Molecules

46 pages, 1615 KB

Open AccessReview

Experimental Models and Translational Strategies in Neuroprotective Drug Development with Emphasis on Alzheimer’s Disease

by Przemysław Niziński, Karolina Szalast, Anna Makuch-Kocka, Kinga Paruch-Nosek, Magdalena Ciechanowska and Tomasz Plech

Molecules 2026, 31(2), 320; https://doi.org/10.3390/molecules31020320 (registering DOI) - 16 Jan 2026

Abstract

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs [...] Read more.

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. Full article

(This article belongs to the Special Issue Small Molecule Drug Discovery and Development to Face Neurodegenerative Threads)

21 pages, 4972 KB

Open AccessArticle

Trichostatin A Influences Dendritic Cells’ Functions by Regulating Glucose and Lipid Metabolism via PKM2

by Xiaoyu Yang, Lihui Men, Yan Guo, Linnan Duan, Meiyi Yu, Leyi Zhang, Tongtong Song, Xiang Li and Xia Chen

Molecules 2026, 31(2), 319; https://doi.org/10.3390/molecules31020319 - 16 Jan 2026

Abstract

Dendritic cells (DCs) play a crucial role in immune protection against myocardial infarction (MI). Through multiple experimental methods including bioinformatics, qPCR, Western blotting, immunofluorescence, MTT assays, echocardiography, TTC staining, and flow cytometry, this study found that metabolism was demonstrated to be markedly altered [...] Read more.

Dendritic cells (DCs) play a crucial role in immune protection against myocardial infarction (MI). Through multiple experimental methods including bioinformatics, qPCR, Western blotting, immunofluorescence, MTT assays, echocardiography, TTC staining, and flow cytometry, this study found that metabolism was demonstrated to be markedly altered under oxygen–glucose deprivation (OGD) conditions in DCs. Pyruvate kinase M2 (PKM2) is a key protein in metabolism, and PKM2 was upregulated under OGD conditions in DCs. Trichostatin A (TSA) alleviated the OGD-induced cellular damage in DCs. Furthermore, TSA was shown to modulate DCs’ function by enhancing glycolysis while suppressing fatty acid synthesis and oxidation pathways. The metabolic changes caused by TSA and OGD were mechanistically mediated by PKM2. Mechanistically, PKM2 modulates glucose and lipid metabolism via its dimer formation. These results deepen our understanding of the interplay among TSA, glucose and lipid metabolism and DC functions in MI. Full article

(This article belongs to the Special Issue Nutritional Components of Non-Animal Origin Foods: Structure, Synthesis, Functions and Mechanisms)

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11 pages, 1734 KB

Open AccessArticle

Click Chemistry-Enabled Parallel Synthesis of N-Acyl Sulfonamides and Their Evaluation as Carbonic Anhydrase Inhibitors

by Oleksii V. Gavrylenko, Bohdan V. Vashchenko, Vasyl Naumchyk, Bohdan S. Sosunovych, Oleksii Chuk, Oleksii Hrabovskyi, Olga Kuchuk, Alla Pogribna, Sergiy O. Nikitin, Anzhelika I. Konovets, Volodymyr S. Brovarets, Sergey A. Zozulya, Dmytro S. Radchenko, Oleksandr O. Grygorenko and Yurii S. Moroz

Molecules 2026, 31(2), 318; https://doi.org/10.3390/molecules31020318 - 16 Jan 2026

Abstract

A synthetically accessible library of N-acyl sulfonamides was constructed using a combination of copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and N-acylation of primary sulfonamides. The proposed two-step reaction sequence had a high experimentally confirmed synthetic success rate (up to 85%) and gave reasonable [...] Read more.

A synthetically accessible library of N-acyl sulfonamides was constructed using a combination of copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and N-acylation of primary sulfonamides. The proposed two-step reaction sequence had a high experimentally confirmed synthetic success rate (up to 85%) and gave reasonable product yields (up to 61%). As a result of the validation process, a 262-member compound library (out of >70K accessible combinations) was prepared. Biological profiling of the synthesized library by differential scanning fluorimetry and enzymatic assays identified several low micromolar inhibitors of human carbonic anhydrase. The interaction of the discovered hits with the biological target was studied by docking and molecular dynamics. Full article

(This article belongs to the Special Issue Heterocyclic Molecules in Drug Discovery)

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30 pages, 7513 KB

Open AccessArticle

Characterization and Identification of the Ent-Kaurane Diterpenoids in Isodonis Excisoidis Herba Using UHPLC-LTQ-Orbitrap-MS

by Xiaoya Sun, Lingxia Zhang, Conglong Lian, Suiqing Chen, Liping Dai and Yaozu Han

Molecules 2026, 31(2), 317; https://doi.org/10.3390/molecules31020317 - 16 Jan 2026

Abstract

Isodonis Excisoidis Herba (IEH) is a newly discovered herbal medicine used to treat esophageal cancer, chronic pharyngitis, and hepatitis, and ent-kaurane diterpenoids are its main active components. However, systematic studies on the chemical profile of ent-kaurane diterpenoids are lacking. In this study, UHPLC-LTQ-Orbitrap-MS [...] Read more.

