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1.
BMC Genom Data ; 25(1): 85, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39379846

RESUMO

Angiogenesis-osteogenesis coupling is critical for proper functioning and maintaining the health of bones. Any disruption in this coupling, associated with aging and disease, might lead to loss of bone mass. Osteoporosis (OP) is a debilitating bone metabolic disorder that affects the microarchitecture of bones, gradually leading to fracture. Computational analysis revealed that normal angiogenesis is disrupted during the progression of OP, especially postmenopausal osteoporosis (PMOP). The genes associated with OP and PMOP were retrieved from the DisGeNET database. Hub gene analysis and molecular pathway enrichment were performed via the Cytoscape plugins STRING, MCODE, CytoHubba, ClueGO and the web-based tool Enrichr. Twenty-eight (28) hub genes were identified, eight of which were transcription factors (HIF1A, JUN, TP53, ESR1, MYC, PPARG, RUNX2 and SOX9). Analysis of SNPs associated with hub genes via the gnomAD, I-Mutant2.0, MUpro, ConSurf and COACH servers revealed the substitution F201L in IL6 as the most deleterious. The IL6 protein was modeled in the SWISS-MODEL server and the substitution was analyzed via the YASARA FoldX plugin. A positive ΔΔG (1.936) of the F201L mutant indicates that the mutated structure is less stable than the wild-type structure is. Thirteen hub genes, including IL6 and the enriched molecular pathways were found to be profoundly involved in angiogenesis/endothelial function and immune signaling. Mechanical loading of bones through weight-bearing exercises can activate osteoblasts via mechanotransduction leading to increased bone formation. The present study suggests proper mechanical loading of bone as a preventive strategy for PMOP, by which angiogenesis and the immune status of the bone can be maintained. This in silico analysis could be used to understand the molecular etiology of OP and to develop novel therapeutic approaches.


Assuntos
Osteoporose , Humanos , Osteoporose/genética , Osteoporose/etiologia , Osteoporose/metabolismo , Osteoporose/patologia , Simulação por Computador , Polimorfismo de Nucleotídeo Único , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Osteoporose Pós-Menopausa/genética , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/etiologia , Feminino , Biologia Computacional/métodos , Angiogênese
2.
Front Immunol ; 15: 1466029, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39364409

RESUMO

A total of 138 cDEGs were screened from mediastinal lymph nodes and peripheral whole blood. Among them, 6 hub cDEGs including CTSS, CYBB, FPR2, MNDA, TLR1 and TLR8 with elevated degree and betweenness levels were illustrated in protein-protein interaction network. In comparison to healthy controls, CTSS (1.61 vs. 1.05), CYBB (1.68 vs. 1.07), FPR2 (2.77 vs. 0.96), MNDA (2.14 vs. 1.23), TLR1 (1.56 vs. 1.09), and TLR8 (2.14 vs. 0.98) displayed notably elevated expression levels within pulmonary sarcoidosis PBMC samples (P < 0.0001 for FPR2 and P < 0.05 for others), echoing with prior mRNA microarray findings. The most significant functional pathways were immune response, inflammatory response, plasma membrane and extracellular exosome, with 6 hub cDEGs distributing along these pathways. CTSS, CYBB, FPR2, MNDA, TLR1, and TLR8 could be conducive to improving the diagnostic process and understanding the underlying mechanisms of pulmonary sarcoidosis.


Assuntos
Mapas de Interação de Proteínas , Sarcoidose Pulmonar , Humanos , Sarcoidose Pulmonar/genética , Sarcoidose Pulmonar/diagnóstico , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Transcriptoma
3.
BMC Musculoskelet Disord ; 25(1): 834, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39438952

