KEGG Pathway Enrichment Research Articles

Interferon-stimulated gene subtypes as key indicators of immune landscape and survival outcomes in ovarian cancer

PurposeOvarian cancer (OV) remains the most lethal gynecological malignancy, underscoring the critical need for robust prognostic biomarkers to enhance patient outcomes. In this study, we classified OV patients by their interferon-stimulated gene (ISG) expression profiles and investigated the associations between these subtypes, the immune microenvironment, and survival outcomes.MethodsWe employed consensus clustering in the TCGA-OV cohort (n = 376) to classify patients into ISG-related subgroups. Survival analysis, differential gene expression (DESeq), KEGG and GSEA pathway enrichment analyses, genomic variation assessments, immune cell profiling using the CIBERSORT algorithm, and TIDE analysis were conducted in the TCGA-OV cohort. In addition, immune checkpoint marker expressions were assessed using data from the TCGA-OV cohort and multiplex immunofluorescence (mIF) staining on an independent cohort (n = 80).ResultsTwo distinct ISG subtypes were identified: ISG Cluster A and ISG Cluster B. Patients in ISG Cluster B exhibited significantly improved overall survival (OS) (p = 0.0442). A total of 328 dysregulated genes were identified, with Cluster B showing overexpression of immune-related genes and enhanced involvement in immune signaling pathways. ISG Cluster B also presented higher tumor mutation burden (TMB) and an enriched immune profile, including M1 macrophages and CD8 + T cells. TIDE analysis indicated a more favorable response to immune checkpoint inhibitors in this cluster, corroborated by high expressions of PD-L1 and ISG15, which were associated with prolonged OS.ConclusionsOur findings demonstrate that ISG-related subtypes are significantly associated with the immune microenvironment and survival outcomes in OV. The biomarkers identified in this study have the potential to inform precision therapy development, thereby enhancing treatment efficacy and personalized care for OV patients.

Study on the Improvement of Cognitive Impairment Induced by Scopolamine in Mice by Forsythia suspensa Essential Oil

ABSTRACTIn this study, the mechanism of Forsythia suspensa essential oil (FSEO) on cognitive disorders was investigated based on network pharmacology and animal experiments. The common targets of AD diseases and the main components of FSEO were collected through GeneCards, PubChem, STRING and other databases, and protein–protein interaction (PPI) network maps were established. GO functional enrichment analysis and KEGG pathway enrichment analysis were performed using DAVID and Metascape databases, and the enrichment results were verified using the scopolamine (SCO) cognitive impairment mouse model. The results of network pharmacological analysis showed that FSEO involved 107 potential therapeutic targets, among which MAPK1, MAPK3 and ESR1 were the core targets, which were closely related to the regulatory pathways of MAPK cascade, 5‐hydroxytryptaminergic synapses, dopaminergic synapses and oxidoreductase activity. The results of animal experiments showed that FSEO improved cognitively impaired behaviours, reduced central cholinergic neuron damage and oxidative stress in the mouse brain and increased the content of monoamine transmitters in the mouse brain. Animal experiments further validated the results of the FSEO network pharmacology analysis.

Integration analysis of microRNAs as potential biomarkers in early-stage lung adenocarcinoma: the diagnostic and therapeutic significance of miR-183-3p

IntroductionLung adenocarcinoma (LUAD) poses a significant therapeutic challenge, primarily due to delayed diagnosis and the limited efficacy of existing treatments.MethodsTo understand the pathogenesis and identify diagnostic biomarkers for LUAD in the early stage, we investigated differential miRNA expression in 33 stage I LUAD patients between tumor and matched paracancerous tissues by Illumina Sequencing. Target genes of differentially expressed miRNAs were predicted using TargetScan and miRDB databases and further analyzed by GO and KEGG pathway enrichment analysis. The miRNAs expression results were verified using qRT-PCR. Additionally, we evaluated the clinical significance of miRNAs by the TCGA database. miR-183-3p was chosen for subsequent biological functional studies by cell proliferation assays, cell migration and cell invasion assays, cell apoptosis and cell cycle assays in LUAD cells. The clinical relevance target genes of miR-183-3p were predicted by TargetScan databases and bioinformatics assays. Gene-specific experimental validation was performed using qRT-PCR, western blotting and luciferase reporter assays.ResultsWe identified 36 differentially expressed miRNAs between LUAD tissues and matched paracancerous tissues. Target genes for these miRNAs revealed associations with processes and pathways such as RNA biosynthesis, intracellular signaling, protein transport, and the Ras, MAPK, and PI3K-AKT pathways. The qRT-PCR results were in alignment with the sequencing data for 19 out of these 21 miRNAs which not yet implicated in LUAD, 13 were up-regulated, 6 were down-regulated. The clinical relevance assays showed that 5 up-regulated miRNAs have diagnostic value for LUAD. miR-183-3p showed significant advantages in the result of sequencing, qRT-PCR, and clinical relevance assay. Biological functional assays showed that miR-183-3p emerged as a key regulator, promoting LUAD cell proliferation, decreasing apoptosis, and augmenting migration and invasion capabilities. The clinical relevance assays and experimental validation showed SESN1 as a clinical significance target of miR-183-3p.DiscussionOur study lays the foundation for investigating miRNAs with diagnostic significance in early-stage LUAD, pointing out that inhibition of miR-183-3p may serve as a novel therapeutic in LUAD.