Isodonis Excisoidis Herba (IEH) is a newly discovered herbal medicine used to treat esophageal cancer, chronic pharyngitis, and hepatitis, and ent-kaurane diterpenoids are its main active components. However, systematic studies on the chemical profile of ent-kaurane diterpenoids are lacking. In this study, UHPLC-LTQ-Orbitrap-MS was performed to investigate the fragmentation behaviors of three different types of ent-kaurane diterpenoids from IEH. Bridgehead-unsubstituted 7,20-epoxy-ent-kaurane diterpenoids yielded ions with typical losses of R₇H, R₁H, R₁₄H, CH₂O, CO, and R₆H. The [M + NH₄ − NH₃ − R₂₀]⁺ precursor ions at 331.1895 and the characteristic ions at m/z 313.1792, 295.1686, 285.1842, 277.1581, 267.1737, and 249.1632 were the most possible fragmentation pathways for bridgehead-substituted 7,20-epoxy-ent-kaurane diterpenoids. Fragmentation with the successive loss of multiple 18, 42, or 60 Da occurring in the OH groups and OAc groups is characteristic of 7,20-non-epoxy-kaurane diterpenoids. Using accurate mass measurements for each precursor ion and the subsequent fragmented ions, a total of 94 ent-kaurane diterpenoids were identified or tentatively characterized in IEH, including 48 potentially new ent-kaurane diterpenoids. Full article

(This article belongs to the Special Issue The Application of LC-MS in Pharmaceutical Analysis—2nd Edition)

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19 pages, 4459 KB

Open AccessArticle

Rubia cordifolia L. Dichloromethane Extract Ameliorates Contrast-Induced Acute Kidney Injury by Activating Autophagy via the LC3B/p62 Axis

by Xiaoying Sun, Kangxu He, Guanzhong Chen, Xiaoda Yang, Xinhui Pan and Kai Liao

Molecules 2026, 31(2), 316; https://doi.org/10.3390/molecules31020316 - 16 Jan 2026

Abstract

Contrast-induced acute kidney injury (CIAKI) has emerged as the third most prevalent etiology of clinically acquired acute kidney injury, with a lack of specific preventive and therapeutic strategies. Rubia Cordifolia L. (madder root), a medicinal herb with a long-standing history and extensive clinical [...] Read more.

Contrast-induced acute kidney injury (CIAKI) has emerged as the third most prevalent etiology of clinically acquired acute kidney injury, with a lack of specific preventive and therapeutic strategies. Rubia Cordifolia L. (madder root), a medicinal herb with a long-standing history and extensive clinical application, exhibits multiple pharmacological activities. This study aimed to clarify the renal protective effect of Rubia cordifolia L. dichloromethane extract (RCDE) on CIAKI modeling rats and investigate potential anti-apoptotic and autophagy-inducing effects molecular mechanisms. In this study, RCDE constituents were identified by UPLC-Q-TOF-MS. A CIAKI rat model was established to evaluate the nephroprotective effect of RCDE. The results showed that RCDE high-dose group significantly decreased serum SCr and BUN levels, attenuated renal histopathological damage, and modulated oxidative stress markers by decreasing MDA and CAT while increasing SOD, compared with the model group. It downregulated the expressions of Bcl-2, caspase-3 and p62, upregulated the expressions of Bax, Beclin1 and reduced the LC3B-II/LC3B-I ratio in renal tissues. Molecular docking indicates that anthraquinone compounds are probably the principal active constituents of RCDE. This study provides experimental evidence for the intervention efficacy of RCDE against CIAKI. Full article

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18 pages, 1396 KB

Open AccessArticle

Cycloruthenated Imines: A Step into the Nanomolar Region

by Arsenii A. Vasil’ev, Ivan I. Troshin, Pavel G. Shangin, Ksenia M. Voroshilkina, Ilya A. Shutkov, Alexey A. Nazarov and Aleksei V. Medved’ko

Molecules 2026, 31(2), 315; https://doi.org/10.3390/molecules31020315 - 16 Jan 2026

Abstract

A new series of promising and easily accessible antiproliferative agents based on cycloruthenated imines of benzene and thiophene carbaldehydes has been developed and fully characterized using UV-Vis spectroscopy, X-ray diffraction, NMR, HRMS, and cyclic voltammetry. The biological activity of these compounds was tested [...] Read more.

