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Preclinical atherosclerosis and prediabetes are key targets of preventive medicine as their prevalence rises. Therefore, it is crucial to identify early processes and limit confounders such as lipid-lowering or antidiabetic therapy and advanced atherosclerosis. Proteomics enables the identification of biomarkers and molecular pathways related to atherogenesis in prediabetes. To investigate the relationship between prediabetes and preclinical atherosclerosis in apparently healthy individuals using a comprehensive proteomic approach. This cross-sectional, population-based study included 389 participants (mean age 49 ± 10 years; 47% males) from the Białystok PLUS cohort in Poland. Individuals with known diabetes, major cardiovascular, inflammatory, or malignant diseases, or those receiving steroidal or lipid-lowering therapy were excluded. Carotid ultrasound was used to assess preclinical atherosclerosis, and prediabetes was defined as impaired fasting glucose, impaired glucose tolerance, or HbA1c 5.7–6.4%. Proteomic profiling was performed using the Olink® Reveal platform, enabling deep profiling of 1050 proteins with the Proximity Extension Assay and next-generation sequencing readout, yielding log2-scaled NPX (Normalized Protein eXpression) values. In preliminary analyses, we identified proteins associated with prediabetes and then linked them to early atherosclerotic lesions. A block-sPLS-DA model integrating clinical and proteomic data revealed clear separation between participants with and without prediabetes. The clinical block comprised eight variables reflecting cardiometabolic status, whereas the proteomic block retained 45 proteins across two components. The heatmap shows pairwise Pearson correlations between selected serum proteins and clinical variables (Fig. 1). Vascular and age measures cluster together and share correlation patterns distinct from those of BMI and glycaemic parameters. A protein module including the ectodysplasin A2 receptor (EDA2R) and leiomodin 1 (LMOD1) correlates positively with age and vascular parameters, and inversely with GFR and HDL-C. Multivariable linear regression analyses were performed with selected vascular parameters as dependent variables and clinical covariates, together with proteins identified in Component 2, which are weakly related to clinical parameters and thus may represent novel biomarkers associated with prediabetes (Fig. 2). Expression of EDA2R (B = 0.05; An integrative block-sPLS-DA approach separated individuals with prediabetes from those without and revealed a proteomic signature independent of clinical covariates. Within this signature, the expression of LMOD1, EDA2R, and C16orf89 showed robust associations with atherosclerosis-related vascular traits. Enrichment analyses highlighted proteins involved in neuronal processes as candidate pathways linking early glucose disturbances with preclinical atherosclerosis. The online version contains supplementary material available at 10.1186/s12933-026-03128-w. Show less

This study aimed to identify CSF and plasma proteins that mediate the association between age and mild cognitive impairment (MCI) and Alzheimer's disease using mediation analysis. By focusing on proteins significantly associated in both CSF and plasma, we sought to identify biomarkers accessible for clinical applications. Proteomic measurements were obtained from CSF and plasma from a cohort of cognitively normal and MCI patients at the Johns Hopkins Alzheimer's Disease Research Center using Olink Proximity Extension Assay technology. Mediation effects were estimated using single- and multiple-mediator models and validated in three independent datasets: Duke (CSF), ADNI (CSF), and UK Biobank (plasma). Over 3000 proteins in 86 patients were analyzed. Three candidates, leiomodin-1 (LMOD1), glial fibrillary acidic protein (GFAP), and elastin (ELN), met the criteria for mediation in both CSF and plasma. Multiple mediator models demonstrated a significant combined mediation effect on MCI in CSF (OR: 1.122, 95 % CI: 1.026-1.439) and plasma (OR: 1.142, 95 % CI: 1.058-1.410). Across validation cohorts, GFAP consistently showed significant mediation effects (Duke CSF: OR: 1.114, 95 % CI: 1.069-1.206; ADNI: OR: 1.004, 95 % CI: 1.000-1.009; UK Biobank: OR: 1.030, 95 % CI: 1.026-1.034). In contrast, ELN and LMOD1 demonstrated mediation effects in the discovery dataset but were not consistently reproduced in external cohorts. Our findings highlight GFAP as a robust mediator of age-related risk of cognitive impairment across CSF and plasma, supporting its utility as a practical biomarker. ELN and LMOD1 may represent exploratory candidates reflecting extracellular matrix and vascular processes requiring further validation. Show less