Potential role of Mappain, a prenylated stilbene, in reducing SARS-CoV-2 envelope protein-induced inflammation

As of right now, more than 776 million people have contracted the COVID-19-causing SARS-CoV-2 virus, which has also resulted in over 7 million deaths. A dysregulated host's innate immune response to the virus exacerbates clinical outcomes and leads to cytokine storm. Developing a drug targeting the multiple aspects of the SARS-CoV-2 virus-host cell interactions is essential for effective treatment. The 75 amino acid-long SARS-CoV-2 envelope (2E) protein is a small structural transmembrane protein that plays a crucial role in the viral life cycle and pathogenesis. Mappain is a plant-derived stilbene from Macaranga species that previously demonstrated antiviral potential against enteroviruses in tissue culture. This study aims to assess the inhibitory potential of Mappain against SARS-CoV-2 key proteins and induced hyperinflammation using computational and in-vitro approaches. Autodock Vina was used to evaluate mappain interaction with SARS- CoV-2 antiviral targets including Spike, Envelope, Membrane, 3CLPro, PLpro, Nucleocapsid N and C termini, RdRP, and host receptors—TLR2, TLR3, TLR7, and TLR8. Afterwards, mappain was subjected to in-vitro bioassay testing using inhibition 2E-induced cytokines (IL-6 and TNF-α) in human peripheral blood mononuclear cells, measured by ELISA; Amantadine as control. KEGG pathway enrichment analysis was further performed using network pharmacology to elucidate the mechanism. Mappain demonstrated a high binding score with all the targets, especially with the envelope protein (− 9.6 kcal/mol) and TLR2 (− 9.7 kcal/mol) compared to Amantadine (− 6.1 kcal/mol and − 5.5 kcal/mol, respectively). Mappain also significantly reduced the expression of 2E-induced Interleukin 6 (p ≤ 0.001) and tumour necrosis factor-alpha (p ≤ 0.01) in the PBMCs, when compared to Amantadine HCl. The KEGG Pathway enrichment analysis supports the anti-inflammatory potential of mappain in the virus-induced cytokine storm by specifically targeting TLR signalling and COVID-19 pathways.

The Effect of Atorvastatin on Oncogenic miRNAs in Hematological Malignancies: A Central Study

The efficacy of statins as anti-cancer drugs has been demonstrated in several malignancies but has been poorly investigated in hematological malignancies (HM). By studying its effect on oncogenic miRNAs, we investigated the effect of statin therapy on HM patients. The data were used to identify enriched pathways that were altered due to statin treatment. The main aim of this study was to identify significantly differentially expressed miRNAs and involved regulatory pathways post-atorvastatin treatment in HM patients. A panel of 95 plasma circulating miRNAs involved in tumorigenesis, apoptosis, and differentiation were relatively quantified using qPCR for blood samples obtained from 12 HM patients, 4 with Chronic Myeloid Leukemia (CML), 4 with Non-Hodgkin Lymphoma (NHL), and 4 with Essential Thrombocythemia. Pre- and post-administration of a 6-week atorvastatin course miRNA expression levels were measured. Significantly differentially expressed miRNAs were those with a fold change >2 or <0.5 using the Livak method with a two-sided p-value < 0.05. To further understand the underlying mechanism of statin regulated miRNA, GO and KEGG pathway enrichment analyses were conducted for identified target genes using the DAVID 6.8 bioinformatics tool. Out of 95 miRNAs, 14 exhibited significant fold changes post-treatment with statins including miR-198, miR-29a+b+c, miR-204, miR-222, miR-224, miR-155, miR-128b, miR-296, miR-199a+b, miR-194, miR-125a, miR-200a, and the let-7-family that were upregulated and miR-150 that was downregulated post-statin treatment. Higher mir-222, mir-194, mir-128b, and mir-199b expressions were significantly associated with better overall survival using the Cancer Genomic Atlas leukemia and lymphoma patient cohorts. Enrichment analysis identified the PI3k-Akt pathway as well as other pathways involved in the epithelial–mesenchymal transition. Atorvastatin upregulated several tumor suppressor genes involved in mediating better prognosis. The data can be used to enhance personalized treatments for patients with hematological malignancies by helping to predict the different pathways that may be targeted and, therefore, result in better survival outcomes in these patients.

