Search Results (315)

Di(2-ethylhexyl) phthalate (DEHP), a widely employed exogenous plasticizer, has become pervasive in the environment and living organisms due to its extensive use in food packaging, medical devices, and daily consumer products, and is established as a typical endocrine-disrupting chemical. Growing evidence indicates a strong association between DEHP exposure and the incidence of chronic bone disorders, including osteoporosis (OP), osteoarthritis (OA), and osteonecrosis of the femoral head (ONFH). However, the molecular mechanisms underlying its pathogenic effects across these diseases remain poorly defined. In this study, we applied an environmental network toxicology approach to integrate predicted protein targets of DEHP with known disease-associated targets of the three bone disorders using multiple databases. Through Venn analysis, protein–protein interaction (PPI) network construction, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, we identified core targets and key signaling pathways. Molecular docking and molecular dynamics (MD) simulations were further employed to validate the binding modes and stability between DEHP and the core targets, thereby elucidating common and distinct mechanisms of DEHP across these bone diseases. A total of 109 overlapping targets of DEHP and the three bone diseases were identified, among which 7 core targets—AKT1, SRC, ESR1, CASP3, MMP9, BCL2, and BCL2L1—were common to all three disorders. These are implicated in critical biological processes such as apoptosis regulation, inflammation, extracellular matrix degradation, and estrogen signaling. KEGG enrichment analysis revealed significant involvement of the PI3K-Akt, MAPK, Ras, TNF, and estrogen signaling pathways across all three diseases. Molecular docking and MD simulations confirmed stable binding of DEHP to key targets including AKT1, ESR1, and MMP9, supporting its potential to disrupt bone metabolic homeostasis via multi-target and multi-pathway mechanisms. Further analysis indicated that DEHP exerts both shared and disease-specific effects: it disrupts osteoblast/osteoclast balance in OP, amplifies inflammatory responses and matrix degradation in OA, and contributes to impaired angiogenesis and osteocyte necrosis in ONFH. This study systematically reveals how DEHP disrupts bone homeostasis through a multi-target and multi-pathway network, constructing a cross-disease osteotoxicity framework. It is the first to delineate the common and distinct molecular mechanisms of DEHP in OP, OA, and ONFH. Although these insights are derived from computational models and require further experimental validation, they provide a novel theoretical basis for combined intervention strategies targeting multiple bone diseases and for environmental health risk assessment. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades—cAMP/PKA, PI3K/Akt, and MAPK pathways—that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood–brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications. Full article

Background: Reproductive efficiency is a significant hurdle to the sustainability of the beef cattle industry. Method: This study employed transcriptomic profiling to investigate endometrial gene expression differences in heifers with divergent fertility outcomes. Caruncular endometrial samples from fertile (n = 7) and subfertile (n = 5) heifers were subjected to RNA-Seq analysis, yielding 894 differentially expressed genes (DEGs) (p ≤ 0.05 and |log2FC| ≥ 0.5). Results: The MAPK (Mitogen-activated protein kinase) and Rap1 (Ras-associated protein 1) signaling pathways and immune response regulation were identified among the over-represented pathways underlying the DEGs. Transcriptional regulators, such as DUSP2, DUSP10, and MAPK13, were downregulated in subfertile heifers, suggesting disrupted signal transduction and immune function. Gene co-expression network analysis showed network rewiring and increased connectivity of genes related to cilium organization, motility, and microtubule-based processes in the subfertile group. Over-represented hub genes were enriched in the subfertile endometrium, including DNAH2, DNAI2, DNAAF4, CCDC65, and the transcription factor FOXJ1. Our results suggest that impaired ciliary function and disrupted MAPK and immune signaling could potentially contribute to subfertility. Conclusions: This study highlights novel molecular signatures in the uterine endometrium that may serve as predictive markers of fertility potential in beef heifers, providing a foundation for targeted strategies to improve reproductive performance in cattle. Full article