RESUMO

Sepsis-induced myopathy is one of the serious complications of sepsis, which severely affects the respiratory and peripheral motor systems of patients, reduces their quality of life, and jeopardizes their lives, as evidenced by muscle atrophy, loss of strength, and impaired regeneration after injury. The pathogenesis of sepsis-induced myopathy is complex, mainly including cytokine action, enhances free radical production in muscle, increases muscle protein hydrolysis, and decreases skeletal muscle protein synthesis, etc. The above mechanisms have been demonstrated in existing studies. However, it is still unclear how the overall pattern of gene co-expression affects the pathological process of sepsis-induced myopathy. Therefore, we intend to identify hub genes and signaling pathways. Weighted gene co-expression network analysis was our main approach to study gene expression profiles: skeletal muscle transcriptome in ICU patients with sepsis-induced multi-organ failure (GSE13205). After data pre-processing, about 15,181 genes were used to identify 13 co-expression modules. Then, 16 genes (FEM1B, KLHDC3, GPX3, NIFK, GNL2, EBNA1BP2, PES1, FBP2, PFKP, BYSL, HEATR1, WDR75, TBL3, and WDR43) were selected as the hub genes including 3 up-regulated genes and 13 down-regulated genes. Then, Gene Set Enrichment Analysis was performed to show that the hub genes were closely associated with skeletal muscle dysfunction, necrotic and apoptotic skeletal myoblasts, and apoptosis in sepsis-induced myopathy. Overall, 16 candidate biomarkers were certified as reliable features for more in-depth exploration of sepsis-induced myopathy in basic and clinical studies.


Assuntos
Redes Reguladoras de Genes , Doenças Musculares , Mapas de Interação de Proteínas , Sepse , Humanos , Sepse/genética , Sepse/metabolismo , Sepse/complicações , Doenças Musculares/genética , Doenças Musculares/etiologia , Doenças Musculares/diagnóstico , Perfilação da Expressão Gênica , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Transcriptoma , Transdução de Sinais/genética
4.
J Invertebr Pathol ; 207: 108214, 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39366479

RESUMO

Beauveria bassiana (B. bassiana) is a common fungal disease in sericulture. Previous research has primarily focused on investigating genes involved in innate immunity. However, the response of Bombyx mori (B. mori) to B. bassiana requires the coordination of other biological processes in addition to the immune system. We measured protein expression profile of B. mori after inoculating B. bassiana using iTRAQ technology in previous. Here we constructed a co-expression protein-protein interaction network of B. mori in response to B. bassiana infection. Subnetworks and modules were analyzed, and the functions of these modules were annotated. The results revealed the identification of numerous proteins associated with cellular immunity, including those involved in phagosomes, lysosomes, mTOR signaling, sugar metabolism, and the ubiquitin-proteasome pathway. Meanwhile, we observed that the pathways involved in protein synthesis were activated, including pyruvate and purine metabolism, RNA transport, ribosome, protein processing in endoplasmic reticulum, and protein export pathways, during B. bassiana infection. Based on this analysis, we selected six candidate genes (shock protein, ribosome, translocon, actin muscle-type A2, peptidoglycan recognition protein, and collagenase) that were found to be related to the response to B. bassiana. Further verification experiments demonstrated significant changes in their expression levels after inoculation with B. bassiana. These research findings provide new insights into the molecular mechanism of insect immune response to fungal infection.

5.
Adv Biomed Res ; 13: 42, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224401

RESUMO

Background: Celiac disease (CeD) is an autoimmune enteropathy triggered by dietary gluten. Almost 90% of CeD patients have HLA-DQ2 or -DQ8 haplotypes. As a high proportion of first-degree relatives (FDRs) of CeD patients have the same haplotype, it is assumed that they are at a higher risk of disease development than the general population. Nevertheless, the prevalence of CeD among FDRs is considerably low (7.5%). Materials and Methods: In order to figure out this discrepancy, a microarray dataset of intestinal mucosal biopsies of CeD patients, FDRs, and control groups was reanalyzed, and a protein-protein interaction network was constructed. Results: Principal component analysis showed that CeD and FDR groups are far away in terms of gene expression. Comparing differentially expressed genes of both networks demonstrated inverse expression of some genes mainly related to cell cycle mechanisms. Moreover, analysis of the modular structures of up- and downregulated gene networks determined activation of protein degradation mechanisms and inhibition of ribosome-related protein synthesis in celiac patients with an upside-down pattern in FDRs. Conclusions: The top-down systems biology approach determined some regulatory pathways with inverse function in CeD and FDR groups. These genes and molecular mechanisms could be a matter of investigation as potential druggable targets or prognostic markers in CeD.