Targeting autophagy in HCC treatment: exploiting the CD147 internalization pathway

Background/AimsChemotherapy resistance in liver cancer is a major clinical issue, with CD147 playing a vital role in this process. However, the specific mechanisms underlying these processes remain largely unknown. This study investigates how CD147 internalization leads to cytoprotective autophagy, contributing to chemotherapy resistance in hepatocellular carcinoma (HCC).MethodsUtilizing bioinformatics methods for KEGG pathways enrichment and screening key molecules associated with chemotherapy resistance through analyses of GEO and TCGA databases. An overexpression/knockdown system was used to study how CD147 internalization leads to autophagy in vitro and in vivo. The process was observed using microscopes, and molecular interactions and autophagy flux were analyzed. Analyzing the internalization of CD147 intracellular domains and the interaction with G3BP1 in clinical chemotherapy recurrence HCC tissues by immunohistochemistry, tissue immunofluorescence, and mass spectrometry. A tumor xenograft mice model was used to study cytoprotective autophagy induced by CD147 and test the effectiveness of combining cisplatin with an autophagy inhibitor in nude mice models.ResultsIn our study, we identified the tumor-associated membrane protein CD147, which implicated in chemoresistance lysosome pathways, by evaluating its protein degree value and betweenness centrality using Cytoscape. Our findings revealed that CD147 undergoes internalization and interacts with G3BP1 following treatment with cisplatin and methyl-β-cyclodextrin, forming a complex that is transported to lysosomes via Rab7A. Notably, higher doses of cisplatin enhanced CD147-mediated lysosomal transport while concurrently inhibiting SG assembly. The CD147-G3BP1 complex additionally inhibits mTOR activity, promoting autophagy and augmenting chemoresistance in hepatoma cells. In vivo studies investigations and analyses of clinical samples revealed that elevated internalization of CD147 is associated with chemotherapy recurrence in liver cancer and the maintenance of stem cells. Mice experiments found that the combined administration of cisplatin and hydroxychloroquine enhanced the efficacy of treatment.ConclusionsThis study reveals that CD147 internalization and CD147-G3BP1 complex translocation to lysosomes induce cytoprotective autophagy, reducing chemotherapy sensitivity by suppressing mTOR activity. It is also shown that chemotherapy drugs combined with autophagy inhibitors can improve the therapeutic effect of cancer, providing new insights into potential targeted therapeutic approaches in treating HCC.

Bioactive Constituents and the Molecular Mechanism of Melastoma dodecandrum Lour. in the Treatment of Inflammation Based on Network Pharmacology and Molecular Docking

Background: Melastoma dodecandrum Lour. (MD) is a component used in traditional Chinese medicine that is widely distributed in southern China. MD has long been used clinically to treat various diseases, such as inflammation. However, the potential anti-inflammatory mechanism of MD remains to be elucidated. Objective: In this study, network pharmacology and experimental validation have been used to explore the underlying mechanism of MD in inflammation. Methods: The chemical composition of MD was determined using ultra-high performance liquid chromatography-electrospray ionization-high resolution mass spectrometry (UHPLC-ESI-HRMS). The effects of MD on pro-inflammatory cytokines, such as NO, i-NOS, IL-1β, and TNF-α, in RAW264.7 cells stimulated by lipopolysaccharide (LPS) were determined by ELISA and QRT-PCR. Through the analysis of multiple databases, targets for the treatment of inflammation with MD were identified. Other extensive analyses included PPI, GO, and KEGG pathway enrichment, which were completed through the use of the STRING database, Cytoscape software, and the DAVID database. Key targets and key components have been selected for molecular docking. Results: A total of 33 active components were identified in MD, and 134 common targets were obtained and used to construct the networks. Of these, 10 core components and 10 core targets of MD in the treatment of inflammation were identified. The GO and KEGG enrichment analyses revealed that the common targets were involved in multiple signaling pathways, including the PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, chemokine signaling pathway, and IL-17 signaling pathway. The molecular docking methods confirmed the high affinity between bioactive molecules of MD and their targets in inflammation. Two core targets (PIK3CA and AKT) and three core components (asiatic acid, apigenin, and kaempferol) were found to be closely related to MD in the treatment of inflammation. In vitro, MD exerted a significant effect on LPS-stimulated NO, IL- 1β, and TNF-α secretion, and iNOS, IL-1β, and TNF-α expressions in macrophages. Conclusion: This study has demonstrated the bioactive constituents and mechanisms of MD in inhibiting the secretion of inflammatory factors and the multicomponent, multitarget, and multipathway treatment characteristics involved in inflammation, but this still needs further in vivo/in vitro experiments.