This study aims to provide potential biomarkers and reveal the molecular mechanism of sudden coronary death (SCD). Rat models of atherosclerotic death (ASD), coronary atherosclerosis (AS), and acute myocardial ischemia (AMI) and sham groups were established via the gavage of high-fat emulsion and left coronary artery ligation. The myocardium was collected, and transcriptome sequencing was performed. Differentially expressed miRNAs (DEmiRNAs) were identified using edeR software. The target genes were predicted using TargetScan, and functional enrichment analysis was performed via KEGG. Then, an miRNA–mRNA interaction network was constructed using Cytoscape. The key miRNAs with biomarker potential were identified using LASSO regression. A total of 217, 224, and 86 DEmiRNAs were identified in the ASD, AS, and AMI groups compared with the sham group, respectively. The Ras and Rap1 pathways were mainly expressed in ASD. The β-alanine and sphingolipid metabolisms were expressed in AMI. Finally, miR-106b, miR-195, miR-33, miR-652, miR-466b, and miR-6321 were identified as biomarkers of ASD. MiR-205, miR-877, miR-325, and miR-344b were identified as biomarkers of AMI. miR542-Atg12 was involved in the RIG-I-like receptor signaling pathway, miR6328-Gstz1 was involved in tyrosine metabolism, and miR483-Dusp5 was involved in the MAPK signaling pathway. This study provides a reference for the identification of SCD in forensic pathology. Full article

(1) Background: This study aims to systematically identify key candidate genes and the regulatory networks governing ovarian development in sheep breeds with divergent fecundity. Focusing on elucidating the central regulatory roles of these factors during distinct ovarian developmental stages in highly prolific breeds, the research seeks to reveal the mechanism by which multilevel regulatory networks synergistically determine ewe reproductive capacity. (2) Methods: This study utilized the ovaries from the low-fecundity sheep breed Ujumqin sheep, the high-fecundity breed small-tailed Han sheep, and various developmental stages of small-tailed Han sheep as research subjects. Through whole-transcriptome sequencing analysis, differentially expressed mRNAs(DEGs) and non-coding RNAs (ncRNAs) were screened, and a ceRNA regulatory network was constructed and subjected to bioinformatic analysis. The dual-luciferase reporter gene detection system was employed to validate the targeting relationships within the obtained key circRNA-miRNA-mRNA networks. Finally, qRT-PCR was used to verify the accuracy of the sequencing results. (3) Results: Our analysis constructed two distinct ceRNA networks: one from different fecundity groups (116 DECs, 46 DEMs, 82 DEGs) and another from different ovarian stages (186 DECs, 143 DEMs, 338 DEGs). Functional enrichment revealed key reproduction-related pathways, including Mitogen-Activated Protein Kinase(MAPK), Janus Kinase-Signal Transducer and Activator of Transcription(JAK-STAT), and WNT signaling in the fecundity comparison, and MAPK, Ras, WNT, Hippo signaling in the developmental stage comparison. Integrated analysis identified a core circRNA-miRNA-mRNA network, pinpointing circRNA2058-miR-9226-5p-MET as a central regulatory axis. The dual-luciferase assay confirmed that circRNA2058 acts as a sponge for miR-9226-5p, thereby mediating MET expression. qRT-PCR validation of randomly selected RNAs confirmed the sequencing reliability. (4) Conclusions: this study deciphers a synergistic regulatory network and identifies, for the first time, the pivotal circRNA2058-miR-9226-5p-MET ceRNA axis as an potential critical molecular switch driving follicular dominance in sheep. This discovery provides a molecular foundation for targeting core regulators of ovine reproductive efficiency and offers significant insights for innovative strategies in enhancing sheep reproduction. Full article

Carcinogenesis is driven by aberrant activation of molecular signaling pathways governing cell proliferation, apoptosis, and differentiation. Among these, the RAS/RAF/MEK/ERK (RAS/MAPK) cascade is one of the most frequently dysregulated oncogenic pathways, driving tumor initiation and progression across diverse cancer types. Although inhibitors of BRAF and MEK have achieved clinical success in selected malignancies, adaptive resistance often undermines therapeutic durability. This has spurred interest in alternative nodes within the pathway. The kinase suppressor of Ras (KSR) is a scaffold protein that organizes RAF, MEK, and ERK into functional complexes, ensuring efficient and sustained signal transmission. Once regarded as a passive structural component, KSR1 is now recognized as an active regulator of pathway dynamics. Emerging evidence indicates that KSR1 overexpression promotes cancer cell proliferation and survival, while genetic or pharmacologic inhibition of KSR1 attenuates RAS/MAPK signaling and suppresses tumor growth in preclinical models. In this review, we provide a comprehensive overview of accessory and scaffold proteins modulating the RAS/MAPK pathway, with a particular focus on KSR1. We highlight its structural and functional properties, summarize preclinical evidence for KSR1-targeted interventions, and discuss its therapeutic potential in cancer, with emphasis on hepatocellular carcinoma (HCC). Full article

