Pharmaceuticals

28 pages, 1818 KB

Open AccessReview

Advances in Methods for Accurate Prediction of RNA–Small Molecule Binding Sites: From Isolated to AI-Integrated Strategies

by Jiaming Gao, Chen Zhuo, Chengwei Zeng, Haoquan Liu and Yunjie Zhao

Pharmaceuticals 2025, 18(10), 1593; https://doi.org/10.3390/ph18101593 - 21 Oct 2025

Viewed by 703

Abstract

Predicting RNA–small molecule binding sites is essential for developing RNA-targeted drugs. Identifying these sites experimentally is often costly, making computational methods essential for drug discovery. While traditional approaches rely on limited information, recent AI advancements allow the integration of diverse features, improving prediction [...] Read more.

Predicting RNA–small molecule binding sites is essential for developing RNA-targeted drugs. Identifying these sites experimentally is often costly, making computational methods essential for drug discovery. While traditional approaches rely on limited information, recent AI advancements allow the integration of diverse features, improving prediction accuracy. As methods for predicting RNA–small molecule binding sites continue to evolve, this review provides a timely overview of recent developments. It systematically traces the evolution from physics-based, isolated strategies to AI-integrated approaches, explains the fundamental principles behind different features, compares the tendencies of various features between binding and non-binding sites, evaluates the performance of approaches using different feature combinations on various test sets, and outlines remaining opportunities and challenges, offering guidance for researchers aiming for higher prediction accuracy. Full article

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

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29 pages, 2256 KB

Open AccessReview

Cyclodextrins as Active Therapeutic Agents: Beyond Their Role as Excipients

by Andreea Silvia Pirvu, Renata-Maria Varut, Diana-Maria Trasca, George Alin Stoica, Kristina Radivojevic, Sirbulet Carmen, Cristian Cosmin Arsenie and Cristina Popescu

Pharmaceuticals 2025, 18(10), 1592; https://doi.org/10.3390/ph18101592 - 21 Oct 2025

Viewed by 974

Abstract

Cyclodextrins (CDs) have traditionally been recognized as excipients that enhance solubility and stability of drugs. However, growing evidence shows that CDs themselves can act as active therapeutic agents. Their unique supramolecular properties enable them to interact with biological membranes, mobilize cholesterol, and modulate [...] Read more.

Cyclodextrins (CDs) have traditionally been recognized as excipients that enhance solubility and stability of drugs. However, growing evidence shows that CDs themselves can act as active therapeutic agents. Their unique supramolecular properties enable them to interact with biological membranes, mobilize cholesterol, and modulate immune responses. This review highlights four therapeutic areas where CDs demonstrate particular promise. First, in gene and mRNA therapy, cationic CD derivatives form nanoparticles that protect nucleic acids, promote endosomal escape, and achieve targeted delivery. Second, in neurodegenerative disorders such as Niemann–Pick type C and Alzheimer’s disease, hydroxypropyl-β-CD facilitates cholesterol clearance and reduces pathological lipid accumulation. Third, in detoxification, the γ-CD derivative sugammadex exemplifies a clinically approved agent that encapsulates neuromuscular blockers to reverse anesthesia. Finally, CDs have emerged as safe vaccine adjuvants, inducing robust systemic and mucosal immunity with reduced IgE responses compared to alum. Together, these examples illustrate a paradigm shift: CDs are not only versatile excipients but also active molecules with direct therapeutic effects. Future translation will require careful optimization of safety, scalability, and regulatory compliance, but CDs are poised to contribute meaningfully to next-generation medicines. Full article

(This article belongs to the Section Pharmaceutical Technology)

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41 pages, 4538 KB

Open AccessArticle

Polyprenylated Acylphloroglucinols from Hypericum rochelii and Hypericum olympicum—Cytotoxic Effects on Non-Tumorigenic Cell Lines and Antibacterial Potential

by Yana Ilieva, Maya M. Zaharieva, Lyudmila Dimitrova, Mila D. Kaleva, Teodor Marinov, Lili I. Dobreva, Tanya Chan Kim, Zlatina Kokanova-Nedialkova, Iliyan Trayanov, Sofia Titorenkova, Stanislava S. Boyadzhieva, Svetla Danova, Paraskev Nedialkov and Hristo Najdenski

Pharmaceuticals 2025, 18(10), 1591; https://doi.org/10.3390/ph18101591 - 21 Oct 2025

Viewed by 440

Abstract

Objectives: Research on the antimicrobial effect of Hypericum plant constituents is very rarely accompanied by studies of the cytotoxic effect on cell lines. In the current study, besides microbiological tests, an investigation of the cytotoxicity of Hypericum active ingredients on five non-tumorigenic [...] Read more.

Objectives: Research on the antimicrobial effect of Hypericum plant constituents is very rarely accompanied by studies of the cytotoxic effect on cell lines. In the current study, besides microbiological tests, an investigation of the cytotoxicity of Hypericum active ingredients on five non-tumorigenic cell lines, as well as research into the effect on other factors of host homeostasis, was performed. Methods: The main methods applied included an MTT assay, the broth microdilution method (BMD), real-time PCR, live cell imaging with Hoechst dye, Western blot, an enzyme-linked immunosorbent assay (ELISA), and skin irritation test on rabbits. Results: The mean inhibitory concentrations (IC₅₀) of six selected agents—previously phytochemically characterized extracts and compounds—ranged from 0.63 to 48 µg/mL. Due to their strong antimicrobial effect and favorable cytotoxic profile, the extract RochC from Hypericum rochelii and the compound olympiforin B from Hypericum olympicum were selected for subsequent studies at their previously determined minimum inhibitory concentrations (MICs) against Staphylococcus aureus—0.625 and 1 µg/mL, respectively. These doses were lower than their IC₅₀ values and the maximum tolerated concentrations (MTCs), according to ISO 10993-5, Annex C, for fibroblast cells, including a human gingival line. The MIC values of RochC and Olympiforin B against the cariogenic Streptococcus mutans were 6 and 3 µg/mL, respectively, values lower than the IC₅₀ values of the gingival cells. Olympiforin B inhibited the gene expression of the staphylococcal biofilm-related genes icaA and icaD, while RochC induced icaA and had a versatile effect on icaD. The MIC values for lactobacilli strains were higher than for S. aureus. The phytoconstituents did not cause cytopathic effects or apoptosis in CCL-1 fibroblasts at 2 × MIC. However, the agents at 1 × MIC significantly induced Atg5 and Atg7, proteins related to autophagy. Cytochrome P450 was not induced in liver cells, with the exception of a dose of 2 × MIC of RochC. The agents did not irritate rabbit skin in vivo at a dose of even 10 × MIC. Conclusions: The extract and compound have potential for further pharmacological development. Full article

(This article belongs to the Section Medicinal Chemistry)

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16 pages, 1280 KB

Open AccessSystematic Review

Efficacy of Lamotrigine in the Treatment of Unipolar and Bipolar Depression: Meta-Analysis of Acute and Maintenance Randomised Controlled Trials

by Danilo Arnone, Linda Östlundh, Meena Mosa, Brianne MacDonald, Jonathan Oldershaw, Tarik Qassem and Allan H. Young

Pharmaceuticals 2025, 18(10), 1590; https://doi.org/10.3390/ph18101590 - 21 Oct 2025

Viewed by 1808

Abstract

Background/Objectives: Lamotrigine has been widely investigated in the treatment and prevention of the emergence of symptoms of depression in unipolar and bipolar depression. This work systematically appraises published and unpublished double-blind randomised controlled trials of lamotrigine to provide up-to-date guidance on the use [...] Read more.

