Pharmaceuticals

19 pages, 4308 KiB

Open AccessArticle

Histology of Pompia Peel and Bioactivity of Its Essential Oil: A New Citrus-Based Approach to Skin Regeneration

by Emma Cocco, Giulia Giorgi, Valeria Marsigliesi, Francesco Mura, Jorge M. Alves-Silva, Mónica Zuzarte, Lígia Salgueiro, Valentina Ghiani, Enrico Sanjust, Danilo Falconieri, Delia Maccioni, Alessio Valletta, Elisa Brasili and Andrea Maxia

Pharmaceuticals 2025, 18(9), 1256; https://doi.org/10.3390/ph18091256 - 24 Aug 2025

Abstract

Background/Objectives: Pompia is an ancient, endemic citrus ecotype native to Sardinia (Italy), characterized by distinctive morphology and high content of bioactive compounds. Despite increasing interest, several aspects of this fruit, including its histological characteristics, remain poorly understood. This study aims to address [...] Read more.

Background/Objectives: Pompia is an ancient, endemic citrus ecotype native to Sardinia (Italy), characterized by distinctive morphology and high content of bioactive compounds. Despite increasing interest, several aspects of this fruit, including its histological characteristics, remain poorly understood. This study aims to address this gap by investigating the anatomical features and spatial distribution of secretory cavities involved in essential oil (EO) production and accumulation, while also evaluating the EO’s chemical profile and associated biological activity. Methods: Pompia peel (flavedo and albedo) was subjected to histological analysis through fixation, dehydration, resin inclusion and sectioning. Sections were stained with 0.05% toluidine blue and observed under a light microscope to measure different parameters of secretory cavities. Essential oil (EO) was obtained from Pompia peel by hydrodistillation and characterized by gas chromatography–mass spectrometry (GC–MS) analysis. The biological activity of Pompia EO was assessed in vitro using NIH/3T3 fibroblasts, where wound-healing was evaluated by scratch assay and anti-senescence effects by β-galactosidase and γH2AX activity. Results: Microscopic analysis of the peel revealed pronounced variability in depth and size of the secretory cavities, along with the presence of lenticel-like structures in the epidermis. GC–MS analysis showed that Pompia EO is dominated by limonene (89%), with minor compounds including myrcene, geranial and neral. In vitro biological assays demonstrated that the EO promotes cell migration in a wound-healing model at concentrations ≥ 12.5 µg/mL and reduces markers of cellular senescence, including β-galactosidase activity and γH2AX foci, in etoposide-induced senescent fibroblasts. Conclusions: Overall, this study provides the first histological characterization of Pompia peel and confirms the bioactive potential of its EO. These findings support future applications in skin regeneration and anti-aging strategies and contribute to the valorization of this underexplored Citrus ecotype. Full article

(This article belongs to the Special Issue Advances in the Chemical-Biological Knowledge of Essential Oils)

► Show Figures

Graphical abstract

18 pages, 997 KiB

Open AccessArticle

Use of TLC and Computational Methods to Determine Lipophilicity Parameters of Selected Neuroleptics: Comparison of Experimental and Theoretical Studies

by Daria Klimoszek, Małgorzata Dołowy, Małgorzata Jeleń and Katarzyna Bober-Majnusz

Pharmaceuticals 2025, 18(9), 1255; https://doi.org/10.3390/ph18091255 - 24 Aug 2025

Abstract

Background: Compound lipophilicity is a fundamental physicochemical property for determining the pharmacokinetic and pharmacodynamic profiles of therapeutic substances. It is successfully used in the early stages of drug candidates’ design and development. Aim: Taking into account the importance of this parameter, we [...] Read more.

Background: Compound lipophilicity is a fundamental physicochemical property for determining the pharmacokinetic and pharmacodynamic profiles of therapeutic substances. It is successfully used in the early stages of drug candidates’ design and development. Aim: Taking into account the importance of this parameter, we aimed to assess and compare the utility of a hybrid procedure based on calculation methods and an experimental one for rapid and simple estimation of the lipophilicity of selected neuroleptics such as fluphenazine, triflupromazine, trifluoperazine, flupentixol and zuclopenthixol and their potential new derivatives. Methods: Log P values of the studied compounds were predicted by means of different platforms and algorithms: AlogPs, ilogP, XlogP3, WlogP, MlogP, milogP, logPsilicos-it, logP_consensus, logP_chemaxon and logP_ACD/Labs. The experimental determination of lipophilicity was carried out by reverse-phase thin-layer chromatography (RP-TLC) using three types of stationary phases—RP-2F₂₅₄, RP-8F₂₅₄ and RP-18F₂₅₄—and mobile phases consisted of acetone, acetonitrile and 1,4-dioxane as organic modifiers. Results: Our results provide a confident proposal of optimal chromatographic conditions to experimentally determine the lipophilicity of neuroleptic drugs, including new derivatives. Conclusions: Additionally, for the first time, the paper shows the application of selected topological indices in determining lipophilicity factors and other ADMET parameters of neuroleptics and, in the future, the newly synthesized quinoline derivatives of the studied compounds. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—New Insights in Medicinal Chemistry of Nitrogen-Containing Compounds)

21 pages, 2872 KiB

Open AccessArticle

ε-Viniferin Rejuvenates Senescence via RGS16 Regulation: In Vitro Evidence

by Ji Ho Park, Yun Haeng Lee, Kyeong Seon Lee, Yoo Jin Lee, Jee Hee Yoon, Byeonghyeon So, Duyeol Kim, Minseon Kim, Hyung Wook Kwon, Youngjoo Byun, Ki Yong Lee and Joon Tae Park

Pharmaceuticals 2025, 18(9), 1254; https://doi.org/10.3390/ph18091254 - 24 Aug 2025

Abstract

Background: Reactive oxygen species (ROS) generated due to mitochondrial dysfunction are one of the primary causes of the initiation and progression of senescence. Although reducing mitochondrial ROS production is known as an effective strategy for the treatment of aging, effective components that [...] Read more.