Widely Targeted Metabolomics Revealed the Metabolic Basis of Physiological Function and Flavor of Natto

Background: Natto is a fermented product derived from soybeans through the action of Bacillus subtilis natto, possessing various pharmacological and health-promoting properties. However, due to the absence of large-scale and systematic investigations into its metabolite profile, the mechanisms governing the biological functions and flavor characteristics of natto remain incompletely elucidated. Methods: In this study, a comprehensive, widely targeted metabolome analysis was conducted using UHPLC-MS/MS to compare soybeans and natto. Results: A total of 569 metabolites were identified, of which 160 exhibited differential expression between natto and soybeans, including 28 amino acids and their derivatives, 19 flavonoids, 18 alkaloids, and 10 nucleotides and their derivatives. Pathway enrichment analysis further demonstrated significant differences in the metabolic pathways between natto and soybeans, with these 160 differentially expressed metabolites primarily distributed across 40 metabolic pathways. KEGG pathway enrichment analysis of natto metabolites revealed that the majority of these mapped to three key metabolic pathways. Variations in the content of flavonoids and alkaloids, as well as changes in amino acid and saccharide composition and abundance, were found to collectively contribute to the distinctive flavor and biological functionality of natto. Conclusions: This study lays the foundation for future efforts to enhance the quality of natto.

Folic acid mitigates the developmental and neurotoxic effects of bisphenol A in zebrafish by inhibiting the oxidative stress/JNK signaling pathway

Bisphenol A (BPA) is a widespread environmental endocrine disruptor (EED) that can cause various environmental and health issues by inducing oxidative stress. The c-Jun N-terminal kinase (JNK) signaling pathway plays a crucial role in oxidative stress-mediated cellular damage. Although folic acid (FA) has demonstrated antioxidant properties, its potential protective effects against BPA-induced developmental and neurotoxicity, as well as the mechanisms involved in the JNK signaling pathway, are still not completely understood. Zebrafish embryos were exposed to different concentrations of BPA ranging from 20 to 40 µM, with or without treatment of 50 µM FA, starting at 6 hours post-fertilization (hpf). Various parameters such as hatchability, survival rate, body length, and heart rate were measured and analyzed. Transcriptome sequencing was conducted to study the changes in gene expression. Oxidative stress markers, including reactive oxygen species (ROS), lipid peroxidation (LPO), hydrogen peroxide (H2O2), and catalase (CAT) activity, were assessed. The expression of proteins related to the mitogen-activated protein kinase (MAPK)/JNK pathway was analyzed using western blot. Neurodevelopmental and apoptotic outcomes were evaluated through behavioral tests, immunofluorescence and RT-qPCR examinations. The study found that exposure to BPA led to a decrease in hatchability, survival, body length, heart rate, total antioxidant capacity and promoted apoptosis in zebrafish larvae. However, supplementation with FA was able to alleviate these negative effects. BPA exposure increased levels of ROS, LPO, and H2O2, while decreasing CAT activity in zebrafish larvae. Treatment with FA effectively reduced BPA-induced oxidative stress and restored antioxidant defense systems. Moreover, KEGG pathway enrichment analysis revealed that the MAPK signaling pathway was the most enriched signaling pathway. Further studies revealed that BPA activated the JNK signaling pathway, while FA suppressed this activation. Additionally, FA significantly improved BPA-induced neurobehavioral deficits and protected against neurocytological alterations. Our findings demonstrate that FA effectively protects against BPA-induced developmental and neurotoxic effects in zebrafish by suppressing oxidative stress and inhibiting the JNK signaling pathway. This study provides new strategies and insights for preventing BPA-induced developmental and neurotoxicity in aquatic organisms.

