponectin may shift the central nervous system toward a pro-inflammatory and metabolically compromised state that predisposes to neurodegeneration. Beyond their mechanistic relevance, adipokines hold translational promise as biomarkers for early risk stratification and therapeutic monitoring. Importantly, natural compounds, including polyphenols, alkaloids, and terpenoids, have shown the capacity to modulate adipokine signaling, restore metabolic homeostasis, and attenuate AD-related pathology in preclinical models. This positions adipokines not only as pathogenic mediators but also as therapeutic targets at the intersection of diabetes, obesity, and dementia. By integrating mechanistic, clinical, and pharmacological evidence, this review emphasizes adipokine signaling as a novel axis for intervention and highlights natural compound-based strategies as emerging therapeutic approaches in obesity-associated AD. Beyond nutraceuticals, antidiabetic agents also modulate adipokines and AD-relevant pathways. GLP-1 receptor agonists, metformin, and thiazolidinediones tend to increase adiponectin and reduce inflammatory tone, while SGLT2 and DPP-4 inhibitors exert systemic anti-inflammatory and hemodynamic benefits with emerging but still limited cognitive evidence. Together, these drug classes offer mechanistically grounded strategies to target the adipokine–inflammation–metabolism axis in obesity-associated AD. Full article

(This article belongs to the Special Issue Emerging Therapies for Diabetes and Obesity)

► Show Figures

Figure 1

79 pages, 5283 KB

Open AccessReview

Monoamine Oxidase Inhibitors in Drug Discovery Against Parkinson’s Disease: An Update

by Luana Vergueiro Ribeiro, Larissa Emika Massuda, Vanessa Silva Gontijo and Claudio Viegas Jr.

Pharmaceuticals 2025, 18(10), 1526; https://doi.org/10.3390/ph18101526 - 10 Oct 2025

Viewed by 399

Abstract

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with substantial socioeconomic impact, characterized by the gradual loss of dopaminergic neurons, dopamine deficiency, and pathological processes such as neuroinflammation, oxidative stress, and α-synuclein aggregation. Monoamine oxidases (MAOs) are enzymes responsible for the degradation [...] Read more.

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with substantial socioeconomic impact, characterized by the gradual loss of dopaminergic neurons, dopamine deficiency, and pathological processes such as neuroinflammation, oxidative stress, and α-synuclein aggregation. Monoamine oxidases (MAOs) are enzymes responsible for the degradation of neuroactive amines, including dopamine, a neurotransmitter essential for motor, cognitive, and behavioral functions. Among these, MAO-B plays a central role in dopamine metabolism, producing reactive metabolites and oxidative species that contribute to the oxidative stress associated with PD pathophysiology. In this context, MAO-B inhibition has emerged as a promising therapeutic strategy. However, specific limitations, such as motor complications linked to prolonged levodopa use and the adverse effects of currently available MAO inhibitors, remain significant clinical challenges. Methods: A comprehensive literature search was conducted using PubMed and SciFinder databases. Keywords such as “MAO inhibitors”, “Parkinson’s pathology,” and “Parkinson’s disease” were combined with Boolean operators (AND, OR, NOT). The search covered publications from 2010 to 2025. Results: While previous reviews, particularly those by the groups of Guglielmi and Alborghetti, mainly emphasized the clinical use of MAO-B inhibitors and advances in patents, the present review identified approximately 300 compounds synthesized and evaluated as MAO inhibitors, encompassing diverse chemical classes. Among them, selective MAO-B inhibitors exhibited the greatest pharmacological potential, reinforcing the relevance of this isoform as a strategic target in PD therapy. Conclusion: These findings highlight the advances of Medicinal Chemistry in the development of novel MAO-B inhibitors, both as monotherapies for early-stage PD and as adjuvants to levodopa in advanced disease. Collectively, they emphasize the promise of MAO-B inhibitors as candidates for more effective therapeutic interventions in Parkinson’s disease. Full article

(This article belongs to the Special Issue Potential Pharmacotherapeutic Targets in Neurodegenerative Diseases)

► Show Figures

Graphical abstract

42 pages, 3246 KB

Open AccessReview

Wound Healing: Molecular Mechanisms, Antimicrobial Peptides, and Emerging Technologies in Regenerative Medicine

by Ana Paula de Araújo Boleti, Ana Cristina Jacobowski, Breno Emanuel Farias Frihling, Maurício Vicente Cruz, Kristiane Fanti Del Pino Santos, Ludovico Migliolo, Lucas Rannier Melo de Andrade and Maria Ligia Rodrigues Macedo

Pharmaceuticals 2025, 18(10), 1525; https://doi.org/10.3390/ph18101525 - 10 Oct 2025

Viewed by 105

Abstract

Wound healing is a dynamic process involving distinct phases that are regulated by cellular and molecular interactions. This review explores the fundamental mechanisms involved in wound healing, including the roles of cytokines and growth factors within the local microenvironment, with a particular focus [...] Read more.

