Pharmaceuticals

19 pages, 3230 KiB

Open AccessArticle

Unlocking the Neuroprotective Effect of Quercetin Against Cadmium-Induced Hippocampal Damage in Rats: PPARγ Activation as a Key Mechanism

by Doha M. Al-Nouri

Pharmaceuticals 2025, 18(5), 657; https://doi.org/10.3390/ph18050657 (registering DOI) - 29 Apr 2025

Abstract

Background: This study investigates the effects of cadmium chloride (CdCl₂) on hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) expression and examines whether PPARγ activation mediates the neuroprotective effects of quercetin (QUR). Methods: Sixty adult male rats were included in this study, separated [...] Read more.

Background: This study investigates the effects of cadmium chloride (CdCl₂) on hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) expression and examines whether PPARγ activation mediates the neuroprotective effects of quercetin (QUR). Methods: Sixty adult male rats were included in this study, separated into 12 rats per group as follows: control, CdCl₂ (0.5 mg/kg), CdCl₂ + PPARγ agonist (Pioglitazone, 10 mg/kg), CdCl₂ + QUR (25 mg/kg), and CdCl₂ + QUR + PPARγ antagonist (GW9662, 1 mg/kg). Treatments were administered orally for 30 days. At the end of the experiment, behavioral memory tests, hippocampal histology, markers of cholinergic function, neuroplasticity, oxidative stress, inflammation, and apoptosis, as well as transcription levels of some genes were carried out. Results: CdCl₂ exposure significantly reduced hippocampal PPARγ mRNA and DNA binding potential and nuclear levels. Additionally, CdCl₂ impaired spatial, short-term, and recognition memory, decreased granular cell density in the dentate gyrus (DG), and reduced levels of neuroprotective factors, including Nrf2, brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), and several antioxidant enzymes including heme-oxygenase-1 (HO-1) and superoxide dismutase (SOD), as well as reduced glutathione (GSH). Conversely, CdCl₂ elevated levels of oxidative stress, inflammation, and apoptosis markers such as interleukin-6 (IL-6), malondialdehyde (MDA), Bax, tumor necrosis factor-α (TNF-α), and cleaved caspase-3. QUR and Pioglitazone reversed these effects, restoring expression and PPARγ activation, improving memory, and modulating antioxidant and anti-inflammatory pathways. In contrast, blocking PPARγ with GW9662 negated the neuroprotective effects of QUR, exacerbating oxidative stress and inflammation by reversing all their beneficial effects. Conclusions: Activation of PPARγ by QUR or Pioglitazone offers a promising therapeutic strategy for mitigating CdCl₂-induced neurotoxicity. Full article

(This article belongs to the Section Natural Products)

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23 pages, 4228 KiB

Open AccessArticle

Diosmin Potentiates the Antidiabetic Effects of Linagliptin in Nicotinamide/Streptozotocin-Induced Diabetic Wistar Rats

by Eman B. Abbas, Asmaa M. El-Kalaawy, Noha A. Ahmed, Anwar Shams, Amal K. Khaliefa and Osama M. Ahmed

Pharmaceuticals 2025, 18(5), 656; https://doi.org/10.3390/ph18050656 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Natural therapeutics for the treatment of diabetes mellitus represent a common challenge for many researchers. Thus, the aim of this study was to evaluate the antihyperglycemic and anti-inflammatory effects and the hepatic antioxidant activities of both diosmin and linagliptin on nicotinamide/streptozotocin-induced diabetes [...] Read more.

Background/Objectives: Natural therapeutics for the treatment of diabetes mellitus represent a common challenge for many researchers. Thus, the aim of this study was to evaluate the antihyperglycemic and anti-inflammatory effects and the hepatic antioxidant activities of both diosmin and linagliptin on nicotinamide/streptozotocin-induced diabetes mellitus in rats. Methods: Induction of diabetes mellitus was produced by injecting an intraperitoneal dose of nicotinamide (60 mg/kg) to 16-hour-fasted rats, then after 15 min, an intraperitoneal dose of streptozotocin (60 mg/kg) was injected. The rats with diabetes were orally treated with linagliptin (1 mg/kg), diosmin (10 mg/kg), and both of them every other day for 4 weeks. Results: The elevated hepatic glucose-6-phosphatase and glycogen phosphorylase activities, the lowered concentrations of serum insulin, C-peptide, and hepatic glycogen, and the diminished hepatic antioxidant defense system of nicotinamide/streptozotocin-induced diabetic rats were all potentially improved by the therapies. The treatments also improved the deteriorated adiponectin and resistin mRNA expression in visceral adipose tissue of nicotinamide/streptozotocin-induced diabetic rats. In addition, the treatments induced a recovery of damaged islets of Langerhans and a regeneration of islet cells in association with the enhancement of the formation of insulin granules in β-cells and the improvement of kidney function; the combined effect was the most potent. Conclusions: Diosmin alone or in combination with linagliptin has potent antidiabetic effects, which were managed through their insulinotropic and insulin-improving actions. The diosmin in combination with linagliptin has the most potent antihyperglycemic effects. Full article

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

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22 pages, 1460 KiB

Open AccessArticle

Development of Rifampicin Eye Drops for the Treatment of Exudative Age-Related Macular Degeneration

by Valory Anne S. Vailoces, Andrew J. Tolentino, Jose Fernando Arevalo, Ron A. Adelman, Robert Bhisitkul, Diana V. Do, Quan Dong Nguyen, Michael J. Tolentino, Masaki Tanito and Hiroaki Serizawa

Pharmaceuticals 2025, 18(5), 655; https://doi.org/10.3390/ph18050655 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Exudative age-related macular degeneration (AMD) is a disease of choroidal neovascularization that causes blindness. Current treatments to preserve vision in this prevalent and blinding condition are repeat intraocular injections of anti-vascular endothelial growth factor medicines for a patient’s lifetime to preserve [...] Read more.