The efficient separation of bioactive components from Eucommia ulmoides Oliver using membrane filtration technology and its mechanisms in preventing alcoholic liver disease

The efficient extraction and purification of active components from Eucommia ulmoides Oliver (EUO) are crucial for their utilization. The structure and properties of the prepared EUO leaf polysaccharides (ELPs) and extractum (ELE) were comprehensively characterized in this study, and the intervention mechanism of the EUO polysaccharides and extractum in alcoholic liver disease (ALD) were investigated. The yield of EUO extractum was 24.82 %, from which nine active components were identified. The yield of EUO leaf polysaccharides was 8.06 %, and the polysaccharides were fractionated into three components ELP1, ELP2, and ELP3 through ultrafiltration technology, with yields of 4.19 %, 1.26 %, and 2.59 %, respectively. Ultrafiltration significantly reduced protein content, enhanced polysaccharide homogeneity, and altered monosaccharide composition. ELP3 exhibited higher scavenging efficacy on •OH and ABTS•+ than ELP1 and ELP2, reaching 82.53 % and 88.41 % respectively. ELP3 and ELE intervention preserved liver integrity, mitigated lipid accumulation and inflammation, and regulated hepatic oxidative stress. Moreover, they maintained intestinal barrier function, suppressed harmful bacteria (Escherichia-Shigella, and UBA1819), and promoted beneficial bacteria (Dubosiella, Monoglobus, and Lachnospiraceae). Thirteen hallmark differential metabolites were identified, and KEGG pathway enrichment analysis suggested that ELP3 and ELE may ameliorate ALD through pathways like longevity regulation, choline metabolism in cancer, oxidative phosphorylation, and AMPK signaling pathway. This investigation holds significance in delineating the beneficial effects of ELP3 and ELE in ALD alleviation.

Investigation of Ginseng-Ophiopogon Injection on Enhancing Physical Function by Pharmacogenomics and Metabolomics Evaluation.

Ginseng-ophiopogon injection (GOI) is a clinically commonly used drug for Qi deficiency syndrome characterized by decreased physical function in China. This study aimed to clarify common pharmacological mechanisms of GOI in enhancing physical function. We performed an integrative strategy of weight-loaded swimming tests in cold water (5.5°C), hepatic glycogen and superoxide dismutase (SOD) detections, GC-TOF/MS-based metabolomics, multivariate statistical techniques, network pharmacology of known targets and constituents, and KEGG pathway analysis of GOI. Compared with the control group, GOI showed significant increases in the weightloaded swimming time, hepatic levels of glycogen and SOD. Additionally, 34 significantly differential serum metabolites referred to glycolysis, gluconeogenesis and arginine biosynthesis were affected by GOI. The target collection revealed 98 metabolic targets and 50 experimentreported drug targets of ingredients in GOI involved in enhancing physical function. Further, the PPI network analysis revealed that 8 ingredients of GOI, such as ginsenoside Re, ginsenoside Rf, ginsenoside Rg1, and notoginsenoside R1, were well-associated with 48 hub targets, which had good ability in enhancing physical function. Meanwhile, nine hub proteins, such as SOD, mechanistic target of Rapamycin (mTOR), and nitric oxide synthases, were confirmed to be affected by GOI. Finally, 98 enriched KEGG pathways (P<0.01 and FDR<0.001) of GOI were obtained from 48 hub targets of the PPI network. Among them, pathways in cancer, Chagas disease, lipid and atherosclerosis, and PI3K-Akt signaling pathway ranked top four. This study provided an integrative and efficient approach to understand the molecular mechanism of GOI in enhancing physical function.

The key metabolite of fruit flavor change in different ripening stages of Baccaure ramiflora

Baccaurea ramiflora has an unstable ripening period. Herein, five typical periods of fruit ripening of ‘LR’ Baccaurea ramiflora were analyzed by non-targeted metabolomics techniques. The results showed that ripening started 73 days after flowering and reached the ripening criterion at 93 days, a total of 451 differential metabolites were identified for the five periods. KEGG enrichment pathway showed that significant changes in citric acid were significantly correlated with changes in the downstream substance spermine (R2 = 0.9068, y = −5.49 + 0.66×), while citric acid (R2 = 0.9982) and spermine (R2 = 0.9841) were negatively correlated with the sugar-acid ratio. Citric acid was the main component of titratable acid and spermine (R2 = 0.9991) was positively correlated with titratable acid. We speculated that citric acid is a key taste marker for fruit ripening in ‘LR’ B. ramiflora. The results of the study provide new metabolic evidence for flavor changes and scientific basis for their quality improvement and exploitation in B. ramiflora.

Genetic insights into kidney stone formation: a Mendelian randomization study of protein quantitative trait loci.

Kidney stones are a common urological condition caused by a complex interaction of genetic, metabolic, and environmental factors. Recent genomic research has shed light on the genetic basis of kidney stone susceptibility.This study aims to identify protein quantitative trait loci (pQTL) associated with kidney stone formation and explore their causal relationships using Mendelian randomization.We conducted two-sample Mendelian Randomization (MR) analyses utilizing Genome-Wide Association Study (GWAS) summary data to assess the causal impact of pQTL on kidney stone formation. Data sources included the UK Biobank dataset "ukb-b-8297" and an external validation dataset "ukb-b-13537". We employed inverse variance weighting (IVW) as the primary MR method, supplemented by sensitivity analyses such as MR-PRESSO, Leave-One-Out, and Cochran Q tests to validate the robustness of our findings.Our analyses identified significant associations between several pQTL and kidney stones. Key proteins such as CD27, CXCL9, and TNFRSF1A exhibited significant centrality in the protein-protein interaction (PPI) network, suggesting their critical roles in kidney stone pathogenesis. The KEGG pathway enrichment analysis revealed significant pathways, including cytokine-cytokine receptor interaction and osteoclast differentiation, highlighting the involvement of immune response and inflammatory processes in kidney stone formation.This study underscores the significance of pQTL in kidney stone research, identifying key proteins and pathways that may serve as biomarkers or therapeutic targets. The findings provide insights into the genetic and molecular mechanisms underlying kidney stone formation, offering potential avenues for future research and therapeutic interventions.

Exploring the potential mechanisms of Acer tegmentosum Maxim in preventing alcoholic liver disease based on network pharmacology and molecular docking

To investigate the potential mechanisms of Acer tegmentosum Maxim (AT) in preventing Alcoholic liver disease (ALD), this study used network pharmacology and molecular docking methods to screen the main active ingredients of AT for preventing core target proteins related to ALD, conducted GO and KEGG pathway enrichment analysis and performed molecular docking and visualisation. The results showed that AT’s top five active components were kaempferol-3-rhamnoside, salidroside, linoleic acid, ethyl linoleate, and tyrosol. The top five core target proteins for preventing ALD with AT were SRC, AKT1, STAT3, MAPK1, and ESR1. Gene enrichment analysis indicated that AT may inhibit the occurrence of ALD by improving inflammation and cancer pathways, and the core components of AT were well combined with critical targets, further elucidated the preventive mechanism of ALD through multiple components, targets, and pathways. It can provide a new idea for studying the mechanism of AT active ingredients to prevent ALD.

Metabolome-Wide Mendelian Randomization Assessing the Causal Relationship Between Blood Metabolites and Primary Ovarian Insufficiency

Background & aimsPrimary ovarian insufficiency (POI) is a significant clinical syndrome that leads to female infertility, and its incidence continues to increase. We used metabolome-specific Mendelian randomization (MR) to identify causally associated metabolites and explore the relationship between candidate metabolites and upstream genetic variations. MethodsThe primary MR analysis utilized the inverse variance weighted (IVW) method as the primary approach to assess the causal relationship between exposure and POI. Multiple sensitivity analyses included MR-Egger, weighted median, and weighted mode methods. ResultsAfter using genetic variants as probes, we identified 27 metabolites of 278 that are associated with the risk of POI, including dodecanedioate (OR 0.052, 95% CI 0.010 – 0.265; P < 0.001), adrenate (OR 0.113, 95% CI 0.016 – 0.822; P = 0.031), indolepropionate (OR 0.174, 95% CI 0.051 – 0.593; P = 0.005), homocitrulline (OR 0.194, 95% CI 0.051 – 0.741; P = 0.016), and 3-methylhistidine (OR 0.404, 95% CI 0.193 – 0.848; P = 0.017). Our study indicated the presence of heterogeneity; therefore, we employed the IVW random-effects model as the primary approach. KEGG pathway enrichment analysis identified six significant metabolic pathways, primarily including biosynthesis of unsaturated fatty acids, phenylalanine, tyrosine and tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, linoleic acid metabolism, valine, leucine and isoleucine biosynthesis, ubiquinone and other terpenoid-quinone biosynthesis. ConclusionsBy integrating genomics and metabolomics, this study provides novel insights into the causal relationship linking circulating metabolites and the onset of POI.

Mechanisms Underlying the Therapeutic Effects of Yiqi Wenyang Huwei Decoction in Treating Asthma Based on GEO Datasets, Network Pharmacology, Experimental Validation, and Molecular Docking.

The Yiqi Wenyang Huwei Decoction (YWHD) is an herbal formula frequently utilized to treat asthma. Despite its wide usage, the specific mechanism of action remains unknown. Through an in-depth investigation utilizing network pharmacology, molecular docking techniques, and experimental validation, this study aims to uncover the molecular mechanism and material basis of YWHD in the treatment of asthma. The compounds and targets of YWHD were gathered from various databases such as TCMSP, PubMed, and CNKI. Additionally, asthma-related targets were obtained by combining the GEO dataset with GeneCards and OMIM databases. The STRING platform was employed to establish protein-protein interactions. GO and KEGG pathway enrichment analyses were conducted using DAVID. Molecular docking was utilized to assess the binding affinity between potential targets and active compounds. The asthma rat model was established through OVA induction, and a lung function meter was used to detect Mch-induced Max Rrs. HE staining was conducted to observe pathological changes, while ELISA was used to detect levels of inflammatory factors IL4, IL6, IL13, and IgE in BLAF. Furthermore, qPCR was used to detect levels of IL-1β, IL-6, JUN, and PTGS2 mRNA, while Western blot assay was employed to measure phosphorylation levels of NF-κB and IKKα. A comprehensive study revealed that YWHD has 188 active compounds and 250 corresponding targets. After conducting a topological analysis of the PPI network, the study identified 14 high-activity targets, including JUN, PTGS2, IL6, IL1B, CXCL8, MMP9, IL10, ALB, TGFB1, CCL2, IFNG, IL4, MAPK3, and STAT3. Further, GO and KEGG pathway enrichment analysis indicated that YWHD targets inflammation-related genes and regulates IL- 17 and NF-kappa B signaling pathways. Animal studies have shown that YWHD can effectively minimize airway Max Rrs, reduce the levels of inflammatory factors IL4, IL13, IL6, and IgE in BLAF, and improve airway inflammation in rats with asthma. Molecular experiments have also demonstrated that YWHD achieves this by down-regulating the expression levels of IL-1β, IL-6, JUN, and PTGS2 mRNA, inhibiting the phosphorylation modification levels of NF-κB and IKKα, and reducing the levels of inflammatory cytokines IL4, IL13, IL6, and IgE in BALF of rats. Interestingly, molecular docking has revealed that the active compounds in YWHD have a strong binding ability to the screening targets. This research endeavor systematically explicated the active constituents, prospective targets, and signaling pathways of YWHD for asthmatic intervention. The study provides an innovative notion and dependable resource for comprehending the molecular mechanism and pharmaceutical screening of YWHD in the context of asthma treatment.

Decoding the anti-hypertensive mechanism of α-mangostin based on network pharmacology, molecular docking and experimental validation.

Hypertension is a leading risk factor for disability and deaths worldwide. Evidence indicates that alpha-mangostin(α-MG) can reduce blood pressure and improve target organ damage. Nonetheless, its pharmacological targets and potential mechanisms of action remain inadequately elucidated. We used SwissTargetPrediction to identify α-MG's drug targets and DisGeNET, GeneCards, CTD, and GEO databases for hypertension-related targets, and then determined antihypertensive therapeutic targets of α-MG by intersecting these targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were conducted using the DAVID database and R package "clusterprofile", visualized with Cytoscape software. The binding affinity of α-MG to identified targets was confirmed through molecular docking using Autodock Vina v.1.2.2 software. The impact of α-MG on target genes was validated using an Angiotensin II-induced hypertensive mouse model and RT-qPCR. A total of 51 potential antihypertensive therapeutic targets for α-MG were identified by intersecting 109 drug targets with 821 disease targets. Furthermore, 10 cellular component terms, 10 disease terms, and the top 20 enriched biological processes, molecular functions, and KEGG pathways related to α-MG's antihypertensive effects were documented. Molecular docking studies indicated a strong binding affinity of α-MG with the HSP90AA1 domain. In Ang II-induced hypertensive mice aorta, treatment with α-MG effectively reversed the aberrant mRNA expression of TNF, HSP90AA1, NFKB1, PPARG, SIRT1, PTGS2, and RELA. Our analyses showed that TNF, HSP90AA1, NFKB1, PPARG, SIRT1, PTGS2, and RELA might be α-MG's potential therapeutic targets for hypertension, laying groundwork for further investigation into its pharmacological mechanisms and clinical uses.

Identification of key neutrophil extracellular trap genes in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that is associated with neuroinflammation. Neutrophil extracellular traps (NETs) are web-like structures that cause inflammation, but its involvement in AD pathogenesis is unclear. This study aimed to identify key NETs related genes associated with AD. A total of 180 samples from the GSE122063 and GSE36980 dataset were obtained from the GEO repository. The representative genes were obtained, and its diagnostic performance was evaluated by analyzing operating characteristic curves. Consensus clustering and principal component analysis were performed to cluster AD samples. Gene ontology, KEGG pathway enrichment, and protein interaction network were analyzed. Peripheral blood samples were collected from 5 AD patients and 5 healthy donors to determine the expression of representative proteins or genes using WB, ELISA, and RT-qPCR. A total of 297 differentially expressed genes (DEGs) were associated with AD, 18 NETs genes showed potential diagnostic value. NETs genes expression effectively distinguished AD patients into 2 subgroups. The AD1 cluster showed higher abundance of activated dendritic cells, monocytes, and neutrophils, the AD2 cluster showed higher levels of naive B cells, eosinophils, and activated NK cells. We randomly selected and measured the levels representative genes in AD patients. The levels of NETs and CCL2, TLR2 expressions were significantly increased, whereas the level of BDNF was significantly decreased in AD patients comparing with healthy controls. This study identified key NET genes including BDNF, CCL2, and TLR2 to be associated with AD pathogenesis and classification.

Interpretation of the pathogenesis and therapeutic mechanisms of first-episode major depressive disorder based on multiple amino acid metabolic pathways: a metabolomics study.

Given the unclear etiology and treatment mechanisms of depression, we aim to explore the metabolic differences between patients with major depressive disorder (MDD) and the healthy population, as well as before and after treatment with escitalopram (ESC). Recruit first-episode drug-naïve MDD (DN-MDD) patients and healthy controls (HCs). Clinical data and serum samples from all subjects were collected at baseline and patients' samples were collected again after ESC monotherapy for four weeks. Perform non-targeted metabolomic analysis and apply MetaboAnalyst 5.0 to identify differential metabolites and execute KEGG pathway enrichment. Through metabolomic analysis of serum samples, 904 differential metabolites were identified in the DN-MDD group compared to the HCs, and 455 metabolites in treated patients compared to DN-MDD patients. In the pathway analysis, DN-MDD state regulated functions of histidine, beta-alanine, aspartate, and tryptophan metabolism, while ESC treatment produced an influence on the biological process of aspartate and sphingolipid. We respectively depicted metabolism-related biomolecular changes in the serum of patients suffering from MDD and undergoing ESC treatment. Multiple amino acid metabolism pathways were adjusted in MDD patients, and levels of aspartate, arginine and sphingolipids were regulated after ESC monotherapy. These biomolecular changes may bring new insights into the biology and treatment of MDD from the perspective of the serum metabolites.

Genetic diagnosis of peripheral blood interleukin-1 in premature infants based on bioinformatics and optical imaging

Preterm labor is a severe health concern among expectant mothers, affecting approximately 5 % to 7 % of all pregnancies worldwide, and is associated with various factors, including genes, peripheral blood, and immunological functions. In our study, we examined the role of familial genetics in preterm labor to address knowledge gaps and provide more evidence on the concept. We searched the GEO database for applicable genes and found that the GSE26315 and GSE73685 series were relevant. We then performed an analysis using the GEO2R, GEPIA2, STRING, and KEGG enrichment pathways. Our findings are consistent with the literature regarding the association between preterm birth and familial genetics, peripheral blood, and interleukin-1. Interleukin-1 exploits immunological functions by inducing uterine inflammation, creating an unfavorable environment for fetal survival. Similarly, peripheral blood induces premature labor, with higher levels in the amniotic fluid indicating a higher rate of preterm birth. Inheritance of the familial genes responsible for preterm birth passes down the trait.