Search Results (1,240)

As the core molecular chaperones of the cellular stress response, the heat shock protein (HSP) family has gained extensive attention for its role in the occurrence, development, and target organ damage of hypertension. This review aimed to comprehensively summarize the research progress of the HSP family in the field of hypertension, and to analyze its key roles in the pathogenesis of hypertension, including its regulatory effects on key pathological processes such as endothelial dysfunction, proliferation and migration of vascular smooth muscle cells, oxidative stress, and inflammatory responses. It also summarized the potential value of HSPs as biomarkers in the early diagnosis, condition monitoring, and prognostic evaluation of hypertension. Moreover, it discussed in depth the efficacy and safety of intervention strategies targeting HSPs, including the regulation of HSPs by gene editing, the targeted effects of small-molecule inhibitors, and the modulatory effects of natural products. We need to strengthen interdisciplinary collaboration mechanisms, accelerate the transformation of basic research results into clinical applications, carry out large-scale clinical trials, and develop specific modulators in the future, so as to ultimately provide solid scientific theoretical support and a practical clinical basis for the precise prevention and treatment of hypertension. The findings of this review not only provide novel insights into the pathogenesis of hypertension but also lay a theoretical foundation for the development of HSP-based biomarkers and targeted therapeutic strategies. Full article

Neurodegenerative disorders and epilepsy remain major clinical challenges, due to complex etiologies involving protein misfolding, excitotoxicity, metabolic dysregulation, and impaired cellular resilience. These unmet medical needs have stimulated interest in small-molecule modulators capable of targeting multiple pathogenic pathways. Cyclitols, a diverse family of inositol stereoisomers, play essential roles in cellular signaling and brain metabolism; among them, scyllo-inositol (SCI) has gained attention due to its distinct stereochemistry, capacity to cross the blood–brain barrier, and emerging neuroactive properties. Current pharmacokinetic data indicate that SCI exhibits dose-dependent systemic exposure, and good penetration into the central nervous system. Moreover, its supplementation seems to be well-tolerated. In experimental studies both on animals and humans, SCI has been shown to modulate amyloid-β aggregation, stabilize neuronal homeostatic pathways, and reduce network hyperexcitability, suggesting relevance for both neurodegenerative and epileptic phenotypes. Despite promising results, there is still a need for further analyses to define dosing, transporter involvement, and brain exposure thresholds. Collectively, the available data position SCI as a compelling candidate for translational development, warranting further investigation into its therapeutic window and disease-modifying potential across neurological disorders. Full article

DMG, including DIPG, is a highly aggressive pediatric brain tumor with dismal clinical outcomes. Radiotherapy remains the cornerstone of treatment, yet responses are transient and resistance is nearly universal. Emerging evidence indicates that EVs are key mediators of radiation response, facilitating intercellular communication and the propagation of radioresistant phenotypes within the tumor microenvironment. EVs carry diverse molecular cargo, including RNAs, proteins, and lipids, that can dynamically influence tumor behavior and treatment response. In this review, we focus on the role of EVs in shaping radiation response in DMG, while also examining their broader functions in tumor biology, biomarker development, and therapeutic delivery. We summarize evidence for EV-mediated regulation of tumor growth, invasion, microenvironmental interactions, and immune modulation. We further discuss the potential of EVs as minimally invasive biomarkers for liquid biopsy, highlighting both their advantages and current limitations relative to circulating tumor DNA (ctDNA) approaches. In addition, we review emerging strategies utilizing EVs as therapeutic delivery platforms capable of crossing the blood–brain barrier (BBB) and delivering small molecules and nucleic acid-based therapies. Finally, we explore the role of EVs in modulating radiation response, including their contribution to radioresistance and their potential as biomarkers of treatment efficacy. Although EV-based approaches hold significant promise in DMG, challenges related to standardization, specificity, and clinical validation remain. Continued investigation into EV biology and translational applications may provide new opportunities for improving diagnosis, monitoring, and treatment of this devastating disease. Full article

Mitochondrial electron transport chain (ETC) dysfunction is a major driver of bioenergetic failure, redox imbalance, and drug toxicity, yet strategies to restore oxidative phosphorylation under ETC blockade remain limited. Redox-active small molecules could, in principle, shuttle electrons from NADH to distal ETC components and oxygen, thereby modulating both respiration and reactive oxygen species (ROS) formation. Here, we show that the enzyme-independent redox cycler phenazine methosulfate (PMS) rewires mitochondrial redox circuits and restores respiration in human glioblastoma cells and cell-free systems under ETC inhibition. At subtoxic concentrations, PMS acutely increased oxygen consumption and mitochondrial superoxide generation via NADH–PMS–O₂ redox cycling, while restoring mitochondrial membrane potential and ATP synthesis under ETC blockade, and shifting metabolism away from glycolytic lactate production. This profile is consistent with a protective redox-bypass role, distinct from the pro-apoptotic effects reported following high-dose, prolonged PMS exposure. The PMS-driven restoration of electron flow, mitochondrial membrane potential, and respiratory ATP synthesis under inhibition of Complex I (rotenone), III (antimycin A and myxothiazol), and/or IV (cyanide) is consistent with direct cytochrome c reduction, as demonstrated herein, and engagement of multiple ETC redox centers, including coenzyme Q₁₀. In metformin-treated cells, PMS reversed suppression of respiration and lactate accumulation, outperforming existing redox-bypass strategies. These findings identify PMS-driven redox cycling as a previously unrecognized chemical redox-bypass mechanism that both regenerates mitochondrial bioenergetics and reshapes ROS production, suggesting a potential approach to counteract drug- and toxin-induced mitochondrial dysfunction and to exploit redox vulnerabilities in cancer. Full article

Melasma is a chronic hyperpigmentation disorder that significantly impacts quality of life. Given the persistent challenges in melasma management, there is a need to evaluate therapies that may offer long-term treatment. This descriptive review analyzes interventional clinical studies involving melasma patients and placebo or hydroquinone (HQ) comparators published between 2014 and 2024. Two human authors screened studies and extracted data, with artificial intelligence used as a human-supervised support tool for screening assistance, data extraction, and discussion synthesis. Study limitations were evaluated descriptively. Treatments were grouped into five categories: HQ-based Standard Treatments, Isolated Molecules as Depigmenting Therapies, Botanical and Antioxidant-Based Therapies, Regenerative and Microenvironment-Modulating Therapies, and Procedure-Assisted and Combination Treatments. HQ remained a key benchmark, although recurrence and tolerability limitations were frequently observed. Several non-HQ or adjunctive approaches demonstrated benefit when administered orally, topically, intradermally, or via iontophoresis. Botanical antioxidants, synbiotics, epidermal growth factor, and platelet-rich plasma also showed promising efficacy. Nevertheless, the evidence base was constrained by small sample sizes, heterogeneous comparators, inconsistent endpoints, mixed objective and subjective assessments, and variable follow-up durations, which prevented meta-analysis. Research on melasma treatment is growing worldwide, with several promising non-HQ and adjunctive strategies emerging. However, standardization of outcomes, comparator selection, and longer follow-up periods is needed to clarify efficacy, tolerability, and relapse prevention throughout diverse skin tones. Full article

Endocrine therapy is an effective and common treatment strategy for estrogen receptor (ER)-positive breast cancers. However, the development of endocrine resistance, through genetic mutations and epigenetic alterations, in about 40% of treated patients remains a significant therapeutic challenge. Liver X receptors (LXRs) are nuclear receptors that regulate lipid metabolism and cholesterol homeostasis and have been implicated in metabolic reprogramming in breast cancers and other malignancies. We previously identified a novel LXR ligand GAC0001E5 (1E5), with potent antiproliferative activity across breast cancer subtypes. Here, we investigate its mechanisms of action in responsive (MCF-7) and endocrine-resistant (MCF-7-TamR) ER-positive breast cancer cells. Treatment with 1E5 resulted in the downregulation of LXR and its target genes, and significantly reduced ERα expression and the expression of ER-responsive genes. Aberrant expression of androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2), both implicated in endocrine resistance, were downregulated following 1E5 treatment. siRNA-mediated knockdown of LXR expression only partially recapitulated the actions of 1E5, suggesting the involvement of LXR-dependent and independent mechanisms. Collectively, these findings reveal potential crosstalk between LXR and the genetic and epigenetic regulation of pathways involved in endocrine response and alternative signaling mechanisms, highlighting potential targets in endocrine-resistant breast cancer. Full article

DNA viruses rely extensively on host cellular machinery, including replication factors and transcriptional systems, to persist after infection. These mechanisms make studying and targeting DNA viral proteins challenging, as they also play key roles in mammalian processes. Traditional strategies include CRISPR-mediated gene disruption and small interfering RNA (siRNA) to target host proteins. However, Proteolysis Targeting Chimeras (PROTACs) offer a novel strategy by enabling the selective and rapid degradation of specific viral or host proteins involved in the DNA viral lifecycle. PROTACs are heterobifunctional molecules composed of three key components: a ligand that binds the target protein, a chemical linker, and a ligand that recruits an E3 ubiquitin ligase. By simultaneously binding both the target protein and the E3 ligase, PROTACs form a ternary complex. This proximity enables the E3 ligase to ubiquitinate the target protein, marking it for recognition and subsequent degradation by the intracellular proteasome. This approach represents a promising avenue for targeting previously undruggable proteins and improving therapeutic outcomes in virus-associated malignancies. In this perspective, we describe studies that use PROTACs as tools to modulate host proteins to investigate DNA viral processes with temporal control of host protein expression, as well as the use of PROTACs as antivirals to directly target DNA viral proteins. We also provide a detailed chart summarizing known host-targeting PROTACs and their potential applications across different stages of DNA viral lifecycles, highlighting opportunities for future DNA virus research. Full article

Although antiviral development against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been dominated by replication-directed strategies, structural and accessory proteins offer a complementary and increasingly important opportunity for small-molecule intervention. These proteins control key processes outside the core replication machinery, including viral entry, membrane remodelling, virion assembly, egress, and host immune modulation, thereby expanding the mechanistic scope of antiviral design. However, many of these targets are membrane-associated, oligomeric, conformationally dynamic, or function through protein–protein interactions, creating distinct challenges in target validation, assay design, and chemical optimisation. In this review, we comprehensively and critically evaluate the structural and accessory proteomes of SARS-CoV-2, with a strict focus on small-molecule tractability and translational relevance. We highlight the most credible direct-acting opportunities, focusing on the membrane (M), envelope (E), and nucleocapsid (N) structural proteins, together with the accessory protein open reading frame 3a (ORF3a), for which emerging chemical matter strengthens confidence in druggability. In contrast, Spike (S) and several host-interface accessory proteins, including ORF6, ORF8, ORF9b, and ORF10, are best viewed as more selective or earlier-stage opportunities that require stronger on-target chemical validation. Emphasis is placed on structural accessibility, mechanism-based assay systems, evidence quality, cellular and in vivo activity, and developability constraints relevant to exposure at the infection site. Rather than replacing replication-directed antivirals, these non-canonical targets are best considered adjunctive or complementary components of future combination strategies designed to broaden antiviral coverage, enhance robustness, and improve pandemic preparedness. Full article

Heat shock proteins (HSPs) are highly conserved molecular chaperones that play a key role in maintaining protein homeostasis and cellular survival under stress conditions. Clinically relevant human pathogenic fungi include opportunistic fungi, dimorphic fungi, dermatophytes, Mucorales, and other pathogenic groups. HSPs, including Hsp90, Hsp70, Hsp60, Hsp40, and Hsp110, are essential for the correct nascent protein folding, aggregation prevention, and degradation of misfolded polypeptides. Fungal pathogens frequently encounter environmental and host-imposed stresses, including oxidative stress, temperature fluctuations, and antifungal treatments. This review synthesizes and critically analyzes current evidence on the role of HSP families in essential processes linked to fungal virulence, including morphogenetic transitions, biofilm formation, maintenance of cell wall integrity, and interactions with host immune cells. Beyond their canonical chaperone functions, HSPs act as central mediators in pathogenic processes, such as morphogenesis transitions, biofilm formation, cell wall integrity, and interactions with host immune cells. Hsp90 stabilizes key signaling proteins involved in stress responses, morphogenesis, and antifungal resistance, while Hsp60 and Hsp70 contribute to mitochondrial function, cell wall integrity, and immune modulation. Disruption of these chaperones impairs growth, reduces virulence, and increases susceptibility to antifungal agents. The rise of antifungal resistance underscores the urgent need for new therapeutic strategies. Targeting fungal HSPs has emerged as a promising approach due to their essential roles in stress tolerance and pathogenesis. Hsp90 inhibitors, including geldanamycin derivatives and other small molecules, have demonstrated the ability to impair fungal growth, reduce virulence traits, and sensitize resistant strains to conventional antifungal drugs. Combining HSP inhibitors with existing antifungal drugs represents a potential strategy to overcome resistance and improve treatment outcomes. This review summarizes the current knowledge on HSPs in pathogenic fungi, focusing on their roles in stress adaptation, virulence, host-pathogen interaction, antifungal resistance, and their potential as targets for novel antifungal therapies. Full article

Neospora caninum is a major apicomplexan pathogen responsible for significant reproductive losses in livestock, yet lacks effective therapeutics. Here, we identify and functionally characterize a previously unstudied OTU-like deubiquitinase (ncOTU; XP_003886403) as a key modulator of host–pathogen interactions. Sequence and structural analyses revealed conservation of the catalytic triad (D257, C260, H362) and a Y305-W315-G316 inhibition pocket analogous to viral OTU proteases. Recombinant ncOTU exhibited robust deubiquitinase activity and significantly reduced global ubiquitination levels in mammalian cells, preferentially targeting mono-ubiquitinated and low-molecular-weight substrates. Transcriptomic analysis demonstrated that ncOTU expression correlates with suppressed NF-κB signaling, type I interferon responses, and downstream antiviral effectors, while partially uncoupling upstream nucleic acid sensing pathways. Structure-based virtual screening and biochemical validation identified multiple small-molecule inhibitors targeting the conserved inhibition pocket. Dose-response analysis revealed submicromolar potency for ncOTUi-9 (IC₅₀ = 0.1 μM), ncOTUi-8 (0.2 μM), and ncOTUi-19 (0.3 μM), whereas ncOTUi-3 showed lower activity (7.1 μM). Interaction analyses confirmed stable binding within the inhibition pocket, with more extensive contact networks correlating with increased potency. Collectively, these findings establish ncOTU as a functional deubiquitinase that contributes to evasion and highlight it as a promising therapeutic target for neosporosis. Full article

Parkinson’s disease is strongly linked to lysosomal dysfunction, particularly reduced activity of glucocerebrosidase (GCase) encoded by the GBA1 gene. Stabilizing GCase using small-molecule modulators represents a promising therapeutic strategy. In this study, phytochemicals from Xylia xylocarpa (Roxb.) Taub., a medicinal plant with reported neuroprotective potential, were profiled using LC-QTOF-MS and evaluated as GCase stabilizers through an integrated computational approach. LC-MS analysis in positive and negative modes tentatively identified 19 metabolites, of which 13 low-molecular-weight compounds (<500 Da) were selected for molecular docking against human GCase. Docking revealed six compounds with higher predicted binding affinity than the reference activator Pyrrolopyrazine. Pharmacokinetic screening based on Lipinski’s rule of five and ADMET predictions identified Senbusine A as a viable lead candidate. It exhibited favorable binding interactions, forming stabilizing contacts within a non-catalytic inter-monomer interface associated with structural modulation of GCase. PASS analysis suggested a high probability of neuroactive properties. Molecular dynamics simulations (200 ns) confirmed stable binding and reduced conformational fluctuations compared to apo and control systems. Overall, computational predictions identify Senbusine A as a potential pharmacological chaperone-like stabilizer of GCase, exhibiting a favorable pharmacological profile and warranting further experimental validation. Full article

Immune checkpoint modulation has emerged as a promising strategy in cancer therapy, including the treatment of aggressive tumors such as glioblastoma. Among these targets, programmed death-ligand 1 (PD-L1) plays a key role in tumor immune evasion and represents an attractive target for small-molecule inhibitor development. In this study, a virtual screening approach was applied to identify potential PD-L1 modulators within a library of nucleoside-related compounds and structurally similar molecules. A dataset of 400 compounds was evaluated using molecular docking to predict their binding affinity (free energy values and binding pose) toward PD-L1. The resulting complexes were analyzed to identify nonbond interactions within the hydrophobic pocket formed at the PD-L1 dimer interface. In addition to docking results, physicochemical descriptors associated with drug-likeness and blood-brain barrier penetration were calculated, including lipophilicity, molecular weight, hydrogen bond donors and acceptors, as well as topological polar surface area. To integrate these parameters, a multiparameter optimization (MPO) score was implemented. Finally, molecular dynamics simulations of protein-ligand interactions were performed to explore the structural stability for 100 ns using the most promising ligands. The analysis revealed that several top-ranked compounds exhibited favorable docking scores and physicochemical properties compatible with drug-like behavior. Interestingly, BMS-1, a known PD-L1 inhibitor, was identified among the highest-scoring compounds, supporting the reliability of the MPO protocol. Furthermore, multiple candidates displaying nucleoside-like scaffolds combined with reduced polarity and moderate lipophilicity emerged as promising molecules according to the MPO ranking. Overall, the results suggest that nucleoside-derived scaffolds may represent a viable starting point for the development of small-molecule PD-L1 modulators with potential applicability in glioblastoma therapy. Full article

Background/Objectives: Osteoporosis remains a clinically important metabolic bone disorder with limited bone-forming therapeutic options. SET domain bifurcated protein 1 (SETDB1) is involved in osteogenic epigenetic regulation, but small-molecule discovery guided by SETDB1-associated structural regions remains limited. This study aimed to identify a candidate compound with in silico relevance to a SETDB1-associated ligand-bound pocket and assess its association with early osteogenic readouts. Methods: A computational–experimental workflow was used, including hierarchical molecular docking, MM-GBSA rescoring, ADMET-based prioritization, redocking validation, molecular dynamics simulations, and preliminary in vitro evaluation in MC3T3-E1 cells. Compound 271 (C271) was selected based on structure-based screening results and predicted developability-related properties. Cytocompatibility, alkaline phosphatase (ALP) activity and staining, selected molecular markers, and SETDB1–H3 molecular dynamics behavior were evaluated. Results: Redocking reproduced the reference binding mode, and molecular dynamics simulations indicated that C271 maintained a relatively persistent conformation around the predicted SETDB1-associated pocket. Comparative SETDB1–H3 simulations showed altered H3 dynamics and SETDB1–H3 contact patterns in the C271-containing system. In cell-based assays, C271 showed no appreciable cytotoxicity within the tested concentration range and was associated with increased ALP activity and staining. C271 treatment was accompanied by higher global H3K9me3 and Runx2 levels, whereas SETDB1 protein abundance remained largely unchanged. Conclusions: C271 was identified as a computationally prioritized SETDB1-related candidate compound associated with early osteogenic-associated cellular responses. The evidence supports computational plausibility and cell-level association, but does not establish direct SETDB1 engagement, SETDB1 enzymatic modulation, SETDB1-dependent causality, or late-stage osteogenic maturation/mineralization. Given the single-compound evaluation, further target-engagement, enzymatic, and functional studies are needed. Full article

Molecular trajectory prediction is fundamental to computational chemistry, drug discovery, and materials simulation, enabling insights into dynamics, reaction pathways, and conformational stability. Its natural alignment with graph-structured spatiotemporal data has made it a key frontier in GNN research. However, current mainstream spatiotemporal GNNs, while enforcing E(3)-equivariance, treat atoms as unconstrained point masses and lack explicit rigid geometric constraints, often yielding unphysical deformations that compromise predictive interpretability. To address this challenge, we propose STEGMN—the first spatiotemporal graph architecture for molecular trajectory prediction that explicitly encodes rigid constraints. Inspired by Graph Mechanics Networks, we design a constraint-preserving equivariant spatiotemporal attention mechanism that captures temporal dependencies while rigorously maintaining both E(3)-equivariance and rigid-body constraints. Additionally, we introduce a constraint-preserving equivariant pooling module that generates future states by performing a learnable weighted aggregation of historical angular velocities, followed by forward kinematics mapping. This ensures that all outputs simultaneously satisfy E(3)-equivariance and strict bond-length conservation. Evaluated on real-world molecular dynamics datasets, STEGMN consistently outperforms strong baselines. On the rMD17 benchmark, it achieves an average ∼40% reduction in prediction MSE relative to representative spatiotemporal graph models (ST-GNN, ST-GCN, and ST-EGNN) across eight small-molecule systems, highlighting the critical value of explicit constraint modeling for physically stable trajectory prediction. Full article

An isolate of the diatom Staurosirella pinnata is a promising platform for drug discovery due to its ability to produce bioactive metabolites. As previously shown, S. pinnata extracts exhibit bioactivities, with hydrophilic fractions showing selective cytotoxicity against human melanoma cells and lipidic fractions promoting thermogenesis in murine white adipocytes. In this work, we focused on the interaction between S. pinnata metabolism and light irradiance exposure to evaluate bioactivity targeting medulloblastoma cells. Cultures under standard, control, irradiance (80 µmol photons m⁻² s⁻¹) were exposed in the stationary phase to increased light intensities (200 and 600 µmol photons m⁻² s⁻¹) for 126 h. Growth, photosynthetic performance and metabolic profile were monitored, while the bioactivity of small-molecule fractions was assessed at the end. Exposure to 200 µmol photons m⁻² s⁻¹ significantly enhanced growth (92.6% increase in absorbances compared to the control), whereas 600 µmol photons m⁻² s⁻¹ induced growth inhibition (41.3% decrease in absorbances with respect to the control culture) and impaired photosynthesis. Metabolomic analysis revealed a shift from carbohydrate to lipid metabolism. Bioactivity assays showed that extracts from the highest irradiance exhibited cytotoxic effects on medulloblastoma cells, similar to the 80 µmol photons m⁻² s⁻¹ cultures on DAOY (68% vs. 82% of cell death induction levels, respectively), while intermediate irradiance did not show a significant effect in any of the tested cell lines. The results showed that different light intensities impact S. pinnata metabolism, demonstrating effects exploitable for drug discovery and the importance of investigating the impact of cultivation parameters in modulating S. pinnata bioactivity potential. Full article