Background/Objectives: Lamotrigine has been widely investigated in the treatment and prevention of the emergence of symptoms of depression in unipolar and bipolar depression. This work systematically appraises published and unpublished double-blind randomised controlled trials of lamotrigine to provide up-to-date guidance on the use of lamotrigine in the presence of depressive symptoms. Methods: Systematic searches identified 32 randomised controlled trials, of which 24 were included in the meta-analysis, involving 2257 patients and 2320 controls. Results: Evidence supports the use of lamotrigine in the acute phase of bipolar depression in monotherapy vs. placebo (SMD: 0.155; CI: 0.005–0.305) in the absence of significant heterogeneity and small study effects. In the prophylaxis of bipolar depression, lamotrigine reduced the risk of the emergence of depressive symptoms (RR: 0.78; CI: 0.63, 0.98) and prolonged the duration of symptoms survival (RR: 1.59; CI: 1.19, 2.11) compared to placebo, with no evidence of publication and small study bias. Lamotrigine was not found to be superior to lithium in the acute treatment and prophylaxis of bipolar depression. In the treatment of unipolar depressive episodes, with the inclusion in the analyses of three unpublished studies, lamotrigine was not superior to placebo in monotherapy and as adjunct treatment. There were no maintenance studies in unipolar depression. Conclusions: There is evidence supporting the use of lamotrigine in monotherapy as acute and prophylactic treatment of bipolar depression. Evidence of the use of lamotrigine in unipolar disorders is lacking. PROSPERO registration ID: CRD42025633709. Full article

(This article belongs to the Special Issue Affective Disorders Psychopharmacology)

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26 pages, 3991 KB

Open AccessArticle

Unraveling the Antihyperglycemic Effects of Dipeptyl Peptidase-4 Inhibitors in Rodents: A Multi-Faceted Approach Combining Effects on Glucose Homeostasis, Molecular Docking, and ADMET Profiling

by Raquel N. S. Roriz, Claudia J. P. Cardozo, Gabriela A. Freire, Caio B. R. Martins, Raimundo Rigoberto B. X. Filho, Landerson Lopes Pereira, Gisele F. P. Rangel, Tiago L. Sampaio, Lyanna R. Ribeiro, Gisele Silvestre Silva, Isabelle Maia, Deysi Viviana Tenazoa Wong, Daniele O. B. Sousa, Ariclécio Cunha de Oliveira, Eduardo Reina, Lidia Moreira Lima, Walter Peláez, Matheus Nunes da Rocha, Márcia Machado Marinho, Hélcio Silva dos Santos, Emmanuel Silva Marinho, Jane Eire Silva Alencar de Menezes, Fátima Regina Mena Barreto Silva, Kirley Marques Canuto, Nylane M. N. Alencar and Marisa Jadna Silva Frederico Show full author list Hide full author list

Pharmaceuticals 2025, 18(10), 1589; https://doi.org/10.3390/ph18101589 - 21 Oct 2025

Viewed by 528

Abstract

Background/Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. [...] Read more.

Background/Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. Methods: We evaluated the antihyperglycemic activity of β-aminohydrazine and β-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (Mus musculus). Results: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. Conclusions: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus. Full article

(This article belongs to the Special Issue Potential Therapeutic Targets for the Management of Diabetes Mellitus, Obesity and Cancer)

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18 pages, 1273 KB

Open AccessArticle

Comparative Safety of Empirical Antibiotic Classes in Newly Hospitalized COVID-19 Patients

by Kalynn Park, Sohyeon Park, Jung Yoon Choi, Chaeyoon Kim, Jeongha Yun, Jiyeon Bae, Ji Yun Bae, Kang-Il Jun, Jeong-Han Kim, Chung-Jong Kim, Hee Jung Choi and Sandy Jeong Rhie

Pharmaceuticals 2025, 18(10), 1588; https://doi.org/10.3390/ph18101588 - 21 Oct 2025

Viewed by 342

Abstract

Background: Empirical antibiotic use is common in hospitalized patients with COVID-19 despite the low prevalence of bacterial coinfection, raising concerns about antimicrobial resistance and inappropriate prescribing. However, the comparative safety of commonly used antibiotic classes in this context remains unclear. Methods: [...] Read more.

Background: Empirical antibiotic use is common in hospitalized patients with COVID-19 despite the low prevalence of bacterial coinfection, raising concerns about antimicrobial resistance and inappropriate prescribing. However, the comparative safety of commonly used antibiotic classes in this context remains unclear. Methods: We conducted a retrospective cohort study using real-world clinical data standardized through the Observational Medical Outcomes Partnership Common Data Model from 1 January 2020 to 31 May 2025. Adults with confirmed COVID-19 who were administered empirical antibiotics on the admission day were included. Empirical antibiotic exposure was categorized as third-generation cephalosporins (3GCs), fluoroquinolones, or aminopenicillins with β-lactamase inhibitors (PEN–BLis). Results: Compared with 3GCs, fluoroquinolone use was associated with significantly higher risks of mechanical ventilation (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.12–2.00), ICU admission (HR: 1.54; 95% CI: 1.10–2.15), vasopressor use (HR: 1.35; 95% CI: 1.11–1.63), all-cause in-hospital mortality (HR: 1.55; 95% CI: 1.22–1.96), and the composite outcome (HR: 1.32; 95% CI: 1.10–1.60). PEN–BLis showed no significant differences from 3GCs across outcomes. Conclusions: Empirical fluoroquinolone use at COVID-19 admission may be associated with greater risks of critical care interventions and in-hospital mortality compared to those of 3GCs. These findings highlight the need for careful patient selection and clinical judgment when initiating empirical antibiotic therapy for viral respiratory infections such as COVID-19. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 5136 KB

Open AccessArticle

Anti-Trichomonas vaginalis Activity of Triterpenes from Tagetes nelsonii Greenm

by Mario Alberto Hernández-Torres, Sara García-Davis, José J. Fernández, Ana R. Diaz-Marrero, Magda Elizabeth Hernández-García, Irma Edith Carranza-Torres and Ezequiel Viveros-Valdez

Pharmaceuticals 2025, 18(10), 1587; https://doi.org/10.3390/ph18101587 - 21 Oct 2025

Viewed by 538

Abstract

Background: Trichomonas vaginalis is the causative agent of human trichomoniasis, the most common non-viral sexually transmitted infection. This disease is associated with an increased susceptibility to HIV and HPV infections. Currently, resistance to metronidazole (MTZ), the main drug used for treatment, has been [...] Read more.

Background: Trichomonas vaginalis is the causative agent of human trichomoniasis, the most common non-viral sexually transmitted infection. This disease is associated with an increased susceptibility to HIV and HPV infections. Currently, resistance to metronidazole (MTZ), the main drug used for treatment, has been reported in up to 9.6% of cases; additionally, the compound is also associated with adverse side effects. Therefore, it is urgent to identify new treatment options. Objective: In this study, we investigated for the first time the in vitro and in silico activity against T. vaginalis of betulin and stigmasterol isolated from Tagetes nelsonii Greenm, as well as their hemolytic activity. Methods: Plant specimen was collected in Chiapas, Mexico. Hexane and methanol extracts were prepared through sonication-assisted maceration. The antiprotozoal and hemolytic activities were evaluated in vitro against Trichomonas vaginalis trophozoites and human erythrocytes. The most active extract was fractionated using chromatographic techniques in a bioassay-guided study. The active metabolites were identified by ¹H and ¹³C-NMR spectroscopy, and their biological activity was further assessed in silico against lactate dehydrogenase (LDH), pyruvate ferredoxin oxidoreductase (PFOR) methionine gamma-lyase (MGL) and purine nucleoside phosphorylase (PNP) T. vaginalis enzymes. Results: Both triterpenes showed anti-trichomonal activity and no hemolytic activity at 100 µg/mL. Molecular docking studies predicted promising interactions of triterpenes with T. vaginalis drug target proteins, TvpFOR and TvLDH. Conclusions: Our results revealed that betulin and stigmasterol are potential molecules for the development of new trichomonacidal therapies against T. vaginalis. Full article

(This article belongs to the Special Issue Recent Advancements in the Development of Antiprotozoal Agents)

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2 pages, 153 KB

Open AccessCorrection

Correction: Onodera et al. Prognostic Factors and Talaporfin Sodium Concentration in Photodynamic Therapy for Recurrent Grade 4 Glioma. Pharmaceuticals 2025, 18, 583

by Mikoto Onodera, Shuji Kitahara, Yasuto Sato, Takakazu Kawamata, Yoshihiro Muragaki and Ken Masamune

Pharmaceuticals 2025, 18(10), 1586; https://doi.org/10.3390/ph18101586 - 21 Oct 2025

Viewed by 194

Abstract

In the original publication [...] Full article

20 pages, 5232 KB

Open AccessArticle

Enhanced Skin Permeation of Diclofenac Sodium Using Mango Seed Kernel Starch Nanoparticles

by Sesha Rajeswari Talluri, Namrata S. Matharoo, Nirali Dholaria, Nubul Albayati, Shali John and Bozena Michniak-Kohn

Pharmaceuticals 2025, 18(10), 1585; https://doi.org/10.3390/ph18101585 - 20 Oct 2025

Viewed by 554

Abstract

Background: Mango seed kernels, an agro-industrial waste byproduct, constitute approximately 40–50% of the fruit’s weight and serve as a substantial source of starch. There are only a few reported studies on the pharmaceutical applications of Mango Seed Kernel Starch (MSKS) and drug carriers [...] Read more.