Acute lymphoblastic leukemia is the most common cause of cancer-related death in children and represents a poor prognosis for patients in high-risk groups. Current treatment protocols are based on intensive polychemotherapy, which is associated with a significant toxicity profile. Due to their higher specificity and lower toxicity, immunotherapies based on monoclonal antibodies, in particular antibody–drug conjugates (ADCs), are revolutionizing cancer therapy. However, reports on the potential efficacy of ADC-targeted therapy in ALL and its subgroups are limited. Gene expression data suggest that potentially new ADC antigens are highly abundant in ALL subgroups and represent promising targets for cancer therapy. In addition, the PI3K/AKT and RAS/MAPK signaling pathways are often persistently activated in ALL and recent data showed that active feedback loops following inhibition of these pathways can lead to redundancy of cell surface receptors that can potentially serve as antigens for ADC treatment. Therefore, we provide here an overview of the most interesting receptors of the various ALL subgroups and discuss the influence that feedback loops of the PI3K/AKT and RAS/MAPK signaling pathways may have on increasing protein expression of the aforementioned receptors, which could lead to targeted combination therapy approaches in the future. Full article

Retinoic acid (RA) binds RA (RAR) and Retinoid X (RXR) receptors to elicit biological effects by regulating transcription. RA is also known to have non-canonical activities mediated, primarily, by cellular retinoic acid-binding protein 1 (CRABP1) which forms protein complexes named “CRABP1 signalosomes” to regulate cytosolic signaling independent of RARs/RXRs. This review focuses on therapeutic applications in neurodegeneration by targeting CRABP1 signalosomes including CRABP1–MAPK, CRABP1–CaMKII, CRABP1–eIF2α, and others recently identified from our proteomic studies. The mouse Crabp1 gene is regulated by various epigenetic factors and is important for the health of multiple cell types including motor neurons (MNs). In humans, CRABP1 gene expression is reduced in ALS- and SMA-patient MNs. RA is a therapeutic agent for leukemias and dermatological disorders and is being investigated for managing neurodegenerative diseases, but its therapeutic effects are accompanied by RAR-mediated toxic effects. We have uncovered a novel class of synthetic retinoids that bind CRABP1 without acting on RARs, circumventing RAR-mediated toxic effects. These first-generation CRABP1-selective compounds C3, C4, and C32 target CRABP1–MAPK and/or CRABP1–CaMKII signalosomes. This knowledge, together with emerging structural information, sheds lights on the strategies in designing next-generation CRABP1-signalosome-selective retinoids for the management of neurodegenerative diseases. Full article

Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with low-grade serous and mucinous subtypes frequently driven by KRAS mutations. These mutations activate downstream MAPK and PI3K/AKT signaling pathways, contributing to tumor progression and resistance to therapy. Although the MEK inhibitor trametinib is used to target these pathways, its efficacy is limited in KRAS-mutant OCa due to compensatory activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) axis. In this study, we evaluated the therapeutic potential of combining trametinib with EC359, a selective LIFR inhibitor, in Ras/Raf-driven OCa models. EC359 significantly reduced cell viability, clonogenic survival, and induced cell death via ferroptosis in vitro. Mechanistic studies revealed that EC359 suppressed trametinib-induced activation of LIFR downstream signaling. RNA-seq analysis showed that combination therapy downregulated mitochondrial translation and MYC target genes while upregulating apoptosis-related genes. In vivo, EC359 and trametinib co-treatment significantly reduced tumor growth in xenograft and PDX models without inducing toxicity. Our studies identify LIFR signaling as a critical vulnerability in Ras/Raf-mutant and low grade serous OCa. Further, it provides strong preclinical rationale for EC359 and trametinib combination therapy as a new therapeutic strategy for treating Ras/Raf-driven OCa and low-grade serous OCa. Full article

