Search Results (6,808)

Brain metastases are the third most common metastatic site in melanoma patients, with 40% of melanoma patients developing melanoma brain metastasis (MBM). Symptomology of MBM ranges from headaches, neurological deficits, cognitive changes, and seizures, resulting from MBM embedding in areas of highest blood flow following the breakdown of the blood–brain barrier (BBB) via genetic, cytokine, and molecular processes. The BBB is highly restrictive, making MBM difficult to treat. Challenges in MBM treatment are evident in adverse therapeutic effects, such as neurocognitive decline with whole-brain radiation therapy (WBRT), increased risk of radiation necrosis with stereotactic radiosurgery (SRS), and reduced penetration into the brain, which can lead to drug resistance with prolonged use of MAPK inhibitors. This review investigates current and novel treatments against MBM, including radiotherapy, chemotherapy, targeted therapies such as BRAF/MAPK inhibitors, and immunotherapy. Full article

The immune system plays a pivotal role in the maintenance of homeostasis and protection from pathogens. With increasing public interest in immune health, functional foods and herbal formulations are gaining attention as potential immunomodulators. Therefore, we aimed to investigate the combined immune-enhancing effects of HemoHIM (HIM) and Hwaljingigo (HGG) through combination treatment based on the recommended daily intake in RAW 264.7 macrophages. Cell viability, nitric oxide (NO) production, and cytokine (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) expression levels were assessed using the XTT, Griess, and enzyme-linked immunosorbent assay (ELISA), respectively. Immunoblotting was conducted to confirm changes in protein expression. Neither HIM nor HGG was cytotoxic at any of the tested concentrations. Both the single and combination treatments increased NO production and cytokine expression in a concentration-dependent manner. Furthermore, the combination of HIM (one sachet) and HGG (three sachets) resulted in the highest levels of NO and cytokine production. Bliss Independence analysis revealed synergistic interactions for IL-1β and IL-6, while NO and TNF-α showed additive effects. These findings suggest that the combination of HIM and HGG enhances immune responses by stimulating macrophage activity, thereby supporting the potential application of multi-herbal formulations as functional immunomodulatory agents. Full article

Chronic kidney disease (CKD) is a progressive global health challenge. While empagliflozin, a selective SGLT2 inhibitor, is known to attenuate CKD progression through mechanisms beyond glycemic control, the precise molecular pathways remain incompletely characterized and warrant further investigation. This study employed an integrated network pharmacology and molecular docking approach to elucidate the multi-target mechanisms of empagliflozin in CKD. Initial evaluation demonstrated that empagliflozin exhibits favorable physicochemical properties, drug-likeness, and ADMET profiles, supporting its potential as an effective orally administered therapeutic option for CKD management. Network analysis identified 221 shared molecular targets between empagliflozin and CKD-associated genes. Topological analysis of the protein–protein interaction (PPI) network revealed ten critical hub proteins—GAPDH, IL6, EGFR, HSP90AA1, NFKB1, HSP90AB1, MTOR, MAPK3, IL2, and PIK3CA—which serve as key regulators in CKD pathophysiology. Gene Ontology and KEGG pathway enrichment analyses indicated that these shared targets are significantly involved in phosphorylation, signal transduction, and central signaling cascades associated with CKD progression, including the PI3K-Akt, FoxO, HIF-1, and AGE-RAGE pathways. Molecular docking simulations corroborated empagliflozin’s multi-target affinity, demonstrating particularly strong binding energies toward HSP90AB1 (−10.85 kcal/mol), MAPK3 (−9.46 kcal/mol), and EGFR (−9.38 kcal/mol). Empagliflozin maintained stable hydrogen bonding throughout the 200-ns molecular dynamics simulation, primarily with GLN18, GLU42, SER45, ASN46, ASN101, GLY130, and TYR134, underscoring its persistent and well-anchored interaction with HSP90AB1. Collectively, these findings provide crucial mechanistic insights, suggesting that empagliflozin might exerts therapeutic effects by modulating interconnected pathways regulating inflammation, oxidative stress, and metabolic homeostasis, thereby reinforcing its role as a comprehensive, multi-target therapeutic strategy for CKD management. Nonetheless, validation through in vitro experiments remains necessary. Full article

Thyroid cancer is the most common malignancy of the endocrine system and represents a biologically heterogeneous disease driven by the interplay between endocrine regulation, oncogenic signaling pathways, and tumor microenvironment dynamics. Although most follicular cell-derived thyroid cancers follow an indolent clinical course, a subset progresses toward aggressive, therapy-refractory phenotypes, underscoring the need for refined molecular understanding and improved biomarkers. This review comprehensively examines the molecular determinants of thyroid cancer progression, with particular emphasis on Thyroid Hormone (TH) signaling, the Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)/AKT pathways, and the emerging role of microRNAs (miRNAs). We discuss how oncogenic alterations, most notably the ^V600EBRAF mutation, act as central drivers of tumor initiation and aggressiveness by sustaining MAPK/ERK signaling, promoting dedifferentiation, metabolic reprogramming, immune evasion, and resistance to targeted therapies. The cooperative role of PI3K/AKT signaling in reinforcing survival, invasion, and treatment resistance is highlighted, emphasizing the network-level integration of oncogenic pathways rather than linear dependency on single drivers. In parallel, thyroid hormones exert context-dependent effects on tumor biology through both genomic actions mediated by nuclear thyroid hormone receptors and non-genomic mechanisms initiated at the integrin αvβ3 receptor, linking endocrine status to cancer progression and therapeutic response. Finally, we review the expanding evidence supporting miRNAs as critical regulators of thyroid carcinogenesis and as promising diagnostic, prognostic, and predictive biomarkers. The clinical validation of miRNA-based panels and circulating miRNAs offers new opportunities to improve preoperative risk stratification, reduce overtreatment, and guide personalized therapeutic strategies. Collectively, these insights support a multidimensional framework for understanding thyroid cancer progression and highlight future directions for precision oncology. Full article

Grain number and size are important agronomic traits determining grain yield, and yield improvement depends on exploring functional variations of key regulatory genes. Mitogen-activated protein kinase 6 (MAPK6) plays a key role in crop development; however, its function and variation in wheat remain largely unclear. In this study, we aimed to characterize the function and haplotype variations of TaMAPK6-7A in wheat and develop functional molecular markers for marker assisted breeding. We identified three TaMAPK6 homoeologs on 7A, 7B, and 7D in wheat through bioinformatics analysis and revealed their evolutionary trajectory by phylogenetic analysis, with clear monocot-dicot lineage divergence and TaMAPK6 homoeolog clustering matching with hexaploid wheat’s allopolyploid origin. Spatiotemporal expression analysis showed that the TaMAPK6 homoeologs constitutively expressed in wheat tissues and were highly abundant in endosperm, spike, grain, and anther, with TaMAPK6-7A showing slightly higher transcript levels. In an ethyl methanesulfonate (EMS)-induced Jing411 mutant library, we identified a loss-of-function mutant of TaMAPK6-7A (J7633452), which exhibited severely reduced grain number per spike, impaired anther fertility, and increased grain size. Natural variation analysis of a large set of wheat accessions identified two major haplotypes of TaMAPK6-7A, with Type I was identical to the reference genome cultivar ‘Chinese Spring’, and Type II was consistent with the elite wheat cultivar ‘AK58’. We developed a PCR marker to accurately distinguish the two haplotypes and genotyped 192 wheat cultivars and elite breeding lines. Phenotypic evaluation indicated that Type II was an elite haplotype significantly associated with higher grain number per spike. This study characterizes TaMAPK6-7A as a key regulator of grain number per spike, providing a gene and molecular marker for marker-assisted breeding to improve grain yield. Full article

Background: Translocation morphology renal cell carcinoma (tRCC) accounts for nearly half of all pediatric RCC cases. Biological study AREN14B4-Q aimed to characterize the molecular landscape of tRCC using samples acquired from patients enrolled in the Children’s Oncology Group Risk Classification and Biobanking study AREN03B2. Methods: From 2006 to 2014, patients <30 yr old with renal tumors were prospectively enrolled in AREN03B2, a Central IRB-approved biobanking study. All pediatric RCC cases underwent a detailed central pathology review and molecular diagnostics to accurately classify RCC subtypes. Samples with confirmed tRCC and appropriate informed consent were identified with adequate tissue for RNA and DNA extraction, along with germline DNA, for whole-genome sequencing (WGS), RNA sequencing, and DNA methylation analyses. Results: From 41 patients, high-quality samples allowed for 18 tumors and non-tumor DNA to be analyzed via WGS, 19 via DNA methylation, and 36 RNA samples via transcriptome sequencing. Consistent with and extending clinical cytogenetic findings, WGS and fusion transcript analyses confirmed very few additional mutations beyond the tRCC translocation. No recurrent genomic copy number gains/losses were found. RNA and WGS analyses enabled sub-classification of tRCC, closely aligning with the different TFE3 fusion partners. DNA methylation analyses demonstrated less tRCC sub-stratification compared with RNA analyses. Pathways activated in tRCC were involved in epithelial differentiation, extracellular matrix organization, apoptosis, immune regulation, signal transduction, and angiogenesis. Conclusions: Arrested epithelial differentiation is the overarching driver in tRCC and is strongly correlated with the specific subclasses of fusion transcript generated by the genetic translocation TFE fusion partner. Negative regulation of apoptosis, increased M2 macrophage expression, and enhanced angiogenesis also appear to be functional features of tRCCs, as are increased expression of matrix metalloproteinases, PI3K-AKT/mTOR/MAPK signaling, and mitochondrial metabolism, highlighting potential therapeutic options beyond direct targeting of the oncogenic driver fusions. Full article

This study conducted a genome-wide identification and functional analysis of the glutathione S-transferase (GST) gene family in the xerophytic desert shrub Reaumuria soongorica. A total of 67 GST genes were identified, classified into seven subfamilies, including Phi and Tau, with family expansion primarily attributed to small-scale duplication events. The findings revealed that ResoGST52, a member of the Tau subfamily, serves as a core gene in drought response, exhibiting significant upregulation of 2.40-fold in leaves and 9.01-fold in roots under drought stress. Mechanistic investigations indicated that the expression of ResoGST52 is likely directly regulated by the transcription factor ResoDof17, with specific hydrogen bonding interactions identified between the two. Co-expression network analysis further demonstrated that ResoGST52 cooperates with key pathways such as plant hormone signaling, MAPK cascades, and glutathione metabolism to collectively respond to drought stress. Notably, evolutionary analysis revealed that ResoGST52 has undergone positive selection, with three positively selected sites identified. Among these, the p.Ala115Ser mutation increases the volume of the protein’s active site pocket, while the remaining mutations enhance surface hydrophobicity, thereby improving protein stability and catalytic efficiency under extreme drought conditions. In summary, this study not only systematically identifies the GST gene family in R. soongorica but also elucidates the central role of ResoGST52 in drought adaptation through multiple layers—from transcriptional regulation and co-expression networks to protein structural adaptive evolution—providing valuable candidate genes and theoretical insights for genetic improvement of drought tolerance in crops. Full article

Type 2 diabetes mellitus (T2DM) is driven by insulin resistance and β-cell dysfunction. While Ras GTPases are known for oncogenic signaling, emerging evidence implicates the Ras–Ral axis as a critical regulator of glucose homeostasis. This review synthesizes the distinct roles of Ras and Ral in metabolism. Ras hyperactivation promotes insulin resistance and inflammation via MAPK/PI3K pathways, whereas RalA supports GLUT4 translocation and insulin granule exocytosis. We propose a dual-pathway hypothesis: T2DM pathophysiology involves an imbalance characterized by excessive Ras signaling and insufficient Ral-mediated metabolic actions. Consequently, we explore the therapeutic potential of rebalancing this axis through combinatorial strategies, that selectively inhibit pathogenic Ras while enhancing protective Ral activity. We critically evaluate current Ras-targeted agents (e.g., farnesyltransferase inhibitors, allele-specific inhibitors) and discuss the emerging frontier of Ral-specific enhancers. Finally, we outline key translational challenges and future directions for validating this axis as a target for precision medicine in T2DM. Full article

Unravelling the cellular and molecular mechanisms underlying lung injury and repair requires precise spatial context. Profiling cell-to-cell transcriptional variability and spatial orientation has become increasingly sophisticated, but validating results at the protein level still remains challenging, particularly for low-expressed proteins or small-scale samples. Here, we present a workflow established by our group for spatial protein analysis in the lung by combining two commercially available platforms: (1) laser-assisted microdissection (LMD) with (2) a capillary electrophoretic-based immunoassay (CEI). Using this workflow, we demonstrate a simple, accessible, and sensitive method for spatially capturing regions of interest to investigate small-scale samples or low-expressed proteins. This workflow provides an additional option for orthogonal validation for researchers using omics-based approaches. Furthermore, we validated transcriptome analysis results at the protein level by applying this workflow to a pre-clinical model of cigarette smoke (CS)-induced lung injury. In line with the previous findings, the results showed a significant downregulation of the endothelial cell marker in LMD-enriched alveolar regions, suggesting spatial capillary rarefaction, and activation of the mitogen-activated protein kinase (MAPK) signalling pathway in pulmonary vasculature of CS-exposed mice. Our approach overcomes traditional challenges and provides new opportunities for understanding complex disease pathomechanisms and identifying potential therapeutic targets. Full article

Gabapentin is widely used for epilepsy and neuropathic pain. Beyond neurological indications, preclinical evidence suggests that gabapentin may exert anti-inflammatory effects that have not been systematically reviewed. A systematic review (2015–2025) was performed, resulting in thirteen in vitro and in vivo studies evaluating gabapentin’s impact on inflammatory signaling pathways, cytokine production, immune cell activity, and tissue inflammation. Outcomes included molecular pathways, inflammatory mediators, histopathological changes, and functional inflammatory measures. Risk of bias and study quality were assessed using the SYRCLE RoB tool for in vivo studies and the SciRAP approach for in vitro studies. Gabapentin demonstrated potential modulation of inflammatory responses in neuropathic pain, neuroinflammation, uveitis, and sepsis models through inhibition of MAPK and NF-κB signaling, reduction in pro-inflammatory cytokines, modulation of PPAR signaling pathways, and activation of Nrf2/HO-1 pathway. Gabapentin’s pharmacological actions extend beyond neuronal excitability to include modulation of inflammatory pathways, supporting a broader biological role for gabapentin. Although preclinical data support gabapentin’s potential anti-inflammatory properties, further targeted experimental and clinical studies are warranted to confirm these findings. Full article

Background: Polycystic ovary syndrome (PCOS) is a complex endocrine–metabolic disorder characterized by interconnected dysregulation of steroidogenesis and insulin signaling. Multi-target therapeutic strategies are increasingly needed to address its heterogeneous pathophysiology. Methods: An integrative approach combining transcriptomic analysis of GSE137684, including stratification of normoandrogenic and hyperandrogenic PCOS subtypes to capture androgen-related heterogeneity, network pharmacology, molecular docking, and in vitro validation was employed. Principal component analysis (PCA), differential expression analysis, and enrichment analyses were used to identify candidate genes and pathways. Molecular docking evaluated interactions between phytochemicals from Cinnamomum burmannii and Myristica fragrans and key PCOS targets. Functional validation was performed in insulin-resistant 3T3-L1 adipocytes and DHEA-induced KGN cells, assessing cell viability, lipid accumulation, glucose uptake, gene expression, and hormone levels. Results: PCA revealed partial separation between PCOS and the control samples, with PC1 and PC2 explaining 44.8% and 12.5% of variance, respectively. No genes remained significant after multiple testing correction; however, nominally significant candidates (p < 0.01) highlighted pathways related to steroidogenesis and metabolic regulation. Network analysis identified key hub genes including CYP17A1, CYP19A1, AKT1, ESR1, and MAPK1. Molecular docking demonstrated strong binding affinities, with top compounds showing binding energies up to −11.4 kcal/mol (CYP17A1) and −10.9 kcal/mol (AKT1). In vitro, cell viability remained above 80% across all tested concentrations, indicating low cytotoxicity. Treatment significantly reduced lipid accumulation and enhanced glucose uptake in insulin-resistant 3T3-L1 cells (p < 0.05). Additionally, expression of AKT1 and MAPK1 was significantly restored (p < 0.05). In KGN cells, testosterone levels were significantly decreased while the estradiol levels increased (p < 0.05), accompanied by the downregulation of CYP17A1 and upregulation of CYP19A1 (p < 0.05). The combination treatment exhibited more consistent effects across metabolic and hormonal endpoints. Conclusions:Cinnamomum burmannii and Myristica fragrans exert multi-target effects on metabolic and steroidogenic pathways relevant to PCOS. This integrative study demonstrates that transcriptomics-guided network pharmacology combined with experimental validation can identify synergistic phytotherapeutic strategies for complex endocrine disorders. Full article

Periplaneta americana extract can promote wound healing and may play an important role in skin wound healing. In this study, we identified a peptide (DL-13) from Periplaneta americana L. and explored its role and mechanisms in skin wound healing. In vitro, the effects of DL-13 on proliferation, migration, and related gene/protein expression in HaCaT keratinocytes were assessed via qRT-PCR and Western blot. In vivo, rat wound healing assays confirmed its efficacy. Results showed DL-13 accelerated rat wound healing. In in vitro studies, DL-13 activated EGFR and its downstream PI3K/AKT/mTOR, ERK/MAPK, and JAK2/STAT3 pathways, upregulated EMT-related proteins (N-cadherin, MMP-2, p-FAK, β-catenin), partially regulated macrophage cytokine secretion, and promoted HaCaT proliferation/migration, thereby facilitating re-epithelialization at skin injury sites. Overall, DL-13 may enhance the function of HaCaT cells by activating the EGFR signaling pathway and regulate inflammatory factors in macrophages, thereby promoting the healing of skin wounds in rats. The results of this study will lay an experimental and scientific foundation for the discovery of new compounds for wound healing and their application. Full article