Background/Objectives: Exudative age-related macular degeneration (AMD) is a disease of choroidal neovascularization that causes blindness. Current treatments to preserve vision in this prevalent and blinding condition are repeat intraocular injections of anti-vascular endothelial growth factor medicines for a patient’s lifetime to preserve and prevent vision loss leading to blindness. Rifampicin, a small-molecule antibiotic, has previously been reported to exhibit anti-angiogenic properties and a topical safety profile that is well-tolerated. Based on this evidence, we investigated the feasibility of formulating rifamycin as an ophthalmic drop capable of delivering therapeutic concentrations to the posterior segment of the eye. Methods: Inhibition of neovascularization by administration of rifampicin was analyzed in the rat oxygen-induced retinopathy (OIR) and mouse laser-induced choroidal neovascularization (CNV) models. Pharmacokinetic (PK) studies were conducted in mice, rats, and rabbits by dosing various formulations containing rifampicin, and the compound was quantified by LC/MS analysis. Results: Results from dose escalation studies in the mouse laser-induced CNV model suggested the minimum effective dose of rifampicin required for inhibiting neovascularization in subretinal tissues to be 0.7 mg/kg, which is substantially lower than the 20 mg/kg dosage approved for infectious disease treatments. The previous studies did not report the minimum effective dose in the anti-angiogenesis effects. The effective area under the concentration-time curve (AUC) in the sub-retina was evaluated as 0.27 h·ng/mg. In rabbits, rifampicin was delivered to the sub-retina by a single topical application of various formulations in a dose-dependent manner. The topical application of the formulations containing 1% rifampicin, which was well-tolerated in clinical trials previously reported for ocular trachoma, achieved subretinal delivery approximately 2–32 times greater than the effective AUC. Plasma exposure of the compound by the topical application was evaluated to range approximately 0.5–10 ng/mL. Conclusions: Rifampicin was delivered to the sub-retina in rabbits with an efficiency greater than the effective dose required for inhibiting neovascularization. Limited amounts of plasma exposure by the topical application were detected. These results suggested the therapeutic potential of the rifampicin formulations for the topical treatment of exudative macular degeneration. Full article

(This article belongs to the Section Pharmaceutical Technology)

16 pages, 280 KiB

Open AccessArticle

The Effect of Adding Remifentanil to Thiopental for Anaesthesia Induction on the Success of Classic Laryngeal Mask Airway Insertion: A Randomised Double-Blind Clinical Trial

by Mensure Çakırgöz, İsmail Demirel, Mert Akan, Ömürhan Saraç, Ergin Alaygut, Aysun Afife Kar, Oğuzhan Demirel and Emre Karagöz

Pharmaceuticals 2025, 18(5), 654; https://doi.org/10.3390/ph18050654 (registering DOI) - 29 Apr 2025

Abstract

Background: Remifentanil, an ultra-short-acting µ-receptor agonist, is used with propofol for optimal laryngeal mask airway (LMA) insertion. However, no studies have assessed its effects when combined with thiopental on LMA conditions. The combined use of thiopental and remifentanil may offer advantages, such [...] Read more.

Background: Remifentanil, an ultra-short-acting µ-receptor agonist, is used with propofol for optimal laryngeal mask airway (LMA) insertion. However, no studies have assessed its effects when combined with thiopental on LMA conditions. The combined use of thiopental and remifentanil may offer advantages, such as enhanced cardiovascular and respiratory stability. This study aims to compare the administration of thiopental with different doses of remifentanil to assess their combined effects on LMA insertion conditions and success in a prospective, randomised double-blind study. Method: A total of 100 ASA I–II patients (18–65 years), including both male and female participants, were randomly assigned to four remifentanil dose groups (0.5–3 µg.kg⁻¹). Induction involved thiopental (5 mg.kg⁻¹) after remifentanil. LMA insertion conditions were evaluated using a six-variable scale. Systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), heart rate (HR), and bispectral index monitor (BIS) values, as well as apnoea duration, eyelash reflex loss time, and insertion attempts, were recorded at baseline, before insertion, and at 5 min post-insertion. Results: Time to eyelash reflex loss and LMA insertion were shorter in Groups III and IV than in Groups I and II (p < 0.001). Apnoea duration was longest in Group IV, followed by Group III (p < 0.001). Groups III and IV had significantly better LMA placement, mouth opening, and ease of insertion (p < 0.05). Coughing and gagging were highest in Group I (p < 0.001). SAP, MAP, HR, and DAP were significantly lower in Group IV at various time points (p < 0.05). HR was significantly higher in Group I compared to Groups II and III at multiple time points (p < 0.05). Conclusions: The administration of 5 mg.kg⁻¹ thiopental with 2 μg.kg⁻¹ remifentanil has been found to provide a stable haemodynamic response and 96% excellent or satisfactory laryngeal mask insertion conditions without increasing the duration of apnoea. Full article

(This article belongs to the Special Issue Use of Anesthetic Agents: Management and New Strategy)

15 pages, 2870 KiB

Open AccessArticle

5-Fluorouracil Toxicity: Revisiting the Relevance of Pharmacokinetic Parameters

by Hans Mielke, Engi Abd Elhady Algharably and Ursula Gundert-Remy

Pharmaceuticals 2025, 18(5), 653; https://doi.org/10.3390/ph18050653 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: 5-fluorouracil (5-FU) is used in the treatment of solid cancer types. Because of its narrow therapeutic window, drug monitoring is recommended. We were confronted to answer a question on the relevance of concentration as opposed to the area under the plasma [...] Read more.

