This study integrates metabolites from Forsythia suspensa (FS) and gut microbiota GM to assess combined therapeutic efficacy against drug-induced liver injury (DILI) using network pharmacology and molecular docking. Metabolites of FS and GM were retrieved from the NPASS and gutMGene databases, respectively. Relevant targets for metabolites and DILI-related targets were identified through public databases. The PPI network and KEGG pathway analysis were employed to identify hub targets and key signalling pathways. Furthermore, we performed a molecular docking assay on the active metabolites and targets to verify the network pharmacological concept. The physicochemical properties and toxicity of identified key metabolites were assessed using in silico platforms. 19 final targets were recognized as key proteins responsible for the alleviation of DILI by FS and GM metabolites, with ESR1 emerging as a central target in the PPI network. The estrogen signalling pathway, particularly involving ESR1, ESR2 and JUN genes, was identified as a key mediator in the therapeutic effects. Four GM metabolites (baicalein, luteolin, lunularin and 2,3-bis(3,4-dihydroxybenzyl)butyrolactone) and two FS metabolites (pinoresinol and isolariciresinol) were identified as non-toxic, promising candidates. In conclusion, metabolites from FS and GM may exert a potent synergistic effect on DILI through modulation of the estrogen signalling pathway.

Naringenin is a natural flavanone with potent pharmacological properties. It has demonstrated therapeutic potential in treating various diseases and organ injuries, including radiation-induced lung injury (RILI). Ferroptosis is a newly type of cell death, and naringenin has been shown to attenuates ferroptosis.

To evaluate the inhibitory effect and molecular mechanism of naringenin on ferroptosis during RILI process.

Firstly, BEAS-2B and HUVECs cells were pre-incubated with naringenin for 1 h prior to 8 Gy of X-ray irradiation to evaluate oxidative stress, inflammation, and the mRNA levels of ferroptosis-related genes. Next, target genes of naringenin, RILI, and ferroptosis were identified using the TCMSP, SwissTargetPrediction, and GeneCards databases. The target network was constructed with Cytoscape and STRING. Finally, the core target genes were identified through in vitro experiments by qRT-PCR, western blot and immunofluorescence staining.

Naringenin effectively reduced radiation-induced increasement of oxidative stress, inflammation, and ferroptosis markers in both cell lines. Network pharmacology identified 14 target genes, with prostaglandin endoperoxide synthase (PTGS2) and Valosin-containing protein (VCP) mRNA levels being prominent, which were crucial for ferroptosis regulation. Molecular docking revealed strong binding interactions between naringenin and the two target proteins. Subsequently, experimental validation confirmed that naringenin reduced the elevated levels of PTGS2 and VCP induced by radiation.

Naringenin alleviates radiation-induced lung damage by inhibiting ferroptosis, with PTGS2 and VCP emerging as potential therapeutic targets.

Egg weight is a primary economic trait in poultry breeding. Putian Black duck, an excellent local laying duck breed in Fujian Province, includes two different strains, black feather strain and white feather strain. The white feather strain of Putian Black duck is also known as Putian White duck. Except for the different feather colors, these two strains differ in egg weight. In this study, whole-genome resequencing was conducted on Putian Black duck and Putian White duck to explore the differences in the genetic mechanism of egg weight. LRP8, VLDLR, and LPL were identified as key candidate genes affecting egg weight. Mass spectrometry was used to detect the SNPs of LRP8, VLDLR, and LPL. Result indicates that the SNPs of LRP8, VLDLR, and LPL in both populations exhibited moderate polymorphism, and Putian Black duck possessed higher genetic variation and potential selectivity. Association analysis indicated that in Putian Black duck, four SNPs in the LRP8 gene were significantly associated with egg weight. These loci can be used as molecular markers for improving egg weight in Putian Black duck.

The placenta is vital for fetal growth, and its methylation patterns reflect placental function, affecting the fetus and providing insights into disease origins. While cord blood methylation is convenient for assessing the fetal environment, methylation profiles vary by tissue due to variance in cell populations, function, and life stage. As tissue differences extensively contribute to the DNA methylation patterns, using surrogate samples such as cord blood may result in inconsistent findings. In this study, we aim to quantify the correlation of cytosine-phosphate-guanine dinucleotides (CpGs) between paired cord blood and placenta samples. Using the Infinium Human Methylation 450 K BeadChip, we compared methylation patterns in cord blood mononuclear cells (CBMC; n = 54), the maternally-facing side of placental tissue (MP; n = 68), and the fetal-facing side of placental tissue (FP; n = 67). Methylation patterns from the FP (6,021 CpGs) were significantly correlated with CBMC compared to the MP (2,862 CpGs). These CpGs were related to the biological (mitotic cell) process and molecular function (ribonucleoprotein complex binding). Our findings quantified CpG site correlation between cord blood and placenta, providing a valuable reference for future studies on placental health that rely on cord blood methylation in the absence of placental biospecimens.

To explore the effect and the probable mechanisms of JLD in the treatment of type 2 diabetes mellitus (T2DM) - associated cognitive impairment (TDACI).

The effect of JLD in combating TDACI was assessed in T2DM model mice by conducting Morris water maze (MWM) behaviour testing. Active components and their putative targets, as well as TDACI-related targets, were collected from public databases. Protein-protein interactions (PPIs), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and molecular docking were then utilized to explore potential molecular network mechanisms. Finally, the main targets were verified in animal model experiments.

MWM test showed that JLD improved aspects of behaviour in T2DM model mice. JLD improved glucose intolerance, tissue insulin sensitivity, lipid metabolism and enhanced synapse-associated protein expression in hippocampus tissue. Network pharmacology revealed 185 active components, 337 targets of JLD, and 7998 TDACI related targets were obtained . PPI network analyses revealed 39 core targets. GO and KEGG analyses suggested that JLD might improve TDACI by regulating gene expression, apoptotic processes and inflammatory responses mainly via PI3K-AKT and AGE-RAGE signaling pathways. Molecular docking revealed strong binding of the main components to core targets. JLD reduced hippocampus tissue expression of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL6), core targets of treatment of TDACI.

The findings suggested that JLD has the potential to improve TDACI through multiple components, multiple targets and multiple pathways. JLD may be a promising treatment for diabetic cognitive impairment.