A new series of promising and easily accessible antiproliferative agents based on cycloruthenated imines of benzene and thiophene carbaldehydes has been developed and fully characterized using UV-Vis spectroscopy, X-ray diffraction, NMR, HRMS, and cyclic voltammetry. The biological activity of these compounds was tested against A2780, cisplatin-resistant A2780, and HEK293 cell lines, and they exhibited nanomolar IC₅₀ values. They also showed a selectivity index of up to 2.5, indicating their potential as promising antiproliferative compounds. Full article

(This article belongs to the Section Organometallic Chemistry)

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13 pages, 1254 KB

Open AccessArticle

Synthesis of N-Difluoromethyl Benzothiazole (or Benzoxazole) Selenones as Novel Inhibitors Against Phytopathogenic Fungi

by Zihao Huang, Zhen Liu, Baixin Zhang, Jing Jiao and Ri-Yuan Tang

Molecules 2026, 31(2), 314; https://doi.org/10.3390/molecules31020314 - 16 Jan 2026

Abstract

Azole selenoureas exhibit diverse biological functions. However, the synthesis and biological activity of benzothiazole and benzoxazole selenones remained unexplored. Herein, we report the base-catalyzed synthesis of N-difluoromethyl benzothiazole (or benzoxazole) selenone derivatives, which demonstrated significant antifungal efficacy against Rhizoctonia solani, Phytophthora [...] Read more.

Azole selenoureas exhibit diverse biological functions. However, the synthesis and biological activity of benzothiazole and benzoxazole selenones remained unexplored. Herein, we report the base-catalyzed synthesis of N-difluoromethyl benzothiazole (or benzoxazole) selenone derivatives, which demonstrated significant antifungal efficacy against Rhizoctonia solani, Phytophthora infestans, Botrytis cinerea, and Fusarium oxysporum. Compound 3b exhibited exceptional antifungal activity against R. solani, with an EC₅₀ of 2.10 mg/L. Moreover, it substantially inhibited sclerotia germination (81.5% at 9 mg/L) and formation (79.3% at 9 mg/L), surpassing octhilinone. The protective effect on detached rice leaves and rice seedlings was found to be 43.4% and 85.2% at 100 mg/L, respectively, and 64.4% and 89.4% at 200 mg/L. These findings suggest that benzothiazole and benzoxazole selenones represent promising lead compounds for sustainable plant disease management. Full article

(This article belongs to the Special Issue Nitrogen Containing Heterocyclic Scaffolds: Synthesis and Bioactivity)

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22 pages, 4199 KB

Open AccessArticle

Omics Reveals the Antibacterial Mechanism of Dihydromyricetin and Vine Tea Extract Against Staphylococcus aureus via Cell Wall and Membrane Disruption

by Qiaoni Hui, Ting Li, Keke He, Wei Ma, Ying Guo, Yao Zhang and Liya Song

Molecules 2026, 31(2), 313; https://doi.org/10.3390/molecules31020313 - 16 Jan 2026

Abstract

Staphylococcus aureus (S. aureus) is a common pathogen that threatens healthcare and food safety. Vine tea extract (VTE) and its major active component, dihydromyricetin (DMY), show antibacterial activity. However, their mechanisms of action are not fully understood. In this study, we [...] Read more.

Staphylococcus aureus (S. aureus) is a common pathogen that threatens healthcare and food safety. Vine tea extract (VTE) and its major active component, dihydromyricetin (DMY), show antibacterial activity. However, their mechanisms of action are not fully understood. In this study, we combined proteomics and lipidomics, with RT–qPCR validation of selected differentially expressed genes, to investigate how DMY and VTE affect S. aureus. Proteomics identified 210 and 535 differentially expressed proteins (DEPs) in the DMY-treated and VTE-treated groups, respectively. These DEPs were mainly enriched in cell wall- and membrane-associated pathways. DMY markedly increased proteins involved in fatty acid degradation, glyceride metabolism, and cell wall synthesis. In contrast, VTE increased proteins related to heme/iron acquisition and cell wall degradation. In addition, VTE altered proteins involved in pyrimidine metabolism and aminoacyl-tRNA biosynthesis, suggesting that non-DMY components in VTE may contribute to the antibacterial activity through additional pathways. Lipidomics further indicated membrane lipid remodeling, including increased fatty acid unsaturation and shorter acyl chain length. Collectively, DMY and VTE may inhibit S. aureus growth by remodeling membrane lipids and disturbing cell wall–cell membrane homeostasis. These findings provide mechanistic support for further development of DMY and VTE as natural antimicrobial candidates. Full article