Background: Mango seed kernels, an agro-industrial waste byproduct, constitute approximately 40–50% of the fruit’s weight and serve as a substantial source of starch. There are only a few reported studies on the pharmaceutical applications of Mango Seed Kernel Starch (MSKS) and drug carriers produced from this source. This study aims to isolate starch from mango seed kernels (MSKS), prepare drug-loaded mango seed kernel starch nanoparticles (MSKSNPs), and study the in vitro transdermal permeation. Methods: The MSKS was prepared using the alkaline method and freeze-dried. The prepared starch was analyzed for physicochemical properties relative to corn starch. The mango seed kernel starch nanoparticles (MSKSNPs) were prepared using mild alkali hydrolysis and the ultrasonication method. The model drug selected for this study was diclofenac sodium (DS), a commonly prescribed non-steroidal anti-inflammatory drug. Results: The average particle size of the drug-loaded nanoparticles was 140.0 ± 3.6 nm, with a PDI of 0.42 ± 0.03. The Transmission Electron Microscopy images confirmed the globular structure of MSKSNPs. X-ray Diffraction revealed that the diclofenac crystal size decreased to 14 nm from 33 nm in the pure drug, confirming the amorphous nature of MSKSNPs. The drug-loaded MSKSNPs showed a % encapsulation efficiency of 92.4 ± 3.7 and % drug loading of 31.08 ± 0.96. The cumulative drug released from MSKSNPs after 6 h, 12 h, and 24 h was found to be 25.58 ± 1.30, 59.68 ± 2.98, and 127.5 ± 6.4 μg/cm^2, respectively, which was more than the ethanolic drug solution with statistical significance (p-value < 0.01) along with enhanced skin retention. Conclusions: MSKSNPs were efficiently synthesized using mild alkali hydrolysis and ultrasonication, showing enhanced transdermal delivery. Skin retention was significantly higher in MSKSNPs (p-value < 0.05). The cytotoxic studies revealed that both formulations exhibit similar dose-dependent cytotoxicity, with no significant difference (p > 0.05) in their potency under the tested conditions. Full article

(This article belongs to the Section Natural Products)

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24 pages, 2218 KB

Open AccessArticle

An Efficacy- and In Vivo Exposure-Oriented Integrated Study to Investigate the Effective Components of Qishen Granule

by Yueting Li, Tengteng Wang, Chao Cheng, Yingying Huo, Ying Tan, Yifan Xu, Jiale Gao, Jie Liu and Hongbin Xiao

Pharmaceuticals 2025, 18(10), 1584; https://doi.org/10.3390/ph18101584 - 20 Oct 2025

Viewed by 451

Abstract

Background: Qishen granule (QSG) is a widely prescribed herbal formula for the treatment of chronic heart failure. The mechanisms of action of QSG have been clarified; however, the effective substances remain unclear. This lack of clarity hinders quality control and the consistency [...] Read more.

Background: Qishen granule (QSG) is a widely prescribed herbal formula for the treatment of chronic heart failure. The mechanisms of action of QSG have been clarified; however, the effective substances remain unclear. This lack of clarity hinders quality control and the consistency of the clinical efficacy of QSG. Methods: In the present study, an integrated strategy for an efficacy- and in vivo exposure-oriented study involving metabolite profiling, molecular docking, in vitro bioassays, and in vivo pharmacokinetics was proposed for investigating the potentially effective components of QSG. Results: In total, 101 prototypes/metabolites were preliminarily identified and characterized by UHPLC-Q TOF-MS/MS. Molecular docking of the absorbed constituents with targeted proteins suggested that 49 potential components were highly related to chronic heart failure (CHF). Then, the effectiveness of these potential compounds was verified by the oxygen glucose deprivation/re-oxygenation (OGD/R)-induced H9c2 cell model. As a result, 14 active components were screened, and their median effective concentration (EC₅₀) was calculated and utilized to generate the weight coefficient for the bioeffect of each constituent. By exploring the kinetic parameters of the active compounds in a pharmacokinetic study, the exposure levels of these pharmacologically active compounds were determined by area under the curve (AUC_0→∞) calculations. Finally, by calculating the effect–constituent index (ECI) for each compound, five key active components (cryptochlorogenic acid, chlorogenic acid, isochlorogenic acid C, salvianolic acid B, and neochlorogenic acid), which possess both pharmacological activities and higher exposure levels, were revealed to be the key effective substances of QSG. Conclusions: This study is the first to combine pharmacological activities with in vivo exposure for investigating the effective components of QSG. The identification of key active components provides a foundation for improving the quality control of QSG in clinics. The efficacy- and in vivo exposure-oriented integrated method could provide reliable references for other traditional Chinese medicines (TCMs). Full article

(This article belongs to the Special Issue Natural Pharmaceutical Component Analysis)

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21 pages, 1974 KB

Open AccessReview

Mining Microbial Dark Matter: Advanced Cultivation Techniques for Bioactive Compound Discovery

by Minhui Ji, Bingda Ma, Jiayu Dong, Shan Liu, Ying Shi, Meiting Bu, Luoyi Wang and Ling Liu

Pharmaceuticals 2025, 18(10), 1583; https://doi.org/10.3390/ph18101583 - 20 Oct 2025

Viewed by 870

Abstract

The vast majority of microorganisms in the environment remain uncultured using conventional laboratory techniques, representing an immense untapped reservoir of genetic and chemical diversity. Recent innovations in cultivation strategies, combined with advances in metagenomics, single-cell genomics, and synthetic biology, have opened new avenues [...] Read more.

The vast majority of microorganisms in the environment remain uncultured using conventional laboratory techniques, representing an immense untapped reservoir of genetic and chemical diversity. Recent innovations in cultivation strategies, combined with advances in metagenomics, single-cell genomics, and synthetic biology, have opened new avenues for accessing and harnessing bioactive natural products from these previously inaccessible microorganisms. This review highlights recent methodological and technological advancements in the cultivation and identification of novel microorganisms, and showcases the resulting discoveries of new natural products, demonstrating their potential for drug development. Full article

(This article belongs to the Special Issue Cutting-Edge Biotechnologies and Applications of Natural Products in Drug R&D and Disease Treatment)

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1 pages, 135 KB

Open AccessRetraction

RETRACTED: Poma et al. In Vitro Modulation of P-Glycoprotein Activity by Euphorbia intisy Essential Oil on Acute Myeloid Leukemia Cell Line HL-60R. Pharmaceuticals 2021, 14, 111

by Paola Poma, Manuela Labbozzetta, Aro Vonjy Ramarosandratana, Sergio Rosselli, Marco Tutone, Maurizio Sajeva and Monica Notarbartolo

Pharmaceuticals 2025, 18(10), 1582; https://doi.org/10.3390/ph18101582 - 20 Oct 2025

Viewed by 308

Abstract

The journal has retracted the article “In Vitro Modulation of P-Glycoprotein Activity by Euphorbia intisy Essential Oil on Acute Myeloid Leukemia Cell Line HL-60R” [...] Full article

25 pages, 831 KB

Open AccessReview

The Multifaceted Antimicrobial Profile of Piperine in Infectious Disease Management: Current Perspectives and Potential

by Aristodemos-Theodoros Periferakis, Grigorios-Marios Adalis, Argyrios Periferakis, Lamprini Troumpata, Konstantinos Periferakis, Christiana Diana Maria Dragosloveanu, Ana Caruntu, Ilinca Savulescu-Fiedler, Serban Dragosloveanu, Andreea-Elena Scheau, Ioana Anca Badarau, Cristian Scheau and Constantin Caruntu

Pharmaceuticals 2025, 18(10), 1581; https://doi.org/10.3390/ph18101581 - 19 Oct 2025

Viewed by 1049

Abstract

Piperine is an alkaloid found in plants of the genus Piper, and particularly in P. nigrum. This compound has been under extensive research lately for its antimicrobial, antiviral, and also anti-inflammatory, anti-oxidant, anticancer, and positive metabolic properties. Regarding its antibacterial applications, current [...] Read more.