6.
Aging Cell ; : e14330, 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39252463

RESUMO

We aimed to develop and validate a protein risk score for predicting Alzheimer's disease (AD) and compare its performance with a validated clinical risk model (Cognitive Health and Dementia Risk Index for AD [CogDrisk-AD]) and apolipoprotein E (APOE) genotypes. The development cohort, consisting of 35,547 participants from England in the UK Biobank, was randomly divided into a 7:3 training-testing ratio. The validation cohort included 4667 participants from Scotland and Wales in the UK Biobank. In the training set, an AD protein risk score was constructed using 31 proteins out of 2911 proteins. In the testing set, the AD protein risk score had a C-index of 0.867 (95% CI, 0.828, 0.906) for AD prediction, followed by CogDrisk-AD risk factors (C-index, 0.856; 95% CI, 0.823, 0.889), and APOE genotypes (C-index, 0.705; 95% CI, 0.660, 0.750). Adding the AD protein risk score to CogDrisk-AD risk factors (C-index increase, 0.050; 95% CI, 0.008, 0.093) significantly improved the predictive performance for AD. However, adding CogDrisk-AD risk factors (C-index increase, 0.040; 95% CI, -0.007, 0.086) or APOE genotypes (C-index increase, 0.000; 95% CI, -0.054, 0.055) to the AD protein risk score did not significantly improve the predictive performance for AD. The top 10 proteins with the highest coefficients in the AD protein risk score contributed most of the predictive power for AD risk. These results were verified in the external validation cohort. EGFR, GFAP, and CHGA were identified as key proteins within the protein network. Our result suggests that the AD protein risk score demonstrated a good predictive performance for AD risk.

7.
Stem Cell Res Ther ; 15(1): 301, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39278909

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressive motoneuron degenerative disorder. There are still no drugs capable of slowing disease evolution or improving life quality of ALS patients. Thus, autologous stem cell therapy has emerged as an alternative treatment regime to be investigated in clinical ALS. METHOD: Using Proteomics and Protein-Protein Interaction Network analyses combined with bioinformatics, the possible cellular mechanisms and molecular targets related to mesenchymal stem cells (MSCs, 1 × 106 cells/kg, intrathecally in the lumbar region of the spine) were investigated in cerebrospinal fluid (CSF) of ALS patients who received intrathecal infusions of autologous bone marrow-derived MSCs thirty days after cell therapy. Data are available via ProteomeXchange with identifier PXD053129. RESULTS: Proteomics revealed 220 deregulated proteins in CSF of ALS subjects treated with MSCs compared to CSF collected from the same patients prior to MSCs infusion. Bioinformatics enriched analyses highlighted events of Extracellular matrix and Cell adhesion molecules as well as related key targets APOA1, APOE, APP, C4A, C5, FGA, FGB, FGG and PLG in the CSF of cell treated ALS subjects. CONCLUSIONS: Extracellular matrix and cell adhesion molecules as well as their related highlighted components have emerged as key targets of autologous MSCs in CSF of ALS patients. TRIAL REGISTRATION: Clinicaltrial.gov identifier NCT0291768. Registered 28 September 2016.


Assuntos
Esclerose Lateral Amiotrófica , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Proteômica , Transplante Autólogo , Humanos , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/terapia , Esclerose Lateral Amiotrófica/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteômica/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/líquido cefalorraquidiano , Idoso , Apolipoproteína A-I/líquido cefalorraquidiano , Apolipoproteína A-I/metabolismo , Adulto , Células da Medula Óssea/metabolismo , Mapas de Interação de Proteínas
8.
J Neurochem ; 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39289039

RESUMO

Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex-dependent differences in the effect of daily nicotine intraperitoneal (i.p.) administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, 0.5 mg/kg nicotine significantly improved performance in the VDR, but not the VD, task, while 0.5 mg/kg nicotine significantly worsened performance in the VD, but not VDR task in female mice. Furthermore, 0.25 mg/kg nicotine significantly worsened performance in the VD and VDR task only in female mice. Next, to investigate the cellular mechanisms that underlie the sex difference in the effects of nicotine on cognition, transcriptomic analyses were performed focusing on the medial prefrontal cortex tissue samples from male and female mice that had received continuous administration of nicotine for 3 or 18 days. As a result of pathway enrichment analysis and protein-protein interaction analysis using gene sets of differentially expressed genes, decreased expression of postsynaptic-related genes in males and increased expression of innate immunity-related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility. Our result suggests that nicotine modulates cognitive function in a sex-dependent manner by alternating the expression of specific gene sets in the medial prefrontal cortex.

