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18 pages, 1688 KB  
Article
Thymoquinone Upregulates microRNA-199a-3p and Downregulates COX-2 Expression and PGE2 Production via Deactivation of p38/ERK/JNK-MAPKs and p65/p50-NF-κB Signaling in Human Lung Cancer Cells
by Yusuf Saleem Khan, Aisha Farhana, Ghorashy E. Y. Mohammed, Abuzar Abdulwahab Osman, Abdullah Alsrhani, Syed M. A. Shahid, Mohammed Kuddus and Zafar Rasheed
Biology 2025, 14(10), 1348; https://doi.org/10.3390/biology14101348 - 2 Oct 2025
Abstract
Chronic inflammation driven by Cyclooxygenase-2 (COX-2) overexpression plays a key role in lung cancer (LC) progression, making it a critical therapeutic target. This study explores thymoquinone (TQ), a potent bioactive phytochemical derived from Nigella sativa, known for its anti-inflammatory and anti-cancer effects, focusing [...] Read more.
Chronic inflammation driven by Cyclooxygenase-2 (COX-2) overexpression plays a key role in lung cancer (LC) progression, making it a critical therapeutic target. This study explores thymoquinone (TQ), a potent bioactive phytochemical derived from Nigella sativa, known for its anti-inflammatory and anti-cancer effects, focusing on its ability to suppress lipopolysaccharide (LPS)-induced COX-2 expression via microRNA hsa-miR-199a-3p modulation in LC cells. Using A549 and SHP-77 LC cells, we tested the effect of TQ under LPS stimulation and miRNA inhibition. Advanced techniques like TaqMan qPCR, luciferase reporter gene constructs, and anti-miRNA transfection confirmed that miR-199a-3p directly silences COX-2. Western blot and ELISA assays revealed that TQ dramatically reduces COX-2 protein and PGE2 levels by boosting miRNA-199a-3p. Importantly, TQ also blocked MAPK (p38, JNK, ERK) and NF-κB activation, even when miR-199a-3p was suppressed, proving its multi-targeted action beyond miRNA regulation. These findings reveal a novel anti-inflammatory mechanism, where TQ curbs COX-2-driven inflammation by enhancing miR-199a-3p, simultaneously shutting down pro-cancer MAPK/NF-κB signaling pathways. Given the strong link between chronic inflammation and LC aggressiveness, this study positions TQ as a promising therapeutic candidate, especially for inflammation-mediated lung cancer progression. Its dual ability to modulate miRNA and key signaling cascades makes it a compelling option for future LC treatment strategies. Full article
(This article belongs to the Special Issue Plant Natural Products: Mechanisms of Action for Promoting Health)
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23 pages, 4307 KB  
Article
Cinnamomum migao H.W. Li Ethanol-Water Extract Suppresses IL-6 Production in Cardiac Fibroblasts: Mechanisms Elucidated via UPLC-Q-TOF-MS, Network Pharmacology, and Experimental Assays
by Yuxin Lu, Yaofeng Li, Can Zhu, Mengyue Guo, Xia Liu and Xiangyun Chen
Curr. Issues Mol. Biol. 2025, 47(10), 798; https://doi.org/10.3390/cimb47100798 - 26 Sep 2025
Abstract
This study aims to elucidate the active components and underlying molecular mechanisms by which the ethanol-water extract of Cinnamomum migao H.W. Li (MG-EWE) inhibits cardiac fibroblast (CF) transdifferentiation and IL-6 production, providing insights into its anti-myocardial fibrosis effects. The chemical composition of MG-EWE [...] Read more.