Piperine is an alkaloid found in plants of the genus Piper, and particularly in P. nigrum. This compound has been under extensive research lately for its antimicrobial, antiviral, and also anti-inflammatory, anti-oxidant, anticancer, and positive metabolic properties. Regarding its antibacterial applications, current data show that piperine is effective against Bacillus sphaericus, Bacterioides fragilis, Escherichia coli, Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus mutans, Pseudomonas aeruginosa, and Vibrio cholerae; its antifungal potency is exerted against Candida albicans and members of the Aspergillus family; antiviral activity has been documented against MERS-CoV, SARS-CoV2, EBOV, DENV, HCV, ZKV, and HPIV; and antiparasitic activity against Leishmania spp., Plasmodium spp., Trichomonas vaginalis, and Trypanosoma spp. While such applications are promising, more research is required to elucidate the mechanisms of action and to discover new ways of administration. Full article

(This article belongs to the Special Issue Natural Products for Therapeutic Potential)

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17 pages, 3759 KB

Open AccessArticle

Disproportionality Analysis of Oral Toxicities Associated with PI3K/AKT/mTOR Pathway Inhibitors Using the FAERS Database

by Monica Marni, Djamilla Simoens, Nicholas Romero, Walter Keith Jones and Simon Kaja

Pharmaceuticals 2025, 18(10), 1580; https://doi.org/10.3390/ph18101580 - 19 Oct 2025

Viewed by 612

Abstract

Background: Stomatitis is a common adverse event associated with targeted therapies for hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer, particularly those inhibiting the PI3K/AKT/mTOR pathway. While mTOR-inhibitor-associated stomatitis is well established, less is known about its occurrence with other kinase inhibitors in real-world [...] Read more.

Background: Stomatitis is a common adverse event associated with targeted therapies for hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer, particularly those inhibiting the PI3K/AKT/mTOR pathway. While mTOR-inhibitor-associated stomatitis is well established, less is known about its occurrence with other kinase inhibitors in real-world settings. We performed a pharmacovigilance disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) to evaluate stomatitis reports for alpelisib, capivasertib, everolimus, and palbociclib. Methods: Events were identified using four term sets—Stomatitis, Original Trial Terms (OTT), Comprehensive Trial Terms (CTT), and Stomatitis-Associated Main Terms (SAMT)—which reflect varying definitions and medical terminologies. Disproportionality analyses using reporting odds ratio (ROR), proportional reporting ratio (PRR), and Information Component (IC) were calculated with 95% confidence intervals. Results: All agents showed ROR and PRR >1, indicating higher odds and reporting proportions of stomatitis compared with other drugs. These findings were confirmed by IC analysis. Everolimus demonstrated the strongest association (ROR: 30.72 [29.61–31.88]), followed by alpelisib (ROR: 13.11 [11.79–14.58]) and palbociclib (ROR: 11.73 [11.35–12.11]). Capivasertib had the lowest reporting odds (ROR: 3.14 [1.81–5.43]), though limited by fewer reports. Differences between CTT and SAMT were minimal (~2%). Conclusions: These results support the use of the SAMT as an efficient screening tool. Furthermore, these findings underscore the need for optimized stomatitis detection and continued monitoring, particularly for PI3K and mTOR inhibitors, in both clinical trials and postmarketing surveillance. Full article

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

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17 pages, 2374 KB

Open AccessArticle

by Desirèe Speranza, Mariapia Marafioti, Martina Musarra, Vincenzo Cianci, Fausto Omero, Calogera Claudia Spagnolo, Marco Calabrò, Nicola Silvestris, Natasha Irrera and Mariacarmela Santarpia

Pharmaceuticals 2025, 18(10), 1574; https://doi.org/10.3390/ph18101574 - 19 Oct 2025

Viewed by 534

Abstract

Background: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs). However, post-marketing pharmacovigilance is crucial to identify real-world safety signals including sex-specific differences that may [...] Read more.

Background: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs). However, post-marketing pharmacovigilance is crucial to identify real-world safety signals including sex-specific differences that may not be evident in controlled trial settings. Methods: This analysis reviewed 845 individual case safety reports (ICSRs) from the EudraVigilance (EV) database between 1 January 2021, and 8 April 2025, involving NSCLC patients treated with sotorasib. Adverse drug reactions (ADRs) were assessed by sex, seriousness, outcome, and system organ class (SOC). Disproportionality analyses were conducted to detect sex-specific safety signals, and results were compared with data from the CodeBreaK200 RCT by using a two-proportion z-test. Results: Among the ICSRs, 49.2% involved male and 40.1% female patients. Serious ADRs accounted for 47.5% of cases, with females at higher risk (relative risk [RR] = 1.31; 95% confidence interval (CI): 1.22–1.40; p < 0.0001). The most frequently reported SOCs were neoplasms (15.8%), gastrointestinal disorders (15.3%), and hepatobiliary disorders (11.5%). Four sex-specific safety signals were identified: women had a significantly increased risk of cholestasis (RR = 3.37) and hepatotoxicity (RR = 3.01), while men were less likely to report decreased appetite (RR = 0.20) and rash (RR = 0.14). Real-world data showed lower reporting of diarrhea, fatigue, nausea, and liver enzyme elevations (p < 0.0001). Conclusions: Real-world pharmacovigilance supports the RCT findings and highlights sex-specific risks, thus emphasizing the importance of sex-aware monitoring and personalized toxicity management. Full article

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

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33 pages, 12187 KB

Open AccessArticle

A Hybrid In Silico Approach for Identifying Dual VEGFR/RAS Inhibitors as Potential Anticancer and Anti-Angiogenic Agents

by Alessia Bono, Gabriele La Monica, Federica Alamia, Dennis Tocco, Antonino Lauria and Annamaria Martorana

Pharmaceuticals 2025, 18(10), 1579; https://doi.org/10.3390/ph18101579 - 18 Oct 2025

Viewed by 447

Abstract

Background: Angiogenesis, the physiological process by which new blood vessels originate from pre-existing ones, can be triggered by tumor cells to promote the growth, survival, and progression of cancer. Malignant tumors require a constant blood supply to meet their needs for oxygen [...] Read more.

Background: Angiogenesis, the physiological process by which new blood vessels originate from pre-existing ones, can be triggered by tumor cells to promote the growth, survival, and progression of cancer. Malignant tumors require a constant blood supply to meet their needs for oxygen and nutrients, making angiogenesis a key process in tumor development. Its pathologic role is caused by the dysregulation of signaling pathways, particularly those involving VEGFR-2, a key mediator of angiogenesis, and the K-RAS G12C mutant, a promoter of VEGF expression. Given their critical involvement in tumor progression, these targets represent promising candidates for new cancer therapies. Methods and Results: In this study, we applied an in silico hybrid and hierarchical virtual screening approach to identify potential dual VEGFR-2/K-RAS G12C inhibitors with anticancer and antiangiogenic properties. To this end, we screened the National Cancer Institute (NCI) database through ADME filtering tools. The refined dataset was then submitted to the ligand-based Biotarget Predictor Tool (BPT) in a multitarget mode. Subsequently, structure-based analysis, including molecular docking studies on VEGFR and K-RAS G12C, was performed to investigate the interactions of the most promising small molecules with both targets. Conclusions: Finally, the molecular dynamics simulations suggested compound 737734 as a promising small molecule with high stability in complex with both VEGFR-2 and K-RAS G12C, highlighting its potential as a dual-target inhibitor for cancer therapy. Full article

(This article belongs to the Special Issue Application of Computer Simulation in Drug Design)

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42 pages, 1849 KB

Open AccessReview

Recommendations on the Clinical Application and Future Potential of α-Particle Therapy: A Comprehensive Review of the Results from the SECURE Project

by Valentina Di Iorio, Anna Sarnelli, Stefano Boschi, Maddalena Sansovini, Rosa Maria Genovese, Cipriana Stefanescu, Vlad Ghizdovat, Wael Jalloul, Jennifer Young, Jane Sosabowski, Petra Kolenc, Rachel Roberts, Govert de With, Dimitris Visvikis and Renata Mikolajczak

Pharmaceuticals 2025, 18(10), 1578; https://doi.org/10.3390/ph18101578 - 18 Oct 2025

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Abstract

This review comprehensively assesses the clinical applications and future potential of alpha-emitting radionuclides available for targeted alpha-particle therapy (TAT) in cancer treatment. The approval of radium-223 therapy in 2013 marked a significant advancement in alpha-emitting therapeutic radiopharmaceuticals, which are primarily used in treatment [...] Read more.