Wound healing is a dynamic process involving distinct phases that are regulated by cellular and molecular interactions. This review explores the fundamental mechanisms involved in wound healing, including the roles of cytokines and growth factors within the local microenvironment, with a particular focus on antimicrobial peptides (AMPs) as immune modulators and therapeutic agents in chronic wounds. Notably, AMPs such as LL-37 have been shown to reduce biofilm density by up to 60%, highlighting their dual role in both modulating host immune responses and combating persistent bacterial infections. It further examines emerging technologies that are transforming the field, extending beyond traditional biological mechanisms to innovations such as smart dressings, 3D bioprinting, AI-driven therapies, regenerative medicine, gene therapy, and organoid models. Additionally, the review addresses strategies to overcome bacterial biofilms and highlights promising approaches including biomaterials, nanomedicine, gene therapy, peptide-loaded nanoparticles, and the application of organoids as advanced platforms for studying and enhancing wound repair. Full article

(This article belongs to the Special Issue New Approaches to Fighting Infectious Diseases: Overcoming the Antimicrobial Resistance in Current Treatments)

► Show Figures

Graphical abstract

21 pages, 2777 KB

Open AccessArticle

Protective Effects of Cuscuta australis Against CCl₄-Induced Hepatic Injury in Rats: Antioxidant, Anti-Inflammatory, and In Silico Insights

by Hanen Baccari, Arij Bedoui, Anouar Feriani, Amal Bouallegue, Nihad Sahri, Sohaib Khatib, Mohamed Kharrat, Nizar Tlili, Mansour Sobeh, Moez Amri and Zouhaier Abbes

Pharmaceuticals 2025, 18(10), 1524; https://doi.org/10.3390/ph18101524 - 10 Oct 2025

Viewed by 165

Abstract

Background/Objectives: The search for new bioactive molecules increasingly extends beyond conventional medicinal plants, highlighting the importance of exploring alternative botanical sources. Parasitic plants represent a promising but underexploited reservoir of pharmacologically relevant compounds. Cuscuta australis (CA), a parasitic species with a history of [...] Read more.

Background/Objectives: The search for new bioactive molecules increasingly extends beyond conventional medicinal plants, highlighting the importance of exploring alternative botanical sources. Parasitic plants represent a promising but underexploited reservoir of pharmacologically relevant compounds. Cuscuta australis (CA), a parasitic species with a history of traditional use, remains poorly characterized. This study aimed to investigate its phytochemical composition and evaluate its antioxidant, anti-inflammatory, and hepatoprotective properties. Methods: The phytochemical profile of CA extract was characterized by LC-MS. Antioxidant capacity was assessed using DPPH and ABTS assays. In vivo hepatoprotection was evaluated in male rats subjected to CCl₄-induced hepatotoxicity and treated orally with CA (30 or 60 mg/kg body weight). Biochemical, lipid, oxidative stress, and histological parameters were determined. Molecular docking was conducted to predict the binding of major identified compounds against selected protein targets. Results: CA significantly and dose-dependently improved biochemical and histological markers. At 60 mg/kg, ALT, AST, ALP, and bilirubin were reduced by 32%, 33%, 63%, and 51%, respectively. Lipid metabolism was improved by decreased TC, TG, and LDL-C with increased HDL-C. Antioxidant defense was enhanced through elevated CAT, SOD, and GPx activities, accompanied by reduced MDA levels. TNF-α and IL-6 decreased by 48% and 53%, respectively. Histopathology confirmed hepatoprotection and reduced fibrosis. Docking studies revealed strong binding affinities (−7.07 to −19.20 kcal/mol) for several metabolites, notably quercetin glucoside, diosmetin glucoside, caffeic acid glucoside, feruloylquinic acid, and isorhamnetin glucoside, against CYP450, IL-2, TNF-α, and IL-6. Conclusions: These findings demonstrate that C. australis is a promising source of bioactive compounds with hepatoprotective, antioxidant, antihyperlipidemic, and anti-inflammatory effects, supporting its potential as a natural therapeutic agent. Full article