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27 pages, 8058 KB

Open AccessArticle

Quality Evaluation and Antioxidant Activity of Cultivated Gentiana siphonantha: An Ethnic Medicine from the Tibetan Plateau

by Jiamin Li, Liyan Zang, Xiaoming Song, Zixuan Liu, Hongmei Li and Jing Sun

Molecules 2026, 31(2), 312; https://doi.org/10.3390/molecules31020312 - 16 Jan 2026

Abstract

Gentiana species are widely used in traditional and modern medicine, and Gentiana siphonantha is an important medicinal representative. To evaluate the quality characteristics of cultivated G. siphonantha roots, the accumulation patterns of iridoid glycosides and antioxidant activities across different cultivation ages and harvest [...] Read more.

Gentiana species are widely used in traditional and modern medicine, and Gentiana siphonantha is an important medicinal representative. To evaluate the quality characteristics of cultivated G. siphonantha roots, the accumulation patterns of iridoid glycosides and antioxidant activities across different cultivation ages and harvest months were investigated. Five major iridoid glycosides were quantified, and antioxidant capacity was assessed through DPPH, ABTS, and FRAP assays. Quality was subsequently multidimensionally evaluated using principal component analysis (PCA), orthogonal partial least squares–discriminant analysis (OPLS-DA), membership function analysis, and entropy weight–TOPSIS analysis, and the relationship between iridoid glycoside content and antioxidant activity was analyzed. Results showed that 3-year-old cultivated roots had the highest total iridoid glycoside content (134.60 mg·g⁻¹ DW), indicating the optimal cultivation age. Peak glycoside accumulation occurred in 4-year-old plants harvested in June–July, identifying this period as the optimal harvest time, as supported by multivariate statistical and comprehensive evaluation. Antioxidant activity increased with cultivation age, with samples collected in June or August showing higher capacities, and it was positively correlated with total iridoid glycoside content, particularly with FRAP (p < 0.05). In conclusion, cultivated G. siphonantha exhibits stable quality and favorable antioxidant activity, providing a basis for standardized cultivation, quality evaluation, and rational utilization. Full article

(This article belongs to the Section Analytical Chemistry)

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21 pages, 1188 KB

Open AccessReview

Antidiabetic and Anti-Inflammatory Potential of Zingiberaceae Plants in Dietary Supplement Interventions

by Natalia Kuzia, Olga Adamska, Natalia Ksepka, Agnieszka Wierzbicka and Artur Jóźwik

Molecules 2026, 31(2), 311; https://doi.org/10.3390/molecules31020311 - 16 Jan 2026

Abstract

Plants from the Zingiberaceae family, particularly Zingiber officinale, Curcuma longa, and Alpinia galanga, are rich sources of bioactive compounds with documented antidiabetic and anti-inflammatory properties. This review summarizes current evidence on their phytochemical profiles and pathways relevant to metabolic regulation. [...] Read more.

Plants from the Zingiberaceae family, particularly Zingiber officinale, Curcuma longa, and Alpinia galanga, are rich sources of bioactive compounds with documented antidiabetic and anti-inflammatory properties. This review summarizes current evidence on their phytochemical profiles and pathways relevant to metabolic regulation. Key compounds, including gingerols, shogaols, curcuminoids, and phenylpropanoids, support glucose homeostasis by enhancing insulin sensitivity, promoting Glucose Transporter Type 4 (GLUT4)-mediated glucose uptake, improving β-cell function, and modulating metabolic signaling pathways such as PI3K/Akt, AMPK, PPARγ, and NF-κB. Their potent antioxidant and anti-inflammatory activities further reduce oxidative stress and chronic low-grade inflammation, both central to the progression of type 2 diabetes and its complications. Evidence from selected clinical and experimental studies suggests that dietary supplementation with whole-rhizome preparations or standardized extracts (including formulation-enhanced products) may improve fasting blood glucose (FBG), glycated hemoglobin (HbA1c), lipid metabolism, and oxidative stress markers. Recent advances in delivery systems, including nanoemulsions, liposomes, and curcumin–piperine complexes, substantially enhance the bioavailability of poorly soluble phytochemicals, strengthening their therapeutic potential. Overall, Zingiberaceae plants emerge as promising natural supplements in nutritional and pharmacological strategies targeting diabetes. Further clinical research is required to refine dosage, confirm long-term efficacy, and support their integration into evidence-based metabolic interventions. Full article

