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Transferosomes as Drug Delivery Systems: Design Principles, Deformability, and Translational Challenges -
Prevention of Intestinal Inflammation and Gut Dysbiosis by Prebiotic Grape Seed Flour in Mice with DSS-Induced Colitis -
Modulation of Mu-Opioid Receptor Expression and Functional Impairment of Natural Killer Cells in Neuropathic Pain: Implications for Biomarker Discovery and Personalized Therapies
Journal Description
Pharmaceuticals
Pharmaceuticals
is a peer-reviewed, open access journal of medicinal chemistry and related drug sciences, published monthly online by MDPI. The Academy of Pharmaceutical Sciences (APS) is affiliated with Pharmaceuticals and its members receive discounts on the article processing charges.
- Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q1 (Pharmacology and Pharmacy) / CiteScore - Q1 (Pharmaceutical Science)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 14.3 days after submission; acceptance to publication is undertaken in 3.6 days (median values for papers published in this journal in the first half of 2026).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- International Electronic Conference on Medicinal Chemistry (https://sciforum.net/series/ecmc/latest)
- Companion journals for Pharmaceuticals include: Psychoactives and Drugs and Drug Candidates.
- Journal Clusters-Pharmaceutical Science: Scientia Pharmaceutica, Marine Drugs, Pharmaceuticals, Pharmaceutics, Pharmacy, Biologics, Future Pharmacology, Pharmacoepidemiology, Drugs and Drug Candidates and Journal of Pharmaceutical and BioTech Industry.
Impact Factor:
5.7 (2025);
5-Year Impact Factor:
5.5 (2025)
Latest Articles
Mapping the Research Landscape of Poria cocos as A Medicinal and Edible Fungus: A Bibliometric Analysis from January 1990 to April 2026
Pharmaceuticals 2026, 19(9), 1421; https://doi.org/10.3390/ph19091421 (registering DOI) - 8 Sep 2026
Abstract
Background:Poria cocos is a medicinal and edible fungus widely used in traditional Chinese medicine and functional food development. However, the global research structure and thematic evolution of this field remain insufficiently characterized. This study aimed to map publication trends, collaboration networks, knowledge
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Background:Poria cocos is a medicinal and edible fungus widely used in traditional Chinese medicine and functional food development. However, the global research structure and thematic evolution of this field remain insufficiently characterized. This study aimed to map publication trends, collaboration networks, knowledge bases, and emerging research themes in Poria cocos research. Methods: Publications related to Poria cocos were retrieved from the Web of Science Core Collection from 1 January 1990 to 1 April 2026. Articles and reviews were included. Bibliometric and visualization analyses were performed using Microsoft Excel and an open-source Python 3.11.8 workflow (NetworkX 3.6.1 and Matplotlib 3.10.8). Co-occurrence analysis was used to count the frequency of co-occurrence of certain elements (e.g., countries, regions, institutions, etc.); cluster analysis was used to classify keywords; and burst analysis was used to identify research trends and hotspots. Results: A total of 1404 records were included. Publication output increased markedly after 2014 and peaked in 2025, whereas 2026 data were incomplete. China contributed the largest share of publications and occupied the central position in international collaboration networks. The Journal of Ethnopharmacology and International Journal of Biological Macromolecules were major publication venues. Keyword and co-citation analyses indicated a thematic shift from phytochemical characterization and resource studies toward polysaccharides, pharmacological mechanisms, network pharmacology, and gut microbiota. Conclusions: This bibliometric analysis provides an overview of the evolving research landscape of Poria cocos. Future studies should strengthen data-driven mechanistic validation, quality standardization, translational pharmacology, and clinical evidence generation.
Full article
(This article belongs to the Section Pharmacology)
Open AccessReview
Current and Emerging Targeted Therapy in Advanced Gastroesophageal Adenocarcinoma
by
Oliver Oakley, Umair Mahmood, Yusuf Ahmad and Elizabeth Smyth
Pharmaceuticals 2026, 19(9), 1420; https://doi.org/10.3390/ph19091420 - 8 Sep 2026
Abstract
Background/Objectives: Advanced gastroesophageal adenocarcinoma (GEA) carries a poor prognosis, with median overall survival of 13–20 months despite standard chemotherapy. Since trastuzumab’s approval, biomarker-driven precision therapies have expanded rapidly. This review comprehensively summarises current and emerging targeted agents across the key molecular targets
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Background/Objectives: Advanced gastroesophageal adenocarcinoma (GEA) carries a poor prognosis, with median overall survival of 13–20 months despite standard chemotherapy. Since trastuzumab’s approval, biomarker-driven precision therapies have expanded rapidly. This review comprehensively summarises current and emerging targeted agents across the key molecular targets driving advanced GEA. Methods: A comprehensive literature review was conducted using PubMed, Google Scholar and Cochrane Library in accordance with PRISMA guidelines, searching English-language human studies published between February and July 2026, supplemented by updates during editing to reflect current standards. Results: HER2-directed therapy has progressed from trastuzumab through dual blockade, immunotherapy combinations, next-generation ADCs (notably trastuzumab deruxtecan) and bispecific antibodies such as zanidatamab, which has now overtaken trastuzumab in the first-line setting. CLDN18.2-targeted zolbetuximab has demonstrated survival benefit in biomarker-selected patients, with newer ADCs, BiTEs and the first approved solid-tumour CAR-T therapy (satricabtagene autoleucel) extending this target further. VEGFR2 inhibition with ramucirumab remains a cornerstone in later lines, while novel VEGF/PD-1(L1) bispecifics are under investigation. FGFR2b-targeted bemarituzumab showed early promise that weakened on phase 3 confirmation, and MET/EGFR-directed agents, including savolitinib and amivantamab, require stringent biomarker selection to demonstrate benefit amid tumour heterogeneity. Conclusions: Novel targeted agents, particularly to HER2 and CLDN18.2, have demonstrated survival benefit despite ongoing challenges. Other lines are more investigational.