This study aims to elucidate the active components and underlying molecular mechanisms by which the ethanol-water extract of Cinnamomum migao H.W. Li (MG-EWE) inhibits cardiac fibroblast (CF) transdifferentiation and IL-6 production, providing insights into its anti-myocardial fibrosis effects. The chemical composition of MG-EWE was characterized using UPLC-Q-TOF-MS. Network pharmacology analysis identified active constituents and their mechanisms in inhibiting IL-6 production in CFs. An isoproterenol (ISO)-induced rat CF model was established to evaluate the effects of MG-EWE and its main monomers, Laurolitsine and Hecogenin, on cell proliferation, migration, collagen metabolism, IL-6 production, and key proteins in the ADRB2/JNK signaling pathway. A total of 173 compounds were identified in MG-EWE, with 14 core constituents regulating IL-6 synthesis via 16 key targets, including ADRB2 and MAPK9. Gene Ontology enrichment indicated that MG-EWE affects phosphorylation and the JNK signaling cascade. Molecular docking showed strong binding affinities between Laurolitsine, Hecogenin, and their targets ADRB2 and JNK. Experimentally, MG-EWE, Laurolitsine, and Hecogenin significantly inhibited ISO-induced CF proliferation, migration, and hydroxyproline synthesis, as well as the expression of p-ADRB2, p-JNK, p-c-Jun, and IL-6. MG-EWE inhibits CF transdifferentiation and IL-6 production via the ADRB2/JNK/c-Jun signaling axis, mediated by its constituents Laurolitsine and Hecogenin, highlighting its potential for drug development targeting myocardial fibrosis. Full article
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26 pages, 2624 KB  
Review
The Dual Role of RASSF4 in Tumorigenesis: Mechanisms and Epigenetic Targeting Strategies
by Rui Tian, Yixin Wu, Wenbin Yuan, Lingli Tian, Rui Zhang, Hao Lyu, Shuai Xiao, Dong Guo, Qi Zhang, Declan William Ali, Marek Michalak, Cefan Zhou, Jingfeng Tang and Xing-Zhen Chen
Biology 2025, 14(9), 1289; https://doi.org/10.3390/biology14091289 - 18 Sep 2025
Viewed by 348
Abstract
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 [...] Read more.
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
(This article belongs to the Special Issue Signalling Pathways in Cancer and Disease)
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18 pages, 604 KB  
Review
MicroRNA (miRNA) in the Pathogenesis of Diabetic Retinopathy: A Narrative Review
by Stamatios Lampsas, Chrysa Agapitou, Alexandros Chatzirallis, Georgios Papavasileiou, Dimitrios Poulakis, Sofia Pegka, Panagiotis Theodossiadis, Vaia Lambadiari and Irini Chatziralli
Genes 2025, 16(9), 1060; https://doi.org/10.3390/genes16091060 - 9 Sep 2025
Viewed by 452
Abstract
Diabetic retinopathy (DR) is the most common microvascular complication associated with diabetes mellitus and represents a leading cause of visual impairment worldwide. Inflammation, endothelial dysfunction, angiogenesis, neurodegeneration, and oxidative stress are key pathogenic processes in the development and progression of DR. Numerous microRNAs [...] Read more.
Diabetic retinopathy (DR) is the most common microvascular complication associated with diabetes mellitus and represents a leading cause of visual impairment worldwide. Inflammation, endothelial dysfunction, angiogenesis, neurodegeneration, and oxidative stress are key pathogenic processes in the development and progression of DR. Numerous microRNAs (miRNAs) show altered expression in DR and modulate critical biological pathways. Pro-inflammatory miRNAs such as miR-155 and miR-21 promote cytokine release and vascular inflammation, while miR-146a acts as a negative regulator of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. MiR-126 and miR-21 regulate endothelial integrity and angiogenesis through pathways involving Vascular Endothelial Growth Factor (VEGF). MiR-200b and miR-126 are downregulated in DR, leading to increased neovascularization via activation of the VEGF/ Mitogen-Activated Protein Kinase (MAPK) cascade. Apoptotic processes are affected by miR-195, which downregulates Sirtuin 1 (SIRT1) and B-cell lymphoma 2 (Bcl-2), promoting retinal cell death, while miR-29b downregulation permits upregulation of the transcription factor SP1, enhancing caspase-mediated apoptosis in Müller cells and endothelial cells. miRNAs collectively modulate an intricate regulatory network that contributes to the underlying mechanisms of diabetic retinopathy development and progression. This narrative review aims to summarize knowledge regarding the mechanisms miRNAs mediating pathogenetic mechanisms of DR. Full article
(This article belongs to the Section RNA)
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58 pages, 1029 KB  
Review
A Review of the Potential Use of Antioxidants in Spinal Cord Injuries
by Agnieszka Nowacka, Maciej Śniegocki and Ewa Ziółkowska
Antioxidants 2025, 14(9), 1081; https://doi.org/10.3390/antiox14091081 - 3 Sep 2025
Viewed by 910
Abstract
Spinal cord injury (SCI) is a debilitating neurological condition marked by primary mechanical damage followed by a complex secondary injury cascade, in which oxidative stress plays a central role. Mitochondrial dysfunction, ionic imbalance, and inflammatory responses drive excessive generation of reactive oxygen and [...] Read more.
