Hereditas最新文献

Background: Age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly population. Accumulating evidence has revealed the possible association between metabolites and AMD. This study aimed to assess the effect of plasma metabolites on AMD and its two subtypes using a bidirectional two-sample Mendelian randomization approach.

Methods: The causality between plasma metabolites and AMD was assessed by a bidirectional two-sample Mendelian randomization (MR) analysis using the genome-wide association studies (GWAS) summary statistics of 1400 genetically determined metabolites (GDMs) and AMD. For this MR analysis, inverse variance weighted (IVW) was used as the primary method, with weighted median, MR-Egger, weighted mode, and simple mode as supplementary methods to examine the causality. MR-Egger intercept, Cochran's Q, and MR-PRESSO test were employed to evaluate possible pleiotropy and heterogeneity.

Results: The results of IVW showed significant causal associations between 13 GDMs and AMD. 1-stearoyl-GPE (18:0), androstenediol (3β,17β) monosulfate, stearoyl sphingomyelin (d18:1/18:0), xylose, and X-11,850 exhibited a protective effect on AMD, while gulonate and mannonate increased the risk of AMD. 1-stearoyl-GPE (18:0) and X-11,850 exhibited protective effects on dry AMD. DHEAS, 1-stearoyl-GPE (18:0), 5α-androstan-3β,17β-diol disulfate, xylose, androstenediol (3β,17β) monosulfate, and N2-acetyl, N6, N6-dimethyllysine exhibited a protective effect on wet AMD, while succinimide, 16a-hydroxy DHEA 3-sulfate, and X-13,553 increased the risk of wet AMD. Horizontal pleiotropy and heterogeneity did not distort the causal estimates. In the reverse MR analysis, AMD reduced the androstenediol (3β,17β) monosulfate level, and increased the stearoyl sphingomyelin(d18:1/18:0) level.

Conclusion: This study supported the effect of plasma metabolites on AMD, providing novel insights for clinical diagnosis and prevention strategy.

Background: Breast cancer is the most common malignancy among women worldwide, characterized by complex molecular and cellular heterogeneity. Despite advances in diagnosis and treatment, there is an urgent need to identify reliable biomarkers and therapeutic targets to improve early detection and personalized therapy. The OAS (2'-5'-oligoadenylate synthetase) family genes, known for their roles in antiviral immunity, have emerged as potential regulators in cancer biology. This study aimed to explore the diagnostic and functional relevance of OAS family genes in breast cancer.

Methodology: Breast cancer cell lines and controls were cultured under specific conditions, and DNA and RNA were extracted for downstream analyses. RT-qPCR, bisulfite sequencing, and Western blotting were employed to assess gene expression, promoter methylation, and knockdown efficiency of OAS family genes. Functional assays, including CCK-8, colony formation, and wound healing, evaluated cellular behaviors, while bioinformatics tools (UALCAN, GEPIA, HPA, OncoDB, cBioPortal, and others) validated findings and explored correlations with clinical data.

Results: The OAS family genes (OAS1, OAS2, OAS3, and OASL) were found to be significantly upregulated in breast cancer cell lines and tissues compared to normal controls. This overexpression was strongly associated with reduced promoter methylation. Receiver operating characteristic (ROC) analysis demonstrated high diagnostic accuracy, with area under the curve (AUC) values exceeding 0.93 for all four genes. Increased OAS expression correlated with advanced cancer stages and poor overall survival in breast cancer patients. Functional analysis revealed their involvement in critical biological processes, including immune modulation and oncogenic pathways. Silencing OAS genes in breast cancer cells significantly inhibited cell proliferation and colony formation, while unexpectedly enhancing migratory capacity. Additionally, correlations with immune cell infiltration, molecular subtypes, and drug sensitivity highlighted their potential roles in the tumor microenvironment and therapeutic response.