Full article
(This article belongs to the Special Issue Advances in Targeted Therapy for Gastrointestinal Cancers)
Open AccessArticle
Modulation of Caffeine-Induced Behavioral Alterations by N-Acetylcysteine in a Pharmacological Challenge Model
by
Cǎtǎlina Ionescu, Ramona-Alexandra Ciauşu, Mǎlina Visternicu, Viorica Rarinca, Gabriel-Ionut Plavan, Mircea-Nicusor Nicoara, Alin Ciobîcǎ, Andrei Luca, Daniel Timofte, Otilia Novac, Bogdan Novac, Ancuța Andreea Miler, Mihai Hogaş and Simona Hogaş
Pharmaceuticals 2026, 19(9), 1419; https://doi.org/10.3390/ph19091419 - 8 Sep 2026
Abstract
Background: Caffeine is a widely consumed psychostimulant that may affect anxiety-like, aggression-like, and social behaviors, potentially in association with oxidative imbalance. Objectives: This study evaluated the behavioral and biochemical effects of acute caffeine exposure in adult zebrafish and investigated the potential
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Background: Caffeine is a widely consumed psychostimulant that may affect anxiety-like, aggression-like, and social behaviors, potentially in association with oxidative imbalance. Objectives: This study evaluated the behavioral and biochemical effects of acute caffeine exposure in adult zebrafish and investigated the potential protective effects of N-acetylcysteine (NAC). Methods: Sixty adult wild-type AB zebrafish (Danio rerio), approximately 9–10 months old, were assigned to six groups (n = 10/group): control, caffeine (25 or 60 mg/L), NAC (1 mg/L), and NAC combined with either caffeine concentration. Behavioral effects were assessed using the Social Preference Test, Mirror-Biting Test, and Novel Tank Test. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured as oxidative stress-related markers. Results: Caffeine increased locomotor activity and induced anxiety-like and aggression-like behavioral alterations, including increased bottom-dwelling, thigmotaxis, and mirror-directed behavior, while reducing social preference. Caffeine significantly increased SOD activity at 25 mg/L (p = 0.010) and 60 mg/L (p = 0.008), and GPx activity at 25 mg/L (p = 0.008) and 60 mg/L (p = 0.006), compared with controls. NAC attenuated caffeine-induced hyperlocomotion and several anxiety-like and aggression-like alterations and modulated antioxidant enzyme responses, but did not fully restore social preference. Conclusions: Acute caffeine exposure produces behavioral alterations and changes in antioxidant enzyme activity in adult zebrafish. NAC partially attenuates these effects, particularly hyperlocomotion, anxiety-like behavior, and aggression-like responses, while showing more limited effects on caffeine-induced social alterations.
Full article
(This article belongs to the Special Issue Application of 2D and 3D-QSAR Models in Drug Design: 2nd Edition)
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Open AccessArticle
Biological Activities and In Silico Molecular Docking of an Aqueous Extract of Nigella sativa L. Seeds: A Focus on Antioxidant, Cytotoxic, and Diuretic Effects
by
Otmane Zouirech, Rafik El-Mernissi, Mohamed Amine el Hajjaji, Marouane Takie, Mohammed Bouslamti, Abdelkrim Agour, Jawaher H. Alqahtani, Moneerah J. Alqahtani, Naoufal El Hachlafi, Joe Miantezila Basilua and Elhoussine Derwich
Pharmaceuticals 2026, 19(9), 1418; https://doi.org/10.3390/ph19091418 - 8 Sep 2026
Abstract
Background: Nigella sativa L. is a medicinal plant widely recognized for its diverse pharmacological properties. This study aimed to evaluate the antioxidant, diuretic, and cytotoxic effects of an aqueous seed extract and its effects on selected biochemical parameters in rats. The pharmacokinetic
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Background: Nigella sativa L. is a medicinal plant widely recognized for its diverse pharmacological properties. This study aimed to evaluate the antioxidant, diuretic, and cytotoxic effects of an aqueous seed extract and its effects on selected biochemical parameters in rats. The pharmacokinetic potential of identified bioactive compounds was also investigated in silico. Methods: The aqueous extract was prepared by maceration. Antioxidant activity was assessed using DPPH, reducing power, and total antioxidant capacity (TAC) assays. We evaluated the diuretic effect in vivo in Wistar rats by measuring urinary concentrations of Na+, K+, Cl−, and creatinine, using furosemide as a reference drug. Cytotoxicity was assessed in splenocytes and thymocytes. We analyzed seven identified compounds in silico for physicochemical properties, Lipinski compliance, intestinal absorption, cytochrome P450 inhibition, and blood–brain barrier permeability. Results: The extract showed significant antioxidant activity, with a DPPH IC50 of 0.254 ± 0.002 mg/mL and a TAC of 125.01 ± 4.220 mg AAE/g. It significantly increased urinary electrolyte and urinary concentration, indicating a diuretic effect lower than that of furosemide. Plasma analyses showed decreased electrolyte concentrations and increased creatinine levels. Cell viability exceeded 90%, indicating no significant cytotoxicity. Most compounds complied with Lipinski’s rule of five and showed favorable predicted intestinal absorption, with limited cytochrome P450 inhibition. Several compounds were predicted to cross the blood–brain barrier. Conclusions: The aqueous extract of N. sativa demonstrated antioxidant and diuretic activities without significant cytotoxicity. These findings support its pharmacological potential and warrant further investigation of its mechanisms of action and therapeutic relevance.
Full article
(This article belongs to the Special Issue The Modes of Action of Herbal Medicines and Natural Products, 2nd Edition)
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Open AccessArticle
Protective Effects of Ethyl Pyruvate and Rutin Hydrate Against Colistin-Induced Nephrotoxicity in Rats
by
Mehmet Nuri Gorduk, Ilker Kelle, Meral Erdinc, Meryem Seyda Kaya and Firat Asir
Pharmaceuticals 2026, 19(9), 1417; https://doi.org/10.3390/ph19091417 - 8 Sep 2026
Abstract
Background: Colistin is increasingly being used as a last-line treatment option for multidrug-resistant Gram-negative infections; however, its clinical use remains limited due to its nephrotoxic side effects. This study investigated the potential nephroprotective effects of ethyl pyruvate (EP) and rutin hydrate (RH),
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Background: Colistin is increasingly being used as a last-line treatment option for multidrug-resistant Gram-negative infections; however, its clinical use remains limited due to its nephrotoxic side effects. This study investigated the potential nephroprotective effects of ethyl pyruvate (EP) and rutin hydrate (RH), alone and in combination, against colistin-induced renal damage. Methods: Forty-nine adult male Wistar albino rats were allocated into seven groups, and all agents were administered intraperitoneally once daily for seven days. On the eighth day, one kidney of each animal was perfused using a Langendorff system to measure perfusion pressure, while samples from the contralateral kidney and blood were used for biochemical, molecular, and histopathological analyses. Results: In the colistin group, urea, creatinine, total oxidant status, and perfusion pressure were significantly higher than in the control, EP, and RH groups (p < 0.05). Oxidative stress index, tissue MDA, KIM-1, caspase-3, and PUMA levels were also markedly increased. All of these parameters decreased in the treatment groups, with the lowest values for most parameters in the group receiving both EP and RH, which also showed the best-preserved renal architecture. Conclusions: These findings suggest that EP and RH may be promising adjuvant agents against colistin-induced nephrotoxicity. Combined EP and RH co-treatment showed numerically greater protection across most assessed parameters, although an overall advantage over single-agent co-treatment was not statistically established.