(This article belongs to the Special Issue Chemical Composition and Functional Properties of Food By-Products)

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1 pages, 289 KB

Open AccessCorrection

Correction: Yang et al. Synthesis and Fungicidal Activities of (Z/E)-3,7-Dimethyl-2,6-octadienamide and Its 6,7-Epoxy Analogues. Molecules 2015, 20, 21023–21036

by Mingyan Yang, Hongbo Dong, Jiazhen Jiang and Mingan Wang

Molecules 2026, 31(2), 310; https://doi.org/10.3390/molecules31020310 - 16 Jan 2026

Abstract

In the original publication [...] Full article

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15 pages, 1564 KB

Open AccessArticle

Regioselective Glycosylation of Demethylbellidifolin by Glycosyltransferase AbCGT Yields Potent Anti-Renal Fibrosis Compound

by Limin Zeng, Shichao Cui, Xingyu Ji, Yuhong Liu, Guozhang Long, Yulan Xia, Gang Cheng, Jingya Li and Youhong Hu

Molecules 2026, 31(2), 309; https://doi.org/10.3390/molecules31020309 - 15 Jan 2026

Abstract

Glycosylation serves as an effective strategy to enhance the solubility, bioavailability, and pharmacological activity of polyhydroxyphenols. In this study, we explored the glycosylation of natural and natural-inspired phenolic compounds using the glycosyltransferase AbCGT and evaluated the anti-renal fibrotic potential of the resulting glycosides. [...] Read more.

Glycosylation serves as an effective strategy to enhance the solubility, bioavailability, and pharmacological activity of polyhydroxyphenols. In this study, we explored the glycosylation of natural and natural-inspired phenolic compounds using the glycosyltransferase AbCGT and evaluated the anti-renal fibrotic potential of the resulting glycosides. Among them, 1,3,5,8-tetrahydroxyxanthone 5-O-β-D-glucopyranoside (2-1a), synthesized via the regioselective 5-O-glycosylation of demethylbellidifolin, demonstrated significant anti-renal fibrotic activity. In contrast, its homologous glycosyltransferase, UGT73AE1, predominantly glycosylated demethylbellidifolin at the 3-OH position. Molecular docking studies revealed the structural basis for this regioselectivity difference. To enhance the production of 2-1a, we established a UDP-glucose (UDPG) recycling system by coupling AbCGT with Glycine max sucrose synthase (GmSuSy) and subsequently optimized the reaction conditions. Furthermore, targeted mutagenesis of AbCGT informed by molecular docking analysis identified a F138A mutant that enhanced glycosylation yield by 2.3-fold. This work develops a novel glycosyltransferase-based catalytic system and identifies a new compound with potential anti-renal fibrotic activity. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds, 3rd Edition)

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18 pages, 1305 KB

Open AccessArticle

Varietal Discrimination of Purple, Red, and White Rice Bran Oils Based on Physicochemical Properties, Bioactive Compounds, and Lipidomic Profiles

by Peng Zheng, Yuyue Qin, Xiaoyu Yin, Jianxin Cao, Shujie Wang and Guiguang Cheng

Molecules 2026, 31(2), 308; https://doi.org/10.3390/molecules31020308 - 15 Jan 2026

Abstract

Rice bran oil (RBO) is increasingly valued for its bioactive constituents and associated health benefits. This study presents a comprehensive comparative analysis of RBOs derived from purple (PRBO), red (RRBO), and white (WRBO) rice bran, focusing on their physicochemical properties, fatty-acid profiles, bioactive [...] Read more.

Rice bran oil (RBO) is increasingly valued for its bioactive constituents and associated health benefits. This study presents a comprehensive comparative analysis of RBOs derived from purple (PRBO), red (RRBO), and white (WRBO) rice bran, focusing on their physicochemical properties, fatty-acid profiles, bioactive components, antioxidant activity, oxidative stability, and lipidomics. Our results demonstrate that PRBO consistently exhibited a more favorable fatty-acid composition, characterized by a higher proportion of unsaturated fatty acids and significantly greater concentrations of bioactive compounds (including tocopherols/tocotrienols, γ-oryzanol, phytosterols, and squalene). Accordingly, PRBO showed the highest radical-scavenging activity and storage oxidative stability, followed by RRBO and WRBO. Additionally, untargeted lipidomics using UPLC–MS–MS identified 2908 lipid species spanning 57 subclasses and revealed distinct variety-specific lipid signatures. PRBO was uniquely enriched in lipid species such as ceramide phosphate (CerP) and monogalactosyldiacylglycerol (MGDG). RRBO was characterized by a distinct abundance of sitosteryl esters (SiE), phosphatidic acid (PA), and cardiolipin (CL), while WRBO was distinguished by phosphatidylethanol (PEt), lysodimethylphosphatidylethanolamine (LdMePE), and sphingomyelin (SM). Overall, PRBO possessed not only a broader repertoire of lipid species but also higher relative abundances of nutritionally significant lipids. These results enable quality evaluation and varietal authentication of colored RBOs and guide their targeted use in health-oriented foods and nutritional interventions. Full article

(This article belongs to the Special Issue Novel Food Processing Technologies and Their Effects on Bioactive Components in Foods)

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22 pages, 3068 KB

Open AccessArticle

Hydroalcoholic Extracts of Cucumis prophetarum L. Affect the Insulin Signaling Pathway in an In Vitro Model of Insulin-Resistant L6 Myotubes

by Zewdie Mekonnen, Giuseppe Petito, Getasew Shitaye, Gianluca D’Abrosca, Belete Adefris Legesse, Sisay Addisu, Antonia Lanni, Roberto Fattorusso, Carla Isernia, Lara Comune, Simona Piccolella, Severina Pacifico, Rosalba Senese, Gaetano Malgieri and Solomon Tebeje Gizaw

Molecules 2026, 31(2), 307; https://doi.org/10.3390/molecules31020307 - 15 Jan 2026

Abstract

Type 2 diabetes mellitus (T2DM) can be traditionally treated by edible and medicinal species rich in flavonoids and triterpenoids known for their metabolic benefits. Cucumis prophetarum L. has shown antioxidant and antidiabetic properties in decoction extracts. Since solvent polarity strongly influences the extraction [...] Read more.

Type 2 diabetes mellitus (T2DM) can be traditionally treated by edible and medicinal species rich in flavonoids and triterpenoids known for their metabolic benefits. Cucumis prophetarum L. has shown antioxidant and antidiabetic properties in decoction extracts. Since solvent polarity strongly influences the extraction of secondary metabolites, this study investigated the hydroalcoholic extracts of C. prophetarum L. to explore their chemical composition and insulin-sensitizing potential. Hydroalcoholic extracts from the leaf, stem, and root of C. prophetarum L. were analyzed by UV-Vis spectroscopy, ATR-FTIR, and UHPLC-ESI-QqTOF–MS/MS to profile their secondary metabolites. The insulin-sensitizing potential of each extract was assessed using an in vitro model of palmitic-acid-induced insulin resistance in L6 skeletal muscle cells, followed by Western blot analysis of key insulin-signaling proteins. Flavonoid glycosides such as apigenin-C,O-dihexoside, apigenin-malonylhexoside, and luteolin-C,O-dihexoside were abundant in leaf and stem extracts, while cucurbitacins predominated in the root. MTT assay confirmed that hydroalcoholic stem and root extracts of C. prophetarum L. were non-cytotoxic to L6 myotubes, whereas the leaf extract reduced viability only at higher concentrations. Oil Red O staining revealed a pronounced decrease in lipid accumulation following stem and root extract treatment. Consistently, the stem extract enhanced insulin signaling through the activation of the IRS-1/PI3K/Akt pathway, while the root extract primarily modulated the AMPK–mTOR pathway. Importantly, both extracts promoted GLUT4 translocation to the plasma membrane, highlighting their complementary mechanisms in restoring insulin sensitivity. Hydroalcoholic extracts of C. prophetarum L. alleviate insulin resistance through multiple molecular mechanisms, with bioactivity and composition differing markedly from previously reported in the decoctions, which highlight a promising source of insulin-sensitizing phytochemicals and underscore the importance of solvent selection in maximizing therapeutic potential. Full article

(This article belongs to the Special Issue Bioactive Natural Products and Derivatives)

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15 pages, 1929 KB

Open AccessArticle

Metal Preference Hierarchy in the HDAC8 Active Site: A DFT Study

by Nikolay Toshev, Diana Cheshmedzhieva, Yordanka Uzunova, Kristiyan Velichkov and Todor Dudev

Molecules 2026, 31(2), 306; https://doi.org/10.3390/molecules31020306 - 15 Jan 2026

Abstract

HDAC8 is a histone deacetylase enzyme that plays a key role in the development of various diseases in humans, including cancers, neurodegenerative diseases, and alcohol use disorder. Although HDAC8 is classified as a Zn²⁺-dependent metalloenzyme, available data regarding the affinity of [...] Read more.

HDAC8 is a histone deacetylase enzyme that plays a key role in the development of various diseases in humans, including cancers, neurodegenerative diseases, and alcohol use disorder. Although HDAC8 is classified as a Zn²⁺-dependent metalloenzyme, available data regarding the affinity of other biologically relevant ions, such as Fe²⁺, Ni²⁺, Co²⁺, and Mg²⁺, for the HDAC8 enzyme active site remain unclear and contradictory. The mechanism by which these ions compete with Zn²⁺ for the HDAC8 active site is not well understood. In this study, we performed density functional theory (DFT) calculations at the B3LYP/6-31+G(d) level of theory, combined with polarizable continuum model computations (PCM) in water (ε = 78) and methanol (ε = 32). The results show that Zn²⁺ remains the thermodynamically preferred cofactor across all modeled reactions. Although Fe²⁺ and Co²⁺ gain partial stabilization upon increasing coordination number, the associated entropic and desolvation penalties prevent them from outcompeting Zn²⁺ under physiologically relevant conditions. Only a limited number of substitution reactions for Fe²⁺ and Co²⁺ yield ∆G values near thermodynamic neutrality, and only in specific coordination states. In contrast, all modeled Ni²⁺ substitution reactions are unfavorable, and Mg²⁺ is strongly excluded from the HDAC8 active site in all reactions. The resulting metal preference hierarchy—Zn²⁺ > Co²⁺ ≈ Fe²⁺ > Ni²⁺ > Mg²⁺—supports experimental observations and clarifies the intrinsic selectivity of the HDAC8 enzyme towards Zn²⁺. These insights provide a molecular basis for understanding HDAC8 metallo-regulation and may guide the rational design of novel, isoform-specific HDACi with improved binding properties. Full article

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31 pages, 1648 KB

Open AccessReview

Beyond the Solvent: Engineering Ionic Liquids for Biomedical Applications—Advances, Challenges, and Future Directions

by Amal A. M. Elgharbawy, Najihah Mohd Noor, Nor Azrini Nadiha Azmi and Beauty Suestining Diyah Dewanti

Molecules 2026, 31(2), 305; https://doi.org/10.3390/molecules31020305 - 15 Jan 2026

Abstract

Ionic liquids (ILs) have emerged as multifunctional compounds with low volatility, high thermal stability, and tunable solvation capabilities, making them highly promising for biomedical applications. First explored in the late 1990s and early 2000s for enhancing the thermal stability of enzymes, antimicrobial agents, [...] Read more.

Ionic liquids (ILs) have emerged as multifunctional compounds with low volatility, high thermal stability, and tunable solvation capabilities, making them highly promising for biomedical applications. First explored in the late 1990s and early 2000s for enhancing the thermal stability of enzymes, antimicrobial agents, and controlled release systems, ILs have since gained significant attention in drug delivery, antimicrobial treatments, medical imaging, and biosensing. This review examines the diverse functions of ILs in contemporary therapeutics and diagnostics, highlighting their transformative capabilities in improving drug solubility, bioavailability, transdermal permeability, and pathogen inactivation. In drug delivery, ILs improve solubility of bioactive compounds, with several IL formulations achieving substantial solubility enhancements for poorly soluble drugs. Bio-ILs, in particular, show promise in enhancing drug delivery systems, such as improving transdermal permeability. ILs also exhibit significant antimicrobial and antiviral activity, offering new avenues for combating resistant pathogens. Despite their broad potential, challenges such as cytotoxicity, long-term metabolic effects, and the stability of ILs in physiological conditions persist. While much research has focused on their physicochemical properties, biological activity and in vivo studies are still underexplored. The future directions for ILs in biomedical applications include the development of bioengineered ILs and hybrid ILs, combining functional components like nanoparticles and polymers to create multifunctional materials. These ILs, derived from renewable resources, show great promise in personalized medicine and clinical applications. Further research is necessary to evaluate their pharmacokinetics, biodistribution, and long-term safety to fully realize their biomedical potential. This study emphasizes the potential of ILs to transform therapeutic and diagnostic technologies by highlighting present shortcomings and offering pathways for clinical translation, while also debating the need for continuous research to fully utilize their biomedical capabilities. Full article

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17 pages, 719 KB

Open AccessArticle

Phenolic Composition and Antioxidant Properties of Bee Bread Collected in Three Consecutive Beekeeping Seasons in Poland

by Teresa Szczęsna, Katarzyna Jaśkiewicz, Natalia Skubij and Jacek Jachuła

Molecules 2026, 31(2), 304; https://doi.org/10.3390/molecules31020304 - 15 Jan 2026

Abstract

Bee bread contains numerous bioactive compounds, including phenolic compounds, which have been associated with antioxidant properties. In this study, we determined the phenolic composition of Polish bee bread collected over three consecutive years using HPLC-DAD. We also measured total phenolic content (TPC) and [...] Read more.

Bee bread contains numerous bioactive compounds, including phenolic compounds, which have been associated with antioxidant properties. In this study, we determined the phenolic composition of Polish bee bread collected over three consecutive years using HPLC-DAD. We also measured total phenolic content (TPC) and antioxidant activity, expressed as DPPH radical scavenging activity. The highest concentrations were observed for p-coumaric, trans-ferulic, and caffeic acids, as well as for two flavonoids—rutin and hesperidin. The contents of individual phenolic compounds varied across the years of sample collection, with the exception of p-coumaric and vanillic acids. Despite year-to-year differences in TPC, no significant correlation with antioxidant activity (>90% in all samples) was observed, indicating a substantial contribution of non-phenolic compounds to antioxidant capacity. Principal Component Analysis revealed that almost all samples clustered into three groups according to their year of collection. We conclude that the year-to-year variation in phenolic compound content in bee bread is likely attributable to differences in available pollen sources. Our findings expand the current knowledge of the nutritional value of bee bread produced in Poland and strengthen the premises for its use as a functional food. Full article

(This article belongs to the Special Issue Biological Activity and Chemical Composition of Honeybee Products)

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24 pages, 1552 KB

Open AccessReview

Georgian Grapes and Wines as a Source of Phenolic Compounds: Composition, Antioxidant Activity, and Traditional Winemaking

by Valentina Mittova, Zurab R. Tsetskhladze, Nino Motsonelidze, Rosanna Palumbo and Giovanni N. Roviello

Molecules 2026, 31(2), 303; https://doi.org/10.3390/molecules31020303 - 15 Jan 2026

Abstract

Georgia is recognized as one of the world’s earliest known centers of grape cultivation and wine production, as well as the home of 525 indigenous grape varieties. Phenolic compounds are a diverse group of secondary metabolites which are present in both grapes and [...] Read more.

Georgia is recognized as one of the world’s earliest known centers of grape cultivation and wine production, as well as the home of 525 indigenous grape varieties. Phenolic compounds are a diverse group of secondary metabolites which are present in both grapes and wine, with the phenolic derivatives determining the organoleptic properties and the antioxidant activity of the resulting wines. Remarkably, the content and composition of phenolic compounds in wine are mainly influenced by the grape variety and the winemaking method. In this context, herein we review the present knowledge on the phenolic composition of the most common Georgian grape varieties and discuss available molecular insights on the resulting wines. The comparison of traditional European and traditional Georgian “qvevri” winemaking methods revealed that this method provides high antioxidant activity of Georgian wines, as well as a unique phenolic composition of red and white Georgian wines. Full article

(This article belongs to the Special Issue NUCLEO-OMICS24)

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14 pages, 1836 KB

Open AccessArticle

Development of a Peptide-Based Photoimmunotherapy Drug Targeting PD-L1

by Takuya Otani, Naoya Kondo, Ayaka Kanai and Hirofumi Hanaoka

Molecules 2026, 31(2), 302; https://doi.org/10.3390/molecules31020302 - 14 Jan 2026

Abstract

Near-infrared photoimmunotherapy (NIR-PIT) has recently attracted attention as a highly selective cancer treatment, with good treatment outcomes observed from the only antibody-based drug currently available for clinical use. However, since only a single agent is currently used clinically and the development of new [...] Read more.

Near-infrared photoimmunotherapy (NIR-PIT) has recently attracted attention as a highly selective cancer treatment, with good treatment outcomes observed from the only antibody-based drug currently available for clinical use. However, since only a single agent is currently used clinically and the development of new antibodies is costly, exploring other therapeutic modalities is important. In this study, we investigated a novel peptide-based PIT drug targeting programmed death-ligand 1 (PD-L1), which is overexpressed in many types of cancer. The WL12 peptide, which is known to bind to PD-L1, was conjugated with the photoabsorber IRDye700DX (IR700), and its usefulness was evaluated in vitro and in vivo. In therapeutic experiments on PD-L1-positive cells, NIR-PIT with WL12-IR700 induced PIT-like morphological changes in cells and reduced cancer cell viability in an NIR light dose- and drug concentration-dependent manner. In vivo experiments showed significant suppression of tumor growth and an extended overall survival rate. These results indicate that the developed peptide-based drug can be used for PD-L1-targeted NIR-PIT. Full article

(This article belongs to the Special Issue Exploring the Therapeutic Potential of Peptides in Anti-Cancer Treatments)

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