Background/Objectives: 5-fluorouracil (5-FU) is used in the treatment of solid cancer types. Because of its narrow therapeutic window, drug monitoring is recommended. We were confronted to answer a question on the relevance of concentration as opposed to the area under the plasma concentration–time curve (AUC) to predict toxicity when we had to assess the case of a patient who died after an erroneously high infusion rate. Methods: We used physiologically-based pharmacokinetic modeling (PBPK) to simulate the concentration–time profile of 5-FU data on doses, dosing schedules and life-threatening toxicity for both the patient in question as well as data from the literature. Furthermore, steady-state 5-FU concentrations were calculated from an additional set of data found in the literature on AUCs and non-life-threatening toxicity. Results: The model predictions matched well with experimental data, confirming the suitability of the model. Life-threatening toxicity was related to a concentration above 6 mg/L, whereas non-life-threatening toxicity was low at concentrations less than 3 mg/L but steeply increased between 3 and 4 mg/L. Data analysis supported by a decision algorithm suggests that the 5-FU steady-state plasma concentration is a better toxicity predictor than the AUC. Conclusions: We recommend monitoring the concentration one hour after infusion starts when about 50% of the steady state is reached in patients for whom higher doses are clinically considered relevant. Monitoring the concentration one hour after starting the infusion has the advantage that dose correction could be made early before toxicity can be observed. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Adverse Drug Reactions: 2nd Edition)

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12 pages, 2012 KiB

Open AccessSystematic Review

Efficacy of Anlotinib Plus Docetaxel in Advanced NSCLC Previously Treated with Platinum-Based Chemotherapy: A Systematic Review and Meta-Analysis

by Helal F. Hetta, Saleh F. Alqifari, Khaled Alshehri, Amirah Alhowiti, Saud S. Alharbi, Hyder Mirghani, Tariq Alrasheed, Mohamed E. A. Mostafa, Mohammed Sheikh, Mahmoud Elodemi, Sultan A. Alhumaid, Yasmin N. Ramadan, Noura H. Abd Ellah and Reem Sayad

Pharmaceuticals 2025, 18(5), 652; https://doi.org/10.3390/ph18050652 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Anlotinib is a novel oral antiangiogenic tyrosine kinase inhibitor (TKI) approved as a third-line treatment for advanced non-small-cell lung cancer (NSCLC). However, its efficacy in combination with docetaxel remains incompletely understood. Given the need for effective second-line therapies after platinum-based chemotherapy, [...] Read more.

Background/Objectives: Anlotinib is a novel oral antiangiogenic tyrosine kinase inhibitor (TKI) approved as a third-line treatment for advanced non-small-cell lung cancer (NSCLC). However, its efficacy in combination with docetaxel remains incompletely understood. Given the need for effective second-line therapies after platinum-based chemotherapy, this systematic review aims to evaluate the therapeutic potential of anlotinib plus docetaxel in advanced NSCLC. Methods: The PubMed, WOS, Medline, and Scopus databases were screened for published articles up to 12 April 2024. We included RCTs comparing anlotinib plus docetaxel with docetaxel alone in advanced NSCLC after receiving platinum-based chemotherapy, reporting progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) as outcomes for both groups. Results: Our systematic review included three randomized controlled trials (RCTs) with a total of 151 patients in the anlotinib plus docetaxel group and 132 in the docetaxel-only group. Meta-analysis results demonstrated that the combination therapy significantly prolonged PFS (mean difference (MD) = 2.98, 95% confidence interval (CI), 1.95–4.00; p < 0.00001) and improved ORR (risk ratio (RR) = 3.04, 95% CI = 1.77–5.24; p < 0.00001). Additionally, the DCR was notably higher in the combination group (RR = 1.58, 95% CI = 1.34–1.87; p < 0.00001). Conclusions: Anlotinib plus docetaxel appears to be more effective as a second-line treatment of advanced NSCLC than docetaxel in prolonging PFS and increasing ORR and DCR. Full article

(This article belongs to the Special Issue Cancer Chemoradiotherapy)

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12 pages, 996 KiB

Open AccessArticle

Lercanidipine Enhances Cisplatin Activity: Dual Anticancer and Anti-Inflammatory Effects via Caspase Activation and MAPK Inhibition

by Tugce Uskur, Sevde Nur Biltekin, Gokhan Faikoglu, Kubra Saygisever-Faikoglu and Barkın Berk

Pharmaceuticals 2025, 18(5), 651; https://doi.org/10.3390/ph18050651 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Lercanidipine is a third-generation dihydropyridine calcium channel blocker. In addition to their well-established cardiovascular effects, calcium channel blockers are increasingly recognized for their therapeutic potential in various cancers. This study aimed to investigate the potential anticancer effects of lercanidipine on cancer [...] Read more.