Background: Reactive oxygen species (ROS) generated due to mitochondrial dysfunction are one of the primary causes of the initiation and progression of senescence. Although reducing mitochondrial ROS production is known as an effective strategy for the treatment of aging, effective components that reduce mitochondrial ROS production or effective treatments that utilize them have not yet been developed. Methods: Screening of plant-generated secondary metabolites to overcome ROS-mediated stress found that ε-viniferin, a dimer of resveratrol, effectively reduces mitochondrial ROS production. Results: ε-viniferin induced efficient electron transport and reduced mitochondrial ROS, a consequence of inefficient electron transport. In addition, ε-viniferin acted as a senolytic that selectively eliminates senescent fibroblasts, thereby restoring mitochondrial function and senescence-associated phenotypes. RNA sequencing analysis revealed that regulator of G protein signaling 16 (RGS16) was an important gene for ε-viniferin-mediated senescence rejuvenation. Upregulation of RGS16 showed similar effects as ε-viniferin in reducing mitochondrial ROS production and restoring mitochondrial function. Conclusions: This study discovered a novel mechanism by which ε-viniferin rejuvenates senescence by lowering ROS production in mitochondria. The novel mechanism will serve as a basis for developing therapeutics that regulate mitochondrial ROS production to treat aging. Full article

(This article belongs to the Special Issue The Role of Phytochemicals in Aging and Aging-Related Diseases)

► Show Figures

Figure 1

16 pages, 1474 KiB

Open AccessArticle

Development, Validation and Application of the Dried Blood Spot Analysis Method for the Determination of Ustekinumab in Patients with Inflammatory Bowel Disease

by Panagiotis-Dimitrios Mingas, Jurij Aguiar Zdovc, Iztok Grabnar, David Drobne and Tomaž Vovk

Pharmaceuticals 2025, 18(9), 1253; https://doi.org/10.3390/ph18091253 - 24 Aug 2025

Abstract

Background: Ustekinumab (UST) is a monoclonal antibody (mAb) used in the treatment of inflammatory bowel disease (IBD). Elevated serum concentrations are typically associated with improved therapeutic outcomes, and therapeutic drug monitoring (TDM) is a useful tool for guiding mAbs treatment. This study [...] Read more.

Background: Ustekinumab (UST) is a monoclonal antibody (mAb) used in the treatment of inflammatory bowel disease (IBD). Elevated serum concentrations are typically associated with improved therapeutic outcomes, and therapeutic drug monitoring (TDM) is a useful tool for guiding mAbs treatment. This study aimed to develop a dried blood spot (DBS) method for TDM of UST in patients with IBD. Methods: The commercial enzyme-linked immunosorbent assay for plasma samples was optimized for DBS samples and subsequently validated according to international guidelines for classical and DBS-specific validation parameters. It was then applied to analyze serum and DBS samples obtained from venous and capillary blood of IBD patients undergoing UST therapy. Results: The method was linear (3–12 mg/L) with acceptable inter-day accuracy (90.1–106%) and precision (<12%). We confirmed that there was no hematocrit effect and that DBS samples were stable for one month under room conditions. A linear model was developed between venous DBS and serum UST concentrations, which showed no systemic bias, and 71% of the samples were within ±20% of the mean. In addition, a linear correlation between venous DBS and capillary DBS samples was established, showing no significant bias, with 84% of samples within ±20% of the mean. Finally, a novel strategy was developed to overcome the limitations of poor-quality samples (irregular shapes) based on area image analysis. Conclusions: The newly developed DBS method is the first to enable reliable measurement of UST in capillary blood, appropriate clinical interpretation of the measured concentrations, and remote monitoring of patients in the early phase of therapy. Full article

(This article belongs to the Special Issue Innovative Tools for Drug Analysis and Therapeutic Drug Monitoring (TDM))

► Show Figures

Graphical abstract

25 pages, 1030 KiB

Open AccessArticle

Real-World Evidence of Neuropsychiatric Adverse Reactions to Isotretinoin: Insights from EudraVigilance (2005–2025)

by Denisa Viola Szilagyi, Delia Mirela Tit, Claudia Teodora Judea-Pusta, Andrei-Flavius Radu, Gabriela S. Bungau, Ada Radu, Laura Maria Endres and Ruxandra-Cristina Marin

Pharmaceuticals 2025, 18(9), 1252; https://doi.org/10.3390/ph18091252 - 24 Aug 2025

Abstract

Background/Objectives: Isotretinoin is a highly effective therapy for severe acne, but its potential neuropsychiatric adverse reactions (NPsRs) have been controversial. This study evaluated EudraVigilance data from 2005 to 2025 to better understand the frequency, typology, and predictors of such events. Methods: We conducted [...] Read more.

Background/Objectives: Isotretinoin is a highly effective therapy for severe acne, but its potential neuropsychiatric adverse reactions (NPsRs) have been controversial. This study evaluated EudraVigilance data from 2005 to 2025 to better understand the frequency, typology, and predictors of such events. Methods: We conducted a retrospective analysis of 33,381 individual case safety reports (ICSRs) related to isotretinoin. Using descriptive statistics, chi-square tests, and logistic regression, we assessed associations between NPsRs and variables such as age, sex, geographic region, and reporter type. Results: A total of 9793 cases (29.3%) involved at least one NPsR. Depression (31%) and suicidal ideation (8.6%) were the most frequently reported symptoms. Adolescents (12–17 years) had the highest proportion of NPsR cases, while male patients and reports submitted by non-healthcare professionals were significantly overrepresented. Reports from non-European Economic Area countries also had slightly increased odds of including NPsRs. All predictors were statistically significant in the logistic regression model, though the explained variance was modest (Nagelkerke R² = 0.065). Conclusions: Neuropsychiatric reactions remain a prominent and persistent signal in isotretinoin pharmacovigilance, particularly among younger patients and non-professional reporters. Although causality cannot be inferred from spontaneous reporting data and confounding factors like acne-related depression cannot be excluded, these findings highlight the clinical value of pre-treatment psychiatric screening, patient-centered education, and proactive mental health monitoring throughout isotretinoin therapy. Full article