(This article belongs to the Section Natural Products)

► Show Figures

Figure 1

19 pages, 73359 KB

Open AccessArticle

Multi-Omics and Experimental Insights into the Protective Effects of Sesquiterpenoid Lactones from Eupatorium lindleyanum DC. in Acute Lung Injury: Regulation of PI3K-Akt and MAPK-NF-κB Pathways

by Chen Luo, Yan Yang, Lian Xia, Keyun Zhou, Chuanxin Liu, Ling Yao, Weiguo Cao and Xianqin Luo

Pharmaceuticals 2025, 18(10), 1523; https://doi.org/10.3390/ph18101523 - 10 Oct 2025

Viewed by 96

Abstract

Background: Acute lung injury (ALI) is a life-threatening respiratory condition and one of the leading causes of mortality worldwide, accounting for approximately 20% of global annual deaths. Despite its high prevalence and severity, effective therapeutic options remain limited. Eupatorium lindleyanum DC., a traditional [...] Read more.

Background: Acute lung injury (ALI) is a life-threatening respiratory condition and one of the leading causes of mortality worldwide, accounting for approximately 20% of global annual deaths. Despite its high prevalence and severity, effective therapeutic options remain limited. Eupatorium lindleyanum DC., a traditional medicinal herb, has demonstrated therapeutic potential against pulmonary diseases, particularly ALI, in both clinical and experimental settings. However, the protective effects and underlying mechanisms of its characteristic sesquiterpene lactone components against ALI remain unclear. Objective: This study aimed to evaluate the protective effects of sesquiterpene lactones from Eupatorium lindleyanum DC. (SLEL) against lipopolysaccharide (LPS)-induced ALI both in vivo and in vitro. Furthermore, it sought to elucidate the underlying mechanisms by integrating network pharmacology, multi-omics approaches (transcriptomics, metabolomics, and 16S rRNA sequencing), and various molecular biology techniques. Results: SLEL significantly attenuated inflammatory injury in alveolar epithelial cells and alleviated pulmonary edema, hemorrhage, and inflammatory infiltration in rats, accompanied by reduced TNF-α, IL-6, and IL-1β levels and improved lung injury indices. Mechanistically, SLEL exerted dual suppression of the PI3K-Akt and MAPK-NF-κB pathways. Network pharmacology, molecular docking, and UPLC-MS analyses identified Eupalinolide A and Eupalinolide K as potential bioactive constituents, which were further validated to inhibit phosphorylation of key signaling proteins, thereby partially accounting for SLEL’s pharmacological effects. Multi-omics integration further revealed that SLEL restored bile acid metabolism, reshaped gut microbial diversity, and reconstructed the microbiota–metabolite–inflammatory cytokine network, thereby maintaining gut–lung axis homeostasis and enhancing anti-inflammatory effects. Conclusions: SLEL alleviates ALI through multi-component synergistic actions that suppress pro-inflammatory signaling and modulate the gut–lung axis. These findings highlight the potential of SLEL as a promising therapeutic candidate for the treatment of ALI. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

15 pages, 2615 KB

Open AccessReview

IL-1β and HMGB1 in Epileptogenesis: Recent Advances and Clinical Translation

by Huali Geng, Leihao Sha and Lei Chen

Pharmaceuticals 2025, 18(10), 1522; https://doi.org/10.3390/ph18101522 - 10 Oct 2025

Viewed by 94

Abstract

Epilepsy is one of the most prevalent and disabling neurological disorders, affecting approximately one percent of the population. Due to the complex pathophysiology underlying drug-resistant epilepsy, nearly one-third of patients with epilepsy do not benefit from current treatments. Neuroinflammation is one of the [...] Read more.