Background/Objectives: Lercanidipine is a third-generation dihydropyridine calcium channel blocker. In addition to their well-established cardiovascular effects, calcium channel blockers are increasingly recognized for their therapeutic potential in various cancers. This study aimed to investigate the potential anticancer effects of lercanidipine on cancer cell lines—particularly in combination with cisplatin—by assessing parameters such as cell viability (MTT assay), proliferation, MAPK pathway activity, caspase enzyme levels, and TNF-α expression. Methods: In this study, the effects of lercanidipine, both alone and in combination with cisplatin, on cell viability were evaluated using the MTT assay in MCF-7, SH-SY5Y, PC3, and HEK293 cell lines. To assess intracellular signaling and apoptotic pathways, MAPK inhibition, as well as caspase-3 and caspase-8 activities, were measured using ELISA. Additionally, to evaluate the anti-inflammatory potential, TNF-α levels in LPS-stimulated RAW264.7 cells were analyzed via. Results: The study revealed that lercanidipine showed significant cytotoxic effects, particularly in SH-SY5Y and PC3 cancer cell lines, while it did not induce a 50% loss of viability in healthy HEK293 cells. When combined with cisplatin, lercanidipine enhanced cytotoxicity by 2.7-fold in neuroblastoma (SH-SY5Y) cells, 1.6-fold in breast cancer (MCF7) cells, and 1.9-fold in prostate cancer (PC3) cells. MAPK activity was inhibited by 83.6% at 20 μM lercanidipine, while dose-dependent increases in caspase-3 and caspase-8 activities were observed. Additionally, lercanidipine decreased TNF-α levels in LPS-stimulated RAW264.7 cells, indicating its potential anti-inflammatory effect. Conclusions: In conclusion, lercanidipine demonstrated selective anticancer effects in cancer cell lines and showed synergistic cytotoxicity when combined with cisplatin. It also significantly inhibited MAPK signaling, activated apoptotic caspases, and reduced TNF-α levels, suggesting potential anti-inflammatory activity. These findings highlight lercanidipine’s potential for repurposing as an adjunct in cancer therapy. Full article

(This article belongs to the Section Pharmacology)

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27 pages, 3509 KiB

Open AccessArticle

A Comparative Study of N-Acetyl Cysteine, Rosuvastatin, and Vitamin E in the Management of Patients with Non-Alcoholic Steatohepatitis: A Randomized Controlled Trial

by Amr Y. Zakaria, Rehab Badawi, Hasnaa Osama, Mona A. Abdelrahman and Asmaa M. El-Kalaawy

Pharmaceuticals 2025, 18(5), 650; https://doi.org/10.3390/ph18050650 (registering DOI) - 29 Apr 2025

Abstract

Background: Non-alcoholic steatohepatitis (NASH) is characterized by increased production of proinflammatory cytokines, fibrosis, and hepatocyte apoptosis. This study aimed to assess the efficacy of N-acetyl cysteine (NAC), rosuvastatin (RSV), and vitamin E (VE) in patients with NASH. Methods: A double-blinded, parallel, [...] Read more.

Background: Non-alcoholic steatohepatitis (NASH) is characterized by increased production of proinflammatory cytokines, fibrosis, and hepatocyte apoptosis. This study aimed to assess the efficacy of N-acetyl cysteine (NAC), rosuvastatin (RSV), and vitamin E (VE) in patients with NASH. Methods: A double-blinded, parallel, randomized, controlled study was conducted and registered on clinicaltrials.gov (Identifier: NCT06105060), involving 135 NASH participants, who were divided into three groups: the control group (group 1), consisting of patients receiving standard therapy VE at a dosage of 400 IU twice daily. In the treated group (group 2), patients were administered NAC at a dosage of 1200 mg twice daily, while treatment (group 3) received RSV at a dosage of 20 mg once daily. FibroScan^® examination of liver tissue and fibrosis scores, along with tests for liver aminotransferases, lipid profile, glycemic parameters, and renal and hepatic functions, were assessed before and after six months of treatment. Results: The analyzed groups demonstrated a significant reduction in steatosis and lipid peroxidation (p < 0.05). The NAC group demonstrated greater anti-inflammatory and anti-apoptotic effects compared to the RSV group, although this difference was not significant in the control group. NAC is conceded as the only significant antifibrotic agent in liver stiffness measurement (LSM), biological marker findings, and non-invasive liver fibrosis scores (p < 0.05), in addition to its improvement of several metabolic parameters and health-related quality of life. Conclusions: Patients receiving NAC demonstrated safety and efficacy in enhancing steatosis, fibrosis, and metabolic parameters, representing a novel strategy in the management of NASH. Full article

(This article belongs to the Special Issue New and Emerging Treatment Strategies for Gastrointestinal Diseases)

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15 pages, 3083 KiB

Open AccessArticle

Unveiling the Antioxidant Power and Secondary Metabolites of Tabebuia chrysantha (Jacq.) Leaves and Flowers from Ecuador

by Raluca A. Mihai, Ramiro Fernando Vivanco Gonzaga, Nelson Santiago Cubi Insuaste, Nilo Rigoberto Maza Morocho and Rodica D. Catana

Pharmaceuticals 2025, 18(5), 649; https://doi.org/10.3390/ph18050649 (registering DOI) - 29 Apr 2025

Abstract

Background: Tabebuia chrysantha (Jacq.) Nichols, commonly known as Guayacan, is a prominent species within the Bignoniaceae family known for its medicinal value and ecological significance. This study aimed to characterize the antioxidant capacity and secondary metabolite composition of Guayacan leaves and flowers [...] Read more.

