Search Results (4,244)

Background/Objectives: The clinical management of visceral pain remains a significant challenge. Our previous study confirmed the analgesic efficacy of dexmedetomidine (Dex) in a mouse model of inflammatory visceral pain (IVP). However, the underlying molecular mechanism, particularly regarding immune regulation, has not been fully elucidated. Methods: In the present study, transcriptomic profiling of both physiological and disease states was performed to characterize associated molecular and immune signatures. Key driver genes were identified by integrating differentially expressed genes (DEGs) from the IVP model with potential Dex targets derived from network pharmacology. Molecular docking simulations evaluated binding interactions. The correlations between Dex’s targets and immune cell infiltration patterns, with a focus on macrophages, were analyzed. Results: Multi-tissue analysis revealed a strong association between IVP pathogenesis and pro-inflammatory immune responses, specifically a shift in macrophage polarization. Within this dysregulated network, seven proteins were identified as direct potential targets of Dex. Among these, six core targets, such as ADGRF1, IDO1, JAK3 and NR1H4, demonstrated the most significant correlations with M1-like macrophages and exhibited strong in silico binding potential with Dex. Conclusions: This integrated analysis suggests that Dex may alleviate visceral pain by modulating a specific gene network linked to pro-inflammatory macrophage activation, thereby promoting the restoration of immune balance. Our findings provide a novel mechanism-informed perspective for the application of Dex in visceral pain therapy. Full article

Background/Objectives: Water deficit during the pod filling stage severely limits the productivity of common beans (Phaseolus vulgaris). Although the effects of water scarcity have been extensively studied in leaves and roots, the contribution of xylem sap to systemic metabolic adaptation remains poorly understood. This study investigated genotype-specific metabolic changes in xylem sap exudates in response to water deficit in two common bean genotypes with contrasting growth rates. The OTI genotype has a growth cycle of 120 days, while Rosa La Bufa (RB) completes its cycle in 80 days under both well-watered and water deficit conditions. Methods: Physiological responses were evaluated, and xylem sap exudate metabolites were profiled using untargeted UPLC–ESI–QTOF–MS. Protein–metabolite interaction networks were reconstructed using STITCH v5 to identify genotype-specific metabolic organization under stress. Results: Water deficit reduced the abundance of multiple xylem metabolites, including flavonoids, isoflavones, phenolic acids, sugars, amino acids, and oxylipin-related compounds, indicating systemic metabolic contraction. OTI exhibited extensive metabolic changes characterized by enrichment of citrate, aromatic amino acids, glycolytic intermediates, flavonoid glycosides, and detoxification-associated metabolites, consistent with active carbon remobilization and oxidative stress responses. In contrast, RB accumulated isoflavones, including genistein, biochanin A, and baicalein, together with glycosylated triterpenoid saponins. Network analysis revealed that OTI developed a broad stress-responsive interactome that integrated phenylpropanoid metabolism, carbon remobilization, and detoxification pathways, whereas RB maintained a compact interactome reinforced by oxylipin-, jasmonate-, and isoflavone-associated modules. Conclusions: Xylem sap undergoes genotype-dependent metabolic adjustment under water deficit, suggesting contrasting drought adaptation strategies. Long growth cycle genotypes activate extensive metabolic plasticity, whereas reduced growth cycle genotypes rely on more specialized defense networks. These findings highlight xylem metabolomics as a valuable approach for understanding systemic drought adaptation and identifying putative metabolic biomarkers associated with drought resilience in common beans. Full article

Reducing sodium in meat products is nutritionally desirable, but salt reduction often weakens myofibrillar protein gelation and reduces texture quality and water retention. This study investigated the effects of L-lysine (Lys) and konjac glucomannan (KGM) on the physicochemical properties, gel characteristics, and structural changes of beef myofibrillar protein (MP) gels under low-salt conditions. The results indicated that reducing NaCl from 0.6 to 0.2 M decreased water-holding capacity (WHC), increased cooking loss, and produced a loose gel network. Compared with the 0.2 M NaCl group, the combined Lys-KGM treatment increased WHC from 28.53% to 56.70% and reduced cooking loss to 22.19% (p < 0.05). Texture analysis showed that Lys-KGM increased hardness and springiness by 69.40% and 80.43%, respectively (p < 0.05). LF-NMR indicated a higher proportion of immobilized water and reduced water mobility in the combined treatment. Lys increased reactive sulfhydryl content and surface hydrophobicity, whereas KGM reduced surface hydrophobicity and enhanced water immobilization. Lys-KGM slightly but significantly decreased α-helix and increased β-sheet contents (p < 0.05), accompanied by changes in the relative contributions of intermolecular forces and a more continuous gel network. Molecular docking and molecular dynamics simulations provided supporting evidence for different interaction patterns between myosin and Lys/KGM. These results suggested that Lys and KGM might help maintain the quality of low-salt meat protein gels and provide a formulation basis for reduced-sodium meat products. Full article

