Pharmaceuticals

16 pages, 3056 KiB

Open AccessReview

by Wayne Childers, Khaled Elokely and Magid Abou-Gharbia

Pharmaceuticals 2025, 18(3), 386; https://doi.org/10.3390/ph18030386 (registering DOI) - 8 Mar 2025

The neurological effects of opium were first described over 8000 years ago. Morphine was isolated in 1803 and by the mid-1800s had become both a pain-relieving blessing and an addictive curse. As part of the crusade to identify safer and more reliable alternatives [...] Read more.

The neurological effects of opium were first described over 8000 years ago. Morphine was isolated in 1803 and by the mid-1800s had become both a pain-relieving blessing and an addictive curse. As part of the crusade to identify safer and more reliable alternatives to morphine, dezocine (Dalgan^®) was marketed in the US in 1986. Its use was discontinued in the US in 2011 without revealing the reasons, but it remains one of the most widely used analgesic agents in China today. Dezocine’s unique pharmacology makes it an effective analgesic with limited opioid-associated side effects and little or no reported potential for dependence and addiction. In addition, dezocine’s blocking effect on serotonin and norepinephrine transporters recommends its further exploration as a potential treatment for various chronic and neuropathic pain conditions. Most recently, data suggest that dezocine might represent a viable treatment for addiction management. This report focuses on the data supporting dezocine’s non-addictive profile and its potential use to treat opioid addiction and withdrawal, as well as recent efforts to generate formulations of dezocine that support sub-chronic and chronic dosing. Full article

(This article belongs to the Special Issue Pharmacology and Toxicology of Opioids)

► Show Figures

Figure 1

Figure 1
Written records describing opium date back over 5000 years to Sumarian clay tablets from Nippur, Iraq. Used under license from Shutterstock. Full article ">Figure 2
Structures of dezocine and the opioid agonists, partial agonists, and antagonists discussed in this paper. Full article ">Figure 3
Impurities from the large-scale synthesis of dezocine ((a,b) less potent; (c) more potent). Full article ">Figure 4
Signaling pathways used by opioid receptors. Opioid receptors signal through three distinctive pathways. (Left) G-protein dependent pathway, wherein the receptor engages G-proteins to initiate intracellular signaling; (Middle) arrestin-dependent pathway, wherein the receptor becomes phosphorylated and engages beta-arrestins, resulting in receptor desensitization and internalization; (Right) Gi/arrestin complex pathway, wherein the receptor forms a complex with Gi and beta arrestins, resulting in ERK-associated downstream signaling. Reproduced with permission from Che et al., 2021 [<a href="#B21-pharmaceuticals-18-00386" class="html-bibr">21</a>]. Full article ">Figure 5
Structures of selected MOR biased agonists. Full article ">Figure 6
Docking models of dezocine (Cyan) with the human serotonin and norepinephrine transporters. (Left) Dezocine is predicted to occupy the same binding site as the SSRI fluvoxamine (magenta, docking model using the co-crystal structure of fluvoxamine bound to the human SERT, PDB 6AWP, Coleman and Gouaux, 2017) [<a href="#B37-pharmaceuticals-18-00386" class="html-bibr">37</a>]; (Right) dezocine is predicted to occupy the same binding site as the NRI reboxetine (magenta, docking model using the cryo-EM structure of reboxetine bound to the human NET, PDB 8ZP1, Song and Wu, 2024 [<a href="#B38-pharmaceuticals-18-00386" class="html-bibr">38</a>]). Full article ">Figure 7
Examples of dezocine prodrugs in the recent patent literature. Full article ">Scheme 1
Original synthesis of dezocine described in [<a href="#B7-pharmaceuticals-18-00386" class="html-bibr">7</a>] (Freed et al., 1973). Full article ">

18 pages, 1460 KiB

Open AccessReview

Glioblastoma Tumor Microenvironment and Purinergic Signaling: Implications for Novel Therapies

by Martina Bedeschi, Elena Cavassi, Antonino Romeo and Anna Tesei

Pharmaceuticals 2025, 18(3), 385; https://doi.org/10.3390/ph18030385 (registering DOI) - 8 Mar 2025

Abstract

Glial-origin brain tumors, particularly glioblastomas (GBMs), are known for their devastating prognosis and are characterized by rapid progression and fatal outcomes. Despite advances in surgical resection, complete removal of the tumor remains unattainable, with residual cells driving recurrence that is resistant to conventional [...] Read more.

Glial-origin brain tumors, particularly glioblastomas (GBMs), are known for their devastating prognosis and are characterized by rapid progression and fatal outcomes. Despite advances in surgical resection, complete removal of the tumor remains unattainable, with residual cells driving recurrence that is resistant to conventional therapies. The GBM tumor microenviroment (TME) significantly impacts tumor progression and treatment response. In this review, we explore the emerging role of purinergic signaling, especially the P2X7 receptor (P2X7R). Due to its unique characteristics, it plays a key role in tumor progression and offers a potential therapeutic strategy for GBM through TME modulation. We discuss also the emerging role of the P2X4 receptor (P2X4R) as a promising therapeutic target. Overall, targeting purinergic signaling offers a potential approach to overcoming current GBM treatment limitations. Full article

(This article belongs to the Special Issue Purinergic Signaling in Cancer Therapy: From Mechanisms to Targeting Strategies)

► Show Figures

Figure 1

16 pages, 988 KiB

Open AccessReview

AMPA Receptor Modulation in the Treatment of High-Grade Glioma: Translating Good Science into Better Outcomes

by Daniel P. Radin

Pharmaceuticals 2025, 18(3), 384; https://doi.org/10.3390/ph18030384 (registering DOI) - 8 Mar 2025

Viewed by 11

Abstract

Glioblastoma (GB) treatment, despite consisting of surgical resection paired with radiation, temozolomide chemotherapy and tumor-treating fields, yields a median survival of 15–20 months. One of the more recently appreciated hallmarks of GB aggressiveness is the co-opting of neurotransmitter signaling mechanisms that normally sustain [...] Read more.

Glioblastoma (GB) treatment, despite consisting of surgical resection paired with radiation, temozolomide chemotherapy and tumor-treating fields, yields a median survival of 15–20 months. One of the more recently appreciated hallmarks of GB aggressiveness is the co-opting of neurotransmitter signaling mechanisms that normally sustain excitatory synaptic communication in the CNS. AMPA-glutamate receptor (AMPAR) signaling governs the majority of excitatory synaptic activity in the mammalian brain. AMPAR activation in glioma cells activates cellular pathways that enhance proliferation and invasion and confer resistance to approved GB therapeutics. In addition, this review places a specific emphasis on discussing the redefined GB cytoarchitecture that consists of neuron-to-glioma cell synapses, whose oncogenic activity is driven by AMPAR activation on glioma cells, and the discovery of tumor microtubes, which propagate calcium signals throughout the tumor network in order to enhance resistance to complete surgical resection and radiotherapy. These new discoveries notwithstanding, some evidence suggests that AMPAR activation can produce excitotoxicity in tumor cells. This disparity warrants a closer examination at how AMPAR modulation can be leveraged to produce more durable outcomes in the treatment of GB and tumors in peripheral organs that express AMPAR. Full article

(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)

► Show Figures

Figure 1

12 pages, 2429 KiB

Open AccessArticle

Huperzine A Production and Acetylcholinesterase Inhibition by Phlegmariurus taxifolius Cell Suspension Culture: A Comparative Study in Flasks and an Airlift Bioreactor

by Rocío del Carmen Pérez Aguilar, Talia Rodríguez Salgado, Olga Lidia Cruz-Miranda, Alexis Uriel Soto Díaz, Ariadna Zenil Rodríguez, Lamine Bensaddek, Christian Carreño-Campos, María Luisa Villarreal, Anabel Ortiz-Caltempa and Alexandre Toshirrico Cardoso-Taketa

Pharmaceuticals 2025, 18(3), 383; https://doi.org/10.3390/ph18030383 (registering DOI) - 8 Mar 2025

Viewed by 6

Abstract

Background: The callus cultures from the fronds of the lycophyte Phlegmariurus taxifolius produce the huperzine A (HupA) alkaloid, which is used in Alzheimer’s disease treatment. This study aimed to establish the growth kinetics and HupA production by the newly HupS21 cell line [...] Read more.

Background: The callus cultures from the fronds of the lycophyte Phlegmariurus taxifolius produce the huperzine A (HupA) alkaloid, which is used in Alzheimer’s disease treatment. This study aimed to establish the growth kinetics and HupA production by the newly HupS21 cell line grown in 250 mL flasks and in a 2 L airlift bioreactor. Methods: Batch-type kinetics were carried out for 60 days in 250 mL flasks and for 20 days in a 2 L airlift bioreactor. Measurements of dry weight (DW), specific growth rate (μ), doubling time (dt), pH, carbohydrate consumption, and HupA quantification were performed. The acetylcholinesterase (AChE) inhibitory assay of the HupS21 alkaloidal extract was determined. Results: The 250 mL flasks kinetic reached a maximum cell growth of 8.17 g/L DW, with a μ of 0.045 day⁻¹ and a dt of 15.40 days. The maximum HupA production was of 2.03 μg/g DW at day 45. In the 2 L airlift reactor, a maximum growth of 16.70 g/L DW, a μ of 0.062 day⁻¹, a dt of 11.20 days, and HupA production of 2.48 μg/g DW at day 15 were obtained. The alkaloidal extract from the HupS21 cell line at 100 μg/mL showed an AChE inhibitory activity of 85.6 ± 1.27%. Conclusions: The airlift reactor outperformed the flask cultures in maximum cell growth, specific growth rate, doubling time, and HupA production. To our knowledge, this research is the first report on the establishment of suspension cell cultures of P. taxifolius in shaken flasks and in an airlift bioreactor, providing a foundation for scaling up HupA production for pharmaceutical use. Full article

(This article belongs to the Special Issue Plant-Based Extracts and the Therapeutic Potential of Bioactive Compounds)

► Show Figures

Figure 1

Figure 1
Establishment of the liquid suspension culture cells of P. taxifolius HupS21 line: (A) grown of friable calli on solid media; (B) calli grown in liquid media in three-baffled flasks; and (C) cell suspension culture. Full article ">Figure 2
HPLC profiling of the HupS21 total alkaloid extract (blue line) and the huperzine A standard (red line). Chromatographic conditions: C18 column, mobile phase of H2O/TFA (0.0125%):CH3CN (85:15), at 1 mL/min, and detection at 310 nm. Full article ">Figure 3
Kinetic study and production of HupA in cell suspension culture of P. taxifolius HupS21 line grown in 250 mL flask: (A) cell viability; (B) pH; (C) carbohydrate consumption; (D) HupA production. HupA production. Bars represent ±SD (n = 3). See <a href="#app1-pharmaceuticals-18-00383" class="html-app">Table S1</a>: R2 biomass vs. depletion of carbon source; and <a href="#app1-pharmaceuticals-18-00383" class="html-app">Table S2</a>: R2 biomass vs. HupA production. Full article ">Figure 4
HupS21 line scale-up in 2 L airlift bioreactor: (A) day 0; (B) day 10; (C) day 15; and (D) day 20. The medium B5 was supplemented with NAA (0.5 mg/L), ZT (0.5 mg/L), CW (20 mL/L), sucrose (20 g/L), polyvinylpyrrolidone (PVP) at 1 g/L, and potassium nitrate at 5 g/L. Full article ">Figure 5
Kinetic study and production of HupA in cell culture of P. taxifolius HupS21 line grown in 2-L airlift bioreactor: (A) cell viability; (B) pH; (C) carbohydrate consumption; (D) HupA production. Bars represent ± SD (n = 3). See <a href="#app1-pharmaceuticals-18-00383" class="html-app">Table S3</a>: R2 biomass vs. depletion of carbon source; and <a href="#app1-pharmaceuticals-18-00383" class="html-app">Table S4</a>: R2 biomass vs. HupA production. Full article ">

20 pages, 2897 KiB

Open AccessArticle

Behavioral and Biochemical Insights into the Therapeutic Potential of Mitocurcumin in a Zebrafish–Pentylenetetrazole (PTZ) Epilepsy Model

by Alin Dumitru Ciubotaru, Carmen-Ecaterina Leferman, Bogdan-Emilian Ignat, Anton Knieling, Irina Mihaela Esanu, Delia Lidia Salaru, Liliana Georgeta Foia, Bogdan Minea, Luminita Diana Hritcu, Cristina Daniela Dimitriu, Laura Stoica, Ioan-Adrian Ciureanu, Alin Stelian Ciobica, Andrei Neamtu, Bogdan Alexandru Stoica and Cristina Mihaela Ghiciuc

Pharmaceuticals 2025, 18(3), 382; https://doi.org/10.3390/ph18030382 - 7 Mar 2025

Viewed by 78

Abstract

Background/Objectives: Epilepsy is a complex neurological disorder with a strong link to oxidative stress, which contributes to seizure susceptibility and neuronal damage. This study aims to investigate the effects of curcumin (Cur), sodium valproate (VPA), and mitocurcumin (MitoCur), a mitochondria-targeted curcumin, on [...] Read more.