Background: Tabebuia chrysantha (Jacq.) Nichols, commonly known as Guayacan, is a prominent species within the Bignoniaceae family known for its medicinal value and ecological significance. This study aimed to characterize the antioxidant capacity and secondary metabolite composition of Guayacan leaves and flowers grown in Ecuador, a region where its chemical profile remains unexplored. Methods: Comprehensive analyses were conducted to determine the total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activity using ABTS, DPPH, FRAP assays, and LC-MS. Results: The results revealed remarkable differences between mature leaves and flowers. Leaves exhibited consistently higher flavonoid levels (e.g., 0.280 ± 0.005 mg QE/g DW) and superior antioxidant capacity across all assays (e.g., 10.84 ± 0.51 µmol Trolox g⁻¹ DW in ABTS) compared to flowers, which showed greater variability but lower overall activity. These findings highlight a functional specialization, with leaves synthesizing more flavonoids to mitigate oxidative stress from environmental factors such as UV radiation. LC-MS analysis unveiled various bioactive compounds, including phenolic acids, flavonoids, and terpenoids. Unique metabolites like α-lipoamide in leaves and oleanolic acid in flowers suggest distinct adaptive roles, potentially linked to stress tolerance and reproductive functions. Additionally, strong correlations among antioxidant assays (e.g., FRAP vs. DPPH, r = 0.993, p < 0.001) emphasize the pivotal role of phenolics and flavonoids in free radical scavenging and reduction mechanisms. Conclusions: The findings of this study demonstrate the superior antioxidant capacity of leaves, driven by their higher accumulation of flavonoids and phenolic compounds. This research represents a foundational step toward uncovering the therapeutic potential of Ecuadorian Guayacan as a source of natural antioxidants and bioactive compounds, supporting its future applications in phytotherapy and drug development. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals—4th Edition)

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18 pages, 16781 KiB

Open AccessArticle

Exploring Ginseng Bioactive Compound’s Role in Hypertension Remedy: An In Silico Approach

by Sagar Kurmi, Rita Majhi, Hilal Tayara and Kil To Chong

Pharmaceuticals 2025, 18(5), 648; https://doi.org/10.3390/ph18050648 (registering DOI) - 28 Apr 2025

Abstract

Background/Objectives: Ginseng has been a traditional remedy for centuries, known for its diverse benefits such as anti-inflammation, antioxidant, bactericidal, fungicidal antidiabetic, and anticancer effects. This study employs a network pharmacology approach with molecular dynamics simulation to investigate the potential mechanisms through which [...] Read more.

Background/Objectives: Ginseng has been a traditional remedy for centuries, known for its diverse benefits such as anti-inflammation, antioxidant, bactericidal, fungicidal antidiabetic, and anticancer effects. This study employs a network pharmacology approach with molecular dynamics simulation to investigate the potential mechanisms through which ginseng-derived compounds control hypertension. Methods: The total of 70 bioactive compounds were identified from the literature and classified as ginsenosides, which fall under Protopanaxadiol-type ginsenosides, Protopanaxatriol-type ginsenosides, and Ocotillol-type saponins. The target proteins related to hypertension were collected from the drug bank, and interactions between proteins network were examined using STRING 12.0 and Cytoscape 3.10.1. Bioinformatics tools were used to analyze the biological enrichment of genes. The core targets extracted through network pharmacology were subjected to molecular docking studies. Similarly, the docking score below −6.0 kcal/mol was further visualized by performing molecular dynamics simulation to see the binding affinity between the complexes. Finally, pharmacokinetics and toxicity of the compounds were evaluated using computational tools. Results: Molecular docking and simulation results revealed that Floralquinquenoside C, Ginsenoside Rg6, Notoginsenoside T1, and Floralquinquenoside B exhibited strong binding and stability with Angiotensin-converting enzyme (ACE) and Carbonic Anhydrase-I (CA-I), which alters the renin–angiotensin system, calcium signaling pathway, adrenergic signaling in cardiomyocytes, c-GMP-PKG signaling pathway, etc., to regulate high blood pressure. Conclusions: The results show that the phytochemicals from ginseng could act as potential candidates for the management of hypertension, which may help minimize the side effects caused by synthetic anti-hypertensive drugs available on the market. Full article

(This article belongs to the Special Issue Promising Natural Products in New Drug Design and Therapy)

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13 pages, 1731 KiB

Open AccessArticle

Beyond Cannabidiol: The Contribution of Cannabis sativa Phytocomplex to Skin Anti-Inflammatory Activity in Human Skin Keratinocytes

by Marco Fumagalli, Giulia Martinelli, Giuseppe Paladino, Nora Rossini, Umberto Ciriello, Vincenzo Nicolaci, Nicole Maranta, Carola Pozzoli, Safwa Moheb El Haddad, Elisa Sonzogni, Mario Dell’Agli, Stefano Piazza and Enrico Sangiovanni

Pharmaceuticals 2025, 18(5), 647; https://doi.org/10.3390/ph18050647 (registering DOI) - 28 Apr 2025

Abstract

Background: Cannabis sativa L. (C. sativa) has a long history of medicinal use. Its inflorescences contain bioactive compounds like non-psychotropic cannabidiol (CBD), which is well known for its anti-inflammatory potential in skin conditions such as psoriasis, and psychotropic Δ-9-tetrahydrocannabinol (THC). [...] Read more.