RASSF4 is a key member of the Ras-associated domain family (RASSF) that exhibits dual functionality in tumorigenesis, playing critical yet context-dependent roles in various malignancies. Its expression is epigenetically regulated through promoter hypermethylation, histone modifications, and microRNAs including miR-155 and miR-196a-5p, which directly target its 3′ untranslated region. In most cancers, such as non-small cell lung cancer (NSCLC) and gastric adenocarcinoma (GAC), RASSF4 acts as a tumor suppressor by inhibiting the RAS/MAPK pathway while activating the Hippo signaling cascade, ultimately inducing cell cycle arrest and apoptosis. Conversely, in aRMS, RASSF4 is upregulated by the PAX3-FOXO1 fusion oncoprotein and promotes tumor growth through MST1 inhibition and subsequent YAP activation. This review systematically analyzes current evidence regarding RASSF4’s complex regulatory mechanisms and clinical significance. We propose targeted therapeutic strategies including epigenetic reactivation, gene intervention, and combination therapies. Furthermore, we identify RASSF4 as a promising diagnostic biomarker and therapeutic target based on integrated mechanistic and clinical evidence. Future research should focus on elucidating context-dependent regulatory switches, developing targeted delivery systems, and validating clinical utility through prospective trials. Full article

Histiocytic sarcoma (HS) is an ultra-rare hematopoietic neoplasm that frequently occurs in extranodal sites of adults. Clinically, HS demonstrates aggressive behavior and can arise de novo or in association with other hematological neoplasms. The median overall survival from the time of diagnosis is approximately six months. Histologically, HS is composed of sheets of large, round to oval cells with abundant eosinophilic cytoplasm and can be confused with a variety of benign and malignant conditions. Immunohistochemistry plays a crucial role in the diagnosis of HS, showing expression of CD163, CD68, lysozyme, and PU.1 and negative staining with follicular dendritic cell markers and myeloid cell markers. Recent studies have demonstrated a high rate of PD-L1 expression, suggesting a potential therapeutic target. Several genomic alterations have been identified in HS, including mutations involving the RAS/MAPK and PI3K/AKT/mTOR signaling pathways, CDKN2A mutations/deletions, and TP53 mutations. There is no standard protocol for the management of HS. Surgical resection with or without radiotherapy is the most common first-line treatment for unifocal/localized disease. The systemic treatment options for multifocal/disseminated disease are very limited. This review provides an overview of the current knowledge on the clinicoradiological features, histopathology, pathogenesis, and management of HS. Full article

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer-related death. Hyperactivation of oncogenes and suppression of tumor suppressor genes/proteins drive HCC initiation and progression. MicroRNAs (miRNAs) critically modulate HCC biology by regulating proliferation, apoptosis, and metastasis. Acting either as tumor suppressors or oncomiRs, they shape core signaling pathways, including PI3K/Akt/mTOR, Hippo–YAP/TAZ, Wnt/β-catenin, RAS/MAPK, and p53. Their dysregulation in tissues and body fluids renders them promising diagnostic biomarkers and therapeutic targets. Preclinical studies demonstrate that miRNA-based strategies—either restoring tumor-suppressive miRNAs (e.g., miR-34a, miR-125a-5p) or inhibiting oncogenic miRNAs (e.g., miR-660-5p)—can suppress HCC progression and reduce treatment resistance. Combination approaches, such as pairing miR-122 mimics with miR-221 inhibitors or delivering miR-326 via nanoparticles, further enhance efficacy by simultaneously targeting multiple oncogenic pathways. This review summarizes recent advances in miRNA-mediated regulation of HCC signaling and highlights their clinical potential, including ongoing trials of miRNA-based diagnostics and therapeutics for early detection, prognostication, and personalized treatment. Full article