Background/Objectives: Epilepsy is a complex neurological disorder with a strong link to oxidative stress, which contributes to seizure susceptibility and neuronal damage. This study aims to investigate the effects of curcumin (Cur), sodium valproate (VPA), and mitocurcumin (MitoCur), a mitochondria-targeted curcumin, on behavioral and oxidative stress parameters in a zebrafish model of pentylenetetrazole (PTZ)-induced seizures. Methods: Adult zebrafish were exposed to two concentrations (0.25 and 0.5 µM for Cur and MitoCur; 0.25 and 0.5 mM for VPA). Behavioral assessments, including locomotion, spatial exploration, and directional movement, were conducted using EthoVision XT tracking software. Oxidative stress markers, including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPx), and total antioxidant status (TAS), were analyzed in brain homogenates. Results: Behavioral analyses indicated dose-dependent effects, with higher doses generally reducing activity. MitoCur at 0.25 µM enhanced antioxidant defenses and reduced oxidative damage, while higher doses exhibited a pro-oxidant shift. VPA at 0.25 mM improved TAS without significantly altering MDA levels. Conclusions: These findings emphasize the importance of dose optimization in antioxidant-based epilepsy treatments and highlight the potential of MitoCur as a targeted therapeutic option. Full article

(This article belongs to the Special Issue Plant-Derived Natural Compounds as Bioactive Molecules with Beneficial Effects on Human Health)

► Show Figures

Figure 1

Figure 1
Time spent in different zones of the tank (mean ± SD): (a) Time spent at the top (seconds): VPA 0.25 mM significantly increased the time spent at the top compared to the control (p = 0.031) and MitoCur 0.25 μM (p = 0.008); (b) time spent at the bottom (seconds): VPA 0.25 mM significantly decreased the time spent at the bottom compared to the control (p = 0.044) and MitoCur 0.25 μM (p = 0.013). One-way ANOVA followed by Tukey’s post hoc test (α = 0.05) with * p < 0.05, ** p < 0.01 indicating statistical significance. Full article ">Figure 2
Number of transitions between different zones of the tank (mean ± SD): (a) Transitions from top to bottom: no statistically significant differences were observed between the control group and any treatment group; (b) transitions from bottom to top: similarly, no statistically significant differences were observed. One-way ANOVA followed by Tukey’s post hoc test (α = 0.05). Full article ">Figure 3
Number of rotations (mean ± SD): (a) Clockwise rotations: No statistically significant differences were observed between the control group and any treatment group. (b) Counterclockwise rotations: Significant reductions were observed for Cur 0.25 μM (p = 0.002), VPA 0.25 mM (p = 0.027), VPA 0.5 mM (p = 0.033), and MitoCur 0.25 μM (p < 0.001) compared to the control. MitoCur 0.5 μM did not show significant differences compared to the control. No significant differences were observed among the treatment groups. One-way ANOVA followed by Tukey’s post hoc test (α = 0.05) with * p < 0.05, ** p < 0.01, and *** p < 0.001 indicating statistical significance. Full article ">Figure 4
Locomotor activity (mean ± SD): (a) Time spent moving (seconds): The control group spent significantly more time moving compared to Cur 0.25 μM (p < 0.01), VPA 0.5 mM (p < 0.001), MitoCur 0.25 μM (p < 0.001), and MitoCur 0.5 μM (p < 0.01). (b) Time spent not moving (seconds): Cur 0.25 μM (p < 0.001), VPA 0.5 mM (p < 0.01), MitoCur 0.25 μM (p < 0.001), and MitoCur 0.5 μM (p < 0.01) significantly increased immobility compared to the control. One-way ANOVA followed by Tukey’s post hoc test (α = 0.05) with * p < 0.05, ** p < 0.01, and *** p < 0.001 indicating statistical significance. Full article ">Figure 5
Effects of Cur, VPA, and MitoCur on oxidative stress and antioxidant markers (Mean ± SD): (a) SOD. The control group exhibited the highest SOD activity, which was significantly reduced by all treatments except VPA 0.25 mM. (b) MDA. MDA levels were elevated by Cur 0.25 µM and 0.5 µM and MitoCur 0.5 µM, while VPA 0.25 mM and 0.5 mM and MitoCur 0.25 µM showed no significant changes. (c) GPx. GPx activity was significantly increased across all treatments compared to Control, indicating a compensatory antioxidant response. (d) TAS. TAS was notably elevated by VPA 0.25 mM, while Cur 0.25 µM and 0.5 µM and MitoCur 0.25 µM and 0.5 µM significantly reduced TAS, suggesting a depletion of overall antioxidant capacity. One-way ANOVA followed by Tukey’s post hoc test (α = 0.05) with * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001 indicating statistical significance. Full article ">Figure 6
The structure of the mitocurcumin used in the present study. TPP = triphenylphosphonium. Generated with ChemSketch (Freeware) 2024.1.3. Full article ">Figure 7
Schematic illustration of the experimental workflow. Adult zebrafish were immersed for 30 min in one of three compound solutions—Cur (0.25 µM or 0.5 µM), VPA (0.25 mM or 0.5 mM), or MitoCur (0.25 µM or 0.5 µM). Immediately afterward, each fish was placed in a test tank for 4 min to assess baseline locomotor and exploratory parameters (e.g., time spent in top vs. bottom, rotational movements, transitions, distance moved, and velocity). Next, the animals were transferred to a separate tank containing PTZ (5 mM) for 10 min (600 s) to induce and observe seizure activity. Following these behavioral assessments, the fish were euthanized, and brain tissues were collected for biochemical analyses of oxidative stress and antioxidant defense markers, including SOD, MDA, GPx, and TAS. Full article ">Figure 8
Examples of behavioral patterns and swimming paths; trends in behavioral responses. The 2D heat maps illustrate the spatial distribution of zebrafish swimming behavior across treatment groups for the YZ axis (front view). This visualization demonstrates changes in locomotor and exploratory behaviors across the tested conditions, reflecting compound-specific and dose-dependent effects on zebrafish activity prior to PTZ-induced seizures. Full article ">

30 pages, 11585 KiB

Open AccessArticle

Polylactic-Co-Glycolic Acid/Alginate/Neem Oil-Reduced Graphene Oxide as a pH-Sensitive Nanocarrier for Hesperidin Drug Delivery: Antimicrobial and Acute Otitis Media Assessments

by Saeed Abdul Kareem Saeed Al-Zuhairy, Sammar Fathy Elhabal, Mohamed Fathi Mohamed Elrefai, Sandra Hababeh, Jakline Nelson, Marwa Fady, Nahla A. Elzohairy, Tassneim M. Ewedah, Ibrahim S. Mousa and Ahmed Mohsen Elsaid Hamdan

Pharmaceuticals 2025, 18(3), 381; https://doi.org/10.3390/ph18030381 - 7 Mar 2025

Viewed by 136

Abstract

Background/Objectives: Hesperidin (HSP) is a potent phytochemical antioxidant and anti-inflammatory agent that protects against otitis media. However, due to its low solubility and bioavailability, a suitable delivery method is needed to overcome these problems. A hydrogel is a promising nanocarrier for controlled [...] Read more.

Background/Objectives: Hesperidin (HSP) is a potent phytochemical antioxidant and anti-inflammatory agent that protects against otitis media. However, due to its low solubility and bioavailability, a suitable delivery method is needed to overcome these problems. A hydrogel is a promising nanocarrier for controlled drug delivery in response to external stimuli, such as pH variations. Methods: Graphene oxide (GO)-based nanocarriers that encapsulate hesperidin (HSP) were further coated with a polylactic-co-glycolic acid/alginate (PLGA-Alg) hydrogel before being integrated into a green neem oil (N.O.) double emulsion to produce a synergistic effect and then characterized by different assays. Results: The nanocarriers exhibited a substantial particle size (168 ± 0.32 nm), with high encapsulation (89.86 ± 0.23%) and a zeta potential of 37 ± 0.43 mV. In vitro release studies conducted over 96 h indicated a sustained HSP release of 82% at pH 5.4 and 65% at pH 7.4. The GO-HSP-loaded neem oil double emulsion formulation exhibits substantial antibacterial activity, as evidenced by inhibition zones of 39 ± 0.02 mm against Staphylococcus epidermidis, and considerable antifungal activity against Candida albicans, with an inhibition zone of 43 ± 0.13 mm, along with biofilm inhibition activity. The formulation demonstrated antioxidant activity (5.21 µg/mL) and increased cell viability (90–95%) while maintaining low cytotoxicity in HSE-2 cells. A histopathological analysis confirmed that treatment with the nanocarriers reduced the levels of pro-inflammatory cytokines (IL-1β, TNF-α, TLR4, IL-6) and raised the levels of antioxidant markers (Nrf-2, SOD) in an in vivo rat model of otitis media. Conclusions: GO-based nanocarriers integrated into a neem oil double emulsion and coated with PLGA-Alg hydrogel deliver hesperidin with sustained release and enhanced antibacterial, antifungal, and antioxidant properties. This formulation may be used to treat otitis media and other oxidative stress diseases. Full article

(This article belongs to the Special Issue Progress of Hydrogel Applications in Novel Drug Delivery Platforms)

28 pages, 1451 KiB

Open AccessReview

Extraction Yields of Psilocybin and Psilocin: A Short Review of Current Methods and Their Implications

by Taynah P. Galdino, Lucas C. Oliveira, Mateus A. Luz, Raquel A. Jesus, Eunice P. N. Lima, Maria C. M. Torres, Katia Sivieri, Victor I. Afonso, João M. P. Q. Delgado, Antonio G. B. Lima, Suédina M. L. Silva and Marcus V. L. Fook

Pharmaceuticals 2025, 18(3), 380; https://doi.org/10.3390/ph18030380 - 7 Mar 2025

Viewed by 83

Abstract

The growing body of evidence supporting the therapeutic efficacy of psychoactive substances, like psilocybin, has driven significant interest in recent decades due to their low toxicity and potential applications in treating various mental health disorders. However, producing pharmaceutical-grade psilocybin remains challenging, with three [...] Read more.