(This article belongs to the Special Issue Pharmacovigilance Insights: Addressing Drug Misuse and Enhancing Drug Safety)

► Show Figures

Figure 1

27 pages, 3086 KiB

Open AccessArticle

Trimetazidine–Profen Hybrid Molecules: Synthesis, Chemical Characterization, and Biological Evaluation of Their Racemates

by Diyana Dimitrova, Stanimir Manolov, Iliyan Ivanov, Dimitar Bojilov, Nikol Dimova, Gabriel Marc, Smaranda Oniga and Ovidiu Oniga

Pharmaceuticals 2025, 18(9), 1251; https://doi.org/10.3390/ph18091251 - 23 Aug 2025

Abstract

Background: Trimetazidine is a clinically established cardioprotective agent with anti-ischemic and antioxidant properties, widely used in the management of coronary artery disease. Combining its metabolic and cytoprotective effects with the potent anti-inflammatory activity of profens presents a promising therapeutic strategy. Methods: Five novel [...] Read more.

Background: Trimetazidine is a clinically established cardioprotective agent with anti-ischemic and antioxidant properties, widely used in the management of coronary artery disease. Combining its metabolic and cytoprotective effects with the potent anti-inflammatory activity of profens presents a promising therapeutic strategy. Methods: Five novel trimetazidine–profen hybrid compounds were synthesized using N,N′-dicyclohexylcarbodiimide-mediated coupling and structurally characterized by NMR and high-resolution mass spectrometry. Their antioxidant activity was evaluated by hydroxyl radical scavenging assays (HRSA), and the anti-inflammatory potential was assessed via the inhibition of albumin denaturation (IAD). Lipophilicity was determined chromatographically. Molecular docking and 100 ns molecular dynamics simulations were performed to investigate the binding modes and stability in human serum albumin (HSA) binding sites. The acute toxicity of the hybrid molecules was predicted in silico using GUSAR software. Results: All synthesized hybrids demonstrated varying degrees of biological activity, with compound 3c exhibiting the most potent antioxidant (HRSA IC₅₀ = 71.13 µg/mL) and anti-inflammatory (IAD IC₅₀ = 108.58 µg/mL) effects. Lipophilicity assays indicated moderate membrane permeability, with compounds 3c and 3d showing favorable profiles. Docking studies revealed stronger binding affinities of S-enantiomers, particularly 3c and 3d, to Sudlow sites II and III in HSA. Molecular dynamics simulations confirmed stable ligand–protein complexes, highlighting compound 3c as maintaining consistent and robust interactions. The toxicity results indicate that most hybrids, particularly compounds 3b–3d, exhibit a favorable safety profile compared to the parent trimetazidine. Conclusion: The hybrid trimetazidine–profen compounds synthesized herein, especially compound 3c, demonstrate promising dual antioxidant and anti-inflammatory therapeutic potential. Their stable interaction with serum albumin and balanced physicochemical properties support further development as novel agents for managing ischemic heart disease and associated inflammatory conditions. Full article

(This article belongs to the Special Issue Advances in the Medicinal Synthesis of Bioactive Compounds)

► Show Figures

Figure 1

13 pages, 2086 KiB

Open AccessArticle

Bioactivity-Guided Fractionation and Mechanistic Insights into Aristolochia ringens Root Extract-Induced G₁ Phase Arrest and Mitochondria-Mediated Apoptosis in Human Colon Adenocarcinoma Cells

by Saheed O. Anifowose, Abdalrhaman M. Salih, Musa K. Oladejo, Ahmad Rady, Mobarak S. Al Mosallam, Hasan A. Aljohi, Mansour I. Almansour, Saad Hussin Alkahtani, Ibrahim O. Alanazi and Badr A. Al-Dahmash

Pharmaceuticals 2025, 18(9), 1250; https://doi.org/10.3390/ph18091250 - 23 Aug 2025

Abstract

Background/Objectives: Aristolochia ringens, a medicinal plant widely used in traditional medicine, has shown potential therapeutic applications. This study aimed to investigate the anticancer mechanism of action of its crude extract against human colorectal adenocarcinoma cells (Caco-2 and HT-29). Methods: Cell [...] Read more.

Background/Objectives: Aristolochia ringens, a medicinal plant widely used in traditional medicine, has shown potential therapeutic applications. This study aimed to investigate the anticancer mechanism of action of its crude extract against human colorectal adenocarcinoma cells (Caco-2 and HT-29). Methods: Cell viability was assessed using the MTT assay to determine IC₅₀ values. Immunofluorescence microscopy was used to examine nuclear morphology and microtubule integrity. Flow cytometry with PI staining was used for cell cycle analysis and Annexin V-FITC/PI staining for apoptosis detection. Mitochondrial membrane potential was evaluated using JC-1 dye. Bioactivity-guided fractionation was performed via HPLC, and GC–MS was used to profile active constituents. Results: The extract exhibited dose-dependent cytotoxicity with IC₅₀ values below 30 µg/mL in colon adenocarcinoma cell lines. Treated Caco-2 cells showed nuclear shrinkage and disrupted microtubules. PI-based flow cytometry revealed G₁ phase arrest, and Annexin V-FITC/PI staining indicated enhanced late apoptosis. JC-1 staining demonstrated mitochondrial depolarization. HPLC fractionation identified fractions 2 and 3 as active, and preliminary GC–MS analysis tentatively annotated the presence of alkaloids, sesquiterpenes/diterpenes, and steroidal compounds. Conclusions: A. ringens exerts anticancer effects through a mitochondria-mediated apoptotic pathway, involving G₁ checkpoint arrest and cytoskeletal disruption. These findings provide the first integrated cellular and mechanistic evidence of its anticancer potential in colorectal cancer, supporting its promise as a source of novel therapeutic lead compounds. Full article

(This article belongs to the Special Issue Natural Compounds as Potential Anticancer, Anti-inflammatory and Antioxidant Agents in Medicine)

