The lack of a sufficient number of validated miRNA targets severely hampers the understanding of their biological function. Even for the well-studied miR-155-5p, there are only 239 experimentally validated targets out of 42,554 predicted targets. For a more complete assessment of the immune-related miR-155 targetome, we used an inverse correlation of time-resolved mRNA profiles and miR-155-5p expression of early CD4+ T cell activation to predict immune-related target genes. Using a high-throughput miRNA interaction reporter (HiTmIR) assay we examined 90 target genes and confirmed 80 genes as direct targets of miR-155-5p. Our study increases the current number of verified miR-155-5p targets approximately threefold and exemplifies a method for verifying miRNA targetomes as a prerequisite for the analysis of miRNA-regulated cellular networks.

Multiple myeloma (MM) is a hematological malignancy with the proliferation of malignant plasma cells. Numerous studies have highlighted the critical role of ferroptosis in MM. However, how to use ferroptosis-related genes (FRGs) for prognostic prediction and treatment guidance in MM remains unknown.

By analysis of GEO databases, the prognostic gene was identified and a therapeutic strategy for MM patients based on FRGs was explored. A total of 12 FRGs were identified, utilizing the STRING database and Cytoscape software, and the PPI networks were constructed to identify hub genes and further functional enrichment analyses. Based on the aforementioned data, this study analyzed the expression of RUVBL2 in MM patients by qRT-PCR and Western blotting. To validate the functional role of RUVBL2 in the MM cells, cellular experiments were ultimately conducted.

The analysis highlighted six hub genes, including TP53, MCM5, TLR4, RUVBL2, GCLM and ITGA6, and functional enrichment analyses indicating enrichment in DNA replication, regulation of apoptotic signaling pathway and PI3K/AKT signaling pathway. Prognostic analysis indicated that TP53, RUVBL2, and MCM5 are associated with MM prognosis, with RUVBL2 displaying a notable area under the curve (AUC) of 0.823 in ROC analysis. The study first determined that RUVBL2 is highly expressed in MM, siRUVBL2-mediated deletion of RUVBL2 inhibited proliferation, promoted apoptosis and increased the sensitivity of BTZ in MM cells, and also overcame BTZ resistance in CD138+ primary cells from MM patients.

Our study first suggested that RUVBL2 may be regarded as potential therapeutic targets and prognostic value in MM.

The gut microbiota is a crucial link between diet and cardiovascular disease (CVD). Using fecal metaproteomics, a method that concurrently captures human gut and microbiome proteins, we determined the crosstalk between gut microbiome, diet, gut health, and CVD. Traditional CVD risk factors (age, BMI, sex, blood pressure) explained < 10% of the proteome variance. However, unsupervised human protein-based clustering analysis revealed two distinct CVD risk clusters (low-risk and high-risk) with different blood pressure (by 9 mmHg) and sex-dependent dietary potassium and fiber intake. In the human proteome, the low-risk group had lower angiotensin-converting enzymes, inflammatory proteins associated with neutrophil extracellular trap formation and auto-immune diseases. In the microbial proteome, the low-risk group had higher expression of phosphate acetyltransferase that produces SCFAs, particularly in fiber-fermenting bacteria. This model identified severity across phenotypes in heart failure patients and long-term risk of cardiovascular events in a large population-based cohort. These findings underscore multifactorial gut-to-host mechanisms that may underlie risk factors for CVD.

The Coronavirus Disease 2019 (COVID-19) pandemic has led to numerous cases of co-infection with SARS-CoV-2 and other viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), worldwide. This co-infection has increased patient mortality due to the lack of efficient bi-targeted drugs. Cambogin, a bioactive natural product, has been shown to effectively induce regression of KSHV-latently infected tumours in xenograft mice models; however, its impact on SARS-CoV-2 infection remains unclear. Here, we report that Cambogin targets 46 host genes commonly affected by both SARS-CoV-2 and KSHV infections, as identified through bioinformatics analysis. These genes are related with 14 key upstream signalling pathways, particularly those involved in inflammation regulation, protein phosphorylation, metabolic processes, and cellular stress response. Within the transcriptional factor (TF)-miRNA co-regulatory network, ten out of 46 hub-target genes are closely linked to Cambogin and KSHV/SARS-CoV-2. Importantly, Cambogin not only efficiently blocks the replication and virion production of SARS-CoV-2 in vitro and in vivo by reducing the expression of EGFR and Cyclin A2, but also simultaneously inhibits both SARS-CoV-2 infection and the growth of KSHV-induced tumours in vivo using a murine xenograft model. These findings provide an alternative strategy for the potential use of Cambogin in the treatment of SARS-CoV-2 patients, particularly those with KSHV co-infection.

Skin hyperpigmentation is a type of difficult-to-treat disease that frequently results from the improper metabolism of facial pigment. The herb Forsythiae Fructus (FF) possesses whitening and freckle-removal properties. Its probable active components and anti-hyperpigmentation mechanism, however, are still unknown. In the current investigation, the active components were initially identified and screened by UHPLC-Q-Orbitrap HRMS/MS employing B16 cell-specific extraction and plasma pharmaceutical chemistry, respectively. Subsequently, the component-target-disease network and protein-protein interaction (PPI) network of FF were built by using a network pharmacology approach. The probable targets and pathways were found using gene ontology (GO) and KEGG enrichment analysis. The essential elements and core genes causing illnesses were identified through molecular docking. Lastly, based on network analysis, cell experiments were carried out to further explore the efficacy of the main active ingredients in the treatment of abnormal melanosis. As a result, 37 ingredients were identified in FF extract, 22 compounds in the decoction had a specific affinity with B16 mouse melanoma cells, and a total of 10 prototype compounds and 11 metabolites were detected in rat plasma. Through in vitro and in vivo screening methods, 16 potential active ingredients were obtained, and 229 biological targets and 1515 disease-related targets were predicted by network pharmacology. In addition, in vitro cell experiments revealed that kaempferol, luteolin, and wogonin all exhibited inhibition of melanin production and tyrosinase activity. The proposed combination method of rapid screening of active ingredients in vivo and integrated network pharmacology in vitro could explore the therapeutic mechanism of FF against hyper-pigmentation, and provide a theoretical evidence for the development and utilization of FF.

The S100 family of calcium-binding proteins (S100s) had been tightly related to the biological processes of various cardiovascular diseases. This study aims to investigate the expression of S100s in Atherosclerosis (AS) and explore their potential as diagnostic biomarkers and therapeutic targets.

