Pharmaceuticals

29 pages, 1811 KB

Open AccessReview

Alpha Particle Emitter Radiolabeled Antibodies in Cancer Therapy: Current Status, Challenges, and Future Prospects

by Citra R. A. P. Palangka, Isa Mahendra, Rien Ritawidya, Naoya Kondo and Takahito Nakajima

Pharmaceuticals 2025, 18(9), 1316; https://doi.org/10.3390/ph18091316 - 2 Sep 2025

The utilization of antibodies to target radionuclides, known as radioimmunotherapy (RIT), has been actively researched for nearly five decades. Numerous significant preclinical and clinical studies in cancer therapy have been highlighted. Among them, RIT using alpha-emitting nuclides has shown high effectiveness and has [...] Read more.

The utilization of antibodies to target radionuclides, known as radioimmunotherapy (RIT), has been actively researched for nearly five decades. Numerous significant preclinical and clinical studies in cancer therapy have been highlighted. Among them, RIT using alpha-emitting nuclides has shown high effectiveness and has attracted much interest in recent years. This review presents an overview of the basic elements of alpha-RIT, namely the target proteins (monoclonal antibodies and antibody-derived proteins), alpha-emitting radionuclides, and labeling methods, which are currently being adapted in cancer therapy. It also highlights efforts to expand the potential of alpha-RIT, including the control of radioactivity distribution in the body. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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19 pages, 1729 KB

Open AccessArticle

Effect of Drying Methods on Bioactivity of Pyrostegia venusta Extracts: Antioxidant Assays, Cytotoxicity, and Computational Approaches

by Milena Cremer de Souza, Letícia Bertini, Julia Estrella Szmaruk, Matheus Ribas de Almeida, Maria Luisa G. Agneis, Roberta Carvalho Cesário, Wesley Ladeira Caputo, Christiane Luciana da Costa, Vitor Augusto dos Santos Garcia and Fábio R. F. Seiva

Pharmaceuticals 2025, 18(9), 1315; https://doi.org/10.3390/ph18091315 - 2 Sep 2025

Abstract

Background/Objectives: Pyrostegia venusta (Cipó-de-São-João), a native Brazilian Cerrado plant, is rich antioxidant phytochemicals. The efficacy of herbal extracts, particularly their phenolic content and antioxidant potential, is influenced by the extraction method used. This study investigated the effects of two drying methods, hot-air oven [...] Read more.

Background/Objectives: Pyrostegia venusta (Cipó-de-São-João), a native Brazilian Cerrado plant, is rich antioxidant phytochemicals. The efficacy of herbal extracts, particularly their phenolic content and antioxidant potential, is influenced by the extraction method used. This study investigated the effects of two drying methods, hot-air oven drying and freeze-drying, on the antioxidant activity, cytotoxicity, and molecular interactions of aqueous extracts from the flowers and leaves of P. venusta. Methods: antioxidant capacity was assessed using DPPH, FRAP, and Folin–Ciocalteu assays; phenolic profiles were characterized by UHPLC; and cytotoxicity was evaluated via the MTT assay in HaCaT human keratinocyte cells. Additionally, in silico ADMET predictions were conducted to assess pharmacokinetics and potential toxicity, followed by molecular docking to evaluate interactions with the proliferation markers Ki-67 and PCNA. Results: that freeze-dried extracts, particularly from the flowers, contained higher concentrations of phenolic compounds and exhibited superior antioxidant activity compared to hot-air oven-dried extracts. UHPLC analysis identified a range of bioactive phenolics including caffeic, chlorogenic, gallic, ferulic, and p-coumaric acids, quercetin, and anthocyanidins such as pelargonidin-3-O-glucoside and peonidin-3-O-glucoside, with distinct compositional differences between leaves and flowers. ADMET analysis revealed generally favorable pharmacokinetic properties for most compounds. Docking simulations indicated that multiple phenolics showed synergistic interactions with Ki-67 and PCNA. Conclusions: our findings highlight freeze-drying as the optimal method for preserving bioactive compounds in P. venusta and support the therapeutic potential of its flower extracts. The evidence supports the notion that the biological effects of P. venusta are driven by synergism among multiple constituents rather than isolated compounds. Full article

(This article belongs to the Section Natural Products)

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27 pages, 1004 KB

Open AccessArticle

Comparing the Metabolic, Systemic, and Neuropsychiatric Impacts of Olanzapine and Clozapine in Patients with Schizophrenia

by Nayef Samah Alharbi, Noha Alaa Hamdy, Esam M. Aboubakr, Mansour Alharbi, Mostafa A. Ali, Ghaleb Alharbi and Ahmed Ibrahim ElMallah

Pharmaceuticals 2025, 18(9), 1314; https://doi.org/10.3390/ph18091314 - 1 Sep 2025

Abstract

Background/Objectives: The clinical impact of antipsychotics on the human body remains inadequately investigated, hence we aimed to compere the effects olanzapine (OLZ) and Clozapine (CLZ) on different body systems. Methods: 48 patients and 24 healthy individuals were involved, and followed over six [...] Read more.