This review comprehensively assesses the clinical applications and future potential of alpha-emitting radionuclides available for targeted alpha-particle therapy (TAT) in cancer treatment. The approval of radium-223 therapy in 2013 marked a significant advancement in alpha-emitting therapeutic radiopharmaceuticals, which are primarily used in treatment of prostate cancer. The EU SECURE project was introduced as a major initiative to enhance the sustainability and safety of medical alpha-emitting radionuclides production in Europe. This literature review was conducted by a multidisciplinary team on selected radionuclides, including actinium-225, bismuth-213, astatine-211, lead-212, terbium-149, radium-223 and thorium-227. These were selected based on their clinical significance, as identified in the EU PRISMAP project and subsequent literature searches. The review process involved searching major databases using specific keywords related to alpha-emitter therapy and was limited to articles in English. For each selected radionuclide, the physical characteristics, the radiochemistry, and the pre-clinical and clinical studies are explored. Actinium-225 is the most widely studied alpha emitter, with several preclinical and clinical studies on prostate cancer and neuroendocrine tumours. Other types of tumours (such as glioblastoma) still require preclinical and clinical development. Bismuth-213 bound to antibodies, peptides and nanobodies has shown optimal results in preclinical and clinical studies, with increased median survival and no significant toxicity. Astatine-211 differs from most other α-emitters relevant to TAT, since it yields one α-particle per decay. This offers certain translational advantages, including the simplification of radiation dosimetry calculations and quality control (QC). Lead-212 has the advantage of being an in situ generator with likely widespread availability. Although clinical data are limited, the findings are promising at this stage. The unconventional production of Terbium-149 is the primary reason it has not yet progressed to clinical trials. Overcoming this production obstacle would allow more detailed preclinical investigations. Optimal results with Thorium-227-labelled agents have been observed in preclinical studies, including delays in cellular growth, multiple double-strand breaks and complete regression. Intermediate phase I trial results have also been reported, demonstrating safety and tolerability, as well as an objective response rate of 25%.: The results highlight the advantages of alpha particles in targeting cancer cells with minimal radiation to normal tissue, emphasising the need for high specificity and stability in delivery mechanisms, as well as suggesting that the full clinical potential of alpha particle therapy remains unexplored. Theranostic approach and dosimetric evaluations still represent relevant challenges. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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19 pages, 3307 KB

Open AccessArticle

Structure-Guided Discovery of Benzoic-Acid-Based TRPC6 Ligands: An Integrated Docking, MD, and MM-GBSA SAR Study: Potential Therapeutic Molecules for Autism Spectrum Disorder

by Nicolás Ignacio Silva, Gianfranco Sabadini, David Cabezas, Cristofer González, Paulina González, Jiao Luo, Cristian O. Salas, Marco Mellado, Marcos Lorca, Javier Romero-Parra and Jaime Mella

Pharmaceuticals 2025, 18(10), 1577; https://doi.org/10.3390/ph18101577 - 18 Oct 2025

Viewed by 452

Abstract

Background: TRPC6 is recognized as a therapeutically relevant cation channel, whose activation is governed by specific ligand–pocket interactions. Methods: An integrated in silico workflow was employed, comprising structure-based docking, 100-nanosecond molecular dynamics (MD) simulations, and MM-GBSA calculations. Benzoic-acid–based compounds were designed [...] Read more.

Background: TRPC6 is recognized as a therapeutically relevant cation channel, whose activation is governed by specific ligand–pocket interactions. Methods: An integrated in silico workflow was employed, comprising structure-based docking, 100-nanosecond molecular dynamics (MD) simulations, and MM-GBSA calculations. Benzoic-acid–based compounds were designed and prioritized for binding to the TRPC6 pocket, using a known literature agonist as a reference for benchmarking. Results: Within the compound series, BT11 was found to exhibit a representative interaction profile, characterized by a key hydrogen bond with Trp680 (~64% occupancy), persistent salt-bridge interactions with Lys676 and Lys698, and π–π stacking with Phe675 and Phe679. A favorable docking score (−11.45 kcal/mol) was obtained for BT11, along with a lower complex RMSD during MD simulations (0.6–4.8 Å), compared with the reference compound (0.8–7.2 Å). A reduction in solvent-accessible surface area (SASA) after ~60 ns was also observed, suggesting decreased water penetration. The most favorable binding energy was predicted for BT11 by MM-GBSA (−67.72 kcal/mol), while SOH95 also ranked highly and slightly outperformed the reference. Conclusions: These convergent computational analyses support the identification of benzoic-acid–derived chemotypes as potential TRPC6 ligands. Testable hypotheses are proposed, along with structure–activity relationship (SAR) guidelines, to inform experimental validation and guide the design of next-generation analogs. Full article

(This article belongs to the Special Issue Pharmacological Strategies to Modulate Symptoms in Autism Spectrum Disorders (ASD))

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20 pages, 611 KB

Open AccessReview

A Review on Phytochemistry, Ethnopharmacology, and Antiparasitic Potential of Mangifera indica L.

by Diana Mendonça, Yen-Zhi Tan, Yi-Xin Lor, Yi-Jing Ng, Abolghasem Siyadatpadah, Chooi-Ling Lim, Roghayeh Norouzi, Roma Pandey, Wenn-Chyau Lee, Ragini Bodade, Guo-Jie Brandon-Mong, Ryan V. Labana, Tajudeen O. Jimoh, Ajoy Kumar Verma, Tadesse Hailu, Shanmuga S. Sundar, Anjum Sherasiya, Sónia M. R. Oliveira, Ana Paula Girol, Veeranoot Nissapatorn and Maria de Lourdes Pereira Show full author list Hide full author list

Pharmaceuticals 2025, 18(10), 1576; https://doi.org/10.3390/ph18101576 - 18 Oct 2025

Viewed by 1090

Abstract

Parasitic infections remain a major global health challenge, particularly in resource-limited settings where they are closely tied to poverty and inadequate sanitation. The increasing emergence of drug resistance and the limited accessibility of current therapies highlight the urgent need for novel, safe, and [...] Read more.

Parasitic infections remain a major global health challenge, particularly in resource-limited settings where they are closely tied to poverty and inadequate sanitation. The increasing emergence of drug resistance and the limited accessibility of current therapies highlight the urgent need for novel, safe, and affordable alternatives. Mangifera indica L. (mango), a widely cultivated fruit tree deeply rooted in traditional medicine, has long been used to treat conditions symptomatic of parasitic diseases, including fever, diarrhea, and dysentery. Phytochemical investigations have revealed a rich spectrum of bioactive compounds, notably mangiferin, phenolic compounds and terpenoids, which exhibit antimicrobial, antioxidant, and immunomodulatory activities. This review critically synthesizes evidence on the antiparasitic potential of M. indica against protozoa, such as Plasmodium, Leishmania, Trypanosoma, Toxoplasma gondii, Entamoeba histolytica, and free-living amoebae, as well as helminths. Strongest evidence exists for malaria and helminth infections, where both crude extracts and isolated compounds demonstrated significant activity in vitro and in vivo. Encouraging but limited findings are available for leishmaniasis and trypanosomiasis, while data on toxoplasmosis and amoebiasis remain largely speculative. Variations in efficacy across studies are influenced by plant parts and extraction methods, with ethanolic extracts and mangiferin often showing superior results. Despite promising findings, mechanistic studies, standardized methodologies, toxicological evaluations, and clinical trials are scarce. Future research should focus on elucidating molecular mechanisms, exploring synergistic interactions with existing drugs, and leveraging advanced delivery systems to enhance bioavailability. Full article

(This article belongs to the Special Issue Bioactive Compounds Derived from Plants and Their Medicinal Potential, 2nd Edition)

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24 pages, 729 KB

Open AccessReview

Targeting Polycystic Ovary Syndrome (PCOS) Pathophysiology with Flavonoids: From Adipokine–Cytokine Crosstalk to Insulin Resistance and Reproductive Dysfunctions

by Sulagna Dutta, Pallav Sengupta, Sowmya Rao, Ghada Elsayed Elgarawany, Antony Vincent Samrot, Israel Maldonado Rosas and Shubhadeep Roychoudhury

Pharmaceuticals 2025, 18(10), 1575; https://doi.org/10.3390/ph18101575 - 18 Oct 2025

Viewed by 1354

Abstract

Polycystic ovary syndrome (PCOS) represents one of the most prevalent endocrine–metabolic disorder in women of reproductive age, which includes but not restricted to reproductive disruptions, insulin resistance (IR), hyperandrogenism, and chronic low-grade inflammation. Its heterogeneous pathophysiology arises from the interplay of metabolic, endocrine, [...] Read more.

