Pharmaceuticals

27 pages, 4318 KiB

Open AccessArticle

Unveiling Therapeutic Powers of Indigenous Flora: Antimicrobial, Antioxidant, and Anticancer Properties of Horwoodia dicksoniae

by Khadijah A. Altammar

Pharmaceuticals 2025, 18(5), 765; https://doi.org/10.3390/ph18050765 (registering DOI) - 21 May 2025

Abstract

Background: Horwoodia dicksoniae Turrill. (Brassicaceae) and Stipa capensis Thunb. (Poaceae) are commonly grown in the eastern region of Saudi Arabia. Methods: This study evaluated the antibacterial and antifungal potential of these plants. H. dicksoniae extract was further subjected to antioxidant, anticancer, [...] Read more.

Background: Horwoodia dicksoniae Turrill. (Brassicaceae) and Stipa capensis Thunb. (Poaceae) are commonly grown in the eastern region of Saudi Arabia. Methods: This study evaluated the antibacterial and antifungal potential of these plants. H. dicksoniae extract was further subjected to antioxidant, anticancer, GC-MS, LC-MS/MS, and in silico analyses. Results: H. dicksoniae extract presented a higher antimicrobial efficiency than S. capensis extract by effectively inhibiting the growth of Staphylococcus aureus, Escherichia coli, Proteus vulgaris, Bacillus subtilis, and Candida albicans. H. dicksoniae ethanolic extract also demonstrated promising antioxidant and anticancer properties against the human colon cancer cell line HCT-116. GC-MS analysis revealed the presence of 12 natural compounds in the H. dicksoniae extract, whereas LC-MS/MS analysis revealed 19 different compounds in negative ion mode and 25 in positive ion mode. Furthermore, the presence of bioactive compounds in the H. dicksoniae extract, such as flavonoids (acacetin and hesperetin) and caffeic acid, confirmed the observed antibacterial, antifungal, antioxidant, and anticancer activities. Molecular docking revealed promising interactions between various bioactive compounds and target proteins associated with antimicrobial, antioxidant, and anticancer activities. Conclusions: This study is the first to report GC-MS and LC-MS/MS analyses of H. dicksoniae ethanolic extract. The findings provide valuable insights into the potential mechanisms and therapeutic applications of the identified bioactive compounds. Thus, the present work can serve as a platform for the isolation of natural compounds from H. dicksoniae extract, which may play a significant role in the discovery and design of new drugs for the treatment of human diseases. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals 2024)

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23 pages, 1563 KiB

Open AccessArticle

Bioactive Compounds, Antioxidant, Cytotoxic, and Genotoxic Investigation of the Standardized Liquid Extract from Eugenia involucrata DC. Leaves

by Monatha Nayara Guimarães Teófilo, Leonardo Gomes Costa, Jamira Dias Rocha, Fernando Gomes Barbosa, Anielly Monteiro de Melo, Grazzielle Guimarães de Matos, Cristiane Maria Ascari Morgado, Amanda Silva Fernandes, Lucas Barbosa Ribeiro de Carvalho, Clayson Moura Gomes, Milton Adriano Pelli de Oliveira, Joelma Abadia Marciano de Paula, Elisa Flávia Luiz Cardoso Bailão and Leonardo Luiz Borges

Pharmaceuticals 2025, 18(5), 764; https://doi.org/10.3390/ph18050764 - 21 May 2025

Abstract

Background: Eugenia involucrata DC., a Cerrado native plant, is recognized for its medicinal properties. However, its bioactive compounds remain inadequately explored. Objectives: This study investigated bioactive compounds from a standardized liquid extract from E. involucrata leaves that can act with antioxidant, [...] Read more.

Background: Eugenia involucrata DC., a Cerrado native plant, is recognized for its medicinal properties. However, its bioactive compounds remain inadequately explored. Objectives: This study investigated bioactive compounds from a standardized liquid extract from E. involucrata leaves that can act with antioxidant, cytogenotoxic, cytoprotective, and genoprotective effects. Methods: The phenolic compounds in the standardized liquid extract from E. involucrata leaves were screened by HPLC-DAD. The capture of the free radicals DPPH, ABTS⁺, and the metal reduction power FRAP determined the antioxidant potential. Cytotoxicity was evaluated in RAW 264.7 macrophages (MTT assay), and (anti)cytotoxic and (anti)genotoxic effects were assessed in human lymphocytes using the Trypan blue exclusion method and comet assay, respectively. Results: The extracts present key phenolic compounds, such as ellagic acid, myricitrin, and epicatechin gallate. The standardized extract demonstrated antioxidant capacity, evidenced by its ability to reduce iron and scavenge free radicals. The liquid extract from E. involucrata leaves exhibited cytotoxic effects on RAW 264.7 macrophages at higher concentrations, while demonstrating (anti)cytotoxic activity on human lymphocytes from all tested concentrations. The highest concentration tested of the standardized liquid extract from E. involucrata leaves (250 µg/mL) showed genotoxicity against human lymphocytes compared to the negative control. In contrast, the lowest concentration (62.5 µg/mL) exhibited an antigenotoxic effect on human lymphocytes, reducing the genotoxicity of doxorubicin by approximately 27%. Conclusions: The bioactive compounds in the standardized liquid extract from E. involucrata leaves exhibited antioxidant and antigenotoxic properties, suggesting potential value for nutraceutical and pharmaceutical applications, particularly those related to oxidative stress associated withaging and disease progression. Full article

(This article belongs to the Special Issue Bioactive Compounds From Plants and Their Therapeutic Applications in Lifestyle-Related Diseases)

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15 pages, 5463 KiB

Open AccessArticle

Protective Effect of Obeticholic Acid on Sepsis-Induced Liver Dysfunction via Regulating Bile Acid Homeostasis

by Jiahui Wang, Li Ma, Yuan An, Yan Ge, Dan Xu and Enqiang Mao

Pharmaceuticals 2025, 18(5), 763; https://doi.org/10.3390/ph18050763 - 21 May 2025

Abstract

Background/Objectives: Abnormal bile acid (BA) pool may play an important role in inducing liver damage in sepsis. Farnesoid X receptor (FXR) is a main negative feedback regulator of BA metabolism. This study aims to explore the protective effect and mechanism of the FXR [...] Read more.

Background/Objectives: Abnormal bile acid (BA) pool may play an important role in inducing liver damage in sepsis. Farnesoid X receptor (FXR) is a main negative feedback regulator of BA metabolism. This study aims to explore the protective effect and mechanism of the FXR agonist obeticholic acid (OCA) on liver dysfunction when sepsis occurs. Methods: A rat model of sepsis was induced by cecal ligation and puncture (CLP) for 24 h. Systematic inflammation, tissue injury, hepatic FXR, and BA transporter expression were investigated in the CLP rats and sham-operated control rats with and without OCA pre-treatment (10 mg/kg, gavage) at 2 h before operation. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay was performed to access BA composition in the rats’ serum and livers. The injury and inflammatory effects of the elevated unconjugated BAs found in the CLP rats was further verified in a hepatic cell line BRL-3A in vitro. Results: Hepatic FXR was repressed in CLP rats, whereas OCA upregulated liver FXR and hepatic BA transporter expression, reduced total serum BA concentration, ameliorated the elevation of serum levels of IL-1β and IL-6, and improved liver and ileal tissue injuries. OCA administration reduced the elevated unconjugated BAs in both serum and liver, and effectively inhibited increases in cholic acid (CA), deoxycholic acid (DCA), and 7-ketoDCA concentrations in CLP rat livers. These BA fractions promoted the release of aspartate aminotransferase (AST) from BRL-3A cells and increased IL-6, CXCL2, and monocyte chemoattractant protein-1 (MCP-1) expression in the cells, along with enhanced transcription factor nuclear factor-κB activation. Conclusions: Liver inflammation and dysfunction during sepsis is attributable to significant changes in bile acid composition in the blood and liver. FXR activation reduces systemic inflammation and liver dysfunction by regulating bile acid homeostasis, especially inflammatory unconjugated bile acid components. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 2300 KiB

Open AccessArticle

Targeting Hyperuricemia and NLRP3 Inflammasome in Gouty Arthritis: A Preclinical Evaluation of Allopurinol and Disulfiram Combination Therapy

by Yahya I. Asiri, Manimekalai Pichaivel, Selva Prasanthi Parameshwaran, Krishnaraju Venkatesan, Saud Alqahtani, Taha Alqahtani, Rehab Ahmed, Hassabelrasoul Elfadil, Mahmoud Elodemi, Shaimaa Genena, Durgaramani Sivadasan and Premalatha Paulsamy

Pharmaceuticals 2025, 18(5), 762; https://doi.org/10.3390/ph18050762 - 21 May 2025

Abstract

Background/Objectives: Gouty arthritis (GA) is a chronic inflammatory condition characterized by hyperuricemia and NLRP3 inflammasome activation, leading to joint damage and systemic inflammation. Although allopurinol (ALP), a xanthine oxidase inhibitor, effectively lowers serum urate levels, it has limited anti-inflammatory effects. This study investigated [...] Read more.

