Search Results (3,952)

Neuroinflammation plays a central role in the pathogenesis of Alzheimer’s disease (AD), with amyloid-β (Aβ) deposition and neurofibrillary tangles driving both central and peripheral inflammatory responses. This study investigated the neuroprotective and anti-inflammatory effects of Vitex trifolia (VT), Plantago major (PM), Apocyni Veneti Folium (AVF), and Eucommiae folium (EF) using network pharmacology and a co-culture model of PC12 neuronal and Caco-2 intestinal epithelial cells. Bioactive compounds were identified via high-performance liquid chromatography (HPLC) and screened with network pharmacology analysis, yielding 27 for VT, 10 for PM, 6 for AVF, and 3 for EF. Molecular docking confirmed strong binding affinities between the key bioactive compounds and AD-related targets. A co-culture system of PC12 neuronal and Caco-2 intestinal epithelial cells was established to evaluate the effects of VT, PM, AVF, and EF extracts (at concentrations of 10 µg/mL, 20 µg/mL, and 50 µg/mL) and donepezil hydrochloride (positive-control) on Aβ_25–35-induced neurotoxicity and lipopolysaccharide (LPS)-induced intestinal inflammation, to assess cell viability, and effects on oxidative stress, mitochondrial function, and inflammatory markers. The VT, PM, AVF, and EF extracts activated phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3β (GSK-3β) signaling, enhanced phosphorylation of AMP kinase, suggesting inhibition of Aβ accumulation and tau hyperphosphorylation (p < 0.05). However, donepezil hydrochloride only enhanced AMPK phosphorylation. The extracts reduced lipid peroxidation and acetylcholinesterase by about 5-fold. JC-1 staining confirmed preserved mitochondrial membrane potential, while hematoxylin and eosin staining indicated improved intestinal barrier integrity (p < 0.05). PM and AVF reduced the number of mast cells (p < 0.05). In conclusion, these findings highlight the multi-target potential of VT, PM, AVF, and EF in mitigating both neuronal and intestinal inflammation. Their dual regulatory effects on the gut–brain axis suggest promising therapeutic applications in AD through the modulation of central and peripheral immune responses. Full article

Once a protein of relative obscurity, inositol polyphosphate multikinase (IPMK) emerged as a versatile and indispensable enzyme in cellular biology. With dual inositol and lipid kinase activities, IPMK generates pivotal signaling molecules such as InsP4 (inositol tetraphosphate), InsP5 (inositol pentaphosphate), and PIP3 (phosphoinositide 3,4,5-trisphosphate), positioning it as a critical regulator of cellular mechanisms. Initially identified in yeast and later recognized as essential for mammalian embryonic development, IPMK has transitioned from a niche interest to a focal point in studies of nutrient sensing, growth factor signaling, mRNA transport, and transcription regulation. Over two decades, multidisciplinary research has unveiled its far-reaching biological roles and implications in diverse diseases, including neurodegeneration, cancer, and inflammation. This review charts IPMK’s journey from obscurity to prominence, examining its structure–function relationships, cellular roles, and emerging physiological impacts, while highlighting its potential as a therapeutic target in human health and disease. Full article

Phytophthora fruit rot caused by Phytophthora capsici is a devastating disease in many solanaceous vegetables, resulting in tremendous yield and economic losses. However, the underlying resistance or susceptibility to P. capsici in eggplant remains obscure. In this study, the transcriptomic analysis was performed between the resistant (G42) and susceptible (EP28) eggplant genotypes at 0, 1, 3 and 5 days post-inoculation (dpi). Taking 0 dpi as the control, a total of 4111, 7496 and 7325 DEGs were expressed at 1, 3 and 5 dpi, respectively, in G42 and 5316, 12675 and 12048 DEGs were identified at 1, 3 and 5 dpi, respectively, in EP28. P. capsici infection induced substantial transcriptional changes in the inoculated fruits. The analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) identified defense-related pathways including ‘plant-pathogen interactions’, ‘mitogen-activated protein kinase (MAPK)’ and ‘hormone biosynthesis and signal transduction’. The hormone-related genes encompassing ethylene, abscisic acid, auxins and gibberellins showed differential expression between G42 and EP28 eggplant genotypes, signifying their important roles in plant disease resistance. P. capsici infection induced the expression of major transcription factors such as MYB, NAC/NAM, bHLH, WRK, HSF, HD-ZIPAP2/ERF and Mad-box. qRT-PCR validation of the selected genes corroborates with RNA-seq, depicting the precision and consistency of the transcriptomic data. According to qRT-PCR and RNA-seq analyses, the expression of the pathogenesis-related gene transcriptional activator, SmPTI6 (Smechr0603020), is upregulated in G42 and downregulated in EP28. This differential expression suggests a potential role in the resistance to P. capsici. Functional analysis via a virus-induced gene silencing (VIGS) system found that silencing SmPTI6 in G42 enhanced infection by P. capsici, indicating that SmPTI6 performs a critical role in response to pathogen attack. The comprehensive results obtained in this study provide a valuable resource for understanding the molecular mechanisms underlying eggplant resistance to P. capsici and for establishing breeding resistant eggplant genotypes to P. capsici. Full article

Background/Objectives: Nanobubble water (NBW) is being studied increasingly for its potential benefits in sports nutrition. This study aimed to evaluate whether supplementation with ozone-enriched NBW (O₃-NBW) could improve integrated exercise capacity—encompassing endurance performance, muscle strength, and postexercise recovery as well as body composition and metabolic adaptations in mice. Methods: Male ICR mice (n = 24) were allocated into Control, Air-NBW, or O₃-NBW (0.2–1 mg/L ozone) groups for 4 weeks. Results: O₃-NBW treatment considerably enhanced forelimb grip strength and treadmill running endurance compared to the Control group (both p < 0.05). Analyses of body composition revealed a higher proportion of lean mass and muscle glycogen storage in NBW groups, notably with O₃-NBW. Serum markers gathered post-exercise demonstrated a reduction in ammonia and blood urea nitrogen (BUN), suggesting improved nitrogen metabolism. Levels of resting serum creatine kinase (CK) and uric acid were also lower in O₃-NBW mice, indicating potential benefits for muscle recovery. In addition, O₃-NBW treatment significantly enhanced oxygen consumption (VO₂) and reduced the respiratory quotient (RQ), signifying amplified fat oxidation, while also lowering total energy expenditure (all p < 0.05). Spontaneous wheel-running activity remained consistent across all the groups. Conclusions: Taken as a whole, these findings emphasize that O₃-NBW supplementation offers ergogenic and metabolic advantages by improving integrated exercise capacity and efficiency of gas exchange, without adverse effects. Full article

BQ323636.1 (BQ) is a splice variant of NCOR2. Its overexpression is associated with endocrine therapy and chemoresistance in estrogen receptor-positive (ER+ve) breast cancer. This study investigates how BQ overexpression drives doxorubicin (DOX) resistance by enhancing androgen receptor (AR) signaling and non-homologous end joining (NHEJ). BQ overexpressed breast cancer cell lines (MCF-7, T-47D, BT-549, MDA-MB-453), showed increased AR activity (ARE-luciferase assay) and demonstrated DOX resistance (EC50 > 10-fold with DHT, p < 0.05), as assessed via cell viability, TUNEL, and comet assays. RNA-sequencing (GSE295979, GSE2048) revealed the involvement of AR signaling. BQ upregulated cell cycle-related kinase (CCRK), stabilizing KU70, a key NHEJ protein, resulting in enhanced NHEJ activity (EJ5-GFP assay, p < 0.01). Co-immunoprecipitation confirmed the interaction between CCRK and KU70, and CCRK was found to modulate the protein stability of KU70. AR inhibition with bicalutamide in BQ overexpressing cells reversed DOX resistance. Xenograft models validated AR-dependent DOX resistance. In ER+ve breast cancer patient samples, high CCRK expression correlated with DOX resistance (p = 0.002) and metastasis (p = 0.001). Kaplan–Meier analysis showed poorer overall survival (p < 0.001) and disease-specific survival (p < 0.001) in cancers with high CCRK. Cox-regression analysis showed that high CCRK was a poorer prognostic factor of overall survival (p < 0.001; RR 3.056, 95% CI 1.661, 5.621, AR (p < 0.001; RR 3.420, 95% CI 1.783, 6.562), and disease-specific survival (p < 0.001; RR 2.731, 95% CI 1.472, 5.067). The BQ-AR-CCRK-KU70 axis represents a novel mechanism of DOX resistance in ER+ve breast cancer, suggesting AR or CCRK inhibition as a potential therapeutic strategy. Full article