Polycystic ovary syndrome (PCOS) represents one of the most prevalent endocrine–metabolic disorder in women of reproductive age, which includes but not restricted to reproductive disruptions, insulin resistance (IR), hyperandrogenism, and chronic low-grade inflammation. Its heterogeneous pathophysiology arises from the interplay of metabolic, endocrine, and immune factors, including dysregulated adipokine secretion, cytokine-mediated inflammation, oxidative stress (OS), and mitochondrial dysfunction. Current pharmacological therapies, such as metformin, clomiphene, and oral contraceptives, often provide partial benefits and are limited by side effects, necessitating the exploration of safer, multi-target strategies. Flavonoids, a structurally diverse class of plant-derived polyphenols, have gained attention as promising therapeutic candidates in PCOS due to their antioxidant, anti-inflammatory, insulin-sensitizing, and hormone-modulating properties. Preclinical studies in rodent PCOS models consistently demonstrate improvements in insulin sensitivity, normalization of ovarian morphology, restoration of ovulation, and reduction in hyperandrogenism. Human clinical studies, though limited in scale and heterogeneity, report favorable effects of flavonoids such as quercetin, isoflavones, and catechins on glucose metabolism, adipokine balance, inflammatory markers, and reproductive functions. This evidence-based study critically synthesizes mechanistic insights into how flavonoids modulate insulin signaling, adipokine–cytokine crosstalk, OS, and androgen excess, while highlighting translational evidence and emerging delivery systems aimed at overcoming bioavailability barriers. Collectively, flavonoids represent a promising class of nutraceuticals and adjuncts to conventional therapies, offering an integrative strategy for the management of PCOS. Full article

(This article belongs to the Special Issue Flavonoids in Medicinal Chemistry: Trends and Future Directions)

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19 pages, 788 KB

Open AccessReview

The Other Side of the Same Coin: Beyond the Coding Region in Amyotrophic Lateral Sclerosis

by Paola Ruffo, Benedetta Perrone, Francesco Perrone, Francesca De Amicis, Rodolfo Iuliano, Cecilia Bucci, Angela Messina and Francesca Luisa Conforti

Pharmaceuticals 2025, 18(10), 1573; https://doi.org/10.3390/ph18101573 - 18 Oct 2025

Viewed by 538

Abstract

Transposable elements (TEs), once regarded as genomic “junk,” are now recognized as powerful regulators of gene expression, genome stability, and innate immunity. In the context of neurodegeneration, particularly Amyotrophic Lateral Sclerosis (ALS), accumulating evidence implicates TEs as active contributors to disease pathogenesis. ALS [...] Read more.

Transposable elements (TEs), once regarded as genomic “junk,” are now recognized as powerful regulators of gene expression, genome stability, and innate immunity. In the context of neurodegeneration, particularly Amyotrophic Lateral Sclerosis (ALS), accumulating evidence implicates TEs as active contributors to disease pathogenesis. ALS is a fatal motor neuron disease with both sporadic and familial forms, linked to genetic, epigenetic, and environmental factors. While coding mutations explain a subset of cases, advances in long-read sequencing and epigenomic profiling have unveiled the profound influence of non-coding regions—especially retrotransposons such as LINE-1, Alu, and SVA—on ALS onset and progression. TEs may act through multiple mechanisms: generating somatic mutations, disrupting chromatin architecture, modulating transcriptional networks, and triggering sterile inflammation via innate immune pathways like cGAS-STING. Their activity is normally repressed by epigenetic regulators, including DNA methylation, histone modifications, and RNA interference pathways; however, these controls are compromised in ALS. Taken together, these insights underscore the translational potential of targeting transposable elements in ALS, both as a source of novel biomarkers for patient stratification and disease monitoring, and as therapeutic targets whose modulation may slow neurodegeneration and inflammation. This review synthesizes the current knowledge of TE biology in ALS; integrates findings across molecular, cellular, and systems levels; and explores the therapeutic potential of targeting TEs as modulators of neurodegeneration. Full article

(This article belongs to the Special Issue Advances in Regulatory Mechanisms and Therapeutic Potential of Non-Coding RNAs in Neurodegenerative Diseases)

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30 pages, 5192 KB

Open AccessArticle

Rational Design, Computational Analysis and Antibacterial Activities of Synthesized Peptide-Based Molecules Targeting Quorum Sensing-Dependent Biofilm Formation in Pseudomonas aeruginosa

by Shokhan Jamal Hamid, Twana Mohsin Salih and Tavga Ahmed Aziz

Pharmaceuticals 2025, 18(10), 1572; https://doi.org/10.3390/ph18101572 - 18 Oct 2025

Viewed by 445

Abstract

Background/Objective: The rise in bacterial resistance necessitates novel therapeutic strategies beyond conventional antibiotics. Antimicrobial peptides represent promising candidates but face challenges such as instability, enzymatic degradation, and host toxicity. To overcome these limitations, conjugation and structural modifications are being explored. This study focuses [...] Read more.

Background/Objective: The rise in bacterial resistance necessitates novel therapeutic strategies beyond conventional antibiotics. Antimicrobial peptides represent promising candidates but face challenges such as instability, enzymatic degradation, and host toxicity. To overcome these limitations, conjugation and structural modifications are being explored. This study focuses on designing peptide-based inhibitors of the quorum-sensing (QS) regulator LasR in Pseudomonas aeruginosa, a key mediator of biofilm formation and antibiotic resistance. Methods: Rationally designed tripeptides and dipeptides conjugated with coumarin-3-carboxylic acid and dihydro-3-amino-2-(3H)-furanone were evaluated using molecular docking. The most promising ligand–protein complexes were further analyzed using molecular dynamics (MD) simulations conducted with the CHARMM-GUI and AMBER tools to assess the stability of the ligand–protein complex systems, and the binding affinities were evaluated using Molecular Mechanics–Poisson Boltzmann Surface Area (MM-PBSA) calculations. Pharmacokinetic and toxicity profiles were predicted using ADMETLab 3.0. Selected compounds were synthesized via solid-phase peptide synthesis, structurally confirmed by ¹H NMR and ESI-MS, and tested for antibacterial and antibiofilm activity against P. aeruginosa ATCC 27853. Results: Computational analyses identified several promising inhibitors with stronger binding affinities than the native autoinducer OdDHL. Coumarin conjugates C004 and C006 showed superior docking scores, while MM-PBSA indicated P004 and C004 had the most favorable binding energies. MD simulations confirmed stable ligand–protein complexes. ADMET predictions highlighted C004 and C006 as having excellent pharmacokinetic properties. Experimental assays showed moderate antibacterial activity (MIC 512–1024 µg/mL) and strong antibiofilm inhibition, particularly for C004 (83% inhibition at ½ MIC). Conclusions: The study demonstrates that peptide–coumarin conjugates, especially C004, are promising tools for disrupting QS and biofilm formation in P. aeruginosa. Further optimization and in vivo validation are needed to advance these compounds toward therapeutic application. Full article

(This article belongs to the Section Medicinal Chemistry)

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16 pages, 292 KB

Open AccessReview

Long-Acting Injectable Antipsychotics in Adolescents: From Current Evidence and Gaps to Clinical Practice

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

Pharmaceuticals 2025, 18(10), 1571; https://doi.org/10.3390/ph18101571 - 18 Oct 2025

Viewed by 1144

Abstract

Background: Adolescence is a vulnerable period for the onset of severe psychiatric conditions, such as psychotic spectrum disorders. Non-adherence to antipsychotics is a common problem in young people with these conditions and paves the way for relapse, rehospitalization, and functional impairment. Co-occurring substance [...] Read more.