Background/Objectives: Gouty arthritis (GA) is a chronic inflammatory condition characterized by hyperuricemia and NLRP3 inflammasome activation, leading to joint damage and systemic inflammation. Although allopurinol (ALP), a xanthine oxidase inhibitor, effectively lowers serum urate levels, it has limited anti-inflammatory effects. This study investigated whether combining disulfiram (DSF), a known NLRP3 inflammasome inhibitor, with ALP enhances therapeutic outcomes in a rat model of gout. Methods: Thirty male Albino Wistar rats (150–200 g) were randomly assigned to five groups (n = 6): control, disease control, ALP-treated, DSF-treated, and ALP + DSF combination. Hyperuricemia was induced using potassium oxonate, followed by MSU crystal injection to trigger acute gout. Treatment lasted 30 days. Efficacy was assessed through clinical scoring, paw swelling, serum uric acid levels, ELISA-based cytokine profiling (IL-1β, TNF-α, IL-6), renal function tests, radiography, and histopathology. Results: Combination therapy with ALP + DSF significantly reduced paw swelling (p < 0.05), inflammation index (p < 0.001), serum uric acid (p < 0.001), and pro-inflammatory cytokines compared to monotherapy. Histopathology revealed preserved synovial architecture and reduced inflammatory infiltration. Radiographic imaging showed attenuated soft tissue swelling and joint erosion. Renal function markers were also improved in the combination group. Conclusions: The combination of ALP and DSF provided superior anti-inflammatory and urate-lowering effects compared to individual treatments. These findings support the potential of disulfiram as an adjunct to conventional ULTs in gout management through dual modulation of urate metabolism and inflammasome-driven inflammation. Full article

(This article belongs to the Special Issue Pharmacological Activities and Therapeutic Potential of Novel Drug Derivatives)

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14 pages, 4486 KiB

Open AccessArticle

Method-Driven Physicochemical Profiling of Aconitum pendulum Bush Polysaccharides and Optimization of Extraction Protocols

by Mingkun Meng, Linlin Zhao, Chunqiao Shi, Yuying Song, Qingya Yu, Mengjia Li, Xing Yang, Yue Liu, Tong Xu and Yi Zhang

Pharmaceuticals 2025, 18(5), 760; https://doi.org/10.3390/ph18050760 - 21 May 2025

Abstract

Background/Objectives: This study aimed to characterize the physicochemical properties and antioxidant activities of polysaccharides from Aconitum pendulum Bush processed through different methods (the polysaccharide from A. pendulum (DT), the polysaccharide from A. pendulum processed with zanba (Z-DT), the polysaccharide from A. pendulum [...] Read more.

Background/Objectives: This study aimed to characterize the physicochemical properties and antioxidant activities of polysaccharides from Aconitum pendulum Bush processed through different methods (the polysaccharide from A. pendulum (DT), the polysaccharide from A. pendulum processed with zanba (Z-DT), the polysaccharide from A. pendulum processed with highland barley wine (Q-DT), and the polysaccharide from A. pendulum processed with hezi (H-DT)). Additionally, the research focused on optimizing the hot water extraction process for DT using response surface methodology (RSM) to enhance extraction efficiency and establish a scientific basis for pharmaceutical applications. Methods: The physicochemical properties and antioxidant activities of the four polysaccharides were systematically evaluated. RSM with a 17-run Box–Behnken design was employed to investigate the extraction process, examining three factors: extraction runs, liquid–solid ratio, and extraction time. Results: The physicochemical properties and antioxidant assays demonstrated that the DT exhibited significantly higher properties. The factors influencing the extraction process were ranked as extraction runs > liquid–solid ratio > extraction time. The optimal conditions for DT were a liquid–solid ratio of 25 mL/g, extraction time of 2.5 h, and four extraction runs, yielding a sugar content of 63.4%. Under these conditions, the extraction rate of DT was significantly higher than before optimization. Conclusions: The study demonstrated distinct structural features among the four polysaccharides, providing a scientific framework for their potential pharmaceutical applications. What’s more, the optimized hot water extraction protocol for DT was validated for high extraction rate and reproducibility. Full article

(This article belongs to the Section Medicinal Chemistry)

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11 pages, 339 KiB

Open AccessArticle

Pregabalin Safety in Pregnancy: A Disproportionality Analysis of VigiBase Spontaneous Reporting System

by Sarah Mondada, Francesca Bedussi, Jonathan L. Richardson, Roberta Noseda and Alessandro Ceschi

Pharmaceuticals 2025, 18(5), 759; https://doi.org/10.3390/ph18050759 - 20 May 2025

Abstract

Background/Objectives: Some product information on pregabalin suggests a potential risk for congenital anomalies (CAs), although evidence remains inconsistent and lacks clear patterns. This study aimed to provide additional safety information on pregabalin use in pregnancy by analyzing VigiBase, the World Health Organization’s [...] Read more.

Background/Objectives: Some product information on pregabalin suggests a potential risk for congenital anomalies (CAs), although evidence remains inconsistent and lacks clear patterns. This study aimed to provide additional safety information on pregabalin use in pregnancy by analyzing VigiBase, the World Health Organization’s global pharmacovigilance database of individual case safety reports (ICSRs). Methods: The analysis included de-duplicated ICSRs related to pregabalin exposure in pregnancy, collected up to 16 January 2024. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated for CA categories reported in at least 10 ICSRs, with a statistical threshold defined as a 95% CI lower bound > 1. Results: Among 410 ICSRs, the majority originated from Europe (64.8%) and North America (26.5%). Of these, 59 (14.4%) ICSRs documented only pregabalin exposure in pregnancy, while 351 (85.6%) also reported adverse events in pregnancy. CAs occurred in 82 ICSRs (23.3%), most commonly involving heart defects (30), nervous system anomalies (18), and limb anomalies (12). No signals of disproportionate reporting were identified for these categories compared to the full database (heart defects: ROR 0.587, 95% CI 0.410–0.839; nervous system anomalies: ROR 0.588, 95% CI 0.370–0.933; limb anomalies: ROR 0.671, 95% CI 0.381–1.183). Conclusions: Future disproportionality analyses, along with pharmacovigilance and pharmacoepidemiological studies using patient registries and large-scale collaborative projects, are essential for the ongoing monitoring of pregabalin safety in pregnancy. Full article

(This article belongs to the Special Issue Pharmacovigilance in Drug Therapy: Drug–Drug Interactions and Safety Evaluation, 2nd Edition)

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18 pages, 1461 KiB

Open AccessArticle

Safety, Tolerability, and Pharmacokinetics of Filapixant, a Highly Selective P2X3 Receptor Antagonist, in an Ascending-Single-Dose First-in-Human Study

by Klaus Francke, Sybille Baumann, Isabella Gashaw, Stefan Klein, Beate Rohde, Oliver Zolk, Oliver M. Fischer and Christian Friedrich

Pharmaceuticals 2025, 18(5), 758; https://doi.org/10.3390/ph18050758 - 20 May 2025

Abstract

Background/Objectives: P2X3 receptor antagonists have been suggested as a potential treatment for urogenital, respiratory and pain conditions. This first-in-human (FiH) study evaluated filapixant, a new P2X3 receptor antagonist with high receptor selectivity. It was anticipated that filapixant would cause fewer taste-related side effects [...] Read more.

Background/Objectives: P2X3 receptor antagonists have been suggested as a potential treatment for urogenital, respiratory and pain conditions. This first-in-human (FiH) study evaluated filapixant, a new P2X3 receptor antagonist with high receptor selectivity. It was anticipated that filapixant would cause fewer taste-related side effects compared to the unselective P2X3/P2X2/3 antagonist gefapixant and the less selective P2X3 antagonist eliapixant. This study assessed the tolerability, safety and PK of filapixant, the effect of food on PK and relative BA of a tablet vs. solution. Methods: This study (NCT03212586) followed a randomized, double-blind single-ascending-dose design. A total of 72 healthy male subjects received a solution (6–60 mg) or immediate-release tablets (120–1250 mg) of filapixant or corresponding placebo in fasted state. The subjects at 60 mg were re-dosed with 60 mg tablets in both fasted and fed states. The endpoints included PK parameters, dose proportionality, adverse events, and taste assessments (taste strips; dysgeusia questionnaire). Results: Filapixant showed dose-proportional PK with a half-life (about 10–15 h), supporting once-daily dosing. Food minimally affected PK and BA was comparable between tablet and solution. Filapixant was well tolerated; however, the number of taste side effects was unexpectedly high. Comparing the results observed across clinical filapixant studies, the threshold for such side effects seems to be well below the in vitro IC₅₀ for P2X2/3. Conclusions: Treatment with filapixant was safe and well tolerated. Filapixant showed dose-proportional PK, bioavailability similar to that of a solution and a tablet, and a minor effect of food on PK. The number of taste side effects was unexpectedly high considering the high in vitro P2X3 receptor selectivity. Factors other than selectivity are needed to explain taste profile differences between P2X3 antagonists. Full article

(This article belongs to the Special Issue P2X Receptors and Their Pharmacology)

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26 pages, 4306 KiB

Open AccessArticle

Metformin-Induced Apoptosis Is Mediated Through Mitochondrial VDAC1

by Anna Shteinfer-Kuzmine, Meital M. Moyal, Aditya Karunanithi Nivedita, Sweta Trishna, Almog Nadir, Shubhandra Tripathi and Varda Shoshan-Barmatz

Pharmaceuticals 2025, 18(5), 757; https://doi.org/10.3390/ph18050757 - 20 May 2025

Abstract

Background: Besides diabetes mellitus, metformin has been identified as a potential therapeutic agent for treating various other conditions that include various cancers, cardiovascular diseases, neurodegenerative diseases, and aging. In cancer, metformin increased apoptotic cell death, while inhibiting it in neurodegenerative diseases. Thus, different [...] Read more.