Background: Cannabis sativa L. (C. sativa) has a long history of medicinal use. Its inflorescences contain bioactive compounds like non-psychotropic cannabidiol (CBD), which is well known for its anti-inflammatory potential in skin conditions such as psoriasis, and psychotropic Δ-9-tetrahydrocannabinol (THC). Keratinocytes, the main cells in the epidermis, are crucial for regulating skin inflammation by producing mediators like IL-8 when stimulated by agents like TNFα. Methods: This study explores the anti-inflammatory effects of a standardized C. sativa extract (CSE) with 5% CBD and less than 0.2% THC in human keratinocytes challenged by TNFα. The aim of this study is to analyze the specific contributions of the main constituents of CSE to inflammatory responses in human keratinocytes by fractionating the extract and examining the effects of its individual components. Results: MTT assays showed that CSE was non-toxic to HaCaT cells up to 50 μg/mL. CSE inhibited NF-κB activity and reduced IL-8 secretion in a concentration-dependent manner, with mean IC₅₀ values of 28.94 ± 10.40 μg/mL and 20.06 ± 2.78 μg/mL (mean ± SEM), respectively. Fractionation of CSE into four subfractions revealed that the more lipophilic fractions (A and B) were the most effective in inhibiting NF-κB, indicating that cannabinoids and cannflavins are key contributors. Pure CBD is one of the most active cannabinoids in reducing NF-κB-driven transcription (together with THC and cannabigerol), and due to its abundance in CSE, it is primarily responsible for the anti-inflammatory activity. Conclusions: This study highlights CBD’s significant role in reducing inflammation in human keratinocytes and underscores the need to consider the synergistic interactions of several molecules within C. sativa extracts for maximum efficacy. Standardized extracts are essential for reproducible results due to the variability in responses. Full article

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19 pages, 12057 KiB

Open AccessArticle

Tuo-Min-Ding-Chuan Decoction Alleviates Asthma via Spatial Regulation of Gut Microbiota and Treg Cell Promotion

by Yanfei Hong, Zheng Yang, Zirui Liu, Na Li, Jingbo Qin, Dongyu Ge, Guiying Peng, Ji Wang and Qi Wang

Pharmaceuticals 2025, 18(5), 646; https://doi.org/10.3390/ph18050646 (registering DOI) - 28 Apr 2025

Abstract

Objective: Tuo-Min-Ding-Chuan decoction (TMDC), a traditional Chinese prescription, has demonstrated significant clinical efficacy in treating allergic asthma. This study aimed to investigate the mechanism of TMDC in treating asthma from the perspective of Treg cells and gut microbiota across distinct gut segments [...] Read more.

Objective: Tuo-Min-Ding-Chuan decoction (TMDC), a traditional Chinese prescription, has demonstrated significant clinical efficacy in treating allergic asthma. This study aimed to investigate the mechanism of TMDC in treating asthma from the perspective of Treg cells and gut microbiota across distinct gut segments (jejunum, ileum, cecum, and colon). Methods: An ovalbumin (OVA)-induced asthma model was established in mice, followed by oral administration of TMDC at high, medium, and low dose. Immune cells and lung inflammation were examined to assess asthma severity. Microbial composition was determined by 16S rRNA sequencing. Antibiotic cocktail and Lactobacillus rhamnosus GG (LGG) were administrated to confirm the key role of specific bacteria. Results: TMDC attenuated lung inflammation (p < 0.01) and eosinophilic infiltration (p < 0.01) as well as IL-4 and IL-5 secretion (p < 0.01); it was also associated with an increase in Treg cells in the lung, small intestine (SI), and colon (p < 0.05). Meanwhile, TMDC restored the number of microbiota species and the Shannon index in the hindgut and reinstated beneficial bacteria, such as Allobaculum and Turicibacter, which were diminished in asthmatic mice. Notably, TMDC significantly enriched Bifidobacterium and Lactobacillus, particularly in the hindgut. Lactobacillus abundance was significantly correlated (p < 0.05) with Treg cells, IL-4, IL-5, and eosinophils. Furthermore, LGG supplementation restored elevated lung inflammation (p < 0.05) and decreased Treg cells (p < 0.01) due to antibiotic-induced microbiota depletion. Conclusion: TMDC alleviated asthma by promoting Treg cell expansion in a Lactobacillus-dependent manner across different gut segments, providing new insights into its therapeutic mechanisms. Full article

(This article belongs to the Special Issue Natural Products in Gut Microbiome Modulation: From Mechanisms to Clinical Applications)

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2 pages, 780 KiB

Open AccessCorrection

Correction: Kamel et al. Experimental Evidence for Diiodohydroxyquinoline-Induced Neurotoxicity: Characterization of Age and Gender as Predisposing Factors. Pharmaceuticals 2022, 15, 251

by Ahmed S. Kamel, Ahmed F. Mohamed, Mostafa A. Rabie, Marwa E. Elsherbiny, Kawkab A. Ahmed, Mahmoud M. Khattab and Noha F. Abdelkader