Background: Adolescence is a vulnerable period for the onset of severe psychiatric conditions, such as psychotic spectrum disorders. Non-adherence to antipsychotics is a common problem in young people with these conditions and paves the way for relapse, rehospitalization, and functional impairment. Co-occurring substance use disorders (SUDs) further undermine adherence and worsen outcomes. Long-acting injectable antipsychotics (LAIs) improve adherence and outcomes in adults, but none are licensed for use in individuals under 18. This review seeks to distill the available evidence on LAIs’ use in adolescents, from efficacy to safety, and to outline clinical practice recommendations. Methods: A narrative review was conducted. The evidence was organized by drug class: risperidone, paliperidone, aripiprazole, and other antipsychotics (olanzapine, haloperidol, first-generation depots). Results: Evidence in adolescents remains sparse and heterogeneous. Risperidone LAI has shown improvements in symptom severity, functioning, and behavioral control in bipolar disorder and schizophrenia, though commonly associated with side effects. Paliperidone palmitate demonstrated benefit in first-episode schizophrenia and autism spectrum disorder with intellectual disability, reducing hospital use but carrying risks of EPS and hyperprolactinemia. Aripiprazole LAI showed functional gains, short-term tolerability, and encouraging acceptance in case reports. Other LAIs were used in highly resistant cases with some clinical benefit, though extrapyramidal adverse events were common. Conclusions: The current literature provides limited data, and no clinical guidelines exist for the use of LAI in adolescents. Nonetheless, off-label use is reported in selected cases in clinical practice. Best practice is to start with oral stabilization, then use the lowest effective LAI with psychosocial support and close monitoring. When SUD co-occurs, LAIs may also help mitigate risks related to misuse/diversion of oral medication, provided that care includes systematic SUD screening and early intervention. Prospective controlled studies are urgently needed to establish long-term efficacy and safety in this vulnerable population. Full article

(This article belongs to the Special Issue Clinical Advances in the Neuropharmacological Treatment of Substance Use Disorders: 2nd Edition)

3 pages, 138 KB

Open AccessEditorial

The Evolving Field of Tumor Immunopharmacology

by Marco A. Velasco-Velázquez

Pharmaceuticals 2025, 18(10), 1570; https://doi.org/10.3390/ph18101570 - 18 Oct 2025

Viewed by 278

Abstract

Tumor immunopharmacology has evolved from the use of broad, highly toxic immune stimulants to the development of targeted immunomodulators [...] Full article

(This article belongs to the Special Issue Tumor Immunopharmacology)

20 pages, 4202 KB

Open AccessReview

Multi-Target Therapeutic Potential of Arctii Fructus Lignans in Diabetes Mellitus and Its Complications: A Mechanistic Review

by Shuaiyi Lv, Jieming Li, Yulong Hu, Juntao Cai, Guanglei Nan, Yuanfang Kong, Xu Shen, Lifeng Zhu, Shaohua Yang and Chunhong Dong

Pharmaceuticals 2025, 18(10), 1569; https://doi.org/10.3390/ph18101569 - 17 Oct 2025

Viewed by 629

Abstract

This narrative review systematically evaluates the therapeutic potential and mechanisms of action of Arctii Fructus lignans (from Arctium lappa L.) in managing diabetes mellitus (DM) and its complications. To ensure a comprehensive evidence synthesis, a systematic literature search was conducted using PubMed, Web [...] Read more.

This narrative review systematically evaluates the therapeutic potential and mechanisms of action of Arctii Fructus lignans (from Arctium lappa L.) in managing diabetes mellitus (DM) and its complications. To ensure a comprehensive evidence synthesis, a systematic literature search was conducted using PubMed, Web of Science, CNKI, and Wanfang Data for publications between January 2000 and June 2024. Study selection was based on predefined inclusion and exclusion criteria focusing on lignan-specific antidiabetic effects and mechanistic insights. The accumulated evidence demonstrates that Arctii Fructus lignans exhibit multi-targeted pharmacological effects through several key mechanisms: (1) improving glucose homeostasis via α-glucosidase inhibition and AMPK/PI3K pathway activation; (2) protecting pancreatic β-cell function through anti-inflammatory and anti-apoptotic actions; and (3) mitigating diabetic complications by reducing oxidative stress, modulating TGF-β/VEGF signaling, and restoring autophagy balance. Notably, these lignans show particular efficacy in early-stage diabetes models, with reduced effectiveness in advanced stages featuring significant β-cell dysfunction, suggesting a critical therapeutic window for intervention. Future research should prioritize well-designed clinical trials using standardized extracts, investigations into structure–activity relationships, and exploration of synergistic effects within traditional formulations to advance the translational potential of these promising natural compounds. Full article

(This article belongs to the Section Natural Products)

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30 pages, 1615 KB

Open AccessArticle

Innovative Galenic Formulation of Prussian Blue Tablets: Advancing Pharmaceutical Applications

by Borja Martínez-Alonso, Guillermo Torrado Durán, Norma S. Torres Pabón and M. Ángeles Peña Fernández

Pharmaceuticals 2025, 18(10), 1568; https://doi.org/10.3390/ph18101568 - 17 Oct 2025

Cited by 1 | Viewed by 403

Abstract

Background/Objectives: Given the persistent threat of war and nuclear accidents, and the global reliance on marketed Prussian blue capsules manufactured in only a few countries without an openly accessible quantitative formulation, there is a critical need for robust tablet alternatives that ensure stability, [...] Read more.

Background/Objectives: Given the persistent threat of war and nuclear accidents, and the global reliance on marketed Prussian blue capsules manufactured in only a few countries without an openly accessible quantitative formulation, there is a critical need for robust tablet alternatives that ensure stability, scalability, and rapid deployment. This study focuses on the design and development of PB tablets for oral administration as decorporation agents for radioactive and toxic species, particularly for treatment in nuclear and radiological emergencies. Methods: Advanced tableting processes, including direct compression, wet granulation, and dry granulation, were employed to develop innovative Prussian blue tablet formulations and to provide significant flexibility for industrial-scale production. Comprehensive physicochemical and pharmacotechnical characterizations were performed to support the formulation and to ensure both the safety and efficacy of the PB tablets. Stability studies were conducted in accordance with ICH guidelines to evaluate product performance over time and to confirm that quality and performance attributes remained within specification. Results: Among the formulations evaluated, the direct compression (DC5) was recommended for industrial production due to its simplicity, short cycle time, and high throughput. Stability studies up to 18 months confirmed that the PB tablets remained within specification, and the program is ongoing at 24, 36, 48, and 60 months. Conclusions: This research provides a promising advancement in countermeasures for nuclear and radiological incidents by delivering a robust, scalable PB tablet formulation that can be rapidly manufactured and deployed in emergency situations. Full article

(This article belongs to the Section Pharmaceutical Technology)

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21 pages, 2971 KB

Open AccessArticle

Design of Hybrid Quinoline–Chalcone Compounds Against Leishmania amazonensis Based on Computational Techniques: 2D- and 3D-QSAR with Experimental Validation

by Marcos Lorca, Gisela C. Muscia, Jaime Mella, Luciana Thomaz, Jenicer K. Yokoyama-Yasunaka, Daniel Moraga, Yeray A. Rodriguez-Nuñez, Silvia E. Asís, Mauro Cortez and Marco Mellado

Pharmaceuticals 2025, 18(10), 1567; https://doi.org/10.3390/ph18101567 - 17 Oct 2025

Viewed by 556

Abstract

Background: Leishmania amazonensis, one of the causative agents of cutaneous leishmaniasis, is responsible for a neglected tropical disease affecting nearly one million individuals worldwide. Although clinical treatments are available, their effectiveness is often compromised by high toxicity and limited selectivity. Methods [...] Read more.

Background: Leishmania amazonensis, one of the causative agents of cutaneous leishmaniasis, is responsible for a neglected tropical disease affecting nearly one million individuals worldwide. Although clinical treatments are available, their effectiveness is often compromised by high toxicity and limited selectivity. Methods: From a database, 64 chalcone derivatives were studied using Comparative Molecular Similarity Indices Analysis (CoMSIA) and Hansch analysis (2D-QSAR) to construct predictive computational models. Internal and external validation criteria were applied to identify structural determinants associated with antileishmanial activity. Based on these insights, twelve novel quinoline–chalcone hybrids were designed, synthesized, and biologically evaluated against L. amazonensis. Results: The most robust CoMSIA model combined steric and hydrogen-bond acceptor fields (CoMSIA-SA), while Hansch analysis highlighted electronic descriptors—specifically LUMO energy and the global electrophilicity index—as critical for parasite growth inhibition. Guided by these computational findings, a new series of 12 hybrid quinoline–chalcone derivatives (E001–E012) was synthesized through a two-step procedure, achieving overall yields of 43–71%. Biological assays demonstrated that four compounds displayed inhibitory activity comparable to amphotericin B. Furthermore, physicochemical profiling and in silico pharmacokinetic predictions for the most active compounds (E003, E005, E006, and E011) indicated favorable biocompatibility and drug-like properties. Conclusions: These results underscore the value of an integrative computational–experimental approach in the rational design of next-generation L. amazonensis inhibitors, reinforcing chalcone-based scaffolds as promising pharmacophoric frameworks for antileishmanial drug discovery. Full article

(This article belongs to the Special Issue QSAR and Chemoinformatics in Drug Design and Discovery)

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28 pages, 2481 KB

Open AccessSystematic Review

Safety of Roxadustat in Chronic Kidney Disease Patients: An Updated Systematic Review and Meta-Analysis

by Patricia Martínez-Miguel, Encarnación Fernández-Antón, Diego Rodríguez-Puyol, Francisco J. de Abajo and Susana López Ongil

Pharmaceuticals 2025, 18(10), 1566; https://doi.org/10.3390/ph18101566 - 17 Oct 2025

Viewed by 767

Abstract

Background/Objectives: Roxadustat is a new treatment for the anemia of chronic kidney disease (CKD) that has comparable efficacy to erythropoietic-stimulating agents (ESAs), with the advantage of oral administration and increased iron bioavailability. It appears to be a safe treatment in terms of the [...] Read more.