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(This article belongs to the Section Pharmacology)
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Open AccessReview
Cooperation or Conflict? Molecular and Physiological Cross-Talk Between the Aryl Hydrocarbon and Vitamin D Receptors
by
Mohammed A. Alqahtani
Pharmaceuticals 2026, 19(9), 1416; https://doi.org/10.3390/ph19091416 - 8 Sep 2026
Abstract
The aryl hydrocarbon receptor (AHR) and the vitamin D receptor (VDR) were long regarded as independent transcription factors governing distinct physiology—xenobiotic sensing and calcium–vitamin D homeostasis, respectively. AHR, a basic helix–loop–helix/PAS protein, heterodimerizes with ARNT and binds xenobiotic response elements (XREs) to drive
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The aryl hydrocarbon receptor (AHR) and the vitamin D receptor (VDR) were long regarded as independent transcription factors governing distinct physiology—xenobiotic sensing and calcium–vitamin D homeostasis, respectively. AHR, a basic helix–loop–helix/PAS protein, heterodimerizes with ARNT and binds xenobiotic response elements (XREs) to drive cytochrome P450 genes such as CYP1A1; VDR, a nuclear receptor activated by 1,25-dihydroxyvitamin D3, heterodimerizes with RXR and binds vitamin D response elements (VDREs). Although their genes reside on separate chromosomes (AHR, Chr 7; VDR, Chr 12), an integrated view recognizes the two pathways as extensively cross-regulatory. This review synthesizes the molecular, immunological, and tissue-level evidence for VDR–AHR interplay. At the molecular level, the receptors cooperate at composite promoter architectures—most notably an everted-repeat VDRE positioned adjacent to an XRE in the CYP1A1 promoter—while AHR ligands reciprocally enhance CYP24A1-mediated catabolism of active vitamin D. Tryptophan metabolism provides a bidirectional hub: kynurenine and the UVB photoproduct FICZ serve as endogenous AHR ligands whose balance, modulated by VDR, shapes signaling output. The tumor suppressor p53 functions as a shared upstream regulator coupling genotoxic stress to both receptors, with convergence on the CDKN1A (p21) checkpoint. Functionally, AHR and VDR converge on the regulatory T cell (Treg)/Th17 axis to influence immune tolerance: sustained AHR activation by TCDD favors Foxp3+ Treg differentiation, transient FICZ-driven activation promotes Th17 responses, and VDR reinforces the tolerogenic arm while independently repressing IL-17. The receptors further cooperate in maintaining intestinal epithelial barrier integrity and NF-κB restraint, with parallel impairment in inflammatory bowel disease, and are co-activated in skin by solar UVB, which simultaneously generates vitamin D3 and the AHR ligand FICZ within keratinocytes. In cancer, VDR acts as a tumor suppressor, AHR exhibits context-dependent pro- and anti-tumor roles, and a three-way AHR–VDR–p53 interaction—inverted by mutant p53—forms a critical regulatory node. Throughout, the direction and magnitude of cross-talk prove highly dependent on cell type, ligand identity and kinetics, and species—distinctions often underappreciated in the literature. Clarifying these context-specific determinants is essential for translating AHR–VDR cross-regulation into rational therapies in autoimmunity, mucosal inflammation, dermatology, and oncology.
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(This article belongs to the Section Pharmacology)
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Open AccessArticle
Lycopene Attenuates Acute Cyclophosphamide-Induced Renal Injury in Mice: Renal Function, Cytokine Transcription, and Histopathological Evidence
by
Elif Ece Akgun, Esra Bilici and Busra Gulbenli Turkoglu
Pharmaceuticals 2026, 19(9), 1415; https://doi.org/10.3390/ph19091415 - 7 Sep 2026
Abstract
Background/Objectives: Cyclophosphamide (CP) can produce acute renal toxicity through overlapping oxidative, inflammatory, and apoptotic processes. Although lycopene is widely studied for antioxidant and anti-inflammatory activity, its renal effects during acute CP exposure remain incompletely defined. We investigated whether a 10-day course of oral
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Background/Objectives: Cyclophosphamide (CP) can produce acute renal toxicity through overlapping oxidative, inflammatory, and apoptotic processes. Although lycopene is widely studied for antioxidant and anti-inflammatory activity, its renal effects during acute CP exposure remain incompletely defined. We investigated whether a 10-day course of oral lycopene before CP administration altered early biochemical, transcriptional, histological, and apoptosis-related renal responses. Methods: Twenty-eight male CD-1 mice were assigned equally to control, lycopene (20 mg kg−1 day−1), CP (200 mg kg−1 intraperitoneally on day 10), or CP + lycopene groups (n = 7). At 24 h after CP administration, serum BUN and creatinine were measured together with renal TBARS-derived MDA-equivalent values, SOD activity, TNF-α/IL-6/IL-1β mRNA abundance, histopathological injury, and cleaved caspase-3 immunoreactivity. Results: CP increased BUN, creatinine, and renal TBARS-derived MDA-equivalent values; decreased SOD activity; increased all three inflammatory transcripts; worsened tubular and tubulointerstitial injury; and increased cleaved caspase-3 labeling. Compared with CP alone, lycopene pretreatment reduced BUN, renal TNF-α, IL-6, and IL-1β mRNA, tubular and tubulointerstitial damage, and cleaved caspase-3 labeling. Creatinine, renal TBARS-derived MDA-equivalent values, and SOD activity were not significantly different between the CP and CP + lycopene groups. Conclusions: In this prophylactic model (20 mg kg−1 day−1 for 10 days; 24 h assessment), lycopene provided partial early protection against CP-associated renal injury. The response was evident in BUN, inflammatory transcription, tissue injury, and apoptotic labeling, but not in creatinine or the two measured redox indices. The study does not establish pathway causality and does not support extrapolation to post-injury treatment or long-term protection.