Conclusion: The findings of this study established OAS family genes as potential biomarkers and key players in breast cancer progression, offering promise as diagnostic biomarkers and therapeutic targets to address unmet clinical needs.

Purpose: Mitochondria are involved in septic shock and inflammatory response syndrome, which severely affects the life security of patients. It is necessary to recognize and explore the immune-mitochondrial genes in septic shock.

Methods: The GSE57065 dataset was acquired from the Gene Expression Omnibus (GEO) database and filtered by limma and the weighted correlation network analysis (WGCNA) to identify mitochondrial-related differentially expressed genes (MitoDEGs) in septic shock. The function of MitoDEGs was analyzed using the Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), respectively. The Protein-Protein Interaction (PPI) network composed of MitoDEGs was established using Cytoscape. Support Vector Machine Recursive Feature Elimination (SVM-RFE), Random Forest (RF), and Least Absolute Shrinkage and Selection Operator (LASSO) were used to identify diagnostic MitoDEGs, which were validated using receiver operating characteristic (ROC) analysis and Quantitative Real-time Reverse Transcription Polymerase Chain Reaction (qRT-PCR). Furthermore, the infiltration of immunocytes was analyzed using CIBERSORT, and the correlation between diagnostic MitoDEGs and immunocytes was explored using Spearman.

Results: A total of 44 MitoDEGs were filtered, and functional enrichment analysis showed they were associated with mitochondrial function, and the PPI network had 457 nodes and 547 edges. Four diagnostic genes, MitoDEGs, PGS1, C6orf136, THEM4, and EPHX2, were identified by three machine learning algorithms, and qRT-PCR results obtained similar expression levels as bioinformatics analysis. Furthermore, the diagnostic model constructed by the diagnostic genes had fine diagnostic efficacy. Immunocyte infiltration analysis showed that activated immunocytes were abundant and correlated with hub genes, with neutrophils accounting for the largest proportion in septic shock.

Conclusions: In this study, we recognized four immune-mitochondrial key genes (PGS1, C6orf136, THEM4, and EPHX2) in septic shock and designed a novel gene diagnosis model that provided a new and meaningful way for the diagnosis of septic shock.

Background: Platinum-based chemotherapy is one of the main treatments for lung adenocarcinoma (LUAD). However, the toxic side effects and drug resistance of chemotherapeutic drugs on normal cells are still a thorny problem in clinical treatment. Dendrobium is one of the three largest genera of Orchidaceous family, which has ornamental and medicinal value. Dendrobium is mainly distributed in the tropics and subtropics of South Asia, Oceania and other regions, with 1547 species of Dendrobium currently known. In China, "Shi hu" and "Tie pi shi hu" are well-known traditional medicines and have been included in the Chinese Pharmacopoeia (Editorial Board of Chinese Pharmacopoeia, 2020). Erianin is a natural product isolated from Dendrobium and is considered as a potential anticancer molecule due to its remarkable anti-tumor effects through various mechanisms, among which induced cancer cell apoptosis, inhibited invasion and migration. This study preliminarily explored the mechanism of Erianin inhibiting the progression of cisplatin (DDP) resistant LUAD in vivo and in vitro.

Methods: The effect of Erianin on the proliferation of DDP-resistant LUAD cells was detected by CCK-8 assay, wound healing assay and cloning assay. Transwell assay was used to evaluate the effect of Erianin on cell invasion and migration. The changes of cell cycle and apoptosis were detected by flow cytometry and TUNEL assay. Finally, the effects of Erianin on cell function and signaling pathway-related protein expression in vivo and in vitro were examined based on the enrichment analysis.

Results: Erianin could inhibit the proliferation, invasion and migration, induce apoptosis, altered cell cycle of DDP-resistant LUAD cells, and reverse the resistance to DDP. Western blotting results showed that Erianin exerted its anti-tumor effects by regulating the Wnt/β-catenin cascade in DDP-resistant LUAD cells.