Background/Objectives: The clinical impact of antipsychotics on the human body remains inadequately investigated, hence we aimed to compere the effects olanzapine (OLZ) and Clozapine (CLZ) on different body systems. Methods: 48 patients and 24 healthy individuals were involved, and followed over six months. PANSS, metabolic, cardiovascular, inflammatory, and neuronal transmitter parameters were determined. Results: No significant difference was found between the effects of the two drugs on blood mineral and cardiovascular parameters, except for CK-MB, which showed a greater increase in the OLZ group than in the CLZ group. Both drugs increased the lipid profile and HbA1C levels, with the effect of CLZ being more prominent. Both drugs increased the patients’ body weights, with no significant difference between their effects. Regarding renal and hepatic functions, OLZ had a more notable effect on creatinine and albumin levels than CLZ, while AST and ALT showed markedly greater increases in the CLZ-treated group than in the OLZ-treated group. Regarding the effects on neurotransmitters and inflammatory mediators, both drugs increased serotonin and ghrelin levels, in addition to decreasing leptin concentrations, and decreased the inflammatory mediators IL-1β, IL-6, and –TNF-α, with the effect of OLZ being more prominent. Regarding therapeutic efficacy, CLZ was more effective at reducing general and negative symptoms than OLZ. Conclusions: The present study revealed that CLZ had a greater impact on metabolic parameters and better therapeutic efficacy in attenuating both general and negative symptoms, whereas OLZ had more detectable anti-inflammatory effects, aid determining the appropriate treatment for schizophrenic patients. Full article

(This article belongs to the Special Issue Neuropsychiatric Disorders: Pharmacological Aspects)

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3 pages, 154 KB

Open AccessEditorial

Advances in Fungal Natural Products: Insights into Bioactivity and Therapeutic Potential

by Katarzyna Kała

Pharmaceuticals 2025, 18(9), 1313; https://doi.org/10.3390/ph18091313 - 1 Sep 2025

Abstract

Medicinal fungi represent a unique and underexploited reservoir of structurally diverse natural products with profound biological activities [...] Full article

(This article belongs to the Special Issue Natural Products Derived from Fungi and Their Biological Activities, 2nd Edition)

24 pages, 20800 KB

Open AccessArticle

Excavating Precursors from Herb Pairs Polygala tenuifolia and Acori tatarinowii: Synthesis and Anticonvulsant Activity Evaluation of 3,4,5-Trimethoxycinnamic Acid (TMCA) Piperazine Amide Derivatives

by Zefeng Zhao, Mengchen Lei, Yongqi Wang, Yujun Bai and Haifa Qiao

Pharmaceuticals 2025, 18(9), 1312; https://doi.org/10.3390/ph18091312 - 1 Sep 2025

Abstract

Background: Epilepsy is a cluster of central nervous system (CNS) disorders identified by recurrent seizures, which affects about 60 million people around the world. In this research, a total of 40 types of 3,4,5-trimethoxycinnamic acid (TMCA) piperazine amide derivatives were designed and [...] Read more.

Background: Epilepsy is a cluster of central nervous system (CNS) disorders identified by recurrent seizures, which affects about 60 million people around the world. In this research, a total of 40 types of 3,4,5-trimethoxycinnamic acid (TMCA) piperazine amide derivatives were designed and synthesized, inspired by the traditional Chinese medicine (TCM) herb pair drugs Polygala tenuifolia and Acori tatarinowii, followed by determination of their anticonvulsant potency. Methods: All the TMCA analogues were tested for their anticonvulsant potential through two acute models of seizures induced in mice: the maximal electroshock (MES) and sc-pentylenetetrazole (PTZ) models. In addition, the lactate dehydrogenase (LDH) inhibitory activity was determined in vitro. Results: The results showed that compounds A3, A9, A12, A14, B9, and B12 exhibited preferable anticonvulsant activity in the primary evaluation. In addition, the molecular docking results predicted good interactions of screened analogues with the LDH. Molecular dynamic simulation was used to reveal the consensual binding affinity between the most promising compound (B9) and active site interactions with LDH. Electroencephalogram (EEG) analysis and silver and immunofluorescence staining were performed to illustrate the anti-epilepsy potential of compound B9. Conclusions: Novel derivatives in this study provide new cores for the further design and optimization inspired by TCM herb pair drugs P. tenuifolia and A. tatarinowii, with the aim to explore new anticonvulsant agents. Full article

(This article belongs to the Section Medicinal Chemistry)

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19 pages, 1553 KB

Open AccessArticle

Analysis of Upper Gastrointestinal Adverse Events Associated with Oral Anticoagulants and Potential Drug Interactions with Cardiovascular Drugs: Exploratory Study Using FDA Adverse Event Reporting System

by Seunghyun Cheon, Jiyeon Park, Dosol Oh, Young Seo Kim and Jee-Eun Chung

Pharmaceuticals 2025, 18(9), 1311; https://doi.org/10.3390/ph18091311 - 1 Sep 2025

Abstract

Background: This study aimed to evaluate the risk of upper gastrointestinal (UGI) adverse events (AEs) associated with oral anticoagulants (OACs) and identify potential interactions with cardiovascular (CV) drugs. Methods: Individual case safety reports (ICSRs) from the FDA Adverse Event Reporting System from July [...] Read more.

Background: This study aimed to evaluate the risk of upper gastrointestinal (UGI) adverse events (AEs) associated with oral anticoagulants (OACs) and identify potential interactions with cardiovascular (CV) drugs. Methods: Individual case safety reports (ICSRs) from the FDA Adverse Event Reporting System from July 2014 to December 2023 were analyzed. Dataset I was constructed to assess the associations between OACs and UGI AEs using disproportionality analysis. Dataset Ⅱ included OAC-related ICSRs to explore potential interactions with CV drugs through logistic regression. Positive signals were defined as potential associations identified by disproportionality analysis metrics, such as reporting odds ratios (RORs) or adjusted RORs (aRORs) accounting for confounders. Results: Dataset I included 12,905,290 ICSRs, and a positive signal for dabigatran was detected with an ROR of 1.19 (95% CI, 1.13–1.25). A total of 364,044 OAC-related ICSRs were included in dataset II. At the pharmacologic drug class level, several positive signals were identified, represented as aRORs with 95% CIs: for warfarin, amiodarone analogs (1.22; 1.04–1.43); for apixaban, angiotensin-converting enzyme inhibitors (1.34; 1.24–1.45), angiotensin receptor blockers (1.23; 1.14–1.33), dihydropyridine calcium channel blockers (1.30; 1.21–1.41), and digitalis glycosides (1.72; 1.49–2.00); and for edoxaban, angiotensin receptor blockers (1.88; 1.48–2.37), amiodarone analogs (1.73; 1.06–2.85), and anti-platelets (1.56; 1.20–2.03). No signals were observed for rivaroxaban or dabigatran. At the individual drug level, 62 OAC-CV pairs were identified as having potential interactions. Conclusions: Drug-specific interaction profiles should be considered to ensure safe and personalized use of OACs in clinical practice. Full article