Spinal cord injury (SCI) is a debilitating neurological condition marked by primary mechanical damage followed by a complex secondary injury cascade, in which oxidative stress plays a central role. Mitochondrial dysfunction, ionic imbalance, and inflammatory responses drive excessive generation of reactive oxygen and nitrogen species, leading to lipid peroxidation, protein and DNA damage, apoptosis, and progressive neurological impairment. Antioxidant-based therapies have emerged as promising neuroprotective strategies, with compounds such as A91 peptide, curcumin, edaravone, ginsenosides, and glutathione demonstrating preclinical efficacy in reducing oxidative damage, restoring redox balance, modulating signaling pathways (e.g., Nrf2, NF-κB, MAPK, PI3K/Akt), and enhancing neuronal survival. While therapeutic outcomes depend on injury severity, timing, and combinatorial approaches, translating these findings into clinical practice and integrating antioxidants with cell-based therapies, biomaterials, and rehabilitation offers a critical avenue for improving functional recovery in SCI. Full article
(This article belongs to the Special Issue Antioxidant Phytochemicals for Promoting Human Health and Well-Being)
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34 pages, 1064 KB  
Review
Beyond the Biomarker: Monomeric CRP as a Driver of Multisystem Pathology in Rheumatoid Arthritis
by Andreea Lazarut-Nistor and Mark Slevin
Int. J. Mol. Sci. 2025, 26(17), 8227; https://doi.org/10.3390/ijms26178227 - 25 Aug 2025
Viewed by 1067
Abstract
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 [...] Read more.
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
(This article belongs to the Special Issue Forward in Vasculitis: Genetics and Beyond)
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26 pages, 3012 KB  
Article
Cytoprotective Effects of Gymnema inodorum Against Oxidative Stress-Induced Human Dermal Fibroblasts Injury: A Potential Candidate for Anti-Aging Applications
by Wattanased Jarisarapurin, Thanchanok Puksasook, Sarawut Kumphune, Nattanicha Chaiya, Pawinee Pongwan, Rawisada Pholsin, Issara Sramala and Satita Tapaneeyakorn
Antioxidants 2025, 14(9), 1043; https://doi.org/10.3390/antiox14091043 - 24 Aug 2025
Viewed by 750
Abstract
Repeated UV exposure, air pollution, and toxins promote skin oxidative stress. ROS destroy macromolecules, changing cellular mechanisms and signaling cascades. Inflammation and injury to skin cells degrade function and accelerate aging, causing wrinkles, firmness loss, and dermatological disorders. Gymnema inodorum (GI) contains phytochemical [...] Read more.