The growing body of evidence supporting the therapeutic efficacy of psychoactive substances, like psilocybin, has driven significant interest in recent decades due to their low toxicity and potential applications in treating various mental health disorders. However, producing pharmaceutical-grade psilocybin remains challenging, with three primary approaches: chemical synthesis, biosynthesis, and extraction from Psilocybe mushroom fruiting bodies. This systematic review evaluates the extraction and quantification methods for psilocybin and psilocin, aiming to contribute to the development of standardized protocols that ensure compound quality and purity. A total of 25 relevant studies were selected from an initial pool of 9152 publications indexed in platforms such as Scopus, ScienceDirect, Web of Science, and PubMed. The findings indicate that both the extraction method and the choice of mushroom species significantly influence compound yields. Ultrasonic bath extraction was identified as the most efficient technique, particularly for species including Psilocybe cyanescens and Psilocybe cubensis. High-performance liquid chromatography (HPLC) was the most-used method for identifying and quantifying these compounds. Furthermore, polar solvents were critical for effective solubilization, with parameters such as temperature, solvent-to-material ratio, and extraction time playing key roles in optimizing yields. This review serves as a key scientific reference for advancing research, enhancing analytical precision, and ensuring reproducibility through the standardization of extraction and quantification protocols. Full article

(This article belongs to the Section Pharmaceutical Technology)

► Show Figures

Figure 1

15 pages, 1649 KiB

Open AccessArticle

The Impact of Montelukast Duration on the Risk of Neuropsychiatric Disorders in Children with Asthma: A Population-Based Cohort Study

by Wei-Te Lei, Chien-Yu Lin, Szu-Hung Chu, Li-Ching Fang, Yu-Hsuan Kao, Po-Li Tsai, Yu-Wen Lin, Fung-Chang Sung and Shu-I Wu

Pharmaceuticals 2025, 18(3), 379; https://doi.org/10.3390/ph18030379 - 7 Mar 2025

Viewed by 56

Abstract

Background/Objectives: Asthma is one of the most common chronic diseases in children, and montelukast is widely prescribed to manage symptoms. However, concerns have emerged regarding its potential association with neuropsychiatric disorders. This study aims to investigate the impact of montelukast duration on neuropsychiatric [...] Read more.

Background/Objectives: Asthma is one of the most common chronic diseases in children, and montelukast is widely prescribed to manage symptoms. However, concerns have emerged regarding its potential association with neuropsychiatric disorders. This study aims to investigate the impact of montelukast duration on neuropsychiatric risks in children with asthma. Methods: A cohort study was conducted using Taiwan’s National Health Insurance Research Database (NHIRD), including children diagnosed with asthma between 2004 and 2007. A total of 14,606 children in the montelukast cohort and 8432 in the non-montelukast cohort were analyzed, with propensity score matching applied to reduce confounding bias. Neuropsychiatric outcomes, including Tics/Tourette’s syndrome, were evaluated using Cox proportional hazard models. Results: Overall, montelukast use did not increase the risk of neuropsychiatric disorders. However, among children aged 6–15 years, prolonged use beyond 63 days was associated with a significantly elevated risk of Tics/Tourette’s syndrome, with a 2.6-fold increase observed in girls and a 1.8-fold increase in boys. Conversely, shorter montelukast use in children aged 0–6 years was linked to a lower risk of neuropsychiatric disorders. Conclusions: Although montelukast generally does not elevate neuropsychiatric risks, extended use in older children may increase the likelihood of developing Tics/Tourette’s syndrome. These findings highlight the importance of cautious prescribing in pediatric asthma management. Further research is necessary to validate these associations and inform clinical decision making. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

13 pages, 274 KiB

Open AccessArticle

A Preliminary Report on the Effects of Daridorexant in Patients with Comorbid Insomnia and Substance Use Disorders

by Marco Di Nicola, Maria Pepe, Lorenzo Bonomo, Miriam Milintenda, Isabella Panaccione, Roberto Brugnoli and Gabriele Sani

Pharmaceuticals 2025, 18(3), 378; https://doi.org/10.3390/ph18030378 - 6 Mar 2025

Viewed by 138

Abstract

Background. Sleep disturbances are frequent in patients with substance use disorders (SUDs) and are associated with craving and addiction relapses, leading to increased clinical severity and detrimental outcomes. Daridorexant, a selective dual orexin receptor antagonist, has been approved for persistent insomnia disorder [...] Read more.

Background. Sleep disturbances are frequent in patients with substance use disorders (SUDs) and are associated with craving and addiction relapses, leading to increased clinical severity and detrimental outcomes. Daridorexant, a selective dual orexin receptor antagonist, has been approved for persistent insomnia disorder (ID), but specific insights on patients with SUDs are lacking. Methods. This observational, retrospective study investigated the effects of a three-month treatment with daridorexant (50 mg/day) in 41 outpatients with comorbid IDs and SUDs. Improvement in subjective sleep measures, assessed with the Insomnia Severity Index (ISI) and subjective total sleep time, was the primary outcome measure. Changes in anxiety and depression symptoms, quality of life, clinical global severity, and craving were also investigated through the following: Hamilton Anxiety and Depression Rating Scale; Five-item World Health Organization Well-Being Index; Clinical Global Impression Severity Scale; Visual Analog Scale for Craving. Results. All sleep outcomes significantly improved throughout treatment, which was generally safe and well tolerated, with mild and transient drowsiness and sluggishness reported in 21.1% of patients. Similar improvements were observed in psychopathology, quality of life, and craving, and positive correlations were found among ISI scores and anxiety/depression symptoms and craving. An abstinence rate (i.e., absence of any substance use, regardless of the amount, throughout treatment) of 65.8% was also detected at the endpoint. Conclusions. These preliminary findings suggest that daridorexant might represent a promising tool for treating insomnia in patients with SUDs. Identifying interventions effectively targeting insomnia with a good safety/tolerability profile in SUDs is crucial to achieve remission and full functional recovery. Full article

(This article belongs to the Special Issue Exploring Biomarkers and Pharmacotherapies for Substance Use Disorders)

► Show Figures

Graphical abstract

25 pages, 17447 KiB

Open AccessArticle

BuZhong YiQi Formula Alleviates Diabetes-Caused Hyposalivation by Activating Salivary Secretion Pathway in the Parotid and Submandibular Glands of Rats

by Ming-Yu Wang, Zhen-Ran Hu, Liang Wang, Xin-Xin Zeng, Xiang-Ke Li, Guo-Jun Fei, Jing-Li Zhang, Jing-Ru Chen and Ze-Min Yang

Pharmaceuticals 2025, 18(3), 377; https://doi.org/10.3390/ph18030377 - 6 Mar 2025

Viewed by 98

Abstract

Background/Objectives: BuZhong Yiqi Formula (BZYQF) has significant ameliorative effects on type 2 diabetes mellitus (T2DM). However, its efficacy in alleviating the hyposalivation caused by T2DM needs to be confirmed, and its mechanism is unclear. Methods: Network pharmacology and molecular docking were [...] Read more.

Background/Objectives: BuZhong Yiqi Formula (BZYQF) has significant ameliorative effects on type 2 diabetes mellitus (T2DM). However, its efficacy in alleviating the hyposalivation caused by T2DM needs to be confirmed, and its mechanism is unclear. Methods: Network pharmacology and molecular docking were combined to analyze the molecular mechanism by which BZYQF alleviates T2DM-caused hyposalivation. A T2DM rat model was induced to evaluate the efficacy of BZYQF. The total saliva before and after acid stimulation was collected to determine the salivary flow rate and salivary alpha-amylase (sAA) activity. The parotid (PG) and submandibular glands (SMG) of experimental rats were removed to perform histopathology observation, biochemical indicator determination, and expression detection of signaling molecules in the salivary secretion pathway. Results: The present study screened out 1014 potential targets of BZYQF regarding the treatment of T2DM. These targets were mainly involved in the formation of the receptor complex, exercising the neurotransmitter receptor activity and regulating secretion. They were significantly enriched in the salivary secretion pathway of β1-AR/PKA/AMY1 and CHRM3/IP3R/AQP5. Furthermore, in BZYQF, nine validated compounds were able to dock into the active site of β1-AR, and three validated compounds were able to dock into the active site of CHRM3. Animal experiments confirmed that BZYQF significantly reduces fasting blood glucose, total cholesterol and triglyceride levels; enhances insulin level and HOMA-IS (p < 0.05); and increases salivary flow rate (Basal: increase from 21.04 ± 14.31 to 42.65 ± 8.84 μL/min, effect size of Cohen’s d = 6.80, p = 0.0078; Stimulated: increase from 36.88 ± 17.48 to 72.63 ± 17.67 μL/min, effect size of Cohen’s d = 7.61, p = 0.0025) and sAA activity (Basal: increase from 0.68 ± 0.32 to 2.17 ± 0.77 U/mL, effect size of Cohen’s d = 9.49, p = 0.0027; Stimulated: increase from 1.15 ± 0.77 to 4.80 ± 1.26 U/mL, effect size of Cohen’s d = 13.10, p = 0.0001) in basal and stimulated saliva in T2DM rats. Further mechanistic studies revealed that BZYQF reduces glucose and lipid accumulation, enhances acetylcholine content, improves pathological lesions and inflammation, and significantly increases the expression of salivary secretion pathway signaling molecules, including PKA, IP3R, β1-AR, AQP5, CHRM3, and AMY1 in the PG and SMG of T2DM rats (p < 0.05). Conclusions: The present study demonstrated that BZYQF is able to alleviate T2DM-caused hyposalivation by improving glucose metabolism and activating the salivary secretion pathway in the PG and SMG of T2DM rats. This study might provide a novel rationale and treatment strategy for BZYQF in diabetes-induced hyposalivation in a clinical setting. Full article

(This article belongs to the Section Natural Products)

► Show Figures

Figure 1

15 pages, 255 KiB

Open AccessReview

A 5-Year Update on the Clinical Development of Cancer Cell-Based Vaccines for Glioblastoma Multiforme

by Almohanad A. Alkayyal and Ahmad Bakur Mahmoud

Pharmaceuticals 2025, 18(3), 376; https://doi.org/10.3390/ph18030376 - 6 Mar 2025

Viewed by 329

Abstract

Glioblastoma multiforme (GBM) is considered one of the most aggressive forms of brain cancer with a 15-month median survival, despite advancements in surgery, radiotherapy, and chemotherapy. The immune-suppressed tumor microenvironment and the blood–brain barrier are major contributors to its poor prognosis and treatment [...] Read more.

Glioblastoma multiforme (GBM) is considered one of the most aggressive forms of brain cancer with a 15-month median survival, despite advancements in surgery, radiotherapy, and chemotherapy. The immune-suppressed tumor microenvironment and the blood–brain barrier are major contributors to its poor prognosis and treatment resistance. In the last decade, significant progress has been made in developing cell-based vaccines to boost immune responses against GBM. This review provides an extensive update on recent clinical trials involving various cancer cell vaccines, including ICT-107, the α-type-1 DC vaccine, and others. Although these trials have demonstrated potential improvements in progression-free survival (PFS) and overall survival (OS), the diverse and immune-suppressed nature of GBM poses challenges for consistent therapeutic success. We discuss the details of these trials along with the potential mechanism of vaccine efficacy and immune activations. The findings of these trials highlight the significance of a personalized immunotherapy approach and suggest that patient stratification could significantly advance the clinical management of GBM. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Treatment of Brain Cancer: Recent Advances and Future Trends)

33 pages, 6857 KiB

Open AccessArticle

Synthesis, Structure, and Stability of Copper(II) Complexes Containing Imidazoline-Phthalazine Ligands with Potential Anticancer Activity

by Łukasz Balewski, Iwona Inkielewicz-Stępniak, Maria Gdaniec, Katarzyna Turecka, Anna Hering, Anna Ordyszewska and Anita Kornicka

Pharmaceuticals 2025, 18(3), 375; https://doi.org/10.3390/ph18030375 - 6 Mar 2025

Viewed by 161

Abstract

Background/Objectives: Recently, there has been great interest in metallopharmaceuticals as potential anticancer agents. In this context, presented studies aim to synthesize and evaluate of two copper(II) complexes derived from phthalazine- and imidazoline-based ligands against on three human cancer cell lines: cervix epithelial [...] Read more.