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(This article belongs to the Special Issue Organ Protection: Mechanisms and Therapeutic Strategies)
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Open AccessReview
Oxidative Stress as a Pathophysiological Core of Obesity: Preclinical Evidence for Antioxidant-Based Therapy Strategies
by
Mariana Maciel Pereira, Carolinne Souza de Amorim, Aline Cristina Casimiro de Albuquerque Gomes, Helber da Maia Valenca, Mariana Renovato-Martins, Manuella Lanzetti, Samuel Santos Valenca and João Alfredo de Moraes
Pharmaceuticals 2026, 19(9), 1414; https://doi.org/10.3390/ph19091414 - 7 Sep 2026
Abstract
Obesity is increasingly recognized as a complex metabolic disorder characterized by persistent redox imbalance, rather than merely excess body weight. Its pathophysiology extends beyond energy imbalance to encompass chronic redox disruption. Expansion of adipose tissue, particularly in visceral depots, exceeds mitochondrial capacity, impairs
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Obesity is increasingly recognized as a complex metabolic disorder characterized by persistent redox imbalance, rather than merely excess body weight. Its pathophysiology extends beyond energy imbalance to encompass chronic redox disruption. Expansion of adipose tissue, particularly in visceral depots, exceeds mitochondrial capacity, impairs antioxidant defenses such as superoxide dismutase, catalase, and glutathione peroxidase, and perpetuates chronic low-grade inflammation via nuclear factor kappa B (NF-kB) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathways. This review synthesizes preclinical evidence for diverse interventions, including vitamins A, B, C, E, and D; minerals such as zinc and selenium; amino acids such as N-acetylcysteine (NAC), L-carnitine, and taurine; various antioxidant compounds; and approved drugs including metformin, exenatide, fenofibrate, and orlistat. Despite differing structures and mechanisms, these interventions converge on restoring redox balance by activating nuclear factor erythroid 2–related factor 2 (Nrf2)/AMP-activated protein kinase (AMPK), increasing glutathione, and stabilizing mitochondria. However, translation of these preclinical findings into clinical practice requires further clarification of dosing, delivery methods, and long-term safety.
Full article
(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy, 2nd Edition)
Open AccessReview
Phytochemicals Modulating Receptor Tyrosine Kinase Signaling Networks in Endometriosis
by
Che-Fang Hsu and Ching-Feng Weng
Pharmaceuticals 2026, 19(9), 1413; https://doi.org/10.3390/ph19091413 - 7 Sep 2026
Abstract
Endometriosis is a chronic, estrogen-dependent inflammatory condition that is marked by the growth of lesions outside the uterus, along with angiogenesis, fibrosis, immune dysregulation, and pain sensitization. There is now growing evidence that receptor tyrosine kinase (RTK) signaling networks are central to these
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Endometriosis is a chronic, estrogen-dependent inflammatory condition that is marked by the growth of lesions outside the uterus, along with angiogenesis, fibrosis, immune dysregulation, and pain sensitization. There is now growing evidence that receptor tyrosine kinase (RTK) signaling networks are central to these processes, integrating proliferative, angiogenic, inflammatory, endocrine, and microenvironmental signals. This review summarizes the roles of six major RTK axes in endometriosis and evaluates their receptor-specific mechanisms, therapeutic relevance, and modulation by representative phytochemicals. An English-language literature search of PubMed was conducted with no publication date restrictions using combinations and variations of the following keywords: phytochemicals, endometriosis, EGFR, VEGFR, IGF1R, PDGFR, FGFR, MET, curcumin, resveratrol, epigallocatechin gallate (EGCG), quercetin, naringenin, berberine, apigenin, luteolin, genistein, and baicalein. Additional search terms related to receptor signaling mechanisms, downstream pathways, cellular phenotypes, and therapeutic relevance were also incorporated to ensure comprehensive coverage of the literature. The RTK signaling pathways control stromal activation, lesion survival, angiogenic support, extracellular matrix remodeling, neuroimmune sensitization, and malignant progression. Of the six RTK axes examined, EGFR, VEGFR, and IGF1R have the strongest mechanistic and pharmacological support, whereas PDGFR, FGFR, and MET remain biologically plausible targets. Even though phytochemicals do not consistently act as receptor-selective RTK inhibitors, evidence shows they reduce RTK-centred signaling networks by targeting common downstream hubs. As a result of their effects at the network level, the phytochemicals may help to suppress lesion proliferation, angiogenesis, invasion, fibrosis, inflammation, oxidative stress, and pain sensitization. Endometriosis should be viewed as an RTK-centered network disease rather than a single-pathway disorder. In this context, phytochemicals act as modulators that attenuate signaling hubs, offering a mechanistically aligned strategy for a disease driven by redundancy and microenvironmental crosstalk.