We analyzed multiple sequencing datasets from the GEO database to compare the expression profiles of S100s in AS tissues versus normal samples. Employing unsupervised clustering techniques, AS subtypes were discerned based on the intricate variations in S100-related gene expression profiles. Subsequent analyses delved into immune cell infiltration and GSVA pathway enrichment, shedding light on the nuanced immune landscape characterizing diverse AS subtypes. Machine learning techniques were employed to develop a diagnostic model for AS. Single-cell RNA analysis was utilized to investigate the cellular distribution of S100 hub genes in AS.

Unsupervised clustering analysis identified two distinct AS subtypes (C1 and C2), characterized by specific S100 gene expression patterns. The RF-based diagnostic model exhibited the highest efficacy (AUC=0.881), and the top five genes (S100A4, S100A10, S100A11, S100A13, S100Z) were used to construct a diagnostic nomogram.

This study systematically elucidates the roles of S100s in AS, offering insights into molecular subtyping, immune characteristics, and diagnostic model construction. The findings provide valuable implications for the precise treatment and prognosis assessment of AS and pave the way for further research into related mechanisms.

Our study shows that Bifidobacterium spp. supplementation reduces lung damage in acute lung injury by enhancing immune cell activity and restoring thrombospondin-1 levels, offering a promising therapeutic approach for the treatment of ALI/ARDS.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions characterized by severe lung inflammation and damage, often exacerbated by mechanical ventilation. Probiotics, particularly those containing Bifidobacterium spp. (Bifidus) have shown promise in modulating immune responses and reducing inflammation.

In this study, we investigated the effects of Bifidus supplementation in a mouse model of lipopolysaccharide induced ALI and ventilator-induced lung injury.

Our results demonstrate that Bifidus significantly ameliorates lung injury by enhancing efferocytosis and reducing pro-inflammatory cytokine levels. Single-cell RNA sequencing revealed significant changes in lung immune cell populations, particularly macrophages and monocytes, which showed increased efferocytosis activity and modulation of key signaling pathways such as TNF, MAPK and TLR. Notably, Bifidus feeding restored thrombospondin-1 levels in lung tissue, facilitating clearance of apoptotic cells and promoting resolution of inflammation.

Overall, our study highlights the potential of Bifidus as a therapeutic strategy to mitigate lung injury in ALI/ARDS.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social communication, restricted interests, repetitive behavior and irritability. Exposure to valproic acid (VPA) during pregnancy has been shown to increase the risk of autism in children and has led to the development of the in-utero VPA rat model that elicits neurodevelopmental autistic-like features. Offspring exhibit behavioral and neurobiological alterations modelling ASD symptoms. We performed a behavioral and molecular assessment in a rat in-utero VPA model treated with a novel botanical cannabinoid, JZP541. Male offspring from dams treated with VPA were tested acutely and sub-chronically with JZP541 (10, 30, or 100 mg/kg, intraperitoneally). A behavioral testing battery was performed, and brain frontal cortex and hippocampus used for RNA sequencing. In utero exposure to VPA resulted in progeny showing behavioral phenotypes characteristic of ASD. JZP541 attenuated these deficits in social, stereotypic, hyperactivity and irritability behavior in a dose-dependent fashion. VPA exposure was associated with a substantial transcriptional dysregulation impacting multiple key biological processes in a tissue-dependent manner. The expression profiles were integrated with publicly available datasets of autism-associated genes to support the validity of the model used and to focus on the effects of treatment on known autism-relevant transcriptional targets. This approach indicated a strong and dose-dependent reduction of the autism-associated gene expression signature in brain samples from animals dosed with JZP541. Our findings demonstrate JZP541 was able to ameliorate ASD associated behavioral deficits, and this was supported by improvements in putative transcriptional biomarkers of ASD.

Although a wide variety of medicinal interventions and lifestyles have been endeavored so far for the treatment of diabetes mellitus, it is still intractable. The current study aimed to examine the effect of mesenchymal stem cells (MSCs) and/or placental extract (PE) on streptozotocin (STZ) induced diabetic rats.

Fifty male albino rats were used. Ten of them as negative control (group I) and the remaining forty rats were subjected to diabetes induction using 50 mg/kg STZ then divided into; group II (positive controls), group III (MSCs treated), group IV (PE treated), and group V (MSCs/PE combination treated). After 4 weeks of treatment, animals were sacrificed; blood samples were collected for determination of glycated hemoglobin by HPLC, and serum was separated for determination of glucose spectrophotometrically and insulin by ELISA. Pancreatic tissues were harvested for histopathological examination and pancreatic duodenal homeobox 1 (Pdx1) gene expression by PCR.

The three treated groups showed significant enhancement in glycemic parameters and Pdx1 gene expression compared with positive control group (P < 0.05). Histopathological examination revealed great improvement in the three treated groups where group V showed the best picture and the best glycemic control.

This study points to the possible role of PE in DM treatment. The MSCs/PE combination had the ability to return all parameters and Pdx1 gene expression to their normal levels. This action could be attributed to MSCs homing into the pancreas and the pancreatic rejuvenation provided by PE contents of growth factors; EGF, HGF, IGF-1 and IGF-II.

JOURNAL/nrgr/04.03/01300535-202508000-00026/figure1/v/2024-09-30T120553Z/r/image-tiff Interferon regulatory factor 7 plays a crucial role in the innate immune response. However, whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown. Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells. Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype. In addition, siRNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase, tumor necrosis factor α, CD16, CD32, and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1. Taken together, our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

In this study, using RNA-Seq gene expression data and advanced machine learning techniques, we identified distinct gene expression profiles between male and female pancreatic ductal adenocarcinoma (PDAC) patients. Building on this insight, we developed sex-specific 3-year survival predictive models alongside a single comprehensive model. Despite smaller sample sizes, the sex-specific models outperformed the general model. We further refined our models by selecting the most important features from the initial models. The refined sex-specific predictive models achieved higher accuracy and consistently outperformed the refined comprehensive model, highlighting the value of sex-specific analysis. To ensure robustness, all refined sex-specific models were calibrated and then evaluated using an independent dataset. Random Forest models emerged as the most effective predictors, achieving accuracies of 90.33 % for males and 90.40 % for females on the training dataset, and 81.25 % for males and 89.47 % for females on the independent test dataset. These top-performing models were integrated into Gap-App, a web application that leverages individual gene expression profiles and sex information for personalized survival predictions. As the first online tool bridging complex genomic data with clinical application, Gap-App facilitates more precise, individualized cancer care, marking a significant step in personalized prognosis prediction. This study underscores the importance of incorporating sex differences in predictive modeling and sets the stage for the shift from traditional one-size-fits-all to more personalized and targeted medicine. The Gap-App service is freely available for patients and clinicians at www.gap-app.org.