The aim of this study was to investigate the effect of ice-temperature (IT) storage on the umami-enhancing nucleotide content in white mullet (Ophiocephalus argus var. Kimnra) meat. White mullet dorsal muscle was used as the raw material, and 4 °C chilled storage was used as a reference. After determining the ice temperature (−0.6 °C) of the dorsal muscle, the effect of IT storage on its umami-enhancing nucleotides was investigated. The umami nucleotide levels, physicochemical properties (pH, muscle color, water-holding capacity, and cooking loss rate), glycolytic metabolites (lactic acid, pyruvic acid, and glycogen), and enzyme activities (lactate dehydrogenase, pyruvate kinase, and 5′-nucleotidase) in the dorsal muscle were examined. The results indicate that IT storage significantly (p < 0.05) lowered pH while improving the water-holding capacity compared to 4 °C chilled storage. Both storage conditions showed an initial increase followed by a decrease in the inosine 5′-monophosphate (IMP) content, while the content of guanosine 5′-monophosphate (GMP) progressively declined. IT storage maintained significantly (p < 0.05) higher IMP and GMP levels than chilled storage in the late storage stage. The accumulation of the bitter taste substances hypoxanthine (Hx), lactic acid, and pyruvic acid was reduced under IT storage. These findings demonstrate that IT storage effectively inhibits the degradation of umami-enhancing nucleotides and is beneficial for preserving the meaty taste of white mullet meat. Full article

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein promoting tumor progression via multiple pathways. Its prognostic significance in lung cancer remains unclear. We analyzed tumor samples from 53 patients with lung cancer undergoing curative surgical resection without prior chemotherapy or radiotherapy. Immunohistochemical staining and H-score quantification were performed to assess CIP2A and related protein expression. Patients were stratified based on CIP2A expression (cutoff value = 218.33). Kaplan–Meier survival analysis produced curves and log-rank tests. Correlations with clinicopathological and molecular markers were assessed. High CIP2A expression was significantly associated with poorer survival (log-rank, p = 0.0051). Pearson correlation analysis revealed that CIP2A expression was positively correlated with clusters of differentiation 31 (r = 0.420, p = 0.002), epithelial cadherin (r = 0.372, p = 0.006), and phosphorylated protein kinase B (r = 0.332, p = 0.015), and negatively correlated with phosphorylated AMP-activated protein kinase (r = −0.474, p < 0.001), suggesting potential roles for CIP2A in promoting angiogenesis, sustaining epithelial traits, and suppressing metabolic regulation via AMPK signaling. CIP2A is a significant prognostic biomarker in lung cancer, contributing to tumor progression through modulation of angiogenesis and metabolic pathways. Exploration of its therapeutic potential and underlying mechanisms is warranted. Full article

Ceramide 1-phosphate (C1P) is a key regulator of cell proliferation and survival in both normal and transformed cells. Major pathways implicated in the mitogenic actions of C1P include activation of the mitogen-activated protein kinases (MAPKs) ERK1-2 and JNK, as well as stimulation of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, the product of retinoblastoma, or the sphingomyelin synthase (SMS)/diacylglycerol (DAG)/protein kinase C-alpha (PKC-α) pathway. C1P-stimulated cell proliferation can also be mediated through enhanced secretion of vascular endothelial growth factor (VEGF) in macrophages or by releasing lysophosphatidic acid (LPA) in myoblasts. Also, the production of low levels of reactive oxygen species (ROS) can mediate the stimulation of cell growth by C1P, particularly in macrophages. Upregulation of the PI3K/Akt/mTOR pathway is also involved in the inhibition of cell death by C1P, which can also contribute to cell survival by blocking the activity of the ceramide-generating enzymes acid sphingomyelinase (ASMase) and serine palmitoyl transferase (SPT). Moreover, C1P-promoted cell survival involves upregulation of inducible nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Using photosensitive C1P analogues, it could be concluded that promotion of cell growth and inhibition of cell death were elicited by intracellularly generated C1P in a receptor-independent manner. The aim of the present review is to evaluate in detail the implication of the CerK/C1P axis in controlling cell proliferation and survival in mammalian cells, as well as to discuss and update on the molecular mechanisms by which C1P can accomplish these actions. Full article

Pancreatic ductal adenocarcinoma (PDA) exhibits diverse molecular aberrancies that contribute to its aggressive behaviour and poor patient survival. P-21-activated kinase 1 (PAK1) and PAK4 drive the tumorigenesis of PDA. However, their roles in tumour vasculature and the impact on immune response are unclear. This study aims to investigate the effects of PAK1 and PAK4 on tumour vasculature, immune cell infiltration, and the connection between using PAK1-knockout (KO), PAK4 KO, and wild-type (WT) PDA cells in cell-based and mouse experiments. Tumour tissues isolated from a syngeneic mouse model were immuno-stained to determine the changes in tumour vasculature and immune cell infiltration/activation, followed by a proteomic study to assess biological processes involved. PAK1KO or PAK4KO suppressed tumour growth by reducing angiogenesis while enhancing vascular normalisation, enhanced the infiltration/activation of T-cells and dendritic cells associated with upregulation of ICAM-1 and VCAM-1 in the tumour microenvironment, and stimulated vascular immune crosstalk via an ICAM-1-mediated mechanism. This was supported by proteomic profiles indicating the regulation of endothelial cell and leukocyte trans-endothelial migration in PAK1- or PAK4-knockout tumours. In conclusion, PAK1KO or PAK4KO enhanced tumour vascular normalisation while reducing angiogenesis, stimulating immune cell infiltration and activation to suppress tumour growth. Full article

Background: Osteosarcoma (OS) is a fast-growing malignant bone tumor that occurs most often in children and teenagers. Development of pulmonary metastasis is the primary cause of treatment failure and mortality. Our previous studies demonstrated that cytoplasmic p27 interacts with PAK1, enhancing PAK1 phosphorylation and promoting OS pulmonary metastasis. However, the cellular functions of p27 and PAK1 are primarily regulated by phosphorylation, and the roles of specific phosphorylation residues in modulating OS metastatic potential remain unclear. Methods: To study tumor invasiveness and lung metastasis, we employed a CRISPR-based knock-in method to introduce specific mutations—p27-T157A, p27-T157D, PAK1-T423E, and PAK1-K299R—into the 143B OS cell line, followed by in vitro invasion and orthotopic xenograft mouse experiments. These residues were selected for their therapeutic potential, as T157 regulates p27 nuclear–cytoplasmic shuttling, while T423 and K299 modulate PAK1 kinase activity. Results: No significant differences in pulmonary metastasis were observed across p27 mutants compared to parental controls. However, the p27-T157D mutant exhibited increased cytoplasmic mislocalization, elevated PAK1-S144 phosphorylation, and enhanced in vitro invasiveness compared to the p27-T157A mutant and parental 143B cells. The PAK1-K299R mutant, designed to be kinase-dead, showed negligible S144 phosphorylation, consistent with loss of kinase activity. Unexpectedly, this mutant displayed increased T423 phosphorylation and in vitro invasiveness, and significantly enhanced pulmonary metastasis in vivo compared to the PAK1-T423E mutant and parental controls. Conclusions: These findings highlight the complexity of targeting specific p27 and PAK1 phosphorylation sites as an anti-metastatic strategy for OS. While p27-T157 phosphorylation influences cytoplasmic localization and invasiveness, it does not significantly alter metastatic outcomes. Conversely, PAK1-T423 phosphorylation is critical in driving OS metastatic potential, and the kinase-dead K299R mutant’s unexpected pro-metastatic effect suggests that kinase-independent mechanisms or compensatory pathways may contribute to metastasis. Our findings suggest the necessity for a more comprehensive understanding of the phosphorylation dynamics of p27 and PAK1 in metastatic OS. They also indicate that conventional kinase inhibition may be insufficient and underscore the potential benefits of alternative or combinatorial therapeutic strategies, such as targeting kinase-independent functions or other upstream kinases involved in these regulatory pathways. Full article

MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces injection-site reactions in most patients and is used experimentally to probe MRGPRX2 function in skin tests. While reported to be G-protein-biased, it is unknown how skin MCs respond to icatibant, although these are the primary target cells during therapy. We therefore compared responses to icatibant with those induced by the balanced agonist substance P (SP) in skin MCs. Degranulation and desensitization were assessed via β-hexosaminidase release, receptor internalization by flow cytometry, and downstream signaling by immunoblotting. Skin MCs degranulated in response to SP and icatibant, relying on Gi proteins and calcium channels; Gq and PI3K (Phosphoinositide 3-kinase) contributed more strongly to exocytosis following icatibant, while JNK (c-Jun n-terminal kinase) was more relevant for SP. Both agonists activated ERK, PI3K/AKT, and (weakly) p38. Surprisingly, and in contrast to the LAD2 (Laboratory of Allergic Diseases 2 mast cell line) MC line, icatibant was at least as potent as SP in eliciting MRGPRX2 internalization and (cross-)desensitization in skin MCs. These findings suggest that icatibant functions differently in primary versus transformed MCs, acting as a fully balanced ligand in the former by triggering not only degranulation but also receptor internalization and desensitization. Therefore, not only the ligand but also the MRGPRX2-expressing cell plays a decisive role in whether a ligand is balanced or biased. These findings are relevant to our understanding of icatibant’s clinical effects on edema and itch. Full article

The effects of storage temperature (4 °C, −1 °C, and −4 °C) after the very fast chilling (VFC) treatment on the glycolysis in lamb were investigated. The meat tenderness, glycolytic rates, activity, phosphorylation, and acetylation levels of glycolytic enzymes in meat stored at different temperatures were measured. It was shown that there was no significant difference in the degradation degree of desmin and troponin T in meat at different storage temperatures after VFC treatment (p < 0.05). The decrease rate of pH and ATP in meat was the same under different storage temperatures. The promoted phosphorylation and acetylation levels of phosphofructokinase (PFKM) and phosphoglycerate kinase (PGK) and inhibited acetylation level of aldolase (ALDOA) in the samples stored at different temperatures maintained the same glycolytic rate. In conclusion, chilling treatment is the key step in improving meat tenderness rather than storage temperature, which is achieved by the increased phosphorylation of ALDOA, PFKM, and PGK and decreased acetylation of ALDOA. It indicated that the chilling rate promoted the improvement of meat quality mainly by delaying glycolysis compared to the storage temperature. Full article

Mannan oligosaccharide (MOS), a prebiotic derived from yeast cell walls, has been shown to enhance growth performance and health status in various aquatic species. As an exogenous antigen adjuvant, MOS modulates T-cell-mediated immune responses, thereby improving immune function and suppressing excessive inflammatory reactions. This study aimed to evaluate the effects of dietary MOS supplementation on growth performance, serum biochemical parameters, muscle composition, digestive enzyme activity, antioxidant and immune status, and the mTOR signaling pathway in juvenile GIFT tilapia (Oreochromis niloticus). Juveniles (initial body weight: 16.17 ± 1.32 g) were randomly assigned to six treatment groups (three replicate tanks per group) and fed diets supplemented with MOS at 0, 0.2%, 0.4%, 0.6%, 0.8%, and 1% (equivalent to 0, 2, 4, 6, 8, and 10 g/kg of diet, respectively) for 60 days. Compared with the control group, fish fed MOS-supplemented diets exhibited significantly higher (p < 0.05) weight gain rates, specific growth rates, and protein efficiency ratios, along with a significantly lower (p < 0.05) feed conversion ratio. Serum albumin, high-density lipoprotein, and lysozyme levels were significantly increased (p < 0.05), whereas triglycerides, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels were significantly decreased (p < 0.05). In the liver, head kidney, and spleen, the expression of pro-inflammatory genes (tumor necrosis factor α, interleukin 1β, interleukin 6, interleukin 8, and interferon γ) was significantly downregulated (p < 0.05), while the expression of antioxidant and protective genes (superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, nuclear factor erythroid 2-related factor 2, lysozyme, alkaline phosphatase, interleukin-10, transforming growth factor β, and heat shock protein 70) as well as mTOR signaling pathway-related genes (mammalian target of rapamycin, akt protein kinase B, phosphatidylinositol 3 kinase, and ribosomal protein S6 kinase polypeptide 1) was significantly upregulated (p < 0.05). Overall, MOS positively affects tilapia’s growth, health, and immunity, with 0.60% identified as the optimal dietary level based on growth performance. Full article

Glaesserella parasuis (GPS) is a Gram-negative, pathogenic bacterium that colonizes the upper respiratory tract of piglets and causes Glässer’s disease with peritonitis under stress conditions. The mechanism underlying GPS-induced peritonitis in piglets remains unclear. Baicalin is one of the main active ingredients of Huangqin (Scutellaria baicalensis), which has a significant anti-inflammatory effect on inflammatory diseases. Therefore, this study aimed to elucidate the molecular mechanism by which baicalin alleviates GPS-induced peritonitis in piglets, specifically focusing on the role of the ADAM17/EGFR signaling axis. We investigated the effects of baicalin in vitro using porcine peritoneal mesothelial cells (PPMCs) and in vivo in GPS-infected piglets. Our results showed that baicalin reduced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) in PPMCs and the peritoneum of piglets after GPS infection. Concurrently, baicalin significantly reduced the upregulation of disintegrin and metalloproteinase 17 (ADAM17), phosphorylated epidermal growth factor receptor (p-EGFR)/EGFR, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK induced by GPS infection in PPMCs and the peritoneum of piglets. Crucially, in vitro mechanistic investigations revealed that baicalin can significantly reduce the upregulation of ADAM17, p-EGFR/EGFR, p-ERK/ERK, TNF-α, IL-1β, and IL-6 induced by ADAM17 overexpression in PPMCs. Furthermore, ADAM17 small interfering RNA can significantly reduce the upregulation of ADAM17, p-EGFR/EGFR, p-ERK/ERK, TNF-α, IL-1β, and IL-6 induced by GPS infection in PPMCs. These findings demonstrate that baicalin can inhibit the expression of inflammatory factors TNF-α, IL-1β, and IL-6 through the ADAM17/EGFR axis, and then alleviate the peritonitis caused by GPS in piglets. This provides a theoretical basis for developing novel non-antibiotic strategies, including phytochemical therapeutics and feed additives, for preventing and controlling GPS. Full article

The human airway surface is covered by a mucus layer composed primarily of the mucins MUC5AC and MUC5B. Excessive mucin production and secretion by airway epithelial cells in patients with asthma result in airway obstruction and worsened asthma symptoms. This study investigated the effects of liquiritin, a widely used flavonoid, on intracellular and secreted MUC5AC and MUC5B levels in the NCI-H292 human airway epithelial cell line. Liquiritin treatment suppressed both mucin types in a dose-dependent manner, accompanied by decreased activity of extracellular signal-regulated kinase (ERK) and p38. The effect of liquiritin was further examined in cells stimulated with phorbol 12-myristate 13-acetate (PMA) to induce excessive mucin production and secretion. Liquiritin dose-dependently reduced PMA-induced increases in intracellular and secreted MUC5AC and MUC5B levels as well as PMA-induced ERK and p38 activity. Overall, these results suggest that liquiritin reduces intracellular and secreted MUC5AC and MUC5B levels by suppressing the ERK and/or p38 signaling pathway. Full article