9.
Heliyon ; 10(14): e34300, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39108872

RESUMO

All-trans retinoic acid (ATRA) has promising activity against breast cancer. However, the exact mechanisms of ATRA's anticancer effects remain complex and not fully understood. In this study, a network pharmacology and molecular docking approach was applied to identify key target genes related to ATRA's anti-breast cancer activity. Gene/disease enrichment analysis for predicted ATRA targets was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID), the Comparative Toxicogenomics Database (CTD), and the Gene Set Cancer Analysis (GSCA) database. Protein-Protein Interaction Network (PPIN) generation and analysis was conducted via Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and cytoscape, respectively. Cancer-associated genes were evaluated using MyGeneVenn from the CTD. Differential expression analysis was conducted using the Tumor, Normal, and Metastatic (TNM) Plot tool and the Human Protein Atlas (HPA). The Glide docking program was used to predict ligand-protein binding. Treatment response predication and clinical profile assessment were performed using Receiver Operating Characteristic (ROC) Plotter and OncoDB databases, respectively. Cytotoxicity and gene expression were measured using MTT/fluorescent assays and Real-Time PCR, respectively. Molecular functions of ATRA targets (n = 209) included eicosanoid receptor activity and transcription factor activity. Some enriched pathways included inclusion body myositis and nuclear receptors pathways. Network analysis revealed 35 hub genes contributing to 3 modules, with 16 of them were associated with breast cancer. These genes were involved in apoptosis, cell cycle, androgen receptor pathway, and ESR-mediated signaling, among others. CCND1, ESR1, MMP9, MDM2, NCOA3, and RARA were significantly overexpressed in tumor samples. ATRA showed a high affinity towards CCND1/CDK4 and MMP9. CCND1, ESR1, and MDM2 were associated with poor treatment response and were downregulated after treatment of the breast cancer cell line with ATRA. CCND1 and ESR1 exhibited differential expression across breast cancer stages. Therefore, some part of ATRA's anti-breast cancer activity may be exerted through the CCND1/CDK4 complex.

10.
Arch Pharm (Weinheim) ; : e2400418, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39086040

RESUMO

Green seaweed (Ulva sp.) is frequently used as a food component and nutraceutical agent because of its high polysaccharide and natural fiber content in Asian countries. This study investigates both metabolomic profiling of Ulva sp. and the neuroprotective efficacy of its ethanol extract and its underlying mechanisms in a rotenone-induced rat model of neurodegeneration, mimicking Parkinson's disease (PD) in humans. Metabolomic profiling of Ulva sp. extract was done using liquid chromatography high resolution electrospray ionization mass spectrometry and led to the identification of 22 compounds belonging to different chemical classes.Catenin Beta Additionally, this study demonstrated the neuroprotective properties against rotenone-induced PD, which was achieved through the suppression of elevated levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 together with the inhibition of reactive oxygen species (ROS) generation, apoptosis, inflammatory mediators, and the phosphoinositide 3-kinases/serine/threonine protein kinase (PI3K/AKT) pathway. Using a protein-protein interaction network, AKT1, GAPDH, TNF-α, IL-6, caspase 3, signal transducer and activator of transcription 3, Catenin Beta 1, epidermal growth factor receptor, B-cell lymphoma -2, and HSP90AA1 were identified as the top 10 most significant genes. Finally, molecular docking results showed that compounds 1, 3, and 7 might possess a promising anti-parkinsonism effect by binding to active sites of selected hub genes. Therefore, it is hypothesized that the Ulva sp. extract has the potential to be further developed as a potential therapeutic agent for the treatment of PD.