Pharmaceuticals 2025, 18(5), 645; https://doi.org/10.3390/ph18050645 (registering DOI) - 28 Apr 2025

Abstract

In the original publication [...] Full article

16 pages, 1159 KiB

Open AccessReview

Cancer and Traditional Medicine: An Integrative Approach

by Cheruthazhakkat Sulaiman, Blassan P. George, Indira Balachandran and Heidi Abrahamse

Pharmaceuticals 2025, 18(5), 644; https://doi.org/10.3390/ph18050644 (registering DOI) - 28 Apr 2025

Abstract

Despite numerous advances in treatment, cancer still remains a leading cause of death worldwide. Given the significant health and economic burden this disease imposes, it is important to explore more effective treatment strategies. A major drawback of conventional cancer therapies is the persistence [...] Read more.

Despite numerous advances in treatment, cancer still remains a leading cause of death worldwide. Given the significant health and economic burden this disease imposes, it is important to explore more effective treatment strategies. A major drawback of conventional cancer therapies is the persistence of drug resistance, adverse reactions to chemotherapy, digestive damage, reduced quality of life, and high treatment costs. To address these challenges, researchers have been investigating the utility of using complementary and alternative medicine (CAM) alongside conventional cancer treatments. Some of these CAM approaches have been reported to enhance patients’ quality of life and reduce the severity of adverse effects from conventional therapies. This review explores the utility of traditional Chinese, Korean, Indian, Japanese, and South African medicines as supportive therapies for conventional cancer treatments. We also discuss the concept of integrative oncology and its global relevance, as CAM approaches typically emphasize whole-person care, including diet, lifestyle, and mental/emotional well-being. In addition, we identify key active phytochemicals and herbal medicines used in these traditional systems for cancer treatment. Our discussion aims to provide a foundation for future research into integrative oncology, fostering an interdisciplinary and complementary approach to cancer management. Full article

(This article belongs to the Section Natural Products)

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14 pages, 780 KiB

Open AccessReview

New Challenging Systemic Therapies for Juvenile Scleroderma: A Comprehensive Review

by Chiara Sassetti, Claudia Borrelli, Martha Mazuy, Cristina Guerriero, Donato Rigante and Susanna Esposito

Pharmaceuticals 2025, 18(5), 643; https://doi.org/10.3390/ph18050643 (registering DOI) - 28 Apr 2025

Abstract

Background: Juvenile scleroderma (JS) comprises a group of rare chronic autoimmune and fibrosing disorders in children, primarily presenting as juvenile localized scleroderma (jLS) or juvenile systemic sclerosis (jSS). While jLS predominantly affects the skin and subcutaneous tissues, jSS may involve multiple internal organs [...] Read more.

Background: Juvenile scleroderma (JS) comprises a group of rare chronic autoimmune and fibrosing disorders in children, primarily presenting as juvenile localized scleroderma (jLS) or juvenile systemic sclerosis (jSS). While jLS predominantly affects the skin and subcutaneous tissues, jSS may involve multiple internal organs and is associated with increased morbidity and mortality. Due to the scarcity of pediatric-specific clinical trials, the current treatment strategies are largely empirical and often adapted from adult protocols. Objective: This narrative review aims to provide a comprehensive update on emerging systemic therapies for juvenile scleroderma, focusing on biologics, small molecule inhibitors, and advanced cellular interventions, to support the development of more personalized and effective pediatric treatment approaches. Methods: A literature search was conducted through PubMed and a manual bibliographic review, covering publications from 2001 to 2024. Only English-language studies involving pediatric populations were included, comprising randomized controlled trials, reviews, and case reports. Additional searches were performed for drugs that are specifically used in juvenile scleroderma. Results: Biologic agents such as tocilizumab, rituximab, and abatacept, along with small molecules including Janus kinase (JAK) inhibitors and imatinib, have demonstrated potential in managing refractory cases by reducing skin fibrosis and pulmonary involvement. Novel approaches—such as pamrevlumab, nintedanib, and chimeric antigen receptor (CAR-T) cell therapy—target fibrotic and autoimmune pathways but remain investigational in children. Autologous stem cell transplantation (ASCT) has also been explored in severe, treatment-resistant cases, although data are extremely limited. The overall evidence base is constrained by small sample sizes, a lack of controlled pediatric trials, and reliance on adult extrapolation. Conclusions: While innovative systemic therapies show promise for juvenile scleroderma, their widespread clinical application remains limited by insufficient pediatric-specific evidence. Large, multicenter, long-term trials are urgently needed to establish safety, efficacy, and optimal treatment algorithms that are tailored to the pediatric population. Full article

(This article belongs to the Section Biopharmaceuticals)

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15 pages, 3850 KiB

Open AccessArticle

3-(3-Azabicyclo[2, 2, 1]heptan-2-yl)-1,2,4-oxadiazoles as Novel Potent DPP-4 Inhibitors to Treat T2DM

by Tatiana V. Zinevich, Ivan O. Maslov, Olga G. Kirichenko, Sergey V. Shorshnev, Maxim A. Gureev, Fedor M. Dolgushin, Yuri B. Porozov and Vladimir M. Trukhan

Pharmaceuticals 2025, 18(5), 642; https://doi.org/10.3390/ph18050642 (registering DOI) - 28 Apr 2025

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease with global implications, necessitating effective management strategies. Dipeptidyl peptidase IV (DPP-4) inhibitors have shown promise as potent agents for T2DM treatment. Methods: This study combines chemical synthesis, molecular modelling, and [...] Read more.