Repeated UV exposure, air pollution, and toxins promote skin oxidative stress. ROS destroy macromolecules, changing cellular mechanisms and signaling cascades. Inflammation and injury to skin cells degrade function and accelerate aging, causing wrinkles, firmness loss, and dermatological disorders. Gymnema inodorum (GI) contains phytochemical antioxidants such polyphenols and triterpenoids that lower ROS and strengthen skin. GI extracts (GIEs) have never been examined for their effects on dermal skin fibroblasts’ oxidative stress and intracellular cytoprotective mechanisms. In this study, GIEs were prepared as a water extract (GIE0) and ethanol extracts with concentrations ranging from 20% to 95% v/v (GIE20, GIE40, GIE60, GIE80, and GIE95). These extracts were assessed for phytochemical content, antioxidant capacity, and free radical scavenging efficacy. The results were compared to a commercially available native Gymnema extract (NGE) obtained from Gymnema sylvestre. During principal component analysis (PCA), the most effective extracts were identified and subsequently evaluated for their ability to mitigate oxidative stress in fibroblasts. Cytoprotective effects of GIE and NGE against H2O2-induced human dermal fibroblast injury were investigated by cell viability, intracellular ROS production, and signaling pathways. GIE0, GIE80, GIE95, and NGE were the best antioxidants. By preserving ROS balance and redox homeostasis, GIE and NGE reduce fibroblast inflammation and oxidative stress-induced damage. Decreased ROS levels reduce MAPK/AP-1/NF-κB and PI3K/AKT/NF-κB signaling pathways, diminishing inflammatory cytokines. In conclusion, GIE and NGE have antioxidant and anti-inflammatory capabilities that can reduce H2O2-induced fibroblast oxidative stress and damage, thereby preventing skin aging and targeting cancer-associated fibroblasts. Full article
(This article belongs to the Section Natural and Synthetic Antioxidants)
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44 pages, 1023 KB  
Review
Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure Across the CNS
by Victor Voicu, Corneliu Toader, Matei Șerban, Răzvan-Adrian Covache-Busuioc and Alexandru Vlad Ciurea
Biomedicines 2025, 13(8), 2025; https://doi.org/10.3390/biomedicines13082025 - 20 Aug 2025
Cited by 2 | Viewed by 1871
Abstract
Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization—spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) [...] Read more.
Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization—spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways—including PI3K–AKT–mTOR, MAPK, Wnt/β-catenin, and integrated stress response cascades—undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome–lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3–CR3 axis), and excitatory–inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network “meaning-making”—a collapse of coordinated signal interpretation, triage prioritization, and adaptive response—the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning—a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration. Full article
(This article belongs to the Special Issue Cell Signaling and Molecular Regulation in Neurodegenerative Disease)
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20 pages, 3163 KB  
Article
Walnut Green Husk Extract Enhances Antioxidant, Anti-Inflammatory, and Immune Functions by Regulating Gut Microbiota and Metabolites in Fattening Pigs
by Jing Wang, Mingyang Jia, Qi Zhang, Xiangzhou Yan, Yaping Guo, Lei Wang and Baosong Xing
Animals 2025, 15(16), 2395; https://doi.org/10.3390/ani15162395 - 15 Aug 2025
Viewed by 480
Abstract
This study investigates the effect of walnut green husk extract (WE) on gut microbiota, metabolites, and immune-antioxidant changes in fattening pigs through gut microbiota-metabolite interactions. A total of 60 healthy fattening pigs (Duroc × Landrace × Yorkshire) with an initial body weight of [...] Read more.
This study investigates the effect of walnut green husk extract (WE) on gut microbiota, metabolites, and immune-antioxidant changes in fattening pigs through gut microbiota-metabolite interactions. A total of 60 healthy fattening pigs (Duroc × Landrace × Yorkshire) with an initial body weight of 65.2 ± 3.1 kg were randomly assigned to two groups (n = 30 per group): the control group (NC), which was fed a basal diet, and the WE group, which was fed the basal diet supplemented with 0.1% walnut green husk extract (WE). Dietary supplementation with 0.1% WE significantly increased the relative abundances of beneficial bacteria (e.g., Firmicutes, Lactobacillus) and reduced pathogenic bacteria (e.g., Proteobacteria, Shigella). Untargeted metabolomics identified 170 differentially accumulated metabolites, among which propionic acid—a key short-chain