11.
BMC Musculoskelet Disord ; 25(1): 634, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39118036

RESUMO

BACKGROUND: Although rheumatoid arthritis (RA) is a chronic systemic tissue disease often accompanied by osteoporosis (OP), the molecular mechanisms underlying this association remain unclear. This study aimed to elucidate the pathogenesis of RA and OP by identifying differentially expressed mRNAs (DEmRNAs) and long non-coding RNAs (lncRNAs) using a bioinformatics approach. METHODS: Expression profiles of individuals diagnosed with OP and RA were retrieved from the Gene Expression Omnibus database. Differential expression analysis was conducted. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) pathway enrichment analyses were performed to gain insights into the functional categories and molecular/biochemical pathways associated with DEmRNAs. We identified the intersection of common DEmRNAs and lncRNAs and constructed a protein-protein interaction (PPI) network. Correlation analysis between the common DEmRNAs and lncRNAs facilitated the construction of a coding-non-coding network. Lastly, serum peripheral blood mononuclear cells (PBMCs) from patients with RA and OP, as well as healthy controls, were obtained for TRAP staining and qRT-PCR to validate the findings obtained from the online dataset assessments. RESULTS: A total of 28 DEmRNAs and 2 DElncRNAs were identified in individuals with both RA and OP. Chromosomal distribution analysis of the consensus DEmRNAs revealed that chromosome 1 had the highest number of differential expression genes. GO and KEGG analyses indicated that these DEmRNAs were primarily associated with " platelets (PLTs) degranulation", "platelet alpha granules", "platelet activation", "tight junctions" and "leukocyte transendothelial migration", with many genes functionally related to PLTs. In the PPI network, MT-ATP6 and PTGS1 emerged as potential hub genes, with MT-ATP6 originating from mitochondrial DNA. Co-expression analysis identified two key lncRNA-mRNA pairs: RP11 - 815J21.2 with MT - ATP6 and RP11 - 815J21.2 with PTGS1. Experimental validation confirmed significant differential expression of RP11-815J21.2, MT-ATP6 and PTGS1 between the healthy controls and the RA + OP groups. Notably, knockdown of RP11-815J21.2 attenuated TNF + IL-6-induced osteoclastogenesis. CONCLUSIONS: This study successfully identified shared dysregulated genes and potential therapeutic targets in individuals with RA and OP, highlighting their molecular similarities. These findings provide new insights into the pathogenesis of RA and OP and suggest potential avenues for further research and targeted therapies.


Assuntos
Artrite Reumatoide , Biologia Computacional , Perfilação da Expressão Gênica , Osteoporose , RNA Longo não Codificante , Humanos , Artrite Reumatoide/genética , RNA Longo não Codificante/genética , Osteoporose/genética , Mapas de Interação de Proteínas , RNA Mensageiro/genética , Redes Reguladoras de Genes , Feminino , Masculino , Ontologia Genética , Transcriptoma
12.
Comput Biol Med ; 180: 108987, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39116715

RESUMO

Type 2 diabetes mellitus (T2D) has been linked with female infertility (FI). Nevertheless, our understanding of the molecular hallmarks and underlying mechanisms remains elusive. This research article aimed to find the hub genes, pathways, transcription factors, and miRNA involved. For this study, softwares like cytoscape, string, Enrichr, FFL loop, etc., were utilized. This research article employed differentially expressed genes (DEGs) to identify multiple biological targets to understand the association between T2D and female infertility (FI). Between T2D and FI, we found 3869 differentially expressed genes. We have also analyzed different pathways like thyroid hormone signaling pathways, AGE-RAGE signaling pathways in diabetic complications and ubiquitin-mediated proteolysis through pathway analysis. Moreover, hub genes MED17, PRKCG, THRA, FOXO1, NCOA2, PLCG2, COL1A1, CXCL8, PRPF19, ANAPC5, UBE2I, XIAP and KEAP1 have been identified. Additionally, these hub genes were subjected to identify the miRNA-mRNA regulation network specific to T2D-associated female infertility. In the FFL study (Feed Forward Loop), transcription factor (SP1, NFKB1, RELA and FOX01), miRNA (has-mir-7-5p, has-let-7a-5p, hsa-mir-16-5p, hsa-mir-155-5p, has-mir-122-5p, has-let-7b-5p, has-mir-124-3p, has-mir-34a-5p, has-mir-130a-3p, has-let-7i-5p, and hsa-mir-27a-3p) and six genes (XIAP, THRA, NCOA2, MED17, FOXO1, and COL1A1) among the thirteen key genes were recognized as regulator and inhibitor. Our analysis reveals that these genes can serve as a significant biomarker for female infertility linked with Type 2 Diabetes, through the prioritization of candidate genes. This study gives us insight into the molecular and cellular mechanism of T2D-associated FI. This finding helps in developing novel therapeutic approaches and will improve efficacy and reduce side effects of the treatment. This research requires further experimental investigation of the principal targets.