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18 pages, 3143 KB

Open AccessArticle

Antidiabetic Activity of Silver Nanoparticles Biosynthesized with Stenocereus queretaroensis Flower Extract

by Angélica Sofía González-Garibay, Iván Moisés Sánchez-Hernández, Omar Ricardo Torres-González, Ana Del Socorro Hernández-Aviña, Ariadna Abigail Villarreal-Amézquita and Eduardo Padilla-Camberos

Pharmaceuticals 2025, 18(9), 1310; https://doi.org/10.3390/ph18091310 - 1 Sep 2025

Abstract

Background/Objectives: Diabetes mellitus (DM) is one of the most common metabolic disorders, with a continually increasing population incidence. One of the main therapeutic approaches for this condition involves the inhibition of alpha-amylase and alpha-glucosidase—key enzymes involved in carbohydrate breakdown. Silver nanoparticles have exhibited [...] Read more.

Background/Objectives: Diabetes mellitus (DM) is one of the most common metabolic disorders, with a continually increasing population incidence. One of the main therapeutic approaches for this condition involves the inhibition of alpha-amylase and alpha-glucosidase—key enzymes involved in carbohydrate breakdown. Silver nanoparticles have exhibited inhibitory activity against both enzymes, suggesting their potential in regulating postprandial blood glucose levels. This study aimed to evaluate the antidiabetic potential of silver nanoparticles biosynthesized with Stenocereus queretaroensis flower extract. Methods: The flower extract was prepared and, following a qualitative and quantitative phytochemical analysis, was utilized in the reaction to biosynthesize S. queretaroensis flower extract nanoparticles (SAgNPs). The SAgNPs were characterized using UV–visible spectroscopy, dynamic light scattering (DLS), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), X-ray diffraction (XRD), and Fourier transform infrared spectrophotometry (FTIR). The antidiabetic potential of the biosynthesized SAgNPs was evaluated in vitro using alpha-amylase and alpha-glucosidase inhibitory assays, while an animal model was used for postprandial hypoglycemic activity in healthy mice. Results: The phytochemical analyses showed the presence of phenolic compounds and flavonoids like sinapic acid, p-coumaroyl tyrosine, procyanidin dimer β1, and dihydroquercetin in the flower extract. The SAgNPs were found to be rough and spherical in shape, with an average size of 99.5 nm. The inhibition of alpha-amylase and alpha-glucosidase by SAgNPs exhibited an IC₅₀ of 4.92 µg/mL and 0.68 µg/mL, respectively. The animal model results suggested that SAgNPs at 100 mg/kg caused a significant decrease in the postprandial glucose level; this effect is likely attributable to delayed carbohydrate digestion, as supported by the in vitro findings. Conclusions: S. queretaroensis-synthesized silver nanoparticles may constitute a promising option for antidiabetic therapy. Full article

(This article belongs to the Special Issue Therapeutic Potential of Silver Nanoparticles (AgNPs), 2nd Edition)

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16 pages, 2125 KB

Open AccessArticle

Granzyme B PET Imaging Enables Early Assessment of Immunotherapy Response in a Humanized Melanoma Mouse Model

by Priska Summer, Naomi Gallon, Niklas Bulmer, Umar Mahmood and Pedram Heidari

Pharmaceuticals 2025, 18(9), 1309; https://doi.org/10.3390/ph18091309 - 31 Aug 2025

Abstract

Background/Objectives: This study evaluated a novel PET tracer, ⁶⁸Ga-NOTA-CYT-200, which targets human granzyme B (GZB) as a biomarker for cytotoxic T-cell activation in a clinically relevant model of melanoma-bearing mice with a humanized immune system treated with immune checkpoint inhibitor (ICI) [...] Read more.

Background/Objectives: This study evaluated a novel PET tracer, ⁶⁸Ga-NOTA-CYT-200, which targets human granzyme B (GZB) as a biomarker for cytotoxic T-cell activation in a clinically relevant model of melanoma-bearing mice with a humanized immune system treated with immune checkpoint inhibitor (ICI) therapy. Methods: The binding affinity of the tracer was determined using an enzymatic colorimetric assay. Tumor-bearing humanized NSG mice underwent PET imaging before and during ICI monotherapy or combination therapy to assess ⁶⁸Ga-NOTA-CYT-200 uptake within tumors and other organs. The tumor growth was carefully monitored. The treatment response was evaluated based on the percentage change in tumor size at days 5 and 15 after the treatment started. A tracer biodistribution study and immunohistochemical staining of the tumors and organs were also performed. Results: The inhibition constant (Ki) of ⁶⁸Ga-NOTA-CYT-200 was estimated at 4.2 nM. PET imaging showed a significantly higher ⁶⁸Ga-NOTA-CYT-200 uptake in mice receiving the combination therapy compared to those receiving monotherapy or a vehicle (p < 0.0001 or p = 0.0005, respectively), which correlated with the greatest reduction in tumor size in the combination ICI group. Regardless of treatment, the responders presented with a significantly higher ⁶⁸Ga-NOTA-CYT-200 uptake at days 4 or 7 after the treatment began (p = 0.0002 and p = 0.0109, respectively). An increased uptake of ⁶⁸Ga-NOTA-CYT-200, especially in the intestines and liver within the combination ICI group, suggested immune-related adverse events (IrAEs). Conclusions: Our study demonstrates that ⁶⁸Ga-NOTA-CYT-200 PET imaging can predict the early treatment response in melanoma models treated with ICI and may also help in detecting IrAEs. Full article