fatty acid with immunomodulatory effects—was significantly upregulated by 1.09-fold (p = 0.03) and showed a positive correlation with beneficial microbial abundances. These metabolites were enriched in glycerophospholipid and α-linolenic acid metabolism pathways, where eicosadienoic acid inhibited the nuclear factor kappa-B (NF-κB) pathway for anti-inflammatory effects, and methyl cinnamate synergistically regulated mitogen-activated protein kinase (MAPK) signaling with Lactobacillus. Serum analyses showed that WE significantly enhanced IgA, IgM, and IgG levels by 3.97-fold, 4.67-fold, and 4.43-fold (p < 0.01), reduced malondialdehyde (MDA) concentration by 82.8% (p < 0.01), and trended to improve antioxidant capacity via glutamine. Mechanistically, WE promoted short-chain fatty acid production by beneficial bacteria, forming a “microbiota–metabolite–immunity” cascade to enhance lipid metabolism and alleviate intestinal inflammation. These findings highlight that WE provides multi-omics evidence for its application as a functional feed additive. Full article
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20 pages, 1126 KB  
Review
Review of the Role of TRAF7 in Brain Endothelial Integrity and Cerebrovascular Aging
by Jennifer Ihuoma, Sherwin Tavakol, Sharon Negri, Cade Ballard, Khanh Phan, Albert Orock, Zeke Reyff, Madison Milan, Eva Troyano-Rodriguez, Rakesh Rudraboina, Anna Csiszar, Anthony C. Johnson, Ian F. Dunn and Stefano Tarantini
Life 2025, 15(8), 1280; https://doi.org/10.3390/life15081280 - 12 Aug 2025
Viewed by 802
Abstract
Tumor necrosis factor (TNF) receptor-associated factor 7 (TRAF7) is a signal transducer in the TNF receptor superfamily. TRAF7 is unique among its superfamily in that it does not contain a TRAF-C domain but does contain WD-40 domains. TRAF7 interacts with mitogen-activated protein kinases [...] Read more.
Tumor necrosis factor (TNF) receptor-associated factor 7 (TRAF7) is a signal transducer in the TNF receptor superfamily. TRAF7 is unique among its superfamily in that it does not contain a TRAF-C domain but does contain WD-40 domains. TRAF7 interacts with mitogen-activated protein kinases (MAPK), which are known regulators of inflammation and shear stress response. Notably, these molecular interactions have profound implications for the function of brain endothelial cells (ECs), which are pivotal for sustaining the integrity of the blood–brain barrier (BBB), orchestrating neurovascular coupling (NVC), and modulating the vascular architecture. By directly influencing MAPK signaling pathways, particularly the shear stress-responsive MAPK kinase kinase 3 (MEKK3)–MAPK kinase 5 (MEK5)–extracellular-regulated protein kinase 5 (ERK5) cascade, TRAF7 contributes to vascular homeostasis, as exemplified by its role in phosphorylating ERK5. Such molecular events underpin the capacity of brain ECs to regulate substance exchange, adjust blood flow in response to neural activity, and maintain efficient cerebral perfusion, all of which are essential for preserving brain health and cognitive performance. By synthesizing the current evidence regarding TRAF7’s molecular functions and its impact on brain endothelial integrity, cerebrovascular aging, and exploring implications for therapeutic strategies targeting vascular dysfunction in the aging brain, this review fills a crucial gap in the literature. Given the limited number of original studies directly addressing these contexts, the review will integrate broader insights from related literature to provide a foundational overview for future research in this developing field. The culmination of this literature will provide a rationale for the development of novel TRAF7-targeted therapies to restore vascular integrity in the context of aging, which could maintain cognitive health. Although TRAF7 has been implicated in regulating endothelial permeability during inflammation, its precise functions in brain ECs and the subsequent effects on cerebrovascular structure and cognitive function remain to be fully elucidated. Full article
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12 pages, 2363 KB  
Article
MCC950 Alleviates Fat Embolism-Induced Acute Respiratory Distress Syndrome Through Dual Modulation of NLRP3 Inflammasome and ERK Pathways
by Chin-Kuo Lin, Zheng-Wei Chen, Yu-Hao Lin, Cheng-Ta Yang, Chung-Sheng Shi, Chieh-Mo Lin, Tzu Hsiung Huang, Justin Ching Hsien Lu, Kwok-Tung Lu and Yi-Ling Yang
Int. J. Mol. Sci. 2025, 26(15), 7571; https://doi.org/10.3390/ijms26157571 - 5 Aug 2025
Viewed by 790
Abstract
Fat embolism is a critical medical emergency often resulting from long bone fractures or amputations, leading to acute respiratory distress syndrome (ARDS). The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity, is activated by reactive oxygen species and [...] Read more.