Mass spectrometry-based retina proteomics is an emerging method applied to a better understanding of glaucomatous neurodegeneration. This study reports the identification of retinal proteins and processes associated with elevated intraocular pressure using the magnetic microbead model of glaucoma in mice with consideration of sex as a biological variable. The harvested retinas were analyzed by shotgun proteomics via nanoflow liquid chromatography–electrospray ionization tandem mass spectrometry and label-free quantifications. Ingenuity Pathway Analysis^® was used for biological interpretation of the resulting dataset. Sex had a statistically significant influence on elevated intraocular pressure-induced changes of retinal protein expressions, and principal component analysis of all identified, verified, and quantified proteins indicated a clear separation of the ocular hypertensive versus normotensive clusters in males, while this separation was far less pronounced in females. Metabolic functions were among the most predominant biological features affected by the increased intraocular pressure. While our results overlapped with many previous findings regarding disease pathology, they have also revealed previously unreported proteins, as well as molecular and physiological functions potentially implicated in glaucomatous neurodegeneration of the retina in a sex-dependent manner. Full article

Network pharmacology studies of medicine–food homology plants have identified broad injury response pathways and hubs that cannot support compound-level or Parkinson’s disease (PD)-specific claims. We developed a traceable, non-weighted framework that separates regulatory provenance, PD-context evidence, structural support, and safety/developability liabilities. A ten-plant feasibility panel was locked before overlap with a 1631-gene PD union, yielding 382 plant-associated targets and 190 strict intersections. Leave-one-plant-out analysis retained 173–190 targets, whereas disease source and threshold stress tests showed curation dependence. Whole-blood classifiers showed modest five-fold discrimination (area under the curve, 0.606–0.682) and were excluded from candidate decisions. Redocking-validated AutoDock Vina and protein–ligand interaction fingerprints retained baicalein–MMP9, baicalein–AKT1, and baicalein–BCL2 as caution-tagged follow-up pairs. Quercetin–MMP9 was retained as a liability-tagged comparator, while KCNH2 relations were safety-only. Because no biological validation is presented, these pairs remain hypotheses for prospective MPP⁺-treated SH-SY5Y testing with orthogonal injury, dopaminergic phenotypes, target dependency, material confirmation and safety controls. Baicalein remains source-pending for the material chain. Full article

Background: Autophagy is a process that diversely impacts the stages of both tumor initiation and progression. Elucidating the molecular mechanisms underlying autophagy and its role in tumorigenesis is a key component of anticancer strategies in both prostate cancer and other malignancies. Because advanced prostate cancer frequently exploits enhanced autophagy as a defense mechanism against therapy-induced stress (e.g., from abiraterone), the pharmacological modulation of miRNA levels presents a tremendous opportunity to block the tumor’s escape route and overcome drug resistance. Methods: A comprehensive literature review was conducted to evaluate the molecular pathways determining cancer cell survival and death. The analysis focused on the dual nature of autophagy (functioning as a ‘double-edged sword’) within the tumor microenvironment, microRNA (miRNA) regulatory networks, and the efficacy of synergistic therapeutic strategies in overcoming treatment resistance. Results: The primary focus of this paper is the dual and complex role of autophagy, which serves, on the one hand, as a cellular protective shield against metabolic stress—thereby facilitating metastasis—and, on the other hand, as a potential pathway leading to autophagic cell death. The progression of this crucial process is regulated by intricate interactions (crosstalk) with apoptotic pathways, mediated by Bcl-2 family proteins, key kinases (such as mTOR, JNK, and DAPK), and transcription factors, such as p53. Furthermore, the autophagic machinery is precisely regulated by specific miRNA molecules (e.g., miR-21, miR-141, and miR-375). These not only act as crucial intracellular modulators of autophagy but also serve as promising circulating biomarkers, enabling the monitoring of this process’s activity throughout disease progression. Conclusions: Autophagy, and in particular its modulation via miRNA signaling networks, represents a major and highly promising translational target. By directly impairing this autophagic survival mechanism, ‘double-hit’ combination therapies—integrating autophagy inhibitors (such as hydroxychloroquine or VPS34 inhibitors) with standard antiandrogen or cytotoxic agents—demonstrate promising preclinical potential in overcoming treatment resistance and favorably modulating the immune microenvironment in advanced prostate cancer. Full article

Biomaterial-associated infection remains a persistent challenge for implantable devices, catheters, wound dressings, and tissue-engineering scaffolds. This structured narrative review critically evaluates biomimetic superwetting polysaccharide-based composite hydrogel interfaces based on chitosan, alginate, hyaluronic acid, cellulose/nanocellulose, bacterial cellulose, and dextran. The analysis links polymer network design and cross-linking strategy to pore architecture, swelling, mechanical properties, hydration-layer stabilization, protein adsorption, bacterial adhesion, biofilm development, and cytocompatibility. Stable interfacial hydration can increase the energetic penalty for protein and bacterial approach, but high water uptake alone is insufficient: excessive swelling, low network density, poorly controlled pore interconnectivity, and weak wet-state fixation can compromise durability or provide protected sites for bacterial retention. Study-level comparisons therefore emphasize reported values for network structure, swelling, mechanics, wettability or hydration, and antibacterial/antibiofilm performance, with unreported parameters identified as such. Notably, interactions among biomaterials, bacteria, and host tissues exhibit synergistic and co-evolutionary characteristics, forming a dynamically evolving microecological balance. This eco-synergistic perspective provides a useful conceptual framework for proposing antifouling strategies that aim to regulate rather than eradicate bacterial colonization. Future work should prioritize eco-synergistic design, durable hydration, mechanically stable and porous-yet-cleanable networks, selective interfacial regulation, dynamic characterization, standardized testing, and manufacturable formulations with the minimum necessary active components. Full article

Parkinson’s disease (PD) is a multisystem disorder in which gastrointestinal dysfunction often precedes motor symptoms, yet the molecular links between peripheral stress and central neurodegeneration remain unclear. We investigated whether genes commonly dysregulated in PD and a classic model of intestinal inflammation (IBD) might reveal conserved stress-responsive molecules relevant to brain pathology. Shared gene signatures between PD and inflammatory bowel disease (IBD) were identified from peripheral blood transcriptomes using weighted gene co-expression network analysis (WGCNA). Hub genes were prioritized via protein–protein interaction (PPI) analysis and evaluated for expression consistency in independent brain tissue transcriptomic datasets. Single-cell RNA sequencing (scRNA-seq) of the PD substantia nigra was used to define the cellular context of the key hub gene, and CellChat analysis assessed intercellular communication changes. Immunofluorescence validation was performed in an MPTP-induced PD mouse model. We identified 79 shared genes and 6 hub genes, among which only HSP90AA1 showed consistent upregulation across independent PD transcriptomic validation datasets. Functional enrichment highlighted inflammation-related pathways. Because peripheral immune infiltration showed only minor changes, we further investigated the cellular context of HSP90AA1 within the PD brain. ScRNA-seq analysis of the PD substantia nigra demonstrated that HSP90AA1 was expressed across multiple cell populations. Integration with transcriptional regulatory analysis identified TP53 as a potential upstream regulator, and the strongest TP53–HSP90AA1 co-expression and cellular colocalization signals were observed in astrocytes, prompting further astrocyte-focused investigation. CellChat analysis revealed altered intercellular communication patterns in PD substantia nigra, including changes in synapse-associated ligand–receptor interaction signatures, particularly involving NCAM-related pathways. In the MPTP-induced PD mouse model, immunofluorescence identified astrocytic HSP90α upregulation, and increased nuclear p53 signal in astrocytes, accompanied by dopaminergic neuron loss. Conclusion: Astrocytic upregulation of HSP90AA1 is associated with altered synapse-related intercellular communication patterns in the PD substantia nigra, potentially involving a predicted TP53 associated regulatory component. These findings, validated in an MPTP mouse model, identify HSP90AA1 as a candidate stress-responsive hub linking peripheral inflammatory states with astrocyte-associated molecular alterations in PD, providing a framework for further experimental investigation. Full article

Background/Objectives: Sphagneticola trilobata is a phytochemically rich medicinal plant, yet its antioxidant-active fractions and redox-related mechanisms remain incompletely characterized. This study combined metabolite profiling, antioxidant screening, network pharmacology, pharmacokineticprediction, and molecular docking to characterize active flower and leaf fractions and prioritize antioxidant-related targets. Methods: Petroleum ether, methylene chloride, and ethyl acetate fractions of S. trilobata flowers and leaves were analyzed by ultra-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC–ESI–MS/MS). The predominant metabolite was isolated and spectroscopically characterized. Antioxidant activity was assessed using 2,2′-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and ferric reducing antioxidant power (FRAP). Metabolites from the most active fractions were investigated by target prediction, protein–protein interaction (PPI) analysis, enrichment analysis, SwissADME, and docking. Results: UPLC–ESI–MS/MS tentatively identified 59, 18, and 16 metabolites in the petroleum ether, methylene chloride, and ethyl acetate fractions, respectively, including diterpenes, phenolic acids, flavonoids, fatty acids, triterpenes, and coumarin-related metabolites. Butein was isolated as the predominant metabolite from the ethyl acetate flower fraction, which showed the strongest antioxidant activity, with IC₅₀ values of 5.85 ± 0.14 µg/mL in ABTS and 9.11 ± 0.75 µg/mL in FRAP, followed by the ethyl acetate leaf fraction. Network analysis identified 61 and 82 antioxidant-relevant targets for the flower and leaf ethyl acetate fractions, respectively, with enrichment in inflammation-, apoptosis-, transcription-, hypoxia-, lipid stress-, and kinase-related pathways. Docking suggested fraction-specific compatibility with EGFR/PTGS2/STAT3 for flower metabolites and AKT1/PTGS2 for leaf metabolites. Conclusions: S. trilobata ethyl acetate fractions, particularly the flower fraction, represent promising antioxidant sources with experimentally supported activity and computationally prioritized redox-related hypotheses requiring further validation. Full article

Neuroprotection in childhood developmental and epileptic encephalopathies may require approaches, distinct from adult brain injury models of neuroprotection, with a primary focus on preservation of synaptic density rather than prevention of cellular necrosis. There is growing evidence to indicate early-life seizures activate complement cascade proteins C1q and C3. Subsequently, localized microglia may excessively phagocytose structurally intact synaptic neurons disrupting normal brain maturation. This review incorporates kinetic models of neuro-immune interactions based on human histopathology from epileptogenic tissues and quantitative neuro-immune biomarkers to provide suggestions that complement-mediated synaptic pruning may contribute to structural network disruption and cognitive decline in pediatric epilepsy. While standard anti-seizure medications effectively stabilize electrical activity, they do not mitigate underlying neuro-inflammatory responses. Consequently, targeted pharmacological inhibition of the complement microglia axis may provide a potential disease modifying strategy to protect developing neural circuits. The translational feasibility of using targeted complement inhibitors should be evaluated addressing critical challenges such as central nervous system drug delivery across the blood–brain barrier, immunosuppression management and the application of non-invasive biomarkers to define the precise therapeutic window for intervention. Full article

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT–CD155–CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies. Full article

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of clinically aggressive mature T-cell and natural killer (NK)-cell neoplasms that account for approximately 10–15% of all non-Hodgkin lymphomas in Western countries . The most common subtypes include extranodal NK/T-cell lymphoma (ENKTL), nodal T-follicular helper cell lymphomas, peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALK-positive and ALK-negative), and T-cell lymphoblastic lymphoma. Non-coding RNAs (ncRNAs) constitute the majority of the human transcriptome and play critical roles in regulating gene expression, cellular proliferation, differentiation, migration, and apoptosis. Among these, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have emerged as key regulators of lymphomagenesis and disease progression in PTCLs. These molecules modulate diverse oncogenic pathways through chromatin remodeling, transcriptional regulation, competing endogenous RNA activity, and interactions with RNA-binding proteins, thereby influencing proliferation, immune evasion, treatment resistance, and clinical outcomes. Representative examples include the lncRNA TCLlnc1, which promotes PTCL progression through activation of transforming growth factor-β (TGF-β) signaling, and the circRNAs circKIF4A, circADARB1, and circ-LAMP1, which regulate miRNA-dependent signaling networks involving PDK1/BCL11A, STAT3, and DDR2, respectively. In this review, we summarize the current understanding of the biological and clinical roles of lncRNAs and circRNAs in PTCL and related T-cell and NK-cell neoplasms and highlight their potential as diagnostic and prognostic biomarkers as well as therapeutic targets. We also discuss recent advances and future directions for integrating ncRNA-based approaches into precision medicine for T-cell lymphoma. Full article

Background: Siraitia grosvenorii (monk fruit) is a dioecious medicinal crop native to southern China, yet its terpene synthase (TPS) gene family and the molecular basis of floral sexual dimorphism remain unexplored. Methods: Genome-wide identification of the TPS gene family was performed using HMMER and BLAST-based approaches. Phylogenetic classification, gene structure and conserved motif characterization, and comparative synteny analyses were conducted. Transcriptome data from leaves and fruits at different developmental stages were analyzed for tissue-specific expression profiling. Promoter cis-element analysis, protein–protein interaction network prediction, and molecular docking were performed to characterize the fruit-specific candidate SgTPS49. Results: A total of 58 SgTPS genes were identified and classified into six subfamilies, with TPS-a and TPS-b comprising 72.4% of the family. Approximately 88% of SgTPS genes arose from lineage-specific tandem duplication. Female flowers exhibited monoterpene-dominant scents and smaller corollas, whereas male flowers displayed a mid-morning sesquiterpene burst and greater morphological variation. SgTPS49 was specifically upregulated at 20 days post-pollination and possessed a unique promoter architecture devoid of classical hormone-responsive elements. Molecular docking supported its annotation as a putative monoterpene synthase with favorable GPP binding. Conclusions: This study provides the first comprehensive genomic resource for the SgTPS family in S. grosvenorii, reveals significant sexual dimorphism in floral traits, and identifies SgTPS49 as a key candidate for future functional validation. Full article

Four sesquiterpenes, namely tomentosin, 11α,13-dihydrotomentosin, inuviscolide, and α-costic acid, were isolated from the aerial parts of the medicinal plant Dittrichia viscosa (L.) Greuter and evaluated for antiproliferative activity against HCT116 colorectal and A549 lung cancer cells. All compounds reduced cell viability in a concentration-dependent manner, with tomentosin and inuviscolide exhibiting the greatest activity among the tested compounds and IC₅₀ values in the moderate micromolar range. Evaluation in non-malignant human neonatal dermal fibroblasts (HDFn) revealed compound- and cancer-type-dependent selectivity, with inuviscolide showing greater selectivity toward HCT116 cells and tomentosin showing moderate selectivity toward both cancer cell lines. In silico ADMET and DFT analyses characterized the predicted drug-likeness, pharmacokinetic, toxicity-related, and electronic properties of the compounds, particularly tomentosin and inuviscolide. Network pharmacology prioritized STAT3, ESR1, and PTGS2 as candidate hub targets associated with both cancer types, while enrichment analyses identified pathways related to tumor proliferation, inflammation, immune regulation, and cellular stress. Noncovalent molecular docking, 200 ns molecular dynamics simulations, and MM/GBSA calculations supported possible modeled interactions of tomentosin and inuviscolide with these proteins, with tomentosin displaying the most favorable predicted binding profile. Covalent docking further identified structurally feasible STAT3 CYS687-linked poses with the two sesquiterpenes, although covalent adduct formation and direct target engagement remain to be experimentally validated. Overall, the integrated findings prioritize tomentosin and inuviscolide as D. viscosa-derived natural-product scaffolds with moderate antiproliferative activity for further structural optimization, selectivity assessment, and experimental mechanistic validation. Full article

Background/Objectives: Dibutyl phthalate (DBP) is a ubiquitous environmental plasticizer that has been associated with metabolic dysfunction and steatotic liver injury. Hesperetin, a citrus flavonoid, has reported hepatoprotective properties, but its potential protective mechanisms against DBP-associated steatotic liver injury remain incompletely characterized. Methods: This study integrated network toxicology, network pharmacology, protein–protein interaction analysis, Gene Ontology and KEGG enrichment, molecular docking with redocking validation, sensitivity analysis, and an adverse outcome pathway (AOP) framework to systematically explore the predictive networks linking DBP exposure, MASLD (historically termed NAFLD)-related targets, and hesperetin intervention. Results: The DBP-MASLD network identified TP53, PPARG, TNF, AKT1, and CASP3 as candidate hub targets associated with toxicity, whereas the hesperetin-MASLD network highlighted HSP90AA1, PPARG, ESR1, TNF, and MDM2 as candidate modulatory targets. Integrated pathway analysis indicated that these targets converged mainly on the lipid and atherosclerosis pathway (hsa05417). Triplicate molecular docking, AUC-ROC differentiation validation, and PLIP analysis suggested that Hesperetin (and its glucuronide metabolite) may competitively interact with the exact same active pockets as DBP (and its MBP metabolite). These computational predictions suggest a structural basis for potential interaction, but do not confirm physiological competitive displacement. Conclusions: This in silico study identifies PPARG and TNF as candidate hub targets, providing a structural hypothesis for hesperetin’s potential modulatory effects on DBP-induced steatotic liver injury. These computational predictions establish a theoretical dual-network framework that warrants subsequent in vitro and in vivo experimental validation. Full article