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(This article belongs to the Special Issue Pharmacotherapy of Endometriosis)
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Open AccessArticle
Long-Term Monitoring of Everolimus Concentrations in Routine Clinical Practice: Evaluation of Patient Percentiles as Quality Indicator and Impact of Analytical Method Change
by
Anders O. Larsson, Anna-Karin Hamberg and Mats B. Eriksson
Pharmaceuticals 2026, 19(9), 1412; https://doi.org/10.3390/ph19091412 - 7 Sep 2026
Abstract
Background: Everolimus, an mTOR inhibitor used in oncology and organ transplantation, requires therapeutic drug monitoring due to the narrow therapeutic range of everolimus and substantial pharmacokinetic variation. Patient-derived data can function as a supplementary quality indicator for laboratory methods by providing real-world
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Background: Everolimus, an mTOR inhibitor used in oncology and organ transplantation, requires therapeutic drug monitoring due to the narrow therapeutic range of everolimus and substantial pharmacokinetic variation. Patient-derived data can function as a supplementary quality indicator for laboratory methods by providing real-world information on analytical performance. Methods: All routine whole-blood everolimus measurements performed at Akademiska University Hospital, Uppsala, Sweden, 2012 to 2025 were retrospectively evaluated. In total, 9,089 results were included. Annual and monthly concentration distributions were assessed using the 10th, 25th, 50th, 75th, and 90th percentiles. Long-term trends, sex differences, seasonal variation, and the impact of a method change from Architect (Abbott/Microgenics) to Cobas Pro e 801 (Roche) in 2021 were investigated. Results: Of 9089 results, 3335 were from females and 5754 from males. Concentration distributions were similar between sexes, with median concentrations of 4.47 and 4.33 µg/L, respectively; the overall median was 4.37 µg/L. Annual testing volumes remained stable. Median concentrations gradually declined from 5.22 µg/L in 2012 to approximately 4.0 µg/L in 2019–2020. Following introduction of the Cobas assay, patient concentration distributions shifted upward; compared with 2020, the 10th percentile increased by 45%, the median by 21%, and the 90th percentile by 11%. External quality assessment and method-comparison studies supported an analytical explanation. Conclusions: Everolimus concentration distributions were stable over time and showed no meaningful sex-related or seasonal variation. Patient percentile monitoring detected a clear analytical shift after method implementation and may serve as a practical supplementary quality indicator for TDM assays.
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(This article belongs to the Special Issue Innovative Tools for Drug Analysis and Therapeutic Drug Monitoring (TDM): 2nd Edition)
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Open AccessArticle
An Explainable Machine Learning-Based QSAR Framework for Predicting Thrombin Inhibitory Activity
by
Ali Onur Kaya and Mert Can Emre
Pharmaceuticals 2026, 19(9), 1411; https://doi.org/10.3390/ph19091411 - 7 Sep 2026
Abstract
Background/Objectives: Public thrombin bioactivity records contain heterogeneous endpoints, replicate measurements, related chemical series, and potentially reactive compounds that may bias quantitative structure–activity relationship models. In this study, we developed an explainable, assay-aware, and leakage-safe machine learning framework for predicting thrombin-inhibitory activity. Methods: Exact
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Background/Objectives: Public thrombin bioactivity records contain heterogeneous endpoints, replicate measurements, related chemical series, and potentially reactive compounds that may bias quantitative structure–activity relationship models. In this study, we developed an explainable, assay-aware, and leakage-safe machine learning framework for predicting thrombin-inhibitory activity. Methods: Exact Ki and IC50 records for human thrombin (CHEMBL204) were standardized, converted to pActivity, and aggregated using predefined criteria. The final dataset comprised 5189 unique compounds represented by development-filtered Mordred descriptors and Morgan fingerprint. The models were optimized using development-only out-of-fold validation and evaluated using random and scaffold-disjoint held-out tests. Results: In the random-split analysis, ConsensusAll achieved an out-of-fold R2 of 0.7588 and a held-out test R2 of 0.7480, with an RMSE of 0.7360, MAE of 0.5307, and concordance correlation coefficient of 0.8540. In the scaffold-disjoint locked test, ConsensusTop5 achieved R2 = 0.5831, RMSE = 0.9484, and MAE = 0.7290, respectively. The applicability domain covered 92.68% of the locked test compounds and yielded R2 = 0.6041. One hundred Y-randomization runs produced a mean R2 of −0.1233 (empirical p = 0.0099). Conclusions: The framework provides useful predictions within the represented chemical space and measurable generalization for unseen scaffolds. This supports compound prioritization, although prospective biochemical validation remains necessary.
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(This article belongs to the Section AI in Drug Development)
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Open AccessArticle
Effects of Sarpogrelate Hydrochloride in Combination with Aspirin on Blood Viscosity and Hemorheological Parameters in Patients with Peripheral and Coronary Artery Disease: A Randomized Controlled Trial
by
Yuran Ahn, Jaehyuk Jang, Seonghyeon Bu, Nay Aung, Hyo-Suk Ahn and Keun-Sang Yum
Pharmaceuticals 2026, 19(9), 1410; https://doi.org/10.3390/ph19091410 - 7 Sep 2026
Abstract
Background/Objectives: Hemorheological abnormalities, including increased blood viscosity and impaired red blood cell (RBC) deformability, contribute to poor vascular outcomes in patients with atherosclerotic diseases. Although sarpogrelate has shown vascular benefits, its additive effect with aspirin on blood viscosity remains unclear. This study aimed
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Background/Objectives: Hemorheological abnormalities, including increased blood viscosity and impaired red blood cell (RBC) deformability, contribute to poor vascular outcomes in patients with atherosclerotic diseases. Although sarpogrelate has shown vascular benefits, its additive effect with aspirin on blood viscosity remains unclear. This study aimed to evaluate whether adding sarpogrelate hydrochloride to aspirin improves blood viscosity and hemorheological parameters compared with aspirin monotherapy in patients with peripheral arterial disease (PAD) and coronary artery disease (CAD). Methods: This single-center, randomized, open-label trial evaluated sarpogrelate hydrochloride (300 mg/day) plus aspirin (100 mg/day) versus aspirin monotherapy over 12 weeks in patients with PAD and CAD. Patients were assigned using a computer-generated sequence. The primary analysis used the full analysis set. The primary outcome was change in systolic and diastolic blood viscosity. Secondary outcomes included RBC deformability, aggregation index, critical shear stress, flow-mediated dilation (FMD), metabolic parameters, and quality of life. FMD was performed using standardized protocols with blinded assessment. Results: Sixty-eight patients were randomized (34 per group), of whom 61 were included in the full analysis set (experimental group, n = 31; control group, n = 30). At week 12, systolic blood viscosity remained stable in the experimental group (4.51 → 4.49 cP) but increased in the control group (4.67 → 4.87 cP). The unadjusted mean between-group differences in change from baseline (experimental minus control) were −0.23 cP (95% CI, −0.66 to 0.20) for systolic blood viscosity and −0.55 cP (95% CI, −2.03 to 0.93) for diastolic blood viscosity; the corresponding longitudinal between-group p-values from the MMRM analyses were 0.9481 and 0.9630, respectively. FMD showed no significant between-group difference at week 12 (unadjusted mean difference, −0.60%; 95% CI, −2.05 to 0.85; MMRM p = 0.7727). Patient-reported outcomes (SF-36 and visual analog scale scores) did not differ significantly between groups. Conclusions: In patients with PAD and CAD, no statistically significant additional hemorheological benefit of sarpogrelate combined with aspirin was demonstrated compared with aspirin monotherapy.