Conclusion: Erianin may exerted its anti-tumor effect in DDP-resistant LUAD cells by regulating the Wnt3/β-Catenin/Survivin/Bcl-2/Caspase-3/Cyclin D1 axis.

Background: Indole-3-acetic acid (IAA), an indole analog produced by intestinal microorganisms metabolizing tryptophan, has anti-inflammatory and antioxidant properties and thus has potential applications in ovarian protection, although the exact mechanism is unknown. The present study preliminarily investigated the pharmacological mechanism of IAA in alleviating diminished ovarian reserve (DOR) by network pharmacology and molecular docking.

Methods: Relevant target proteins of IAA were searched in SwissTargetPrediction, PharmMapper, TargetNet, BATMAN-TCM, and SuperPred databases. The potential targets of DOR were obtained from GeneCards, DisGenet, OMIM, and Drugbank databases. Both common targets were then imported into the String website to construct a PPI network, and these targets were analyzed for GO and KEGG enrichment. Finally, we utilized molecular docking to validate the possible binding conformations between IAA and the candidate targets. We used in vitro experiments to preliminarily investigate the effects of IAA on DOR.

Results: We obtained 88 potential targets for IAA and DOR interaction. We received 16 pivotal targets by constructed protein interaction screening. KEGG enrichment analysis mainly included the AGE-RAGE signaling pathway, IL-17 signaling pathway, Chemical carcinogenesis-reactive oxygen species in diabetic complications, etc. GO functional analysis showed that IAA treatment of DOR may involve biological processes such as response to external stimuli, hypoxia, gene expression, and regulation of enzyme activity. Molecular docking and in vitro experiments further revealed the potential effects of IAA on MMP2, TNF-α, AKT1, HSP90AA1, and NF-κ B.

Conclusion: We preliminarily revealed the potential protective effects of IAA against DOR through multiple targets and pathways, which provides a new research strategy for the molecular mechanism of IAA to alleviate DOR in the future. However, further studies need to demonstrate whether IAA can be used as a compound to prevent and treat DOR.

Infertility is a global problem being associated with emotional and financial burden. Recent studies have shown contribution of a group of non-coding RNAs, namely circular RNAs (circRNAs) to the etiology of some infertility conditions. CircRNA are transcribed from exons and form a circular RNA molecule, being abundant in eukaryotes. Traditionally classified as non-coding RNA, these transcripts are endogenously produced through either non-canonical back-splicing or linear splicing, typically produced from precursor messenger ribonucleic acid (pre-mRNA). While during the canonical splicing process the 3' end of the exon is joined to the 5' end of the succeeding exon to form linear mRNA, during backsplicing, the 3' end to the 5' end of the same exon is joined to make a circular molecule. circRNAs are involved in the regulation of several aspects of spermatogenesis. They appear to influence how stem germ cells grow and divide during the sperm production process. Malfunctions in circRNA activity could contribute to male infertility issues stemming from abnormalities in spermatogenesis. In the current review, we highlight the exciting potential of circRNAs as key players in the male fertility.

Background: Stage 4 neuroblastoma (NBL), a solid tumor of childhood, has a poor prognosis. Despite intensive molecular genetic studies, no targetable gene abnormalities have been identified. Stage 4S NBL has a characteristic of spontaneous regression, and elucidation of the mechanistic differences between stages 4 and 4S may improve treatment. Conventional NBL studies have mainly focused on the detection of abnormalities in individual genes and have rarely examined abnormalities in gene networks. While the gene coexpression network is expected to contribute to the detection of network abnormalities, the fragility of the network due to data noise and the extraction of arbitrary topological structures for the high-dimensional network are issues.

Results: The present paper concerns the classification method of stages 4 and 4S NBL patients using highly accurate gene coexpression network analysis based on RNA-sequencing data of transcription factors (TFs). In particular, after applying a noise reduction method RECODE, generalized topological overlapping measure (GTOM), which weighs the connections of nodes in the network structure, succeeded in extracting a cluster of TFs that showed high classification performance for stages 4 and 4S. In addition, we investigated how these clusters correspond to clinical information and to TFs which control the normal adrenal tissue and NBL characters.

Conclusions: A clustering method is presented for finding intermediate-scale clusters of TFs that give considerable separation performance for distinguishing between stages 4 and 4S. It is suggested that this method is useful as a way to extract factors that contribute to the separation of groups from multiple pieces of information such as gene expression levels.

Objective: Gastric cancer (GC) is characterized by its high malignancy and poor prognosis. However, the role of Inhibin subunit beta A (INHBA) in GC remains insufficiently understood. This study aims to comprehensively evaluate the clinical significance, biological roles, and possible mechanisms of INHBA in GC.

Methods: Expression levels and survival analyses of the Inhibin beta family were assessed using online databases. A prediction model based on INHBA was developed. In addition, the associations between INHBA expression and immune status, and chemotherapy sensitivity were explored. In vitro experiments were conducted to investigate the biological impact of INHBA on GC cells. Pyrosequencing and the DNA methylation inhibitor, 5-AZA-2'-deoxycytidine (5-AZA-dC) were employed to elucidate the mechanisms underlying INHBA function.

Results: Our findings revealed that INHBA exhibited high expression in GC patients, and elevated INHBA expression correlated with worse outcomes. We developed a novel nomogram incorporating INHBA, age, and tumor node metastasis (TNM) stage to predict the prognosis of GC patients. Additionally, INHBA was found to be associated with suppressed infiltration of immune cells and chemosensitivity. Functionally, INHBA promoted the proliferation and invasiveness of GC cells. Mechanistically, pyrosequencing revealed DNA Hypomethylation of INHBA in the first exon region, and the effects of INHBA silencing were rescued by 5-AZA-dC treatment.

Conclusion: Our study suggests that DNA hypomethylation of INHBA contributes to the progression of GC. Furthermore, INHBA holds promise as a valuable biomarker for prognostic evaluation and immune status prediction in GC patients.

Background: Diabetic kidney disease (DKD) is a complication caused by end-stage diabetes mellitus and usually results in glomerular podocyte injury. Exosomes are important for intercellular information exchange. However, the effect of podocyte exosomes on DKD has not been elucidated.

Methods: GEO, PROMO, and GSE1009 databases were used to identify the gene APOC1 and transcription factor HOXD9. qRT-PCR, western blot, and transmission electron microscopy (TEM) were investigated to confirm APOC1 change in high glucose-treated podocytes and exosomes. Flow cytometry, immunofluorescence, qPCR, immunoblotting, wound healing, Transwell invasion assays, dual luciferase assay, and ChIP-PCR assay were performed to detect the effect of APOC1 and HOXD9 on macrophage polarization in high glucose-treated podocytes and exosomes. qRT-PCR and immunoblotting assays were employed to assess the impact of APOC1 knockdown on the M1 polarization of macrophages in response to liraglutide treatment.

Results: The results suggested that the expression of APOC1 in human podocytes (HPC) and exosomes was elevated. High glucose-treated HPC exosomes promoted macrophage M1-type polarization, which was reversed by adding sh-APOC1. Afterward, HOXD9 was identified as a potential transcription factor for APOC1. Knockdown of HOXD9 led to macrophage M2 polarization, and overexpression of APOC1 polarized macrophage M1. In addition, enhanced p65 phosphorylation verified that HOXD9/APOC1 induced macrophage M1-type polarization by activating the NF-κB signaling pathway. Knocking down APOC1 enhanced the inhibitory effect of liraglutide on macrophage M1 polarization.

Conclusion: Our findings highlighted that HOXD9/APOC1 was a key player in causing podocyte injury in diabetic kidney disease and led to macrophage M1 polarization through the NF-κB signaling pathway.