In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow-derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8+ T cells prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of Spg15-driven neuropathology.

Two percent of patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a concurrent disruption in white matter integrity. In this study, we demonstrate that deletion of Zdhhc9 in mice disrupts the balance of mature oligodendrocyte subtypes within the corpus callosum. While overall mature oligodendrocyte numbers are unchanged, there is a marked increase in MOL5/6 cells that are enriched in genes associated with cell adhesion and synapses, and a concomitant decrease in MOL2/3 cells that are enriched in genes associated with myelination. In line with this, we observed a decrease in the density of myelinated axons and disruptions in myelin compaction in the corpus callosum of Zdhhc9 knockout mice. RNA sequencing and proteomic analysis further revealed a reduction in genes and proteins essential for lipid metabolism, cholesterol synthesis, gene expression, and myelin compaction, offering insights into the underlying mechanisms of the pathology. These findings reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte subtype determination and myelinogenesis, offering mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.

Anacyclus pyrethrum (l.) DC has potential value in treating Parkinson's disease (PD)-mild cognitive impairment (MCI), manifesting as impaired memory, attention, executive function, and language. However, the specific targets and modes of action of A. pyrethrum remain unclear.

The aim of this study was to identify the active components of A. pyrethrum and examine their effectiveness in treating a mouse model of PD-MCI.

We generated ethanol extracts of A. pyrethrum root (EEAP) and identified its active components and related targets using UHPLC-MS/MS and network pharmacology.The PD-MCI model was induced via intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). After following continuous administration of EEAP,Altered learning or memory, as well as anxiety, were tested using the morris water maze, eight-arm radial arm maze (RAM), and open-field test,elevated plus-maze. Brain histopathology and ultrastructural changes were examined using brightfield microscopy, and electron microscopy, respectively. Furthermore, protein expression was assessed using western blotting.Stool samples were used for metabolomics analysis by UHPLC-MS/MS and for 16S rDNA sequencing to determine the compositional changes of the gut microbiota.We conducted a short-chain fatty acid targeted metabolomics experiment to study their role in the gut-brain axis in PD-MCI.

Using UPLC-MS-MS, 126 compounds were identified from A. pyrethrum samples.After searching the databases and literature reports, 31 active components and 544 drug-disease targets were screened. Biological processes and molecular functions, such as energy channels, cell signaling, and metabolism, were discovered through GO analysis. The water maze experiment showed that the average swimming distance and escape latency of mice in EEAP groups decreased. The eight-arm maze experiment showed that model had a much higher number of errors related to working memory than the control mice. In the open field experiment, compared with the control group, the mice in the EEAP group exhibited an increase in the average movement speed and total movement distance, along with a decrease in the residence time.In the elevated plus maze, the control had less anxiety than the Model. Donepezil/Levodopa(D/l) mitigated anxiety-like behavior, and EEAP (100-400 mg/kg) showed a dose-dependent increase in open-arm metrics, suggesting it may ease anxiety in mice.Hippocampal tissue of mice treated with different doses of EEAP showed intact cellular layers and the hematoxylin-eosin-stained cones were slightly better;cells were arranged neatly; their morphology was normal, and were distributed uniformly. Electron microscopy revealed that the nuclear membrane, chromatin, and nucleoli were clearly demarcated in the hippocampus of mice treated with different doses of EEAP, contrary to that in the model group. In brain extracts of the EEAP group, lighter thinner bands for amyloid precursor protein (APP) and Aβ were observed compared to those in the model group. In model mice, APP and Aβ protein expression was higher than in the blank group, as shown by stronger bands. In EEAP-treated mice, the bands were weaker, indicating reduced expression. In the model group had lower Bcl-2 and higher Bax levels. EEAP treatment increased Bcl-2 and decreased Bax expression.Compared to the control group, the model showed substantially low glutathione peroxidase (GSH-Px),superoxide dismutase(SOD),catalase (CAT)activity (p < 0.05),much higher (p < 0.05) in the EEAP-H group than that in the model. EEAP intervention significantly modulated the fecal metabolic profile of PD-MCI mice. The abundance of steroid and lipid metabolites, including linoleylethanolamine, was markedly altered in the model group compared to the control group, with EEAP treatment reversing several of these abnormalities. PLS-DA and OPLS-DA revealed significant separation between groups (Q2= 0.542, p < 0.01), confirming a dose-dependent effect. Random forest analysis identified 15 key metabolic markers, such as dose-dependent changes in d-glutamine and hydrocodone. Metabolic pathway analysis demonstrated significant enrichment in phenylalanine, tyrosine, tryptophan metabolism, and arginine biosynthesis pathways (p < 0.05). The Support Vector Machine (SVM) model achieved an AUC approaching 1, indicating substantial differences in metabolite profiles. EEAP intervention significantly influenced the composition and functional profile of the intestinal microbiota. The Venn diagram illustrates that each group shared 342 operational taxonomic units (OTUs), with the EEAP 400 group exhibiting a distinct Bacteroidetes proportion. LEfSe analysis identified g_Prevotella as the characteristic bacterium in the control group, c_Epsilonproteobacteria in the model group, and g_Adlercreutzia in the EEAP 100 group. The Faith's Phylogenetic Diversity (PD) index was highest in the EEAP 100 group, and Non-metric Multidimensional Scaling (NMDS)/Principal Coordinates Analysis (PCoA) revealed significant differences in microbial community structure. Short-chain fatty acids (SCFAs) analysis indicated that acetic acid was the predominant metabolite, while EEAP dose-dependently regulated propionic acid and isovaleric acid levels (VIP > 1, p < 0.001). These findings demonstrate that EEAP exerts its regulatory effects by reshaping the structure and metabolic functions of the gut microbiota.

EEAP holds great promise as a potential therapeutic agent for PD-MCI, exerting its effects through multiple mechanisms, including regulating protein expression, modulating the fecal metabolic profile, and reshaping the gut microbiota and its metabolites.