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(This article belongs to the Section Pharmacology)
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Open AccessSystematic Review
Addictive Potential of Methylphenidate: A Systematic Review of Human and Preclinical Behavioral, Clinical and Neurobiological Evidence
by
Rafał Bieś, Adam Chabrzyk, Katarzyna Zborowska, Krzysztof Krysta and Marek Krzystanek
Pharmaceuticals 2026, 19(9), 1409; https://doi.org/10.3390/ph19091409 - 6 Sep 2026
Abstract
Background/Objectives: Methylphenidate is one of the most widely prescribed psychostimulants for attention-deficit/hyperactivity disorder, with increasing global use. Its pharmacological action on dopaminergic pathways raises concerns regarding its addictive potential. This systematic review aims to synthesize current evidence on the addictive properties of
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Background/Objectives: Methylphenidate is one of the most widely prescribed psychostimulants for attention-deficit/hyperactivity disorder, with increasing global use. Its pharmacological action on dopaminergic pathways raises concerns regarding its addictive potential. This systematic review aims to synthesize current evidence on the addictive properties of methylphenidate, including misuse, abuse, tolerance, craving, and withdrawal symptoms. Methods: This systematic review was conducted in accordance with PRISMA guidelines and registered in the PROSPERO database under registration number CRD420261303803. Literature searches were performed in PubMed, Web of Science, and Google Scholar without time restrictions. Studies assessing behavioral, subjective, or neurobiological indicators of methylphenidate addiction were included. Eligible designs comprised randomized controlled trials, observational studies, neuroimaging studies, case reports, and relevant preclinical models. Study quality was assessed using the EPHPP tool. A total of 35 studies were included in the qualitative synthesis. Results: The evidence demonstrated that methylphenidate produced measurable reinforcing effects and subjective drug liking, which were found to be closely related to craving and to depend on dose, pharmacokinetics, and route of administration. Rapid increases in brain dopamine levels, particularly following non-oral or high-dose administration, were associated with higher abuse potential. Misuse was observed to be more common among individuals without ADHD and was often motivated by cognitive enhancement rather than euphoria. In contrast, appropriately monitored therapeutic use was associated with a low observed risk of substance use disorders. Pharmacodynamic tolerance was identified in a subset of patients, whereas a classical withdrawal syndrome was not consistently observed and was generally limited to symptom recurrence. Conclusions: Methylphenidate exhibits measurable addictive potential. However, its clinical significance is context-dependent. Under therapeutic conditions, the risk of addiction is low, whereas it increases substantially with non-medical use, high doses, and alternative routes of administration. These findings support careful patient selection, preference for extended-release formulations, and monitoring of misuse risk.
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(This article belongs to the Special Issue Effects of Drug Abuse and Its Consequences on Health)
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Open AccessReview
Camelid VHHs as a Versatile Platform for Combating Viral Infections
by
Mohammed Mufrrih and Thamir A. Alandijany
Pharmaceuticals 2026, 19(9), 1408; https://doi.org/10.3390/ph19091408 - 6 Sep 2026
Abstract
Viral infections continue to pose a major global health challenge because of rapid viral evolution, immune escape, and the emergence of novel pathogens. This review examines the biological characteristics, antiviral mechanisms, production strategies, and therapeutic potential of camelid VHH as next-generation antiviral agents.
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Viral infections continue to pose a major global health challenge because of rapid viral evolution, immune escape, and the emergence of novel pathogens. This review examines the biological characteristics, antiviral mechanisms, production strategies, and therapeutic potential of camelid VHH as next-generation antiviral agents. The review synthesizes current evidence on the structural and functional properties of VHH, their methods of generation and engineering, and their applications against a broad range of respiratory and non-respiratory viruses. Camelid VHH nanobodies exhibit high specificity and affinity, exceptional physicochemical stability, efficient tissue penetration, and the unique ability to recognize conserved and cryptic epitopes that are often inaccessible to conventional antibodies. Engineering approaches, including multivalent, bispecific, Fc-fused, and half-life-extended constructs, further enhance their antiviral potency and pharmacokinetic properties. Evidence from preclinical studies demonstrates potent antiviral activity against multiple viral pathogens through mechanisms that include blocking viral attachment and fusion, inhibiting intracellular replication, targeting conserved viral proteins, and reducing the likelihood of viral escape. The review also highlights emerging advances in recombinant production platforms, artificial intelligence-assisted nanobody design, targeted delivery technologies, and One Health applications. Collectively, the available evidence indicates that camelid VHH represent a highly versatile and adaptable platform for antiviral therapeutics and diagnostics, with considerable potential to support pandemic preparedness and the development of broad-spectrum interventions against current and emerging viral diseases.
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(This article belongs to the Special Issue Next-Generation Targeted Therapy: vNARs, VHH, and Peptides as Drug Carriers and Intracellular Neutralizing Agents)
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Open AccessReview
Neuroprotective Effects and Mechanisms of Carvacrol and Thymol in Alzheimer’s Disease: A Scoping Review
by
Shabbir Adnan Shakir, Juen Kiem Tan and Kok-Yong Chin
Pharmaceuticals 2026, 19(9), 1407; https://doi.org/10.3390/ph19091407 - 6 Sep 2026
Abstract
Background/Objectives: Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition characterised by cognitive impairment, cholinergic deficiency and neuroinflammation. Carvacrol and thymol are two related natural monoterpenes with reported antioxidant, anti-inflammatory, anti-apoptotic and cholinesterase-inhibiting properties. This scoping review aims to map the current evidence regarding
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Background/Objectives: Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition characterised by cognitive impairment, cholinergic deficiency and neuroinflammation. Carvacrol and thymol are two related natural monoterpenes with reported antioxidant, anti-inflammatory, anti-apoptotic and cholinesterase-inhibiting properties. This scoping review aims to map the current evidence regarding the effects of carvacrol and thymol on AD-related pathologies and identify their mechanisms of action. Methods: A systematic literature search was conducted in February 2026 across PubMed, Scopus and Web of Science. This review included original, English-language primary research articles investigating the effects of carvacrol and thymol on AD using in vitro, in vivo, or in silico models. Results: From an initial pool of 87 unique records, 30 primary studies met the inclusion criteria, encompassing direct AD pathology models (e.g., amyloid-beta), AD-associated risk models (e.g., metabolic or hypertensive impairment), and general cognitive impairment models. Both carvacrol and thymol reduced escape latency during spatial learning acquisition training and increased time spent in the target quadrant during probe trials, indicating improvements in both learning and memory retention, although several studies reported non-linear relationships. At the cellular level, carvacrol and thymol modulated distinct redox and inflammatory pathways, including nuclear factor erythroid 2-related factor 2 upregulation and tumour necrosis factor-alpha suppression. Synthetic derivatives and nanocarrier formulations (e.g., liposomes, nanoemulsions) demonstrated enhanced acetylcholinesterase inhibition and biological stability relative to parent monoterpenes. No clinical trials were identified, and formal critical appraisal was not performed. Conclusions: Preclinical evidence indicates that carvacrol and thymol show potential multi-targeted neuroprotective activity across diverse models of cognitive dysfunction. However, clinical translation remains unproven due to heterogeneous experimental designs, pharmacokinetic limitations, a lack of human trials, and unassessed study quality.