(This article belongs to the Special Issue Innovative Approaches to Radiopharmaceuticals: Advances in Design, Labeling, and Applications)

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25 pages, 1710 KB

Open AccessArticle

Phytochemical Profiling, Antioxidant Activity, and In Vitro Cytotoxic Potential of Mangrove Avicennia marina

by Federico Cerri, Beatrice De Santes, Francesca Spena, Lucia Salvioni, Matilde Forcella, Paola Fusi, Stefania Pagliari, Henrik Stahl, Paolo Galli, Miriam Colombo, Marco Giustra and Luca Campone

Pharmaceuticals 2025, 18(9), 1308; https://doi.org/10.3390/ph18091308 - 31 Aug 2025

Abstract

Background: Avicennia marina (Forsk.) Vierh., a widely distributed mangrove species, is known for its diverse secondary metabolites with potential pharmacological applications. Despite its dominance in the Arabian Gulf, where A. marina may have adapted to extreme environmental conditions with a distinct set [...] Read more.

Background: Avicennia marina (Forsk.) Vierh., a widely distributed mangrove species, is known for its diverse secondary metabolites with potential pharmacological applications. Despite its dominance in the Arabian Gulf, where A. marina may have adapted to extreme environmental conditions with a distinct set of bioactive molecules, research in this region remains limited. Methods: This study investigates the phytochemical composition, antioxidant activity, and in vitro cytotoxicity of extracts from different plant parts, including roots, leaves, propagules, pericarps, and cotyledons, collected in the United Arab Emirates (UAE). Extracts were analyzed using ultra-pressure liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). Antioxidant activity was assessed using DPPH and ABTS assays, while cytotoxicity was evaluated against human cancer and normal cell lines. Results: Analysis revealed 49 compounds, including iridoid glycosides, hydroxycinnamic acids, phenylethanoid glycosides, flavonoid glycosides, and triterpene saponins, several reported for the first time in A. marina and mangroves. The pericarp and root extracts exhibited the highest scavenging activity (DPPH: 187.14 ± 2.87 and 128.25 ± 1.12; ABTS: 217.16 ± 2.67 and 147.21 ± 2.42 μmol TE/g, respectively), correlating with phenylethanoid content. The root extract also displayed the highest cytotoxicity, with IC₅₀ values of 58.46, 81.98, and 108.10 μg/mL against MDA-MB-231, SW480, and E705, respectively. In silico analysis identified triterpene saponins as potential contributors. Conclusions: These findings highlight the root extract of A. marina as a promising source of bioactive compounds with potential antioxidant and anticancer applications, supporting further exploration for novel therapeutic candidates. Full article

(This article belongs to the Special Issue Plant-Based Extracts and the Therapeutic Potential of Bioactive Compounds, 2nd Edition)

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37 pages, 11682 KB

Open AccessArticle

Isoliquiritigenin as a Neuronal Radiation Mitigant: Mitigating Radiation-Induced Anhedonia Tendency Targeting Grik3/Grm8/Grin3a via Integrated Proteomics and AI-Driven Discovery

by Boyang Li, Suqian Cheng, Han Zhang and Bo Li

Pharmaceuticals 2025, 18(9), 1307; https://doi.org/10.3390/ph18091307 - 30 Aug 2025

Abstract

Background/Objectives: Radiotherapy can cause severe and irreversible brain damage, including cognitive impairment, increased dementia risk, debilitating depression, and other neuropsychiatric disorders. Current radioprotective drugs face limitations, such as single-target inefficacy or manufacturing hurdles. Isoliquiritigenin (ISL), a natural flavonoid derived from licorice root, [...] Read more.

Background/Objectives: Radiotherapy can cause severe and irreversible brain damage, including cognitive impairment, increased dementia risk, debilitating depression, and other neuropsychiatric disorders. Current radioprotective drugs face limitations, such as single-target inefficacy or manufacturing hurdles. Isoliquiritigenin (ISL), a natural flavonoid derived from licorice root, exhibits broad bioactivities. It exhibits anti-inflammatory, anti-cancer, immunoregulatory, hepatoprotective, and cardioprotective activities. This study aimed to elucidate ISL’s neuronal radiation mitigation effects and key targets. Methods: In vitro and in vivo models of radiation-induced neuronal injury were established. ISL’s bioactivities were evaluated through cellular cytotoxicity assays, LDH release, ROS, ATP, glutamate, and GSH levels. In vivo, ISL’s radiation mitigation effect was evaluated with sucrose preference test, IL-β level, histopathological analysis, and Golgi-Cox staining analysis. Proteomics, pathway enrichment, and ensemble models (four machine learning models, weighted gene co-expression network, protein–protein interaction) identified core targets. Molecular docking and dynamic simulations validated ISL’s binding stability with key targets. Results: ISL attenuated radiation-induced cellular cytotoxicity, reduced LDH/ROS, restored ATP, elevated GSH, and mitigated glutamate accumulation. In rats, ISL alleviated anhedonia-like phenotypes and hippocampal synaptic loss. ISL also significantly suppressed radiation-induced neuroinflammation, as evidenced by reduced levels of the pro-inflammatory cytokine IL-1β. Proteomic analysis revealed that ISL’s main protective pathways included the synaptic vesicle cycle, glutamatergic synapse, MAPK signaling pathway, SNARE interactions in vesicular transport, insulin signaling pathway, and insulin secretion. Grm8, Grik3, and Grin3a were identified as key targets using the integrated models. The expression of these targets was upregulated post-radiation and restored by ISL. Molecular docking and dynamic simulations indicated that ISL showed stable binding to these receptors compared to native ligands. Conclusions: ISL demonstrates multi-scale radiation mitigation activities in vitro and in vivo by modulating synaptic and inflammatory pathways, with glutamate receptors as core targets. This work nominates ISL as an important natural product for mitigating radiotherapy-induced neural damage. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Their Analogues, Third Edition)