► Show Figures

Graphical abstract

22 pages, 9849 KiB

Open AccessArticle

Exploring the In Vitro Mechanism of Action of β-Acetoxyisovalerylalkannin on Inflammatory Skin Diseases Using Network-Based Pharmacology and Non-Targeted Metabolomics

by Yinglan Ma, Xuehong Ma, Yue Ma, Liuqian Peng, Zixin Zhang, Jinyan Li, Lu Zhang and Jianguang Li

Pharmaceuticals 2025, 18(9), 1249; https://doi.org/10.3390/ph18091249 - 22 Aug 2025

Abstract

Objective: Lithospermum erythrorhizon has been extensively used for the clinical treatment of skin diseases, but its material basis and mechanism of action remain unclear. This study integrates network pharmacology, untargeted metabolomics, and in vitro experimental validation to elucidate the anti-inflammatory effects and underlying [...] Read more.

Objective: Lithospermum erythrorhizon has been extensively used for the clinical treatment of skin diseases, but its material basis and mechanism of action remain unclear. This study integrates network pharmacology, untargeted metabolomics, and in vitro experimental validation to elucidate the anti-inflammatory effects and underlying mechanisms of β-acetoxyisovalerylalkannin, a bioactive naphthoquinone compound isolated from Arnebiae Radix, using inflammatory skin disease models. Methods: Core targets for β-Acetoxyisovalerylalkannin and skin inflammation were identified via network pharmacology and validated through molecular docking. In vitro assays assessed β-Acetoxyisovalerylalkannin’s impact on keratinocyte proliferation, migration, apoptosis, and inflammatory factors (CXCL1, CXCL2, CXCL8, CCL20, IFN-γ, MCP-1, TNF-α, NF-κB). Non-targeted metabolomics identified differential metabolites and pathways. Results: Network pharmacology revealed 66 common targets significantly enriched in the MAPK/STAT3 signaling pathway. In vitro, β-Acetoxyisovalerylalkannin suppressed proliferative viability and hypermigration and induced apoptosis in HaCaTs. Moreover, it downregulated the mRNA levels of inflammatory markers (CXCL1, CXCL2, CXCL8, CCL20, IFN-γ, MCP-1, TNF-α, and NF-κB) by inhibiting the activation of the MAPK/STAT3 signaling pathway. Metabolomics identified 177 modified metabolites, associating them with the arginine/proline, glycine/serine/threonine, glutathione, and nitrogen metabolic pathways. Conclusions: β-Acetoxyisovalerylalkannin exerts protective effects against skin inflammation by reducing abnormal cell proliferation and inflammatory responses, promoting apoptosis, and effectively improving the metabolic abnormalities of HaCaTs. β-Acetoxyisovalerylalkannin is, therefore, a potential therapeutic option for mitigating skin inflammation-related damage. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Figure 1

23 pages, 2178 KiB

Open AccessReview

Comparison of the Effectiveness Differences Between Western and Chinese Medicinal Ointments Against Eczema

by Siu Kan Law, Yanping Wang and Xiao Xiao Wu

Pharmaceuticals 2025, 18(9), 1248; https://doi.org/10.3390/ph18091248 - 22 Aug 2025

Abstract

Eczema is the most common skin disease among Hong Kong’s adults and children, affecting an estimated 30% of the total population. Western and Chinese medicinal ointments are the usual treatment for eczema. Conventional Western medicinal ointments are topical corticosteroids and non-steroidal agents. Eczema [...] Read more.

Eczema is the most common skin disease among Hong Kong’s adults and children, affecting an estimated 30% of the total population. Western and Chinese medicinal ointments are the usual treatment for eczema. Conventional Western medicinal ointments are topical corticosteroids and non-steroidal agents. Eczema skin products include “Aveeno Parabens Lotion”, “Cerave Moisturizing Cream”, and “Cetaphil Lotion”. However, these are not a long-term solution for managing significant erythema. Chinese medicinal ointments are based on adjusting the formula, including the ingredients and amount, to address an individual’s skin condition and other factors that may be worsening symptoms. This approach aims to regulate the immune system and make it less reactive to environmental and food allergies. This approach is mainly for local topical use. The ingredients of eczema skin products should include Coptis chinensis Franch, Phellodendron chinense Schneid, Angelica sinensis (Oliv.) Diels, Rehmannia glutinosa Libosch, Curcuma longa L., and sesame oil. Chinese medicinal ointments are natural ingredients, personalized formulas, and concerned with holistic healing, while Western medicinal ointments provide fast-acting relief, targeted action, and a standardized dosage. Methods: Nine electronic databases, such as WanFang Data, PubMed, Science Direct, Scopus, Web of Science, Springer Link, SciFinder, and the China National Knowledge Infrastructure (CNKI), were searched mainly within the past twenty years and without any language restrictions. The inclusion criteria were the keywords “Western medicine and ointment”, “Chinese medicine and ointment”, and “Western and Chinese medicines and ointment”. Differences in effectiveness between Western and Chinese ointments were evaluated to determine if they had functions against eczema. This review included an analysis and summary of all relevant papers. Results: Western medicinal ointments are topical corticosteroids, and they exert their pharmacological activities via many mechanisms, including anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects on eczema. Similarly, Chinese medicinal ointments have the same pharmacological functions, but they may focus on the immune system for the treatment of inflammatory and skin conditions, including erythema, edema, dryness, desquamation, and callus exfoliation. Conclusion: Based on the clinical research, the effectiveness rate of integrated Chinese and Western medicines was 88%, which was greater than the 70% rate for using Western medicine alone to treat eczema. Western and Chinese medicinal ointments have different active ingredients with advantages and disadvantages for eczema or when acting as skin care products. The most important thing is knowing “How” to use Western and Chinese medicinal ointments properly, especially for some formulations of Chinese ointments. It may be beneficial to consider the pharmacokinetic studies of herbal ingredients, which offer personalized formulas tailored to individual body constitutions and conditions, as well as to emphasize holistic healing, addressing both symptoms and underlying imbalances in the body. Much more work needs to be carried out, such as safety assessments of these ointments for use as skin care products for eczema. Full article