Epilepsy is one of the most prevalent and disabling neurological disorders, affecting approximately one percent of the population. Due to the complex pathophysiology underlying drug-resistant epilepsy, nearly one-third of patients with epilepsy do not benefit from current treatments. Neuroinflammation is one of the most well-studied pathways in epileptogenesis, and inflammatory mediators play a crucial role in this process. The IL-1β/IL-1R1/IL-1Ra and HMGB1/TLR4 pathways play significant roles in epileptogenesis in both animal and human studies. Interventional investigations on the IL-1β/IL-1R1/IL-1Ra and HMGB1/TLR4 pathways showed antiseizure effects, suggesting that these pathways could be therapeutic targets for epilepsy. However, related targeted treatments are limited in clinical practice. In this work, we evaluated the advances of the IL-1β/IL-1R1/IL-1Ra and HMGB1/TLR4 pathways in epileptogenesis, as well as clinical trials or interventional investigations of current medications or substances targeting these pathways. To facilitate clinical translation, we highlighted the gap between research advancements and clinical practice and presented several strategies for closing the gap to fulfill the urgent requirements of patients with epilepsy. Full article

(This article belongs to the Special Issue Drug Treatment for Epilepsy)

► Show Figures

Figure 1

36 pages, 774 KB

Open AccessReview

Targeting Ion Channels for Cancer Therapy: From Pathophysiological Mechanisms to Clinical Translation

by Sha Zhou, Xiong Song, Weian Zeng and Dongtai Chen

Pharmaceuticals 2025, 18(10), 1521; https://doi.org/10.3390/ph18101521 - 10 Oct 2025

Viewed by 81

Abstract

Cancer remains a major global health burden, representing one of the leading causes of mortality among noncommunicable diseases worldwide. Although conventional treatment modalities, including surgical resection, chemotherapy, radiotherapy, targeted therapy, and immunotherapeutic interventions, have demonstrated clinical benefits, their therapeutic efficacy is often constrained [...] Read more.

Cancer remains a major global health burden, representing one of the leading causes of mortality among noncommunicable diseases worldwide. Although conventional treatment modalities, including surgical resection, chemotherapy, radiotherapy, targeted therapy, and immunotherapeutic interventions, have demonstrated clinical benefits, their therapeutic efficacy is often constrained by inherent limitations such as low specificity, systemic toxicity, or tumor heterogeneity. These challenges underscore the imperative for developing innovative treatment strategies. Emerging evidence has implicated ion channels as critical players in oncogenesis and cancer progression. These proteins modulate diverse oncogenic phenotypes, including uncontrolled proliferation, metastatic dissemination, and apoptotic resistance. Their frequent dysregulation in malignancies correlates with disease aggressiveness and clinical outcomes, positioning them as promising targets for precision oncology. Notably, pharmacological modulation of ion channels exerts multifaceted antitumor effects, with several channel-targeting agents advancing through clinical trials. This review explores recent advances in ion channel-targeted therapies, emphasizing their mechanisms, clinical applications, and challenges. Furthermore, we examine the pathophysiological contributions of ion channels to tumor biology and evaluate their emerging utility as predictive biomarkers, providing perspectives on addressing critical gaps in current oncologic management. Full article

(This article belongs to the Special Issue Ion Channels as Pharmacological Targets in Cancer)

► Show Figures

Figure 1

14 pages, 7102 KB

Open AccessArticle

Tumor-Derived Microvesicles Promote Kidney Regeneration and Cytoprotective Immunomodulation

by Galina V. Seledtsova, Victor I. Seledtsov, Ayana B. Dorzhieva, Elena A. Blinova, Adas Darinskas, Elena A. Prokopyeva and Alexei A. von Delwig

Pharmaceuticals 2025, 18(10), 1520; https://doi.org/10.3390/ph18101520 - 10 Oct 2025

Viewed by 86

Abstract

Background: A comparative study was conducted to evaluate the potential of extracellular, tumor-derived microvesicles (MVs)s in promoting kidney regeneration. Methods: MVs were collected from L929 sarcoma, LLC, and B16 melanoma cells, and mesenchymal stem cells (MSCs). The regenerative activity of MVs was evaluated [...] Read more.