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19 pages, 5197 KB

Open AccessArticle

Herbacetin Alleviates Influenza Virus-Induced Lung Injury and Fibrosis by Targeting the Neuraminidase Protein

by Feng Liao, Sha Li, Liumei Wu, Jiafan Chen, Ziqing Luo, Ming Zhong, Qiuhong Li, Wenbiao Wang and Geng Li

Pharmaceuticals 2025, 18(9), 1306; https://doi.org/10.3390/ph18091306 - 30 Aug 2025

Abstract

Background: Influenza A virus (IAV) is a major human pathogen, contributing to substantial morbidity and mortality during seasonal outbreaks and pandemics. Human infection with IAV can lead to pneumonia and acute respiratory distress syndrome (ARDS), and numerous clinical and basic research studies have [...] Read more.

Background: Influenza A virus (IAV) is a major human pathogen, contributing to substantial morbidity and mortality during seasonal outbreaks and pandemics. Human infection with IAV can lead to pneumonia and acute respiratory distress syndrome (ARDS), and numerous clinical and basic research studies have established an association between IAV and pulmonary fibrosis (PF). However, the treatment of IAV-induced PF fibrosis has not been studied and discussed. Methods: An IAV-induced PF mouse model was established. Herbacetin (HBT) was identified as the most effective compound in the in vitro study of seven components of Rhodiola rosea L. (R. rosea L.). The effect of HBT on IAV-induced lung injury and PF was evaluated in vivo and in vitro. The binding between HBT and neuraminidase (NA) protein was investigated by biological layer interferometry (BLI) and cell thermal shift assay (CETSA). Results: Following IAV infection, the TGF-β/Smad3 pathway is activated, leading to the upregulation of fibrosis-related proteins that promote fibrosis. HBT exhibited a significant ability to reduce influenza virus-induced lung injury and fibrosis both in vitro and in vivo. Mechanistically, HBT binds to the NA protein of the influenza virus, reducing viral infection and the activation of the TGF-β/Smad3 pathway, thereby mitigating the formation of lung injury and PF. Conclusions: HBT represents a promising therapeutic agent for modulating influenza virus-induced lung injury and PF, marking a significant step toward the development of effective treatments for influenza-induced PF. Full article

(This article belongs to the Section Pharmacology)

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18 pages, 2647 KB

Open AccessArticle

J3ExoA: A Novel Anti-HIV Immunotoxin Fusion of Anti-Gp120 J3VHH and PE38 Fragment of Pseudomonas Exotoxin A

by Seth H. Pincus, Kun Luo, Tami Peters, James T. Gordy, Frances M. Cole, Grant Klug, Kelli Ober, Tamera K. Marcotte and Richard B. Markham

Pharmaceuticals 2025, 18(9), 1305; https://doi.org/10.3390/ph18091305 - 30 Aug 2025

Abstract

Background. We are developing cytotoxic anti-HIV immunoconjugates to attack the reservoir of infected cells that persist after years of fully suppressive anti-retroviral therapy. Methods. We have produced a chimeric fusion protein, J3ExoA, consisting of J3VHH, a broadly reactive anti-gp120 camelid nanobody, joined to [...] Read more.

Background. We are developing cytotoxic anti-HIV immunoconjugates to attack the reservoir of infected cells that persist after years of fully suppressive anti-retroviral therapy. Methods. We have produced a chimeric fusion protein, J3ExoA, consisting of J3VHH, a broadly reactive anti-gp120 camelid nanobody, joined to the de-immunized PE38 fragment of Pseudomonas exotoxin A. The efficacy of J3ExoA was compared to that of a well-studied anti-gp41 immunotoxin (IT), 7B2-dgA, in cytotoxicity assays and for inhibition of infectivity. Immunogenicity of the ITs was tested in mice. Results. J3ExoA killed cells expressing the HIV envelope with specificity in concentrations in the ng/mL range. Of all anti-HIV ITs we have tested, only J3ExoA compared to 7B2-dgA in cytotoxic efficacy, although there were differences between the two ITs on different target cells. J3ExoA suppressed the spread of HIV infection in tissue culture. J3ExoA was less immunogenic than 7B2-dgA, but mice made antibodies to both portions of the fusion protein. Conclusions. J3ExoA represents a novel IT that may be used to eliminate infected cells in the persistent HIV reservoir of infection, the barrier to an HIV “cure.” Additional approaches for addressing IT immunogenicity are discussed. Full article

(This article belongs to the Section Biopharmaceuticals)

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16 pages, 2663 KB

Open AccessArticle

From Gene Networks to Therapeutics: A Causal Inference and Deep Learning Approach for Drug Discovery

by Sudhir Ghandikota and Anil G. Jegga

Pharmaceuticals 2025, 18(9), 1304; https://doi.org/10.3390/ph18091304 - 30 Aug 2025

Abstract

Background/Objectives: Drug discovery is a lengthy and expensive process, taking an average of 10 years and more than USD 2 billion from target discovery to drug approval. It is even more challenging in complex diseases due to disease heterogeneity and limited knowledge about [...] Read more.