Background: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease with global implications, necessitating effective management strategies. Dipeptidyl peptidase IV (DPP-4) inhibitors have shown promise as potent agents for T2DM treatment. Methods: This study combines chemical synthesis, molecular modelling, and inhibitory activity assays to characterise the structure–activity relationship of novel isomeric 1,2,4-oxadiazole-substituted derivatives of the 2-azabicyclo[2.2.1]heptane scaffold acylated with (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid. Results: In this article, we demonstrate the efficacy of new compounds as robust inhibitors of DPP-4. The attempts to further modify neogliptin (our lead compound described previously) resulted in a more potent DPP-4 inhibitor 9a (IC₅₀ = 4.3 nM), which did not mediate any substantial inhibition of DPP-8 and DPP-9. Conclusions: This study demonstrates that pseudo peptides incorporating (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, a 2-aza-bicyclo[2.2.1]heptane moiety, and 1,2,4-oxadiazole substituents act as potent and selective DPP-4 inhibitors. By the stereochemical refinement of oxadiazole derivatives of neogliptin, we discovered compound 9a, a strong candidate for further development in T2DM treatment. Full article

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

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2 pages, 661 KiB

Open AccessCorrection

Correction: Altyar et al. Malva parviflora Leaves and Fruits Mucilage as Natural Sources of Anti-Inflammatory, Antitussive and Gastro-Protective Agents: A Comparative Study Using Rat Models and Gas Chromatography. Pharmaceuticals 2022, 15, 427

by Ahmed E. Altyar, Ans Munir, Saiqa Ishtiaq, Muhammad Rizwan, Khizar Abbas, Osama Kensara, Sameh S. Elhady, Waleed Y. Rizg, Fadia S. Youssef and Mohamed L. Ashour

Pharmaceuticals 2025, 18(5), 641; https://doi.org/10.3390/ph18050641 (registering DOI) - 28 Apr 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Plant-Derived Anti-inflammatory Agents: Molecular Pharmacology and Further Studies)

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29 pages, 3917 KiB

Open AccessReview

Methionine Dependency and Restriction in Cancer: Exploring the Pathogenic Function and Therapeutic Potential

by Chi Ma, Aoshuang Xu, Liping Zuo, Qun Li, Fengjuan Fan, Yu Hu and Chunyan Sun

Pharmaceuticals 2025, 18(5), 640; https://doi.org/10.3390/ph18050640 (registering DOI) - 28 Apr 2025

Abstract

Methionine, an essential amino acid, is obtained by dietary intake to fulfill the requirements of our bodies. Accumulating evidence indicates that methionine plays a pivotal role in various biological processes, including protein synthesis, energy metabolism, redox balance maintenance, and methylation modifications. Numerous advances [...] Read more.

Methionine, an essential amino acid, is obtained by dietary intake to fulfill the requirements of our bodies. Accumulating evidence indicates that methionine plays a pivotal role in various biological processes, including protein synthesis, energy metabolism, redox balance maintenance, and methylation modifications. Numerous advances underscore the heightened dependence of cancer cells on methionine, which is a significant factor in cancer pathogenesis and development. A profound comprehension of the intricate relationship between methionine metabolism and tumorigenesis is imperative for advancing the field of cancer therapeutics. Herein, we delve into the role of methionine in supporting cancer growth, the impact on epigenetic modifications, and the interaction between methionine and the tumor microenvironment. Additionally, we provide insights into the development of various methionine-targeted therapy strategies. This paper summarizes the current state of research and its translational potential, emphasizing the challenges and opportunities associated with harnessing methionine dependence as a target for innovative cancer treatments. Full article

(This article belongs to the Section Medicinal Chemistry)

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16 pages, 2031 KiB

Open AccessReview

Nanodrug Delivery Systems for Acute Lymphoblastic Leukemia Therapy

by Aiyun Yang, Yuanfang Lu, Zuo Zhang and Jianhua Wang

Pharmaceuticals 2025, 18(5), 639; https://doi.org/10.3390/ph18050639 (registering DOI) - 27 Apr 2025

Abstract

Acute lymphoblastic leukemia (ALL) is a malignant tumor caused by abnormal proliferation of B-line or T-line lymphocytes in the bone marrow. Traditional treatments have limitations. Because of their unique advantages, nanodrug delivery systems (NDDSs) show great potential in the treatment of ALL. In [...] Read more.

Acute lymphoblastic leukemia (ALL) is a malignant tumor caused by abnormal proliferation of B-line or T-line lymphocytes in the bone marrow. Traditional treatments have limitations. Because of their unique advantages, nanodrug delivery systems (NDDSs) show great potential in the treatment of ALL. In this paper, the pathological features of ALL, the limitations of current therapeutic methods, and the definition and composition of NDDSs were reviewed. Research strategies for the use of NDDSs in the treatment of ALL were discussed. In addition, challenges and future development directions of NDDSs in the treatment of ALL were also discussed, aiming to provide reference for the application of NDDSs in the diagnosis and treatment of ALL. Full article

(This article belongs to the Special Issue Nanotechnology in Biomedical Applications)

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