Background: Besides diabetes mellitus, metformin has been identified as a potential therapeutic agent for treating various other conditions that include various cancers, cardiovascular diseases, neurodegenerative diseases, and aging. In cancer, metformin increased apoptotic cell death, while inhibiting it in neurodegenerative diseases. Thus, different modes of metformin action at the molecular level have been proposed. Methods: In this study, we present the mitochondria and the VDAC1 (voltage-dependent anion channel) as a potential target of metformin. Results: Metformin induces VDAC1 overexpression, its oligomerization, and subsequent apoptosis. Metformin analogs phenformin and buformin at much lower concentrations also induce VDAC1 overexpression, oligomerization, and cell death. We demonstrate the interaction of metformin with purified VDAC1, which inhibited its channel conduction in a voltage-dependent manner. Metformin bound to the synthetic VDAC1-N-terminal peptide and binding to this domain was also found by its molecular docking with VDAC1. Moreover, we demonstrated metformin binding to purified hexokinases (HK-I) with a 400-fold lower metformin concentration than that required for cell death induction. In cells, metformin induced HK-I detachment from the mitochondrial VDAC1. Lastly, metformin increased the expression of NLRP3 and ASC and induced their co-localization, suggesting inflammasome activation. Conclusions: The results suggest that VDAC1 is a target for metformin and its analogs, and this is associated with metformin’s adverse effects on many diseases. Full article

(This article belongs to the Section Pharmacology)

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20 pages, 12613 KiB

Open AccessArticle

Skimmianine Modulates Tumor Proliferation and Immune Dynamics in Breast Cancer by Targeting PCNA and TNF-α

by Tuğcan Korak, Hayat Ayaz and Fırat Aşır

Pharmaceuticals 2025, 18(5), 756; https://doi.org/10.3390/ph18050756 - 20 May 2025

Abstract

Background/Objectives: Breast cancer continues to be a major global health challenge, driving the urgent need for innovative therapeutic strategies. This study evaluates the anticancer and immunomodulatory potential of skimmianine in breast cancer through a comprehensive approach, integrating biochemical, histopathological, immunohistochemical, and bioinformatics [...] Read more.

Background/Objectives: Breast cancer continues to be a major global health challenge, driving the urgent need for innovative therapeutic strategies. This study evaluates the anticancer and immunomodulatory potential of skimmianine in breast cancer through a comprehensive approach, integrating biochemical, histopathological, immunohistochemical, and bioinformatics analyses. Methods: Thirty-six female Wistar albino rats were divided into three groups: control, 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer, and DMBA + skimmianine (n = 12/group). Breast cancer was induced with a single oral dose of 50 mg/kg DMBA in sesame oil. After 16 weeks, skimmianine (40 mg/kg) was administered intraperitoneally for four weeks. Serum CA15-3 levels were measured via enzyme-linked immunosorbent assay (ELISA). Histopathological assessment was performed using hematoxylin and eosin (H&E) staining, and proliferating cell nuclear antigen (PCNA) and tumor necrosis factor-alpha (TNF-α) were evaluated immunohistochemically. Pathway and hub gene analyses were performed using Cytoscape, functional annotation with Enrichr, and immune analyses via the Tumor and Immune System Interaction Database (TISIDB) and Sangerbox. Results: The tumor burden in the animals increased after DMBA induction compared to the control groups (0.00 ± 0.00% vs. 89.00 ± 6.60%, respectively, p < 0.001), while skimmianine treatment significantly reduced the tumor burden in the animals (49.00 ± 9.40%, vs. DMBA group, p = 0.191). Histopathological analysis showed DMBA-induced structural disorganization and malignant clustering, whereas skimmianine preserved ductal structures and mitigated the damage. Compared to the control group, DMBA administration markedly elevated serum CA15-3 levels (0.23 ± 0.06 ng/mL vs. 8.57 ± 1.01 ng/mL, respectively), along with PCNA (13.0 ± 3.0% vs. 25.0 ± 4.0%, respectively) and TNF-α (8.4 ± 1.7% vs. 34.0 ± 5.3%, respectively) expression, indicating active tumor progression. Skimmianine treatment significantly reduced CA15-3 (3.72 ± 0.58 ng/mL), PCNA (20.0 ± 4.1%), and TNF-α (25.0 ± 3.9%) levels (p < 0.001). In silico analyses indicated skimmianine’s effects on PCNA influence cell cycle pathways, while TNF-α suppression impacts toll-like receptor (TLR) signaling (adjusted p < 0.05). PCNA- and TNF-α-related anticancer effects were especially notable in basal molecular and C2 immune subtypes (p < 0.05). Related hub proteins may regulate immune dynamics by reducing immunosuppression and tumor-promoting inflammation (p < 0.05). Conclusions: Skimmianine shows promise as a breast cancer therapy by simultaneously targeting tumor growth and immune regulation, with PCNA and TNF-α identified as potential key players. Full article

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

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30 pages, 3204 KiB

Open AccessArticle

Design, Synthesis, and Evaluation of Antinociceptive Properties of Novel CBD-Based Terpene-Cinnamoyl-Acyl-Hydrazone Analogues

by Mikaela Lucinda de Souza, João Pedro Barros de Paiva, Graziella dos Reis Rosa Franco, Vanessa Silva Gontijo, Marina Amaral Alves, Hygor Marcos Ribeiro de Souza, Anna Carolina Pereira Lontra, Eduardo Araújo de Oliveira, Thaís Biondino Sardella Giorno, Isabella Alvim Guedes, Laurent Emmanuel Dardenne, Patrícia Dias Fernandes and Claudio Viegas Jr.

Pharmaceuticals 2025, 18(5), 755; https://doi.org/10.3390/ph18050755 - 20 May 2025

Abstract

Background/Objectives: Cannabidiol (CBD) has been reported for its antinociceptive, anti-inflammatory, and neuroprotective activities. However, several legal restrictions on its medicinal uses and even research have contributed to the development of synthetic analogues. Therefore, the aim of this study was the design and [...] Read more.

Background/Objectives: Cannabidiol (CBD) has been reported for its antinociceptive, anti-inflammatory, and neuroprotective activities. However, several legal restrictions on its medicinal uses and even research have contributed to the development of synthetic analogues. Therefore, the aim of this study was the design and synthesis of a novel series of CBD-based structural analogues, and the in vivo evaluation of their potential antinociceptive activity. Methods: Using a two-step synthetic route, 26 new terpene-cinnamoyl acyl-hydrazone analogues were obtained and were submitted to in vivo screening in the classical formalin-induced paw edema and hot plate assays. Results: The compounds PQM-292, PQM-293, PQM-295, PQM-307, PQM-308, and PQM-309 exhibited the best results in the neurogenic phase (first phase) of the formalin-induced licking response, showing comparable results to morphine. Notably, in the inflammatory phase (second phase), compound PQM-292 exhibited the best anti-inflammatory activity. Interestingly, in the hot plate model, six other compounds (PQM-274, PQM-291, PQM-294, PQM-304, PQM-305, and PQM-378) showed the best antinociceptive activity in comparison to morphine, especially PQM-274, which exhibited an antinociceptive effect almost equivalent to the reference drug. Interestingly, these findings suggested that these bioactive compounds, despite their structural similarity, act through different mechanisms, which were investigated by molecular docking with CB1, CB2, and TRPV1 receptors. In silico results indicated that the most active compounds should act through different mechanisms, probably involving interactions with TRPA1. Conclusions: Therefore, due to the promising antinociceptive activity observed for these highlighted compounds, particularly for PQM-292 and PQM-274, without apparent toxicity and psychoactive effects, and the possible involvement of diverse mechanisms of action, these compounds could be considered as promising starting points to the development of new drug candidate prototypes of clinical interest. Full article

(This article belongs to the Special Issue A Commemorative Special Issue in Honor of Professor Carlos Alberto Manssour Fraga: Medicinal Chemistry’s Efforts to Discover Novel Bioactive Molecules for Complex Diseases)

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13 pages, 1642 KiB

Open AccessArticle

Efficacy and Safety of a Single Ivy Extract Versus Two Herbal Extract Combinations in Patients with Acute Bronchitis: A Multi-Center, Randomized, Open-Label Clinical Trial

by Peter Kardos, Justus de Zeeuw, Inga Trompetter, Simon Braun and Yuliya Ilieva

Pharmaceuticals 2025, 18(5), 754; https://doi.org/10.3390/ph18050754 - 20 May 2025

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Abstract

Background: The combination therapy for acute bronchitis with several plant extracts, such as Ivy and Thyme or Primrose and Thyme, is assumed to offer added benefit over single extract preparations. However, no clinical trials have yet demonstrated such a therapeutic advantage. Methods [...] Read more.