Background/Objectives: Recently, there has been great interest in metallopharmaceuticals as potential anticancer agents. In this context, presented studies aim to synthesize and evaluate of two copper(II) complexes derived from phthalazine- and imidazoline-based ligands against on three human cancer cell lines: cervix epithelial cell line (HeLa), breast epithelial-like adenocarcinoma (MCF-7), and triple–negative breast epithelial cancer cell line (MDA-MB-231), as well as non-tumorigenic cell line (HDFa). Moreover their antimicrobial, and antioxidant properties were assessed. Methods: The synthetized compounds—both free ligands L1, L2, L3 and copper(II) complexes C1 and C2—were characterized by elemental analysis, infrared spectroscopy. Additionally, a single-crystal X-ray diffraction studies we performed for free ligand L3 and its copper(II) complex C2. The stability of Cu(II)-complexes C1 and C2 was evaluated by UV-Vis spectroscopy. The cytotoxic potency of free ligands and their copper(II) complexes was estimated on HeLa, MCF-7, MDA-MB-231, as well as non-cancerous HDFa by use of an MTT assay after 48 h of incubation. Moreover, the antimicrobial activity of ligands L1 and L3 and their copper(II) complexes C1 and C2 was evaluated using reference strains of the following bacteria and yeasts: Staphylococcus aureus, Escherichia coli, and Candida albicans. The free radical scavenging properties of free ligands L1, L3 and the corresponding copper(II) complexes C1, C2 was tested with two colorimetric methods—ABTS, DPPH, and reduction ability assay (FRAP). Additionally, the ADME webtool was used to assess the drug-likeness of the synthesized compounds, as well as their physicochemical and pharmacokinetic properties. Results: Copper(II) complex C2 exhibited antitumor properties towards MDA-MB-231 compared with Cisplatin (cancer cell viability rate of 23.6% vs. 22.5%). At a concentration of 200 μg/mL, complexes C1 and C2 were less cytotoxic than the reference Cisplatin against a normal, non-cancerous skin fibroblast cell line (HDFa). According to in vitro tests, C2 reduced the viability of HeLa, MCF-7, and MDA-MB-231 cells by about 57.5–81.2%. It was evident that all compounds were devoid of antibacterial or antifungal activity. In vitro assays revealed that a moderate antiradical effect was observed for free ligand L1 containing phthalazin-1(2H)-imine in the ABTS radical scavenging assay (IC₅₀ = 23.63 µg/mL). Conclusions: The anticancer studies revealed that the most potent compound was copper(II) complex C2 bearing a phthalazin-1(2H)-one scaffold. None of the tested compounds showed antimicrobial or antifungal activity. This feature seems to be beneficial in terms of their potential uses as anticancer agents in the future. In vitro antiradical assays revealed that a moderate antioxidant effect was observed only for free ligand L1 containing phthalazin-1(2H)-imine. Full article

(This article belongs to the Special Issue Development of Copper-Based Drugs: Synthesis, Characterisation and Biological Activity)

► Show Figures

Figure 1

17 pages, 8973 KiB

Open AccessArticle

Gambogenic Acid Suppresses Malignant Progression of Non-Small Cell Lung Cancer via GCH1-Mediated Ferroptosis

by Menghan Wang, Jiao Liu, Wenxi Yu, Jiancang Shao, Yang Bao, Mingming Jin, Qingqing Huang and Gang Huang

Pharmaceuticals 2025, 18(3), 374; https://doi.org/10.3390/ph18030374 - 6 Mar 2025

Viewed by 143

Abstract

Introduction: Non-small cell lung cancer (NSCLC) is a lethal type of lung cancer (LC) with a 5-year survival rate of 19%. Because drug resistance typically develops following chemotherapy, radiotherapy, and immunotherapy, a novel NSCLC therapeutic strategy is urgently demanded. Gambogenic acid (GNA), a [...] Read more.

Introduction: Non-small cell lung cancer (NSCLC) is a lethal type of lung cancer (LC) with a 5-year survival rate of 19%. Because drug resistance typically develops following chemotherapy, radiotherapy, and immunotherapy, a novel NSCLC therapeutic strategy is urgently demanded. Gambogenic acid (GNA), a major bioactive ingredient isolated from gamboge, has multipotent antitumor effects, although activity against NSCLC is unknown. Methods: CCK8, ethynyl deoxyuridine (EdU), the plate colony formation assay, and the transwell and wound healing (WH) assay were used to study the effect of GNA on the proliferation and migration ability of NSCLC. Flow cytometry was used to detect apoptosis and the cell cycle. Proteomic analysis and LiP-SMap were used to detect the downstream target of GNA. Ferroptosis inhibitor ferrostatin-1 was used to detect the effect of GNA on NSCLC ferroptosis. Overexpressing GCH1 was used for a rescue experiment. Subcutaneous tumor and pulmonary metastasis in a mouse model were used to study the effect of GNA on NSCLC growth and metastasis. Results: The results of the present study showed that GNA inhibited the proliferation and migration of NSCLC cells in a dose- and time-dependent manner, which arrested the cell cycle in the G0/G1 phase. In vivo data revealed that GNA inhibited tumor growth and lung metastasis. Proteomic analysis found that GNA significantly inhibited the expression of GTP cyclohydrolase 1 (GCH1). LiP-SMap analysis showed that GNA interacted with ILE248 and ARG249 of GCH1. GCH1 overexpression had a similar role to the ferroptosis inhibitor ferrostatin-1 and restored cell proliferation and migration after GNA treatment. Also, GNA promoted reactive oxygen species (ROS) accumulation, which reduced mitochondrial membrane potential. GCH1 overexpression or ferrostatin-1 treatment reversed GNA regulation of ROS accumulation and mitochondrial membrane potential inhibition. Conclusions: Taken together, these findings confirmed that GNA suppressed the malignant progression of NSCLC by inducing GCH1-mediated ferroptosis. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

18 pages, 517 KiB

Open AccessReview

Bioactive Substances and Skin Health: An Integrative Review from a Pharmacy and Nutrition Perspective

by Rafael Jesús Giménez Martínez, Francisco Rivas García, Joan Carles March Cerdá, Ángela Hernández-Ruíz, Martha Irene González Castro, María-Isabel Valverde-Merino, Felipe José Huertas Camarasa, Fuensanta Lloris Meseguer and Margarita López-Viota Gallardo

Pharmaceuticals 2025, 18(3), 373; https://doi.org/10.3390/ph18030373 - 6 Mar 2025

Viewed by 179

Abstract

The skin is one of the largest and most important organs of our body. There are numerous factors that are related to skin health, including lifestyle factors, nutrition, or skin care. Bioactive substances from plant and marine extracts play a key role in [...] Read more.

The skin is one of the largest and most important organs of our body. There are numerous factors that are related to skin health, including lifestyle factors, nutrition, or skin care. Bioactive substances from plant and marine extracts play a key role in skin health. The aim of this research was to compile the main evidence on skin and bioactive substances. An integrative review was performed, reporting the main findings according to PRISMA (2020). Thirteen search equations were developed. After the applications of the equations and the process of screening and selection of articles, 95 references were compiled. The main results related to bioactive compounds were classified into food-derived components, nutraceuticals, symbiotics, active substances of marine origin, and substances from plant extracts). There are several factors that indicate that the use of bioactive compounds are interesting for skin health, highlighting some dietary nutrients, substances obtained from plant extracts and metabolites of marine origin that, showing anti-inflammatory and antimicrobial effects, are related to the improvement of some skin conditions or are active principles for cosmetics. Full article

(This article belongs to the Special Issue Bioactive Substances and Skin Health: The Role of Pharmacy and Nutrition—Properties and Technology)

► Show Figures

Figure 1

26 pages, 4847 KiB

Open AccessArticle

Investigation on Human Carbonic Anhydrase IX and XII Inhibitory Activity and A549 Antiproliferative Activity of a New Class of Coumarinamides

by Davide Moi, Simone Carradori, Marialucia Gallorini, Noemi Mencarelli, Alberto Deplano, Andrea Angeli, Serena Vittorio, Claudiu T. Supuran and Valentina Onnis

Pharmaceuticals 2025, 18(3), 372; https://doi.org/10.3390/ph18030372 - 5 Mar 2025

Viewed by 263

Abstract

Background—Aggressive solid tumors are commonly characterized by both basic intracellular pH and acidic extracellular pH, which increase cell survival and proliferation. As carbonic anhydrases IX/XII are involved in this pH regulation, their inhibition is an appealing approach in cancer therapy, avoiding cancer [...] Read more.

Background—Aggressive solid tumors are commonly characterized by both basic intracellular pH and acidic extracellular pH, which increase cell survival and proliferation. As carbonic anhydrases IX/XII are involved in this pH regulation, their inhibition is an appealing approach in cancer therapy, avoiding cancer cell survival and proliferation. Substituted coumarins are selective non-classical CA IX and CA XII inhibitors. Methods—In this study, new 7-hydroxycoumarinamides were synthesized and assayed for CA inhibition and antiproliferative activity. Results—All of the coumarinamides showed human CA IX and CA XII selective inhibition over the off-target CA I and CA II isoforms. Coumarin acts as a suicide inhibitor because its heterocyclic ring can be hydrolyzed by CA esterase activity to give the corresponding 2-hydroxycinnamic acid derivative which blocks the entrance of the active site. The 2-hydroxycinnamic acid derivatives deriving from the most potent and selective coumarinamides were docked into CA IX and XII to better understand the activity and selectivity against the two CA isoforms. The most active coumarinamides also produced a decrease of A549 cell proliferation and were able to arrest cells at the G1/S checkpoint. Conclusions—These results may open new perspectives for developing coumarin-based CA IX/XII inhibitors. Full article

(This article belongs to the Section Medicinal Chemistry)