Assuntos
Biologia Computacional , Diabetes Mellitus Tipo 2 , Infertilidade Feminina , MicroRNAs , Biologia de Sistemas , Humanos , Feminino , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Infertilidade Feminina/genética , Infertilidade Feminina/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Redes Reguladoras de Genes , Perfilação da Expressão Gênica , Mapas de Interação de Proteínas/genética
13.
Front Pharmacol ; 15: 1418902, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39211773

RESUMO

Drug combinations have emerged as a promising therapeutic approach in cancer treatment, aimed at overcoming drug resistance and improving the efficacy of monotherapy regimens. However, identifying effective drug combinations has traditionally been time-consuming and often dependent on chance discoveries. Therefore, there is an urgent need to explore alternative strategies to support experimental research. In this study, we propose network-based prediction models to identify potential drug combinations for 11 types of cancer. Our approach involves extracting 55,299 associations from literature and constructing human protein interactomes for each cancer type. To predict drug combinations, we measure the proximity of drug-drug relationships within the network and employ a correlation clustering framework to detect functional communities. Finally, we identify 61,754 drug combinations. Furthermore, we analyze the network configurations specific to different cancer types and identify 30 key genes and 21 pathways. The performance of these models is subsequently assessed through in vitro assays, which exhibit a significant level of agreement. These findings represent a valuable contribution to the development of network-based drug combination design strategies, presenting potential solutions to overcome drug resistance and enhance cancer treatment outcomes.

14.
J Alzheimers Dis ; 101(2): 611-625, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39213070

RESUMO

Background: The connection between diabetes-associated cognitive dysfunction (DACD) and Alzheimer's disease (AD) has been shown in several observational studies. However, it remains controversial as to how the two related. Objective: To explore shared genes and pathways between DACD and AD using bioinformatics analysis combined with biological experiment. Methods: We analyzed GEO microarray data to identify DEGs in AD and type 2 diabetes mellitus (T2DM) induced-DACD datasets. Weighted gene co-expression network analysis was used to find modules, while R packages identified overlapping genes. A robust protein-protein interaction network was constructed, and hub genes were identified with Gene ontology enrichment and Kyoto Encyclopedia of Genome and Genome pathway analyses. HT22 cells were cultured under high glucose and amyloid-ß 25-35 (Aß25-35) conditions to establish DACD and AD models. Quantitative polymerase chain reaction with reverse transcription verification analysis was then performed on intersection genes. Results: Three modules each in AD and T2DM induced-DACD were identified as the most relevant and 10 hub genes were screened, with analysis revealing enrichment in pathways such as synaptic vesicle cycle and GABAergic synapse. Through biological experimentation verification, 6 key genes were identified. Conclusions: This study is the first to use bioinformatics tools to uncover the genetic link between AD and DACD. GAD1, UCHL1, GAP43, CARNS1, TAGLN3, and SH3GL2 were identified as key genes connecting AD and DACD. These findings offer new insights into the diseases' pathogenesis and potential diagnostic and therapeutic targets.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Biologia Computacional , Diabetes Mellitus Tipo 2 , Doença de Alzheimer/genética , Humanos , Disfunção Cognitiva/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Mapas de Interação de Proteínas/genética , Redes Reguladoras de Genes/genética , Animais , Camundongos , Peptídeos beta-Amiloides/metabolismo , Perfilação da Expressão Gênica
15.
Biology (Basel) ; 13(7)2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-39056691

RESUMO

Androgenetic alopecia (AGA) is the most prevalent hair loss disorder worldwide, driven by excessive sensitivity or response to androgen. Herbal extracts, such as Curcuma aeruginosa Roxb., have shown promise in AGA treatment due to their anti-androgenic activities and hair growth effects. However, the precise mechanism of action remains unclear. Hence, this study aims to elucidate the active compounds, putative targets, and underlying mechanisms of C. aeruginosa for the therapy of AGA using network pharmacology and molecular docking. This study identified 66 bioactive compounds from C. aeruginosa, targeting 59 proteins associated with AGA. Eight hub genes were identified from the protein-protein interaction network, namely, CASP3, AKT1, AR, IL6, PPARG, STAT3, HIF1A, and MAPK3. Topological analysis of components-targets network revealed trans-verbenol, myrtenal, carvone, alpha-atlantone, and isoaromandendrene epoxide as the core components with potential significance in AGA treatment. The molecular docking verified the binding affinity between the hub genes and core compounds. Moreover, the enrichment analyses showed that C. aeruginosa is involved in hormone response and participates in HIF-1 and MAPK pathways to treat AGA. Overall, this study contributes to understanding the potential anti-AGA mechanism of C. aeruginosa by highlighting its multi-component interactions with several targets involved in AGA pathogenesis.