Background: The combination therapy for acute bronchitis with several plant extracts, such as Ivy and Thyme or Primrose and Thyme, is assumed to offer added benefit over single extract preparations. However, no clinical trials have yet demonstrated such a therapeutic advantage. Methods: In this three-arm, open-label, randomized clinical trial, patients with acute bronchitis were assigned to groups receiving Ivy extract EA 575 (Prospan^® Cough Drops), Ivy/Thyme extract combination (Bronchipret^® Drops), or Thyme/Primrose extract combination (Bronchicum^® Drops) according to their respective labels. The primary endpoint was the assessment of non-inferiority, and the second endpoint was the assessment of superiority of Ivy vs. each of the two comparators (Ivy/Thyme and Thyme/Primrose) regarding the change in Bronchitis Severity Score between baseline and day 7. In total, 325 adult patients were considered for evaluation. Results: Non-inferiority of Ivy extract was statistically significant against both comparators (both p < 0.0001). Superiority of Ivy extract was statistically significant against Ivy/Thyme extract (p < 0.0001) but missed statistical significance against Thyme/Primrose extract (p < 0.0607). The incidence of adverse events was low and comparable between the groups. All adverse events were non-serious. Conclusions: these data revealed that Ivy extract EA 575 is non-inferior in acute bronchitis treatment compared to both comparators and superior to Ivy/Thyme. Full article

(This article belongs to the Section Natural Products)

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22 pages, 292 KiB

Open AccessReview

Lp(a)-Lowering Agents in Development: A New Era in Tackling the Burden of Cardiovascular Risk?

by Niki Katsiki, Michal Vrablik, Maciej Banach and Ioanna Gouni-Berthold

Pharmaceuticals 2025, 18(5), 753; https://doi.org/10.3390/ph18050753 - 19 May 2025

Viewed by 186

Abstract

Lipoprotein (a) [Lp(a)] has been recognized as an independent, inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, thus representing a major target of residual CV risk. Currently, no drug has been officially approved for lowering Lp(a) levels, and [...] Read more.

Lipoprotein (a) [Lp(a)] has been recognized as an independent, inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, thus representing a major target of residual CV risk. Currently, no drug has been officially approved for lowering Lp(a) levels, and in clinical practice, Lp(a) is mainly used to (re)define CV risk, particularly in individuals at borderline CV risk and people with a family history of premature coronary heart disease, according to various guidelines. Specific Lp(a)-targeted antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) agents have been developed to produce substantial Lp(a) reductions via the inhibition of apo(a) synthesis in the liver. These drugs are conjugated to N-acetylgalactosamine (GalNAc) to ensure their binding to asialoglycoproteins, which are specifically expressed on the surface of the hepatocytes. Such drugs include pelacarsen (an injectable ASO) and olpasiran, zerlasiran, and lepodisiran (injectable siRNA agents). Muvalaplin represents another therapeutic option to lower Lp(a) levels, since it is an oral selective small molecule inhibitor of Lp(a) formation, thus potentially exerting certain advantages in terms of its clinical use. The present narrative review summarizes the available clinical data on the efficacy and safety of these investigational Lp(a)-lowering therapies, as reported in phase 1 and 2 trials. The effects of these drugs on other [aside from Lp(a)] lipid parameters are also discussed. The phase 3 CV trial outcomes are ongoing for some of these agents (i.e., pelacarsen, olpasiran, and lepodisiran) and are briefly mentioned. Overall, there is an urgent need for evidence-based guidelines on Lp(a) reduction in daily clinical practice, following the results of the phase 3 CV trials, as well as for establishing the ideal Lp(a) quantification method (i.e., using an apo(a) isoform-independent assay with appropriate calibrators, reporting the Lp(a) level in molar units). Full article

(This article belongs to the Section Pharmacology)

22 pages, 2577 KiB

Open AccessArticle

Characterization of the Compounds Present in Bougainvillea x buttiana (var. Rose) with Healing Activity in a Murine Model

by Luís Martínez-Cuevas, Mayra Cedillo-Cortezano, Blanca Nury Echeverria Guerrero, Rodolfo Abarca-Vargas and Vera L. Petricevich

Pharmaceuticals 2025, 18(5), 752; https://doi.org/10.3390/ph18050752 - 19 May 2025

Viewed by 273

Abstract

Background/Objective: Bougainvillea x buttiana of the Nyctagenaceae family is widely used in traditional Mexican medicine for treating different diseases. This study was planned to estimate the healing effect of the acetonic extract obtained from Bougainvillea x buttiana (var. Rose). Methods: The bracts [...] Read more.

Background/Objective: Bougainvillea x buttiana of the Nyctagenaceae family is widely used in traditional Mexican medicine for treating different diseases. This study was planned to estimate the healing effect of the acetonic extract obtained from Bougainvillea x buttiana (var. Rose). Methods: The bracts with flowers were subjected to extraction using maceration and concentrated in vacuo. Fractionation with a similar profile resulted in 11 fractions, which were determined using TLC. A mouse wound excision model was tested to evaluate the wound healing effect of the topical treatment pre-formulated with fractions of acetonic extract, which were determined using image analysis techniques. Cytokine levels present in the sera of mice treated or not treated with the acetonic extract were determined using the ELISA method. Results: The results obtained showed that the crude acetonic extract of B. x buttiana and/or its fractions in a pre-formulated hydrogel had wound healing capacity. The wound contraction rate and the healing speed in groups of animals treated with the pre-formulated crude extract and/or its fractions were significantly higher compared with the negative control (p < 0.001). Fraction 2 demonstrated more significant healing, reduced the production of cytokines such as IL-6 and TNF-α, and enhanced the levels of IL-10. Conclusion: The present study showed that the fractions obtained from the acetonic extract of B. x buttiana bracts were able to accelerate the wound healing process through anti-inflammatory mechanisms by regulating inflammatory cytokines. The results presented demonstrate that the extracts from B. x buttiana contain compounds that may be responsible for their healing properties. Full article

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

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24 pages, 1060 KiB

Open AccessReview

Near-Infrared Photoimmunotherapy in Brain Tumors—An Unexplored Frontier

by Haruka Yamaguchi, Masayasu Okada, Takuya Otani, Jotaro On, Satoshi Shibuma, Toru Takino, Jun Watanabe, Yoshihiro Tsukamoto, Ryosuke Ogura, Makoto Oishi, Takamasa Suzuki, Akihiro Ishikawa, Hideyuki Sakata and Manabu Natsumeda

Pharmaceuticals 2025, 18(5), 751; https://doi.org/10.3390/ph18050751 - 19 May 2025

Viewed by 80

Abstract

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer treatment that uses near-infrared light to activate a conjugate of a monoclonal antibody (mAb) and a photoactivatable silica phthalocyanine dye (IRDye700DX: IR700). Unlike conventional photodynamic therapy (PDT), NIR-PIT selectively destroys targeted tumor cells while preserving the [...] Read more.

Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer treatment that uses near-infrared light to activate a conjugate of a monoclonal antibody (mAb) and a photoactivatable silica phthalocyanine dye (IRDye700DX: IR700). Unlike conventional photodynamic therapy (PDT), NIR-PIT selectively destroys targeted tumor cells while preserving the surrounding normal tissue and providing superior tissue penetration. Recently, NIR-PIT has been approved for the treatment of unresectable recurrent head and neck cancers in Japan. It induces highly selective cancer cell death; therefore, it is expected to be a new curative treatment option for various cancers, including brain tumors. In this review, we compare the principles of NIR-PIT and PDT and discuss the potential applications of NIR-PIT for brain tumors. We selected targetable proteins across various types of brain tumors and devised a strategy to effectively pass the mAb–IR700 conjugate through the blood–brain barrier (BBB), which is a significant challenge for NIR-PIT in treating brain tumors. Innovative approaches for delivering the mAb–IR700 conjugate across the BBB include exosomes, nanoparticle-based systems, and cell-penetrating peptides. Small-molecule compounds, such as affibodies, are anticipated to rapidly accumulate in tumors within intracranial models, and our preliminary experiments demonstrated rapid uptake. NIR-PIT also induces immunogenic cell death and activates the anti-tumor immune response. Overall, NIR-PIT is a promising approach for treating brain tumors. It has the potential to overcome the limitations of conventional therapies and offers new hope to patients with brain tumors. Full article

(This article belongs to the Special Issue Antibody-Based Imaging and Targeted Therapy in Cancer)

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24 pages, 1755 KiB

Open AccessArticle

Exploring the Anticancer Properties of 1,2,3-Triazole-Substituted Andrographolide Derivatives

by Joana R. L. Ribeiro, Juliana Calheiros, Rita A. M. Silva, Bruno M. F. Gonçalves, Carlos A. M. Afonso, Lucília Saraiva and Maria-José U. Ferreira

Pharmaceuticals 2025, 18(5), 750; https://doi.org/10.3390/ph18050750 - 19 May 2025

Viewed by 158

Abstract

Background/Objectives: The search for new anticancer agents from natural sources remains a key strategy in drug discovery. This study aimed to synthesize and evaluate novel triazole derivatives of the diterpenic lactone andrographolide for their antiproliferative activity against various cancer cell lines. Methods [...] Read more.

Background/Objectives: The search for new anticancer agents from natural sources remains a key strategy in drug discovery. This study aimed to synthesize and evaluate novel triazole derivatives of the diterpenic lactone andrographolide for their antiproliferative activity against various cancer cell lines. Methods: Twenty-two new triazole derivatives (5–26), of the triacetyl derivative (2) of the diterpenic lactone andrographolide (1), were synthesized via the azide-alkyne “click reaction”. The antiproliferative effects of compounds 1–26 were evaluated using the sulforhodamine B assay against a panel of cancer cell lines and a non-tumorigenic colon cell line. A representative compound, triazole derivative 12, was further evaluated in human pancreatic ductal adenocarcinoma (PANC-1) cells for its effects on the cell cycle, apoptosis, migration, and drug synergy with 5-fluorouracil. Results: Several compounds, specifically, 9, 14, 16, and 17, bearing a phenyl moiety, exhibited improved antiproliferative activity compared to the parental compound 1. Derivative 12, selected for further investigation, induced G2/M cell cycle arrest and apoptosis in a concentration-dependent manner. Additionally, this compound significantly reduced cell migration and demonstrated synergistic effects with 5-fluorouracil in PANC-1 cells. Conclusions: The synthesized andrographolide-based triazole derivatives, particularly compound 12, showed promising antiproliferative activity and mechanisms relevant to cancer therapy. These findings support their potential as lead compounds for further development in anticancer research. Full article

(This article belongs to the Special Issue Drug Target Exploration and Drug Design & Development Based on Small Molecule)

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19 pages, 3107 KiB

Open AccessArticle

Potential of Aframomum melegueta and Xylopia aethiopica Against Taenia spp.: Plant-Based Remedies as Novel Anthelmintics

by Fekandine V. Douti, Gnatoulma Katawa, Kathrin Arndts, Fagdéba D. Bara, Essimanam R. Awesso, Simplice D. Karou, Achim Hoerauf and Manuel Ritter

Pharmaceuticals 2025, 18(5), 749; https://doi.org/10.3390/ph18050749 - 19 May 2025

Viewed by 153

Abstract

Background/Objectives: Taeniasis, a zoonotic infection, is a common foodborne disease. Niclosamide and praziquantel have proven to be effective in treating it, but the use of the same drugs can lead to resistance, so alternative drugs need to be explored. This study investigated the [...] Read more.

Background/Objectives: Taeniasis, a zoonotic infection, is a common foodborne disease. Niclosamide and praziquantel have proven to be effective in treating it, but the use of the same drugs can lead to resistance, so alternative drugs need to be explored. This study investigated the anthelmintic potential of derived fractions from hydroethanolic extracts (HEs) of Aframomum melegueta (AM) and Xylopia aethiopica (XA), two medicinal plants known for their diverse bioactive properties. Methods: AM-HE fractions (dichloromethane fraction (DCMF), ether fraction (EF), aqueous fraction (AF)) and XA-HE fractions (chloroform fraction (CF), ether fraction (EF), and aqueous fraction (AF)) were used, and in vitro anthelmintic activity was assessed against Taenia spp. by using an adult motility assay for the worm’s paralysis time determination. The parasiticidal and parasitostatic activity was also tested on Taenia spp. adult worms. Cell viability was further evaluated using propidium iodide (PI) staining, with albendazole (20 mg/mL) as the reference drug. Results: The three fractions of each plant exhibited significant, dose-dependent anthelmintic activity, with AM-HE and XA-CF showing the greatest effects at 20 mg/mL. AM-EF demonstrated significant activity at 0.4% and 0.8%. Irreversibility tests revealed that most of the treated worms remained paralysis, except those exposed to the AF of both plants. PI staining confirmed the dose-dependent mortality of Taenia cells treated with HE, DCMF, and AF of AM. Conclusions: These results underscore the potential of AM and XA extracts and fractions as alternative treatments for helminth infections. Further, in vivo studies are warranted to confirm their safety and therapeutic efficacy. Full article

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

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14 pages, 1249 KiB

Open AccessArticle

Model-Based Evaluation of HangAmDan-B1 and Afatinib Combination Therapy in HCC827 Xenograft Mice with Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

by Sung-yoon Yang, Lien Thi Ngo, Soyoung Lee, Hwi-yeol Yun, Tham Thi Bui, Dong-Hyeon Kim, Jung-woo Chae and Sojung Park

Pharmaceuticals 2025, 18(5), 748; https://doi.org/10.3390/ph18050748 - 19 May 2025

Viewed by 171

Abstract

Objectives: HangAmDan-B1 (HAD-B1), a blended herbal mixture, has been investigated as an adjuvant therapy with afatinib (AFT) to treat non-small lung cancer (NSCLC). Although preclinical studies demonstrated promising synergistic results, clinical trials have not yet confirmed the expected benefits. This study aims to [...] Read more.

Objectives: HangAmDan-B1 (HAD-B1), a blended herbal mixture, has been investigated as an adjuvant therapy with afatinib (AFT) to treat non-small lung cancer (NSCLC). Although preclinical studies demonstrated promising synergistic results, clinical trials have not yet confirmed the expected benefits. This study aims to quantitatively examine the exposure–response relationship and synergistic interactions through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: A PK/PD model was established and validated based on tumor growth profiles from a xenograft mouse study of gefitinib-resistant HCC827. Model-based simulations were performed to predict and assess therapeutic effects across different treatment groups. Results: The PK/PD model confirmed HAD-B1 enhances the potency of AFT by 1.45-fold. Model-based simulations predicted that combination treatment maintains a lower tumor size compared to AFT monotherapy. Conclusions: This study quantitatively demonstrated the synergistic interaction between HAD-B1 and AFT. The developed PK/PD model provides insights into potential dosing strategies to treat NSCLC resistant to EGFR-TKIs. Further clinical trials are warranted to validate these findings and refine dosing strategies to improve therapeutic outcomes. Full article

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

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13 pages, 2763 KiB

Open AccessCommunication

Comparison of Anti-Renal Fibrosis Activity of Eucommiae cortex Extract and Its Microbial Fermentation Products

by Zhengyou He, Wenyi Jiang, Ruijiao Yao, Wenyan Xiao, Zhiyang Chen, Miao Zheng, Xia Zeng, Jia Li, Zhengwen Li and Yong Jiang

Pharmaceuticals 2025, 18(5), 747; https://doi.org/10.3390/ph18050747 - 19 May 2025

Viewed by 124

Abstract

Background: Renal fibrosis is a common pathological feature of all progressive chronic kidney disease (CKD). Eucommiae cortex (EC) is a valuable economic tree species endemic to China. The microbial fermentation of Chinese medicines can release their active ingredients as effectively as possible or [...] Read more.