Fat embolism is a critical medical emergency often resulting from long bone fractures or amputations, leading to acute respiratory distress syndrome (ARDS). The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity, is activated by reactive oxygen species and tissue damage, contributing to inflammatory responses. This study examines the role of NLRP3 in fat embolism-induced ARDS and evaluates the therapeutic potential of MCC950, a selective NLRP3 antagonist. Fat embolism was induced by fatty micelle injection into the tail vein of Sprague Dawley rats. Pulmonary injury was assessed through lung weight gain as an edema indicator, NLRP3 expression via Western blot, and IL-1β levels using ELISA. Histological damage and macrophage infiltration were evaluated with hematoxylin and eosin staining. Fat embolism significantly increased pulmonary NLRP3 expression, lipid peroxidation, IL-1β release, and macrophage infiltration within four hours, accompanied by severe pulmonary edema. NLRP3 was localized in type I alveolar cells, co-localizing with aquaporin 5. Administration of MCC950 significantly reduced inflammatory responses, lipid peroxidation, pulmonary edema, and histological damage, while attenuating MAPK cascade phosphorylation of ERK and Raf. These findings suggest that NLRP3 plays a critical role in fat embolism-induced acute respiratory distress syndrome, and its inhibition by MCC950 may offer a promising therapeutic approach. Full article
(This article belongs to the Section Molecular Biology)
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22 pages, 6758 KB  
Article
Screening of an FDA-Approved Drug Library: Menadione Induces Multiple Forms of Programmed Cell Death in Colorectal Cancer Cells via MAPK8 Cascades
by Liyuan Cao, Weiwei Song, Jinli Sun, Yang Ge, Wei Mu and Lei Li
Pharmaceuticals 2025, 18(8), 1145; https://doi.org/10.3390/ph18081145 - 31 Jul 2025
Viewed by 793
Abstract
Background: Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy, ranking third in incidence and second in cancer-related mortality. Despite therapeutic advances, challenges such as chemotherapy toxicity and drug resistance persist. Thus, there is an urgent need for novel CRC treatments. However, developing [...] Read more.
Background: Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy, ranking third in incidence and second in cancer-related mortality. Despite therapeutic advances, challenges such as chemotherapy toxicity and drug resistance persist. Thus, there is an urgent need for novel CRC treatments. However, developing new drugs is time-consuming and resource-intensive. As a more efficient approach, drug repurposing offers a promising alternative for discovering new therapies. Methods: In this study, we screened 1068 small molecular compounds from an FDA-approved drug library in CRC cells. Menadione was selected for further study based on its activity profile. Mechanistic analysis included a cell death pathway PCR array, differential gene expression, enrichment, and network analysis. Gene expressions were validated by RT-qPCR. Results: We identified menadione as a potent anti-tumor drug. Menadione induced three programmed cell death (PCD) signaling pathways: necroptosis, apoptosis, and autophagy. Furthermore, we found that the anti-tumor effect induced by menadione in CRC cells was mediated through a key gene: MAPK8. Conclusions: By employing methods of cell biology, molecular biology, and bioinformatics, we conclude that menadione can induce multiple forms of PCD in CRC cells by activating MAPK8, providing a foundation for repurposing the “new use” of the “old drug” menadione in CRC treatment. Full article
(This article belongs to the Section Medicinal Chemistry)
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26 pages, 4256 KB  
Review
Progress in Pharmacokinetics, Pharmacological Effects, and Molecular Mechanisms of Swertiamarin: A Comprehensive Review
by Hao-Xin Yang, Ying-Yue Hu, Rui Liang, Hong Zheng and Xuan Zhang
Cells 2025, 14(15), 1173; https://doi.org/10.3390/cells14151173 - 30 Jul 2025
Viewed by 938
Abstract
Swertiamarin (SW), a natural iridoid glycoside primarily isolated from the genus Swertia, Gentianaceae family, has been extensively utilized in traditional medicine systems, including Ayurveda, Traditional Chinese Medicine, and Tibetan medicine, for treating fever, diabetes, liver disorders, and inflammatory conditions. Pharmacokinetic studies reveal [...] Read more.
