Osteoarthritis (OA) is the most common form of arthritis and joint disorder worldwide. Metabolic reprogramming of osteoarthritic chondrocytes from oxidative phosphorylation to glycolysis results in the accumulation of lactate from glycolytic metabolite pyruvate by lactate dehydrogenase A (LDHA), leading to cartilage degeneration. In the present study, we investigated the protective effects of the intra-articular administration of oxamate (LDHA inhibitor) against OA development and glycolysis-related protein expression in experimental OA rats. The animals were randomly allocated into four groups: Sham, anterior cruciate ligament transection (ACLT), ACLT + oxamate (0.25 and 2.5 mg/kg). Oxamate-treated groups received an intra-articular injection of oxamate once a week for 5 weeks. Intra-articular oxamate significantly reduced the weight-bearing defects and knee width in ACLT rats. Histopathological analyses showed that oxamate caused significantly less cartilage degeneration in the ACLT rats. Oxamate exerts hypertrophic effects in articular cartilage chondrocytes by inhibiting glucose transporter 1, glucose transporter 3, hexokinase II, pyruvate kinase M2, pyruvate dehydrogenase kinases 1 and 2, pyruvate dehydrogenase kinase 2, and LHDA. Further analysis revealed that oxamate significantly reduced chondrocyte apoptosis in articular cartilage. Oxamate attenuates nociception, inflammation, cartilage degradation, and chondrocyte apoptosis and possibly attenuates glycolysis-related protein expression in ACLT-induced OA rats. The present findings will facilitate future research on LDHA inhibitors in prevention strategies for OA progression.

Chronic, dysregulated inflammation contributes to colitis-associated colorectal cancer (CRC), and the cGAS–STING pathway represents a central but therapeutically challenging node because both insufficient and excessive STING activity can be pathogenic. Here, we integrate AlphaFold3 (AF3) receptor modeling, diffusion-based docking, and explicit-solvent molecular dynamics (MD) simulations to characterize how the marine briarane diterpenoid excavatolide B (ExcB) engages the human STING (hSTING) cyclic dinucleotide (CDN)-binding cleft. The structural integrity of the AF3 hSTING model was validated through both intrinsic confidence scores (pLDDT, PAE) and comparative benchmarking against experimental CTD structures (PDB: 4EF5, 6A05). Notably, the local geometries of key pocket-defining residues—including His157, Tyr167, and Thr263—remained consistent with established crystallographic data. Across three independent 100 ns MD replicas, ExcB exhibits a consistent spatial progression from an entrance-proximal pose at the solvent-accessible rim of the cleft (Site-2) to a more embedded, non-canonical corridor on the Cys148-adjacent side (Site-2′). Distance and contact analyses support a predominantly non-covalent within-cleft mechanism and do not indicate a persistent approach to the literature-reported covalent regime near Cys91. Residue-level profiling over the stabilized sampling window defines a reproducible corridor “contact signature” and reveals within-cavity sub-pose diversity rather than a single rigid bound pose. Mechanistically, competitive docking of the native agonist cGAMP to ExcB-conditioned receptor snapshots yields consistently less favorable docking outcomes in ExcB-conditioned conformations than docking to the native/open receptor; retaining ExcB coordinates does not further penalize cGAMP, supporting a receptor-reshaping (conformational conditioning) component rather than persistent static steric clash. Our findings characterize ExcB as a non-covalent modulator targeting a cryptic pocket within the STING CDN-binding cleft, establishing a structural basis for targeted mutagenesis and structure-activity relationship (SAR) studies.

This review provides a comprehensive overview of the structural characteristics, nomenclature, and biological activities of naturally occurring capnosane diterpenoids (3,7-cyclized cembranoids) reported from 1986 to 2025. The compounds covered in this survey have been isolated primarily from octocorals of the genera Alcyonium, Cespitularia, Klyxum, Lobophytum, Sarcophyton, and Sclerophytum, as well as from the tobacco species Nicotiana tabacum. A number of these naturally derived metabolites have demonstrated noteworthy biomedical potential in various biological evaluations.

Chronic, dysregulated inflammation is a recognized driver of colitis‑associated colorectal cancer (CRC). At the molecular level, the cGAS–STING pathway integrates cytosolic DNA sensing with type‑I interferon and NF‑κB responses, yet its pleiotropy complicates intervention: insufficient activity blunts antitumor immunity, whereas over‑activation fuels tissue‑damaging cytokine milieus. Motivated by the anti‑inflammatory efficacy of the marine briarane diterpenoid excavatolide B (ExcB) and recent reports of STING antagonism, we combined AlphaFold3 complex prediction with AI‑assisted docking and short explicit‑solvent MD (10 ns) to map ExcB–human STING (hSTING) interactions. Beyond the canonical Cys148/Tyr240 region (Site‑1), our pipeline identifies an entrance‑proximal pose at the CDN rim (Site‑2) and a buried pose (Site‑2′) that conditions hSTING into a CDN‑averse conformation. Competitive docking of cGAMP onto ExcB‑conditioned snapshots yields qualitatively weaker scores versus native, consistent with allosteric occlusion rather than direct steric clash. As a methodological check, we benchmarked the same docking workflow on two reported STING antagonists, SN‑011 and Astin C, reproducing their canonical CDN‑pocket contacts before applying the pipeline to ExcB. Collectively, these results support ExcB‑like, gate‑closing STING antagonists as tunable non‑activators with favorable developability, and motivate mutagenesis and competition assays around His157/Tyr167/Thr263 to dissect Site‑2 → Site‑2′ contributions.

Objective and design: We tested whether a frozen branch-resolved IFN/STING-linked lesion-state architecture derived from paired psoriasis transcriptomes would transport to an untouched bulk RNA-sequencing cohort and remain detectable within broad cell compartments. Material or subjects: Seven paired bulk cohorts formed the derivation backbone. GSE121212 provided held-out replication using 27 matched lesional/nonlesional pairs; treatment-facing cohorts and GSE228421 provided pharmacodynamic and cellular-context analyses. Treatment: No intervention was administered by the authors; public datasets included ustekinumab-, etanercept-, secukinumab- and risankizumab-exposed samples. Methods: Frozen modules and branches were scored after cohort-wide gene standardization. GSE121212 counts underwent trimmed mean of M-values normalization and log2 counts-per-million transformation. Paired effects, upper-quartile STING-high contrasts, lesional Spearman coupling and prespecified rank concordance were evaluated. Results: GSE121212 lesional-minus-nonlesional effects were 1.288 for STING-core, 1.478 for IFN-responsive activity and 1.188 for proximal-only STING; all lower 95% confidence limits exceeded zero. Coupling-vector concordance was strong (rho = 0.893, P = 0.0068), whereas STING-high effect concordance was moderate (rho = 0.536), yielding partial replication. Conclusions: Held-out replication was partial: the IFN/STING lesion anchor and proximal/IFN-dominant coupling transported, while broader ordering did not fully transport. Transcriptomic findings do not establish biochemical STING activation, causality or clinical thresholds.