Chemistry and Materials Science

Abstract:

This review consolidates current knowledge on the phytochemical composition, traditional uses, pharmacological properties, and industrial application of Ricinus communis L. This plant belongs to the Euphorbiaceae family and is a globally distributed plant of considerable medicinal and industrial importance. It is rich in bioactive compounds, notably ricinoleic acid as the dominant fatty acid in seed oil, as well as ricin, ricinine, phenolic acids and flavonoids distributed across different plant parts. Variations in phytochemical profiles among cultivars and tissues are influenced by genetic and environmental influences. Traditional medicinal uses of the leaves, roots, seeds, and oil particularly for inflammatory conditions, pain, infections, wound healing, and gastrointestinal disorders are critically examined in relation to experimental pharmacological evidence. Castor oil extracted from the R. communis plant remains central to the plant’s industrial value, serving as a renewable feedstock for pharmaceuticals, cosmetics, polymers, lubricants, and biofuels due to the unique hydroxyl functionality of ricinoleic acid. However, the presence of the highly toxic protein ricin in unprocessed seeds necessitates strict processing and safety controls. Overall, R. communis emerges as a chemically versatile species with significant therapeutic and industrial potential, warranting further research into cultivar-specific chemistry, standardisation of extraction and testing methods, and safe value-adding applications.

Abstract: The continuous emergence of SARS-CoV-2 variants necessitates the identification of effective multi-target antiviral agents with enhanced stability and binding efficiency. This study employed an integrated computational approach, including molecular docking, molecular dynamics (MD) simulations, free energy landscape (FEL) analysis, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, to evaluate the inhibitory potential of twenty natural compounds against SARS-CoV-2 proteins 7XJW, 8DRW, and 9PFH. Molecular docking identified Amentoflavone as the most promising candidate, exhibiting strong binding affinities toward all targets through favorable hydrogen-bond and hydrophobic interactions within the active sites. Interaction analysis revealed that its biflavonoid scaffold promoted extensive ligand–protein complementarity through hydroxyl and aromatic functional groups. MD simulations demonstrated stable protein-ligand complexes, characterized by low fluctuations in RMSD, RMSF, SASA, and radius of gyration values throughout the 100 ns trajectories. Persistent hydrogen-bond interactions further supported complex stability. FEL analysis revealed compact low-energy conformational basins, indicating thermodynamically favorable binding states. MM-PBSA calculations confirmed favorable binding free energies primarily driven by van der Waals and electrostatic contributions, with the 7XJW-Amentoflavone complex exhibiting the most favorable energetic profile. Overall, these findings highlight Amentoflavone as a promising multi-target inhibitor and potential lead compound for future antiviral drug development and experimental validation against SARS-CoV-2.

Abstract:

Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disorder with a complex pathomechanism. Acetylcholinesterase (AChE) and monoamine oxidase-B (MAO-B) are key targets regulating neurotransmitter levels, and dual inhibitors (compounds 1–46) were designed as experimental candidates for AD therapy. Methods: Drug-likeness parameters were estimated using pkCSM, SwissADME web tools, and MoloVol software (v1.2.0). SwissADME predicted gastrointestinal absorption and blood–brain barrier penetration, whereas pkCSM evaluated P-glycoprotein recognition and CYP450 inhibition. Toxicological profiles of compounds (1–46) were assessed with DataWarrior software (v06.05.04), which classified them as mutagenic, carcinogenic, reproductive, or irritant. Results: Most compounds complied with Lipinski’s rule (excluding 12 and 35) indicating favorable absorption and permeability. All compounds showed TPSA < 140 Å2, indicating good intestinal absorption, while compounds 1, 3–6, 8, 11-16, 18, 19, 27, 30, 31, 34, 36-38, and 44–46 displayed TPSA < 60 Å2, suggesting blood–brain barrier penetration. The majority of compounds were predicted P-glycoprotein substrates, potentially limiting oral absorption and blood-brain barrier penetration. Metabolic profiling revealed inhibition of CYP1A2, 2C19, 2C9, 2D6, and 3A4, highlighting drug–drug interaction risks. Toxicological analysis identified mutagenicity (compounds 4, 5, 19, 20 and 27), carcinogenicity (compounds 4, 5, 8, 18 and 19), reproductive toxicity (compounds 15, 16 and 19–23), and irritant effects (compounds 7, 11, 17 and 20). Conclusions: Computational findings support further in vitro and in vivo evaluation of compounds 1, 3, 6, 13, 14, 30, 31, 34, 36–38, and 44–46 as dual AChE/MAO-B inhibitors and potentially new drugs for AD treatment.

Abstract: The regeneration of the dentin-pulp complex remains a major challenge in regenerative endodontics. While conventional therapeutic approaches are effective in eliminating infection and preserving dental structure, they fail to restore the biological functionality of the pulp tissue. In recent years, three-dimensional (3D) printing and biopolymer-based bioprinting have opened unprecedented opportunities in dental tissue engineering, enabling the fabrication of biomimetic scaffolds with precisely controlled structural and bioactive properties. This review synthesizes current advances in bioprinting technolo-gies, the diversity of biomaterials and bioinks employed, and the various stem cell sources utilized in pulp regeneration. It further examines how the three-dimensional microenvironment modulates cell viability, odontogenic differentiation, and the pro-motion of angiogenesis and neurogenesis, emphasizing the role of scaffold composition, mechanical properties, and internal architecture in influencing regenerative outcomes. Additionally, persistent challenges are discussed, including the optimization of bioink formulations, the achievement of functional vascular integration, and long-term valida-tion of regenerated tissues, underscoring the need for multidisciplinary strategies to fa-cilitate clinical translation. By integrating recent evidence, this review establishes a conceptual framework for the development of personalized and predictable approaches to dentin-pulp complex reconstruction.

Abstract: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder driven by complex interactions between protein aggregation, oxidative stress, neuroinflammation, and cellular dysfunction. Among plant-derived compounds, curcumin has emerged as one of the most extensively studied polyphenols due to its broad spectrum of biological activities. This review provides a critical synthesis of mechanistic, preclinical, and clinical evidence on curcumin in AD. Experimental studies consistently demonstrate that curcumin modulates key pathogenic processes, including neuroinflammatory signaling, oxidative stress, and amyloid-β aggregation, with more limited evidence for effects on tau pathology. While in vitro studies offer detailed mechanistic insights, in vivo models provide more integrated evidence, including improvements in cognitive performance and reductions in pathological markers. Despite this strong preclinical foundation, clinical evidence remains limited and inconsistent. Randomized controlled trials have not demonstrated clear therapeutic efficacy, with outcomes strongly influenced by formulation, bioavailability, and study design. Poor solubility, rapid metabolism, and limited brain exposure remain key translational barriers. In response, increasing attention has been directed toward formulation strategies and structurally related compounds. Emerging curcuminoids, such as bisdemethoxycurcumin (BDMC), are discussed as potential next-generation candidates. Preliminary evidence suggests that BDMC may modulate oxidative stress, autophagy, astrocyte senescence, and amyloid-related processes, although data remain largely preclinical. Overall, curcumin represents a mechanistically rich and preclinically promising multi-target compound, but with unresolved translational limitations. Future research should prioritize pharmacokinetic optimization, formulation-dependent validation, and exploration of novel curcuminoid strategies to bridge the gap between experimental findings and clinical application in AD.

Abstract: Introduction: Tetrazole and thiazolidine-4-one derivatives are important heterocyclic scaffolds with diverse pharmacological activities, including antimicrobial and antioxidant effects. This study focuses on the design and synthesis of novel Schiff base–derived analogues using a green synthetic approach to improve biological efficacy and reduce environmental impact. Methods: Schiff bases (2a–2h) were synthesized using tetrabutylammonium iodide as a green catalyst in aqueous medium. These were further converted into tetrazole (3a–3h) and thiazolidine-4-one (4a–4h) derivatives using sodium azide and thioglycolic acid. Structures were confirmed by FTIR, ¹H NMR, and ¹³C NMR spectroscopy. Antioxidant activity was evaluated using the DPPH assay, while antimicrobial activity was assessed by the zone of inhibition method. Molecular docking was performed against Penicillin-Binding Protein 4 (3ZG8), CYP51 (5V5Z), and 1OAF. Results: Compounds 2a, 2b, 3a, and 4a showed strong antifungal activity, exceeding standard drugs. Compounds 2d, 3b, and 4b exhibited superior antibacterial activity. Several derivatives demonstrated higher antioxidant activity than ascorbic acid. Docking studies confirmed stable ligand–protein interactions, with compound 4f showing the highest binding affinity. Discussion: Substituent variation influenced biological activity. Electron-donating and withdrawing groups affected potency. Docking results supported experimental findings and confirmed target interactions. The green synthesis improved efficiency and reduced environmental risk. Conclusion: These derivatives show promising antimicrobial and antioxidant potential. Compound 4f emerged as a lead candidate for further optimization and drug development.

Abstract: The hexane extract of Psoralea drupacea Bunge fruits was initially evaluated for antivi-ral activity against SARS-CoV-2 based on GC-MS data indicating high bakuchiol con-tent (87.74%). Unexpectedly, the extract showed no antiviral effect in Vero E6 cells due to cytotoxicity (CC₅₀ = 7.5 μg/mL), while purified bakuchiol demonstrated moderate antiviral activity (IC₅₀ = 6.2 ± 0.8 μg/mL; SI = 2.9). Quantitative NMR revealed that the actual bakuchiol content in the extract was 44.3% — approximately half the GC-MS value — explaining the lack of efficacy at non-cytotoxic concentrations. Both the ex-tract and purified bakuchiol effectively blocked the RBD-ACE2 interaction in a com-petitive ELISA (71.3% inhibition at 50 μM for bakuchiol; IC₅₀ = 18.5 μM). Notably, the extract also inhibited the viral main protease 3CLpro (IC₅₀ = 32.0 ± 3.5 μg/mL), while purified bakuchiol showed no such activity. These findings reveal a dual mechanism: bakuchiol inhibits viral entry via RBD-ACE2 blockade, while other extract components (e.g., angelicin, psoralen) suppress viral replication via 3CLpro inhibition.

Abstract: Aspergillus nidulans, a model filamentous fungus endowed with well-established genetic tools and a repertoire of cryptic secondary metabolite biosynthetic gene clusters (BGCs), is extensively exploited as a microbial chassis for heterologous biosynthesis. Mining of its secondary metabolites facilitates the discovery of novel bioactive compounds and the development and application of chassis cells. In the course of heterologous expression of exogenous genes in A. nidulans, we unexpectedly observed the activation of cryptic host BGCs, which resulted in substantial alterations to its secondary metabolic profile. Four previously undescribed compounds (1–4), together with six known analogs (5–10), were isolated from three recombinant A. nidulans strains. Notably, compounds 1–3 are the first naturally occurring examples of diketopiperazine-isoindolinone hybrid alkaloids, while compound 4 is a previously unreported benzofuran carboxylic acid derivative. Their structures and absolute configurations were assigned by interpretation of a combination of spectroscopic data and electronic circular dichroism calculations. Compounds 4 and 5 exhibited potent DPPH radical scavenging activity (IC₅₀, 6.01 and 7.00 μg·mL^-1, respectively). This study uncovers a "metabolic perturbation" effect on the host metabolic network during heterologous expression and offers a new strategy for activating silent gene clusters and discovering novel natural products through genetic manipulation.

Abstract: Cosmetic preservatives should have reduced percutaneous absorption to lower the risk of systemic exposure and skin irritation. In this work, Escherichia coli β-galactosidase was used to enzymatically modify several of the commonly used cosmetic preservatives to produce their corresponding galactosylated derivatives: benzyl alcohol β-D-galactopyranoside 7, 2-phenoxyethanol β-D-galactopyranoside 8, chlorphenesin β-D-galactopyranoside 9, 1,2-hexanediol β-D-galactopyranoside 10, 1,2-octanediol β-D-galactopyranoside 11, and 2-phenylethyl β-D-galactopyranoside 12. HPLC and NMR spectroscopy were used to analyze the synthesized derivatives. The Franz diffusion cell assay was used to evaluate skin penetration. 2-phenoxyethanol (PE), chlorphenesin (CPN), and 2-phenylethanol (PhE), exhibited measurable skin penetration with flux values ranging from 3.82 to 7.34 µg·h⁻¹·cm⁻² and permeability coefficients (Kp) between 1.38 and 3.00 ×10⁻³ cm·h⁻¹. In contrast, their galactosylated derivatives showed markedly reduced permeation under the same experimental conditions. Moreover, brine shrimp lethality assays indicated that galactosylated derivatives had significantly higher LD₅₀ values (1.6–2.1 mg/mL) than their parent compounds (0.1–0.79 mg/mL), suggesting lower cytotoxicity. These findings suggest that enzymatic galactosylation can significantly decrease skin permeability and the toxicity of cosmetic preservatives, highlighting its potential as a strategy to improve the safety of cosmetic ingredients.

Abstract: Quantitative structure–activity relationship (QSAR) modeling has traditionally relied on expert-designed molecular descriptors to encode chemical structures. DeepSnap is a descriptor-free QSAR approach that converts three-dimensional molecular structures into image representations and feeds them directly into convolutional neural networks for activity prediction. The method generates a conformer for each molecule, renders it as a color-coded molecular image, and captures omnidirectional snapshots from systematically varied viewing angles. This review traces DeepSnap from its introduction in 2018 to its current state. The method has been applied to 35 nuclear receptor endpoints from the Tox21 10K library (mean AUC 0.884), 59 molecular initiating event models spanning the full Tox21 target panel, rat hepatic clearance (ensemble AUC 0.943), and blood–brain barrier penetration (ensemble AUC 0.936). An ensemble strategy combining image-based and descriptor-based predictions has consistently outperformed either approach alone. The computational pipeline has evolved from a DIGITS/Caffe/Jmol system to a TensorFlow/Keras/PyMOL framework. Limitations include endpoint-dependent parameter sensitivity, class imbalance effects, the absence of direct comparisons with graph neural networks, and an interpretability gap addressed in part by CAM-family visualization in the AI-SHIPS platform and S-COPHY. Future directions include systematic application of explainable AI methods, automated hyperparameter optimization, and integration with graph-based approaches.

Abstract: The development of new chronobiotics, substances capable of selectively modulating the parameters of circadian rhythms, is hampered by the fragmented nature and limited volume of available experimental data.In the present study, a comprehensive evaluation of the applicability of the SMILES-Transformer architecture to the classification of circadian rhythm modulators was performed using the specialised ChronobioticsDB resource, and the first systematic virtual screening of the SAVI (Synthetically Accessible Virtual Inventory) library of synthetically accessible compounds for chronobiotic activity was carried out. Rigorous protocols were applied for model training and validation: Data-Efficient Modeling (DEM) assessment with 20 repeats, repeated scaffold validation (5 × 5), and a comparative analysis of training strategies (feature-based vs. end-to-end fine-tuning). The influence of three variants of circadian-effect labelling (raw, aggregated, and expert-curated) and three loss functions (BCE, Focal Loss, and Asymmetric Loss) on the quality of multi-label classification was investigated. The results demonstrate that systematic hyperparameter optimisation in end-to-end mode provides the best predictive performance (ROC-AUC 0.666 for the effect_coarse task), whereas standard fine-tuning without optimisation leads to overfitting (ROC-AUC 0.470). Scaffold validation confirmed the ability of the model to generalise to structurally novel compounds (ROC-AUC 0.587). Expert aggregation of labels improved the recognition of rare classes (F1-macro 0.254 versus 0.148 for the raw labelling). Based on the trained models, a consensus virtual screening of the SAVI library was performed using four independent classifiers (classf, effect_coarse, target, mechanism). From more than five million compounds, 10,000 of the most promising candidates were selected, among which 34 super-candidates (consensus score > 0.9) and 435 strong candidates (> 0.8) were identified. Analysis of the predicted targets revealed dominance of the CLOCK-BMAL1 complex (60.49%), while among effects the circadian phase shift prevailed (37%). All identified candidates are synthetically accessible and are recommended for prioritised experimental verification.

Abstract: Oleoresins are complex natural lipophilic matrices traditionally analyzed using chromatographic techniques that require extensive sample preparation, derivatization, and authentic standards. Amazonian oleoresins from Copaifera and Eperua species (Fabaceae) represent valuable bioresources with recognized pharmacological potential, largely attributed to diterpenoids such as copalic and hardwickiic acids, as well as bioactive sesquiterpenes, including the cannabinoid b-caryophyllene. In this study, we present a proof-of-concept application of Direct Analysis in Real Time coupled with High-Resolution Mass Spectrometry (DART-HRMS) as a rapid, direct, and environmentally friendly approach for chemical fingerprinting and semi-targeted screening of the two most important amazonian oleoresins from these two genera: Eperua oleifera and Copaifera multijuga. Analyses were performed using a Q Exactive Orbitrap coupled to a DART ion source under after conditions optimization. Hardwickiic acid was used as a model compound for method optimization, with optimal performance achieved at 200 °C and 100 V, yielding stable signal intensities (CV &lt; 10%) and high mass accuracy (&lt; 1 ppm). The method enabled reproducible detection of diterpenic acids in both oleoresins, allowing differentiation of their chemical profiles and assessment of short-term stability under ambient conditions. In addition to diterpenes, free fatty acids were also detected, expanding the compositional characterization of these matrices. Compound annotation was performed based on accurate mass measurements and literature comparison, corresponding to Level 5 confidence according to established metabolomics criteria. Although the absence of chromatographic separation limits isomer discrimination and absolute quantification, DART-HRMS provides a rapid and solvent-free strategy for chemical fingerprinting and preliminary characterization of oleoresins. This approach aligns with Green Chemistry principles and shows strong potential as a screening and triage tool for quality control, chemotaxonomic studies, and sustainable valorization of Amazonian natural products.

Abstract: Oleanolic acid (OA) is a hydrophobic pentacyclic triterpene widely distributed in the plant kingdom and characterized by broad biological activity, including antioxidant, anti-inflammatory, neuroprotective, renoprotective, and anticancer effects. Increasing evidence suggests, however, that many of these actions are better explained not by single molecular targets, but by OA-dependent modulation of an integrated organelle stress network involving mitochondria, the endoplasmic reticulum (ER), autophagy, mitophagy, and apoptosis. This review critically analyzes the available evidence on the effects of OA on the mitochondria–ER–autophagy–apoptosis axis, with particular emphasis on mechanisms governing the transition between cellular adaptation and cell death. The available literature indicates that, in non-cancer models, OA most commonly lowers reactive oxygen species (ROS), stabilizes mitochondrial function, attenuates the ER stress signature, and promotes adaptive autophagy and mitophagy. In contrast, in many cancer models, OA may enhance mitochondrial dysfunction, lower the threshold for mitochondrial apoptosis, and induce autophagy that can be either protective or cytotoxic depending on the biological context. Overall, the current evidence supports a model in which OA acts as a context-dependent modulator of the organelle stress threshold rather than as a uniformly cytoprotective or uniformly proapoptotic compound. At the same time, the literature remains heterogeneous with respect to models, doses, exposure times, and markers used, while poor aqueous solubility and limited bioavailability continue to constrain translation. Future studies should therefore integrate analyses of mitochondria, ER, mitochondria–ER contact sites (MERCS), autophagy, apoptosis, pharmacokinetics, formulation, and safety in order to define the true potential of OA as a modulator of biological stress.

Abstract: Belonging to the Euphorbiaceae family, Jatropha genus is a promising source for discovering of antitumor compounds. Jatropha ribifolia is a traditionally used species in folk medicine in the semi-arid region of Brazil with a few chemical and pharmacological reports. Based on that, the aim of the current work is to isolate, structurally characterize, and assess the cytotoxic activity of isolated compounds through in vitro and in silico analyses. To achieve these main goals, the underground parts were dried, extracted and purified using classical and instrumental chromatographic techniques, leading to the isolation of 16 compounds. Altogether with HR-ESI-MS, IR, one- and two-dimensional NMR experiments, eight previously unreported diterpenes, named ribifolones A-H, along eight known compounds, were obtained and are herein described. Regarding their activity against melanoma (SK-MEL-28) and colorectal cancer (HCT-116) cell lines, jatrophone was the most potent with IC50 of 6.19 µM and 10.09 µM followed by ribifolone that exhibited a moderate cytotoxicity with IC₅₀ values of 50.71 µM and 33.39 µM, respectively. Network pharmacology analysis suggests the involvement of PI3K-AKT-mTor pathway in the activity of both compounds, meanwhile molecular docking and dynamics simulations demonstrate the main interactions with key proteins in the pathway and highlighted the estrogen receptor beta (ERβ) as putative target. This work opens new perspectives for the discovery of bioactive compounds found in Euphorbiaceae species, especially from those occurring in Caatinga.

Abstract: Alzheimer’s disease (AD) represents a escalating global neuropharmacological crisis, with prevalence in high-growth demographic regions such as India projected to exceed 14 million by 2040. This study addresses the urgent need for high-potency, dual-site acetylcholinesterase (AChE) inhibitors through an integrated computational pipeline. Background: We address the failure of mono-target paradigms by designing scaffolds capable of simultaneously anchoring the Catalytic Active Site (CAS) and the Peripheral Anionic Site (PAS). Methods: A robust GA-MLR QSAR model was developed from 115 quinoline analogues using 11,135 descriptors. Lead candidates were prioritized via blind molecular docking (7XN1) and 100-ns molecular dynamics (MD) simulations. Results: The five-descriptor model (R2 = 0.7569, QLOO2 = 0.7244) was validated by an external set of 8 experimental compounds (Rext2 = 0.8620). Lead Compound 19 emerged as a superior candidate (ΔG = -11.1 kcal/mol), exhibiting a stable MD trajectory (PL-RMSD ≈ 2.4 Å) and preserving essential Gly121-His447 catalytic anti-correlations. Conclusions: This study provides a statistically validated scaffold and mechanistic foundation for future biomimetic chromatography validation, advancing the high-throughput screening of neuroprotective agents on a global scale.

Abstract: Human African Trypanosomiasis (HAT) and malaria are serious infectious diseases endemic in tropical regions, caused by protozoan parasites, and necessitating an urgent development of new antiprotozoal drugs. As part of our ongoing search for new antiprotozoal steroidal alkaloids from plants, we investigated the methanolic stem bark extract of Holarrhena pubescens (Apocynaceae). H. pubescens is a tropical tree that some Kenyan coastal communities have long used to treat various ailments, including fever and stomach pain. The crude extract, alkaloid fraction, and 16 subfractions acquired through centrifugal partition chromatography (CPC) displayed promising in vitro antiprotozoal activity against Trypanosoma brucei rhodesiense (Tbr) and Plasmodium falciparum (Pf). Partial least squares (PLS) regression modelling of UHPLC/+ESI QqTOF-MS data and antiprotozoal activity data of the crude extract and its fractions was performed to predict compounds that may be responsible for the observed antiplasmodial activity. Chromatographic separation of the alkaloid fraction afforded one new steroidal alkaloid (5), along with 18 known compounds (1, 2, 4, 6–20), and one artifact (3) that was presumably formed during the acid-base extraction process. The structural characterization of the isolated compounds was accomplished using UHPLC/+ESI-QqTOF-MS/MS and NMR spectroscopy. The isolated compounds were tested for their in vitro antiprotozoal properties against the two aforementioned pathogens, as well as for their cytotoxicity against mammalian cells (L6 cell line). Compounds 2 and 16 (IC₅₀ = 0.2 μmol/L) demonstrated the highest antitrypanosomal activity, with compound 2 showing the highest selectivity (SI = 127). The new compound 5 exhibited the strongest antiplasmodial activity and selectivity against Pf (IC₅₀ = 0.7 μmol/L, SI = 43). Our findings provide further promising antiprotozoal leads for HAT and Malaria.

Abstract:

Many cannabinoids are derived from Cannabis and exhibit a diverse range of pharmacological properties. Predictions of bioactivities of these compounds were conducted by molecular docking computation on two transient receptor potential (TRP) receptors (TRPV1 and TRPC5) found on human glioma (U-87 MG) cells. These predictions were experimentally confirmed by monitoring changes in intracellular calcium concentration in U-87 MG cells treated with cannabinol (CBN), cannabichromene (CBC), and cannabicyclol (CBL), as measured using a fluorescence microplate reader. The results indicate that CBN and CBC are bioactive, whereas CBL exhibits minimal activity. These findings are consistent with predictions obtained from molecular docking computation based on AutoDock Vina.

Abstract: The c-Jun N-terminal kinase (JNK) signaling cascade is a central regulator of cellular stress responses and a validated therapeutic target for diverse pathologies, including neurodegeneration, fibrosis, and cancer. However, the development of direct JNK inhibitors has been impeded by challenges regarding isoform selectivity and on-target toxicity. Consequently, medicinal chemistry efforts have shifted upstream to the "gatekeepers" of the pathway: the dual-specificity kinases MKK4 and MKK7. This review provides a comprehensive analysis of the structural biology, physiological functions, and pharmacological inhibition of these critical signaling nodes. We highlight the non-redundant therapeutic potential of these kinases, contrasting the role of MKK4 inhibition in unlocking liver regeneration with the utility of MKK7 inhibition in suppressing fibrosis and chronic inflammation. A systematic overview of small-molecule inhibitors is presented. For MKK4, we discuss the evolution from early promiscuous chemotypes to the first-in-class clinical candidate HRX215, which has demonstrated safety and efficacy in promoting hepatocyte proliferation. For MKK7, we examine the design of covalent inhibitors exploiting the unique hinge-region cysteine (Cys218), as well as emerging modalities such as lysine-targeting binders and peptide inhibitors disrupting protein-protein interactions. Finally, we discuss remaining challenges and future opportunities, including the development of dual inhibitors and proteolysis-targeting chimeras (PROTACs), to fully exploit the therapeutic value of the MKK4/7-JNK axis.

Abstract: Acmella oleracea (L.) R. K. Jansen (Asteraceae), commonly known as the "toothache plant" or "jambu," is a significant medicinal plant that has been traditionally used in Brazil and other tropical and subtropical regions for relieving dental pain, as an anti-inflammatory agent, and as a culinary spice. Due to its versatile utility, this plant has been extensively studied in modern medicine and pharmacy for its diverse pharmacological properties, including anesthetic, analgesic, anti-inflammatory, antioxidant, and antimicrobial activities. Analytical research on the chemical compositions responsible for these activities has led to the identification of approximately 120 secondary metabolites. These findings provide scientific validation for its traditional uses and have spurred research into the development of ingredients for functional foods and cosmetics. This review incorporates the latest research findings, focusing on biological activities and compounds that have been practically isolated or can be isolated based on quantitative experimental data, to serve as a practical reference for industrial development. Furthermore, factors influencing the content of alkylamides and phenolic compounds, two major bioactive groups, are summarized to support material development. Ultimately, this review aims to provide a clearer understanding of the plant’s utility and contribute to the development of products that enhance human health.

Abstract: The human metapneumovirus (HMPV) Fusion (F) glycoprotein is a high-priority target for "fusion-locking" agents that stabilize its metastable prefusion state. While monomeric catechins like EGCG are known antivirals, the molecular basis for the superior activity of structurally complex dimeric catechins remains poorly understood. We employed an advanced biophysical workflow, integrating 100 ns all-atom Molecular Dynamics (MD), Free Energy Landscape (FEL) analysis, and MM/GBSA thermodynamic integration to decode the Structure-Dynamics Relationship (SDR) of 210 Camellia sinensis (Green tea) phytochemicals. The results reveal a "Galloylation-Driven Anchoring" mechanism: the galloyl moiety of prodelphinidin A2 3′-gallate provides critical electrostatic complementarity to the Asp325-Asp336 acidic ridge. FEL analysis quantitatively demonstrates that this anchoring traps the F protein in a deep, kinetically stabilized global minimum (ΔG = 9.357 kJ/mol), effectively raising the energy barrier for the fusogenic conformational shift. This study provides a rigorous thermodynamic proof-of-concept for the use of dimeric natural scaffolds as precision fusion-locking agents, offering a roadmap for experimental biophysical validation.