In this study, we utilized the public database along with single-cell genomics techniques to systematically analyze the expression patterns and clinical significance of key genes in the nicotinamide metabolism pathway in liver cancer samples. The findings indicate that differential nicotinamide metabolism-related key genes are expressed in liver cancer samples. The liver cancer samples were put into separate subgroups using consistency clustering analysis based on differential gene expression levels observed. Additionally, immune infiltration and drug sensitivity analysis also revealed differences between the two subgroups. Survival analysis suggested that the key genes were associated with prognosis. Finally, a prognostic model was established using the key genes, offering a fresh viewpoint on the molecular mechanism investigating liver cancer. This study demonstrated the significant correlation between key genes in the nicotinamide metabolism pathway and the occurrence and progression of liver cancer and indicated that these key genes could serve as prognostic markers and tailored treatment targets for liver cancer.

Chemotherapy-related cognitive impairment (CRCI), is a well-recognized phenomenon in cancer patients who have undergone chemotherapy but the exact molecular mechanisms underpinning CRCI remain elusive. Symptoms reported by people with CRCI resemble those experienced by people with age-related neurodegenerative disorders (ARNDDs), yet no clear connection between CRCI and ARNDDs has been reported to date. The existence of shared mechanisms between these conditions offers opportunities for repurposing drugs already approved for the treatment of ARNDDs to improve symptoms of CRCI. Given that there is no available microarray or RNA-Seq data from the brains of people who have experienced CRCI, we investigated to what extent brain gene expression perturbations from validated rodent models of CRCI induced by chemotherapy compared with validated rodent models of Alzheimer's disease and Parkinson's disease. We utilized multiple bioinformatic analyses, including functional enrichment, protein-protein interaction network analyses, gene ontology analyses and identification of hub genes to reveal connections between comparable gene expression perturbations observed in these conditions. Collectively 165 genes overlapped between CRCI and Parkinson's disease and/or Alzheimer's disease, and 15 overlapped between all three conditions. The joint genes between Alzheimer's disease, Parkinson's disease and CRCI demonstrate an average of 83.65% nucleotide sequence similarity to human orthologues. Gene ontology and pathway enrichment analyses suggest mechanisms involved in neural activity and inflammatory response as the key components of the studied neuropathological conditions. Accordingly, genes in which expression was comparably affected in all three condition models could be attributed to neuroinflammation, cell cycle arrest, and changes in physiological neural activity.

JOURNAL/nrgr/04.03/01300535-202507000-00024/figure1/v/2024-09-09T124005Z/r/image-tiff Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination. Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage. Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation, and plays an important role in the pathological process of ischemic stroke. However, there are few studies on oligodendrocyte progenitor cell ferroptosis. We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia. Bioinformatics analysis suggested that perilipin-2 (PLIN2) was involved in oligodendrocyte progenitor cell ferroptosis. PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation. For further investigation, we established a mouse model of cerebral ischemia/reperfusion. We found significant myelin damage after cerebral ischemia, as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area. The ferroptosis inhibitor, ferrostatin-1, rescued oligodendrocyte progenitor cell death and subsequent myelin injury. We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells. Plin2 knockdown rescued demyelination and improved neurological deficits. Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.

Gelsenicine, the most toxic constituent of Gelsemium elegans Benth., is known for its diverse pharmacological activities alongside potent neurotoxicity, frequently leading to poisoning incidents following mistaken ingestion. However, its molecular mechanisms remain largely unexplored.

This study aimed to elucidate the key mechanistic network underlying gelsenicine-induced neurotoxicity by employing a comprehensive strategy that integrated metabolomics, network toxicology, molecular docking, and experimental validation.

Acute oral toxicity tests were conducted in C57BL/6J mice to assess toxic symptoms, determine the median lethal dose (LD50), and evaluate histopathological changes. Untargeted metabolomics was performed to identify differential metabolites and associated pathways in serum, hippocampus (HIP), and medulla oblongata (MO). Integration of network toxicology pinpointed core targets and pathways, which were further validated through molecular docking and RT-qPCR. A core "compound-target-metabolite-pathway" network involved in gelsenicine-induced neurotoxicity was established.

Gelsenicine exhibited an oral LD50 of approximately 1.82 mg/kg and induced neurotoxic damage in the HIP and MO. Two untargeted metabolomic approaches detected a broad range of metabolites, revealing that gelsenicine markedly altered the metabolic profiles of serum, HIP, and MO. Network toxicology analysis identified 187 key targets associated with gelsenicine neurotoxicity. Integrated analyses with the predicted targets of differential metabolites indicated that gelsenicine primarily interferes with the energy metabolism network centered on the malate-aspartate shuttle (MAS), affecting pathways such as carbon metabolism, amino acid metabolism, TCA cycle, and PPAR signaling pathway. Malate, glutamate, and aspartate were identified as core metabolites and potential biomarkers of gelsenicine poisoning. RT-qPCR validation revealed that gelsenicine interfered with the expression of core targets, including GLUD1, MDH, GOT and ME, all of which exhibited good binding energy with gelsenicine.

This study unveiled a novel mechanistic insight into gelsenicine-induced neurotoxicity, demonstrating its capacity to perturb multiple energy metabolism pathways associated with MAS. These findings could enhance the theoretical understanding of gelsenicine's neurotoxic effects and highlight potential applications in clinical diagnosis and forensic identification.

The role of Ophiostoma quercus in oak decline, a significant threat to European oak ecosystems, has been debated for nearly a century. This long-term field experiment assessed the aggressiveness of O. quercus on Quercus petraea and monitored both fungal spread and tree defense responses, combining pathology, microscopy, X-ray tomography, FTIR, HPLC and proteome analyses. Fifty-nine months post-inoculation, 30 % of trees exhibited decline symptoms, while 70 % displayed extensive cankers and lesions, 28.3 times larger than those on controls. Infected trees responded by forming tyloses, blocking water transport around the inoculation site. Following infection, increased deposition of polyphenolic compounds was observed in both barrier and reaction zones. Histopathological observations and FTIR measurements revealed enhanced local deposition of suberin, lignin, lignin-related compounds, and tannins within the lumens of ray parenchyma cells, and the cell walls of both libriform fibers and vessels. Proteomic analyses suggest that host trees are employing a salicylic acid-based defense strategy. At the tissue level, these analyses indicate a shift in metabolic pathways, with downregulation of lignin biosynthesis and upregulation of flavonoid and stilbenoid biosynthesis, as evidenced by increased chalcone synthase abundance. Our groundbreaking use of submicron-computed X-ray tomography on woody tissues could pave the way for the widespread adoption of non-destructive 3D scanning technology in plant-fungal interaction research. The findings of this study demonstrated the aggressiveness of O. quercus towards adult Q. petraea and its contribution to the widespread syndrome of oak decline.