Endoplasmic reticulum stress (ERS) has been implicated in the pathogenesis of various cancers, including colon cancer, by regulating tumor cell survival, growth, and immune response. However, the specific genes involved in ERS that could serve as prognostic markers in colon cancer remain underexplored. This study aims to identify and validate endoplasmic reticulum stress related genes (ERSRGs) in colon cancer that correlate with patient prognosis, thereby enhancing the understanding of ERS in oncological outcomes and potential therapeutic targeting. We utilized bioinformatics analyses to identify ERSRGs from publicly available colon cancer datasets. Differential expression analysis and survival analysis were performed to assess the prognostic significance of these genes. Validation was conducted through quantitative real-time PCR (RT-qPCR) on selected colon cancer cell lines. Our study identified nine ERS related genes (ASNS, ATF4, ATF6B, BOK, CLU, DDIT3, MANF, SLC39A14, TRAF2) involved in critical pathways including IL-12, PI3K-AKT, IL-7, and IL-23 signaling, and linked to 1-, 3-, and 5-year survival of patients with colon cancer. A multivariate Cox model based on these ERS related genes demonstrated significant prognostic power. Further, TRAF2 strong correlated with immune cells infiltration, suggesting its potential roles in modulating immune responses in the tumor microenvironment. The RT-qPCR validation confirmed the differential expression of these genes in human colon cancer cell lines versus human normal colonic epithelial cell line. The identified ERSRGs could serve as valuable prognostic markers and may offer new insights into the therapeutic targeting of ERS in colon cancer.

Selectively and sensitively detecting specific exosomal markers is critical for early diagnosis of liver cancer. However, identifying specific exosomal biomarkers and establishing accurate, convenient detection methods remain challenging. In this study, we used bioinformatics to identify the higher levels of EpCAM and GPC-3 proteins on liver cancer exosomes. These markers were used to create a dual-antibody functionalized transistor biosensor for precise detection of liver cancer exosomes. The techniques exhibited outstanding specificity and sensitivity. Detection thresholds in PBS and simulated plasma were established at 20 particles/μL and 47 particles/μL, respectively, facilitating the distinction of liver cancer cell-derived exosomes from those originating from various other cancer cells. Furthermore, in clinical samples testing, this approach not only distinguished clinical samples among liver cancer patients and healthy individuals, but also demonstrated the ability to differentiate liver cancer from other types of tumors, achieving a precision and accuracy rate of 100 %. The developed biosensor demonstrates excellent potential for clinical application and this work offers a promising and effective approach for cancer diagnosis.

Liver disease, responsible for around two million deaths annually, remains a pressing global health challenge. Microbial interactions within the microbiota-gut-liver axis play a substantial role in the pathogenesis of various liver conditions, including early chronic liver disease (eCLD), chronic liver disease (CLD), acute liver failure (ALF), acute-on-chronic liver failure (ACLF), non-alcoholic fatty liver disease (NAFLD), steatohepatitis, and cirrhosis. This study aimed to identify key molecular signatures involved in liver disease progression by analyzing transcriptomic and gut microbiome data, and to evaluate their diagnostic utility using machine learning models.

Transcriptomic analysis identified differentially expressed genes (DEGs) that, when integrated with regulatory elements microRNAs, transcription factors, receptors, and the gut microbiome highlight disease-specific molecular interactions. To assess the diagnostic potential of these molecular signatures, a two-step analysis involving principal component analysis (PCA) and Random Forest classification was conducted, achieving accuracies of 75% for ALF and 89% for NAFLD. Additionally, machine learning algorithms, including K-neighbors, multi-layer perceptron (MLP), decision tree, Random Forest, logistic regression, gradient boosting, CatBoost, Extreme Gradient Boosting (XGB), and Light Gradient Boosting Machine (LGBM), were applied to gene expression data for ALF and NAFLD.

Key genes including CLDN14, EGFR, GSK3B, MYC, and TJP2, alongside regulatory miRNAs let-7a-5p, miR-124-3p, and miR-195-5p and transcription factors NFKB1 and SP1 may be suggested as critical to liver disease progression. Additionally, gut microbiota members, Dictyostelium discoideum and Eikenella might be novel candidates associated with liver disease, highlighting the importance of the gut-liver axis. The Random Forest model reached 75% accuracy and 83% area under the curve for ALF, while NAFLD classification achieved 100% accuracy, precision, recall, and area under the curve underscoring robust diagnostic potential.

This study establishes a solid foundation for further research and therapeutic advancement by identifying key biomolecules and pathways critical to liver disease. Additional experimental validation is needed to confirm clinical applicability.

Inflammasomes regulate the host response to intracellular pathogens including mycobacteria. We have previously shown that the course of Mycobacterium marinum infection in adult zebrafish (Danio rerio) mimics the course of tuberculosis in human. To investigate the role of the inflammasome adaptor pycard in zebrafish M. marinum infection, we produced two zebrafish knockout mutant lines for the pycard gene with CRISPR/Cas9 mutagenesis. Although the zebrafish larvae lacking pycard developed normally and had unaltered resistance against M. marinum, the loss of pycard led to impaired survival and increased bacterial burden in the adult zebrafish. Based on histology, immune cell aggregates, granulomas, were larger in pycard-deficient fish than in wild-type controls. Transcriptome analysis with RNA sequencing of a zebrafish haematopoietic tissue, kidney, suggested a role for pycard in neutrophil-mediated defence, haematopoiesis and myelopoiesis during infection. Transcriptome analysis of fluorescently labelled, pycard-deficient kidney neutrophils identified genes that are associated with compromised resistance, supporting the importance of pycard for neutrophil-mediated immunity against M. marinum. Our results indicate that pycard is essential for resistance against mycobacteria in adult zebrafish.

β-Bisabolene, a bioactive sesquiterpene extracted from myrrh-a substance utilized for ischemic stroke treatment-has known therapeutic potential. Nevertheless, the exact mechanisms underlying its beneficial effects on ischemic stroke, along with its potential targets, remain to be fully elucidated. This study aimed to investigate the therapeutic potential of β-Bisabolene in ameliorating ischemic stroke, identify its potential targets and interactions, and explore the underlying pathways involved. Bioinformatics analyses, including network pharmacology and analysis of GEO transcriptomic datasets, were performed to predict the potential targets and mechanisms of β-Bisabolene in ischemic stroke treatment. Preliminary computational validation was achieved through molecular similarity comparisons, molecular docking studies, and molecular dynamics simulations. In vitro experiments were then conducted to confirm the protective effects of β-Bisabolene on microglia injured by oxygen‒glucose deprivation and to validate the findings from the bioinformatics analyses. The results revealed that β-Bisabolene reduces the levels of the proinflammatory cytokines TNF-α, IL-1β and NO; decreases reactive oxygen species levels; and decreases the expression of COX-2, P38, ERK and Keap1. Moreover, it increases the expression of Arg-1, Nrf2, NQO1 and HO-1. These effects are associated with improved survival rates of oxygen-glucose deprivation-damaged microglia. In conclusion, β-Bisabolene may exert anti-inflammatory and antioxidant effects to ameliorate microglial injury induced by ischemic stroke by antagonizing COX-2 and mediating the MAPK signaling pathway and Keap1/Nrf2 pathway. This study provides valuable insights into the therapeutic potential of β-Bisabolene for the treatment of ischemic stroke.