Colorectal cancer (CRC) shows strong heterogeneity in tumor microenvironment (TME) dynamics, but the mechanisms that shape epithelial-stromal crosstalk are still unclear. Here we focus on A-kinase anchor protein 12 (AKAP12) and Leiomodin 1 (LMOD1) and test a compartment-dependent model in which this program aligns with tight-junction features in epithelium but with a fibrotic, immune-suppressive program in stroma. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) were employed to profile gene expression patterns in CRC tissues. Immunohistochemistry (IHC) and multiplex immunofluorescence (mIF) validated protein expression and localization. Cell-cell communication analysis and trajectory inference were used to dissect spatial interaction networks. Functional experiments were employed to validate the role of the AKAP12-LMOD1 axis in CAFs in regulating ECM remodeling and antitumor immunity. AKAP12-LMOD1 exhibited a compartment-dependent pattern in CRC. In ACTA2⁻ epithelial regions, the epithelial AKAP12-LMOD1 signal was lower in tumors than in matched normal epithelium and showed a positive association with the tight-junction marker CLDN1. In ACTA2⁺ stromal regions, AKAP12-LMOD1 was enriched, positively associated with the gap-junction marker GJA4, and higher in tumor stroma than matched normal stroma. In a CAF-macrophage non-contact co-culture model, AKAP12 overexpression supported CAF activation and collagen deposition, and shifted macrophages toward an M2-like phenotype; LMOD1 knockdown or SB-431542 partially reversed these effects. Stromal AKAP12-LMOD1-enriched regions also aligned with fibrosis- and M2-related features, and these stromal patterns were prominent in mucinous carcinoma. This study defines AKAP12-LMOD1 as a compartment-dependent stromal program in CRC that links ACTA2⁺ stroma to gap-junction features, fibrosis, and M2-like macrophage polarization, while showing a distinct epithelial association with tight-junction features. These findings support a stroma-centered working model for AKAP12-LMOD1 in CRC microenvironmental heterogeneity and suggest that stromal modulation of this program, together with targeting fibrosis and M2-like immune features, may be explored as hypothesis-level, subtype-oriented therapeutic directions in stroma-rich CRC. Show less

Calorie restriction (CR; calorie intake reduced by ∼20%-40% below ad libitum, AL, intake) potentiates skeletal muscle insulin sensitivity during old age by incompletely understood mechanisms. We aimed to identify CR-induced changes in muscle insulin signaling that may explain this enhanced sensitivity. We examined how CR (65% of AL intake for 8-weeks) alters muscle insulin action and signaling in aged rats (24-month old) of both sexes. We assessed insulin-stimulated glucose uptake (ISGU) in muscle together with deep phosphoproteomic profiling. CR enhanced ISGU in both sexes, with higher ISGU in females regardless of diet. We identified 590 diet-responsive phosphosites, indicating extensive CR-induced remodelling of muscle phosphorylation, particularly within structural and contractile pathways. Strikingly, 70% of these sites were sex-specific. Numerous insulin-responsive sites were identified (193 in females; 107 in males) with 60 overlapping sites. The magnitude of the insulin-effects among all significantly regulated sites correlated between sexes. S1443 phosphorylation on EH domain-binding protein 1-like protein-1 (Ehbp1l1; a potential regulator of Rab proteins that control GLUT4 glucose transporter trafficking) was insulin-responsive in both sexes but only associated to ISGU in females. Personalized phosphoproteomic analysis also identified insulin-responsive sites on Leiomodin-1 (Lmod1) that correlated with ISGU across individuals. Both Lmod1 and Ehbp1l1 have strong genetic association with glycemic traits in humans, reinforcing their translational relevance. This study revealed sex-dependent and sex-independent phosphosignaling mechanisms that associate with muscle insulin responsiveness as well as hundreds of sex-specific, CR-responsive phosphosites. These findings provide a rich resource for future research on CR and insulin sensitivity. Show less

Gastric cancer (GC) is a common malignant tumor, which originated from the epithelial cells of the stomach. It has the characteristics of high incidence and poor prognosis. Therefore, it is urgent to find new prognostic markers for the diagnosis and treatment of GC. Download gene expression matrix and clinical data from TCGA database and GSE84437 dataset. Through independent prognostic analysis and clinical correlation analysis, 74 prognostic related genes (PRG) were screened out. A PPI network was established for PRG to identify four key genes (KG), namely LMOD1, CRYAB, VCL and MYL9. Survival analysis showed that patients with high expression of KG had poor prognosis. Multivariate Cox regression analysis showed that KG was an independent prognostic factor. TCGA database verifies the importance and significance of KG as a prognostic indicator. Functional enrichment analysis showed that KG was mainly involved in cell adhesion molecules, adhesion spots and PI3K/AKT signaling pathway. KG may be a potential therapeutic target for gastric cancer. Show less

