Search Results (6,465)

Mikania micrantha, commonly known as mile-a-minute weed, is listed among the world’s top 10 worst weeds. Although native to humid regions of South America, it has recently been found to colonize arid habitats as well. Despite pronounced seasonal hydroclimatic variations in South China and increasing drought due to global climate change, the mechanisms underlying M. micrantha’s drought tolerance remain poorly understood. In this study, we compared the photosynthetic responses of M. micrantha leaves and stems between the dry (June) and wet (December) seasons through field experiments. We measured changes in phenotype, photosynthetic characteristics, and the content of antioxidant and osmotic adjustment substances, using the co-occurring native vine Paederia scandens as a control. The results revealed that during the dry season, M. micrantha leaves exhibited wilting, along with significant reductions in relative water content (RWC), chlorophyll (Chl), soluble sugar (SS), and soluble protein (SP). In contrast, the stems of M. micrantha maintained relatively stable phenotypes and chlorophyll levels compared to those of P. scandens. Notably, M. micrantha stems exhibited significant increases in vessel wall thickness, vessel density, total phenol content, and the activities of peroxidase (POD) and ascorbate peroxidase (APX). Furthermore, compared to P. scandens, M. micrantha stems displayed a greater increase in cortex proportion, flavonoid content, and soluble protein content. Expression analysis of bZIP transcription factors further revealed drought-responsive upregulation of specific genes (bZIP60, ZIP42-1), suggesting their potential involvement in drought response. These results indicate that although the leaves of M. micrantha are susceptible to prolonged drought, the stems exhibit considerable resilience, which may be attributed to a combination of traits including structural modifications in stem anatomy, enhanced antioxidant capacity, and osmotic adjustment. These insights suggest that stem-specific adaptations are key to its drought tolerance, providing a theoretical foundation for understanding the habitat distribution of M. micrantha and informing effective management strategies. Full article

Background and Aims: Little is known about metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocellular carcinoma (HCC) in non-cirrhotic (HCC-NC) patients. In-house developed mouse models with defective lipid-metabolizing enzyme long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD), coded by hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) gene, result in MASLD (steatosis) without cirrhosis leading to HCC-NC. The aims of the current investigations are to assess molecular markers and the associated molecular events that may lead to HCC-NC. Methods: cDNA array study of HCC patients was conducted to assess the expression of HADHA transcripts. Differentially expressed proteins identified between wild-type (WT) and heterozygous mice with no cancer (HT) from a previous study were subjected to Ingenuity Pathway Analysis (IPA). Western blotting was performed to assess the expression of proteins. Results: IPA of the differentially expressed proteins between WT and HT mice results in two biological networks (network 1 and network 2), which pointed to an important role of p53 in HCC-NC. Validation of the levels of MDM2 and p53 also highlights the role of MDM2-p53 axis in HCC-NC. All the focus molecules in network 1 and network 2 are either presented as tumor suppressor/promoter of carcinogenesis or serum markers for early HCC diagnosis. The hepatotoxicity report from IPA further identified four functional groups including liver steatosis, glutathione depletion, hepatocellular carcinoma, and liver hyperplasia/hyperproliferation. Conclusions: This study suggests that impaired fatty oxidation may play a role in the development of HCC associated with steatosis but without cirrhosis (HCC-NC). Defective LCHAD is a novel etiology for HCC. Full article

Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK/ERK and PI3K/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target. Full article

Background: Folic acid (FA), also known as vitamin B9, functions as a co-factor in many cellular processes. Ultraviolet radiation (UV) has been shown to cause the formation of free radicals, and chronic exposure of the skin to UV radiation has been demonstrated to result in many adverse effects. Skin protection against harmful environmental factors is one of the aims of cosmetic products. One such substance is folic acid. However, aqueous FA solutions decompose after exposure to UV radiation, and the decomposition products can exhibit variable pro/anti-oxidative roles depending on the cell type and its environment. Objectives: The objective of the present study was to demonstrate the effectiveness of folic acid as a UV-protective agent in vitro cell culture model. Methods: The experimental model comprised an in vitro culture of normal human fibroblasts derived from adult skin (NHDF-Ad). Paramagnetic electron resonance (EPR) was used to assess the interaction of folic acid with free radicals after exposure to UV radiation. RT-qPCR was utilized to evaluate the impact of ultraviolet (UV) radiation on the expression of selected cell cycle regulatory genes (CCND1, P53, BAX, and BCL-2) in vitro cultured fibroblasts that were protected by folic acid. Results: EPR studies revealed the antioxidant properties of folic acid. Free radical forms of folic acid are induced during UV irradiation. The strong effect of UV irradiation on interactions of folic acid with free radicals was observed. The interaction was found to be weaker for the irradiated samples. Molecular studies have demonstrated a decline in the BAX/BCL-2 ratio in cells that have been treated with folic acid and exposed to UV radiation in comparison to the BAX/BCL-2 ratio observed in cells that have been exposed exclusively to UV radiation and not treated with folic acid. Conclusions: Whilst molecular and EPR studies both confirm the effectiveness of folic acid as a UV-protective ingredient in cosmetics and pharmaceutical products, further research in this area is required. Full article

Cold stress significantly impairs plant growth and development, making the study of cold resistance mechanisms a critical research focus. Oreorchis patens (Lindl.) exhibits strong cold hardiness, yet its molecular and physiological adaptations to cold stress remain unclear. This study utilized microscopy, physiological assays, and RNA sequencing to comprehensively investigate O. patens’s responses to cold stress. The results reveal that cold stress altered leaf anatomy, leading to irregular mesophyll cells, deformed chloroplasts, and variable epidermal thickness. Physiologically, SOD and POD activities peaked at 5 °C/−10 °C, while CAT activity declined; osmotic regulators (soluble sugars, proline) increased with decreasing temperatures. Compared to the reference plants (e.g., Erigeron canadensis, Allium fistulosum), O. patens exhibited lower SOD and POD but markedly higher CAT activities, alongside reduced MDA, soluble sugars, proline, and proteins, underscoring its distinctive tolerance strategy. Low temperature stress (≤10 °C/5 °C) significantly decreased the SPAD index; the net photosynthetic rate (Pn) initially increased and then approached zero within the temperature range from 30 °C/25 °C to 25 °C/20 °C; transpiration rate (Tr) and stomatal conductance (Gs) changed synchronously, accompanied by an increase in intercellular CO₂ concentration (Ci). RNA sequencing identified 1139 cold-responsive differentially expressed genes, which were primarily enriched in flavonoid/lignin biosynthesis, jasmonic acid synthesis, and ROS scavenging pathways. qRT-PCR analysis revealed the role of secondary metabolites in O. patens response to cold stress. This study was the first to discuss the physiological, biochemical, and molecular regulatory mechanisms of O. patens resistance to cold stress, which provides foundational insights into its overwintering mechanisms and informs breeding strategies for cold-hardy horticultural crops in northern China. Full article

Background: Differentiated thyroid cancer (DTC) is commonly treated with radioactive iodine (RAI), but resistance to RAI remains a significant clinical challenge. The molecular mechanisms driving dedifferentiation and RAI refractoriness, particularly in BRAF^V600E-mutated tumors, are not fully understood. Methods: RNA sequencing was conducted on BRAF^V600E-mutated DTC and RAIR-DTC tissue samples to identify differentially expressed genes. Gadd45B was identified as significantly downregulated in RAIR-DTC. Functional studies including overexpression and knockdown experiments were performed in thyroid cancer cell lines and xenograft models. Downstream targets, including MAP3K4 and MYCBP, were evaluated through co-immunoprecipitation, luciferase assays, and Western blot. The therapeutic efficacy of recombinant Gadd45B protein in combination with BRAF^V600E and TERT inhibitors was assessed in patient-derived xenograft (PDX) models. Results: Gadd45B overexpression suppressed MAPK pathway activity by interacting with MAP3K4 and downregulated c-MYC stability through competition with MYCBP. These interactions enhanced the expression of iodine-metabolism genes (NIS, TPO, Tg), increased RAI uptake, and reversed tumor dedifferentiation. In vivo, Gadd45B restoration reduced tumor burden and improved RAI uptake. Combined treatment with Gadd45B protein, PLX4720, and BIBR1532 produced synergistic therapeutic effects in PDX models. Conclusions: Gadd45B plays a pivotal role in regulating the differentiation status and RAI sensitivity of BRAF^V600E-mutated thyroid cancer. These findings identify Gadd45B as a promising therapeutic target for restoring RAI responsiveness in RAIR-DTC patients. Full article

The early stages of plant–microbe interaction are critical for establishing beneficial symbioses. We investigated how the endophytic fungus Fusarium solani strain FsK modulates tomato (Solanum lycopersicum) development and hormone pathways during in vitro co-cultivation. Seedlings were sampled at three early interaction stages (pre-contact, T1; initial contact, T2, 3 days post-contact, T3). Root traits and root and leaf transcripts for abscisic acid (ABA) and ethylene (ET) pathways were quantified, alongside fungal ET-biosynthesis genes. FsK altered root system architecture, increasing root area, lateral root number, root-hair length, and fresh biomass. These morphological changes coincided with tissue- and time-specific shifts. In leaves, FsK broadly affected ABA biosynthetic and homeostasis genes (ZEP1, NCED1, ABA2, AAO1, ABA-GT, BG1), indicating reduced de novo synthesis with enhanced deconjugation of stored ABA. ET biosynthesis was curtailed in leaves via down-regulation of ACC oxidase (ACO1–3), with isoform-specific changes in ACC synthase (ACS). The ET receptor ETR1 was transiently expressed early (T1–T2). FsK itself showed staged activation of fungal ET-biosynthesis genes. These results reveal coordinated fungal–plant hormone control at the transcriptional level that promotes root development during early interaction and support FsK’s potential as a biostimulant. Full article

Background/Objectives: The interaction between brain-metastasizing melanoma cells and surrounding microglia shapes the immune tumor microenvironment and influences tumor progression. Gene expression analysis revealed that sphingosine-1-phosphate receptor 1 (S1PR1), encoding the S1P1 receptor, is upregulated in microglia upon interaction with melanoma cells. Here, we investigated the functions of S1P1 in microglia and its contribution to melanoma–microglia crosstalk. Methods: We examined the effects of S1P1 inhibition on microglia and four brain-metastasizing human melanoma cell lines in monocultures and co-cultures using the selective S1P1 antagonist NIBR0213 and S1PR1 gene knockdown. Results: We found that melanoma-secreted IL-6 upregulated S1PR1 expression in microglia. S1P1 inhibition increased expression of CD32, CD150, and CD163 in microglia; however, CD150 and CD163 upregulation was abolished in the presence of melanoma cells. S1P1 inhibition downregulated immunosuppressive and anti-inflammatory factors in microglia, including CD274, SOCS3, TGFBR1, TGFBR2, and JunB, promoting a pro-inflammatory phenotype. It also reduced viability of both melanoma and microglia cells, inducing apoptosis in melanoma-associated microglia, possibly via downregulation of CH25H, an upstream regulator of SREBPs. In co-cultures, melanoma cells were more sensitive than microglia to NIBR0213-induced growth arrest. In 3D spheroid cultures, NIBR0213 delayed melanoma–microglia aggregation. Combined treatment with the BRAF inhibitor Vemurafenib and NIBR0213 enhanced Vemurafenib efficacy in three of four melanoma lines. Conclusions: S1P1 contributes to the immunosuppressive phenotype of microglia. Inhibiting the S1P/S1P1 axis impairs viability and crosstalk between melanoma cells and tumor-activated microglia, offering a potential therapeutic strategy for melanoma brain metastases. Full article

This study examined the effect of long-term physical activity during the finishing period on meat and fat quality, and metabolic gene expression in obese Alentejano (AL) pigs. From 87.3 to 161.6 kg BW and for 130 days, eighteen pigs were assigned to either individual pens without an exercise area (NE, n = 9) or an outdoor park with an exercise area (WE, n = 9). Both groups received identical commercial diets at 85% ad libitum intake. Loin (Longissimus lumborum—LL), tenderloin (Psoas major—PM), and dorsal subcutaneous fat samples were obtained at slaughter, and analyzed for fatty acid composition and gene expression. Physical activity modulated the fatty acid profile and key metabolic genes in muscle and fat tissues. WE pigs showed higher palmitoleic (p = 0.031) and linolenic (p = 0.022) acids in LL, while Fatty acid synthase and Leptin in LL were downregulated (p = 0.071 and p = 0.018, respectively); Fatty acid binding protein 4 was downregulated (p = 0.003) and Stearoyl-CoA desaturase upregulated (p = 0.020) in the PM of WE pigs, indicating changes in lipid metabolism. Also, Myosin heavy chain 7 was upregulated (p = 0.016) in LL, suggesting oxidative muscle remodeling. These findings suggest that moderate, long-term physical activity during finishing induces modest but favorable metabolic adaptations in muscle and fat tissues without compromising meat quality in AL pigs, supporting its use in traditional rearing systems aimed at balancing animal welfare and product quality in local breeds. Full article

Swine manure poses significant challenges for anaerobic digestion due to its low carbon-to-nitrogen (C/N) ratio and elevated ammonia concentrations, both of which restrict methane generation. This study investigated the impact of integrating low-intensity ultrasound with co-digestion of piggery wastewater and food waste leachate. Laboratory-scale upflow anaerobic sludge blanket (UASB) reactors were employed under four operational conditions to evaluate anaerobic digestion performance, track shifts in microbial community structure, and assess the abundance of antibiotic resistance genes (ARGs). Co-digestion significantly enhanced methane production, yielding 1.3–3.2 times more than manure alone, while low-intensity ultrasound further increased methane yields by approximately 36–44% at high loading rates. Moreover, coupling low-intensity ultrasound with co-digestion led to the most rapid recovery following an overloading shock. Unexpectedly, ultrasound treatment alone increased the expression of certain ARGs (tetG, sul1, ermB) and the Integrase gene (intI1), while co-digestion led to a reduction in these genetic markers. These findings clearly indicate that the concurrent application of co-digestion and low-intensity ultrasound achieved the highest methane yield, the fastest recovery after organic overloading, and greater suppression of specific ARGs. Full article

Grass carp (Ctenopharyngodon idella), a key species in freshwater aquaculture, is particularly vulnerable to opportunistic pathogens, including Aeromonas hydrophila and Aeromonas veronii. While the pathogenic mechanisms of individual infections have been extensively characterized, the host immune responses during co-infection remain poorly understood. This research explored the renal pathological alterations and transcriptomic shifts in grass carp subjected to simultaneous infection by A. hydrophila and A. veronii. Mortality occurred as early as 24 h post-challenge, ultimately reaching a cumulative death rate of 65%. Quantitative analysis of renal bacterial burden revealed a marked increase in colonization at 3 days post-infection (dpi). The histopathological assessment showed progressive kidney damage, including tubular collapse, epithelial necrosis, interstitial edema, and widespread epithelial desquamation, with the most severe lesions observed at 5 dpi and partial signs of recovery by 7 dpi. A total of 1106 and 472 genes were found to be differentially expressed at 1 and 5 dpi, respectively, based on transcriptome profiling. The functional enrichment analysis indicated that the differentially expressed genes (DEGs) were mainly involved in the complement and coagulation cascade pathways. Notably, the immune-related genes exhibited a biphasic trend, with predominant downregulation at 1 dpi followed by marked upregulation by 5 dpi, indicating dynamic changes in immune modulation during co-infection. These results provide new insights into host responses during dual bacterial infections in fish and may inform disease prevention strategies in aquaculture. Full article

Background: The androgen receptor (AR) is a ligand-dependent transcription factor of the nuclear steroid receptor superfamily, implicated in the pathogenesis of various solid tumors. The AR gene, located on chromosome Xq11–12, is accompanied by several X-linked genes that modulate AR expression and function, including FLNA, UXT, and members of the melanoma antigen gene (MAGE) family (MAGEA1, MAGEA11, MAGEC1, MAGEC2). While the AR has been investigated in multiple tumor types, its role in adult-type diffuse gliomas remains largely unexplored. Here, we characterized AR protein expression and the promoter methylation status of the AR and associated regulatory genes in adult-type diffuse gliomas. Methods: A retrospective analysis was conducted on 50 patients with adult-type diffuse gliomas, including IDH-mutant gliomas (grades 2–4) and IDH-wildtype glioblastomas (GBMs), classified according to the 2021 WHO criteria. AR nuclear expression was assessed by immunohistochemistry (IHC). Methylation-specific PCR and quantitative DNA methylation analyses were employed to evaluate promoter methylation of the AR and selected co-regulatory genes. Results: AR nuclear positivity correlated significantly with male sex (p = 0.04) and higher tumor grade, with the highest expression in IDH-wildtype GBMs (p = 0.04). In IDH-mutant gliomas, AR immunoreactivity was more prevalent in astrocytomas than in 1p/19q codeleted oligodendrogliomas (p = 0.02). AR expression was associated with unmethylated MGMT promoter status (p = 0.02). DNA methylation analysis revealed AR gene hypomethylation in tumors displaying nuclear AR positivity and in IDH-wildtype GBMs (Kruskal–Wallis p < 0.05). Additionally, methylation patterns of AR co-regulators located on the X chromosome suggest epigenetic regulation of AR signaling in gliomas. Conclusions: The findings reveal distinct AR pathway activation patterns in adult-type diffuse gliomas, particularly IDH-wildtype GBMs, suggesting that further exploration of antiandrogen therapies is warranted. Full article

Background: Alpiniae oxyphyllae-Saposhnikovia divaricata (AS), a traditional Chinese dietary supplement, exhibits potential therapeutic effects against diabetic kidney disease (DKD), though its active compounds and mechanisms require elucidation. Methods: Animal experiments integrated with UHPLC-QE-MS, bioinformatics, and experimental validation were employed to investigate AS’s pharmacodynamic basis against DKD. Results: Thirty-nine compounds were identified in AS, including four key flavonoids (daidzein, kaempferol, tectoridin, baicalin). Bioinformatics screening revealed 516 potential AS targets from PubChem/TCMSP/ETCM databases. Analysis of the GEO dataset (GSE30529) identified 482 DKD-related differentially expressed genes (DEGs). Venny 2.1 analysis yielded 42 co-DEGs and 6 co-core DEGs. Functional enrichment (GO/KEGG/GSEA) demonstrated AS’s modulation of apoptosis and extracellular matrix (ECM) pathways via these DEGs. ROC profiling and renal single-cell sequencing highlighted FOS as a specific regulator of podocyte apoptosis in DKD. Molecular docking confirmed stable binding between the four flavonoids and FOS. Experimentally, AS significantly suppressed expression of ECM-related proteins (Col-IV, LN, IL-6, IL-17) and pro-apoptotic proteins (Bax, Caspase-3), while restoring anti-apoptotic Bcl-2 levels and inhibiting phosphorylation of MEK4, JNK1, c-Jun, and FOS in DKD mice. Conclusion: This study elucidates that AS alleviates DKD by inhibiting the MAPK/FOS pathway, thereby attenuating podocyte apoptosis and ECM accumulation. These findings establish a foundation for targeted AS therapy in DKD. Full article

(1) Background: IgA nephropathy (IgAN) is a leading cause of chronic kidney disease worldwide. Despite its prevalence, the molecular mechanisms of IgAN remain poorly understood, partly due to limited research scale. Identifying key genes involved in IgAN’s pathogenesis is critical for novel diagnostic and therapeutic strategies. (2) Methods: We identified differentially expressed genes (DEGs) by analyzing public datasets from the Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to elucidate the biological roles of DEGs. Hub genes were screened using weighted gene co-expression network analysis combined with machine learning algorithms. Immune infiltration analysis was conducted to explore associations between hub genes and immune cell profiles. The hub genes were validated using receiver operating characteristic curves and area under the curve. (3) Results: We identified 165 DEGs associated with IgAN and revealed pathways such as IL-17 signaling and complement and coagulation cascades, and biological processes including response to xenobiotic stimuli. Four hub genes were screened: three downregulated (FOSB, SLC19A2, PER1) and one upregulated (SOX17). The AUC values for identifying IgAN in the training and testing set ranged from 0.956 to 0.995. Immune infiltration analysis indicated that hub gene expression correlated with immune cell abundance, suggesting their involvement in IgAN’s immune pathogenesis. (4) Conclusion: This study identifies FOSB, SLC19A2, PER1, and SOX17 as novel hub genes with high diagnostic accuracy for IgAN. These genes, linked to immune-related pathways such as IL-17 signaling and complement activation, offer promising targets for diagnostic development and therapeutic intervention, enhancing our understanding of IgAN’s molecular and immune mechanisms. Full article

Background: Oncogenic fusions of MAML2 with CRTC1, CRTC3, YAP1, and NR1D1 retain the MAML2 transactivating domain (TAD) and are believed to drive aberrant gene transcription. While the oncogenic roles of these known fusions have been established, we aimed to identify novel MAML2 fusions across a range of human malignancies. Methods: DNA and RNA sequencing were performed on tumor samples submitted to Caris Life Sciences. MAML2 fusions were identified from RNA transcripts and filtered to include only known pathogenic fusions or recurrent, in-frame fusions containing a C-terminal MAML2 TAD. Fusion burden was defined as the number of unique fusion isoforms per sample. Results: Among 180,124 tumor samples, 143 specimens harbored MAML2 fusions with a MAML2 TAD: >50% of specimens harbored known fusions, but novel fusions with MTMR2 (31/143), SESN3 (11/143), CCDC82 (6/143), FAM76B (4/143), and ATXN3 (3/143) were also identified. Compared to the known fusions, the novel fusions generally had lower expressions (median: 8 vs. 13 junction reads/sample, p = 0.0064), higher fusion burdens (median: 6 vs. 2 unique fusion isoforms/sample, p < 0.0001), more frequent TP53 co-mutations (80% vs. 11.5%, p < 0.0001), and no clear association with the tissue of origin. Excluding ATXN3::MAML2, the novel fusion partners were located near MAML2 in the genome, likely arose from duplications or deletions, and occurred in samples harboring concurrent mutations. In contrast, ATXN3::MAML2 arose via interchromosomal translocation, occurred in samples with a low fusion burden, and was not associated with TP53 mutations. Conclusions: We identified novel MAML2 fusion partners, most of which likely represent passenger alterations, possibly arising from genomic instability or impaired p53 function. However, ATXN3::MAML2 fusions, previously reported in a pre-cancerous pancreatic disease case, may represent a pathogenic alteration warranting further investigation. Full article