(This article belongs to the Special Issue Natural Products for Skin Applications)

43 pages, 18411 KiB

Open AccessReview

Physiological Conditions, Bioactive Ingredients, and Drugs Stimulating Non-Shivering Thermogenesis as a Promising Treatment Against Diabesity

by Diego Salagre, Ciskey V. Ayala-Mosqueda, Samira Aouichat and Ahmad Agil

Pharmaceuticals 2025, 18(9), 1247; https://doi.org/10.3390/ph18091247 - 22 Aug 2025

Abstract

Obesity (lipotoxicity) results from a chronic imbalance between energy intake and expenditure. It is strongly associated with type 2 diabetes mellitus (T2DM, glucotoxicity) and considered a major risk factor for the development of metabolic complications. Their convergence constitutes “diabesity”, representing a major challenge [...] Read more.

Obesity (lipotoxicity) results from a chronic imbalance between energy intake and expenditure. It is strongly associated with type 2 diabetes mellitus (T2DM, glucotoxicity) and considered a major risk factor for the development of metabolic complications. Their convergence constitutes “diabesity”, representing a major challenge for public health worldwide. Limited treatment efficacy highlights the need for novel, multi-targeted therapies. Non-shivering thermogenesis (NST), mediated by brown and beige adipose tissue and skeletal muscle, has emerged as a promising therapy due to its capacity to increase energy expenditure and improve metabolic health. Also, skeletal muscle plays a central role in glucose uptake and lipid oxidation, further highlighting its relevance in diabesity. This review explores current and emerging knowledge on physiological stimuli, including cold exposure, physical activity, and fasting, as well as bioactive ingredients and drugs that stimulate NST in thermogenic tissues. Special emphasis is placed on melatonin as a potential regulator of mitochondrial function and energy balance. The literature search was conducted using MEDLINE and Web of Science. Studies were selected based on scientific relevance, novelty, and mechanistic insight; prioritizing human and high-quality rodent research published in peer-reviewed journals. Evidence shows that multiple interventions enhance NST, leading to improved glucose metabolism, reduced fat accumulation, and increased energy expenditure in humans and/or rodents. Melatonin, in particular, shows promise in modulating thermogenesis through organelle-molecular pathways and mitochondrial protective effects. In conclusion, a multi-target approach through the activation of NST by physiological, nutritional, and pharmacological agents offers an effective and safe treatment for diabesity. Further research is needed to confirm these effects in clinical practice and support their use as effective therapeutic strategies. Full article

(This article belongs to the Special Issue Potential Therapeutic Targets for the Management of Diabetes Mellitus, Obesity and Cancer)

► Show Figures

Graphical abstract

16 pages, 1198 KiB

Open AccessArticle

Leveraging Natural Compounds for Pancreatic Lipase Inhibition via Virtual Screening

by Emanuele Liborio Citriniti, Roberta Rocca, Claudia Sciacca, Nunzio Cardullo, Vera Muccilli, Francesco Ortuso and Stefano Alcaro

Pharmaceuticals 2025, 18(9), 1246; https://doi.org/10.3390/ph18091246 - 22 Aug 2025

Abstract

Background: Pancreatic lipase (PL), the principal enzyme catalyzing the hydrolysis of dietary triacylglycerols in the intestinal lumen, is pivotal for efficient lipid absorption and plays a central role in metabolic homeostasis. Enhanced PL activity promotes excessive lipid assimilation and contributes to positive [...] Read more.

Background: Pancreatic lipase (PL), the principal enzyme catalyzing the hydrolysis of dietary triacylglycerols in the intestinal lumen, is pivotal for efficient lipid absorption and plays a central role in metabolic homeostasis. Enhanced PL activity promotes excessive lipid assimilation and contributes to positive energy balance, key pathophysiological mechanisms underlying the escalating global prevalence of obesity—a complex, multifactorial condition strongly associated with metabolic disorders, including type 2 diabetes mellitus and cardiovascular disease. Inhibition of pancreatic lipase (PL) constitutes a well-established therapeutic approach for attenuating dietary lipid absorption and mitigating obesity. Methods: With the aim to identify putative PL inhibitors, a Structure-Based Virtual Screening (SBVS) of PhytoHub database naturally occurring derivatives was performed. A refined library of 10,404 phytochemicals was virtually screened against a crystal structure of pancreatic lipase. Candidates were filtered out based on binding affinity, Lipinski’s Rule of Five, and structural clustering, resulting in six lead compounds. Results: In vitro, enzymatic assays confirmed theoretical suggestions, highlighting Pinoresinol as the best PL inhibitor. Molecular dynamics simulations, performed to investigate the stability of protein–ligand complexes, revealed key interactions, such as persistent hydrogen bonding to catalytic residues. Conclusions: This integrative computational–experimental workflow highlighted new promising natural PL inhibitors, laying the foundation for future development of safe, plant-derived anti-obesity therapeutics. Full article

(This article belongs to the Special Issue Computer-Aided Drug Design and Drug Discovery, 2nd Edition)

► Show Figures

Graphical abstract

46 pages, 2116 KiB

Open AccessReview

Advances in the Application of Graphene and Its Derivatives in Drug Delivery Systems

by Changzhou Jin, Huishan Zheng and Jianmin Chen

Pharmaceuticals 2025, 18(9), 1245; https://doi.org/10.3390/ph18091245 - 22 Aug 2025

Abstract

Graphene, owing to its exceptionally high specific surface area, abundant surface functional groups, and outstanding biocompatibility, exhibits tremendous potential in the development of nanodrug delivery systems. This review systematically outlines the latest research advancements regarding graphene and its derivatives in drug loading, targeted [...] Read more.