Nephrolithiasis (kidney stones) affects nearly 13 % of the global population, with a high recurrence rate posing significant challenges. Current remedies often fail to prevent recurrence, necessitating new therapeutic approaches. This study explores phytochemicals with potential protective effects against nephrolithiasis using similarity searching, network pharmacology, and molecular docking methods. Six anti-nephrolithiatic parent molecules were identified through a literature review. Structural similarity searches yielded 67 related compounds, which were screened using Lipinski' s rule of five, along with ADME (absorption, distribution, metabolism, excretion) parameters and toxicity profiles, and subsequently compared with standard drugs. The standard drug offered poor results; therefore, we aimed to overcome this limitation by searching for phytochemicals with favorable ADMET properties. Shortlisted compounds and nephrolithiasis-related targets were analyzed using Swiss Target Prediction and GeneCards. Hub genes were identified via Cytoscape' s Cytohubba plugin and subjected to Gene Ontology (GO) and KEGG pathway analysis. Molecular docking evaluated the binding of phytochemical ligands to disease proteins. Five phytochemicals namely 4- 4-Vinylguaiacol, anethole, isoeugenol, nadolol, and silibinin, were identified as potential candidates. Network pharmacology revealed 191 common targets between these compounds and nephrolithiasis. GO analysis highlighted key biological processes (response to organic substances, chemical stimuli), cellular components (nuclear lumen, nucleoplasm), and molecular functions (enzyme binding, catalytic activity). KEGG pathway analysis identified pathways in cancer, hepatitis B, and Kaposi sarcoma-associated herpesvirus infection as relevant to nephrolithiasis. Molecular docking demonstrated strong binding affinities between the shortlisted phytochemicals and disease targets. The multi-level screening and molecular docking findings highlight 4-Vinylguaiacol, anethole, isoeugenol, nadolol, and silibinin as promising therapeutic agents for nephrolithiasis. Among these, silibinin was tested for the in-vitro cytotoxicity assay based on the docking score. Importantly, in vitro validation using NRK-52E cells confirmed nephroprotective efficacy of silibinin. While calcium oxalate crystal exposure significantly reduced cell viability to below 50 %, co-treatment with silibinin improved cell survival to approximately 70 %, underscoring its potential to mitigate oxalate-induced cytotoxicity. Further experimental studies are required to validate these findings.

Stroke is the leading cause of death globally, with stroke-associated pneumonia being a major contributor to its high mortality. Among these complications, cerebral ischemia-reperfusion injury-induced acute lung injury (CIR-ALI) is characterized by high morbidity and mortality rate, which causes a great economic burden to the society. The course of CIR-ALI is complex, in which the inflammatory cascade response plays a central role in the pathogenesis of CIR-ALI. Baicalin (BA), a flavonoid extracted from the natural plant Scutellaria baicalensis, exhibits diverse pharmacological effects, including anti-inflammatory and antioxidant properties. In this study, we investigated the therapeutic effects of baicalin and its delivery system baicalin liposome (BA-LP) on CIR-ALI injury. Using in vitro models of BV2 and Raw264.7 cells, as well as an in vivo model established via the wire bolus method, we measured inflammatory factors and pathological injuries in brain and lung tissues to evaluate the intervention effects of BA and BA-LP. In addition, the preliminary analysis of network pharmacology combined with experimental validation in this study preliminarily elucidated that BA and BA-LP may attenuate CIR-ALI by modulating the PI3K/AKT/mTOR pathway.

Bacterial resistance has emerged as a major clinical challenge globally. Natural products, such as Aloe vera, offer promising antimicrobial potential due to their diverse active components. However, the explicit molecular mechanisms remain unknown. In this study, we employed a multidisciplinary approach integrating network pharmacology, molecular docking, and molecular dynamics simulation to explore the antibacterial mechanism of Aloe vera. We screened the eight major active components of Aloe vera and their targets using multi-source bioinformatics platforms, identifying 55 targets closely associated with the antibacterial effects of Aloe vera. Protein-protein interaction network analysis, revealed potential crucial targets, including cysteine-aspartic acid protease-3 (CASP3) and matrix metalloproteinase-9 (MMP-9). Gene ontology functional enrichment analysis revealed that these targets play critical roles in several essential biological processes, such as "response to xenobiotic stimulus", "positive regulation of gene expression", and "collagen catabolism". The Kyoto Encyclopedia of Genes and Genomes signal pathway analysis indicated that these targets are primarily involved in pathways associated with cancer, lipid metabolism, atherosclerosis, and the AGE/RAGE signaling pathway in diabetes. This finding suggests that Aloe vera may exert its antibacterial effects by regulating the host's immune response and metabolism. Molecular docking and molecular dynamics simulations demonstrated that active ingredients of Aloe vera, such as quercetin and aloe-emodin, can form stable complexes with CASP3 and MMP-9, exhibiting vigorous binding affinity to the active sites of the target. Further antibacterial activity assays and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis demonstrated that aloe-emodin exerts antibacterial effects against gram-positive bacteria and inhibits the expression of the MMP-9 gene. This study provided insight into the antibacterial mechanisms of Aloe vera, highlighting MMP-9 as a key target. These findings lay a foundation for further studies on natural antibacterial agents.

Ring finger protein 125 (RNF125), a ubiquitin E3 ligase, has been reported to act as a tumor suppressor in several cancers, but its precise function in lung adenocarcinoma (LUAD) has not been elucidated. In the present study, through bioinformatics analysis and immunohistochemistry in LUAD and non‑cancerous samples, it was demonstrated that RNF125 was significantly downregulated in lung cancer. Low levels of RNF125 expression were associated with metastatic status, advanced tumor stage and poor overall survival in LUAD. The results of gain‑ and loss‑of‑function experiments demonstrated that RNF125 inhibited proliferation, colony formation, migration and invasion of LUAD cells. In addition, RNF125 increased the sensitivity of LUAD cells to cisplatin. Mechanistically, RNF125 interacted with programmed cell death ligand 1 (PD‑L1) and reduced PD‑L1 expression levels in LUAD cells. Furthermore, IL‑2 secretion by Jurkat T cells was significantly suppressed when co‑cultured with RNF125‑silenced LUAD cells. NK‑92 cell lysis of RNF125‑silenced LUAD cells was also weaker compared with that of control LUAD cells, suggesting that RNF125 knockdown enhanced the immune evasion ability of LUAD cells. Notably, the results of the present study identified that the RNA‑binding protein muscleblind‑like 1 (MBNL1) is the upstream regulator of RNF125 in LUAD. MBNL1 increased the stability of the RNF125 transcript in LUAD cells and knockdown of RNF125 reversed the antitumor effect of MBNL1 on LUAD cells. In conclusion, the present study demonstrated the tumor suppressor role of RNF125 in LUAD and implicated MBNL1 as an upstream regulator of RNF125 in LUAD. These findings contributed to an improved understanding of the molecular features of LUAD progression.