Background: A comparative study was conducted to evaluate the potential of extracellular, tumor-derived microvesicles (MVs)s in promoting kidney regeneration. Methods: MVs were collected from L929 sarcoma, LLC, and B16 melanoma cells, and mesenchymal stem cells (MSCs). The regenerative activity of MVs was evaluated in an experimental murine model of chronic kidney injury (CKI). Results: Both tumor-derived MVs (T-MVs) and MSC-derived MVs (MSC-MVs) significantly improved kidney function and histological structure. Specifically, the height of collecting tubules in the middle third of the renal medulla returned to normal levels following MV treatment. Both T-MVs and MSC-MVs reduced the proportion of pro-inflammatory CD4+CD44+ T cells in renal cell infiltrates and spleens of CKI mice. Furthermore, treatment with these MVs increased the number of natural CD4+CD25+FoxP3+ regulatory T cells in the spleen, indicating their immunomodulatory effects. Conclusions: These findings suggest that T-MVs, similar to MSC-MVs, possess a universal capacity to promote kidney tissue regeneration and exert anti-inflammatory immunomodulatory effects. Full article

(This article belongs to the Special Issue Organ Regeneration by Application of Biomaterials and Stem Cells Technology Tools)

► Show Figures

Figure 1

24 pages, 2042 KB

Open AccessReview

Thermogenic Targets for Obesity Management in the Era of Incretin-Based Therapies

by Sahar Soliman, Rebecca Andrews-Dickert, Petra Rocic and Mihail Mitov

Pharmaceuticals 2025, 18(10), 1519; https://doi.org/10.3390/ph18101519 - 10 Oct 2025

Viewed by 125

Abstract

The global rise in obesity continues to outpace advances in pharmacologic treatment. While incretin-based therapies have demonstrated significant efficacy in promoting weight loss, their widespread use remains limited by gastrointestinal side effects, long-term tolerability concerns, and access issues. Additionally, sustaining weight loss over [...] Read more.

The global rise in obesity continues to outpace advances in pharmacologic treatment. While incretin-based therapies have demonstrated significant efficacy in promoting weight loss, their widespread use remains limited by gastrointestinal side effects, long-term tolerability concerns, and access issues. Additionally, sustaining weight loss over time poses an ongoing clinical challenge. These limitations highlight the need for alternative or complementary pharmacologic strategies. One such approach involves stimulating thermogenesis, particularly through the activation of brown and beige adipose tissue. This narrative review focuses on β3 adrenergic receptors as key mediators of browning and thermogenic energy expenditure. We review preclinical and clinical data, address pharmacokinetic and delivery challenges, and assess the translational potential of targeting thermogenesis in the management of obesity. Future directions are proposed to guide the development of safe and effective therapies that utilize this underexplored pharmacologic pathway. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Obesity, 2nd Edition)

► Show Figures

Graphical abstract

19 pages, 2617 KB

Open AccessReview

Insights into the Therapeutic Use of Kalanchoe pinnata Supplement in Diabetes Mellitus

by Felix Omoruyi, Lauren Tatina, Lizette Rios, Dewayne Stennett and Jean Sparks

Pharmaceuticals 2025, 18(10), 1518; https://doi.org/10.3390/ph18101518 - 10 Oct 2025

Viewed by 123

Abstract

Kalanchoe pinnata, commonly known as the “miracle plant” or “life plant”, is a succulent species traditionally used for various health conditions. Recent research investigations have intensified interest in this species due to its diverse repertoire of bioactive constituents, including flavonoids, alkaloids, triterpenes, [...] Read more.

Kalanchoe pinnata, commonly known as the “miracle plant” or “life plant”, is a succulent species traditionally used for various health conditions. Recent research investigations have intensified interest in this species due to its diverse repertoire of bioactive constituents, including flavonoids, alkaloids, triterpenes, and glycosides. These compounds have been associated with multiple therapeutic effects, notably antioxidant, anti-inflammatory, and antidiabetic activities. Although several studies have highlighted the positive effects of the extracts of K. pinnata on key factors contributing to the pathophysiology and complications of diabetes mellitus, a systematic overview focusing on the use of these extracts and their bioactive constituents in the management of the disease is lacking. This literature review summarizes the phytochemical composition, traditional uses, and recent scientific data supporting the antidiabetic potential of K. pinnata, with a particular focus on its effects on glycemic control, as well as inflammatory and oxidative homeostasis, toxicity, safety, and potential clinical implications. The phytochemical constituents discussed include quercetin, kaempferol, apigenin, epigallocatechin gallate (EGCG), avicularin, and bufadienolides, along with a presentation of representative structures. The review also covers the potential mechanisms of action in diabetes mellitus. The survey of available literature highlights the effects of K. pinnata on indices of diabetes mellitus, including enhancing insulin sensitivity, mitigating oxidative stress and inflammation, lowering blood glucose levels, and the potential adverse effects. These results point to the promising prospect for K. pinnata use in the management of diabetes mellitus and its associated complications, while underscoring the need for more rigorous investigations, including well-controlled clinical trials. Full article