Graphene, owing to its exceptionally high specific surface area, abundant surface functional groups, and outstanding biocompatibility, exhibits tremendous potential in the development of nanodrug delivery systems. This review systematically outlines the latest research advancements regarding graphene and its derivatives in drug loading, targeted delivery, and smart release. It covers delivery strategies and mechanisms for various types of drugs, including small molecules and macromolecules, with a particular emphasis on their applications in major diseases such as cancer, neurological disorders, and infection control. The article also discusses stimulus-responsive release mechanisms, such as pH-responsiveness and photothermal responsiveness, and highlights the critical role of surface functionalization of graphene and its derivatives in enhancing therapeutic efficacy while reducing systemic toxicity. Furthermore, the review evaluates key challenges to the clinical translation of graphene-based materials, including safety, toxicity, and metabolic uncertainties. It points out that future research should focus on integrating structural modulation of materials with biological behavior to construct intelligent nanoplatforms featuring biodegradability, low immunogenicity, and precise therapeutic targeting. The aim of this paper is to provide theoretical insights and technical guidance for the customized design and precision medicine applications of graphene and its derivative-based drug delivery systems. Full article

(This article belongs to the Section Pharmaceutical Technology)

20 pages, 891 KiB

Open AccessReview

Phytocannabinoids and Nanotechnology in Lung Cancer: A Review of Therapeutic Strategies with a Focus on Halloysite Nanotubes

by Dorota Bęben, Helena Moreira and Ewa Barg

Pharmaceuticals 2025, 18(9), 1244; https://doi.org/10.3390/ph18091244 - 22 Aug 2025

Abstract

Lung cancer is the leading cause of cancer mortality worldwide, with a poor prognosis driven by late diagnosis, systemic toxicity of existing therapies, and rapid development of multidrug resistance (MDR) to agents such as paclitaxel and cisplatin. MDR arises through multiple mechanisms, including [...] Read more.

Lung cancer is the leading cause of cancer mortality worldwide, with a poor prognosis driven by late diagnosis, systemic toxicity of existing therapies, and rapid development of multidrug resistance (MDR) to agents such as paclitaxel and cisplatin. MDR arises through multiple mechanisms, including overexpression of efflux transporters, alterations in apoptotic pathways, and tumour microenvironment-mediated resistance. The application of nanotechnology offers a potential solution to the aforementioned challenges by facilitating the enhancement of drug solubility, stability, bioavailability, and tumour-specific delivery. Additionally, it facilitates the co-loading of agents, thereby enabling the attainment of synergistic effects. Halloysite nanotubes (HNTs) are naturally occurring aluminosilicate nanocarriers with unique dual-surface chemistry, allowing hydrophobic drug encapsulation in the positively charged lumen and functionalisation of the negatively charged outer surface with targeting ligands or MDR modulators. This architecture supports dual-delivery strategies, enabling simultaneous administration of phytocannabinoids and chemotherapeutics or efflux pump inhibitors to enhance intracellular retention and cytotoxicity in resistant tumour cells. HNTs offer additional advantages over conventional nanocarriers, including mechanical and chemical stability and low production cost. Phytocannabinoids such as cannabidiol (CBD) and cannabigerol (CBG) show multitarget anticancer activity in lung cancer models, including apoptosis induction, proliferation inhibition, and oxidative stress modulation. However, poor solubility, instability, and extensive first-pass metabolism have limited their clinical use. Encapsulation in HNTs can overcome these barriers, protect against degradation, and enable controlled, tumour-targeted release. This review examined the therapeutic potential of HNT-based phytocannabinoid delivery systems in the treatment of lung cancer, with an emphasis on improving therapeutic selectivity, which represents a promising direction for more effective and patient-friendly treatments for lung cancer. Full article

(This article belongs to the Special Issue Combating Drug Resistance in Cancer)

► Show Figures

Graphical abstract

16 pages, 2209 KiB

Open AccessArticle

ETAS^®, a Standardized Extract of Asparagus officinalis Stem, Alleviates Sarcopenia via Regulating Protein Turnover and Mitochondrial Quality

by Sue-Joan Chang, Yung-Chia Chen, Yun-Ching Chang, Chung-Che Cheng and Yin-Ching Chan

Pharmaceuticals 2025, 18(9), 1243; https://doi.org/10.3390/ph18091243 - 22 Aug 2025

Abstract

Background: ETAS^®, a standardized extract of Asparagus officinalis stem, has been found to alleviate cognitive impairment in senescence-accelerated mice prone 8 (SAMP8) and is now considered a functional food in aging. The present study aimed to investigate the impacts of [...] Read more.

Background: ETAS^®, a standardized extract of Asparagus officinalis stem, has been found to alleviate cognitive impairment in senescence-accelerated mice prone 8 (SAMP8) and is now considered a functional food in aging. The present study aimed to investigate the impacts of ETAS^® on relieving aging-related muscle atrophy in SAMP8 mice. Methods: The SAMP8 mice were fed a regular diet supplemented with 200 or 1000 mg/kg BW ETAS^®50 for 12 weeks. Grip strength, muscle mass, and molecular markers of protein synthesis, degradation, and mitochondrial quality were assessed. Results: We found that ETAS^® significantly increased grip strength and muscle mass in SAMP8 mice. At the molecular level, ETAS^® significantly upregulated protein synthesis via PI3K/Akt/mTOR/p70S6K and downregulated protein degradation via FoxO1a/atrogin-1 and MuRF-1 and myostatin via NFκB expression. In addition, ETAS^® improved mitochondrial quality via promoting mitochondrial biogenesis genes, oxidative respiration genes, fusion/fission genes, PGC1α, and PINK1 proteins and maintained the autophagic flux via reducing ATG13, LC3-II/LC3-I, and p62. Conclusions: ETAS^® exerts beneficial effects on sarcopenia by modulating the positive protein turnover and improving mitochondrial quality in aging. Full article

(This article belongs to the Special Issue Discovering Novel Drugs from Plants)

► Show Figures

Graphical abstract

20 pages, 2004 KiB

Open AccessReview

Chaya Leaf: A Promising Approach for Diabetes Management

by Fabiola Curiel Ayala, Francisco Ignacio García Rodríguez, Sandra N. Jimenez-Garcia and Lina Garcia-Mier

Pharmaceuticals 2025, 18(9), 1242; https://doi.org/10.3390/ph18091242 - 22 Aug 2025

Abstract

Chaya leaf has long been used in folk medicine and is gaining scientific interest for its potential role in diabetes management. Recent research indicates that chaya leaf may help to regulate glucose, enhance insulin secretion, and reduce related complications, primarily due to the [...] Read more.