Swertiamarin (SW), a natural iridoid glycoside primarily isolated from the genus Swertia, Gentianaceae family, has been extensively utilized in traditional medicine systems, including Ayurveda, Traditional Chinese Medicine, and Tibetan medicine, for treating fever, diabetes, liver disorders, and inflammatory conditions. Pharmacokinetic studies reveal that SW exhibits rapid absorption but demonstrates low oral bioavailability due to the first-pass effect. Pharmacological studies have demonstrated that SW possesses a wide range of pharmacological activities, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and neuroprotective activities. Our analysis demonstrates that SW exerts remarkable therapeutic potential across multiple pathological conditions through coordinated modulation of key signaling cascades, including Nrf2/HO-1, NF-κB, MAPK, PI3K/Akt, and PPAR pathways. This comprehensive review systematically consolidates current knowledge on SW’s pharmacokinetic characteristics, toxicity, diverse biological activities, and underlying molecular mechanisms based on extensive preclinical evidence, establishing a scientific foundation for future drug development strategies and potential clinical applications of the potential natural lead compound. Full article
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28 pages, 5315 KB  
Article
Integrated Transcriptome and Metabolome Analysis Provides Insights into the Low-Temperature Response in Sweet Potato (Ipomoea batatas L.)
by Zhenlei Liu, Jiaquan Pan, Sitong Liu, Zitong Yang, Huan Zhang, Tao Yu and Shaozhen He
Genes 2025, 16(8), 899; https://doi.org/10.3390/genes16080899 - 28 Jul 2025
Cited by 1 | Viewed by 733
Abstract
Background/Objectives: Sweet potato is a tropical and subtropical crop and its growth and yield are susceptible to low-temperature stress. However, the molecular mechanisms underlying the low temperature stress of sweetpotato are unknown. Methods: In this work, combined transcriptome and metabolism analysis was employed [...] Read more.
Background/Objectives: Sweet potato is a tropical and subtropical crop and its growth and yield are susceptible to low-temperature stress. However, the molecular mechanisms underlying the low temperature stress of sweetpotato are unknown. Methods: In this work, combined transcriptome and metabolism analysis was employed to investigate the low-temperature responses of two sweet potato cultivars, namely, the low-temperature-resistant cultivar “X33” and the low-temperature-sensitive cultivar “W7”. Results: The differentially expressed metabolites (DEMs) of X33 at different time stages clustered in five profiles, while they clustered in four profiles of W7 with significant differences. Differentially expressed genes (DEGs) in X33 and W7 at different time points clustered in five profiles. More DEGs exhibited continuous or persistent positive responses to low-temperature stress in X33 than in W7. There were 1918 continuously upregulated genes and 6410 persistent upregulated genes in X33, whereas 1781 and 5804 were found in W7, respectively. Core genes involved in Ca2+ signaling, MAPK cascades, the reactive oxygen species (ROS) signaling pathway, and transcription factor families (including bHLH, NAC, and WRKY) may play significant roles in response to low temperature in sweet potato. Thirty-one common differentially expressed metabolites (DEMs) were identified in the two cultivars in response to low temperature. The KEGG analysis of these common DEMs mainly belonged to isoquinoline alkaloid biosynthesis, phosphonate and phosphinate metabolism, flavonoid biosynthesis, cysteine and methionine metabolism, glycine, serine, and threonine metabolism, ABC transporters, and glycerophospholipid metabolism. Five DEMs with identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were selected for correlation analysis. KEGG enrichment analysis showed that the carbohydrate metabolism, phenylpropanoid metabolism, and glutathione metabolism pathways were significantly enriched and played vital roles in low-temperature resistance in sweet potato. Conclusions: These findings contribute to a deeper understanding of the molecular mechanisms underlying plant cold tolerance and offer targets for molecular breeding efforts to enhance low-temperature resistance. Full article
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Article
Precision Oncology Through Dialogue: AI-HOPE-RTK-RAS Integrates Clinical and Genomic Insights into RTK-RAS Alterations in Colorectal Cancer
by Ei-Wen Yang, Brigette Waldrup and Enrique Velazquez-Villarreal
Biomedicines 2025, 13(8), 1835; https://doi.org/10.3390/biomedicines13081835 - 28 Jul 2025
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Abstract
Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of [...] Read more.
Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10−5). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article
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