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

► Show Figures

Figure 1

32 pages, 1390 KB

Open AccessReview

Discovery of Personalized Treatment for Immuno-Metabolic Depression—Focus on 11beta Hydroxysteroid Dehydrogenase Type 2 (11betaHSD2) and Toll-like Receptor 4 (TLR4) Inhibition with Enoxolone

by Harald Murck

Pharmaceuticals 2025, 18(10), 1517; https://doi.org/10.3390/ph18101517 - 10 Oct 2025

Viewed by 94

Abstract

Treatment options for major depression are limited: only about one-third of patients achieve remission with first line treatments with no established predictive markers. Parameters associated with treatment refractory depression, including metabolic markers (increased BMI, increased triglyceride levels), inflammation markers (C-reactive protein, CRP), autonomic [...] Read more.

Treatment options for major depression are limited: only about one-third of patients achieve remission with first line treatments with no established predictive markers. Parameters associated with treatment refractory depression, including metabolic markers (increased BMI, increased triglyceride levels), inflammation markers (C-reactive protein, CRP), autonomic disturbances (reduced blood pressure, reduced heart rate variability), and brain morphology changes (increased volume of the choroid plexus and brain ventricle volumes), may serve such purpose. These features can be linked mechanistically to an increase in aldosterone plasma concentration due to a reduced mineralocorticoid receptor (MR) sensitivity. The primary CNS target of aldosterone is the nucleus of the solitary tract (NTS), which is also the entry point of the vagus nerve. This nucleus integrates signals from endocrine, inflammatory, chemoreceptive, and physiological parameters, including blood pressure. In search of a mechanism to overcome this pathology, we identified a molecule which is derived from the licorice plant glycyrrhiza glabra, namely glycyrrhizin and its biologically active metabolite enoxolone. These molecules potentially reverse the above-described pathology. They inhibit the enzyme 11beta hydroxysteroid-dehydrogenase type 2 (11betaHSD2) and the toll-like receptor 4 (TLR4). 11betaHSD2 regulates the activity of the mineralocorticoid receptor (MR) by degrading cortisol/corticosterone, which allows aldosterone to bind to the MR. TLR4 is the ligand for lipopolysaccharide (LPS, endotoxin) and trigger of innate immunity. Consequently, patients with increased inflammation markers, increased aldosterone, or low blood pressure may preferentially benefit from the treatment with glycyrrhizin/enoxolone. Importantly, these patients can be identified BEFORE treatment is initiated. Clinically, patients sharing these biological indicators are primarily young females or patients with a history of childhood trauma. A combination of enoxolone with standard antidepressants may therefore avoid a trial-and-error approach and allow to achieve recovery faster. Full article

(This article belongs to the Special Issue Discovery of Novel Antidepressants and Anxiolytics)

► Show Figures

Graphical abstract

19 pages, 7053 KB

Open AccessArticle

Investigating the Therapeutic Mechanisms of Shen-Ling-Bai-Zhu-San in Type 2 Diabetes and Ulcerative Colitis Comorbidity: A Network Pharmacology and Molecular Simulation Approach

by Qian Yu, Shijie Sun, Tao Han, Haishui Li, Fan Yao, Dongsheng Zong and Zuojing Li

Pharmaceuticals 2025, 18(10), 1516; https://doi.org/10.3390/ph18101516 - 10 Oct 2025

Viewed by 88

Abstract

Objectives: Shen-Ling-Bai-Zhu-San (SLBZS) is a classical traditional Chinese herbal formula with spleen-invigorating and dampness-resolving properties. Recent pharmacological studies suggest its potential to regulate immune and metabolic disorders. Type 2 diabetes mellitus (T2D) and ulcerative colitis (UC) often coexist as comorbidities characterized by [...] Read more.