► Show Figures

Figure 1

Figure 1
Hydrolysis of coumarin (A) to 2-hydroxycinnamic acid (B). Full article ">Figure 2
Docking poses of the E/Z isomers of hydrolyzed coumarins 7A, 9A, 23A and 38A into hCA IX. (A) (E)-7A, (B) (Z)-7A, (C) (E)-9A, (D) (Z)-9A, (E) (E)-23A, (F) (Z)-23A, (G) (E)-38A, (H) (Z)-38A. Full article ">Figure 3
Docking poses of the E/Z isomers of hydrolyzed coumarins 7A, 9A, 23A and 38A into h-CA XII. (A) (E)-7A, (B) (Z)-7A, (C) (E)-9A, (D) (Z)-9A, (E) (E)-23A, (F) (Z)-23A, (G) (E)-38A, (H) (Z)-38A. Full article ">Figure 4
Cell viability of BEAS (a) and (b) A549 cells exposed to increasing concentrations (0–150 µM) of selected compounds (4-7, 9, 19, 22, 23, 25, 29, 30, 32, 38, 44 and 45) for 48 h. (c) Cell viability of BEAS and A549 cells exposed to doxorubicin (0-10 µM) after 48 h of exposure. Bar graphs represent cell viability percentages. The untreated control (CTRL = 0 µM) is set as the 100%. Data are presented as means ± standard deviations obtained from one experiment in triplicates (n = 3). * = p < 0.01, ** = p < 0.001, *** = p < 0.0001, **** = p < 0.00001 comparing treated to the untreated control. Full article ">Figure 5
(a) Cytotoxicity occurrence in A549 cells exposed to increasing concentrations (0–150 µM) of compounds 7, 9, 23 and 38 after 24 h. The bar graphs show the amount of lactate dehydrogenase (LDH) released from treated A549 cells as a fold increase respective to that secreted by untreated cells (CTRL = 0 µM) after 24 h of exposure. (b) Light phase-contrast images of A549 cells 48 h after treatment. Magnification 10×. Yellow arrows highlight morphological changes in the cell population. Data are presented as means ± standard deviations obtained from one experiment in triplicates (n = 3). ** = p < 0.001, **** = p < 0.00001 comparing treated to the untreated control. Full article ">Figure 6
(a) Cell cycle analysis in A549 cells exposed to increasing concentrations (0–150 µM) of compounds 7, 9, 23 and 38 after 48 h. Data are presented as means ± standard deviations from three independent experiments (n = 3). Bars highlight cell percentages in the various phases of the cell cycle (G1, S, and G2) of A549. * = p < 0.01, ** = p < 0.001, *** = p < 0.0001, **** = p < 0.00001 comparing treated with the untreated control (G1 phase). § = p < 0.01, §§ = p < 0.001, §§§ = p < 0.0001, §§§§ = p < 0.00001 comparing treated with the untreated control (S phase). # = p < 0.01, ## = p < 0.001, ### = p < 0.0001, #### = p < 0.00001 comparing treated with the untreated control (G2 phase). (b) The top panel displays the DNA profile of cells 48 h after treatment. Peaks are generated by the emission of PI in the FL3 fluorescence channel. The bottom panel is a dot plot representing the gating strategy. Full article ">Scheme 1
General synthetic procedure for 7-hydroxycoumarin amides 4–45. Reagents and conditions are as follows: (i) CH3COONH4, water, reflux 15 h, 87% yield; (ii) substituted benzylamines, EDCI, HOBt, dry MeCN, r.t. 6 h, 44–92% yield; (iii) substituted phenylethylamines, EDCI, HOBt, dry MeCN, r.t. 6 h, 70–90% yield; (iv) substituted piperazines, EDCI, HOBt, dry MeCN, r.t. 6 h, 47–82% yield. Full article ">Scheme 2
Hydrolysis of coumarins 7, 9, 23 and 38 to 2,4-dihydroxycinnamic acid amides 7A, 9A, 23A and 38A. Full article ">

17 pages, 1939 KiB

Open AccessReview

Exosomes in Ovarian Cancer: Towards Precision Oncology

by Maria Grazia Perrone, Silvana Filieri, Amalia Azzariti, Domenico Armenise, Olga Maria Baldelli, Anselma Liturri, Anna Maria Sardanelli, Savina Ferorelli, Morena Miciaccia and Antonio Scilimati

Pharmaceuticals 2025, 18(3), 371; https://doi.org/10.3390/ph18030371 - 5 Mar 2025

Viewed by 132

Abstract

Background: Identification of targetable biomarkers to improve early disease detection and overall patient outcomes is becoming an urgent need in clinical oncology. Ovarian cancer (OC) has one of the highest mortality rates among gynecological cancers. It is asymptomatic and almost always diagnosed [...] Read more.

Background: Identification of targetable biomarkers to improve early disease detection and overall patient outcomes is becoming an urgent need in clinical oncology. Ovarian cancer (OC) has one of the highest mortality rates among gynecological cancers. It is asymptomatic and almost always diagnosed at an advanced stage (III or IV), leading to a 5-year survival rate of approximately 35%. Methods: Current therapeutic approaches for OC are very limited and mainly consist of cytoreductive surgery and cisplatin plus taxane-based chemotherapy. No gender and tumor specific biomarkers are known. Exosomes, lipid bilayer vesicles of endocytic origin secreted by most cell types, represent sources of information for their involvement in the onset and progression of many diseases. Hence, research on exosome contents as tools and targets in precise oncology therapy provides knowledge essential to improving diagnosis and prognosis of the disease. Results: This review attempts to give an overview of how exosomes are implicated in ovarian carcinoma pathogenesis to trigger further cancer exosome-based investigations aimed at developing ovarian cancer fine-tuning diagnostic methodologies. Conclusions: It is essential to investigate exosome-based cancer drugs to advance understanding, improve treatment plans, create personalized strategies, ensure safety, and speed up clinical translation to increase patients’ overall survival and quality of life. Papers published in PubMed and Web of Science databases in the last five years (2020–2024) were used as a bibliographic source. Full article

(This article belongs to the Special Issue Current Therapies for Endometriosis, Adenomyosis and Endometrial Cancer)

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
Schematic representation of exosome biogenesis, secretion, and molecular content release. Exosomes protrude from the surface of the membrane and, degraded by lysosomes or secreted as multivesicular bodies, release their cargo in various body fluids, e.g., saliva, blood, breast milk (BM), tears, urine, cerebrospinal fluid (CSF), and ascites. Created with <a href="http://Biorender.com" target="_blank">Biorender.com</a>. Full article ">Figure 2
Strategies for leveraging exosomes in cancer therapy. Created with <a href="http://Biorender.com" target="_blank">Biorender.com</a>. Full article ">Figure 3
Exosomal microRNAs released by adipose-derived mesenchymal stem cells (MSCs), macrophages, and fibroblasts in ovarian cancer cells. miRNAs released by adipose MSCs induce apoptosis by decreasing BCL-2 and increasing BAX expression that induce Caspase-3 activation increasing apoptosis. miR-7, miR-29-a, and miR-223 reduce metastasis, induce T-cell balance, and induce drug resistance, respectively. TGFβ1 induces EMT via the SMAD pathway. Created with <a href="http://Biorender.com" target="_blank">Biorender.com</a>. Full article ">Figure 4
Two main strategies for OC-specific exosome drug delivery: passive and active. Passive loading relies on diffusion-based methods like co-incubation and other physical treatments to enhance exosome permeability, e.g., electroporation, sonication, freeze–thaw cycles, dialysis, extrusion, surfactant treatment, and in situ synthesis. Active loading leverages cellular mechanisms to incorporate proteins or nucleic acids during exosome biogenesis, often through genetic modification of parental cells. Created with <a href="http://Biorender.com" target="_blank">Biorender.com</a>. Full article ">

20 pages, 3112 KiB

Open AccessArticle

Anti-Inflammatory Activity of Cannabis sativa L. Extract in 2,4-Dinitrochlorobenzene-Induced Dermatitis in Rats

by Renata Wolińska, Maria Zalewska, Piotr Poznański, Agata Nawrocka, Agnieszka Kowalczyk, Mariusz Sacharczuk and Magdalena Bujalska-Zadrożny

Pharmaceuticals 2025, 18(3), 370; https://doi.org/10.3390/ph18030370 - 5 Mar 2025

Viewed by 165

Abstract

Background: Cannabis sativa L. and its products are becoming popular for the treatment of inflammatory diseases. One of the main phytocannabinoids contained in cannabis is cannabidiol (CBD), which is a component of numerous cosmetic preparations used to treat inflammatory skin diseases such [...] Read more.

Background: Cannabis sativa L. and its products are becoming popular for the treatment of inflammatory diseases. One of the main phytocannabinoids contained in cannabis is cannabidiol (CBD), which is a component of numerous cosmetic preparations used to treat inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. However, current data regarding the efficacy and safety of CBD for dermatological indications are limited. Therefore, the aim of the present study was to evaluate the anti-inflammatory effect of high-CBD Cannabis sativa L. extract (eCBD) in a model of AD. Methods: Dermatitis was induced by repeated application of 2,4-dinitrochlorobenzene (DNCB) to the skin of the rats’ ears. The therapeutic effect of eCBD was evaluated in behavioral, histopathological, and hematological studies following topical application as an ointment containing 2% CBD. Results: Application of the ointment containing eCBD resulted in attenuation of DNCB-induced inflammation. Interestingly, an anti-edematous effect was more pronounced in rats treated with the eCBD than in rats treated with 1% hydrocortisone ointment. However, eCBD did not reduce the frequency of DNCB-induced scratching, while there was a visible antipruritic effect of 1% hydrocortisone application. Histopathological analysis revealed that both eCBD and 1% hydrocortisone ointments significantly decreased mast cell count compared with the Vaseline control group. Furthermore, treatment with an ointment containing eCBD resulted in a decrease in the number of leukocytes in the blood. Conclusions: Topically administered eCBD had a stronger anti-edematous effect than glucocorticosteroid and differently affected hematological parameters. It is suggested that eCBD has therapeutic potential for the treatment of AD. Full article

(This article belongs to the Section Natural Products)

► Show Figures

Graphical abstract

35 pages, 15385 KiB

Open AccessReview

A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse

by Helena Tsimpili and Grigoris Zoidis

Pharmaceuticals 2025, 18(3), 369; https://doi.org/10.3390/ph18030369 - 5 Mar 2025

Viewed by 232

Abstract

The cholinergic pathways in the central nervous system (CNS) play a pivotal role in different cognitive functions of the brain, such as memory and learning. This review takes a dive into the pharmacological side of this important part of CNS function, taking into [...] Read more.

The cholinergic pathways in the central nervous system (CNS) play a pivotal role in different cognitive functions of the brain, such as memory and learning. This review takes a dive into the pharmacological side of this important part of CNS function, taking into consideration muscarinic receptors and cholinesterase enzymes. Targeting a specific subtype of five primary muscarinic receptor subtypes (M1-M5) through agonism or antagonism may benefit patients; thus, there is a great pharmaceutical research interest. Inhibition of AChE and BChE, orthosteric or allosteric, or partial agonism of M1 mAChR are correlated with Alzheimer’s disease (AD) symptoms improvement. Agonism or antagonism on different muscarinic receptor subunits may lessen schizophrenia symptoms (especially positive allosteric modulation of M4 mAChR). Selective antagonism of M4 mAChR is a promising treatment for Parkinson’s disease and dystonia, and the adverse effects are limited compared to inhibition of all five mAChR. Additionally, selective M5 antagonism plays a role in drug independence behavior. M3 mAChR overexpression is associated with malignancies, and M3R antagonists seem to have a therapeutic potential in cancer, while M1R and M2R inhibition leads to reduction of neoangiogenesis. Depending on the type of cancer, agonism of mAChR may promote cancer cell proliferation (as M3R agonism does) or protection against further tumor development (M1R agonism). Thus, there is an intense need to discover new potent compounds with specific action on muscarinic receptor subtypes. Chemical structures, chemical modification of function groups aiming at action enhancement, reduction of adverse effects, and optimization of Drug Metabolism and Pharmacokinetics (DMPK) will be further discussed, as well as protein–ligand docking. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Medicinal Chemistry)

► Show Figures

Graphical abstract

28 pages, 2271 KiB

Open AccessArticle

Usage Frequency and Ecotoxicity of Skin Depigmenting Agents

by Sandra Mota, Liliana Rego, Emília Sousa, Maria Teresa Cruz and Isabel Martins de Almeida

Pharmaceuticals 2025, 18(3), 368; https://doi.org/10.3390/ph18030368 - 4 Mar 2025

Viewed by 160

Abstract

Background/Objectives: Depigmenting cosmetic products are a fast-growing segment of the health products market, driven by consumer demand to address skin hyperpigmentation. Simultaneously, interest in products with a reduced environmental impact is increasing. However, the potential environmental risks, especially in aquatic ecosystems, of depigmenting [...] Read more.