Chronic inflammation underpins the pathogenesis of both rheumatoid arthritis (RA) and neurodegenerative conditions such as Alzheimer’s disease (AD). This narrative review explores the role of C-reactive protein (CRP), particularly its monomeric form (mCRP), as a central molecular link connecting systemic autoimmune inflammation with neuroinflammatory and vascular pathology. In RA, fibroblast-like synoviocytes (FLSs) are activated by CRP through CD32/CD64-mediated signaling, triggering proinflammatory cascades involving NF-κB and p38 MAPK. Recent studies have highlighted that locally synthesized CRP within the synovium may convert to mCRP, amplifying inflammation and tissue damage. Beyond RA, mCRP has been identified within amyloid-beta (Aβ) plaques in AD brains, suggesting a direct role in neurodegenerative pathology. Experimental models also demonstrate that mCRP is upregulated in stroke-affected brain regions and associated with complement activation and blood–brain barrier (BBB) disruption, which is central to AD progression. The convergence of pathways involving IL-6, RAGE (receptor for advanced glycation end-products), and mCRP-mediated complement activation reveals a shared axis of inflammation between RA and AD. This highlights the potential of mCRP not only as a biomarker of chronic inflammation but also as a therapeutic target. Furthermore, evidence from periodontal disease and cardiovascular comorbidities highlights the systemic nature of mCRP-driven inflammation, offering insights into the mechanisms of disease overlap. This review advocates for further mechanistic studies into mCRP signaling, particularly its role at the interface of systemic and neuroinflammation, with the goal of identifying new interventional strategies for patients with RA at elevated risk of neurodegenerative and vascular complications. Full article

Alzheimer’s disease (AD) and major depressive disorder (MDD) are prevalent central nervous system (CNS) disorders that share overlapping symptoms but differ in underlying molecular mechanisms. Distinguishing these mechanisms is essential for developing targeted diagnostic and therapeutic strategies. In this study, we integrated multi-tissue transcriptomic datasets from brain and peripheral samples to identify differentially expressed microRNAs (miRNAs) in AD and MDD. Functional enrichment analyses (KEGG, GO) revealed that dysregulated miRNAs in AD were associated with MAPK, PI3K–Akt, Ras, and PD-1/PD-L1 signaling, pathways linked to synaptic plasticity, neuroinflammation, and immune regulation. In contrast, MDD-associated miRNAs showed enrichment in Hippo signaling and ubiquitin-mediated proteolysis, implicating altered neurogenesis and protein homeostasis. Network analysis highlighted key disease- and tissue-specific miRNAs, notably hsa-miR-1202 and hsa-miR-24-3p, with potential roles in neuronal survival and molecular network regulation. These findings suggest that miRNAs may serve as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring in both disorders. While therapeutic targeting of miRNAs offers promise, challenges such as blood–brain barrier penetration and tissue-specific delivery remain. This integrative approach provides a translational framework for advancing miRNA-based strategies in CNS disease research. Full article

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by synovial hyperplasia and joint destruction. Previous studies have demonstrated that the alkaloids of Rushanhu (ARSHs), the dried root and stem of Zanthoxylum nitidum var. tomentosum, exhibit favorable therapeutic effects on RA, and this study aims to investigate the underlying molecular mechanisms involved. Methods: A complete Freund’s adjuvant (CFA)-induced arthritis model in male SD rats (n = 64) was used to evaluate ARSHs. Groups included control, model, methotrexate (MTX), and ARSH-treated. Therapeutic effects were assessed via arthritis index, paw swelling, and serum cytokines (IL-1β, IL-6, IL-17A). Network pharmacology identified bioactive alkaloids and core targets, validated by molecular docking. In vitro mechanisms (proliferation, apoptosis, signaling pathways) were examined in MH7A synovial cells. Results: ARSHs significantly attenuated joint inflammation and damage in CFA rats (* p < 0.01 vs. model), reducing pro-inflammatory cytokines. Fifteen alkaloids (e.g., dihydrochelerythrine, magnoflorine) and 24 targets (e.g., SRC, STAT3, MAPK3) were prioritized. Molecular docking confirmed strong binding (binding energy < −7.0 kcal/mol). In vitro, ARSHs suppressed MH7A proliferation and induced apoptosis via Bcl-2/Bax dysregulation and the inhibition of SRC/STAT3/MAPK3 phosphorylation. Conclusions: ARSHs mitigate RA pathogenesis by targeting the SRC/STAT3/MAPK3 signaling axis in synovial cells. This study provides mechanistic validation of ARSHs as multi-target phytotherapeutic agents against inflammatory arthritis. Full article