Dermal papilla (DP) cells orchestrate hair follicle growth and cycling by secreting signaling molecules that stimulate follicular epithelial stem cells. The signal peptide CUB-EGF-like domain-containing protein 3 (SCUBE3) was recently identified as a potent anagen stimulator secreted by DP cells. Ageratum houstonianum ethanolic extract (AHE) and its active constituent agerarin exhibit anti-inflammatory properties; however, their effects on hair follicle growth remain unclear. This study aimed to investigate the effects of AHE and agerarin on SCUBE3 expression in primary human DP cells and to elucidate the underlying molecular signaling pathway. Cell viability was assessed by measuring cell confluency. Ex vivo hair growth was analyzed using organ cultures of human hair follicles. Gene and protein expression were determined using reverse transcription-PCR, immunoblot analysis, immunofluorescent staining, tyramide signal amplification-based multiplex immunohistochemistry, and gene promoter-reporter assay in primary human follicle DP cells. In a hair follicle organ culture model, both AHE and agerarin increased the population of the anagen phase and promoted hair shaft elongation. AHE and agerarin significantly upregulated SCUBE3 expression at both the mRNA and protein levels. Mechanistically, AHE and agerarin induced activator protein-1 (AP-1) expression by activating mitogen-activated protein kinase signaling pathways, thereby increasing SCUBE3 gene promoter activity. AHE and agerarin promoted hair follicle growth by upregulating SCUBE3 expression via activation of the MAPK–AP-1 signaling axis. In conclusion, AHE and agerarin may serve as potential therapeutic agents for the prevention and treatment of alopecia (hair loss). Full article

Background/Objectives: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the clonal proliferation of Langerhans-like dendritic cells and constitutive activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) signaling pathway. Nearly 80% of ERK pathway activation can be attributed to B-Raf proto-oncogene, serine/threonine kinase (BRAF V600E), and mitogen-activated protein kinase kinase 1 (MAP2K1) variants, with BRAF V600E specifically detected in approximately 50% of pediatric LCH cases and associated with a higher risk of severe disease and treatment failure. The use of the HistioTrak clinical assay to detect the presence of BRAF V600E mutations in peripheral blood mononuclear cells (PBMCs) has emerged as a useful diagnostic tool and biomarker. Methods: This study is a single-center retrospective study that explores the favorable outcomes of treatment with trametinib on a small number of patients with LCH. We retrospectively analyzed the records of 11 children with LCH treated with trametinib at diagnosis as front-line therapy (n = 6), due to progressive disease (n = 3) or intolerance (n = 1) to chemotherapy, or at relapse (n = 1). Results: HistioTrak identified the presence of BRAF V600E PBMCs in five patients. In this small single-center retrospective cohort, trametinib was associated with favorable short-term outcomes in all patients, and serial HistioTrak testing appeared feasible in selected patients. Conclusions: Prospective studies are needed before routine diagnostic or monitoring use can be recommended. Full article

Background/Objectives: Mitochondria are dynamic organelles that continuously undergo balanced cycles of fusion and division to maintain optimal function. Mitochondrial division is mediated by Dynamin-Related Protein 1 (DRP1), a cytosolic large GTPase whose phosphorylation at serine 616 (DRP1-S616Ⓟ) promotes its translocation to the outer mitochondrial membrane and organelle division. Dysregulated mitochondrial division disrupts cellular homeostasis and contributes to disease pathogenesis, including cancer. Our prior work demonstrated that the oncogene-induced mitogen-activated protein kinase (MAPK) pathway constitutively phosphorylates DRP1 at serine 616, which is essential to cellular transformation and correlates with oncogene status in patient tissues. Similarly, DRP1-S616Ⓟ is subject to pharmacologic control by targeted therapies against oncogenic MAPK signaling. Methods: Building upon this foundation, we developed and characterized a recombinant murine monoclonal antibody (referred to as 3G11) with high specificity for human DRP1-S616Ⓟ, raised against a peptide derived from the human DRP1 sequence. Results: Using diverse experimental platforms, we demonstrate the robust utility of 3G11 to detect DRP1-S616Ⓟ in melanoma cell extracts and isolated organelles. Immunofluorescence revealed that pharmacologic inhibition of oncogenic MAPK signaling reduces DRP1-S616Ⓟ levels, which correlates with mitochondrial hyperfusion, while immunohistochemistry showed that elevated DRP1-S616Ⓟ expression in human tissues correlates with BRAF^V600E disease. Conclusions: 3G11 is a new recombinant antibody for detecting DRP1-S616Ⓟ and supports studies of mitochondrial division in cancer. Together, these findings establish 3G11 as a specific, versatile, renewable, and cost-effective tool for studying mitochondrial division, with strong potential for clinical applications. Full article