Background/Objectives: Depigmenting cosmetic products are a fast-growing segment of the health products market, driven by consumer demand to address skin hyperpigmentation. Simultaneously, interest in products with a reduced environmental impact is increasing. However, the potential environmental risks, especially in aquatic ecosystems, of depigmenting products remain unexplored. This study assesses the usage frequency of skin depigmenting agents in cosmetic products and compiles data on the biodegradability and acute aquatic toxicity of the most prevalent compounds. Methods: A market analysis of Portuguese pharmacies and parapharmacies in 2022 identified prevalent depigmenting agents. Scientific evidence on their biodegradability and acute aquatic toxicity was compiled, and when data was unavailable, in silico predictions were conducted. Results: The study identified the ten most-used depigmenting agents in cosmetic products, including hydroxy/keto acids, as well as vitamin C and derivatives, with a usage frequency surpassing 50%. While most were naturally derived and showed low environmental risk, synthetic and highly lipophilic depigmenting agents found in 35 of 70 products (ascorbyl tetraisopalmitate/tetrahexyldecyl ascorbate and resorcinol derivatives) showed a higher potential for environmental hazard. Conclusions: The findings underscore the need for further research on the presence of these cosmetic ingredients in aquatic ecosystems and a reassessment of regulatory frameworks concerning their environmental impact. Mitigation strategies should emphasize biodegradable alternatives, renewable sources, and molecular modifications to reduce toxicity while maintaining depigmenting efficacy and skin safety. This study provides original insights into commonly used depigmenting agents in the health products market and their chemical structures, offering valuable opportunities for innovation in chemical/pharmaceutical industries. Full article

(This article belongs to the Section Pharmaceutical Technology)

► Show Figures

Figure 1

35 pages, 2569 KiB

Open AccessReview

Seaweed in the Diet as a Source of Bioactive Metabolites and a Potential Natural Immunity Booster: A Comprehensive Review

by Amiya Kumar Mandal, Sudhamayee Parida, Akshaya Kumar Behera, Siba Prasad Adhikary, Andrey A. Lukatkin, Alexander S. Lukatkin and Mrutyunjay Jena

Pharmaceuticals 2025, 18(3), 367; https://doi.org/10.3390/ph18030367 - 4 Mar 2025

Viewed by 185

Abstract

Seaweed plays an essential role in the survival of marine life, provides habitats and helps in nutrient recycling. It is rich in valuable nutritious compounds such as pigments, proteins, polysaccharides, minerals, vitamins, omega-rich oils, secondary metabolites, fibers and sterols. Pigments like fucoxanthin and [...] Read more.

Seaweed plays an essential role in the survival of marine life, provides habitats and helps in nutrient recycling. It is rich in valuable nutritious compounds such as pigments, proteins, polysaccharides, minerals, vitamins, omega-rich oils, secondary metabolites, fibers and sterols. Pigments like fucoxanthin and astaxanthin and polysaccharides like laminarin, fucoidan, galactan and ulvan possess immune-modulatory and immune-enhancing properties. Moreover, they show antioxidative, antidiabetic, anticancer, anti-inflammatory, antiproliferative, anti-obesity, antimicrobial, anticoagulation and anti-aging properties and can prevent diseases such as Alzheimer’s and Parkinson’s and cardiovascular diseases. Though seaweed is frequently consumed by Eastern Asian countries like China, Japan, and Korea and has gained the attention of Western countries in recent years due to its nutritional properties, its consumption on a global scale is very limited because of a lack of awareness. Thus, to incorporate seaweed into the global diet and to make it familiar as a functional food, issues such as large-scale cultivation, processing, consumer acceptance and the development of seaweed-based food products need to be addressed. This review is intended to give a brief overview of the present status of seaweed, its nutritional value and its bioactive metabolites as functional foods for human health and diseases owing to its immunity-boosting potential. Further, seaweed as a source of sustainable food and its prospects along with its issues are discussed in this review. Full article

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

► Show Figures

Graphical abstract

14 pages, 10702 KiB

Open AccessArticle

Antimicrobial and Antiherpetic Properties of Nanoencapsulated Hypericum perforatum Extract

by Yoana Sotirova, Nadezhda Ivanova, Neli Ermenlieva, Neli Vilhelmova-Ilieva, Lora Simeonova, Miroslav Metodiev, Viliana Gugleva and Velichka Andonova

Pharmaceuticals 2025, 18(3), 366; https://doi.org/10.3390/ph18030366 - 4 Mar 2025

Viewed by 199

Abstract

Background/Objectives: This study aims to gain insights into the antimicrobial and antiherpetic activity of hyperforin-rich Hypericum perforatum L. (HP) extract using nanostructured lipid carriers (NLCs) as delivery platforms. Methods: Two established NLC specimens, comprising glyceryl behenate and almond oil or borage oil, [...] Read more.

Background/Objectives: This study aims to gain insights into the antimicrobial and antiherpetic activity of hyperforin-rich Hypericum perforatum L. (HP) extract using nanostructured lipid carriers (NLCs) as delivery platforms. Methods: Two established NLC specimens, comprising glyceryl behenate and almond oil or borage oil, and their extract-loaded counterparts (HP-NLCs) were utilized. Their minimal bactericidal/fungicidal concentrations (MBC; MFC) were investigated against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa ATCC 10145, Klebsiella pneumoniae ATCC 10031, and Candida albicans ATCC 10231. The anti-herpesvirus (HSV-1) potential was evaluated concerning antiviral and virucidal activity and impact on viral adsorption. Results: The borage oil-based extract-loaded nanodispersion (HP-NLC2) exhibited pronounced microbicidal activity against S. aureus (MBC 6.3 mg/mL), K. pneumoniae (MBC 97.7 µg/mL), and C. albicans (MFC < 48.8 µg/mL), unlike the almond oil-containing sample (HP-NLC1), which showed only weak inhibition of the fungal growth. HP-NLC2 was found to be less cytotoxic and to suppress HSV-1 replication slightly more than HP-NLC1, but generally, the effects were weak. Neither the empty lipid nanoparticles nor the HP extract-loaded carriers expressed activity against E. coli, P. aeruginosa, the HSV-1 extracellular virions, or viral adhesion. Conclusions: It could be concluded that both HP-NLC samples revealed only minor antiherpetic potential of the hyperforin-rich extract, but HP-NLC2 demonstrated significant antibacterial and antimycotic activity. Therefore, the latter was featured as a more convenient HP-carrier system for nano-designed dermal pharmaceutical formulations. Such a thorough investigation of hyperforin-determined anti-HSV-1 effects and antibacterial and antimycotic properties, being the first of its kind, contributes to the fundamental knowledge of HP and reveals new perspectives for the utilization, limitations, and therapeutic designation of its non-polar components. Full article

(This article belongs to the Special Issue Natural Products and Their Modifications as Agents Used in the Fight against Pathogens)

► Show Figures

Graphical abstract

2 pages, 1235 KiB

Open AccessCorrection

Correction: Khan et al. Anti-Oxidative and Anti-Apoptotic Oligosaccharides from Pichia pastoris-Fermented Cress Polysaccharides Ameliorate Chromium-Induced Liver Toxicity. Pharmaceuticals 2024, 17, 958

by Imdad Ullah Khan, Aqsa Aqsa, Yusra Jamil, Naveed Khan, Amjad Iqbal, Sajid Ali, Muhammad Hamayun, Abdulwahed Fahad Alrefaei, Turki Kh. Faraj, Bokyung Lee and Ayaz Ahmad

Pharmaceuticals 2025, 18(3), 365; https://doi.org/10.3390/ph18030365 - 4 Mar 2025

Viewed by 101

Abstract

In the original publication [...] Full article

(This article belongs to the Section Medicinal Chemistry)

► Show Figures

Figure 10

33 pages, 5015 KiB

Open AccessReview

Beyond Conventional Antifungals: Combating Resistance Through Novel Therapeutic Pathways

by Helal F. Hetta, Tameem Melhem, Hashim M. Aljohani, Ayman Salama, Rehab Ahmed, Hassabelrasoul Elfadil, Fawaz E. Alanazi, Yasmin N. Ramadan, Basem Battah, Michelangelo Rottura and Matthew Gavino Donadu

Pharmaceuticals 2025, 18(3), 364; https://doi.org/10.3390/ph18030364 - 4 Mar 2025

Viewed by 170

Abstract

The rising burden of fungal infections presents a significant challenge to global healthcare, particularly with increasing antifungal resistance limiting treatment efficacy. Early detection and timely intervention remain critical, yet fungal pathogens employ diverse mechanisms to evade host immunity and develop resistance, undermining existing [...] Read more.

The rising burden of fungal infections presents a significant challenge to global healthcare, particularly with increasing antifungal resistance limiting treatment efficacy. Early detection and timely intervention remain critical, yet fungal pathogens employ diverse mechanisms to evade host immunity and develop resistance, undermining existing therapeutic options. Limited antifungal options and rising resistance necessitate novel treatment strategies. This review provides a comprehensive overview of conventional antifungal agents, their mechanisms of action, and emerging resistance pathways. Furthermore, it highlights recently approved and investigational antifungal compounds while evaluating innovative approaches such as nanotechnology, drug repurposing, and immunotherapy. Addressing antifungal resistance requires a multifaceted strategy that integrates novel therapeutics, enhanced diagnostic tools, and future research efforts to develop sustainable and effective treatment solutions. Full article

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

► Show Figures

Graphical abstract

Graphical abstract
Full article ">Figure 1
Types of fungal diseases according to CDC categorization. CDC categorizes the illnesses brought on by fungi into four groups: the most prevalent fungal illnesses, those that affect people who live in or travel to particular regions, those that affect immunocompromised people, and other illnesses and health issues brought on by fungi. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>. Full article ">Figure 2
Mechanisms of action of antifungal drugs. They act through the disruption of the cell wall, the disruption of the cell membrane, the inhibition of protein synthesis, the inhibition of nucleic acid synthesis, the disruption of microtubules, or the inhibition of calcinurin signaling. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>. Full article ">Figure 3
Mechanism of resistance to common antifungal medications. (a) Azole resistance develops as a result of point mutations or the overexpression of the ERG11 gene, which encodes the enzyme lanosterol-14-demethylase. (b) Echinocandin resistance develops through a mutation or substitution in the FKS-1 gene, which encodes the β-1,3 glucan synthase enzyme. (c) Polyene resistance develops as a result of the ERG mutation, which leads to decreased ergosterol biosynthesis. (d) Some fungi can form biofilms and acquire resistance to nearly all antifungal classes. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>. Full article ">Figure 4
Difference between de novo synthesis and the repurposing of a drug. The repurposing drug approach overcomes high costs, long periods, and efforts to develop novel drugs. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>. Full article ">Figure 5
Mechanism of action of AgNPs to combat fungal resistance. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>. Full article ">

20 pages, 1376 KiB

Open AccessReview

Cortical Potentiation in Chronic Neuropathic Pain and the Future Treatment

by Shun Hao, Shen Lin, Wucheng Tao and Min Zhuo

Pharmaceuticals 2025, 18(3), 363; https://doi.org/10.3390/ph18030363 - 4 Mar 2025

Viewed by 191

Abstract

Pain, or the ability to feel pain and express the unpleasantness caused by peripheral injuries, are functions of the central nervous system. From peripheral sensory nerve terminals to certain cortical regions of the brain, activation of related neural networks underlies the sensory process. [...] Read more.