Background: Renal fibrosis is a common pathological feature of all progressive chronic kidney disease (CKD). Eucommiae cortex (EC) is a valuable economic tree species endemic to China. The microbial fermentation of Chinese medicines can release their active ingredients as effectively as possible or produce new active ingredients with enhanced efficacy and reduced toxic side effects; Methods: The microbial fermentation of EC can produce pinoresinol (Pin) and dehydrodiconiferyl alcohol (DA). In this study, C57 BL/6 mice were fed a diet containing 0.2% adenine, resulting in a model of chronic kidney disease. The effects of EC and EC ferment (ECF) on CKD were explored by the exogenous supplementation of EC and ECF; Results: The results of the study showed that exogenous supplementation with EC and ECF suc-cessfully reduced creatinine and urea nitrogen levels, down-regulated the expression levels of TGF-β1, α-SMA, Smad3, and phospho-Smad3 in the TGF-β1/Smad signaling pathway, and ameliorated renal fibrosis; Conclusions: Both EC and ECF may have reno-protective effects and provide a reference for relevant clinical drug development. Full article

(This article belongs to the Section Natural Products)

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23 pages, 1422 KiB

Open AccessReview

Harnessing the Power of Nanocarriers to Exploit the Tumor Microenvironment for Enhanced Cancer Therapy

by Bandar Aldhubiab, Rashed M. Almuqbil and Anroop B. Nair

Pharmaceuticals 2025, 18(5), 746; https://doi.org/10.3390/ph18050746 - 19 May 2025

Viewed by 221

Abstract

The tumor microenvironment (TME) has a major role in malignancy and its complex nature can mediate tumor survival, metastasis, immune evasion, and drug resistance. Thus, reprogramming or regulating the immunosuppressive TME has a significant contribution to make in cancer therapy. Targeting TME with [...] Read more.

The tumor microenvironment (TME) has a major role in malignancy and its complex nature can mediate tumor survival, metastasis, immune evasion, and drug resistance. Thus, reprogramming or regulating the immunosuppressive TME has a significant contribution to make in cancer therapy. Targeting TME with nanocarriers (NCs) has been widely used to directly deliver anticancer drugs to control TME, which has revealed auspicious outcomes. TME can be reprogrammed by using a range of NCs to regulate immunosuppressive factors and activate immunostimulatory cells. Moreover, TME can be ameliorated via regulating the redox environment, oxygen content, and pH value of the tumor site. NCs have the capacity to provide site-specific delivery of therapeutic agents, controlled release, enhanced solubility and stability, decreased toxicities, and enhanced pharmacokinetics as well as biodistribution. Numerous NCs have demonstrated their potential by inducing distinct anticancer mechanisms by delivering a range of anticancer drugs in various preclinical studies, including metal NCs, liposomal NCs, solid lipid NCs, micelles, nanoemulsions, polymer-based NCs, dendrimers, nanoclays, nanocrystals, and many more. Some of them have already received US Food and Drug Administration approval, and some have entered different clinical phases. However, there are several challenges in NC-mediated TME targeting, including scale-up of NC-based cancer therapy, rapid clearance of NCs by the mononuclear phagocyte system, and TME heterogeneity. In order to harness the full potential of NCs in tumor treatment, there are several factors that need to be carefully studied, including optimization of drug loading into NCs, NC-associated immunogenicity, and biocompatibility for the successful translation of NC-based anticancer therapies into clinical practice. In this review, a range of NCs and their applications in drug delivery to remodel TME for cancer therapy are extensively discussed. Moreover, findings from numerous preclinical and clinical studies with these NCs are also highlighted. Full article

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

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2 pages, 780 KiB

Open AccessCorrection

Correction: Aboubakr et al. Antioxidant and Anti-Inflammatory Potential of Thymoquinone and Lycopene Mitigate the Chlorpyrifos-Induced Toxic Neuropathy. Pharmaceuticals 2021, 14, 940

by Mohamed Aboubakr, Said M. Elshafae, Ehab Y. Abdelhiee, Sabreen E. Fadl, Ahmed Soliman, Afaf Abdelkader, Mohamed M. Abdel-Daim, Khaled A. Bayoumi, Roua S. Baty, Enas Elgendy, Amira Elalfy, Bodour Baioumy, Samah F. Ibrahim and Ahmed Abdeen

Pharmaceuticals 2025, 18(5), 745; https://doi.org/10.3390/ph18050745 - 19 May 2025

Viewed by 69

Abstract

In the original publication, there was a mistake in Figure 6H as published [...] Full article

22 pages, 9092 KiB

Open AccessArticle

α-Glucosidase Inhibition Mechanism and Anti-Hyperglycemic Effects of Flavonoids from Astragali Radix and Their Mixture Effects

by Xing Han, Pengpu Wang, Jing Zhang, Yang Lv, Zhigao Zhao, Fengxian Zhang, Mingying Shang, Guangxue Liu, Xuan Wang, Shaoqing Cai and Feng Xu

Pharmaceuticals 2025, 18(5), 744; https://doi.org/10.3390/ph18050744 - 18 May 2025

Viewed by 201

Abstract

Background: Inhibition of intestinal α-glucosidase is a key strategy for controlling postprandial hyperglycemia in diabetes. Astragali Radix (AR), a traditional medicinal and dietary herb widely consumed in China, is rich in flavonoids that are believed to exhibit hypoglycemic properties. Methods: A [...] Read more.

Background: Inhibition of intestinal α-glucosidase is a key strategy for controlling postprandial hyperglycemia in diabetes. Astragali Radix (AR), a traditional medicinal and dietary herb widely consumed in China, is rich in flavonoids that are believed to exhibit hypoglycemic properties. Methods: A total of 29 AR-related flavonoids, including both original constituents and metabolites, were screened for α-glucosidase inhibitory activity using in vitro enzymatic assays. Mechanistic investigations were conducted through enzyme kinetics, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), and molecular docking. The in vivo hypoglycemic effects were assessed using a postprandial hyperglycemic mouse model. Additionally, potential mixture effects of flavonoid combinations were evaluated. Results: Of the 29 flavonoids, 16 demonstrated significant α-glucosidase inhibitory activity, with five (C3, C17, C19, C28, and C29) identified as novel inhibitors. Structure–activity relationship (SAR) analysis revealed that hydroxylation, particularly at the C-3 position, enhanced activity, while glycosylation and methoxylation reduced it. Mechanistic studies demonstrated that these compounds bind to distinct amino acid residues within the active site of α-glucosidase, inducing conformational changes and exerting different types of inhibition, leading to varying inhibitory mechanisms. Additionally, 15 compounds reduced postprandial blood glucose levels, with C3, C16, C17, C19, and C28 confirmed as novel in vivo inhibitors. Notably, two compositions of flavonoids combined at their individually ineffective concentrations exhibited significant inhibitory effects. Conclusions: This study provides a comprehensive evaluation of AR-related flavonoids as α-glucosidase inhibitors and offers valuable insights for the development of highly effective, low-toxicity, flavonoid-based, antidiabetic therapeutics and functional foods. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 3321 KiB

Open AccessArticle

Improvement of the Solubility, Permeability, and Pharmacological Activity of Decoquinate-Loaded Hydroxypropyl-β-Cyclodextrin–Tea Saponins Ternary ComplexA

by Wei Wei, Qihong Zhang and Weike Su

Pharmaceuticals 2025, 18(5), 743; https://doi.org/10.3390/ph18050743 - 18 May 2025

Viewed by 156

Abstract

Objectives: This study was performed to simultaneously improve the solubility, permeability, and pharmacological activity of decoquinate (DQ). Methods: A ternary DQ solid dispersion with hydroxypropyl-β-cyclodextrin (HP-β-CD) and tea saponin (TS) was mechanochemically prepared to enhance the efficacy of DQ. [...] Read more.

Objectives: This study was performed to simultaneously improve the solubility, permeability, and pharmacological activity of decoquinate (DQ). Methods: A ternary DQ solid dispersion with hydroxypropyl-β-cyclodextrin (HP-β-CD) and tea saponin (TS) was mechanochemically prepared to enhance the efficacy of DQ. Results: The encapsulation efficiency of the ternary complex reached 93.51%, and the drug loading was 9.48%. The mean particle size was 90.88 ± 0.44 nm. The polydispersity index was 0.244 ± 0.004, and the zeta potential was −38.81 ± 0.75 mV. The sugar ring moiety formed multiple hydrogen bonds with the surface of HP-β-CD, creating favorable conditions for the development of a stable ternary complex through sophisticated molecular interactions that facilitated its assembly. In vivo studies demonstrated that the DQ/HP-β-CD/TS ternary complex drinking water demonstrated superior anticoccidial activity compared to pure DQ and commercial feed formulations against Eimeria tenella. Conclusions: This innovative mechanochemically synthesized ternary complex demonstrates remarkable promise for improving DQ-based formulations, as it simultaneously boosts aqueous solubility, permeability, and therapeutic efficacy. These synergistic enhancements position the compound as a strong candidate for pharmaceutical development. Full article

(This article belongs to the Topic Personalized Drug Formulations)

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27 pages, 550 KiB

Open AccessSystematic Review

Anti-Suicidal Effects of Lithium, Ketamine, and Clozapine—A 10-Year Systematic Review

by Przemyslaw M. Waszak, Jan Opalko, Natalia Olszańska and Paweł Zagożdżon

Pharmaceuticals 2025, 18(5), 742; https://doi.org/10.3390/ph18050742 - 18 May 2025

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Abstract

Background/Objectives: Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality. Methods: A systematic search was conducted across [...] Read more.