Objectives: Shen-Ling-Bai-Zhu-San (SLBZS) is a classical traditional Chinese herbal formula with spleen-invigorating and dampness-resolving properties. Recent pharmacological studies suggest its potential to regulate immune and metabolic disorders. Type 2 diabetes mellitus (T2D) and ulcerative colitis (UC) often coexist as comorbidities characterized by chronic inflammation, microbial imbalance, and insulin dysregulation, yet effective therapies remain limited. This study aimed to investigate the molecular mechanisms through which SLBZS may benefit T2D–UC comorbidity. Methods: An integrative multi-omics strategy was applied, combining network pharmacology, structural bioinformatics, and ensemble molecular docking–dynamics simulations. These complementary approaches were used to identify SLBZS bioactive compounds, predict their putative targets, and examine their interactions with disease-related biological networks. Results: The analyses revealed that flavonoids in SLBZS act on the SLC6A14/PI3K–AKT signaling axis, thereby modulating immune responses and improving insulin sensitivity. In addition, SLBZS was predicted to regulate the NF-

κ

B/MAPK signaling pathways, key hubs linking inflammation and metabolic dysfunction in T2D–UC. These dual actions suggest that SLBZS can intervene in both inflammatory and metabolic processes. Conclusions: SLBZS demonstrates promising therapeutic potential for T2D–UC by targeting interconnected immune–metabolic networks. These findings not only provide mechanistic insights bridging traditional therapeutic concepts with modern pharmacology but also establish a theoretical basis for future experimental validation and clinical application. Full article

(This article belongs to the Special Issue Emerging Therapies for Diabetes and Obesity)

► Show Figures

Figure 1

15 pages, 2054 KB

Open AccessArticle

Paliurus ramosissimus Leaf Extract Inhibits Adipocyte Differentiation In Vitro and In Vivo High-Fat Diet-Induced Obesity Through PPARγ Suppression

by Shin-Hye Kim, Tae Hyun Son, Hye-Lim Shin, Dongsoo Kim, Gwang Hun Park, Jeong Won Seo, Hwan-Gyu Kim and Sik-Won Choi

Pharmaceuticals 2025, 18(10), 1515; https://doi.org/10.3390/ph18101515 - 10 Oct 2025

Viewed by 103

Abstract

Background/Objectives: Obesity, defined by the excessive accumulation of adipose tissue, is associated with an increased risk of type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Obesity treatments based on natural products are receiving increasing attention as viable alternatives to conventional [...] Read more.

Background/Objectives: Obesity, defined by the excessive accumulation of adipose tissue, is associated with an increased risk of type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Obesity treatments based on natural products are receiving increasing attention as viable alternatives to conventional treatments. Methods: To investigate the anti-obesity effects of Paliurus ramosissimus leaf extract (PRLE) in vitro and in vivo, we conducted studies using 3T3-L1 pre-adipocytes. The in vivo studies used high-fat diet (HFD)-fed C57BL/6 mice. PRLE effects were assessed through Oil Red O staining, RT-qPCR, Western blot, and morphological analysis of adipose tissue. Results: PRLE significantly reduced lipid accumulation in 3T3-L1 cells without cytotoxicity. PRLE treatment decreased mRNA expression of adipogenic genes (PPARγ, C/EBPα, FABP4, and leptin) and protein levels of adipogenesis-related markers. In HFD-fed mice, PRLE administration significantly reduced body weight gain (p < 0.001), decreased adipose tissue mass, and diminished the weight and size of white adipose tissue. Conclusions: PRLE exhibits anti-obesity effects both in vitro and in vivo, suggesting its potential as a therapeutic agent for obesity prevention. Full article

(This article belongs to the Section Natural Products)

► Show Figures

Figure 1

25 pages, 2163 KB

Open AccessArticle

Rational Function-Based Approach for Integrating Tableting Reduced-Order Models with Upstream Unit Operations: Lubricants and Glidants Case Study

by Sunidhi Bachawala, Dominik Tomasz Nasilowski and Marcial Gonzalez

Pharmaceuticals 2025, 18(10), 1514; https://doi.org/10.3390/ph18101514 - 9 Oct 2025

Viewed by 140

Abstract

Background/Objectives: Glidants and lubricants are commonly used pharmaceutical excipients that enhance powder flowability and reduce inter-particle friction, respectively, but they also negatively impact critical quality attributes such as tablet tensile strength and drug release rate. Quantifying these effects is essential as the [...] Read more.