Pain, or the ability to feel pain and express the unpleasantness caused by peripheral injuries, are functions of the central nervous system. From peripheral sensory nerve terminals to certain cortical regions of the brain, activation of related neural networks underlies the sensory process. Recently, our knowledge of pain has been increasing dramatically, due to the advancement of scientific approaches. We no longer see the brain as a random matrix for pain but, rather, we are able to identify the step-by-step selective signaling proteins, neurons, and networks that preferentially contribute to the process of chronic pain and its related negative emotions, like anxiety and fear. However, there is still lacking the selective and effective drugs and methods for the treatment of chronic pain clinically. While first-line drugs for acute pain and mental diseases are also applied for the clinical management of chronic pain, their prolonged usage always causes serious side effects. In this short review, we will update and summarize the recent progress in this field and mainly focus on the roles of neural networks and synaptic mechanisms in chronic neuropathic pain. Furthermore, potential drug targets (such as plasticity-related signaling molecules, ionic channels, cytokines, and neuropeptides) and methods for the management of chronic neuropathic pain will be discussed as well. We hope this review can provide new, valuable insight into the treatment of chronic neuropathic pain. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapy of Neuropathic Pain)

► Show Figures

Figure 1

Figure 1
The changes of peripheral and central neural plasticity at different stages of chronic pain. Peripheral sensitization, spinal cord facilitation and sensitization, as well as cortical plasticity contribute to pain perception at different stages of chronic pain. At the early stage of chronic pain after peripheral injury, peripheral and spinal cord sensitization plays an important role in hyperalgesia and allodynia. At the late stage, cortical synapses are also likely undergoing long-term potentiation (LTP). For certain forms of chronic pain, because of cortical excitation and LTPs, patients still complain about pain even after the full recovery of the peripheral injury. Full article ">Figure 2
In vivo LTP in the ACC induced by peripheral single digit amputation in adult rats. (A) Diagram of in vivo fEPSP recording in the rat ACC; The rat was kept in a mildly anesthetized condition using halothane. The recording electrode was positioned in the opposite ACC to the peripheral stimulation electrode. Amputation was conducted on the hindpaw that did not receive stimulation by applying a higher concentration of halothane. (B) An example of a histological section showing the recording site (arrow) labeled with neurobiotin and the track of the recording electrode. (C) Sample traces of synaptic responses to electrical stimulation were applied to the hindpaw at a low intensity (5.0 V) and a higher intensity (25.0 V). An arrow indicates the time of hindpaw electrical stimulation. (D) The representative traces of EPSPs recorded 5 min before (pre) and 115–120 min after (post) sham treatment (Figure Da) or amputation (Figure Db) in the ACC. (Figure Db) The latency of evoked responses remained unchanged after amputation whereas there was a notable increase in the slope of the EPSP. (E) Amputation of the contralateral hindpaw caused LTP response of fEPSPs in the ACC (•). The fEPSP slopes were not significantly changed in the sham group. (○) (Adapted from Wei and Zhuo, J Physiology, 2001 [<a href="#B26-pharmaceuticals-18-00363" class="html-bibr">26</a>]). Cg1, cingulate cortex area 1; Cg2, cingulate cortex area 2. Full article ">Figure 3
Genetic and pharmacological evidence for the contribution of calcium-stimulated AC1 in different types of chronic pain. In mice lacking AC1, behavioral responses to different sensory stimuli were significantly reduced in different chronic pain models. The selective inhibitor of AC1 NB001 shows significant analgesic effects in various models as well. Full article ">

25 pages, 5024 KiB

Open AccessArticle

Synergistic Efficacy of Policosanol (Raydel^®) and Banaba Leaf Extract to Treat Hyperglycemia and Dyslipidemia in Streptozotocin-Induced Diabetic and Hyperlipidemic Zebrafish (Danio rerio): Protection of Liver and Kidney with Enhanced Tissue Regeneration

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

Pharmaceuticals 2025, 18(3), 362; https://doi.org/10.3390/ph18030362 - 3 Mar 2025

Viewed by 459

Abstract

Background: The efficacy of banaba leaf extract was tested against carboxymethyllysine (CML)-induced toxicity in embryos and adult zebrafish. Additionally, the individual and combined effects of banaba (BNB) and policosanol (PCO) were analyzed to alleviate dyslipidemia, hyperglycemia, and associated effects in streptozotocin (STZ)-induced hyperlipidemic [...] Read more.

Background: The efficacy of banaba leaf extract was tested against carboxymethyllysine (CML)-induced toxicity in embryos and adult zebrafish. Additionally, the individual and combined effects of banaba (BNB) and policosanol (PCO) were analyzed to alleviate dyslipidemia, hyperglycemia, and associated effects in streptozotocin (STZ)-induced hyperlipidemic diabetic zebrafish. Methodology: The high cholesterol diet (HCD, final 4%, w/w)-fed zebrafish were injected with STZ to develop diabetes and were subsequently fed with either HCD or HCD+BNB (final 0.1% w/w) or HCD+PCO (final 0.1% w/w) or HCD+BNB+PCO (each final 0.1%, w/w) each for 14 days. The zebrafish tail fin was amputated to assess tissue regeneration, while the organs and blood were collected for histological and biochemical analysis. Results: Severely compromised embryo survivability and developmental defects were noticed in the CML-injected group that significantly improved following BNB exposure. Similarly, CML-induced acute paralysis and mortality of adult zebrafish were effectively mitigated by the treatment with BNB. In the hyperlipidemic diabetic zebrafish, both BNB and PCO supplementation displayed the hypoglycemic effect; however, a remarkable reduction (p < 0.05) in blood glucose levels was observed in the BNB+PCO group, around 14% and 16% less than the BNB group and PCO group, respectively. Likewise, higher tail fin regeneration was noticed in response to BNB+PCO supplementation. Both BNB and PCO have a substantial counter-effect against HCD+STZ-induced dyslipidemia. However, the combined supplementation (BNB+PCO) displayed a significantly better effect than that of BNB and PCO alone to alleviate total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C). The most impressive impact of BNB+PCO was noticed in the elevation of high-density lipoprotein cholesterol (HDL-C), which was ~1.5 times higher than the HDL-C level in response to BNB and PCO. Also, BNB+PCO effectively reduced the malondialdehyde (MDA) and elevated the plasma sulfhydryl content, paraoxonase (PON), and ferric ion reduction (FRA) activity. Histological analyses revealed a significant effect of BNB+PCO in preventing inflammatory infiltration, fatty liver changes, and interleukin-6 production. Similarly, a notably better effect of BNB+PCO compared to their individual effect was noticed in preventing kidney damage and mitigation of ROS generation, apoptosis, and cellular senescence. Conclusions: The finding establishes the substantial effect of BNB and PCO in countering hyperglycemia, dyslipidemia, and associated disorders, which synergistically improved following the combined supplementation with BNB+PCO. Full article

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

► Show Figures

Figure 1

17 pages, 3084 KiB

Open AccessArticle

Rhoifolin Improves Glycometabolic Control in Streptozotocin-Induced Diabetic Rats by Up-Regulating the Expression of Insulin Signaling Proteins and Down-Regulating the MAPK/JNK Pathway

by Maryam Ehsan, Sibtain Ahmed, Wafa Majeed, Asra Iftikhar, Maryam Iftikhar, Mateen Abbas and Tahir Mehmood

Pharmaceuticals 2025, 18(3), 361; https://doi.org/10.3390/ph18030361 - 2 Mar 2025

Viewed by 350

Abstract

Background and Aim: Rhoifolin is a bioactive flavonoid that possesses strong antioxidant and anti-inflammatory activities. The current investigation aimed to examine the anti-diabetic potential of rhoifolin in streptozotocin-induced diabetic rats. Dose-dependent (10 and 20 mg/kg) anti-hyperglycemic, anti-hyperlipidemic, anti-inflammatory, and antioxidant effects of [...] Read more.

Background and Aim: Rhoifolin is a bioactive flavonoid that possesses strong antioxidant and anti-inflammatory activities. The current investigation aimed to examine the anti-diabetic potential of rhoifolin in streptozotocin-induced diabetic rats. Dose-dependent (10 and 20 mg/kg) anti-hyperglycemic, anti-hyperlipidemic, anti-inflammatory, and antioxidant effects of rhoifolin were evaluated by measuring fasting blood glucose, serum glucose, serum insulin, HOMA-IR, lipidemic status, inflammatory cytokines, and hepatic antioxidant markers. To identify the underlying mechanism behind the anti-diabetic activity of rhoifolin, qRT-PCR was carried out using rat pancreatic and hepatic tissues. Results: The results have shown that rhoifolin produced antioxidant effects, as exhibited by DPPH and ABTS⁺ assays, respectively. Rhoifolin showed potent alpha-amylase and alpha-glucosidase inhibitory activities. Rhoifolin enhanced the serum insulin level, significantly decreased the serum glucose, HOMA-IR, and cytokine levels, and improved the lipid profile. Rhoifolin also showed a substantial decline in insulin resistance in the treated rats. Rhoifolin significantly raised catalase and superoxide dismutase levels in hepatic tissues while potentially decreasing the malondialdehyde levels. Moreover, rhoifolin significantly down-regulated the MAPK-8, TRAF-6, and TRAF-4 expressions and up-regulated the PDX-1, SIRT-1, INS-1, and GLUT-4 expressions in treated groups. Conclusions: Our results indicate that rhoifolin exhibits a hypoglycemic effect, which appears to be associated with its regulatory impact on metabolic inflammation and oxidative stress markers. This was accompanied by a lower HOMA-IR index, highlighting its potential role in promoting glucose homeostasis and mitigating insulin resistance. According to preliminary results, rhoifolin could further be tested to introduce it as another viable treatment option for diabetes. Full article

(This article belongs to the Special Issue The Mode of Action of Herbal Medicines and Natural Products)

► Show Figures

Figure 1

Figure 1
(A) DPPH radical-scavenging potential of rhoifolin; (B) ABTS radical-scavenging activity of rhoifolin. Full article ">Figure 2
Effect of rhoifolin on FBG in diabetic rats on 1st, 7th, 14th and 21st days. Data are represented as Mean ± SD (n = 6/group). Values are significant at a*; p < 0.05 represents normal vs. diabetic; b* p < 0.05; diabetic control vs. treated groups. (NC: normal control/non-diabetic control; DC: Diabetic control, Met: Metforfin-treated). Full article ">Figure 3
Effects of rhoifolin on (A) serum glucose; (B) serum insulin; (C) HOMA-IR. Results are displayed as Mean ± SD (n = 6/group). ### p < 0.001 represents normal vs. diabetic; ** p < 0.01, *** p < 0.001; diabetic control group vs. treated groups. Full article ">Figure 4
Effect of rhoifolin on serum pro-inflammatory markers (A) TNF-α; (B) IL-6 are presented as Mean ± SD (n = 6/group). ### p < 0.001 represents normal vs. diabetic; ** p < 0.01, *** p < 0.001; diabetic control group vs. treated groups. Full article ">Figure 5
Effect of rhoifolin on gene expressions (A) PDX-1; (B) INS-1 in diabetic rats. Results are displayed as Mean ± SD (n = 6/group). ### p < 0.001 represents normal vs. diabetic; ** p < 0.01, *** p < 0.001; diabetic control group vs. treated groups. Full article ">Figure 6
Effect of rhoifolin on gene expressions (A) SIRT-1; (B) GLUT-4 in diabetic rats. Results presented as Mean ± SD (n = 6/group). ### p < 0.001 represents normal vs. diabetic; ** p < 0.01, *** p < 0.001; diabetic control group vs. treated groups. Full article ">Figure 7
Effect of rhoifolin on gene expressions (A) MAPK-8; (B) TRAF-4; (C) TRAF-6 in diabetic rats. Results are showed as Mean ± SD (n = 6/group). ### p < 0.001 represents normal vs. diabetic; ** p < 0.01, *** p < 0.001; diabetic control group vs. treated groups. Full article ">

12 pages, 1174 KiB

Open AccessArticle

In Vitro Activity of the Triazinyl Diazepine Compound FTSD2 Against Drug-Resistant Mycobacterium tuberculosis Strains

by Carlos Aranaga, Ruben Varela, Aura Falco, Janny Villa, Leydi M. Moreno, Manuel Causse and Luis Martínez-Martínez

Pharmaceuticals 2025, 18(3), 360; https://doi.org/10.3390/ph18030360 - 2 Mar 2025

Viewed by 297

Abstract

Background/Objectives: Compounds derived from pyrimido-diazepine have shown selective inhibition of the susceptible Mycobacterium tuberculosis strain H37Rv. However, there is a need for studies that evaluate the activity of these compounds against multidrug-resistant strains and clinical isolates. This study aims to evaluate the antitubercular [...] Read more.

