Search Results (2,915)

Atopic dermatitis (AD) is a chronic inflammatory dermatosis driven by skin barrier impairment and immune dysregulation. This study aimed to investigate the anti-inflammatory and barrier-related effects of the ethanol extract of Bidens bipinnata L. fruits (EEBB) in a calcipotriol (MC903)-induced AD-like dermatitis mouse model and lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In vivo, repeated topical application of EEBB (60, 180, and 600 μg/day) significantly attenuated MC903-induced AD-like clinical symptoms, skin weight, and erythema index. Notably, EEBB significantly improved skin hydration-related parameters, including relative skin hydration readings and the post-application moisture retention profile, and partially restored filaggrin and loricrin expression in lesional skin, whereas dexamethasone showed limited effects on these hydration-related parameters under the present conditions. Histopathologically, EEBB ameliorated epidermal lesions and reduced inflammatory cell infiltration. Mechanistically, EEBB suppressed the levels of pro-inflammatory (TNF-α, IFN-γ) and Th2 (IL-4, IL-5) cytokines in lesional skin. In vitro, EEBB significantly inhibited the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂), and downregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in RAW 264.7 cells. These effects were associated with inhibited phosphorylation of JNK and p38 MAPK, with no marked effect on ERK phosphorylation under the present conditions. In conclusion, EEBB effectively alleviated AD-like dermatitis, accompanied by improved skin hydration and restoration of barrier-related protein expression, attenuation of local inflammatory responses, and targeted inhibition of the MAPK signaling pathway. Full article

Improvement in the in vitro maturation (IVM) of oocyte quality is a gateway to enhancing the efficiency of in vitro embryo production. The anti-Müllerian hormone (AMH) is a crucial hormone secreted by granulosa cells that effectively suppresses primordial follicle recruitment and regulates follicular growth and development. This study was designed to investigate the role of AMH on the IVM of sheep oocytes. In this current study, oocytes in vitro were cultured in media supplemented with AMH. We comprehensively analyzed the impact of AMH on various developmental parameters of sheep oocytes, such as cellular activity, cortical granules (CGs) migration, cytoskeleton and mitochondrial function of oocytes. Furthermore, Smart-seq2 single-cell RNA sequencing (scRNA-seq) was employed to elucidate the oocytes’ development. The results showed that treatment with 100 ng/mL improved the maturation rate of the oocytes, the normal distribution rate of cortical granules and mitochondrial function, while reducing the rate of spindle abnormalities in oocytes. A total of 741 differentially expressed genes (DEGs) were observed between the FSH_12 h and AMH_12 h groups, and 746 DEGs were observed between the FSH_24 h and A+F groups. KEGG pathway analysis revealed that the FSH_12 h and AMH_12 h groups significant enrichment in DEGs were associated with p53, MAPK, PI3K-Akt and TGF-beta signaling pathways, and the FSH_12 h and AMH_24 h groups significant enrichment in DEGs were associated with cAMP, AMPK, Hedgehog and estrogen signaling pathways. These findings suggest that AMH may regulates oocytes IVM via several candidate signaling pathways. Our results provide preliminary clues for exploring the regulatory mechanism of sheep oocyte maturation and optimizing relevant culture systems. Full article

Palmatine chloride (berbericinine, C₂₁H₂₂ClNO₄) is a protoberberine alkaloid found in several plants, including Rhizoma Coptidis, Cortex Phellodendri, Rhizoma Corydalis, Guduchi (Tinospora cordifolia), and Tinospora sagittata roots. Palmatine chloride (PA) is known as an inhibitor of dopamine generation. However, its effect on endoplasmic reticulum (ER) stress-related macrophage activation caused by endotoxin (lipopolysaccharide) is not yet well known. In this study, the effects of PA on pyroptotic responses of mouse macrophages (RAW 264.7) activated by endotoxin were investigated using Griess reagent assay for nitric oxide (NO) production, fluo-4 assay for cytosolic calcium release, dihydrorhodamine 123 assay for hydrogen peroxide production, multiple cytokine assay for cytokine production, real-time PCR for inflammatory gene transcriptions, and flow cytometry assay for p38 MAPK activation. Preliminary experiments using THP-1 human monocytic cells demonstrated that PA was not cytotoxic and significantly reduced basal NO production. Results revealed that PA significantly reduced excessive production levels of NO, hydrogen peroxide, pro-inflammatory cytokines (such as interleukin (IL)-6, CCL3 (MIP-1α), and CSF2 (GM-CSF)), and cytosolic calcium release in endotoxin-stimulated RAW 264.7, but significantly increased the production of anti-inflammatory cytokine IL-10. PA inhibited endotoxin-induced transcripts of Chop, Stat1, Fas, and c-Fos in activated RAW 264.7. It also decreased p38 MAPK phosphorylation and level of Fas in RAW 264.7 stimulated by endotoxin. To further interpret these findings, a network pharmacology-informed analysis based on large-scale literature mining was performed, supporting the multi-target regulatory role of PA in ER stress-related pathways. Briefly, PA exerts anti-inflammatory effects on endotoxin-stimulated RAW 264.7 via the calcium-CHOP pathway, consequently reducing endotoxin-induced production of pro-inflammatory mediators (NO, cytokines, etc.) and relieving ER stress-related pyroptotic cascade. Full article

Inflammatory bowel disease (IBD) poses a significant global health burden with rising incidence, particularly in Asia. This study employed an integrative network pharmacology approach combined with molecular docking to elucidate the therapeutic mechanism of ganoderic acid A (GAA) against IBD. Potential GAA targets were retrieved from pharmacogenomic databases, while IBD-related genes were curated from OMIM and GeneCards databases. Weighted gene co-expression network analysis of IBD transcriptomic datasets (GSE38713, GSE126124) identified disease-associated modules, with the yellow module exhibiting the strongest positive correlation. Functional enrichment analyses demonstrated significant involvement of overlapping targets in lipid metabolism, the inflammatory response, and the mitogen-activated protein kinase (MAPK) signaling cascade pathway. We identified 14 IBD-GAA-ferroptosis-related genes and 54 key module genes. Intersection analysis revealed 5 overlapping targets, including tumor necrosis factor-α(TNF-α), peroxisome proliferators-activated receptor γ (PPARγ), MAPK14, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic α (PIK3CA), and Caspase 3 (CASP3). Molecular docking confirmed high-affinity binding of GAA to these targets, with binding energies ranging from −7.3 to −10 kcal/mol. Crucially, experimental evaluation demonstrated the pivotal role of GAA in alleviating disease pathology. GAA treatment suppressed the significantly elevated levels of TNF-α and p-MAPK14 in the organoids using a cytokine/LPS-induced IBD model. These findings collectively suggest a potential involvement of GAA in pathways associated with ferroptosis regulation, although direct experimental evidence for ferroptosis markers remains to be established. The observed multi-target effects on immune regulation and cellular proliferation/differentiation provide a foundation for further mechanistic investigation. Full article

Background: Neutrophil dysregulation drives inflammatory pathologies through mechanisms such as matrix metalloproteinase-9 (MMP-9) release. High-value bioprospecting of agro-industrial residues offers a sustainable strategy to identify novel bioactive compounds. In this study, the immunomodulatory effects of seed oils (SOs) obtained via supercritical fluid extraction from Passiflora edulis and Rubus glaucus byproducts on human neutrophil responses was evaluated. Methods: SO lipid profiles were characterized via GC-MS. Human neutrophils were isolated using Percoll gradients and treated with the SOs (10–50 µg/mL). Cytocompatibility was assessed via MTT and trypan blue assays. MMP-9 activity and ERK1/2/p38 phosphorylation were determined via zymography and Western blotting, respectively. Results of GC-MS revealed matrices rich in unsaturated lipids: R. glaucus SO was dominated by linoleic (50.02%) and α-linolenic (29.84%) acids, whereas P. edulis SO contained linoleic (58.91%) and oleic (19.75%) acids. Both oils were highly biocompatible up to 50 µg/mL. Both SOs significantly increased MMP-9 release; notably, R. glaucus induced a dose-dependent response and a potential priming effect at 10 µg/mL. Interestingly, neither oil induced the phosphorylation of ERK1/2 or p38. Conclusions: Supercritical fluid-extracted SOs from P. edulis and R. glaucus byproducts modulate early neutrophil responses by increasing MMP-9 release through pathways independent of classical MAPK phosphorylation. Further functional and in vivo validation is needed to clarify the precise regulatory roles of these specialized lipid matrices in human inflammation resolution and their potential as bioactive ingredients for nutraceutical or pharmaceutical applications. Full article

The multifaceted oncogenic role of teratocarcinoma-derived growth factor 1 (TDGF1) in colon cancer remains incompletely understood. Through integrative bioinformatic and functional analyses, we identified a novel competing endogenous RNA (ceRNA) axis wherein the long non-coding RNA OLMALINC directly sponges hsa-miR-3614-5p, leading to the derepression of TDGF1. This OLMALINC/miR-3614-5p/TDGF1 axis promoted colon cancer cell proliferation, migration, invasion, and anti-apoptosis in vitro, whereas TDGF1 knockdown significantly suppressed tumor growth in vivo. Mechanistically, TDGF1 co-activated oncogenic signaling via the Thr88-dependent Nodal/Smad2 cascade and the Glypican-1-mediated MAPK/AKT pathway. Beyond cell-autonomous effects, transcriptomic and single-cell analyses revealed that elevated TDGF1 correlates with an immunosuppressive microenvironment, characterized by reduced immune infiltration and altered LGALS9-CD44 malignant-T cell communication. Clinically, high TDGF1 expression in a tissue microarray cohort was significantly associated with advanced T stage, reduced expression of specific mismatch repair proteins (MLH1/PMS2), and poor overall survival. Collectively, this study delineates the OLMALINC/miR-3614-5p/TDGF1 regulatory circuit and establishes TDGF1 as a multifaceted driver of tumor progression, highlighting its potential as a prognostic biomarker and therapeutic target in colon cancer. Full article

Background/Objectives: Cancer, a multifactorial disease with uncontrolled cell growth, oxidative stress, inflammation, genomic instability, and molecular signaling pathways, is a global health concern, leading to the ~20 million newly diagnosed cases annually. Although conventional therapy has been shown to enhance the survival rates of cancer patients, its clinical efficacy is limited by certain side effects that occur as a result of treatment, thus necessitating the exploration of plant-derived bioactive compounds for their potential as safer and alternative supportive therapeutic agents. Aloe vera, known as the plant of immortality, comprises phytochemicals, such as anthraquinones (aloe-emodin, emodin, and aloin), polysaccharides (acemannan), flavonoids, and phenolic acids, which contribute to the pharmacological effect of the compound. Methods: This review summarizes the anticancer potential of Aloe vera, and the data were retrieved from databases, such as PubMed, Google Scholar, ScienceDirect, Web of Science, and Wiley Online Library, during the time period of 2015 to 2025. Results: The literature revealed that Aloe vera and its bioactive compounds have dose-dependent cytotoxic and anti-proliferative properties against hepatocellular, cervical, colorectal, lung, breast, prostate, and hematological cancers, which are significantly mediated by apoptosis and pyroptosis induction, reactive oxygen species (ROS) production, mitochondrial dysfunction, inhibition of angiogenesis and metastasis, and the modulation of key signaling pathways, particularly PI3K/Akt, MAPK, NF-кB, p53, and Wnt/β-catenin. Furthermore, anthraquinones, including Aloe-emodin, demonstrate potent anticancer effects at micro-molar doses, and polysaccharides increase immune reactions and provide tumor immunity. Conclusions: Conclusively, Aloe vera is a promising multi-target natural compound, particularly efficient in the treatment of cancer. However, despite significant therapeutic potential, more research on pharmacokinetics, standard dose, and controlled clinical trials of Aloe vera is required to validate clinical applicability. Full article

Grapevine downy mildew, caused by the oomycete pathogen Plasmopara viticola (P. viticola), is one of the most devastating diseases threatening the global grape industry. The pathogen invades host plants through stomata, triggering a series of highly coordinated physiological disorders and biochemical defense events. This review systematically summarizes the dynamic changes in morphological structures (stomatal characteristics), physiological functions (photosynthesis, membrane system integrity, and carbon metabolism), and multi-level biochemical defense systems (reactive oxygen species (ROS) scavenging enzyme system, phenylpropanoid metabolic pathway, pathogenesis-related proteins, and phenolic compounds) in grapevines following infection. It focuses on analyzing the differences in the timing, intensity, and metabolic reprogramming of defense responses between resistant and susceptible cultivars, pointing out that the essence of disease resistance lies in early pathogen recognition and rapid defense induction. The conflicting conclusions regarding indicators such as soluble sugars, peroxidase (POD), and superoxide dismutase (SOD) are discussed from the perspectives of experimental systems, cultivar genetic backgrounds, and pathogen physiological race differences. Furthermore, the known physiological and biochemical alterations are linked to upstream signaling pathways, including salicylic acid and jasmonic acid (SA/JA), calcium signaling, and mitogen-activated protein kinase (MAPK) cascades. Recent advances in revealing resistance mechanisms in the omics era are also introduced. Finally, future research directions are proposed, including constructing multi-indicator dynamic evaluation models, verifying key gene functions using gene editing, exploring the potential of epigenetic regulation, and developing integrated control strategies combined with microbiome research. This review aims to provide theoretical support for grapevine downy mildew resistance breeding and sustainable disease management. Full article

Background/Objectives: The emergence of drug-resistant Plasmodium falciparum highlights the need for new antiplasmodial compounds with distinct mechanisms of action. Microbial secondary metabolites, particularly from Streptomyces species, remain important sources of bioactive molecules. This study aimed to evaluate antiplasmodial metabolites associated with a Mongolian Streptomyces isolate. Methods: Streptomyces sp. strain D10 was isolated from Mongolian soil samples and extracted with ethyl acetate. Bioassay-guided fractionation was performed, followed by LC–HRMS analysis and GNPS-based spectral dereplication. Antiplasmodial activity was evaluated against P. falciparum 3D7, K1, and Dd2 strains using a SYBR Green I assay. Cytotoxicity was assessed in HSF cells. Stage-specific susceptibility assays were conducted using synchronized 3D7 parasites. Comparative docking analyses against β-hematin and the chloroquine resistance transporter (PfCRT), together with target prediction and molecular docking analyses, were performed to explore potential mechanisms. In vivo efficacy was evaluated using a Plasmodium yoelii 17XNL mouse model. Results: Fractionation yielded an active fraction (C2), and LC–HRMS and GNPS-based dereplication suggested a bile acid-like metabolite, with ursodeoxycholic acid (UDCA) returned as a putative spectral library candidate associated with fraction C2. Fraction C2 and UDCA showed comparable antiplasmodial activity against P. falciparum 3D7 (IC₅₀ = 6.55 ± 3.00 and 4.68 ± 0. 65 µg/mL, respectively) without detectable cytotoxicity up to 200 µg/mL. Activity was retained against multidrug-resistant K1 and Dd2 strains. Stage-specific assays demonstrated inhibitory activity across ring, trophozoite, and schizont stages without significant stage-dependent differences. Comparative docking analyses suggested interaction profiles distinct from chloroquine in β-hematin and PfCRT models. Additional docking analyses identified PfGluPho, PfMAPK, and PfPFT-β as potential targets. In vivo, UDCA reduced parasitemia in a dose-dependent manner without significant toxicity. Conclusions: UDCA exhibited moderate antiplasmodial activity across in vitro, in silico, and in vivo evaluations with a favorable selectivity profile, supporting further investigation of bile acid-like metabolites as potential antimalarial scaffolds. Full article

Liancheng white ducks have a distinctive “white feathers, black beak, and green feet” phenotype, making them a useful model for studying pigmentation traits in waterfowl. The previous study found that the F1 generation of Liancheng white ducks crossed with white-feathered ducks and hemp-feathered ducks were all gray-black in color. This indicates the specificity and complexity of melanin deposition in Liancheng white ducks, which makes the selection and breeding of pigment traits through phenotyping difficult. The aim of this study was to investigate the candidate transcriptomic regulatory signals of melanogenesis in Liancheng white ducks. Skin, mouth skin, foot skin, liver, and muscle samples were collected from 130-day-old Liancheng white ducks. Morphological differences were observed via histological analysis, and extraction-based pigment levels were determined. The results showed that melanin granules were clearly observed in tissues other than the liver and were distributed mainly in the basal layer of the epidermis and around feather follicles; the pigment values in the tissues decreased in the order mouth skin > liver > foot skin > muscle and skin. However, the relatively high liver value should be interpreted cautiously because obvious melanin granule deposition was not observed histologically. Whole-transcriptome sequencing was performed on mouth skin and skin samples. In total, 3074 differentially expressed genes (DEGs) were screened; upregulated genes associated with melanogenesis included melanocyte inducing transcription factor (MITF) and tyrosinase (TYR); downregulated genes included agouti signaling protein (ASIP) and adenylate cyclase 2 (ADCY2). Eighteen differentially expressed microRNAs (DEmiRNAs) were identified. Based on target prediction and pathway enrichment analysis, novel_290 and apl-miR-11588-3p were identified as candidate miRNAs potentially associated with melanogenesis-related pathways, and their predicted target genes included phosphatidylinositol 3-kinase (PI3K) and Janus kinase 1 (JAK1). Additionally, 364 differentially expressed long noncoding RNAs (DElncRNAs) were identified; TCONS_00063335 and TCONS_00019814 were identified as candidate lncRNAs potentially associated with melanogenesis-related genes, including TYR and TYRP1. A putative ceRNA network was constructed based on the predicted miRNA–mRNA and miRNA–lncRNA relationships, and ENSAPLT00000025522–apl-miR-11588-3p–MAPK8IP3 was identified as a candidate network relationship associated with MAPK-related pigmentation pathways. However, because this relationship was inferred mainly from bioinformatic prediction and expression association analysis, further functional validation is required to confirm whether it contributes to melanogenesis regulation. These findings provide candidate transcriptomic and noncoding RNA information for the further investigation of tissue-specific pigmentation in Liancheng white ducks. Full article

Background/Objectives: West Nile virus (WNV) remains a significant threat to human health, with no approved antiviral treatments or vaccine available. A better understanding of the molecular mechanisms governing flavivirus–host interactions is needed to identify host regulatory pathways involved in infection. This study aimed to investigate how WNV infection remodels the host miRNA–mRNA regulatory landscape. Methods: WNV-induced changes in host miRNA expression in HEK-293 cells were profiled using miRNA-Seq. Transcriptome-wide host gene expression changes in WNV-infected cells were analysed using RNA-Seq. Gene Ontology and pathway enrichment analyses were conducted using DAVID. Integrated miRNA–mRNA network reconstruction was performed using Cytoscape based on the experimentally validated miRNA–mRNA interactions in miRNet database. Results: WNV infection induced global changes in host miRNA expression, with pathogenic NY99 and non-pathogenic Kunjin strains of the virus producing overlapping and strain-specific alterations in the miRNA landscape. Transcriptome analysis showed strong induction of interferon-related responses and activation of NF-κB and MAPK signalling pathways in the infected cells. In contrast, pathways associated with RNA processing, splicing, and proteasomal degradation were downregulated. Integrated miRNA–mRNA network analysis identified miR-197-3p, miR-301b-3p, miR-129-3p, miR-3662, and miR-128-5p as candidate regulatory hubs involved in WNV-induced transcriptome remodelling. These networks suggested that miRNA-mediated regulation may influence antiviral signalling, apoptosis, and RNA metabolism during infection. Conclusions: These findings suggest that WNV infection broadly remodels host miRNA–mRNA regulatory networks and identifies candidate miRNAs that may contribute to the regulation of antiviral and cellular stress responses. These predicted regulatory interactions provide a foundation for future experimental validation. Full article

Despite the years that have passed since the pandemic, data regarding the effects of mild SARS-CoV-2 infection and vaccination during pregnancy remain limited. The current study investigated the expression of molecules that may be involved in the placental immune response using real-time PCR and Western blot analysis in a well-characterized cohort of 118 placentas collected between the 37th and 40th week of gestation. Secreted mediators were assessed in the supernatant of placental cell cultures, and histological examinations of the placental tissue were performed. Significant differences in the expression levels of S100B, IL6, and CCL5 were observed in control versus vaccinated and previously infected women, as determined by PCR. Acute SARS-CoV-2 infection decreased the expression of p38 MAPK and Bcl-2 compared to control patients. The secretion of G-CSF, IFN-α2, IL-2, and CXCL8 (IL-8) increased in women who were infected during pregnancy and/or vaccinated. However, histological analysis revealed only minor differences between the groups. In conclusion, SARS-CoV-2 infection or vaccination during pregnancy induced a measurable placental immune response that remained below the threshold of histologically detectable tissue injury. Full article

Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP), fail to capture the complexity, tissue specificity, and causal architecture of inflammaging. Recent experimental evidence has demonstrated that diverse upstream drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge on a limited number of central inflammatory hubs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and p38 mitogen-activated protein kinase (p38 MAPK) signaling. These mechanistic nodes represent promising therapeutic targets, potentially modifiable biological processes, and support the emerging concept of ‘druggable inflammaging’, whereby senotherapeutics, inflammasome inhibitors, innate immune modulators, and metabolic interventions may actively modify aging-associated inflammatory biology rather than simply monitor it through biomarkers. This review highlights a paradigm shift from biomarker-based assessment toward mechanism-based intervention, where inflammaging can be characterized as a modifiable biological process and a central target for precision pharmacological strategies in aging-related diseases. Full article

Early-life factors influence adult-brain vulnerability to sporadic Alzheimer’s disease (AD), but the underlying molecular mechanisms are unknown. In this study, we performed an integrated analysis of mitogen-activated protein kinases (MAPK) pathways’ (ERK1/2, JNK, and p38 MAPK) activity in the hippocampus and prefrontal cortex of OXYS rats (a model of sporadic AD) on postnatal days 3 and 10 (P3 and P10): critical periods of brain maturation. Wistar rats (healthy controls) showed extensive developmental transcriptional remodeling of all MAPK pathways. OXYS rats exhibited alterations, most pronounced in the prefrontal cortex at P3, with the JNK pathway showing the greatest divergence. At the protein level, OXYS rats failed to show the normal age-related increase in hippocampal ERK1/2 phosphorylation and in JNK1/2 levels in both regions, indicating developmental signaling deficits. p38 MAPK remained stable among Wistar and OXYS rats. Thus, delayed brain maturation, which contributes to accelerated brain aging and neurodegeneration in OXYS rats, occurs simultaneously with alterations in MAPK signaling. These aberrations potentially are able to increase brain susceptibility to age-related pathologies later in life. Full article

The interaction between Pneumocystis jirovecii and systemic inflammation has emerged as a potential modulator of cardiovascular risk. This review describes the potential of β-glucans to contribute to atherogenic inflammation. A narrative review was developed on the PubMed/MEDLINE, Scopus, Web of Science and Google Scholar databases. The inflammatory pathways induced by β-glucans from P. jirovecii contrast with the immunometabolic effects of dietary β-glucans. The relevance of serum (1→3)-β-D-glucans as a marker of systemic exposure was also described, although it is not specific to P. jirovecii. P. jirovecii β-glucans activate Syk–CARD9–NFκB, MAPK and STAT3 signalling pathways. This signalling promotes proinflammatory monocyte/macrophage polarization and a systemic microenvironment of low-grade inflammation with proatherogenic potential. The serum persistence of (1→3)-β-D-glucan indicates prolonged exposure, even in the absence of overt clinical manifestations of colonization. Conversely, dietary β-glucans have been observed to elicit regulatory effects facilitated by microbiota and metabolism. In experimental setting, a causal link has been established between fungal β-glucans and atherosclerosis. P. jirovecii β-glucans act as immunological mediators capable of amplifying pulmonary and systemic inflammation, constituting a possible modulator of cardiovascular risk. Distinguishing between fungal and dietary β-glucans is imperative for comprehending emerging mechanisms of vascular inflammation. Full article