Macrophages are essential for the proliferation and spread of Toxoplasma gondii. Modulating macrophage activation to improve the inflammatory environment is an effective approach for disease treatment. However, the molecular mechanism through which T. gondii alters macrophage function remain unknown. Based on transcriptomic data analysis of various macrophage types infected with T. gondii, current research revealed differences in the regulation of macrophage functions among strains with different virulence: RH was primarily involved in cell cycle regulation, ME49 was associated with cAMP signaling, and CEP mainly participated in ion channel activity. All three T. gondii strains were involved in regulating immune response activation, including leukocyte adhesion and the MAPK signaling pathway. Nineteen shared DEGs associated with macrophage phagocytosis or polarization were identified through the GeneCards database, and PPI analysis confirmed Il6 as the hub gene in the regulatory network. In vivo and in vitro experiments showed that the YZ-1 strain significantly regulated the expressions of eight DEGs (Il6, Rel, Cd83, Myc, Adora2b, Egr2, Gja1 and Nr4a2), and promoted macrophage phagocytic activity and induced M1 polarization, confirming a significant correlation with Il6. This study revealed the dissimilarities and commonalities in macrophage function regulated by T. gondii strains of different virulence, and identified key molecules involved in the regulation of macrophage phagocytosis and polarization during T. gondii infection. This is crucial for identifying potential drug targets against T. gondii and provides a new perspective on the etiopathogenesis and therapeutic approaches for toxoplasmosis.

Polycystic ovary syndrome (PCOS) is strongly associated with major depressive disorder (MDD), but the shared pathophysiological mechanisms between them are ambiguous, and the aim of this study was to explore the shared genetic features and associated pathways between these two disorders. MDD-related genes and mitochondrial function genes were downloaded from the GeneCards database. Weighted gene co-expression network analysis of Merge Cohort (GSE80432 and GSE34526) was performed to identify PCOS-related genes. Overlaps between PCOS-related genes, MDD-related genes, and mitochondrial function genes were defined as mitochondrial function-related shared genes. Functional enrichment analysis and protein-protein interaction (PPI) network analysis were performed on the shared genes. Functional genes were then identified using Last Absolute Shrinkage and Selection Operator Regression (LASSO), and a support vector machine (SVM-RFE) was constructed to measure the accuracy of the calculations. Finally, the results were tested using the whole blood datasets GSE54250 (for PCOS) and GSE98793 (for MDD) as external validation sets. A total of 498 PCOS-related genes, 5909 MDD-related genes, and 7232 mitochondrial function genes were acquired, and totally, 40 shared genes were obtained from the overlap of the above three. The shared mitochondrial function genes were enriched for biological processes mainly involving cholesterol biosynthetic process, lipid metabolic process, triglyceride biosynthetic process, response to drug phosphatidic acid biosynthetic process, and endoplasmic reticulum membrane. Based on LASSO regression and SVM-RFE model, NPAS2 and NTS were identified as characteristic genes shared by two disorders. According to two external validation sets for PCOS and MDD, NPAS2 was finally identified as a key shared gene. Our analysis identified a mitochondrial functional gene-NPAS2-as the most critical candidate for linking PCOS and MDD. The present findings may provide new insights into the diagnosis and treatment of PCOS and MDD comorbidities.

Obesity represents a significant risk factor in the development of type 2 diabetes (T2D), a chronic metabolic disorder characterized by elevated blood glucose levels, and a previous step for its development. Significant sex differences have been identified in the prevalence, development, and pathophysiology of obesity and T2D; however, the underlying molecular mechanisms remain unclear. This study aims to identify sex-specific signatures in obesity and T2D and enhance our understanding of the underlying mechanisms associated with sex differences by integrating expression data. We performed a systematic review and individual transcriptomic analysis of eight selected studies which included 302 subcutaneous adipose tissue samples. Then, we conducted different gene-level meta-analyses and functional characterizations for obesity and T2D separately, identifying common and sex-specific transcriptional profiles, many of which were previously associated with obesity or T2D. The obesity meta-analysis yielded nineteen differentially-expressed genes from a sex-specific perspective (e.g., SPATA18, KREMEN1, NPY4R, and PRM3), while a comparison of the expression profiles between sexes in T2D prompted the identification and validation of specific transcriptomic signatures in males (SAMD9, NBPF3, LDHD, and EHD3) and females (RETN, HEY1, PLPP2, and PM20D2). At the functional level, we highlighted the fundamental role of the Wnt pathway in the development of obesity and T2D in females, and the roles of mitochondrial damage and free fatty acids in males. Overall, our sex-specific meta-analyses supported the detection of differentially expressed genes in males and females associated with the development of obesity and further T2D development, emphasizing the relevance of sex-based information in biomedical data and opening new avenues for research.

Celastrol (CEL) has demonstrated promising anti-cancer properties, yet its specific mechanisms against melanoma remain insufficient. This study investigated the CEL's anti-tumor effects and determined its potential mechanisms in the regulation of MHC-I expression in melanoma. In addition, we also tested its efficacy in sensitizing immune checkpoint inhibitors (ICIs) to melanoma.

CEL's anti-tumor activity was evaluated in B16F10 melanoma-bearing C57BL/6 mice across five groups (control, CEL 0.5 mg/kg, CEL 1 mg/kg, CEL 2 mg/kg, and ICIs), the tumor volume, histopathology, and body weight were assessed. Mechanistic insights were obtained through network pharmacology and RNA sequencing in B16F10 cells. Differential gene and pathway analysis were validated using qRT-PCR, Western blotting, and flow cytometry. CD8+T cell activation and cytotoxicity were analyzed in co-culture with CEL-pretreated B16F10 cells using flow cytometry and ELISA. CEL's interaction with potential targets was determined by molecular docking, surface plasmon resonance (SPR), and siRNA. The synergistic effect of CEL combined with ICIs was confirmed in B16F10-bearing C57BL/6 mice, and tumor-infiltrating T cells were assessed by flow cytometry across four groups (control, CEL, ICIs, CEL+ICIs).

CEL exhibited a significant anti-tumor effect in B16F10 melanoma-bearing mice. Mechanistically, CEL-pretreated B16F10 cells notably enhanced CD8+T cell activation and promoted IFNγ and TNFα secretion, leading to B16F10 cell death. CEL upregulated MHC-I expression through activation of the JAK/STAT1 pathway in B16F10 cells. The binding assay revealed that CEL interacted with SHP2, with an affinity of 37.93 μM. When SHP2 was silenced in B16F10 cells by siRNA, CEL failed to induce MHC-I upregulation. Moreover, CEL combined with ICIs produced superior antitumor efficacy compared to ICIs alone, which was accompanied by increased CD8+T cell infiltration in melanoma.

CEL enhanced CD8+T cell immunity by upregulating MHC-I expression in melanoma cells, these effects were at least partially through targeting SHP2 and activating JAK/STAT1 pathway. CEL might be a novel sensitizer for ICIs in melanoma.

The incidence of heart failure with preserved ejection fraction (HFpEF) increases with the ageing of populations. This study aimed to explore ageing-associated gene signatures in HFpEF to develop new diagnostic biomarkers and provide new insights into the underlying mechanisms of HFpEF. Mice were subjected to a high-fat diet combined with L-NG-nitroarginine methyl ester (l-NAME) to induce HFpEF, and next-generation sequencing was performed with HFpEF hearts. Additionally, separate datasets were acquired from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were used to identify ageing-related DEGs. Support vector machine, random forest, and least absolute shrinkage and selection operator algorithms were employed to identify potential diagnostic genes from ageing-related DEGs. The diagnostic value was assessed using a nomogram and receiver operating characteristic curve. The gene and related protein expression were verified by reverse transcription PCR and western blotting. The immune cell infiltration in hearts was analysed using the single-sample gene-set enrichment analysis algorithm. The results showed that the merged HFpEF datasets comprised 103 genes, of which 15 ageing-related DEGs were further screened in. The ageing-related DEGs were primarily associated with immune and metabolism regulation. AGTR1a, NR3C1, and PRKAB1 were selected for nomogram construction and machine learning-based diagnostic value, displaying strong diagnostic potential. Additionally, ageing scores were established based on nine key DEGs, revealing noteworthy differences in immune cell infiltration across HFpEF subtypes. In summary, those results highlight the significance of immune dysfunction in HFpEF. Furthermore, ageing-related DEGs might serve as promising prognostic and predictive biomarkers for HFpEF.

Percutaneous neoadjuvant therapy has proven effective in diminishing tumor size and the surgical intervention area, which couldeffectively mitigate the risk of tumor recurrence and enhance immunotherapy efficacy. Lenalidomide, an approved medication orally used to treat myeloma, was loaded into nanosuspensions-based hydrogels (Len-NBHs) for transdermal administration as a percutaneous neoadjuvant therapy. This study was designed to investigate the inhibitory effect and mechanism of Len-NBHs on melanoma. Network pharmacology and transcriptomic analyses identified key targets and signaling pathways. The effects of lenalidomide on melanoma were further verified through Western blotting, immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction，using both in vitro cell experiments and in vivo melanoma mouse models. Lenalidomide could induce melanoma cells apoptosis, disrupt cell cycle progression, impede cell migration and invasion, and modify tumor microenvironment (TME). Mechanistically, lenalidomide reversed the abnormal activation of the PI3K-AKT signaling pathway and the overexpression of CD93, while also recruiting CD8+ T cells, CD4+ T cells, and dendritic cells to infiltrate the tumor site. Transdermal administration of Len-NBHs represents a promising adjuvant therapy for the treatment of malignant melanoma. Preoperative administration of Len-NBHs can inhibit the outward spread of melanoma, reduce tumor size, thereby decreasing the surgical excision area and improving patient survival rates and prognosis.

The lack of effective drugs for treating ischemia-reperfusion injury (IRI) in lung transplants (LTx) remains an issue. Traditional Chinese medicine (TCM) ingredients are promising but poorly studied in LTx. This study aimed to identify potential ingredients and elucidate their mechanisms.

Ten TCM ingredients, including (-)-epigallocatechin-3-gallate, quercetin, wogonin, triptolide, berberine, fisetin, coumestrol, luteolin, nobiletin, and baicalein, were identified as promising candidates using a network pharmacology approach. All the candidates were tested for their ability to improve clamp-induced IRI. Multiple-dose validation was conducted in LTx models, with a focus on baicalein. The pharmacological efficacy of baicalin was verified in an ex-vivo rat lung perfusion model.

All ten TCM ingredients improved clamp-induced IRI. Multiple-dose validation confirmed that baicalein mitigated IRI-induced graft damage and dysfunction. Baicalein reduced the elevated levels of advanced glycation endproducts (AGEs) and their downstream pathogenic effects induced by IRI. Exogenous AGEs counteracted the therapeutic effect of baicalein. Baicalein inhibited AGE formation by modulating glucose oxidation rather than polyol metabolism.

This study provides a laboratory foundation for the use of TCM ingredients in the treatment of IRI in LTx.

Pre-eclampsia (PE) is a severe vascular disorder during pregnancy, significantly affecting maternal and fetal health worldwide. However, the exact molecular mechanism of its pathophysiology remains unclear, highlighting the need for reliable early diagnostic methods. Our primary aim of this study was to identify key genes (KGs) that may affect the outcome of patients with PE via integrated bioinformatics analysis. We analysed a gene expression dataset from the national center for biotechnology information (NCBI) sequence read archive (SRA) database and performed standard preprocessing steps, including quality assessment, trimming, genome alignment, and feature counts. Following this, normalization and differentially expressed genes (DEGs) were performed using Deseq2, which identified 781 DEGs were identified comprising 457 upregulated and 324 downregulated genes. Identified DEGs were significantly enriched in the cytokine interaction pathway and cellular calcium ion homeostasis. PPI network analysis revealed eight KGs (CXCL8, GAPDH, MMP9, SPP1, PTGS2, LEP, FGF7, and FGF10). These KGs were further found to be regulated by ten transcription factors (TFs), among which NF-kB1 and RELA consistently interact with all the KGs, and four microRNAs (miRNAs) such as hsa-mir-335-5p, has-mir-16a-5p, has-let-7b-5p, and has-mir-204-5p. The least absolute shrinkage and selection operator (LASSO) regression with 10-fold cross-validation (CV) confirmed all eight KGs may act as potential biomarkers based on their coefficients. Among these, GAPDH, SPP1, FGF7, and FGF10 emerged as novel biomarkers. Additionally, receiver operating characteristic (ROC) curve analysis for these novel biomarkers showed an area under the curve (AUC) of 0.869, demonstrating strong discriminatory power between the healthy and EOPE groups. The drug-gene interaction was performed by DrugMap database revealed an important interaction of GAPDH and FGF7 with FDA-approved drugs, indicating their therapeutic significance in PE. This analysis also facilitates drug repurposing for PE treatment.

Epidermal growth factor-like proteins (EGFLs) contain more than a single EGF/EGF-like domain within their protein structure. To date, ten EGFL family members (EGFL1-10) have been characterized across diverse tissues and developmental stages under different conditions. In this review, we conclude that EGFLs are instrumental in regulating biological activities and pathological processes. Under physiological conditions, EGFLs participate in angiogenesis, neurogenesis, osteogenesis, and other processes. Under pathological conditions, EGFLs are linked with different diseases, particularly cancers. Furthermore, we highlight recent advancements in the study of EGFLs in biological conditions and cancers. In addition, the regulatory role and key underlying mechanism of EGFLs in mediating tumorigenesis are discussed. This paper also examines potential antagonists that target EGFL family members in cancer therapeutics. In summary, this comprehensive review elucidates the critical role of EGFLs in neoplastic diseases and highlights their potential as therapeutic targets.

Vasospasm is a potentially preventable cause of poor prognosis in patients with aneurysmal subarachnoid hemorrhage (aSAH). Epigenetics might provide insight on its molecular mechanisms. We aimed to analyze the association between differential DNA methylation (DNAm) and development of vasospasm. We conducted an epigenome-wide association study in 282 patients with aSAH admitted to our hospital. DNAm was assessed with the EPIC Illumina chip (> 850 K CpG sites) in whole-blood samples collected at hospital admission. We identified differentially methylated positions (DMPs) at the CpG level using Cox regression models adjusted for potential confounders, and then we used the DMP results to find differentially methylated regions (DMRs) and enriched biological pathways. A total of 145 patients (51%) experienced vasospasm. In the DMP analysis, we identified 31 CpGs associated with vasospasm at p-value < 10-5. One of them (cg26189827) was significant at the genome-wide level (p-value < 10-8), being hypermethylated in patients with vasospasm and annotated to SUGCT gene, mainly expressed in arteries. Region analysis revealed 13 DMRs, some of them annotated to interesting genes such as POU5F1, HLA-DPA1, RUFY1, and CYP1A1. Functional enrichment analysis showed the involvement of biological processes related to immunity, inflammatory response, oxidative stress, endothelial nitric oxide, and apoptosis. Our findings show, for the first time, a distinctive epigenetic signature of vasospasm in aSAH, establishing novel links with essential biological pathways, including inflammation, immune responses, and oxidative stress. Although further validation is required, our results provide a foundation for future research into the complex pathophysiology of vasospasm.

Glutamate transporters are important for regulating extracellular glutamate levels, impacting neural function and metabolic homeostasis. This study explores the behavioral, lifespan, and proteomic profiles in Caenorhabditis elegans strains with either glt-4 or glt-5 null mutations, highlighting contrasting phenotypes. Δglt-4 mutants displayed impaired mechanosensory and chemotactic responses, reduced lifespans, and decreased expression levels of ribosomal proteins and chaperonins involved in protein synthesis and folding. In contrast, Δglt-5 mutants displayed heightened chemorepulsion, extended lifespans, and upregulation of mitochondrial pyruvate carriers and cytoskeletal proteins. Proteomic profiling via mass spectrometry identified 53 differentially expressed proteins in Δglt-4 mutants and 45 in Δglt-5 mutants. Δglt-4 mutants showed disruptions in ribonucleoprotein complex organization and translational processes, including downregulation of glycogen phosphorylase and V-type ATPase subunits, while Δglt-5 mutants revealed altered metabolic protein expression, such as increased levels of mitochondrial pyruvate carriers and decreased levels of fibrillarin and ribosomal proteins. Gene ontology enrichment analysis highlighted differential regulation of protein biosynthesis and metabolic pathways between the strains. Overall, these findings underscore the distinct, tissue-specific roles of GLT-4 and GLT-5 in C. elegans, with broader implications for glutamate regulation and systemic physiology. The results also reinforce the utility of C. elegans as a model for studying glutamate transporters' impact on behavior, longevity, and proteostasis.

Obstructive sleep apnea syndrome (OSAS) is a common sleep disorder, which is closely related to abnormal mitochondrial energy metabolism in recent years. By analyzing gene expression data of OSAS, we identified differentially expressed genes (DEGs) related to mitochondrial energy metabolism, and further explored the function of NDUFA10 in OSAS and its potential diagnostic value. In this paper, we download OSAS related expression data from a public database and preprocess the data set using a standardized process. Gene set enrichment analysis (GSEA) was used to assess pathways associated with mitochondrial metabolism, and diagnostic models were constructed to assess the expression of key genes. ROC curve analysis was performed for common mitochondrial energy metabolism-related differentially expressed genes (Co-MEMRDEGs) and gene interaction networks were constructed. After data standardization, significantly differentially expressed genes were identified, among which NDUFA10 was identified as one of the genes most associated with OSAS. The constructed diagnostic model showed good prediction accuracy, and ROC curve analysis further verified its clinical diagnostic potential.

As resistance to new anti-androgen drugs occurs more frequently, increasing numbers of researchers are exploring alternative key molecular targets for prostate cancer treatment. The small heat shock protein (sHSP) family is a subclass of heat shock proteins (HSPs). Due to the smaller molecular size of their monomers, they often function as large oligomeric complexes with diverse biological roles, thus garnering increasing attention from urologists. Different members of the sHSP family exhibit distinct biological roles in prostate cancer, offering a new perspective for precision therapy. In this review, we summarize the specific roles of sHSP family members in prostate cancer and analyze their similarities and differences. Additionally, we discuss and review the drugs targeting various sHSPs in prostate cancer, providing new insights into the exploration and further application of sHSP-targeted therapies.

Low back pain is a significant burden worldwide, and intervertebral disc degeneration (IVDD) is identified as the primary cause. Recent research has emphasized the significant role of circadian rhythms (CRs) and immunity in affecting intervertebral discs (IVD). However, the influence of circadian rhythms and immunity on the mechanism of IVDD remains unclear. This study aimed to identify and validate key rhythm-related genes in IVDD and analyze their correlation with immune cell infiltration.

Two gene expression profiles related to IVDD and rhythm-related genes were obtained from the Gene Expression Omnibus and GeneCards databases to identify differentially expressed rhythm-related genes (DERGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were conducted to explore the biological functions of these genes. LASSO regression and SVM algorithms were employed to identify hub genes. We subsequently investigated the correlation between hub rhythm-related genes and immune cell infiltration. Finally, nucleus pulposus-derived mesenchymal stem cells (NPMSCs) were isolated from normal and degenerative human IVD tissues. Hub rhythm-related genes expression in NPMSCs was confirmed by real-time quantitative PCR (RT-qPCR).

Six hub genes related to CRs (CCND1, FOXO1, FRMD8, NTRK2, PRRT1, and TFPI) were screened out. Immune infiltration analysis revealed that the IVDD group had significantly more M0 macrophages and significantly fewer follicular helper T cells than those of the control group. Specifically, M0 macrophages were significantly associated with FRMD8, PRRT1, and TFPI. T follicular helper cells were significantly associated with FRDM8, FOXO1, and CCND1. We further confirmed that CCND1, FRMD8, NTRK2, and TFPI were dysrhythmic within NPMSCs from degenerated IVD in vitro.

Six genes (CCND1, FOXO1, FRMD8, NTRK2, PRRT1 and TFPI) linked to circadian rhythms associated with IVDD progression, together with immunity. The identification of these DEGs may provide new insights for the diagnosis and treatment of IVDD.

The pachysandra alkaloids found in Sarcococca ruscifolia demonstrate notable anti-hepatocellular carcinoma activity. Despite their efficacy, the structural diversity of these compounds remains limited, and their precise antitumor mechanism is still unclear. In pursuit of identifying novel lead compounds with high efficacy and low toxicity for combating hepatocellular carcinoma, twenty-three compounds of C20-ketone pachysandra alkaloid derivatives were designed and synthesized by using 3-dimethylamine pachysandra alkaloids as scaffolds. Subsequent in vitro anticancer activity experiments showed that synthetic pachysandra alkaloids had a stronger effect on HepG2 cells than did their natural counterparts, with low toxicity and high selectivity. The most potent derivative, 6k, had an IC50 value of 0.75 μM, demonstrating 25.7-fold greater anticancer activity than sarcovagine D against HepG2 cells. Through network pharmacology and molecular docking analysis, it was revealed that synthetic pachysandra alkaloids may exert their effects by inhibiting the JAK2/STAT3 pathway, thereby preventing the proliferation of liver cancer cells. Further research through scratch tests, immunofluorescence experiments, and Western blot analysis revealed that compound 6k effectively inhibited the migration of HepG2 cells and induced mitochondria-mediated intrinsic apoptosis of HepG2 cells by regulating the JAK2/STAT3 signaling pathway. The aforementioned results indicate that compound 6k could be developed as a potential candidate for the treatment of hepatocellular carcinoma.

Ovarian cancer, often diagnosed at advanced stages, has a 5-year survival rate below 50%, indicating a critical need for innovative treatments. The Zengmian Yiliu (ZMYL) formula, a Traditional Chinese Medicine (TCM) prescription, has shown potential in enhancing chemotherapy efficacy and improving patients' quality of life, PURPOSE: To investigate the effects of the ZMYL formula on ovarian cancer organoids, focusing on its impact on organoid phenotypes and underlying mechanisms, and to explore its potential as an immunotherapeutic agent.

Ovarian cancer organoids were established from surgical tissues and treated with the ZMYL formula at varying concentrations. Network pharmacology was utilized to predict the formula's therapeutic targets and pathways, and molecular docking was conducted to validate ingredient-target interactions. Phenotypic changes were monitored, and RNA sequencing was performed post-treatment to analyze gene expression alterations.

A total of 34 overlapping targets of 10 compounds in the ZMYL formula and ovarian cancer were predicted by Network pharmacology analysis. The ZMYL formula induced dose-dependent morphological changes in organoids, including a reduction in size and structural sparsity at higher concentrations. RNA sequencing revealed significant modulation of cell cycle and immune response pathways, with a particular focus on immunomodulatory effects. The formula's treatment targeted key genes involved in these processes, reshaping the tumor's molecular landscape.

This study establishes ZMYL's capacity to simultaneously target oncogenic drivers (e.g., cell cycle regulators) and immune checkpoints (e.g., CXCL10-mediated T cell recruitment) in ovarian cancer organoids. Unlike conventional monotherapy-focused approaches, ZMYL's multi-component mechanism offers a synergistic framework for integrating TCM with modern immunotherapies. These findings provide a foundation for future clinical evaluation of ZMYL as a precision medicine strategy to enhance treatment efficacy and mitigate chemoresistance in ovarian cancer.

While interindividual variations in concentration and function of coagulation cascade proteins are established risk factors for venous thromboembolism (VTE), their associations with arterial ischemic stroke are less well defined.

We identified and validated genetic proxies for lifelong, randomized perturbations of coagulation cascade proteins in genome-wide association studies of circulating protein levels (deCODE, n=35 559; UK Biobank, n=46 218) and of VTE risk (81 190 cases and 1 419 671 controls). Study participants were all of European ancestry. We performed 2-sample Mendelian randomization and colocalization analyses to test associations of these genetic proxies with risk of ischemic stroke (62 100 cases and 1 234 808 controls from the GIGASTROKE consortium) and ischemic stroke subtypes, and further contextualized associations with VTE and secondary efficacy and safety outcomes.

We identified genetic proxies for 30 coagulation factors, with cross-trait associations recapitulating canonical coagulation biology. Mendelian randomization and colocalization analyses supported causal associations of genetically proxied levels of 5 proteins with risk of ischemic stroke, with all proteins associating with the cardioembolic stroke subtype: factor XI (odds ratio [OR] of cardioembolic stroke per 1-SD increase, 1.31 [95% CI, 1.19-1.44]; P=3.30×10-8), high-molecular-weight kininogen (OR, 1.19 [95% CI, 1.09-1.30]; P=7.79×10-5), prothrombin (OR, 1.83 [95% CI, 1.31-2.57]; P=4.20×10-4), soluble PROCR (protein C receptor; OR, 0.88 [95% CI, 0.82-0.95]; P=6.19×10-4), and γ' fibrinogen (OR per doubling in VTE risk due to lower γ' fibrinogen levels, 1.44 [95% CI, 1.25-1.66]; P=3.96×10-7). γ' Fibrinogen and prothrombin also associated with large artery atherosclerotic stroke, and no proteins were associated with small vessel stroke risk. By contrast, genetic proxies for several coagulation factors (including proteins C and S and factors V and VII) showed selective associations with VTE.

These data highlight specific coagulation cascade components implicated in ischemic stroke pathogenesis, while identifying proteins with distinct roles in VTE. These findings may inform development of novel anticoagulants and optimize their use in targeted populations with stroke.

Single-cell RNA sequencing measures individual cell transcriptomes in a sample. In the past decade, this technology has motivated the development of hundreds of clustering methods. These methods attempt to group cells into populations by leveraging the similarity of their transcriptomes. Because each method relies on specific hypotheses, their predictions can vary drastically. To address this issue, ensemble algorithms detect cell populations by integrating multiple clustering methods, and minimizing the differences of their predictions. While this approach is sensible, it has yet to address some conceptual challenges in single-cell data science; namely, ensemble algorithms have yet to generate clustering results with uncertainty values and multiple resolutions. In this work, we present an original approach to ensemble clustering that addresses these challenges, by describing the differences between clustering results, rather than minimizing them. We present the scEVE algorithm, and we evaluate it on 15 experimental datasets, and up to 1200 synthetic datasets. Our results reveal that scEVE outperforms the state of the art, and addresses both conceptual challenges. We also highlight how biological downstream analyses will benefit from addressing these challenges. We expect that this work will provide an alternative direction for developing single-cell ensemble clustering algorithms.

Globally, the incidence and prevalence rates of ulcerative colitis (UC) show a rising pattern. The limited efficacy and significant adverse effects associated with current treatment options underscore the need for novel therapeutic approaches. It has been found that linagliptin, a dipeptidyl peptidase-4 inhibitor, activates AMPK in different disease conditions. The main objective of the present work was to elucidate the potential implications of the AMPK/FOXO3a mediated by linagliptin in rats with chronic colitis. The findings of the current report revealed the first robust in-vivo evidence advocating the coloprotective effect of linagliptin against dextran sodium sulfate-induced chronic UC in rats. It has demonstrated potential beyond its antidiabetic effects by modulating FOXO3a localization. By shifting FOXO3a from the cytosol to the nucleus, linagliptin enhanced the transcription of genes involved in attenuation of pro-inflammatory events and restoration of redox homeostasis. Nuclear FOXO3a also impacted NFκB activity, reducing inflammation. This conclusion was fundamentally supported by the documented improvements in histopathological changes evidenced by reduced inflammation, edema, crypt atrophy, and submucosal fibrosis. Moreover, decreased colon weight/length ratio, as well as reduced scores of disease activity and macroscopic damage indices, were observed. Furthermore, it corrected body weight loss during the time frame of the experiment. These findings underscore the anti-inflammatory potential of therapies that promote the nuclear localization of FOXO3a in inflammatory conditions. Linagliptin's ability to modulate FOXO3a localization might be particularly useful for diabetic patients suffering from inflammatory bowel diseases. However, further molecular investigations are required to validate the findings and to assess the clinical application of this approach as a valid tool for alleviating UC.

Renal cell carcinoma (RCC) is the most common kidney cancer. Despite advances in treatment, current therapeutic strategies are often limited by side effects, drug resistance, and low response rates, necessitating alternatives for RCC treatment. Deoxyelephantopin (DEO), a sesquiterpene lactone from Elephantopi Herba, has demonstrated anticancer properties in multiple cancer models; however, its effects on RCC remain unknown. This study aimed to investigate the anti-RCC effects of DEO and its underlying molecular mechanisms. Human RCC cell lines (786-O, Caki-1, A498) and a murine RCC cell line (RENCA) were used for in vitro assays. Results revealed that DEO dose-dependently inhibited cell viability and colony formation in 786-O, Caki-1, A498, and RENCA cells, while also inducing apoptosis in 786-O and Caki-1 cells. A RENCA allograft mouse model was used for in vivo assays. DEO significantly suppressed tumor growth without causing notable changes in body weight, organ coefficients, or serum biochemical markers (ALT, AST, BUN, Cr). Network pharmacology analysis predicted the PI3K/AKT signaling pathway as a key mediator of DEO's anti-RCC effects. Western blotting showed that DEO downregulated the expression of EGFR, p-EGFR (Tyr1068), PI3K p110α, p-Akt (Ser473), mTOR, p-mTOR (Ser2448), p-p70S6K (Thr389), 4E-BP1, p-4E-BP1 (Thr37/46), HIF-1α, and Bcl-2. Overactivation of AKT attenuated DEO's inhibitory effects on cell viability in 786-O cells. In conclusion, this study is the first to demonstrate that DEO exerts anti-RCC effects in both cellular and animal models, primarily through inhibition of the PI3K/AKT pathway. These findings suggest that DEO holds promise as a lead compound for RCC management.

Estrogen's impact on Alzheimer's disease (AD) is multifaceted, with its receptors potentially influencing AD pathology in both beneficial and detrimental ways. This study aims to dissect the intricate cross-talk between estrogen receptor alpha (ERα) and microRNAs (miRNAs) in AD-affected human hippocampus. Through a comprehensive literature review in the PubMed database, coupled with a GeneCards database search, we obtained AD-related key miRNAs and genes in the hippocampus. Using bioinformatics tools, we predicted target genes and miRNAs of ERα, and the targets of the identified miRNAs. The integration of these elements resulted in the construction of an ERα-related FFL network, which includes 13 miRNAs and 56 core genes. Gene ontology (GO) and pathway enrichment analyses were conducted, revealing significant enrichment in biological processes such as neuron death and response to metal ions, and cellular components like membrane microdomains. Notably, the AKT-associated signaling pathway was prominently highlighted, with key genes including GSK3A, CDKN1A, AKT2, and MDM2, and key miRNAs including miR-485 and let-7f, suggesting a potential role of ERα in modulating this pathway in AD. The findings of this study provide a novel perspective on the regulatory network of ERα in the hippocampal region of AD and may pave the way for future research into the therapeutic potential of targeting the ERα pathway in neurodegenerative diseases.

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.

Septicemia triggers a profound systemic inflammatory response, ultimately leading to cellular senescence. Understanding the mechanisms underlying intercellular interactions associated with sepsis is crucial for developing therapeutic strategies targeting sepsis and its associated complications. Neonatal septicemia (NS) is a critical condition characterized by systemic infection in newborns. Currently, there are no effective indicators for the early identification of sepsis and precise screening of newborns who truly require antibiotic treatment, which results in delayed diagnosis of neonatal sepsis and the overuse of antibiotics. We aimed to elucidate cellular senescence-related genes (CSRGs) in the context of NS and to investigate their potential regulatory networks and immune infiltration patterns. Our analysis identified 391 DEGs, including 301 upregulated and 90 downregulated genes and 15 differentially expressed CSRGs (CSRDEGs), including STAT3, MAPK14, IGFBP7, PPARG, and ETS2. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed enrichment in biological processes, including cellular senescence, and pathways involving PD-L1 expression in cancer. Gene Set Enrichment Analysis highlighted significant pathways, including selenoamino acid metabolism and neutrophil degranulation. Protein-protein interaction network analysis identified eight hub genes: STAT3, MAPK14, CEBPB, TLR2, ETS1, JUNB, PPARG, and MAP3K5. Regulatory network analysis revealed interactions between CSRDEGs and multiple transcription factors/miRNAs. Immune infiltration analysis revealed profound differences in the composition of immune cells between the normal and NS groups. Our study findings offer valuable information for future research on therapeutic targets and diagnostic markers of NS.