Background/Objectives: Suicide is a complex issue resulting in approximately 700,000 deaths annually. Individuals with mood disorders or schizophrenia are at an increased risk. Pharmacological interventions, such as lithium, clozapine, and ketamine, show promise in reducing suicidality. Methods: A systematic search was conducted across Google Scholar, Scopus, and PubMed to identify studies evaluating the effects of lithium, clozapine, and ketamine on suicidality. Peer-reviewed articles published between 2014 and 2024 that focused on adult populations were included. After screening 1297 records, 49 studies met the eligibility criteria: 14 on lithium, 23 on ketamine, and 12 on clozapine. Results: Multiple studies highlight lithium’s significant anti-suicidal effects in patients with bipolar disorder, showing superior suicide risk reduction compared to valproate and other mood stabilizers. Ketamine has been shown to rapidly reduce suicidal ideation, with effects observable within hours and lasting up to a week. While most studies support its short-term efficacy, findings regarding its long-term benefits and the impact of repeated dosing remain inconsistent. Clozapine has consistently demonstrated a reduction in suicide risk for individuals with schizophrenia. Large-scale cohort studies report a significant decrease in suicide attempts and mortality when compared to other antipsychotics. Conclusions: Lithium, ketamine, and clozapine were proven to be effective in reducing suicidality. However, limited data, adherence challenges, and methodological differences across studies highlight the need for more robust, large-scale experimental research. Effective suicide prevention is an extremely complex topic and also requires consideration of healthcare and social system factors. Full article

(This article belongs to the Special Issue Recent Advances in Psychiatric Medications)

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22 pages, 7800 KiB

Open AccessArticle

In Silico Identification of 2,4-Diaminopyrimidine-Based Compounds as Potential CK1ε Inhibitors

by Axel A. Sánchez-Álvarez, Marco A. Velasco-Velázquez and Luis Cordova-Bahena

Pharmaceuticals 2025, 18(5), 741; https://doi.org/10.3390/ph18050741 - 17 May 2025

Viewed by 583

Abstract

Background: Casein kinase 1 epsilon (CK1ε) plays a critical role in cancer progression by activating oncogenic signaling pathways, making it a target for cancer therapy. However, no inhibitors are currently available for clinical use, highlighting the need for novel therapeutic candidates. Methods: This [...] Read more.

Background: Casein kinase 1 epsilon (CK1ε) plays a critical role in cancer progression by activating oncogenic signaling pathways, making it a target for cancer therapy. However, no inhibitors are currently available for clinical use, highlighting the need for novel therapeutic candidates. Methods: This study aimed to identify potential CK1ε inhibitors. To achieve this, a modified version of a previously reported pharmacophore model was applied to an ultra-large database of over 100 million compounds for virtual screening. Hits were filtered based on drug-likeness and pH-dependent pharmacophore compliance and then grouped according to their structural core. A representative compound from each structural group underwent molecular dynamic (MD) simulations and binding free energy calculations to predict its stability and affinity, allowing extrapolation of the results to the entire set of candidates. Results: Pharmacophore matching initially identified 290 compounds. After energy minimization, and an assessment of drug-likeness and pharmacophore compliance, we selected 29 structurally related candidates. MD simulations showed that most of the compounds representative of structural groups had stable binding modes, favorable intermolecular interactions, and free energies comparable to those of previously reported CK1ε inhibitors. An analysis of additional members of the most promising structural group showed that two 2,4-diaminopyrimidine-based compounds likely inhibit CK1ε. Conclusions: These findings provide structural insights into the design of CK1ε inhibitors, supporting compound optimization and the eventual development of targeted cancer therapeutics. Full article

(This article belongs to the Section Medicinal Chemistry)

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24 pages, 430 KiB

Open AccessReview

State-of-the-Art Evidence for Clinical Outcomes and Therapeutic Implications of Janus Kinase Inhibitors in Moderate-to-Severe Ulcerative Colitis: A Narrative Review

by Yunseok Choi, Suhyun Lee, Hyeon Ji Kim, Taemin Park, Won Gun Kwack, Seungwon Yang and Eun Kyoung Chung

Pharmaceuticals 2025, 18(5), 740; https://doi.org/10.3390/ph18050740 - 17 May 2025

Viewed by 185

Abstract

Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing inflammation and incomplete response to conventional therapies. Although biologics have advanced UC management, many patients with moderate-to-severe disease experience treatment failure, relapse, or adverse effects. This review evaluates the [...] Read more.

Background/Objectives: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing inflammation and incomplete response to conventional therapies. Although biologics have advanced UC management, many patients with moderate-to-severe disease experience treatment failure, relapse, or adverse effects. This review evaluates the pharmacology, efficacy, and safety of oral Janus kinase (JAK) inhibitors—tofacitinib, upadacitinib, and filgotinib—to guide their clinical use in UC. Methods: A comprehensive literature review was conducted using the PubMed, Embase, Cochrane, and Web of Science databases to identify relevant studies on JAK inhibitors in UC. The review included Phase 3 randomized controlled trials (RCTs), real-world observational studies, and recent network meta-analyses. We assessed pharmacologic profiles, clinical efficacy, and safety data for tofacitinib, upadacitinib, and filgotinib. Additionally, we reviewed emerging pipeline agents and future directions in oral immunomodulatory therapy for UC. Results: All three agents demonstrated efficacy in the induction and maintenance of remission. Upadacitinib showed superior performance, including rapid symptom control, high clinical remission rates, and favorable long-term outcomes in both biologic-naïve and -experienced patients. Tofacitinib offered strong efficacy, particularly in early response, but was associated with higher risks of herpes zoster and thromboembolic events. Filgotinib provided moderate efficacy with a favorable safety profile, making it suitable for risk-averse populations. Meta-analyses consistently ranked upadacitinib highest in clinical efficacy and onset of action. Conclusions: JAK inhibitors offer effective and convenient oral treatment options for moderate-to-severe UC. Upadacitinib emerges as a high-efficacy agent; tofacitinib and filgotinib remain valuable based on patient-specific risk profiles. Future studies are needed to clarify optimal sequencing, long-term safety, and the role of emerging agents or combination therapies. Full article

(This article belongs to the Section Pharmacology)

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26 pages, 7275 KiB

Open AccessArticle

Novel Potent and Selective Dopamine D4 Receptor Piperidine Antagonists as Potential Alternatives for the Treatment of Glioblastoma

by Federica Matteucci, Pegi Pavletić, Alessandro Bonifazi, Rian Garland, Hideaki Yano, Consuelo Amantini, Laura Zeppa, Emanuela Sabato, Giulio Vistoli, Valerio Mammoli, Loredana Cappellacci, Fabio Del Bello, Gianfabio Giorgioni, Riccardo Petrelli, Alessia Piergentili, Wilma Quaglia and Alessandro Piergentili

Pharmaceuticals 2025, 18(5), 739; https://doi.org/10.3390/ph18050739 - 17 May 2025

Viewed by 213

Abstract

Background/Objectives: D4R antagonists have recently been suggested as potential therapeutic alternatives to the standard treatments of glioblastoma (GBM). In this study, new piperidine-based ligands, analogs of the potent and selective D4R compounds 77-LH-28-1 (7) and its 4-benzyl analog 8, [...] Read more.

Background/Objectives: D4R antagonists have recently been suggested as potential therapeutic alternatives to the standard treatments of glioblastoma (GBM). In this study, new piperidine-based ligands, analogs of the potent and selective D4R compounds 77-LH-28-1 (7) and its 4-benzyl analog 8, were synthesized and studied to investigate the effects produced by variations in the distances between the pharmacophoric features on the D4R affinity and selectivity. Methods: All the new compounds 9–20 were evaluated for their radioligand binding affinity at D2-like receptor subtypes and the results were rationalized by docking studies and molecular dynamics (MD) simulations. The functional profiles of the most interesting derivatives were assessed at D4R Go and Gi protein and β-arrestin by BRET assay and their potential anticancer activity was determined in GBM cell lines. Results: Radioligand binding results highlighted that the derivatives bearing a terminal butyl chain showed structure–activity relationships different from those with a benzyl terminal. From functional studies performed on the best derivatives 12 and 16, the response profiles of both compounds were more robust in antagonist mode, with derivative 16 showing higher antagonist potency than 12 across all three transducers. Interestingly, 12 and 16 dose-dependently decreased the cell viability of GBM cells, inducing cell death and cell cycle arrest, promoting an increase in ROS production, causing mitochondrial dysfunction, and significantly inhibiting colony formation. Conclusions: The promising biological profiles of 12 and 16 make them new lead candidates that warrant further investigation to gain a better understanding of the mechanism behind their antitumor activity and better evaluate their potential for GBM treatment. Full article

(This article belongs to the Special Issue Dopamine and Serotonin Receptors: Selective or Multitarget Ligands for the Treatment of Central Nervous System Diseases)

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27 pages, 5990 KiB

Open AccessArticle

Neuroprotective Effects of Qi Jing Wan and Its Active Ingredient Diosgenin Against Cognitive Impairment in Plateau Hypoxia

by Tiantian Xia, Ziqiao Yan, Pan Shen, Mingyang Chang, Nan Zhang, Yunan Zhang, Qi Chen, Rui Wang, Li Tong, Wei Zhou, Zhexin Ni and Yue Gao

Pharmaceuticals 2025, 18(5), 738; https://doi.org/10.3390/ph18050738 - 17 May 2025

Viewed by 111

Abstract

Background/Objectives: High-altitude environments have a significant detrimental impact on the cognitive functions of the brain. Qi Jing Wan (QJW), a traditional herbal formula composed of Angelica sinensis, Astragalus membranaceus, and Rhizoma Polygonati Odorati, has demonstrated potential efficacy in treating [...] Read more.