Background/Objectives: Roxadustat is a new treatment for the anemia of chronic kidney disease (CKD) that has comparable efficacy to erythropoietic-stimulating agents (ESAs), with the advantage of oral administration and increased iron bioavailability. It appears to be a safe treatment in terms of the development of major adverse cardiovascular events (MACEs); however, its long-term safety has not been fully evaluated. In this meta-analysis we evaluate its safety in dialysis-dependent (DD) and non-dialysis-dependent (NDD) CKD patients, considering the comparator used and treatment duration. Methods: The safety of Roxadustat was assessed based on the incidence of serious (SAEs) and non-serious adverse events (AEs). A random-effects method was used to estimate the odds ratios (ORs) and their 95% CIs. Results: Fifteen different randomized controlled clinical trials were included, with a total of 10,284 patients with CKD stages 3–5 treated with Roxadustat, 5604 on dialysis and 4680 not on dialysis. The overall incidence of AEs in the Roxadustat group did not change significantly (OR = 1.13; 1.00–1.27); however, the incidence of SAEs was significantly higher than in the control group (OR = 1.13; 1.04–1.23). Specifically, the incidence of hypertension (OR = 1.39; 1.13–1.73) and hyperkalemia (OR = 1.31; 1.02–1.69) was higher in the Roxadustat group than in the placebo group of NDD patients. All AEs except MACEs and hyperkalemia increased with treatment > 30 weeks. No differences were found in the incidence of any adverse effects studied compared with ESAs. Conclusions: Roxadustat is associated with an increased risk of SAEs, including hypertension and hyperkalemia in NDD patients. Therefore, monitoring potassium levels and blood pressure is recommended in these patients. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 2219 KB

Open AccessArticle

Novel Multifunctional Cannabidiol-Based Analogues with In Silico, In Vitro, and In Vivo Anti-SARS-CoV-2 Effect

by Graziella dos Reis Rosa Franco, Vanessa Silva Gontijo, Flávia Pereira Dias Viegas, Matheus de Freitas Silva, Cindy Juliet Cristancho Ortiz, Caio Miranda Damásio, Isabella Marie Fernandes Silva, Thâmara Gaspar Campos, Erik Vinicius de Sousa Reis, Felipe Alves Clarindo, Thaís de Fátima Silva Moraes, Matheus Müller Pereira da Silva, Patrícia Ribeiro de Carvalho França, Isabella Alvim Guedes, Laurent Emmanuel Dardenne, Jordana Grazziela Alves Coelho dos Reis, Patrícia Dias Fernandes and Claudio Viegas, Jr.

Pharmaceuticals 2025, 18(10), 1565; https://doi.org/10.3390/ph18101565 - 16 Oct 2025

Viewed by 797

Abstract

Background/Objectives: COVID-19 was responsible for millions of deaths worldwide. This study aimed to identify substances with in vitro and in vivo effects against the SARS-CoV-2 virus. Methods: Compounds PQM-243 and PQM-249, two terpene-N-acyl-aryl-hydrazone analogues, were evaluated in vitro against [...] Read more.

Background/Objectives: COVID-19 was responsible for millions of deaths worldwide. This study aimed to identify substances with in vitro and in vivo effects against the SARS-CoV-2 virus. Methods: Compounds PQM-243 and PQM-249, two terpene-N-acyl-aryl-hydrazone analogues, were evaluated in vitro against SARS-CoV-2 to a antiviral activity and inhibitory effect against angiotensin converting enzyme 2 (ACE2). A possible inhibitory effect affecting the interaction between the receptor-binding domain (RBD) protein and/or ACE2 was evaluated using LUMMIT kit. A SARS-CoV-2-induced pulmonary pneumonia model was developed to evaluate the effects of the compounds after 3 days of treatment. Results: Compounds PQM-243 and PQM-249 exhibited IC₅₀ values of 0.0648 ± 0.041 µM and 0.2860 ± 0.057 µM against SARS-CoV-2 with a selective index of >1543.21 and 349.65, respectively, and IC₅₀ values of 12.1 nM and 13.3 nM, respectively, against ACE2. All concentrations used significantly reduced interactions between ACE2 and RBD. Computational studies suggest that these new compounds are potent direct anti-SARS-CoV-2 agents, capable of reducing both virus viability and its invasive ability in the host cells by reducing the interaction between RBD and ACE2. It was also demonstrated that even when administered by the oral route, both compounds reduced SARS-CoV-2-induced lung inflammation. Our data suggests that both compounds can act as potent direct anti-SARS-CoV-2 agents, reducing both viral viability and host cell entry. In addition, they exhibited a significant multi-target-directed pharmacological profile, also reducing SARS-CoV-2-induced lung inflammation when administered orally. Conclusions: Overall, these findings support further investigation of PQM-243 and PQM-249 as promising antiviral and anti-inflammatory multi-target prototypes for the development of innovative drug candidates targeting SARS-CoV-2 and other virus-related respiratory diseases. Full article

(This article belongs to the Special Issue Medicinal Potential of Cannabidiol and New Structural Analogs)

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Open AccessReview

Polyphenols as Modulators of Gastrointestinal Motility: Mechanistic Insights from Multi-Model Studies

by Andrzej Chomentowski, Krzysztof Drygalski, Tomasz Kleszczewski, Marta Berczyńska, Marzena Tylicka, Jacek Kapała, Agnieszka Raciborska, Przemysław Zubrzycki, Hady Razak Hady and Beata Modzelewska

Pharmaceuticals 2025, 18(10), 1564; https://doi.org/10.3390/ph18101564 - 16 Oct 2025

Viewed by 763

Abstract

Dietary polyphenols are recognized as crucial modulators of gastrointestinal motility, holding therapeutic promise for conditions like irritable bowel syndrome, postoperative ileus, and functional dyspepsia. However, their reported effects are heterogeneous, ranging from spasmolytic to prokinetic. This review aims to clarify these inconsistencies by [...] Read more.

Dietary polyphenols are recognized as crucial modulators of gastrointestinal motility, holding therapeutic promise for conditions like irritable bowel syndrome, postoperative ileus, and functional dyspepsia. However, their reported effects are heterogeneous, ranging from spasmolytic to prokinetic. This review aims to clarify these inconsistencies by synthesizing experimental evidence on structure–activity relationships and underlying mechanisms. Relevant publications were identified in PubMed and Google Scholar using terms related to polyphenols and gastrointestinal motility. References were selected for relevance, and the narrative review integrates findings from in vitro, ex vivo, in vivo, and clinical studies. Across various experimental models, polyphenols function as multi-target modulators of gastrointestinal smooth muscle. The primary mechanisms identified involve the blockade of voltage-dependent L-type Ca²⁺ channels, activation of K⁺ channels (BK, K_ATP), and modulation of the NO/cGMP and cAMP/PKA pathways. Flavones and multiple flavonols consistently demonstrate spasmolytic activity via Ca²⁺ channel antagonism. In contrast, flavanones engage BK and K_ATP channels to induce membrane hyperpolarization. Complex extracts from plants like ginger and turmeric exhibit mixed pro- or antimotility effects, reflecting the diverse profiles of their constituent compounds. While robust ex vivo pharmacology and some in vivo and human data exist, a high degree of dataset heterogeneity and inconsistent reporting impedes direct translational efforts. Polyphenols are promising multi-mechanistic modulators of gastrointestinal motility with clear structure–activity patterns. To advance their clinical application, future research must focus on establishing standardized in vivo pharmacokinetics, conducting targeted structure–activity studies, employing bioassay-guided fractionation, and designing rigorous clinical trials. Full article

(This article belongs to the Special Issue Advances in Smooth Muscle Pharmacology)

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Pharmaceuticals, Volume 18, Issue 10 (October 2025) – 169 articles

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