Gastroesophageal reflux disease (GERD) is a chronic inflammatory gastrointestinal disease, which has no thoroughly effective or safe treatment. Elevated oxidative stress is a common consequence of chronic inflammatory conditions. We employed Summary-data based MR (SMR) analysis to assess the associations between gene molecular characteristics and GERD. Exposure data were the summary-level data on the levels of DNA methylation, gene expression, and protein expression, which obtained from related methylation, expression, and protein quantitative trait loci investigations (mQTL, eQTL, and pQTL). Outcome data, Genome-wide association study (GWAS) summary statistics of GERD, were extracted from the Ong's study (discovery), the Dönertaş's study (replication), and the FinnGen study (replication). Colocalization analysis was performed to determine if the detected signal pairs shared a causative genetic mutation. Oxidative stress related genes and druggable genes were imported to explore oxidative stress mechanism underlying GERD and therapeutic targets of GERD. The Drugbank database was utilized to conduct druggability evaluation. After multi-omics SMR analysis and colocalization analysis, we identified seven key genes for GERD, which were SUOX and SERPING1, DUSP13, SULT1A1, LMOD1, UBE2L6, and PSCA. SUOX was screened out to be the mediator, which suggest that GERD is related to oxidative stress. SERPING1, SULT1A1, and PSCA were selected to be the druggable genes. These findings offered strong support for the identification of GERD treatment targets in the future as well as for the study of the oxidative stress mechanism underlying GERD. Show less

Breast cancer has seriously affected women's physical and mental health. This investigation aims at screening differentially expressed genes (DEGs) in breast cancer and illuminating the potential biological functions of Leiomodin 1 (LMOD1) and its behind mechanisms against breast cancer. The common DEGs (co-DEGs) between the GSE22820 and GSE29431 data sets and pivotal genes were screened out using bioinformatics methods. The biological roles of LMOD1 overexpression on malignant phenotypes were validated by functional assays and the impact on fatty acid synthesis was also elucidated in breast cancer cell lines. Additionally, colivelin, a STAT3 activator, was applied for further investigating the role of LMOD1 on the JAK2/STAT3 pathway in vitro. A total of 208 co-DEGs and 5 focal genes were screened through bioinformatics analysis, and 5 focal genes were downregulated in breast cancer cell lines. LMOD1 overexpression retarded proliferative, migratory, invasive capabilities of breast cancer cells. LMOD1 overexpression suppressed fatty acid synthesis. Furthermore, the inhibitory effects on malignant phenotypes of breast cancer cells with LMOD1 overexpression were partially abolished after colivelin treatment. Additionally, LMOD1 could impede fatty acid synthesis in breast cancer cells. Our study highlighted LMOD1 exerted as a tumor-suppressive role in breast cancer, which was correlated with restraining the JAK2/STAT3 pathway activation. Show less

Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare genetic visceral myopathy, with a historically high mortality rate. Its genetic and phenotypic variability and management options remain poorly characterized. This study correlates genotype with phenotype and subsequently analyzes treatment and outcome of patients with pediatric-onset MMIHS. We retrospectively analyzed 26 MMIHS patients (median age 97 months, 62% female) with molecular diagnostics in 19 patients at a German quaternary intestinal rehabilitation center followed between 2012 and 2025. In this second-largest pediatric MMIHS cohort worldwide, genotype correlated with severity and outcomes, with Show less

Skeletal muscle is the largest tissue in mammals, and it plays a crucial role in metabolism and homeostasis. Skeletal muscle development and regeneration consist of a series of carefully regulated changes in gene expression. Leiomodin2 (LMOD2) gene is specifically expressed in the heart and skeletal muscle. But the physiological functions and mechanisms of LMOD2 on skeletal muscle development are unknown. In this study, we examined the expression levels of the LMOD2 in porcine tissues and C2C12 cells. LMOD2 is mainly expressed in the heart, followed by skeletal muscle. The expression level of LMOD2 gradually decreased with skeletal muscle growth, but increased after injury. LMOD2 expression levels increased gradually with C2C12 cells proliferation and differentiation. In terms of function, the muscle fiber types were altered after LMOD2 was knocked out in C2C12 cells, MyHC-I and MyHC-2b were inhibited, whereas MyHC-2a and MyHC-2x were promoted. LMOD2 knockout has different effects on LMOD family, LMOD1 expression level was promoted, while LMOD3 was inhibited. Loss of LMOD2 suppressed cell viability and PAX7 protein expression. At the transcriptome level, proliferation-related genes and muscle contraction-related genes were respectively inhibited after LMOD2 knockout. In terms of molecular networks, a series of experiments have shown that MyoG is a transcription factor for LMOD2, while miR-335-3p can negatively regulate LMOD2 expression. We screened ACTC1 as a candidate interacting protein for LMOD2 using protein prediction software and RNA-seq, and Co-IP experiments confirmed the relationship between LMOD2 and ACTC1. In vivo, Lentivirus-mediated LMOD2 knockdown reduces muscle mass. LMOD2 knockdown inhibited MyHC-I mRNA expression, but had no effect on MyHC-2b. The protein expression of MyHC-I, MyHC-2x, and MyHC-2b was suppressed after LMOD2 knockdown. Collectively, our data indicates that LMOD2 knockout inhibits myoblast proliferation and alters muscle fiber types. MyoG is a transcription factor for LMOD2, while miR-335-3p can negatively regulate LMOD2 expression. Moreover, LMOD2 and ACTC1 interact to regulate myogenic differentiation. Our study provides a new target for skeletal muscle development. Show less