Current therapies for rheumatoid arthritis, including anti-inflammatory agents and immunomodulators, primarily target common inflammatory mechanisms. However, the efficacy of most bioactive compounds claimed to possess anti-arthritic properties remains mechanistically unproven, particularly against progressive conditions like pannus development. This study investigates the pharmacokinetics, toxicity, and impact of reported anti-arthritic polyphenols on HIF-regulated pannus development in rheumatoid arthritis through in silico and in vitro approaches. Eighty bioactive compounds with documented anti-arthritic properties were selected from the literature and subjected to sequential evaluation of pharmacodynamic and pharmacokinetic activity. The study identified five promising candidates qualified to perform in vivo toxicity and in vitro biochemical assays. Toxicity testing using Galleria mellonella larvae indicated dose-dependent effects on the midgut, with no mortality observed at doses up to 2000 mg/kg body weight. In vitro assays, including antioxidant and anti-inflammatory evaluations, further validated the therapeutic potential of these compounds. Compounds that satisfied all predictive criteria were subjected to molecular interaction analysis against hub-gene targets implicated in HIF-regulated angiogenesis in rheumatoid arthritis. RA-associated proteins were identified from NCBI-GEO and DisGeNET (GWAS) databases. Functional annotation and protein-protein interaction analysis identified IL-6, IL-1β, HIF-1α, PPARG, and TIMP1 as key hub targets. Molecular docking using PyRx revealed the binding affinities of the selected bioactive compounds against these targets. These findings suggest that the screened bioactive polyphenols exhibit low toxicity and hold potential as regulators of HIF-mediated angiogenesis in rheumatoid arthritis, offering a novel therapeutic approach for progressive disease management.

Anoectochilus roxburghii (Wall.) Lindl. (A. roxburghii) is an increasingly popular medicinal herb. Arbuscular mycorrhiza (AM) fungi, known for their symbiotic relationships with plant roots, enhance nutrient uptake and disease resistance in host plants. However, their specific regulatory mechanisms in A. roxburghii are not fully understood. In this study, Fujian A. roxburghii was inoculated with the AM fungus Glomus intraradices, and successful root colonization was observed. Following AM fungal colonization, there was a significant upregulation of photosynthesis-related genes in the stems, accompanied by improved canopy phenotypes and root architecture. Consequently, AM-inoculated plants exhibited increased fresh and dry biomass, as well as elevated levels of polysaccharides and flavonoids. Additionally, the incidence of Fusarium oxysporum-induced stalk rot was reduced in AM-inoculated plants. Analysis of defense-related enzymes indicated that AM-inoculated plants exhibited a rapid and robust response to pathogen infection, mitigating oxidative stress. Transcriptomic analysis revealed significant upregulation of genes associated "Fatty acid degradation", "MAPK signaling pathway-plant", and "Plant-pathogen interaction", suggesting their involvement in enhanced disease resistance. A regulatory network centered on ACX1 and calmodulin, involving multiple transcription factors such as WRKY, bHLH, ERF, NAC, and HSF, was implicated in defense responses. These findings demonstrated the beneficial effects of AM fungi on yield, quality, and disease resistance in A. roxburghii, providing a theoretical foundation for its cultivation and genetic improvement.

This study seeks to investigate the fundamental molecular processes through which histone deacetylase 9 (HDAC9) governs the proliferation of glomerular mesangial cells in the context of immunoglobulin A nephropathy (IgAN) and to identify novel targets for clinical research on IgAN.

Data from high-throughput RNA sequencing for IgAN were procured from the Gene Expression Omnibus database to assess the expression profiles and clinical diagnostic significance of histone deacetylase family proteins (HDACs). Blood samples from 20 IgAN patients were employed in RT-qPCR analysis, and the spearman linear regression method was utilized to analyze the clinical correlation. The proliferation of glomerular mesangial cells (GMCs) under the influence of HDAC9 was examined using the 5-ethynyl-2'-deoxyuridine (EdU) assay. Proteins interacting with HDAC9 were predicted utilizing the STRING database. Immunoprecipitation and protein immunoblotting employing anti-acetylated lysine antibodies were conducted to determine the acetylation status of calmodulin-like protein 6 (CALML6).

Analysis of the GSE141295 dataset revealed a significant upregulation of HDAC9 expression in IgAN and the results of RT-qPCR demonstrated a substantial increase in HDAC9 expression in IgAN patients. Receiver operating characteristic (ROC) analysis indicated that the area under the curve (AUC) value for HDAC9 were 0.845 and Spearman correlation analysis showed that HDAC9 expression was positively correlated with blood levels of blood urea nitrogen (BUN) and serum creatinine (Crea). The EdU cell proliferation assay indicated that HDAC9 facilitated the excessive proliferation of GMCs. The STRING database and recovery experiments identified CALML6 as a downstream effector of HDAC9 in controlling abnormal GMC multiplication. Co-immunoprecipitation assays demonstrated that HDAC9 modulates CALML6 expression through acetylation modification.

HDAC9 is markedly upregulated in IgAN, and it mediates the excessive proliferation of GMCs by regulating the deacetylation of CALML6.

Glioblastoma multiforme (GBM) is the most frequent type of primary malignant brain tumor. This study utilized Mendelian randomization (MR) analysis to explore the causal link between proteins in plasma and cerebrospinal fluid and GBM.

This study aimed to identify proteins in both plasma and cerebrospinal fluid (CSF) that could serve as potential therapeutic targets for GBM.

We employed previously published protein quantitative trait loci (pQTL) data from CSF and plasma as the exposure data, alongside aggregated Genome-Wide Association Study (GWAS) data on GBM for our MR analysis. Furthermore, we conducted Bayesian co-localization analysis and examined the protein-protein interaction (PPI) networks of CSF and plasma proteins related to GBM risk.

MR identified three key proteins linked to GBM risk: ribophorin I (RPN1) in plasma, von Willebrand factor (vWF) and macrophage-stimulating protein (MSP). in CSF. Elevated RPN1 and MSP were associated with decreased GBM risk, while increased vWF was linked to higher risk. External validation confirmed that RPN1 served as a key protein in GBM development. Bayesian co-localization showed a 10.35 % probability of a shared causal variant between RPN1 and GBM. Protein-protein interaction analysis further highlighted related proteins for RPN1.

In summary, the plasma protein RPN1 and the CSF proteins vWF and MSP are causally associated with the risk of GBM. Further research is needed to clarify the roles of these candidate proteins in GBM. Notably, RPN1 may serve as a potential therapeutic target for GBM. Future clinical studies on GBM treatment could explore drugs targeting RPN1.

Intense physical activity in endurance horses triggers complex immune and inflammatory responses, yet the molecular mechanisms underlying these adaptations remain unclear. This study investigated immune-related transcriptomic changes following a 160 km endurance ride, focusing on sex-based differences. Using a bioinformatics approach, differentially expressed genes (DEGs), pathways, microRNAs (miRNAs), and transcription factors (TFs) were analyzed before (T0) and after (T1) the ride. A protein-protein interaction (PPI) analysis was conducted to identify key regulatory genes. Pathway enrichment analysis revealed significant activation of immune-regulatory and ribosomal pathways. Notably, TLR4, CXCL8, and CCL5 were identified as key hub genes involved in immune modulation post-exercise. Comparisons between female (FT1 vs FT0) and gelding (GT1 vs GT0) horses revealed distinct molecular responses. Female horses exhibited upregulation of ribosomal protein genes, suggesting enhanced protein synthesis and muscle recovery. In contrast, geldings showed increased expression of inflammatory and stress-related genes, indicating a heightened immune response. Notably, sex-based differences were observed, with FT1 vs FT0 and GT1 vs GT0 comparisons revealing distinct KEGG pathway enrichments. Additionally, miRNA and TF analyses revealed regulatory elements influencing endurance-related immune responses. Our findings demonstrated sex-specific molecular mechanisms underlying endurance exercise adaptation, with females prioritizing protein synthesis and recovery, while geldings exhibit stronger inflammatory responses and stress-related pathways. This study provides critical insights into how sex influences exercise physiology at the transcriptomic level, with potential applications in training and recovery strategies for endurance horses.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) have similar clinical characteristics in the brain and islet, as well as an increased incidence with ageing and familial susceptibility. Therefore, in recent years there has been a great desire for research that elucidates how anti-diabetic drugs affect AD. This work attempts to first elucidate the possible mechanism of action of DPP-IV inhibitors in the treatment of AD by employing techniques from network pharmacology, molecular docking, molecular dynamic simulation, principal component analysis, and MM/PBSA. A total of 463 targets were identified from the SwissTargetPrediction and 784 targets were identified from the SuperPred databases. 79 common targets were screened using the PPI network. The GO and KEGG analyses indicated that the activity of DPP-IV against AD potentially involves the hsa04080 neuroactive ligand-receptor interaction signalling pathway, which contains 17 proteins, including CHRM2, CHRM3, CHRNB1, CHRNB4, CHRM1, PTGER2, CHRM4, CHRM5, TACR2, HTR2C, TACR1, F2, GABRG2, MC4R, HTR7, CHRNG, and DRD3. Molecular docking demonstrated that sitagliptin had the greatest binding affinity of -10.7 kcal/mol and established hydrogen bonds with the Asp103, Ser107, and Asn404 residues in the active site of the CHRM2 protein. Molecular dynamic simulation, PCA, and MM/PBSA were performed for the complex of sitagliptin with the above-mentioned proteins, which revealed a stable complex throughout the simulation. The work identifies the active component and possible molecular mechanism of sitagliptin in the treatment of AD and provides a theoretical foundation for future fundamental research and practical implementation.

Neuroinflammation is a key pathological factor of PD, and T cells play a central role in neuroinflammatory progression. However, the causal effect of T cell-related genes on the risk of PD is still unclear. We explored single-cell RNA sequencing (scRNA-Seq) datasets of the peripheral blood T cells of PD patients and healthy controls, and screened the differentially expressed genes (DEGs) in the cytotoxic CD4 + T cells relative to the other T cell subsets. Pseudo-time series analysis, cell-cell communication analysis, and metabolic pathway analysis was performed for the cytotoxic CD4 + T cells. The DEGs were also functionally annotated through GO and KEGG pathway enrichment analyses. The MR approach was used to establish causal effects of the DEGs (exposure) on PD risk (outcome), and explore new drug targets for PD. The findings of MR analysis were further validated by Steiger filtering, bidirectional MR, Bayesian colocalization analysis, and phenotype scanning, and the GWAS data from an independent PD case-control cohort was used for external validation of the results. Finally, differences in gene expression between PD patients and healthy controls were further validated in scRNA-Seq and bulk transcriptome sequencing data. We found that increased expression of IL-32, GNLY, MT2A, and ARPC2 was significantly associated with a higher risk of PD. In contrast, the increase in ARRB2 was closely related to a lower risk of PD. IL32, GNLY, MT2A, ARRB2, and ARPC2 are the causal genes and potential drug targets of PD. Cytotoxic CD4 + T cells are likely the key effectors of PD-related neuroinflammation. These findings provide new insights into the pathogenesis and treatment options for PD, and further research and clinical trials based on the five potential drug targets and neuroinflammation are necessary.

Liver Hepatocellular Carcinoma (LIHC) and Kidney Renal Clear Cell Carcinoma (KIRC) are leading causes of cancer death worldwide, but their early detections remain hindered by a lack of genetic markers. Our study aims to find prospective biomarkers that could serve as prognostic indicators for efficient drug candidates for KIRC and LIHC treatment.

To detect differentially expressed genes (DEGs), four datasets were used: GSE66271 and GSE213324 for KIRC, and GSE135631 and GSE202853 for LIHC. Visualization of DEGs was done using heatmaps, volcano plots, and Venn diagrams. Hub genes were identified via PPI analysis and the cytoHubba plugin in Cytoscape. Their expression was evaluated using box plots, stage plots, and survival plots for prognostic assessment via GEPIA2. Molecular docking with PyRx's AutoDock Vina identified optimal binding interactions between compounds and proteins. Pharmacokinetic and toxicity analyses reinforced the drug-likeness and safety of these compounds.

In this study, 47 DEGs were identified, with the top 10 hub genes being TOP2A, BUB1, PTTG1, CCNB2, NUSAP1, KIF20A, BIRC5, RRM2, NDC80 and CDC45, chosen for their high MCC scores. Data mining revealed a correlation between TOP2A expression and clinical survival outcomes in KIRC and LIHC patients. Docking studies of the TOP2A structure identified a promising compound from Andrographis paniculata with high binding energy and interactions with TOP2A. Pharmacokinetic and toxicity assessments support its potential as a drug candidate.

Our study emphasizes TOP2A's prognostic significance in KIRC and LIHC and recognizes Andrographis paniculata compound as potential therapeutics, offering prospective for enhanced treatment and patient outcomes in these cancers.

The escalating prevalence of Type-2 diabetes mellitus (T2DM) poses a significant global health challenge. Utilizing integrative proteomic analysis, this study aimed to identify a panel of potential protein markers for T2DM, enhancing diagnostic accuracy and paving the way for personalized treatment strategies.

Proteome profiles from two independent cohorts were integrated: cohort 1 composed of 10 T2DM patients and 10 healthy controls (HC), and cohort 2 comprising 87 T2DM patients and 60 healthy controls. Differential expression analysis, functional enrichment analysis, receiver operating characteristic (ROC) analysis, and classification error matrix analysis were employed.

Comparative proteomic analysis identified the differential expressed proteins (DEPs) and changes in biological pathways associated with T2DM. Further combined analysis refined a group of protein panel (including CA1, S100A6, and DDT), which were significantly increased in T2DM in both two cohorts. ROC analysis revealed the area under curve (AUC) values of 0.94 for CA1, 0.87 for S100A6, and 0.97 for DDT; the combined model achieved an AUC reaching 1. Classification error matrix analysis demonstrated the combined model could reach an accuracy of 1 and 0.875 in the 60% training set and 40% testing set.

This study incorporates different cohorts of T2DM, and refines the potential markers for T2DM with high accuracy, offering more reliable markers for clinical translation.

The online version contains supplementary material available at 10.1007/s40200-025-01562-3.

Aquaporins (AQPs) are specialized membrane proteins that create selective water channels, facilitating the transport of water across cell membranes and playing a vital role in maintaining water balance and regulating osmotic pressure in aquatic animals. This study identified 9 aquaporin genes from the genome of R. philippinarum, and a comprehensive analysis was conducted on their gene structure, phylogenetic relationships, protein structure, and chromosome localization. RNA-seq data analysis revealed that aquaporin genes were differentially expressed at different developmental stages, in tissue distribution, and in response to salinity stress. In addition, qPCR results revealed that the expression levels of aquaporin genes (AQP1, AQP4d, and AQP3) were significantly elevated in response to both acute low and high salinity stress, suggesting their important role in osmotic pressure regulation in R. philippinarum. This study's results offer an important reference for further investigations into the regulation of osmotic pressure and salinity adaptation of aquaporin in R. philippinarum.

Selective estrogen receptor modulators (SERMs) play a vital role in ER + ve breast cancer therapy, but existing synthetic drugs have limitations. This study explores Pyrenacantha volubilis as a potential natural source for SERM using molecular docking, ADMET profiling, molecular dynamics (MD) simulations, and MM-GBSA analysis, using the Schrödinger Suite. Nine metabolites reported from the species were subjected to analysis, and all except one exhibited superior activity compared to the control. Among these, pumiloside (- 13.06 kcal/mol), strictosidine (- 11.808 kcal/mol), deoxypumiloside (- 11.686 kcal/mol), and strictosamide (- 11.479 kcal/mol) demonstrated stronger ERα binding affinities than control drugs tamoxifen and raloxifene. The receptor-ligand complexes of pumiloside and strictosidine exhibited reasonable interactions, with strictosidine showing the highest glide energy (- 52.418 kcal/mol). MD simulations and MM-GBSA analysis further confirmed the stability of these complexes under physiological conditions, with both compounds showing superior free binding energy compared to tamoxifen. Deoxypumiloside also emerged as a promising candidate with no Lipinski rule of five violations and high oral absorption, but required solubility enhancements. Additionally, 10-hydroxy camptothecin, protonated strictosidine, camptothecin, 9-methoxy camptothecin, 20-deoxy camptothecin, and 20-hexanoyl-10-methoxy camptothecin are other metabolites that exhibited good docking scores and favorable drug-like properties. These findings highlight P. volubilis as a promising SERM source, with strictosidine and pumiloside as lead candidates due to their superior receptor interactions, stability, and energetics. Further in vitro and in vivo studies are required to validate their therapeutic potential in breast cancer treatment.

The online version contains supplementary material available at 10.1007/s13205-025-04315-4.

Ovarian hyperstimulation syndrome (OHSS) is a severe complication associated with assisted reproductive technologies, characterized by metabolic, immune and vascular disorders. Understanding the molecular mechanisms underlying OHSS could reveal potential therapeutic targets and improve patient outcomes. In this study, We aimed to utilize proteome-wide Mendelian randomization (MR) and colocalization analysis to identify plasma proteins associated with OHSS and evaluate their potential as therapeutic targets through druggability assessment. We employed proteome-wide MR analysis summary data-based Mendelian randomization (SMR) analysis and phenome-wide association study (PheWAS) analysis to establish causal relationships between plasma proteins and OHSS. Colocalization analysis confirmed overlaps between proteins and genetic signals associated with OHSS. Pathway and network analyses were conducted to explore biological functions and protein interactions, while drug-target databases were queried for potential therapeutic interventions. Our results showed that 4 key proteins, including Suprabasin (SBSN), SLAMF4 (CD244), Enolase 3 (ENO3) and Thioredoxin domain-containing protein 12 (TXNDC12) were identified as significant contributors to OHSS. Pathway enrichment and interaction analyses further supported their involvement in metabolic, immune and structural pathways related to OHSS. Drug availability for colocalized proteins reveled potential drug targets for ENO3 (2-deoxy-D-glucose), CD244 (lenalidomide) and TXNDC12 (Auranofin), while no potential drug targets were identified for SBSN. Over all, our study identified15 plasma proteins, including SBSN, CD244, ENO3, and TXNDC12, as key contributors to the risk of OHSS through MR and colocalization analysis. These proteins were involved in metabolic regulation, immune response and antioxidant pathways, highlighting potential therapeutic targets and suggesting new directions for treatment strategies.

ObjectiveAlthough knee osteoarthritis (KOA) is a common disease, there is a lack of specific prevention and early treatment methods. Hence, this study aimed to examine the molecular changes occurring at different stages of KOA to elucidate the dynamic nature of the disease.DesignUsing a low-force compression model and analyzing RNA sequencing data, we identified molecular changes in the transcriptome of knee joint cartilage, including gene expression and molecular pathways, between the cellular changes and structural damage stages of KOA progression. In addition, we validated hub genes using an external dataset.ResultsGene set enrichment analysis (GSEA) identified the following pathways to be associated with KOA: "B-cell receptor signaling pathway," "cytokine-cytokine receptor interaction," and "hematopoietic cell lineage." Expression analysis revealed 585 differentially expressed genes, with 579 downregulated and 6 upregulated genes. Enrichment and clustering analyses revealed that the main molecular clusters were involved in cell cycle regulation and immune responses. Furthermore, the hub genes Csf1r, Cxcr4, Cxcl12, and Ptprc were related to immune responses.ConclusionsOur study provides insights into the dynamic nature of early-stage KOA and offers valuable information to support the development of effective intervention strategies to prevent the irreversible damage associated with KOA, thereby addressing a major clinical challenge.

We have previously shown that nano-sized graphene oxide (NGO) displays anti-inflammatory activities against NKT cell-mediated sepsis. To address whether NGO could be applied to treat acute skin inflammation, we developed a conventional skin Cetaphil cream containing NGO (denoted as NGO cream) for topical application to skin lesions and investigated its therapeutic efficacy by employing the tape-stripping-induced acute skin inflammation model. Topical application of NGO cream to the wounded area significantly reduced skin lesions compared with application of the control cream. Moreover, NGO cream treatment prevented the tape-stripping-elicited infiltration of, and IL-1β production by, skin neutrophils and dendritic cells. Furthermore, such anti-inflammatory effects of NGO cream were attributed to decreased infiltration of IL-12-producing dendritic cells and IFNγ-producing cells (eg, CD4+ T, CD8+ T, γδ T, NK, and NKT cells) into the skin. In addition, topical NGO cream administration enhanced the expression of suppressive molecules such as FR4 on skin regulatory T cells. Through RNA-sequencing analysis, we found that the preventive effect of NGO cream on acute skin inflammation may be correlated with the activation of keratinocytes located in the epidermis. Our results support NGO cream as a therapeutic option to control acute skin inflammation.

As an important member of global aquaculture, oysters (Crassostrea gigas) have significant economic value. With the development of commercial aquaculture, the frequent occurrence of diseases caused by Vibrio alginolyticus has become a hindrance to high-density aquaculture. Gill tissue, as an important component of immune system of the oysters, plays the key point in the face of invasion by foreign substances. Compared to the diploid oyster, the triploid oyster presents a higher growth rate and lower growth investment, making it a more ideal model for studying oyster immune defense. In this study, triploid oysters were as the research subject, and gill tissues attacked by V. alginolyticus were sequenced. By analyzing samples from different time points, 1746 DEGs were obtained. The KEGG and GO functional enrichment analysis showed that gill tissues mainly participate in immune function through the PIK3-Akt signaling pathway and the MAPK signaling pathway. The protein interaction network revealed three genes (CASP8, CASP9 and PIK3CA) that play core roles in immune defense by analyzing the interaction relationship between genes. Finally, qRT-PCR verified the expression of key genes. This study provides a more effective scientific basis for disease prevention and control of oysters and other bivalve shellfish, and helps to promote the sustainable development of aquaculture.

Intact insulin signaling and glucose transport in adipocytes are crucial to maintaining whole-body energy metabolism. Focal adhesion kinase stands as a central intracellular protein facilitating signaling between the extracellular matrix and the cytoplasm, thereby regulating cellular metabolism. Here, we have investigated the role of focal adhesion kinase in adipocyte glucose transport using an array of methods, including affinity purification combined with quantitative mass spectrometry, glucose tracer assays, western blotting, and confocal imaging. Pharmacological inhibition (PF-573228) of focal adhesion kinase suppressed the interaction of focal adhesion kinase with numerous actin-associated proteins, reduced Rac1 activity, as well as phosphorylation of the Rac1 downstream target PAK1/2, and further led to impaired GLUT4 translocation and glucose uptake. In summary, we demonstrate that focal adhesion kinase plays a key role in controlling actin remodeling, subsequent GLUT4 translocation, and ultimately glucose transport in adipocytes.

Coagulation defects, including purpura and other haemorrhagic conditions, are a critical area of medical research because of their significant health effects worldwide. Understanding the metabolic basis of these conditions may improve therapeutic strategies.

A two-sample Mendelian randomization (MR) approach was employed to evaluate the causal relationships between the levels of 1,400 metabolites and coagulation defects. Colocalization analysis confirmed significant shared genetic influences. Pathway and protein‒protein interaction (PPI) analyses identified rate-limiting enzymes and drug targets. The impacts of lifestyle factors on metabolite levels were also explored through MR.

MR analysis revealed four metabolites whose abundance was significantly associated with coagulation defects: docosapentaenoate n3 DPA 22:5n3 (DPA) (OR: 1.594, 95% CI: 1.263-2.011, P < 0.001), 1-palmitoyl-2-stearoyl-gpc (PSPC) (16:0/18:0) (OR: 1.294, 95% CI: 1.134-1.477, P < 0.001), 1-stearoyl-2-docosahexaenoyl-gpc (SDPC) (18:0/22:6) (OR: 1.232, 95% CI: 1.101-1.380, P < 0.001) and hydroxypalmitoyl sphingomyelin (HPSM) (d18:1/16:0 (OH)) (OR: 0.803, 95% CI: 0.719-0.896, P < 0.001). Colocalization analysis provided robust evidence for shared genetic loci. Pathway analysis highlighted the importance of lipid metabolism, identifying key enzymes such as FADS1, FADS2 and TCP1. PPI analysis revealed an interaction between TCP1 and plasminogen, indicating potential therapeutic synergy. Further analysis revealed that lifestyle factors, including dried fruit and oily fish intake, were linked to the abundance of metabolites associated with coagulation risk.

This study identifies specific metabolites and metabolic pathways involved in coagulation defects, proposes novel therapeutic targets and highlights the roles of dietary and lifestyle interventions in the management of these conditions. These findings pave the way for personalized strategies to manage coagulation-related conditions.