Background/Objectives: High-altitude environments have a significant detrimental impact on the cognitive functions of the brain. Qi Jing Wan (QJW), a traditional herbal formula composed of Angelica sinensis, Astragalus membranaceus, and Rhizoma Polygonati Odorati, has demonstrated potential efficacy in treating cognitive disorders. However, its effects on cognitive dysfunction in plateau hypoxic environments remain unclear. Methods: In this study, acute and chronic plateau cognitive impairment mouse models were constructed to investigate the preventive and therapeutic effects of QJW and its significant active ingredient, diosgenin (Dio). Behavioral experiments were conducted to assess learning and memory in mice. Morphological changes in hippocampal neurons and synapses were assessed, and microglial activation and inflammatory factor levels were measured to evaluate brain damage. Potential active ingredients capable of crossing the blood–brain barrier were identified through chemical composition analysis and network database screening, followed by validation in animal and brain organoid experiments. Transcriptomics analysis, immunofluorescence staining, and molecular docking techniques were employed to explore the underlying mechanisms. Results: QJW significantly enhanced learning and memory abilities in plateau model mice, reduced structural damage to hippocampal neurons, restored NeuN expression, inhibited inflammatory factor levels and microglial activation, and improved hippocampal synaptic damage. Transcriptomics analysis revealed that Dio alleviated hypoxic brain damage and protected cognitive function by regulating the expression of PDE4C. Conclusions: These findings indicate that QJW and its significant active ingredient Dio effectively mitigate hypoxic brain injury and prevent cognitive impairment in high-altitude environments. Full article

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

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Open AccessArticle

Isolation of Ten New Sesquiterpenes and New Abietane-Type Diterpenoid with Immunosuppressive Activity from Marine Fungus Eutypella sp.

by Nina Wang, Chunmei Chen, Qin Li, Qiqiang Liang, Yingjie Liu, Zongze Shao, Xiupian Liu and Qun Zhou

Pharmaceuticals 2025, 18(5), 737; https://doi.org/10.3390/ph18050737 - 16 May 2025

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Background: Ten new sesquiterpenes, including eight eremophilane-type sesquiterpenes (1–8) and two compounds (9–10) with a cyclopentane ring, representing an undescribed subtype of sesquiterpene, along with a new abietane-type diterpenoid (11), were isolated [...] Read more.

Background: Ten new sesquiterpenes, including eight eremophilane-type sesquiterpenes (1–8) and two compounds (9–10) with a cyclopentane ring, representing an undescribed subtype of sesquiterpene, along with a new abietane-type diterpenoid (11), were isolated and identified from a deep-sea-derived fungus: Eutypella sp. Methods: Their structures were elucidated on the basis of various spectroscopic analyses, mainly including nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HRESIMS) data, ¹³C NMR calculations with DP4+ probability analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction experiments. Results: Furthermore, compound 11 exhibited potent immunosuppressive activity with IC₅₀ values of 8.99 ± 1.08 μM in a lipopolysaccharide (LPS) model and 5.39 ± 0.20 μM in a concanavalin A (ConA) model. Full article

(This article belongs to the Special Issue Natural Products Derived from Fungi and Their Biological Activities)

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17 pages, 2538 KiB

Open AccessArticle

Marantodes pumilum var. alata Enhances Fracture Healing Through Gene Regulation in a Postmenopausal Rat Model

by Tijjani Rabiu Giaze, Norazlina Mohamed, Syed Alhafiz Syed Hashim, Ahmad Nazrun Shuid, Ima Nirwana Soelaiman, Norliza Muhammad, Fadhlullah Zuhair Jafar Sidik and Jamia Azdina Jamal

Pharmaceuticals 2025, 18(5), 736; https://doi.org/10.3390/ph18050736 - 16 May 2025

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Background: Marantodes pumilum var. alata (MPva) has been reported to promote fracture repair. This study investigates the role of MPva leaf extract on biochemical markers and bone-repair genes in a postmenopausal rat model to understand its fracture-healing properties. Methods: [...] Read more.

Background: Marantodes pumilum var. alata (MPva) has been reported to promote fracture repair. This study investigates the role of MPva leaf extract on biochemical markers and bone-repair genes in a postmenopausal rat model to understand its fracture-healing properties. Methods: Thirty female Sprague Dawley rats were grouped into sham-operated (Sham), ovariectomized control (OVXC), estrogen treatment (ERT), and plant treatment (MPv20 and MPv100) groups. After ovariectomy, the right tibiae of rats were fractured. The ERT group was treated with 64.5 μg/kg/day of estrogen, while the MPv20 and MPv100 groups received 20 and 100 mg/kg/day doses of MPva leaf extract, respectively, for 8 weeks. Sham and OVXC acted as untreated controls. Blood samples collected before and after treatment were assayed for pro-inflammatory cytokines (IL-6 and TNF-α), while bone samples were assayed for bone-turnover markers: osteocalcin and pyridinoline, oxidative-status markers (GPx, SOD, and MDA), and bone-repair genes (Bglap, Spp1, Dkk1, Igf1, Tnfsf11, and Fgf23). Results: IL-6, GPx, and SOD levels were significantly increased in both MPv groups (p < 0.05). IGF1 was significantly upregulated in both MPv groups, while Tnfsf11 was downregulated in the MPv20 group (p < 0.05). Conclusions: MPva leaf extract may promote bone repair by stimulating pro-inflammatory and antioxidant responses, which are associated with its regulation of Igf1 and Tnfsf11 genes. Full article

(This article belongs to the Special Issue Bioactive Compounds and Their Optimized Structural Derivatives of Natural Products)

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30 pages, 3688 KiB

Open AccessSystematic Review

Risk of Hearing Loss in Patients Treated with Exendin-4 Derivatives: A Network Meta-Analysis of Glucagon-like Peptide-1 Receptor Agonists and Sodium–Glucose Cotransporter 2 Inhibitors

by Jiann-Jy Chen, Chih-Wei Hsu, Chao-Ming Hung, Chih-Sung Liang, Kuan-Pin Su, Andre F. Carvalho, Brendon Stubbs, Yen-Wen Chen, Tien-Yu Chen, Wei-Te Lei, Bing-Yan Zeng and Ping-Tao Tseng

Pharmaceuticals 2025, 18(5), 735; https://doi.org/10.3390/ph18050735 - 16 May 2025

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Abstract

Background/Objectives: Emerging evidence suggests an association between glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose co-transporter 2 (SGLT2) inhibitors with altered risk of damage in the inner ear system. However, limited research exists on the relationship between these medications and subsequent irreversible hearing [...] Read more.

Background/Objectives: Emerging evidence suggests an association between glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose co-transporter 2 (SGLT2) inhibitors with altered risk of damage in the inner ear system. However, limited research exists on the relationship between these medications and subsequent irreversible hearing loss. We conducted this network meta-analysis (NMA) to evaluate the comparative risk of hearing loss associated with such medications. Methods: In this NMA, we used a confirmatory approach to specifically focus on particular adverse effects of interest (i.e., incidence of hearing loss here) based on the Cochrane recommendation. A Bayesian-based NMA of randomized controlled trials (RCTs) of GLP-1 receptor agonists or SGLT2 inhibitors was conducted. The primary outcome was the hearing loss events. Results: Our NMA of 29 RCTs with 145,895 participants found that only two exendin-4 derivatives—lixisenatide and high-dose efpeglenatide (i.e., 6 mg/week)—showed increased hearing loss events compared to controls. No other GLP-1 receptor agonists or SGLT2 inhibitors demonstrated significantly elevated hearing loss risk. Lixisenatide ranked highest in risk among all investigated regimens. Conclusions: This comprehensive NMA identifies a significant association between exendin-4 derivatives (lixisenatide and efpeglenatide) and potential ototoxicity. Clinicians should carefully consider this potential ototoxicity when prescribing exendin-4 derivatives, particularly in patients with pre-existing hearing loss risk factors. Full article

(This article belongs to the Special Issue Small-Molecule Inhibitors for Novel Therapeutics)

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Pharmaceuticals, Volume 18, Issue 5 (May 2025) – 162 articles

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