Background/Objectives: Drug discovery is a lengthy and expensive process, taking an average of 10 years and more than USD 2 billion from target discovery to drug approval. It is even more challenging in complex diseases due to disease heterogeneity and limited knowledge about the underlying mechanisms. We present a novel computational framework that integrates network analysis, statistical mediation, and deep learning to identify causal target genes and repurposable small-molecule candidates. Methods: We applied weighted gene co-expression network analysis (WGCNA) and bidirectional mediation analysis (causal WGCNA) to transcriptomic data from idiopathic pulmonary fibrosis (IPF) patients to identify genes causally linked to the disease phenotype. These genes were used as a phenotypic signature for deep learning-based compound screening using the DeepCE model. Results: Using RNA-seq data from 103 IPF patients and 103 controls, we identified seven significantly correlated modules and 145 causal genes. Five of these genes (ITM2C, PRTFDC1, CRABP2, CPNE7, and NMNAT2) were predictive of disease severity in IPF. Our compound screening identified several promising candidates, such as Telaglenastat (GLS1 inhibitor), Merestinib (MET kinase inhibitor), and Cilostazol (PDE3 inhibitor), with significant inverse correlation with the IPF-specific gene signature. Conclusions: This study demonstrates the utility of combining causal inference and deep learning for drug discovery. Our framework identified novel gene targets and therapeutic candidates for IPF, offering a scalable strategy for phenotype-driven drug discovery and repurposing. Full article

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

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22 pages, 2295 KB

Open AccessArticle

Discovery of a Promising Hydroxyamino-Piperidine HDAC6 Inhibitor via Integrated Virtual Screening and Experimental Validation in Multiple Myeloma

by Federica Chiera, Antonio Curcio, Roberta Rocca, Ilenia Valentino, Massimo Gentile, Stefano Alcaro, Nicola Amodio and Anna Artese

Pharmaceuticals 2025, 18(9), 1303; https://doi.org/10.3390/ph18091303 - 29 Aug 2025

Abstract

Background: Histone deacetylase 6 (HDAC6) is a unique class IIb HDAC isozyme characterized by two catalytic domains and a zinc finger ubiquitin-binding domain. It plays critical roles in various cellular processes, including protein degradation, autophagy, immune regulation, and cytoskeletal dynamics. Due to its [...] Read more.

Background: Histone deacetylase 6 (HDAC6) is a unique class IIb HDAC isozyme characterized by two catalytic domains and a zinc finger ubiquitin-binding domain. It plays critical roles in various cellular processes, including protein degradation, autophagy, immune regulation, and cytoskeletal dynamics. Due to its multifunctional nature and overexpression in several cancer types, HDAC6 has emerged as a promising therapeutic target. Methods: In this study, we employed a ligand-based pharmacophore modeling approach using a structurally diverse set of known HDAC6 inhibitors. This was followed by the virtual screening of over 140,000 commercially available compounds from both the MolPort and Asinex databases. The screening workflow incorporated pharmacophore filtering, molecular docking, and molecular dynamic (MD) simulations. Binding free energies were estimated using Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis to prioritize top candidates. A fluorometric enzymatic assay was used to measure HDAC6 activity, while cell viability assay by Cell Titer Glo was used to assess the anti-tumor activity against drug-sensitive and -resistant multiple myeloma (MM) cells. Western blotting was used to evaluate the acetylation of tubulin or histone H4 after treatment with selected compounds. Results: Three promising compounds were identified based on stable binding conformations and favorable interactions within the HDAC6 catalytic pocket. Among them, Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis identified Compound 10 (AKOS030273637) as the top theoretical binder, with a ΔG_bind value of −45.41 kcal/mol. In vitro enzymatic assays confirmed its binding to the HDAC6 catalytic domain and inhibitory activity. Functional studies on MM cell lines, including drug-resistant variants, showed that Compound 10 reduced cell viability. Increased acetylation of α-tubulin, a substrate of HDAC6, likely suggested on-target mechanism of action. Conclusions: Compound 10, featuring a benzyl 4-[4-(hydroxyamino)-4-oxobutylidene] piperidine-1-carboxylate scaffold, demonstrates potential drug-like properties and a predicted bidentate zinc ion coordination, supporting its potential as an HDAC6 inhibitor for further development in hematologic malignancies. Full article

(This article belongs to the Section Medicinal Chemistry)

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39 pages, 1118 KB

Open AccessArticle

Borylated Five-Membered Ring Iminosugars: Synthesis, Spectroscopic Analysis, and Biological Evaluation for Glycosidase Inhibition and Anticancer Properties for Application in Boron Neutron Capture Therapy (BNCT)—Part 1

by Kate Prichard, Suzuka Yamamoto, Yuna Shimadate, Kosuke Yoshimura, Barbara Bartholomew, Jayne Gilbert, Jennette Sakoff, Robert Nash, Atsushi Kato and Michela Simone

Pharmaceuticals 2025, 18(9), 1302; https://doi.org/10.3390/ph18091302 - 29 Aug 2025

Abstract

Background/Objectives: This article reports pyrrolidine iminosugars of L-gulose absolute stereochemical configuration that are functionalised via N-alkylation to bear boronate ester and boronic acid pharmacophores. Inclusion of boron pharmacophores has been shown to reduce toxicity profiles of drugs and can expand the [...] Read more.