16.
Curr Issues Mol Biol ; 46(7): 7353-7372, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-39057077

RESUMO

Eriocheir sinensis is an economically important aquatic animal. Its regulatory mechanisms underlying many biological processes are still vague due to the lack of systematic analysis tools. The protein-protein interaction network (PIN) is an important tool for the systematic analysis of regulatory mechanisms. In this work, a novel machine learning method, DGO-SVM, was applied to predict the protein-protein interaction (PPI) in E. sinensis, and its PIN was reconstructed. With the domain, biological process, molecular functions and subcellular locations of proteins as the features, DGO-SVM showed excellent performance in Bombyx mori, humans and five aquatic crustaceans, with 92-96% accuracy. With DGO-SVM, the PIN of E. sinensis was reconstructed, containing 14,703 proteins and 7,243,597 interactions, in which 35,604 interactions were associated with 566 novel proteins mainly involved in the response to exogenous stimuli, cellular macromolecular metabolism and regulation. The DGO-SVM demonstrated that the biological process, molecular functions and subcellular locations of proteins are significant factors for the precise prediction of PPIs. We reconstructed the largest PIN for E. sinensis, which provides a systematic tool for the regulatory mechanism analysis. Furthermore, the novel-protein-related PPIs in the PIN may provide important clues for the mechanism analysis of the underlying specific physiological processes in E. sinensis.

17.
Cureus ; 16(4): e58548, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38957825

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact globally, resulting in a higher death toll and persistent health issues for survivors, particularly those with pre-existing medical conditions. Numerous studies have demonstrated a strong correlation between catastrophic COVID-19 results and diabetes. To gain deeper insights, we analysed the transcriptome dataset from COVID-19 and diabetic peripheral neuropathic patients. Using the R programming language, differentially expressed genes (DEGs) were identified and classified based on up and down regulations. The overlaps of DEGs were then explored between these groups. Functional annotation of those common DEGs was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Bio-Planet, Reactome, and Wiki pathways. A protein-protein interaction (PPI) network was created with bioinformatics tools to understand molecular interactions. Through topological analysis of the PPI network, we determined hub gene modules and explored gene regulatory networks (GRN). Furthermore, the study extended to suggesting potential drug molecules for the identified mutual DEG based on the comprehensive analysis. These approaches may contribute to understanding the molecular intricacies of COVID-19 in diabetic peripheral neuropathy patients through insights into potential therapeutic interventions.

18.
J Hazard Mater ; 477: 135298, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-39053055

RESUMO

The biogeochemical cycle of biogenic manganese oxides (BioMnOx) is closely associated with the environmental behavior and fate of various pollutants. It is significantly interfered by many metals, such as Cu and Fe. However, the bacterial molecular responses are not clear. Here, the effects of Cu(II) and Fe(III) on oxidation of manganese by Pseudomonas putida MnB1 and the bacterial molecular response mechanisms have been studied. The bacterial oxidation of manganese were promoted by both Fe(III) and Cu(II) and the final manganese oxidation rate of the Cu(II) group exceeded 16 % that of the Fe(III) group. The results of transcriptome indicated that Cu(II) promoted manganese oxidation by up-regulating the expression levels of multicopper oxidase (MCO) and peroxidase(POD), and by stimulating electron transfer, while Fe(III) promoted this process by accelerating the electron transfer and nitrogen cycling, and activating POD. The protein-protein interaction (PPI) network indicated that the MCO genes (mnxG and mcoA) were directly linked to the copper homeostasis proteins (cusA, cusB, czcC and cusF). Cytochrome c was closely related to the genes related to nitrogen cycling (glnA, glnL, and putA) and electrons transfer (cycO, cycD, nuoA, nuoK, and nuoL), which also promoted manganese oxidation. This study provides a molecular level insight into the oxidation of Mn(II) by Pseudomonas putida MnB1 with Cu(II) and/or Fe(III) ions.