Oxidative stress is crucial in the development of cutaneous melanoma, but its role in melanoma is controversial. We aimed to identify melanoma-associated targets and understand the underlying mechanism. Differential expressed genes (DEGs) were discovered between control and melanoma samples, and a protein-protein interaction (PPI) network was constructed to find key genes. The prediction accuracy of LMOD1 was assessed by receiver operating characteristic (ROC) curves, and pan-cancer analysis was also performed for LMOD1 expression and immune characteristics. The downstream pathway of LMOD1 was found via KEGG analysis. The effects of LMOD1 on oxidative stress, apoptosis, CD4 + T cells and the downstream pathway were evaluated in melanoma cells and mice. We identified ACTG2, CNN1, LMOD1, MYH11, MYL9, MYLK, TAGLN, TPM1 and TPM2 as melanoma-related DEGs, which could separate control and melanoma samples. The area under curve (AUC) of LMOD1 was > 0.89, indicating high prediction accuracy. LMOD1 expression was decreased in melanoma, and LMOD1 notably correlated with B cells, CD4 T cells, neutrophils, macrophages and dendritic cells (DCs). Overexpression of LMOD1 promoted apoptosis, enhanced migration and invasion, and activated oxidative stress in melanoma cells. LMOD1 promoted apoptosis via activating oxidative stress. The RIG-I-like receptor signaling (RLR) was a downstream pathway of LMOD1. Overexpression of LMOD1 activated oxidative stress, increased apoptosis and CD4 + T cells, and elevated RIG-I and MDA5, while Cyclo (Phe-Pro) (cFP) reversed the results. LMOD1 triggers oxidative stress-mediated apoptosis in melanoma via activating the RLR pathway, which provides promising targets and regulatory pathway for melanoma. Show less

Bladder cancer (BC) is one of the most common urological malignancies, ranking as the eleventh most common cause of cancer-related deaths worldwide. The lack of specific and sensitive prognostic biomarkers presents a significant challenge in the early diagnosis and treatment of BC. We used the Gene Expression Omnibus (GEO) dataset GSE13507 and the Cancer Genome Atlas (TCGA) database to screen differentially expressed genes related to BC. By using Weighted Gene Co-expression Network Analysis (WGCNA), two modules associated with BC were investigated in GSE13507 and TCGA. Hub genes were identified through Protein-Protein Interaction (PPI) network analysis and their functions were validated through multiple approaches, including Gene Expression Profiling Interactive Analysis (GEPIA), Western Blotting (WB) assay, Human Protein Atlas (HPA), Oncomine analysis, and quantitative Real-Time PCR (qRTPCR) analysis. Additionally, miRNAs associated with hub gene expression were identified using various databases to predict the progression and prognosis of BC. WCGNA and differential gene expression analysis identified 171 common genes as target genes. Ten genes (MYH11, ACTA2, TPM2, ACTG2, CALD1, MYL9, TPM1, MYLK, SORBS1, and LMOD1) were identified using the PPI tool and the CytoHubba plugin of Cytoscape. The CALD1 and MYLK genes showed a significant prognostic value for overall survival and diseasefree survival in patients with BC. According to the HPA and Oncomine databases, CALD1 and MYLK expression levels were significantly lower in BC tissues than in normal tissues. Additionally, qRT-PCR analysis, WB assay, and immunohistochemical analysis confirmed CALD1 and MYLK as tumor suppressor genes in BC. Furthermore, miR-155 showed a significant positive correlation with MYLK. This study established MYLK as a direct target gene of miR-155, functioning as an actionable survival-related gene correlated with BC development. Show less

Prostate cancer is epithelial malignant prostate hyperplasia caused by a tumor. We found prostate cancer GSE141551 and GSE200879 profiles from gene expression omnibus database, followed by differentially expressed genes (DEGs) analysis, weighted gene co-expression network analysis, protein-protein interaction analysis, gene function enrichment analysis, and comparative toxicology database analysis. Finally, the gene expression heat map was drawn, and miRNA information regulating core DEGs was retrieved. A total of 1151 DEGs were found, most of them focusing on systematic development, cell development, cell differentiation, regulation of multicellular biological processes, anatomical morphogenesis, MAPK signaling pathway, proteoglycans in cancer, fluid shear stress, and atherosclerosis. The core genes (MYL9, TAGLN, SMTN, CNN1, MYH11, MYLK, MYOCD, ACTC1, LMOD1, and TPM2) obtained in end are all lowly expressed in prostate cancer samples and are associated with hypertension, tumor metastasis, prostate tumors, and tumor aggressiveness. LMOD1 and SMTN are lowly expressed in prostate cancer and may be used as markers in prostate cancer nursing. Show less

The transition of smooth muscle cells (SMCs) from a contractile to a synthetic phenotype is a key contributor to cardiovascular disease (CVD) pathologies, such as atherosclerosis and in-stent restenosis. We previously reported that loss of leiomodin 1 (LMOD1), a coronary artery disease risk gene highly expressed in SMCs, promotes SMC phenotypic switching in vitro. However, the in vivo role of LMOD1 and the molecular mechanisms driving this transition remain unknown. In this study, we found that Lmod1 heterozygous mice subjected to carotid artery ligation developed larger neointimal lesions. Histopathological analyses attributed this phenotype to increased SMC proliferation. RNA sequencing studies of LMOD1-deficient SMCs revealed a significant upregulation of genes associated with increased cell proliferation, particularly those involved in the G1/S phase transition. Further analysis identified cyclin-dependent kinase 6 (CDK6) as a potential mediator of this hyperproliferative response. Notably, the knockdown of CDK6 in LMOD1-deficient cultured SMCs restored SMC proliferation to near baseline levels, indicating that the observed phenotype is reversible in vitro. Collectively, these findings indicate that LMOD1 deficiency promotes SMC proliferation by upregulating CDK6 expression and provide mechanistic insight into how reduced LMOD1 expression may contribute to increased neointimal lesion size and vascular remodeling. Show less

Glaucoma is a leading cause of irreversible blindness, normally associated with dysfunction and degeneration of the trabecular meshwork (TM) as the primary cause. Trabecular meshwork stem cells (TMSCs) have emerged as promising candidates for TM regeneration toward glaucoma therapies, yet their molecular characteristics remain poorly defined. In this study, we performed a comprehensive transcriptomic comparison of human TMSCs and human TM cells (TMCs) using RNA sequencing and microarray analyses, followed by qPCR validation. A total of 465 differentially expressed genes were identified, with 254 upregulated in TMSCs and 211 in TMCs. A functional enrichment analysis revealed that TMSCs are associated with development, immune signaling, and extracellular matrix remodeling pathways, while TMCs are enriched in structural, contractile, and adhesion-related functions. A network topology analysis identified Show less

The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons. Show less

The leiomodin (Lmod) family of actin-binding proteins play a critical role in muscle function, highlighted by the fact that mutations in all three family members (LMOD1-3) result in human myopathies. Mutations in the cardiac predominant isoform, LMOD2 lead to severe neonatal dilated cardiomyopathy. Most of the disease-causing mutations in the LMOD gene family are nonsense, or frameshift, mutations predicted to result in expression of truncated proteins. However, in nearly all cases of disease, little to no LMOD protein is expressed. We show here that nonsense-mediated mRNA decay, a cellular mechanism which eliminates mRNAs with premature termination codons, underlies loss of mutant protein from two independent LMOD2 disease-causing mutations. Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression. Our investigation lays the initial groundwork for potential therapeutic intervention in LMOD-linked myopathies. Show less

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is an uncommon genetic disorder inherited in an autosomal recessive pattern that affects the muscles that line the bladder and intestines. The most common genes associated with MMIHS mutations are ACTG2, LMOD1, MYH11, MYL9, MYLK, and PDCL3. However, the complete genetic landscape of MMIHS still needs to be fully understood. The diagnosis of MMIHS can be challenging. However, advances in prenatal and diagnostic techniques, such as ultrasound and fetal urine analysis, have improved the ability to detect the syndrome early. Targeted next-generation sequencing (NGS) and other diagnostic tests can also diagnose MMIHS. The management of MMIHS involves addressing severe intestinal dysmotility, which often necessitates total parenteral nutrition (TPN), which can lead to complications such as hepatotoxicity and nutritional deficiencies. Multivisceral and intestinal transplantation has emerged as therapeutic options, offering the potential for improved outcomes and enteral autonomy. Understanding the genetic underpinnings of MMIHS is crucial for personalized care. While the prognosis varies, timely interventions and careful monitoring enhance patient outcomes. Genetic studies have given us valuable insights into the molecular mechanisms of MMIHS. These studies have identified mutations in genes involved in the development and function of smooth muscle cells. They have also shown that MMIHS is associated with defects in the signaling pathways that control muscle contraction. Continued research in the genetics of MMIHS holds promise for unraveling the complexities of MMIHS and improving the lives of affected individuals. Show less

Prostate cancer (PCa) is a malignant tumor of the male reproductive system, and its incidence has increased significantly in recent years. This study aimed to further identify candidate biomarkers with prognostic and diagnostic significance by integrating gene expression and DNA methylation data from PCa patients through association analysis. To this end, this paper proposes a sparse partial least squares regression algorithm based on hypergraph regularization (HR-SPLS) by integrating and clustering two kinds of data. Next, module 2, with the most significant weight, was selected for further analysis according to the weight of each module related to DNA methylation and mRNAs. Based on the DNA methylation sites in module 2, this paper uses multiple machine learning methods to construct a PCa diagnosis-related model of 10-DNA methylation sites. The results of Receiver Operating Characteristic (ROC) analysis showed that the DNA methylation-related diagnostic model we constructed could diagnose PCa patients with high accuracy. Subsequently, based on the mRNAs in module 2, we constructed a prognostic model for 7-mRNAs (MYH11, ACTG2, DDR2, CDC42EP3, MARCKSL1, LMOD1, and MYLK) using multivariate Cox regression analysis. The prognostic model could predict the disease free survival of PCa patients with moderate to high accuracy (area under the curve (AUC) =0.761). In addition, Gene Set EnrichmentAnalysis (GSEA) and immune analysis indicated that the prognosis of patients in the risk group might be related to immune cell infiltration. Our findings may provide new methods and insights for identifying disease-related biomarkers by integrating DNA methylation and gene expression data. Show less

Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity. Show less

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is defined as a congenital visceral myopathy with genetic mutations. However, the etiology and pathophysiology are not fully understood. We aimed to generate a gene leiomodin-1a (lmod1a) modification technique to establish a zebrafish model of MMIHS. We targeted lmod1a in zebrafish using CRISPR/Cas9. After confirming the genotype, we measured the expression levels of the target gene and protein associated with MMIHS. A gut transit assay and spatiotemporal mapping were conducted to analyze the intestinal function. Genetic confirmation showed a 5-base-pair deletion in exon 1 of lmod1a, which caused a premature stop codon. We observed significant mRNA downregulation of lmod1a, myh11, myod1, and acta2 and the protein expression of Lmod1 and Acta2 in the mutant group. A functional analysis of the lmod1a mutant zebrafish showed that its intestinal peristalsis was fewer, slower, and shorter in comparison to the wild type. This study showed that targeted deletion of lmod1a in zebrafish resulted in depletion of MMIHS-related genes and proteins, resulting in intestinal hypoperistalsis. This model may have the potential to be utilized in future therapeutic approaches, such as drug discovery screening and gene repair therapy for MMIHS. Show less

Depression involves maladaptive processes impairing an individual's ability to interface with the environment appropriately. Long noncoding RNAs (lncRNAs) are gaining traction for their role in higher-order brain functioning. Recently, we reported that lncRNA coexpression modules may underlie abnormal responses to stress in rats showing depression-like behavior. The current study explored the global expression regulation of lncRNAs and messenger RNAs (mRNAs) in the hippocampus of rats showing susceptibility (learned helplessness [LH]) or resiliency (non-LH) to depression and fluoxetine response to LH (LH+FLX). Multiple comparison analysis was performed with an analysis of variance via the Multiple comparison analyses revealed differentially expressed mRNAs and lncRNAs with each phenotype. Integrated bioinformatics analysis identified novel transcripts, specific modules, and regulatory pairs of mRNA-lncRNA in each phenotype. In addition, the machine learning approach predicted lncRNA-regulated The study shows a novel role for lncRNAs in the development of specific depression phenotypes and in identifying newer targets for therapeutic development. Show less