Chaya leaf has long been used in folk medicine and is gaining scientific interest for its potential role in diabetes management. Recent research indicates that chaya leaf may help to regulate glucose, enhance insulin secretion, and reduce related complications, primarily due to the presence of bioactive compounds such as polyphenols and flavonoids. These compounds are believed to enhance insulin sensitivity and offer protection against oxidative stress, a key contributor to diabetes-related complications. Chaya extracts, particularly methanolic and aqueous forms, have shown anti-diabetic effects in animal models, lowering blood glucose, cholesterol, and triglycerides and reducing inflammation; their bioactive compounds, like quercetin, rutin, and ferulic acid, may enhance the insulin response, reduce inflammation, and improve antioxidant activity. Some studies warn of potential interactions with metformin. This review compiles findings from the past five years, drawing from databases such as PubMed, SciELO, ScienceDirect, Dialnet, Web of Science, and Google Scholar. It highlights chaya’s phytochemical profile, explores proposed anti-diabetic mechanisms, and summarizes evidence from in vivo, in vitro, and clinical studies. The results indicate that adding chaya leaf to the diet may help people with diabetes as a complementary therapy to conventional treatment; nonetheless, further clinical studies are required to comprehend the exact mechanisms and define specific usage instructions. Further investigation into the specific types of compounds present in chaya, their effective dosages, and their safety in human populations is essential to support its integration into medical practice. Full article

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

► Show Figures

Graphical abstract

21 pages, 5953 KiB

Open AccessArticle

Network Pharmacology and Experimental Validation Identify Paeoniflorin as a Novel SRC-Targeted Therapy for Castration-Resistant Prostate Cancer

by Meng-Yao Xu, Jun-Biao Zhang, Yu-Zheng Peng, Mei-Cheng Liu, Si-Yang Ma, Ye Zhou, Zhi-Hua Wang and Sheng Ma

Pharmaceuticals 2025, 18(8), 1241; https://doi.org/10.3390/ph18081241 - 21 Aug 2025

Abstract

Background: Despite advances in prostate cancer treatment, castration-resistant prostate cancer (CRPC) remains clinically challenging due to inherent therapy resistance and a lack of durable alternatives. Although traditional Chinese medicine offers untapped potential, the therapeutic role of paeoniflorin (Pae), a bioactive compound derived from [...] Read more.

Background: Despite advances in prostate cancer treatment, castration-resistant prostate cancer (CRPC) remains clinically challenging due to inherent therapy resistance and a lack of durable alternatives. Although traditional Chinese medicine offers untapped potential, the therapeutic role of paeoniflorin (Pae), a bioactive compound derived from Paeonia lactiflora, in prostate cancer has yet to be investigated. Methods: Using an integrative approach (network pharmacology, molecular docking, and experimental validation), we identified Pae key targets, constructed protein–protein interaction networks, and performed GO/KEGG pathway analyses. A Pae-target-based prognostic model was developed and validated. In vitro and in vivo assays assessed Pae effects on proliferation, migration, invasion, apoptosis, and tumor growth. Results: Pae exhibited potent anti-CRPC activity, inhibiting cell proliferation by 60% and impairing cell migration by 65% compared to controls. Mechanistically, Pae downregulated SRC proto-oncogene, non-receptor tyrosine kinase (SRC) mRNA expression by 68%. The Pae-target-based prognostic model stratified patients into high- and low-risk groups with distinct survival outcomes. Organoid and xenograft studies confirmed Pae-mediated tumor growth inhibition and SRC downregulation. Conclusions: Pae overcomes CRPC resistance by targeting SRC-mediated pathways, presenting a promising therapeutic strategy. Our findings underscore the utility of network pharmacology-guided drug discovery and advocate for further clinical exploration of Pae in precision oncology. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

30 pages, 3451 KiB

Open AccessArticle

Smart Formulation: AI-Driven Web Platform for Optimization and Stability Prediction of Compounded Pharmaceuticals Using KNIME

by Artur Grigoryan, Stefan Helfrich, Valentin Lequeux, Benjamine Lapras, Chloé Marchand, Camille Merienne, Fabien Bruno, Roseline Mazet and Fabrice Pirot

Pharmaceuticals 2025, 18(8), 1240; https://doi.org/10.3390/ph18081240 - 21 Aug 2025

Abstract

Background/Objectives: Smart Formulation is an artificial intelligence-based platform designed to predict the Beyond Use Dates (BUDs) of compounded oral solid dosage forms. The study aims to develop a decision-support tool for pharmacists by integrating molecular, formulation, and environmental parameters to assist in [...] Read more.

Background/Objectives: Smart Formulation is an artificial intelligence-based platform designed to predict the Beyond Use Dates (BUDs) of compounded oral solid dosage forms. The study aims to develop a decision-support tool for pharmacists by integrating molecular, formulation, and environmental parameters to assist in optimizing the stability of extemporaneous preparations. Methods: A tree ensemble regression model was trained using a curated dataset of 55 experimental BUD values collected from the Stabilis database. Each formulation was encoded with molecular descriptors, excipient composition, packaging type, and storage conditions. The model was implemented using the KNIME platform, allowing the integration of cheminformatics and machine learning workflows. After training, the model was used to predict BUDs for 3166 APIs under various formulation and storage scenarios. Results: The analysis revealed a significant impact of excipient type, number, and environmental conditions on API stability. APIs with lower LogP values generally exhibited greater stability, particularly when formulated with a single excipient. Excipients such as cellulose, silica, sucrose, and mannitol were associated with improved stability, whereas HPMC and lactose contributed to faster degradation. The use of two excipients instead of one frequently resulted in reduced BUDs, possibly due to moisture redistribution or phase separation effects. Conclusions: Smart Formulation represents a valuable contribution to computational pharmaceutics, bridging theoretical formulation design with practical compounding needs. The platform offers a scalable, cost-effective alternative to traditional stability testing and is already available for use by healthcare professionals. Its implementation in hospital and community pharmacies may help mitigate drug shortages, support formulation standardization, and improve patient care. Future developments will focus on real-time stability monitoring and adaptive learning for enhanced precision. Full article

(This article belongs to the Section Pharmaceutical Technology)

► Show Figures

Graphical abstract

28 pages, 31113 KiB

Open AccessArticle

Multi-Omics and Molecular Docking Studies on Caffeine for Its Skin Rejuvenating Potentials

by Peng Shu, Nan Zhao, Qi Zhou, Yuan Wang and Lanyue Zhang

Pharmaceuticals 2025, 18(8), 1239; https://doi.org/10.3390/ph18081239 - 21 Aug 2025

Abstract

Background: Caffeine (CA) exhibits promising reparative effects against UV-induced skin aging, but the specific mechanisms, including differences in gene and metabolite regulation and the involvement of signaling pathways, are still insufficiently elucidated. Methods: This study is on the repairing capability of [...] Read more.

Background: Caffeine (CA) exhibits promising reparative effects against UV-induced skin aging, but the specific mechanisms, including differences in gene and metabolite regulation and the involvement of signaling pathways, are still insufficiently elucidated. Methods: This study is on the repairing capability of CA to ultraviolet (UV)-induced skin aging and explores the ferroptosis pathway through in vitro cell experiments, a UV-aged mouse skin model, and molecular docking. Results: CA enhanced the vitality and proliferation of HaCaT cells, delayed cell aging, reduced reactive oxygen species levels, increased mitochondrial membrane potential, and activated the peroxisome proliferator-activated receptor pathway, as well as repaired UVB-induced cytoskeletal disorders. Simultaneously, CA reduced other related but undesirable biological mechanisms. Moreover, multi-omics and network pharmacology studies suggested that CA mitigated aging by modulating related metabolic and ferroptosis pathways. Additionally, CA effectively reduced lipid peroxidation and intracellular ferrous ion levels and regulated the expression of key ferroptosis proteins, and its potential anti-aging effects were also confirmed through the modulation of ferroptosis pathways. In addition, molecular docking revealed strong interactions between CA and related key proteins, further supporting the potentiality of CA. Conclusions: This study elucidates the effectiveness and potential mechanism of CA to reduce the UV-induced skin aging. Full article

(This article belongs to the Section Pharmacology)

► Show Figures

Graphical abstract

18 pages, 3771 KiB

Open AccessArticle

VDR Decrease Enhances the Efficacy of 1,25-Dihydroxyvitamin D3 Inhibiting Gefitinib Resistance by Regulating EGFR/FASN Loop in NSCLC Cells

by Junqing Yang, Mingyu Fang, Mengjun Hou, Yalei Duan, Jiali Wang, Kaiyong Hu, Shuo Liu, Xiaoying Liu, Xiaohan Peng, Xuansheng Ding and Zhirong Jia

Pharmaceuticals 2025, 18(8), 1238; https://doi.org/10.3390/ph18081238 - 21 Aug 2025

Abstract

Background: Gefitinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeting EGFR-mutated non-small cell lung cancer (NSCLC) and is a current first-line treatment for NSCLC. However, acquired resistance leads to the failure of treatment and remains a challenge. Therefore, [...] Read more.

Background: Gefitinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeting EGFR-mutated non-small cell lung cancer (NSCLC) and is a current first-line treatment for NSCLC. However, acquired resistance leads to the failure of treatment and remains a challenge. Therefore, identifying novel therapeutic approaches to combat EGFR-TKI resistance is crucial. Methods: The Cancer Genome Atlas (TCGA) database analysis and gefitinib-resistant cell lines were used to analyze VDR expression in NSCLC. Cell proliferation and apoptosis were assessed via MTT assay, colony formation assay, and flow cytometry. Immunofluorescence, qPCR, and Western blotting were used to measure mRNA and protein expression levels of VDR and other related molecules. Xenograft tumors in BALB/c nude mice were employed to investigate the effects of VDR and 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) on gefitinib-resistant tumors in vivo. Results: We found that VDR was significantly upregulated in EGFR-TKI-resistant NSCLC cells. Patients with high VDR expression exhibited poor prognosis. VDR knockdown significantly inhibited cell proliferation, tumor growth, and reduced gefitinib resistance, whereas VDR overexpression enhanced resistance. VDR knockdown downregulated EGFR and FASN expression. Silencing either EGFR or FASN confirmed the existence of a positive feedback regulatory loop involving VDR, EGFR, and FASN. Treatment with 1,25(OH)₂D₃ increased VDR levels but decreased EGFR and FASN expression. VDR knockdown significantly enhanced the inhibitory effect of 1,25(OH)₂D₃ on gefitinib resistance. The combination of VDR knockdown and 1,25(OH)₂D₃ treatment was more effective than either treatment alone in suppressing EGFR and FASN expression. Conclusions: VDR promotes NSCLC resistance to EGFR-TKIs by regulating EGFR and FASN expression through a positive feedback loop. Knocking down VDR effectively enhances the ability of 1,25(OH)₂D₃ to overcome gefitinib resistance, mediated by the synergistic downregulation of EGFR and FASN expression. Targeting VDR represents a potential strategy to enhance the efficacy of 1,25(OH)₂D₃ in overcoming EGFR-TKI resistance. Full article

(This article belongs to the Special Issue Epithelial Plasticity and Therapy Resistance in Cancer)

► Show Figures

Figure 1

Journal Description

Pharmaceuticals

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Conference Reports

Further Information

Guidelines

MDPI Initiatives

Follow MDPI