Background/Objectives: This article reports pyrrolidine iminosugars of L-gulose absolute stereochemical configuration that are functionalised via N-alkylation to bear boronate ester and boronic acid pharmacophores. Inclusion of boron pharmacophores has been shown to reduce toxicity profiles of drugs and can expand the range of interactions between drugs and target enzymes. Methods: The synthetic development, detailed spectroscopic analysis, and biological investigation against glycosidase enzymes and cancer cell lines of these novel five-membered ring iminosugars are reported. Results: This family of iminosugars displays selective, moderate-to-weak inhibition (IC₅₀s = 133–501 μM) of β-d-galactosidase (bovine liver) and emerging inhibition of β-d-glucosidases (almond) and (bovine liver). The boronic acid pharmacophore may be suitable for the management of lysosomal storage disorders to support the restoration of biological activity of mutant enzymes via the chaperone-mediated therapy approach. From a structure–activity perspective, the cancer screening revealed slight growth inhibition in a panel of cancer cell lines, with A2780 ovarian carcinoma cells showing the strongest response across all compounds. Beyond the growth inhibition capabilities, the real therapeutic potential of these borylated drugs lies in their switch-on/switch-off activation under BNCT radiotherapeutic conditions. Conclusions: This is an important novel family of drug leads capable of interacting with drug targets via intermolecular and intramolecular interactions, changing shape and electronics. Introduction of organic boron atoms to organic molecules presents significant synthetic and purification challenges, as well as analysis of the equilibria that arise in aqueous systems. We provide a methodology to achieve all this and introduce boron pharmacophores onto carbohydrate scaffolds in a systematic manner to facilitate a more widespread adoption of boron pharmacophores. Full article

(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)

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22 pages, 1894 KB

Open AccessArticle

Pharmacovigilance Insights into Ibuprofen’s Neuropsychiatric Safety: A Retrospective Analysis of EudraVigilance Reports

by Cristina Anamaria Buciuman, Carmen Maximiliana Dobrea, Anca Butuca, Adina Frum, Felicia Gabriela Gligor, Mihai O. Botea, Laura Grațiela Vicaș, Mariana Eugenia Mureșan, Octavia Gligor, Florin Maghiar, Alexia Manole and Claudiu Morgovan

Pharmaceuticals 2025, 18(9), 1301; https://doi.org/10.3390/ph18091301 - 29 Aug 2025

Abstract

Background/Objectives: Mental health awareness is rising; thus, neurological and psychiatric side effects also benefit from increased attention from the medical and scientific community. Ibuprofen is a well-known non-steroidal anti-inflammatory drug (NSAID) that is often available over-the counter (OTC) for both adults and [...] Read more.

Background/Objectives: Mental health awareness is rising; thus, neurological and psychiatric side effects also benefit from increased attention from the medical and scientific community. Ibuprofen is a well-known non-steroidal anti-inflammatory drug (NSAID) that is often available over-the counter (OTC) for both adults and children, expressing good efficacy in reducing pain and fever through non-selective cyclooxygenase inhibition. As ibuprofen has already been associated with different neuropsychiatric disorders, the aim of this study was to perform an up-to-date analysis of such signals detected in the cases reported in EudraVigilance (EV). Methods: The disproportionality analysis offered a contextual insight into the real-world situation depicted in the analyzed database. Results: From the total cases reported for ibuprofen (n = 58,911), 13.9% contained nervous system disorders (n = 8214) and 10.7% entailed psychiatric disorders (n = 6295). The cases were distributed between all age groups, with a sensible higher incidence in teenagers and in women in general. Severe cases, including deaths, have been reported. By comparison with ketoprofen, acetylsalicylic acid, and diclofenac, ibuprofen presented a higher probability of reporting psychiatric and behavioral symptoms. Regarding cognitive and attention disorders and disturbances, no disproportionate signal was observed between ibuprofen and all other NSAIDs. Sleep disturbances (hypersomnia, narcolepsy and sleep paralysis) are reported as more probable for ibuprofen than for acetylsalicylic acid, naproxen, and diclofenac. A higher risk of reporting suicidal and self-injurious behaviors was noted for ibuprofen versus all other selected NSAIDs. A limitation of the study can be noted as due to suspected causality, not an established one, and EV reports cannot accurately determine adverse drug reaction frequencies. Conclusions: Considering that ibuprofen is easily accessible as an OTC drug and the higher probability of reporting several neuropsychiatric adverse effects as shown by this study, patient counseling, when possible, and general education for the public are valuable tools in managing these adverse reactions. Full article

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

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36 pages, 4105 KB

Open AccessArticle

Synthesis and Structure-Affinity Relationships of Receptor Ligands with 1,3-Dioxane Structure

by Elisabeth Quick, Dirk Schepmann and Bernhard Wünsch

Pharmaceuticals 2025, 18(9), 1300; https://doi.org/10.3390/ph18091300 - 29 Aug 2025

Abstract

Background/Objectives: Ligands blocking σ₁ receptors or NMDA receptors show promising pharmacological properties, such as analgesia or neuroprotection. It had been shown that depending on the stereochemistry and substitution pattern, 1,3-dioxnaes can selectively interact with either σ₁ receptors or the phencyclidine [...] Read more.

Background/Objectives: Ligands blocking σ₁ receptors or NMDA receptors show promising pharmacological properties, such as analgesia or neuroprotection. It had been shown that depending on the stereochemistry and substitution pattern, 1,3-dioxnaes can selectively interact with either σ₁ receptors or the phencyclidine binding site of NMDA receptors. Herein, systematic modifications of homologous aminobutyl substituted 1,3-dioxanes were conducted in order to identify ligands selectively addressing σ receptors or NMDA receptors. Methods: The first step of the synthesis, i.e., the acetalization of benzaldehyde (7a) or propiophenone (7b) with pentane-1,3,5-triol (6), determined the relative configuration of the envisaged 1,3-dioxanes bearing 4-aminobutyl substituents in 4-position. Multi-step homologation of ethanols 8 provided various primary, secondary and tertiary amines 14, 16–19, and 24–27. The affinity towards σ₁ and σ₂ receptors as well as the PCP and ifenprodil binding sites of the NMDA receptor was systematically evaluated in radioligand receptor binding studies. Results: Only the primary amines 14b and 24b derived from propiophenone interacted moderately with the PCP binding site of the NMDA receptor. Within this class of compounds, the N-benzylamines 17 and 18 showed the highest σ₁ affinity with high selectivity over the PCP binding site and at least preference over the σ₂ receptor. The benzylamine 17a (K_i(σ₁) = 31 nM, LLE = 6.19) and the pyrrolidine 19a (K_i(σ₁) = 154 nM, LLE = 6.72) represent the most promising σ₁ ligands of this compound series, when taking the lipophilicity and receptor selectivity into account. Conclusions: Both compounds showed medium metabolic stability in vitro rendering them promising candidates for further studies. Full article

(This article belongs to the Section Medicinal Chemistry)

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14 pages, 3607 KB

Open AccessArticle

Association of Erythrocyte-Related Indices with Immune-Related Adverse Events and Survival of Lung Cancer Patients Receiving Immune Checkpoint Inhibitors

by Zhan Wang, Ting Zou, Chen-Wei Liao, Xiang-Ping Li, Zhao-Qian Liu, Ze-Fu Liu and Juan Chen

Pharmaceuticals 2025, 18(9), 1299; https://doi.org/10.3390/ph18091299 - 29 Aug 2025

Abstract

Background: Lung cancer has the highest lethality rate among malignancies worldwide. Immunotherapy is one of the common treatments for lung cancer patients. There are two main types of immunotherapies: one targets programmed cell death 1 (PD-1), and the other targets programmed cell [...] Read more.

Background: Lung cancer has the highest lethality rate among malignancies worldwide. Immunotherapy is one of the common treatments for lung cancer patients. There are two main types of immunotherapies: one targets programmed cell death 1 (PD-1), and the other targets programmed cell death ligand 1 (PD-L1). These two belong to the class of immune checkpoint inhibitors (ICIs). However, immune-related adverse reactions (irAEs) were the main reasons affecting its clinical therapeutic effect. Methods: This retrospective cohort study analyzed red blood cell count (RBC), hematocrit (HCT), erythrocyte mean corpuscular volume (MCV) and immunotherapy outcomes in 920 lung cancer patients receiving immunotherapy from April 2019 to May 2023. Results: We found that high levels of RBC (>4.105 × 10⁹, p = 0.007, OR = 0.467, 95%CI: 0.268~0.812) and MCV (>86.35, p = 0.017, OR = 0.0.441, 95%CI: 0.224~0.865) were significantly related to the better response of ICIs immunotherapy in patients. Patients with high levels of HCT (>39.75%, p = 0.035, OR = 0.737, 95%CI: 0.555~0.979) may have a lower rate of irAEs occurrence. Meanwhile, patients with a low level of RBCs (≤4.635 × 10⁹, p < 0.001, OR = 1.636, 95%CI: 1.365~1.960) may have a longer period of PFS (progression-free survival), and patients with RBC (≤4.43 × 10⁹, p = 0.033, OR = 0.480, 95%CI: 0.244~0.941) may have a longer time of OS (overall survival). Conclusions: The findings indicate that the levels of RBC, MCV and HCT were significantly associated with the response and irAEs of ICIs in lung cancer patients. The levels of RBC might act as a possible biomarker for predicting the survival of lung cancer patients who are receiving ICI therapy. Full article

(This article belongs to the Special Issue Adjuvant Therapies for Cancer Treatment: 2nd Edition)

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18 pages, 1366 KB

Open AccessReview

Ketamine’s Role in Neuroinflammation and Neuroprotection Across Neurological and Psychiatric Disorders: A Narrative Review

by Gustavo N. Silva, Virna G. A. Brandão, Kenneth Blum, Kai-Uwe Lewandrowski and Rossano K. A. Fiorelli

Pharmaceuticals 2025, 18(9), 1298; https://doi.org/10.3390/ph18091298 - 29 Aug 2025

Abstract

Ketamine, a widely used anesthetic with emerging evidence suggesting neuroprotective and anti-inflammatory properties across various neurological disorders, is recognized for its NMDA receptor antagonism. It has been postulated to play a role in neuroprotection, due to its anti-inflammatory properties, and decrease microglial activation, [...] Read more.

Ketamine, a widely used anesthetic with emerging evidence suggesting neuroprotective and anti-inflammatory properties across various neurological disorders, is recognized for its NMDA receptor antagonism. It has been postulated to play a role in neuroprotection, due to its anti-inflammatory properties, and decrease microglial activation, as well as cytokines TNF and IL-6. Despite its established role, the extent of ketamine’s effects on neuroinflammation and neuroprotection remains to be fully elucidated. Here, we conducted a narrative review synthesizing current knowledge on ketamine’s operating mechanisms, including its modulation of synaptic plasticity, excitotoxicity, and cytokine release, alongside its therapeutic applications in traumatic brain injury, neurodegenerative diseases, psychiatric disorders, and pain management. For this narrative review, we searched the Medline, Embase, Scopus, Web of Science, and PubMed databases. Our findings indicate that ketamine reduces excitotoxicity and inflammation, which may contribute to neuroprotection in acute neurological injuries. These insights underscore ketamine’s potential as an adjunctive neuroprotective agent, warranting further clinical investigation to optimize its therapeutic utility across neurological and psychiatric contexts. Full article

(This article belongs to the Special Issue Pharmacological Insight into NMDA Receptor Antagonists)

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