Hepatic carcinoma is one of the most common types of malignant tumors in the digestive system, and its biological characteristics determine its high rate of metastasis and recurrence after radical resection, leading to a poor prognosis for patients. Increasing evidence demonstrates that phosphoproteins and phosphorylation-mediated molecular pathways influence the occurrence and development of hepatic carcinoma. It is urgent need to develop early-stage biomarkers for improving diagnosis, therapy, medical service, and prognostic assessment. We hypothesize that phosphoproteome and phosphorylation-mediated signaling pathway networks significantly differ in human early-stage primary hepatic carcinomas relative to control liver tissues, which will identify the key differentially phosphorylated proteins and phosphorylation-mediated signaling pathway network alterations in human early-stage primary hepatic carcinoma to innovate predictive diagnosis, prognostic assessment, and personalized medical services and progress beyond the state of the art in the framework of predictive, preventive, and personalized medicine (PPPM). Tandem mass tag (TMT)-based quantitative proteomics coupled with TiO A total of 1326 phosphopeptides derived from 858 DPPs in human early-stage primary hepatic carcinoma were identified. KEGG pathway network analysis of 858 DPPs revealed 33 statistically significant signaling pathways, including spliceosome, glycolysis/gluconeogenesis, B-cell receptor signaling pathway, HIF-1 signaling pathway, and fatty acid degradation. Gene Ontology (GO) analysis of 858 DPPs revealed that protein phosphorylation was involved in 57 biological processes, 40 cellular components, and 37 molecular functions. Protein-protein interaction (PPI) network constructed multiple high-combined scores and co-expressed DPPs. Integrative analysis of transcriptomic data and DPP data identified 105 overlapped molecules (DPPs; DEGs) between hepatic carcinoma tissues and control tissues and 125 OS-related DPPs. Overlapping Venn plots showed 14 common molecules among datasets of DPPs, DEGs, and OS-related DDPs, including FTCD, NDRG2, CCT2, PECR, SLC23A2, PNPLA7, ANLN, HNRNPM, HJURP, MCM2, STMN1, TCOF1, TOP2A, and SSRP1. The drug sensitivities of OS-related DPPs were identified, including LMOD1, CAV2, UBE2E2, RAPH1, ANXA5, HDLBP, CUEDC1, APBB1IP, VCL, SRSF10, SLC23A2, EPB41L2, ESR1, PLEKHA4, SAFB2, SMARCAD1, VCAN, PSD4, RDH16, NOP56, MEF2C, BAIAP2L2, NAGS, SRSF2, FHOD3, and STMN1. Identification and annotation of phosphoproteomes and phosphorylation-mediated signaling pathways in human early-stage primary hepatic carcinoma tissues provided new directions for tumor prevention and treatment, which (i) helps to enrich phosphorylation functional research and develop new biomarkers; (ii) enriches phosphorylation-mediated signaling pathways to gain a deeper understanding of the underlying mechanisms of early-stage primary hepatic carcinoma; and (iii) develops anti-tumor drugs that facilitate targeted phosphorylated sites. We recommend quantitative phosphoproteomics in early-stage primary hepatic carcinoma, which offers great promise for in-depth insight into the molecular mechanism of early-stage primary hepatic carcinoma, the discovery of effective therapeutic targets/drugs, and the construction of reliable phosphorylation-related biomarkers for patient stratification, predictive diagnosis, prognostic assessment, and personalized medical services in the framework of PPPM. The online version contains supplementary material available at 10.1007/s13167-023-00335-3. Show less

The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts, ranging from megacystis to Prune Belly syndrome. We aimed to apply a bespoke virtual genetic panel and describe novel variants associated with this condition using whole genome sequencing data within the Genomics England 100,000 Genomes Project. We screened the Genomics England 100,000 Genomes Project rare diseases database for patients with VM-related phenotypes. These patients were screened for sequence variants and copy number variants (CNV) in We identified 76 patients with phenotypes consistent with a diagnosis of VM. The range of presentations included megacystis/microcolon hypoperistalsis syndrome, Prune Belly syndrome and chronic intestinal pseudo-obstruction. Of the patients in whom we identified heterozygous VM are a group of disorders that are not easily classified and may be given different diagnostic labels depending on their phenotype. Molecular genetic analysis of these patients is valuable as it allows precise diagnosis and aids understanding of the underlying disease manifestations. We identified The online version contains supplementary material available at 10.1007/s44162-023-00012-z. Show less

Coronary artery disease (CAD) is a syndrome resulting from myocardial ischaemia of heterogeneous pathomechanism. Environmental and genetic factors contribute to its development. Atherosclerotic plaques that significantly narrow the lumen of coronary arteries cause symptoms of myocardial ischaemia. Acute coronary incidents are most often associated with plaque rupture or erosion accompanied by local activation of the coagulation system with thrombus formation. Plaque formation and stability are influenced by endothelial function and vascular smooth muscle cell function. In this study, we investigated the association between polymorphisms in genes affecting endothelial and vascular smooth muscle cell (VSMC) function and the occurrence of unstable angina pectoris. The aim of this study was to evaluate the association between the Show less

Epidemiological studies suggest that individuals in the Mediterranean region with deficiency of glucose-6-phosphate dehydrogenase (G6PD) are less susceptible to cardiovascular diseases. However, our knowledge regarding the effects of G6PD deficiency on pathogenesis of vascular diseases caused by factors, like angiotensin II (Ang-II), which stimulate synthesis of inflammatory cytokines and vascular inflammation, is lacking. Furthermore, to-date the effect of G6PD deficiency on vascular health has been controversial and difficult to experimentally prove due to a lack of good animal model. To determine the effect of Ang-II-induced hypertension (HTN) and stiffness in a rat model of the Mediterranean G6PD (G6PD Our findings revealed that infusion of Ang-II (490 ng/kg/min) elicited less HTN and medial hypertrophy of carotid artery in G6PD The G6PD Show less

The prognosis of patients with advanced arteriosclerosis is bleak due to the lack of understanding of arteriosclerosis. Epigenetics-based DNA methylation plays an important role in the pathogenesis of arteriosclerosis. Hence, we aimed to identify the epigenetics-related aberrantly methylated differentially expressed genes (AMDEGs) in arteriosclerosis. A gene expression dataset and DNA methylation dataset were downloaded from the Gene Expression Omnibus database, and AMDEGs were identified on the basis of the relationship between methylation and expression. Subsequently, the expression levels of candidate hub genes were detected in human peripheral blood mononuclear cells (PBMCs) from atherosclerotic patients and control subjects by RT-qPCR and Western blot. Lastly, the methylation level of the target gene was detected using the MassARRAY method. In the present study, the hypermethylated and downregulated genes were mainly involved in vascular smooth muscle contraction. The hypomethylated and upregulated genes were markedly associated with immune-inflammatory processes. Following validation, LMOD1 was identified as the target gene, which was hypermethylated and downregulated in arteriosclerosis. The methylation levels of CpG sites in LMOD1 promoter were detected to be elevated in the PBMCs of atherosclerotic patients. In conclusion, AMDEGs identified in the present study may assist in understanding the pathogenesis of arteriosclerosis. LMOD1 exhibits potential as a promising diagnostic and therapeutic biomarker for arteriosclerosis. Show less

Metabolic syndrome (MetS) amplifies the risks of atherosclerosis. Despite well-known sexual dimorphism in atherosclerosis, underlying mechanisms are poorly understood. Our previous findings highlight a proatherogenic protein, thrombospondin-1 (TSP-1), in hyperglycemia- or hyperleptinemia (mimicking obesity)-induced atherosclerosis. However, the role of TSP-1 in the development of atherosclerosis prompted by co-existing hyperglycemia and obesity, characteristic of MetS, is unknown. The goal of this study was to examine sex-specific differences in lesion progression in a model of combined MetS and atherosclerosis (KKAyApoE) and interrogate how these differences relate to TSP-1 expression. Male and female KKAy Metabolic profiling confirmed MetS phenotype of KKAy Together, the current study implicates a role of plasma testosterone in sex-specific differences in atherosclerosis and TSP-1 expression in MetS vs non-MetS mice. Our data suggest a sex-dependent differential role of TSP-1 on SMC de-differentiation in MetS. Collectively, these findings underscore a fundamental link between TSP-1 and VSMC phenotypic transformation in MetS. Show less

Smooth muscle disorders affecting both the intestine and the bladder have been known for a decade. However, the recent discovery of genes associated with these dysfunctions has led to the description of several clinical phenotypes. We performed a systematic review of all published cases involving seven genes with pathogenic variants, Show less

Despite tens of cell lines originating from fish brain tissue have been constructed, little is known about the definite cell types they belong to. Whether fish cell lines derived from the brain shares similar characteristics is not well-answered yet. Here, we constructed three cell lines designated as LMB-S, LMB-M, LMB-L using brain tissue of spotted sea bass (Lateolabrax maculatus). Among them, LMB-L was identified as astroglia-like cells considering the high expression of GFAP, DCX, PTX, S100b, which are regarded as astrocyte-specific or astrocyte-associated cell markers. LMB-M exhibited smooth muscle-like features showing strong expression of LMOD1, SLAMP, M-cadherin, MGP, which are confirmed as muscle-restricted or myogenesis-involved cell markers. Although LMB-S was not definitely identified, it appeared an activation of WNT/β-catenin pathway. Besides the distinct expression profiles of cell markers, the three cell lines also presented differences in transfection efficiency and susceptibility to iridovirus infection. Relying on the established cell lines, a novel megalocytivirus, named LMIV (Lateolabrax maculatus iridovirus), was first isolated from diseased spotted sea bass. Genetic analysis of major capsid protein (MCP) and adenosine triphosphatase (ATPase) manifested that LMIV was clearly distinguishable from other representative teleost iridoviruses. Further investigations revealed that LMIV could replicate most efficiently in LMB-L cells obtaining the highest viral load (2.16 × 10 Show less