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(This article belongs to the Special Issue Recent Advances in Medicinal Plants and Plant-Derived Compounds: Neuroprotective, Anti-Inflammatory, Antioxidant, Anticancer, and Antimicrobial Applications)
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Open AccessArticle
CB2 Receptor Activation Attenuates IL-1β-Induced Inflammatory Transcriptomic Networks in Human Gingival Fibroblasts
by
Uswa Arain, Keegan Dedman, Matthew Cooper, Obaed Ashfaq, Karima Ait-Aissa, Undral Munkhsaikhan, Ehsanul Hoque Apu, Amal Majed Sahyoun, Mustafa Dabbous, Modar Kassan and Ammaar H. Abidi
Pharmaceuticals 2026, 19(9), 1406; https://doi.org/10.3390/ph19091406 - 6 Sep 2026
Abstract
Background: Periodontitis is a chronic inflammatory disease characterized by dysregulated host immune responses that drive connective tissue destruction and alveolar bone loss. Human gingival fibroblasts (HGFs) are central regulators of periodontal inflammation through their production of cytokines, chemokines, matrix-remodeling enzymes, and other
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Background: Periodontitis is a chronic inflammatory disease characterized by dysregulated host immune responses that drive connective tissue destruction and alveolar bone loss. Human gingival fibroblasts (HGFs) are central regulators of periodontal inflammation through their production of cytokines, chemokines, matrix-remodeling enzymes, and other inflammatory mediators. Although cannabinoid receptor 2 (CB2) activation has demonstrated anti-inflammatory properties, its coordinated effects on multiple inflammatory pathways in gingival fibroblasts remain poorly understood. This study investigated the transcriptomic effects of the selective CB2 agonist HU-308 on IL-1β-induced inflammatory responses in HGFs. Methods: Primary HGFs were divided into untreated controls, IL-1β-stimulated cells (10 ng/mL), and IL-1β-stimulated cells treated with HU-308 (10 μM). Twenty-four hours after stimulation, transcriptome-wide expression profiling was performed using Affymetrix Human Clariom S microarrays, followed by targeted analysis of selected inflammation-related transcriptional domains. Selected transcripts were evaluated within predefined biological domains including cytokines, chemokines, extracellular matrix-associated genes, NO/cGMP-related genes, transporter-associated genes, and GPCR-related transcripts. Gene expression was analyzed using one-way ANOVA with Tukey’s post hoc test. Results: IL-1β induced a coordinated inflammatory transcriptional program characterized by increased expression of pro-inflammatory cytokines, chemokines, matrix metalloproteinases, glucose transporter genes, and multiple GPCR-related transcripts, while suppressing collagen-associated genes, NOS3, GPR4, and GPR78. HU-308 broadly attenuated these inflammatory responses by reducing the expression of cytokines, chemokines, matrix metalloproteinases, and several GPCR-related genes while restoring collagen-associated transcripts, nitric oxide signaling components, anti-inflammatory mediators, and selected glucose transporters toward basal levels. Schematic multidimensional visualizations were used to illustrate relative expression patterns among selected transcripts within each functional domain; these visualizations do not represent statistically derived gene networks or molecular interactions. Conclusions: Pharmacological modulation of CB2 by HU-308 exerts broad immunomodulatory effects in IL-1β-stimulated human gingival fibroblasts by coordinately regulating multiple transcriptional networks involved in periodontal inflammation. These findings demonstrate that HU-308 treatment is associated with coordinated modulation of inflammatory, extracellular matrix, nitric oxide, metabolic, and GPCR-associated transcriptional pathways in IL-1β-stimulated HGFs. The results support the hypothesis that CB2 signaling may participate in the broader regulation of these interconnected responses; however, receptor-specific studies using CB2 antagonism or CNR2 knockdown are required to establish causality.
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(This article belongs to the Special Issue Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success, 2nd Edition)
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Open AccessReview
Efficacy of Curcumin in Neurodegenerative Diseases: From Pharmacokinetic Barriers to Advanced Delivery Systems
by
Alejandra Castello-Guillen, Marta Garrido-Reig, Jordi Caplliure-Llopis, María Jesús Vega-Bello, Celia Almela and José Enrique de la Rubia Ortí
Pharmaceuticals 2026, 19(9), 1405; https://doi.org/10.3390/ph19091405 - 6 Sep 2026
Abstract
Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing
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Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin’s clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut–brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva®, BCM-95®, Longvida®, and Theracurmin®) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut–brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood–brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations.