Background/Objectives: Glidants and lubricants are commonly used pharmaceutical excipients that enhance powder flowability and reduce inter-particle friction, respectively, but they also negatively impact critical quality attributes such as tablet tensile strength and drug release rate. Quantifying these effects is essential as the pharmaceutical industry transitions from batch to continuous manufacturing. Methods: This study develops a rational-function-based modeling approach to capture the effects of lubricants and glidants on tableting. The framework automatically identifies upstream critical material attributes and process parameters, such as excipient concentration and mixing time, and describes their coupling to first and second orders. Reduced-order models were constructed to evaluate the influence of these variables on the four stages of powder compaction—die filling, compaction, unloading, and ejection—using formulations composed of 10% acetaminophen, microcrystalline cellulose, and varying small concentrations of magnesium stearate or colloidal silica. Tablets were fabricated across a wide range of relative densities by varying dosing position and turret speed. Results: The modeling approach successfully quantified the effects of lubricant and glidant mixing conditions on each compaction stage, providing mechanistic insight into how upstream conditions propagate through the tableting process and influence critical quality attributes. Conclusions: Overall, the rational-function-based framework offers a systematic approach to quantify and predict the impact of lubricants and glidants on tablet performance, thereby enhancing product and process understanding in continuous manufacturing. Full article

(This article belongs to the Special Issue Pharmaceutical Process Engineering: Experimental and Computational Innovation)

► Show Figures

Graphical abstract

18 pages, 3814 KB

Open AccessArticle

Daflon Enhances Morphine Analgesia and Mitigates Tolerance in a Rat Neuropathic Pain Model

by Lokesh Kumar Mende, Meng-Lin Lee, Yaswanth Kuthati, Shu-Yi Koh and Chih-Shung Wong

Pharmaceuticals 2025, 18(10), 1513; https://doi.org/10.3390/ph18101513 - 9 Oct 2025

Viewed by 190

Abstract

Objective: Morphine is a widely used analgesic for severe pain, but tolerance is a major challenge in long-term pain management. This study examined the potential of Daflon^® to enhance morphine’s pain-relieving effects and to reduce tolerance in a rat model with neuropathic [...] Read more.

Objective: Morphine is a widely used analgesic for severe pain, but tolerance is a major challenge in long-term pain management. This study examined the potential of Daflon^® to enhance morphine’s pain-relieving effects and to reduce tolerance in a rat model with neuropathic pain induced by partial sciatic nerve transection (PSNT). Methods: Male Wistar rats were divided into five groups: (1) Sham + Saline, (2) PSNT + Saline, (3) PSNT + morphine, (4) PSNT + Daflon, and (5) PSNT + morphine + Daflon. Morphine tolerance was induced through continuous intrathecal infusion (15 µg/µL/h, i.t.) for 7 days, starting on day 7 post-PSNT, while Daflon was administered orally (50 mg/kg/day, oral) for 7 days. Pain relief was assessed using tail-flick and paw withdrawal on days 1, 4, and 7 after osmotic pump implantation. Spinal cords were collected for immunohistochemistry to analyze glial expression, and serum biomarkers (TNF-α, IL-1β, IL-6, and IL-10) were measured to evaluate neuroinflammation. Results: The results showed that oral Daflon significantly enhanced morphine’s analgesic effects, evidenced by improved pain thresholds in all behavioral tests. Moreover, Daflon reduced morphine tolerance. Mechanistically, Daflon upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and activated heme oxygenase-1 (HO-1), reducing oxidative stress and modulating neuroinflammation through glial regulation. Combining morphine and Daflon reduces pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and enhances anti-inflammatory IL-10 serum level, showing a synergistic effect in managing neuropathic pain with greater efficacy and lower drug dependence. Histology and immunohistochemistry evaluations further confirmed that morphine and Daflon co-treatment substantially reduced mononuclear cell infiltration, astrocyte activation (as indicated by GFAP expression), and microglial activation (as indicated by Iba-1 expression) compared to single treatment. Conclusions: Our findings suggest that dual therapy synergistically targets both oxidative stress and inflammatory pathways, leading to stronger neuroprotection and pain relief. Importantly, the combination approach may allow for lower opioid dosages, minimizing the risks of opioid-related side effects. Overall, morphine and Daflon co-administration offers a promising and safer strategy for managing neuropathic pain and preserving spinal cord integrity. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Pharmaceuticals, Volume 18, Issue 10 (October 2025) – 118 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI