International Journal of Molecular Sciences最新文献

This review introduces and elaborates a novel temporal paradigm, the "Gout Inflammation Time Programming" model, conceptualized through the Gout-STAT™ framework. This model redefines gout inflammation as a dynamic continuum progressing through three precisely timed phases: an acute Perception phase (0-24 h) initiated by monosodium urate (MSU) crystal recognition, triggering the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and neutrophil-driven burst; a critical Adaptation phase (24-72 h) where outcomes are determined by immunometabolic reprogramming of macrophages and synovial fibroblasts; and a chronic Tissue Injury phase (>72 h) driven by epigenetic memory, leading to irreversible osteoarticular destruction. Deciphering this programmed timeline reveals distinct therapeutic windows. We propose a shift towards stage-specific precision interventions, targeting upstream triggers (e.g., mitochondrial reactive oxygen species(ROS), neutrophil extracellular trap formation (NETosis)) in the acute phase, correcting metabolic checkpoints (e.g., succinate accumulation, impaired autophagy) during adaptation, and employing tissue-protective strategies (e.g., epigenetic modulators) in the chronic phase. Furthermore, we highlight the pivotal role of cutting-edge translational technologies, such as intelligent drug delivery systems and digital twin joint models, in achieving spatiotemporal precision. Understanding this intrinsic molecular clock is fundamental for advancing gout management from reactive treatment to a predictive, preventive, and personalized 4P medicine approach.

Ascending placentitis is a significant cause of equine pregnancy loss, yet the upstream inflammatory triggers are poorly defined. Recently, we identified S100A8/S100A9 (S100A8/A9) alarmins as potential upstream regulators in a chronic equine placentitis model. The current study aimed to determine whether this upregulation is sustained in the acute model and in clinical cases, and to elucidate the expression of their downstream inflammatory mediators. Using an experimental model, we quantified S100A8/A9 mRNA expression in acute (n = 5) and chronic (n = 6) placentitis induced by Streptococcus equi ssp. zooepidemicus. We found mRNA expression of S100A8 and S100A9 was significantly upregulated in chorioallantois during both acute (p < 0.001) and chronic (p < 0.0001) disease compared to controls (n = 5), demonstrating their role is not limited to chronic pathology. A strong positive correlation (r = 0.945) underscored their coordinated expression. Immunohistochemistry revealed minimal staining in controls but dense infiltrations of S100A8/A9-positive neutrophils and macrophages in placentitis tissues. To define the clinical relevance of the downstream pathway, we analyzed RNA sequencing data from clinical placentitis cases (placentitis, n = 4) compared to normal postpartum placenta (control, n = 4). This confirmed upregulation of S100A8/A9 and revealed a concurrent increase in their receptors (TLR4, RAGE) and a spectrum of NF-κB-driven effectors, including pro-inflammatory cytokines (IL1β, IL6, TNF), chemokines (CXCL8, CCL2, CXCL10), and the apoptotic mediator CASP3. Our findings establish that S100A8/A9 upregulation is a sustained feature of equine placentitis and delineates a coherent S100A8/A9-TLR4/RAGE-NF-κB signaling axis that drives inflammation and tissue damage in clinical disease. These findings highlight the diagnostic potential of S100A8/A9 and position this alarmin system as a promising therapeutic target for mitigating infection-induced pregnancy loss.

Cancer remains one of the most significant global health challenges, with conventional treatments limited by side effects and resistance to drugs. The unique properties of metal-organic frameworks (MOFs), which offer high surface areas, tunable structures, and biodegradable properties, make them promising candidates for cancer therapy. This review focuses on MOF-based drug delivery systems for cancer treatment in biomedical applications. This article discusses various synthesis methods, drug-loading strategies, and cytotoxicity considerations. The relationship between the basic chemistry of MOFs and their biomedical applications is elucidated by how each feature directly affects MOF performance in cancer drug delivery. Therefore, this review is a practical and complete guide for researchers working to translate MOFs into effective cancer treatments. Moreover, the role of stimuli-responsive MOFs in cancer therapy is highlighted, along with recent studies demonstrating the effectiveness of MOF-based drug delivery systems. Overall, MOFs offer opportunities for advancing cancer treatment and controlled drug delivery.

Gallic acid (GA) is a natural polyphenol abundantly found in a variety of fruits, including blackberries, apples, pineapples, strawberries, bananas, and grapes. With prominent anti-inflammatory and antioxidant properties, GA effectively mitigates inflammation and oxidative stress. Furthermore, it plays a significant role in modulating various cellular processes and biological activities, ultimately inhibiting the progression of pathogenesis. This review explores the multifaceted health benefits of GA, highlighting its role as antidiabetic, anti-obesity, anti-arthritis, hepatoprotective, cardioprotective, and neuroprotective effects. Additionally, its impact on the respiratory, digestive, and reproductive systems, along with its related pathogenesis, is described. Additionally, its role as an antimicrobial is defined primarily through mechanisms such as disruption of microbial cell membranes, inhibition of efflux pumps, and antibiofilm activity. Moreover, this review provides a novel, integrative analysis of GA by unifying its mechanistic roles across various pathogenesis. It further describes the role of GA in cancer management via the modulation of signaling pathways. In addition, it demonstrates the synergistic effects of GA when used in combination with other drugs/compounds and discusses nanoformulation approaches that improve its therapeutic efficacy. However, despite significant preclinical outcomes, the clinical application of GA is limited by a shortage of human trials, low bioavailability, and an inadequate understanding of its mechanisms of action and optimal dosage. To overcome these limitations, well-designed clinical trials, in vivo studies, and advanced nanoformulation approaches are required to enhance bioavailability, elucidate mechanisms of action, and increase knowledge of safety and long-term toxicity. Addressing these gaps will enable the full exploration of GA's benefits in disease prevention and management.

Terpenoids constitute the largest class of plant-specialized metabolites, playing essential roles throughout the plants' life cycle and having diverse applications for humans in nutrition, medicine, and flavor. 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGR) is a rate-limiting enzyme of the mevalonate (MVA) pathway, producing sesquiterpenes, saponins, and other terpenoids. HMGR is post-translationally regulated by downstream MVA products through its N-terminal regulatory domain, limiting terpenoid production. To overcome this bottleneck, we employed a virus-based CRISPR/Cas9 system to genetically modify the N-terminal regulatory domain of HMGR in petunia (Petunia × hybrida) and lettuce (Lactuca sativa L.). In petunia, HMGR1-edited lines exhibited vigorous growth, larger flowers, and increased production of sesquiterpenes. Interestingly, they also showed enhanced production of phenylpropanoid volatiles, revealing a connection between these pathways. Transcript analysis revealed altered expression of genes involved in terpenoid biosynthesis, pyruvate metabolism, phenylpropanoid biosynthesis, and gibberellin- and auxin-related pathways, indicating enhanced carbon flux through these metabolic networks. In lettuce, HMGR7-edited plants displayed elevated emission of sesquiterpenes, apocarotenoids, and the phenylpropanoid benzaldehyde. Together, these results establish a transgene-free strategy to enhance the production of terpenoid and phenylpropanoid volatiles, and provide a framework for developing resilient, nutrient-enriched crops.

Cellular senescence is a stress-induced cell-cycle arrest that constrains expansion of ultraviolet-damaged keratinocytes yet can remodel the microenvironment. This systematic review evaluated histological and genetic or epigenetic senescence markers in actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). PubMed, Scopus, and Web of Science were searched (January 2005-May 2025); 34 human studies were included. AK showed an early senescent signature with frequent cyclin-dependent kinase inhibitor p21 (p21CIP1) expression (82.1%) and DNA damage signaling, including phosphorylated histone H2AX (gamma-H2AX) positivity (77%). In invasive cSCC, p21^CIP1 fell to 43.9% and tumor suppressor p53 immunoreactivity often declined, whereas cyclin-dependent kinase inhibitor p16 (p16INK4a) commonly accumulated without arrest, including cytoplasmic staining at invasion fronts. Reported escape pathways involved c-Jun N-terminal kinase 2 activity and long noncoding RNA PVT1-dependent repression of p21. Telomerase reverse transcriptase (TERT) promoter mutations were prevalent in cSCC (about 50%) and BCC (up to 78%) but uncommon in AK, consistent with late telomerase activation. Study heterogeneity, variable antibody scoring, and limited assessment of senescence-associated beta-galactosidase and secretory mediators restricted cross-study comparability. Standardized, spatially resolved profiling may refine risk stratification and support senescence-targeted prevention and therapy in keratinocyte cancers.

Eukaryotic initiation factor 2 (EIF2) signaling plays a crucial role in regulating mRNA translation and initiating eukaryotic protein synthesis. Computational molecular network pathway analysis of the canonical pathways of the coronaviral infection revealed that EIF2 signaling is inactivated when the coronavirus pathogenesis pathway is activated and vice versa. Our computational analyses indicated that the coronavirus pathogenesis pathway and EIF2 signaling had inverse activation states. Computational investigation of upstream or downstream microRNA (miRNA) revealed that EIF2 signaling directly interacted with miRNAs, including let-7, miR-1292-3p (miRNAs with the seed CGCGCCC), miR-15, miR-34, miR-378, miR-493, miR-497, miR-7, miR-8, and MIRLET7. A total of 36 nodes, including 8 molecules (ATF4, BCL2, CCND1, DDIT3, EIF2A, EIF2AK3, EIF4E, and ERK1/2), 1 complex (the ribosomal 40s subunit), and 1 function (apoptosis) in the coronavirus pathogenesis pathway, overlapped with EIF2 signaling. Alterations in EIF2 signaling may play a role in the pathogenesis of coronavirus.

In the original publication [...].

Torsional stress from DNA supercoiling is receiving renewed attention as a driving force for chromosome folding and the establishment of gene activity states. Transcription is a major source of DNA supercoiling, while topoisomerases relax supercoils and solve topological problems that arise during DNA replication, transcription, and chromosome segregation. Recent technological advancements have allowed for the mapping of how torsional stress distributes within the genome and distinguishing between occupancy of topoisomerases on chromatin and sites where they are catalytically engaged. Coupling these innovations to assessments of 3D chromosome conformation and nascent transcription at high resolution have provided a new understanding of the relationships between supercoiling and topoisomerase activity. Here, we summarize the insights obtained from these recent studies and discuss how the interplay between transcription, supercoiling, and topoisomerases shapes cellular gene activity states.

The journal retracts the article titled "Role of Etanercept and Infliximab on Nociceptive Changes Induced by the Experimental Model of Fibromyalgia" [...].