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(This article belongs to the Special Issue Curcumin: Current Status and Future Challenges in Drug Delivery and Advanced Formulations)
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Open AccessArticle
Sesquiterpene Lactone Derivatives of Ambrosia artemisiifolia Act as Agonists of the Transient Receptor Potential Ankyrin 1 Ion Channel
by
Balázs Zoltán Zsidó, Csaba Hetényi, Balázs Kovács, Dezső Csupor, Tivadar Kiss, Boglárka Csupor-Löffler, Zsuzsanna Helyes and Éva Szőke
Pharmaceuticals 2026, 19(9), 1404; https://doi.org/10.3390/ph19091404 - 6 Sep 2026
Abstract
Background: Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are key nociceptive ion channels involved in chemosensation, pain signaling, and neurogenic inflammation. Several sesquiterpene lactones target TRPA1, but the activity profile of these secondary metabolites of the common ragweed (Ambrosia
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Background: Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are key nociceptive ion channels involved in chemosensation, pain signaling, and neurogenic inflammation. Several sesquiterpene lactones target TRPA1, but the activity profile of these secondary metabolites of the common ragweed (Ambrosia artemisiifolia) remains uncharacterized. Purpose: The purpose of this study was to explore the activity of five ragweed sesquiterpene lactones on TRPA1 and TRPV1, respectively. Methods: We investigated the effects of five ragweed-derived sesquiterpene lactones—acetoxydihydrodamsin, costunolide, isoalantolactone, peruvin, and psilostachyin—on TRPA1 and TRPV1 using 45Ca2+ uptake in receptor-overexpressing CHO cells and covalent docking to human TRPA1. Results: Costunolide, isoalantolactone and acetoxydihydrodamsin induced TRPA1 activation (counts per minute of 45Ca2+ uptake at 40 µM concentration: 5070 ± 346.5, 10,197 ± 1237, 3704 ± 1634, respectively) but not TRPV1 activation, as demonstrated by Ca2+ influx. Acetoxydihydrodamsin induced concentration-dependent TRPA1 activation that was significantly inhibited by 10 µM of the selective antagonist HC-030031. Docking studies demonstrated covalent interactions of costunolide, isoalantolactone, and acetoxydihydrodamsin (−47.3, −51.5, and −45.0 kcal/mol FITTED score) with the electrophile-sensitive binding region of TRPA1. Conclusions: Ragweed sesquiterpene lactones act as TRPA1 agonists without detectable TRPV1 activation. This study provides the first data identifying acetoxydihydrodamsin as a TRPA1 agonist, expanding the pharmacological map of ragweed sesquiterpene lactones. These results suggest that these metabolites may contribute to both the irritant properties and the pharmacological potentials of A. artemisiifolia.
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(This article belongs to the Section Natural Products)
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Targeted Alpha Therapy as a Multiscale Design Problem: From Radioactive Decay to Therapeutic Outcome
by
Isidora Lazić, Aljoša Stanković, Nemanja Todorović, Sofija Forkapić and Mladena Lalić-Popović
Pharmaceuticals 2026, 19(9), 1403; https://doi.org/10.3390/ph19091403 - 5 Sep 2026
Abstract
Targeted Alpha Therapy (TAT) is often defined by the favorable physical properties of alpha particles, particularly their high linear energy transfer and short tissue range. However, these properties alone do not determine therapeutic success. The clinical behavior of alpha-emitting radiopharmaceuticals depends on whether
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Targeted Alpha Therapy (TAT) is often defined by the favorable physical properties of alpha particles, particularly their high linear energy transfer and short tissue range. However, these properties alone do not determine therapeutic success. The clinical behavior of alpha-emitting radiopharmaceuticals depends on whether radioactive decay can be matched to an appropriate biological scale and maintained within a chemically and pharmacokinetically coherent system. This review presents TAT as a multiscale design problem in which radionuclide production, radioactive decay, recoil, coordination chemistry, vector compatibility, tissue geometry, microdosimetry, biodistribution, and clinical outcome are interdependent rather than separate considerations. Established and emerging alpha emitters, including radium-223, astatine-211, lead-212/bismuth-212, actinium-225/bismuth-213, thorium-227 and terbium-149, are examined as distinct design solutions rather than interchangeable therapeutic options. Their comparison shows that no single radionuclide is universally optimal, as each occupies a distinct position within a landscape defined by physical, chemical and biological constraints. Viewing TAT as a multiscale design problem shifts radionuclide selection from the search for a universally superior emitter toward the rational matching of radionuclide properties to therapeutic context.
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(This article belongs to the Special Issue Advances in Theranostic Radiopharmaceuticals)
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Open AccessReview
Natural Small Molecules Targeting Mitochondrial Quality Control for the Treatment of Metabolic Diseases: Mechanisms, Novel Formulations, and Translational Perspectives
by
Chongyan Zhao, Yuan Gao, Ting Zhou, Lei Sun and Qingsong Qu
Pharmaceuticals 2026, 19(9), 1402; https://doi.org/10.3390/ph19091402 - 5 Sep 2026
Abstract
Metabolic diseases are jointly driven by insulin resistance, chronic inflammation, lipotoxicity, and disrupted organelle homeostasis arising from sustained nutrient overload. These disorders substantially increase the risk of cardiovascular, renal, and other multi-organ complications and have become a major global public health burden. Mitochondria
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Metabolic diseases are jointly driven by insulin resistance, chronic inflammation, lipotoxicity, and disrupted organelle homeostasis arising from sustained nutrient overload. These disorders substantially increase the risk of cardiovascular, renal, and other multi-organ complications and have become a major global public health burden. Mitochondria are central organelles that integrate energy metabolism with stress signaling. They participate in fatty acid β-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, while also regulating reactive oxygen species generation, mitochondrial DNA-related inflammatory signaling, calcium homeostasis, and cell death. Under chronic metabolic stress, the mitochondrial quality control (MQC) system shifts from adaptive repair toward decompensation, characterized by impaired mitochondrial biogenesis, abnormal mitochondrial dynamics, defective mitophagy, disrupted proteostasis and mitochondrial unfolded protein response, increased oxidative stress, and impaired metabolic reprogramming. Natural small molecules possess structural diversity and multi-target, multi-pathway regulatory properties. They can modulate multiple MQC processes and improve mitochondrial function and metabolic phenotypes in preclinical models. Novel formulations, structural optimization, and mitochondria-targeted delivery can further improve their solubility, bioavailability, tissue exposure, and subcellular localization, thereby enhancing therapeutic efficacy and translational potential. This review systematically summarizes the mechanisms of MQC dysregulation in metabolic diseases, the evidence supporting natural small-molecule interventions, and strategies for formulation and delivery optimization. Future studies should strengthen causal validation of MQC, quantify intramitochondrial drug exposure, and incorporate clinically relevant endpoints to facilitate the translation of natural small-molecule MQC modulators.
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(This article belongs to the Special Issue Cell Death, Mitochondrial Metabolism and Cancer Immunotherapy)
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