Assuntos
Cobre , Compostos de Manganês , Óxidos , Pseudomonas putida , Pseudomonas putida/metabolismo , Pseudomonas putida/genética , Cobre/metabolismo , Cobre/química , Compostos de Manganês/metabolismo , Compostos de Manganês/química , Óxidos/metabolismo , Óxidos/química , Oxirredução , Ferro/metabolismo , Ferro/química , Oxirredutases/metabolismo , Oxirredutases/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética
19.
Biochim Biophys Acta Mol Basis Dis ; 1870(7): 167300, 2024 10.
Artigo em Inglês | MEDLINE | ID: mdl-38880160

RESUMO

BACKGROUND: The pathophysiology of ulcerative colitis (UC) is believed to be heavily influenced by immunology, which presents challenges for both diagnosis and treatment. The main aims of this study are to deepen our understanding of the immunological characteristics associated with the disease and to identify valuable biomarkers for diagnosis and treatment. METHODS: The UC datasets were sourced from the GEO database and were analyzed using unsupervised clustering to identify different subtypes of UC. Twelve machine learning algorithms and Deep learning model DNN were developed to identify potential UC biomarkers, with the LIME and SHAP methods used to explain the models' findings. PPI network is used to verify the identified key biomarkers, and then a network connecting super enhancers, transcription factors and genes is constructed. Single-cell sequencing technology was utilized to investigate the role of Peroxisome Proliferator Activated Receptor Gamma (PPARG) in UC and its correlation with macrophage infiltration. Furthermore, alterations in PPARG expression were validated through Western blot (WB) and immunohistochemistry (IHC) in both in vitro and in vivo experiments. RESULT: By utilizing bioinformatics techniques, we were able to pinpoint PPARG as a key biomarker for UC. The expression of PPARG was significantly reduced in cell models, UC animal models, and colitis models induced by dextran sodium sulfate (DSS). Interestingly, overexpression of PPARG was able to restore intestinal barrier function in H2O2-induced IEC-6 cells. Additionally, immune-related differentially expressed genes (DEGs) allowed for efficient classification of UC samples into neutrophil and mitochondrial metabolic subtypes. A diagnostic model incorporating the three disease-specific genes PPARG, PLA2G2A, and IDO1 demonstrated high accuracy in distinguishing between the UC group and the control group. Furthermore, single-cell analysis revealed that decreased PPARG expression in colon tissue may contribute to the polarization of M1 macrophages through activation of inflammatory pathways. CONCLUSION: In conclusion, PPARG, a gene related to immunity, has been established as a reliable potential biomarker for the diagnosis and treatment of UC. The immune response it controls plays a key role in the progression and development of UC by enabling interaction between characteristic biomarkers and immune infiltrating cells.


Assuntos
Colite Ulcerativa , PPAR gama , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colite Ulcerativa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Animais , Camundongos , Humanos , Biomarcadores/metabolismo , Biomarcadores/análise , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/imunologia , Masculino , Sulfato de Dextrana/toxicidade , Camundongos Endogâmicos C57BL
20.
Genes (Basel) ; 15(4)2024 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-38674345

RESUMO

Integrated networks have become a new interest in genome-scale network research due to their ability to comprehensively reflect and analyze the molecular processes in cells. Currently, none of the integrated networks have been reported for higher organisms. Eriocheir sinensis is a typical aquatic animal that grows through ecdysis. Ecdysone has been identified to be a crucial regulator of ecdysis, but the influence factors and regulatory mechanisms of ecdysone synthesis in E. sinensis are still unclear. In this work, the genome-scale metabolic network and protein-protein interaction network of E. sinensis were integrated to reconstruct a metabolic-protein interaction integrated network (MPIN). The MPIN was used to analyze the influence factors of ecdysone synthesis through flux variation analysis. In total, 236 integrated reactions (IRs) were found to influence the ecdysone synthesis of which 16 IRs had a significant impact. These IRs constitute three ecdysone synthesis routes. It is found that there might be alternative pathways to obtain cholesterol for ecdysone synthesis in E. sinensis instead of absorbing it directly from the feeds. The MPIN reconstructed in this work is the first integrated network for higher organisms. The analysis based on the MPIN supplies important information for the mechanism analysis of ecdysone synthesis in E. sinensis.


Assuntos
Braquiúros , Ecdisona , Mapas de Interação de Proteínas , Ecdisona/metabolismo , Animais , Braquiúros/metabolismo , Braquiúros/genética , Redes e Vias Metabólicas
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