Background/Objectives: Compounds derived from pyrimido-diazepine have shown selective inhibition of the susceptible Mycobacterium tuberculosis strain H37Rv. However, there is a need for studies that evaluate the activity of these compounds against multidrug-resistant strains and clinical isolates. This study aims to evaluate the antitubercular potential of FTSD2 against drug-resistant strains of M. tuberculosis. Methods: The compound 4-(2,4-diamino-8-(4-methoxyphenyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepin-6-yl)-N-(2-(4-(dimethylamino)-6-(4-fluorophenyl)amino-1,3,5-triazin-2-yl)amino)ethyl)benzenesulfonamide (FTSD2) was tested against drug-resistant M. tuberculosis strains at minimal inhibitory and bactericidal concentrations (MIC and MBC). Kill curve assays were performed to assess bactericidal activity, and cytotoxicity was evaluated in human monocyte-derived macrophages and the RAW 264.7 murine macrophage cell line. Intracellular death assays, specifically macrophage infection assays, were also conducted to evaluate the effect of FTSD2 on intracellular M. tuberculosis growth. Results: FTSD2 inhibited the growth of drug-resistant M. tuberculosis at MIC and MBC values between 0.5 and 1 mg/L. Kill curve assays demonstrated concentration-dependent bactericidal activity. No cytotoxicity was observed in macrophages at concentrations below 64 mg/L. Additionally, FTSD2 significantly suppressed intracellular M. tuberculosis growth after 192 h. FTSD2 did not inhibit the growth of nontuberculous mycobacteria, including M. avium, M. abscessus, M. fortuitum, M. chelonae, and M. smegmatis at 50 mg/L. Conclusions: FTSD2 exhibits strong potential as a leading compound for the development of new antitubercular drugs, with selective activity against M. tuberculosis and minimal cytotoxic effects on macrophages. Further studies are needed to explore its mechanisms of action and therapeutic potential. Full article

► Show Figures

Figure 1

Figure 1
Time-kill curve of M. tuberculosis H37Rv. Dose−response of M. tuberculosis H37Rv to FTSD2 concentrations of 1× (1 mg/L), 4× (4 mg/L), and 8× (8 mg/L). Data are expressed as the mean and standard deviation. Full article ">Figure 2
Cytotoxicity of FTSD2 at different concentrations. (a) Percentage viability of hMDM cells. (b) Percentage viability of RAW 264.7 murine macrophage cells after 48 h of treatment with FTSD2 at different concentrations. C+ (positive control): doxorubicin 2 µg/mL; C− (growth control): 0.1% DMSO. Significant differences were determined using one-way ANOVA followed by Tukey’s post hoc test: * p < 0.05, *** p < 0.001. Data are expressed as the mean and standard deviation of a representative experiment. Full article ">Figure 3
Intracellular Growth Inhibition by M. tuberculosis. (a) Effect of FTSD2 on the intracellular growth of M. tuberculosis. (b) Effect of rifampicin on the intracellular growth of M. tuberculosis. (c) Comparison of the effects of FTSD2 and rifampicin at 1× MIC, showing no significant differences. (d) Comparison of the effects of FTSD2 and rifampicin at 4× MIC, showing significant differences after 120 h of exposure. Significant differences were determined using one-way ANOVA followed by Tukey’s post hoc test: * p < 0.05, ** p < 0.01, *** p < 0.001. Data are expressed as the mean and standard deviation of a representative experiment. Full article ">Figure 4
4-(2,4-diamino-8-(p-tolyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepin-6-yl)-N-(2-((4-(dimethylamino)-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)amino)ethyl)benzenesulfonamide (FTSD2). Full article ">

33 pages, 2602 KiB

Open AccessReview

Managing Irinotecan-Induced Diarrhea: A Comprehensive Review of Therapeutic Interventions in Cancer Treatment

by Xiaoqin Yang, Jiamei Chen, Yitao Wang, Yihan Wu and Jinming Zhang

Pharmaceuticals 2025, 18(3), 359; https://doi.org/10.3390/ph18030359 - 2 Mar 2025

Viewed by 185

Abstract

Irinotecan (CPT-11), an inhibitor of DNA topoisomerase I, stands as a pivotal therapeutic agent in oncology. However, its use is primarily constrained by side effects such as neutropenia and the onset of delayed diarrhea. Despite the effective management of neutropenia, CPT-11-induced diarrhea (CID) [...] Read more.

Irinotecan (CPT-11), an inhibitor of DNA topoisomerase I, stands as a pivotal therapeutic agent in oncology. However, its use is primarily constrained by side effects such as neutropenia and the onset of delayed diarrhea. Despite the effective management of neutropenia, CPT-11-induced diarrhea (CID) is often severe, leading to hospitalization, dosage adjustments, and in some cases, treatment discontinuation, which can significantly impact therapeutic outcomes. A multitude of pharmacological agents have been investigated in preclinical and clinical studies with the aim of reducing or preventing the onset of delayed diarrhea associated with CPT-11. This comprehensive review examines the underlying mechanisms of CPT-11-triggered delayed diarrhea and discusses the experimental medications and strategies that have been utilized to combat this adverse effect. This review encompasses an exploration of chemical formulations, the application of traditional Chinese medicine, and the advent of innovative drug delivery systems. It is anticipated that this article will serve as a valuable resource for both novice researchers in the realm of irinotecan chemotherapy and for those who are well-versed in the field, including experts and practicing clinicians. Full article

(This article belongs to the Special Issue Topoisomerases as Targets for Novel Drug Discovery)

► Show Figures

Figure 1

Figure 1
Structure and conformation of irinotecan. The main enzymes implicated in the conversion of irinotecan into its active metabolite SN-38 and the inactive product SN-38G are indicated. Full article ">Figure 2
Overview of irinotecan metabolism. CPT-11 is a prodrug that is converted to active metabolite ethyl-10-hydroxy-camptothecin (SN-38) by liver carboxylesterase-converting enzymes (CES1/2) and is then transported to the liver by 1B1 polypeptide (OATP1B1) and inactivated by microsomal uridine 5′-diphospho-glucuronosyltransferase enzymes (UGTs): UGT1A1. Irinotecan is transported to the bile by a group of ATP-binding cassette transporters (ABC transporters): ABCB1, ABCC2, and ABCG2. Irinotecan is efficiently metabolized by cytochrome P450 enzymes: CYP3A4 and CYP3A5. This results in the generation of less active metabolites APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin) and NPC (7-ethyl-10-[4-amino-1-piperidino] carbonyloxycamptothecin). NPC (but not APC) can be further converted to SN-38 by CES1, and CES2 gut microbiota may also participate in irinotecan metabolism by the production of β-glucuronidase, which catalyzes the breakdown of SN-38G into SN-38. Full article ">Figure 3
The major chemotherapeutic agents for the treatment of CPT-11-induced diarrhea. Full article ">Figure 4
The major traditional Chinese medicine treatment of delayed diarrhea. Full article ">Figure 5
Structural/Chemical modification and novel drug delivery methods. Full article ">

25 pages, 12440 KiB

Open AccessArticle

Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats

by Hanan Abdelmawgoud Atia, Hemat A. Elariny, Marwa H. Abdallah, Amany M. Khalifa, Remon S. Estfanous, Maaly A. Abd Elmaaboud and Ahmed M. Kabel

Pharmaceuticals 2025, 18(3), 358; https://doi.org/10.3390/ph18030358 - 2 Mar 2025

Viewed by 241

Abstract

Background/Objectives: Methotrexate is a folate antagonist that has proven efficacy as an anticancer and immunomodulatory agent. However, the possible incidence of overt hepatotoxicity represents a challenge for its clinical use. Up till now, no single remedy has been considered an effective solution to [...] Read more.

Background/Objectives: Methotrexate is a folate antagonist that has proven efficacy as an anticancer and immunomodulatory agent. However, the possible incidence of overt hepatotoxicity represents a challenge for its clinical use. Up till now, no single remedy has been considered an effective solution to this important adverse effect. Perindopril is an angiotensin-converting enzyme inhibitor that is widely used for the treatment of hypertension. Due to the involvement of the renin–angiotensin system in the pathogenesis of methotrexate-elicited hepatotoxicity, investigating the efficacy of perindopril in this condition may be of particular interest. The current work aimed at an evaluation of the potential effects of perindopril in a rat model of methotrexate-induced hepatotoxicity and tried to precisely determine the molecular mechanisms that may represent the basis of these effects. Methods: In a model of methotrexate-elicited hepatotoxicity in male Wistar rats, the effects of different doses of perindopril were evaluated at the level of the biochemical measurements and the morphological examination. Results: Oral administration of perindopril to methotrexate-injected rats exhibited a dose-dependent significant improvement in daily food intake; the restoration of the functions of hepatocytes; the potentiation of antioxidant defense mechanisms; the abrogation of the different signaling pathways involved in liver inflammation, apoptosis, and fibrosis; and an enhancement in AMPK/mTOR-driven autophagy when compared to animals that received only a methotrexate injection. These events were reflected in the morphological appearance of the different studied groups. Conclusions: This study presents perindopril as a promising remedy for mitigation of the hepatotoxic effects that occur as a consequence of treatment with methotrexate. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

17 pages, 5055 KiB

Open AccessArticle

Effect of Traditional Chinese Medicine on COVID-19 Treatment: A Meta-Analysis of Randomized Clinical Trials

by Marharyta Sobczak and Rafał Pawliczak

Pharmaceuticals 2025, 18(3), 357; https://doi.org/10.3390/ph18030357 - 2 Mar 2025

Viewed by 343

Abstract

Background/Objectives: Traditional Chinese medicine (TCM) has a long history and is known for its anti-inflammatory, antiviral, and immunoregulatory qualities. It has been extensively studied during the COVID-19 pandemic. Therefore, to evaluate the relationship between TCM and the treatment of COVID-19, we conducted [...] Read more.

Background/Objectives: Traditional Chinese medicine (TCM) has a long history and is known for its anti-inflammatory, antiviral, and immunoregulatory qualities. It has been extensively studied during the COVID-19 pandemic. Therefore, to evaluate the relationship between TCM and the treatment of COVID-19, we conducted a meta-analysis. Methods: Our meta-analysis included 22 randomized clinical trials, which investigated the analyzed endpoints: time to recovery from fever, severity of dyspnea or breathlessness according on different scales, time to recovery for coughing, including dry and wet coughing, time to recovery for fatigue, changes in respiratory rate, length of hospitalization, hospital discharging rate, number of intensive care unit (ICU) admissions, number of cases requiring any supplemental oxygenation, number of deaths among COVID-19 patients, conversion rate of SARS-CoV-2 tests on a particular day, and time to viral assay conversion. The relative risk (RR) with 95% confidence intervals (CIs) and the mean difference or standardized mean difference with 95% CIs were calculated to compare the effect. A random effects model was used to calculate effect sizes. Results: We indicated a positive effect of TCM on different COVID-19 symptoms. TCM influences hospitalization duration, ICU admission, mortality, and time to viral assay conversion among COVID-19 patients. Moreover, TCM positively affects SARS-CoV-2 test conversion rates on particular days (RR = 1.21; 95% CI [1.10; 1.32]; p < 0.0001; I² = 84%). Conclusions: TCM may potentially support the standard treatment of COVID-19. Nevertheless, the necessity for further randomized trials with a greater number of participants and in a wider range of countries remains apparent. Full article

(This article belongs to the Section Natural Products)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Pharmaceuticals, Volume 18, Issue 3 (March 2025) – 106 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI