Search Results (10,643)

Background: The dysregulation of both glucose and lipid metabolism is the main clinical features of type 2 diabetes. Qihua Tongtiao Formula (QHTTF) is our team’s current clinical empirical formula, and the related patent has been granted. It is composed of Astragalus membranaceus, Atractylodes macrocephala koidz, Aurantii Fructus Immaturus, Radix Bupleuri, Ligusticum chuanxiong hort, Angelicae sinensis radix, Raphanus sativus, and Polyporus umbellatus. It can alleviate tissue pathological damage in type 2 diabetic rats by improving glycolipid metabolism disorders. Nevertheless, the specific mechanisms of QHTTF in the treatment of type 2 diabetes remain unclear. Purpose: This research aims to explore the fundamental effect and underlying mechanism of the QHTTF formula in ZDF rats via network pharmacology, biological validation, and metabolomics technology. Methods: The chemical compounds of QHTTF were initially identified via UHPLC-MS/MS analysis. Meanwhile, drug targets, genes, related diseases, and differential metabolites of QHTTF in the treatment of T2DM were obtained through network pharmacology, molecular docking, and metabolomics. Then, we conducted animal experiments to further explore the therapeutic molecular mechanism of QHTTF in ZDF rats. Results: A total of 39 main chemical components were recognized through LC-MS/MS technology, and 22 remained after the second screening. Network pharmacology and molecular docking results revealed that 59 intersection targets were involved in the treatment of glycolipid metabolic disorders, and the PPARα, PPARγ, and TNF proteins were identified as crucial targets through PPI network analysis. Additionally, serum metabolomics analysis of ZDF rats showed that QHTTF could regulate linoleic acid metabolism, fructose and mannose metabolism, galactose metabolism, fatty acid biosynthesis, and other related signaling pathways. The results of biological experiments proved that QHTTF effectively lowered blood glucose and lipid levels, alleviated hepatic and pancreatic pathological damage, increased the expression of IRS-1 and GLUT4 in the pancreas, and improved insulin resistance, while inhibiting the inflammatory response and oxidative stress, as well as enhancing the expression of liver PPARα, PPARγ, and AMPK proteins in ZDF rats. Conclusions: In summary, QHTTF exerted a significant effect in improving glycolipid metabolism disorders of ZDF rats, which might show therapeutic effects by relieving insulin resistance, mitigating inflammation and oxidative damage, regulating related glucose, fatty acid, and amino acid metabolism, and increasing the expression of PPARα, PPARγ, and AMPK proteins by combining network analysis, metabolomics, and biological research. Full article

It is of great significance to analyze the molecular mechanism of rice response to heavy ion irradiation and to mine its key response genes for food security. In this study, the regression equation for the dose survival rate was constructed using heavy ion irradiation on rice pollen. Through an immunofluorescence experiment, it was found that DSBs induced by irradiation could be repaired quickly, but the repair of complex damage required more time. RNA-seq of irradiated pollen showed that the gene expression patterns at different time points were significantly different. A total of 5,556 differentially expressed genes (DEGs) were screened out, and the number of DEGs decreased with time. DEGs were mainly involved in stress response, protein folding, DNA repair, and other damage response processes at 0–1 h. At 6 h, the cells turned to normal metabolism functions, such as organic synthesis and protein activity. Combined with weighted gene co-expression network analysis (WGCNA) and trend analysis, the key transcription factor OsERF110 was identified in response to heavy ion irradiation, which acts on the nucleus and cell membrane. A total of 45,680 OsERF110 binding peaks were identified by DNA affinity purification sequencing (DAP-seq) in the whole genome. When this method was combined with RNA sequencing (RNA-seq), 62 OsERF110 target genes were further screened. These target genes were involved in DNA repair, stress response, redox, metabolic regulation, and other processes, forming the OsERF110 mediated radiation response regulatory network. The results of this study provide a new target for rice mutation breeding and lay a theoretical foundation for radiation biology research. Full article

Various signalling molecules and pathways critical for wool production and quality regulate wool secondary follicle (SF) development. Circular RNAs (circRNAs) regulate SF morphogenesis through a competing endogenous RNA (ceRNA) mechanism; these novel cyclic non-coding RNAs are not known to regulate the development of SFs in the foetal period of fine-wool sheep. Here, we analysed circRNA expression profiles in the foetal skin of Gansu Alpine fine-wool sheep at 10 developmental stages (E87, E90, E93, E96, E99, E102, E105, E108, E111, and E138) using RNA sequencing. Among the differentially expressed circRNAs (DE circRNAs), 173 were significantly enriched in signalling pathways related to hair follicle (HF) development, such as Wnt/β-catenin, transforming growth factor-β/Smad, Notch, and mitogen-activated protein kinase. Six HF-development-related circRNAs were expressed at different stages and potentially regulated SF development through the ceRNA network. In total, 16 DE circRNAs and their targets, 44 miRNAs, and 65 mRNAs were screened, and 88 ceRNA regulatory network pathways related to SF development were constructed. These key DE circRNAs could be candidate genes for further exploration of the molecular HF development mechanism, providing an important theoretical basis for unravelling the regulatory network of SF development in fine-wool sheep and genetic wool trait improvement. Full article

Cell-free DNA (cfDNA), shed by malignant tumor cells into extracellular fluid, provides valuable epigenetic information indicative of cancer status. Nipple aspirate fluid (NAF), a noninvasive liquid biopsy from at-risk women, contains nucleic acid and protein biomarkers from adjacent cancer cells, showing promise for breast cancer (BrC) detection. However, despite its potential, the application of cfDNA in NAF for BrC screening is still underexplored. Here, we report a proof-of-concept study for using cfDNA bisulfite sequencing (cfBS) to assess tumor DNA methylation signatures from NAF samples. For four healthy individuals and three BrC patients, cfBS achieved greater than 20× sequencing depth with an average coverage of 26.5× on the genome. A total of 7471 differentially methylated regions were identified, with significant hypermethylation in BrC samples compared to healthy controls. Gene set enrichment analysis indicated that the differentially methylated genes (DMGs) were significantly associated with epithelial–mesenchymal transition (EMT). By developing a novel EMT scoring metric, we found that BrC samples had more of a mesenchymal phenotype than samples from healthy individuals. CDH1, WNT2, and TRIM29 were hypermethylated near the promoter region, while COL5A2 was hypermethylated in the coding region. The DNA methylation and EMT changes were validated through The Cancer Genome Atlas Breast Invasive Carcinoma study, which confirmed that DMGs were associated with gene expression change and that our methylation-based EMT score reliably distinguished tumors from healthy controls. Our findings support the utilization of the NAF cfDNA cfBS methylation profile for noninvasive BrC screening and pave the way for enhanced early detection of this disease. Full article

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) that is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene, resulting in constitutively active FLT3 variants, are frequently found in patients with acute myeloid leukaemia (AML). In particular, patients expressing FLT3 ITD (internal tandem duplications of the juxtamembrane domain of FLT3) correlate with poor patient survival. Targeting FLT3-mutated leukaemic stem cells is therefore a key to the efficient treatment of patients with relapsed/refractory AML. The efficacy of approved tyrosine kinase inhibitors is regularly compromised by various resistance pathways or secondary mutations. Based on the current molecular understanding of aberrant signal transduction pathways and cell transformation, novel alternative treatment approaches can be exploited for therapeutic purposes. In particular, new insights into the regulation of the activity of counteracting protein tyrosine phosphatases (PTPs), the aberrant biogenesis and activation of mutant FLT3 proteins, as well as common factors controlling cell transformation are attractive avenues. This review summarises the current knowledge about the regulation of the oncogenic activities of mutant FLT3 proteins and discusses possible options for alternative treatments. Full article

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide, mainly due to late diagnosis and high metastatic potential. Effective management requires accurate diagnostic, prognostic, and therapeutic strategies, with growing focus on molecular biomarkers. Chemokines, which are small, secreted proteins regulating immune cell migration and tissue homeostasis, shape the tumor microenvironment by promoting tumor growth, angiogenesis, immune evasion, and metastasis. In CRC, the expression of altered chemokine–receptor profiles correlates with progression and clinical outcomes. Chemokines are classified by the presence or absence of the ELR motif, which differentiates CXC subgroups. Selection focused on those consistently altered in CRC tissues or serum and involved in key oncogenic processes. CXCL1 and its receptor CXCR2 are overexpressed and linked to tumor progression, highlighting their diagnostic and therapeutic potential. CXCL8 is elevated in tissues and serum, correlating with metastasis and poor survival. The CXCL12/CXCR4/CXCR7 axis drives metastasis. CXCL13 promotes immune evasion via CXCR5, while CXCL14 is downregulated, suggesting a protective role. Moreover, CXCL16 associates with worse outcomes, whereas CXCR6 may enhance immunotherapy response. Overall, chemokines and receptors are promising blood biomarkers and therapeutic targets in CRC. Further validation is needed using large prospective studies, standardized assays, and multi-marker approaches to establish their potential as non-invasive CRC biomarkers. Full article

Hepatitis E virus (HEV) is one of the pathogens that cause viral hepatitis, and its clinical symptoms can manifest as acute, chronic viral hepatitis, or asymptomatic infection. Among them, swines are the main animal source of HEV. Open reading frame 3 (ORF3) is a multifunctional protein essential for swine hepatitis E virus (SHEV) infection and release, involved in biological processes such as intracellular signal transduction regulation. In our preliminary research, we utilized adenovirus-mediated overexpression of type IV SHEV ORF3 in HepG2 cells, extracted total RNA, and performed high-throughput long non coding RNAs (lncRNAs) and transcriptome sequencing. In this study, we screened and analyzed lncRNAs involved in the GO pathway: viral process (GO: 0016032), and combined them with differentially expressed mRNAs for target gene prediction. We identified two lncRNAs—lncRNA AL137002 (MSTRG. 7478) and lncRNA AL049840 (MSTRG. 8427)—that are associated with viral progression and have p ≤ 0.05 in HepG2 cells expressing ORF3 of porcine hepatitis E virus type IV. We predicted their five lncRNA-mRNA networks, which are lncRNA AL137002 (MSTRG. 7478)-ENST0000375440, lncRNA AL137002 (MSTRG. 7478)-ENST0000375441, lncRNA AL049840(MSTRG. 8427)-ENST0000246489, lncRNA AL049840 (MSTRG. 8427)-ENST0000554280 and lncRNA AL049840 (MSTRG. 8427)-ENST0000452929, and were used to predict their lncRNA mRNA binding sites and construct relevant molecular models. This will lay a solid foundation for further revealing the function of SHEV ORF3 and elucidating the mechanism of SHEV infection. Full article

Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders globally. The molecular relationship between common respiratory infections (RIs) and idiopathic Parkinson’s disease (iPD) remains a controversial issue. Multiple studies have linked acute respiratory infections to PD, but the molecular mechanism behind this connection is not significantly defined. Therefore, the aim of our study was to investigate potential molecular interactions between RIs and PD. We retrieved eight publicly available RNA-seq datasets from the NCBI Gene Expression Omnibus (NCBI GEO) and performed extensive bioinformatics analysis, including differential gene expression (DGE) analysis, the identification of overlapped differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), pathway and functional enrichment analysis, the construction of protein–protein networks, and the identification of hub genes. Additionally, we applied a machine learning method, a Random Forest model (RF), to external RIs datasets to identify the most important genes. We found that ribosomal subunits, mitochondrial complex proteins, proteasome subunits, and proteins encoding ubiquitin are simultaneously downregulated and co-expressed in RIs and PD. Dysregulation of these proteins may disturb multiple pathways, such as those responsible for ribosome biogenesis, protein synthesis, autophagy, and apoptosis; the ubiquitin–proteasome system (UPS); and the mitochondrial respiratory chain. These processes have been implicated in PD’s pathology, namely in the aggregation of α-synuclein, mitochondrial dysfunction, and the death of dopaminergic neuron cells. Our findings suggest that there are significant similarities in transcriptional responses and dysfunctional molecular mechanisms between RIs, PD, and aging. RIs may modulate PD-relevant pathways in an age- or immune-dependent manner; longitudinal studies are needed to examine the RIs risk factor. Therefore, future studies should experimentally investigate the influence of age, vaccination status, infection type, and severity to clarify the role of RIs in PD’s pathogenesis. Full article

Background: Major depressive disorder (MDD) is a prevalent and disabling psychiatric illness with complex etiologies involving both genetic and environmental factors. While environmental stress is a known risk factor of MDD, the molecular mechanisms linking stress exposure to persistent depressive phenotypes remain incompletely understood. Methods: We established a 24-hour restraint stress-induced depression model in mice and performed integrated transcriptomic and proteomic analyses of the medial prefrontal cortex (mPFC) to investigate stress-related molecular alterations. Results: Behavioral assessments confirmed persistent depression-like phenotypes, including anhedonia and behavioral despair, lasting up to 35 days post-stress. RNA sequencing identified differentially expressed genes related to dopaminergic signaling and oxidative stress. Proteomic analysis identified 105 differentially expressed proteins involved in immune response and energy metabolism. Integrated multi-omics analysis highlighted convergent disruptions in immune regulation, metabolism, and epigenetic processes. Notably, clemastine exerts its antidepressant-like effects in part by mitigating neuroinflammation and preserving mitochondrial function. Conclusions: These findings provide novel insights into the molecular basis of stress-induced depression and suggest that clemastine is a potential therapeutic candidate. Full article

Colletotrichum graminicola, the causative agent of maize anthracnose leaf blight and stalk rot, severely jeopardizes the healthy development of the maize industry. Auxiliary activity enzymes (AAs), a vital subclass of carbohydrate-active enzymes, act as beneficial accessory proteins for fungi in degrading lignocellulose. This study identified 127 AA genes from the genome of C. graminicola strain TZ-3 and further analyzed the subcellular localization, conserved motifs, and domains of the proteins encoded by these genes. The CgAA genes exhibited significant variations in gene structure, and the structural motifs within their encoded proteins also differed. Subcellular localization analysis revealed that most CgAA proteins were localized in the extracellular space. Moreover, the CgAA gene family contained abundant conserved domains, suggesting diverse functionalities and potential roles in various fungal biological processes. Multiple cis-acting regulatory elements related to stress responses and plant hormones were detected in the promoter regions of these genes. This study analyzed the expression patterns of CgAA genes during pathogen–host interactions and found that most CgAA genes were differentially expressed in the interaction between C. graminicola and maize. Coupled with GO functional analysis, it was discovered that CgAAs are deeply involved in the interaction between C. graminicola and maize, closely associated with the pathogenic mechanisms of the pathogen, and may play crucial roles in the initiation and expansion of fungal infections. These results provide valuable resources for elucidating the functions of AA genes and lay the groundwork for sustainable agricultural development through the utilization of AA genes in disease control and the breeding of stress-resistant, high-yield crop varieties. Full article

Background: Glucose intolerance (GI) is a metabolic disorder that is a consequence of hyperglycemia. Glucose intolerance can, under some conditions, progress to type 2 diabetes mellitus (T2D), where insulin is insufficiently utilized. As a result of genetic and lifestyle effects, the incidence of T2D has increased worldwide. Pathophysiological consequences of the disease may include retinopathy, nephropathy, and neuropathy. Skeletal muscle is one of the major organs that regulates blood sugar homeostasis, both at rest and during exercise. Thus, understanding the molecular and genetic perspectives on the contribution of skeletal muscles to the predisposition to diabetes is a hot topic in diabetes research. In this study, we conducted a differential analysis of gene expression and compared the expression profiles of all the genes in the skeletal muscles of normal, glucose-intolerant, and diabetic individuals via the Affymetrix HGU133plus2 platform. Data were collected from the Gene-Expression Omnibus (GEO) series GSE18732. Gene Ontology enrichment and perturbed pathways were thoroughly analyzed. Results: We found that genes that were significantly differentially expressed between the different tissues contribute to metabolic pathways related to glucose homeostasis, as well as several signaling pathways related to insulin signaling, e.g., the MAPK, mTOR, Toll-like receptor (TLR), p53, WNT and neurotrophin signaling pathways. Furthermore, some genes related to several malignancies were also differentially expressed across the different clinical groups. Additionally, some of these genes are related to epigenetic regulation. Furthermore, other differentially expressed genes were connected to several myopathies. Conclusions: This study may serve as a gene-based analysis that contributes as a basis for further analysis. This investigation may include gene and protein networks that serve in understanding diabetes, the mechanism of action of the involved proteins, and pharmacology and drug design targeting T2D. Full article

Background: In high-altitude regions, sporadic two-year-old immature Chinese mitten crabs (Eriocheir sinensis) would overwinter and mature in their third year, developing into three-year-old crabs (THCs) with a cold-adaptive strategy. Compared to two-year-old crabs (TWCs) from low-altitude Jiangsu, THCs from Karst landform and high-altitude Guizhou exhibit significantly larger final size but lower gonadosomatic index (GSI) (p < 0.01). Methods: To elucidate the molecular mechanisms underlying this delayed ovarian development, integrated transcriptomic and proteomic analyses were conducted. Results: Results showed downregulation of PI3K-Akt and FoxO signaling pathways, as well as upregulation of protein digestion and absorption pathways. Differentially expressed proteins indicated alterations in mitochondrial energy transduction and nutrient assimilation. Integrated omics analysis revealed significant changes in nucleic acid metabolism, proteostasis, and stress response, indicating systemic reorganization in energy-nutrient coordination and developmental plasticity. Conclusions: The observed growth-reproductive inverse relationship reflects an adaptive life-history trade-off under chronic cold stress, whereby energy repartitioning prioritizes somatic growth over gonadal investment. Our transcriptomic and proteomic data further suggest a pivotal regulatory role for FOXO3 dephosphorylation in potentially coupling altered energy sensing to reproductive suppression. This inferred mechanism reveals a potential conserved pathway for environmental adaptation in crustaceans, warranting further functional validation. Full article

Lacticaseibacillus rhamnosus (Lbs. rhamnosus) is renowned for its tolerance to gastric acid and adaptability to bile and alkaline conditions, and is crucial for intestinal health and immune regulation. In this study, integrated transcriptomic and proteomic analyses were employed to elucidate the response mechanisms of Lbs. rhamnosus under osmotic stress, induced by exposure to 0.6 M sodium lactate, which elevates environmental osmotic pressure. It was shown that 792 differentially expressed genes and 138 differentially expressed proteins were detected in Lbs. rhamnosus ATCC 53103 treated with osmotic stress. The differential regulation of these genes/proteins mainly includes the inhibition of fatty acid metabolism with membrane structural remodeling (downregulation of the acetyl coenzyme A carboxylase family and fatty acid binding protein family expression), dynamic homeostasis of amino acid metabolism (restriction of the synthesis of histidine, cysteine, leucine, etc., and enhancement of the catabolism of lysine, tryptophan, etc.), and survival-oriented reconfiguration of carbohydrate metabolism (gene expression related to the glycolytic pathway increases, while gene expression related to the pentose phosphate pathway decreases). These synergistic alterations in metabolic regulation may facilitate the adaptive response of Lbs. rhamnosus ATCC 53103 to osmotic stress. Overall, our findings deepen the current understanding of the stress response mechanisms in lactic acid bacteria and offer novel insights into the survival strategies employed by Lbs. rhamnosus ATCC 53103 under hyperosmotic conditions. Full article

Background and Objectives: The Drosophila retinal determination network comprises the transcription factor Teashirt (Tsh) and the transcription co-regulator C-terminal Binding Protein (CtBP), both of which are essential for normal adult eye development. Both Tsh and CtBP show a pattern of co-expression in the proliferating cells anterior to the morphogenetic furrow that demarcates the boundary between the anteriorly placed proliferating eye precursor cells and the posteriorly placed differentiating photoreceptor cells in the larval eye-precursor tissue, the eye–antennal disc. The disc ultimately develops into the adult compound eyes, antenna, and other head structures. Both Tsh and CtBP were found to interact genetically during ectopic eye formation in Drosophila, and both were present in molecular complexes purified from gut and cultured cells. However, it remained unknown whether Tsh and CtBP molecules could interact in the eye–antennal discs and elicit an effect on eye development. The present study answers these questions. Methods: 5′ GFP-tagging of the tsh gene in the Drosophila genome and 5′ FLAG-tagging of the ctbp gene were accomplished by the CRISPR-Cas9 and BAC recombineering methods, respectively, to produce GFP-Tsh- and FLAG-CtBP-fused proteins in specific transgenic Drosophila strains. Verification of these proteins’ expression in the larval eye–antennal discs was performed by immunohistological staining and confocal microscopy. Genetic screening was performed to establish functional interaction between Tsh and CtBP during eye development. Scanning Electron Microscopy was performed to image the adult eye structure. Co-immunoprecipitation and GST pulldown assays were performed to show that Tsh and CtBP interact in the cells of the third instar eye–antennal discs. Results: This study reveals that Tsh and CtBP interact genetically and physically in the Drosophila third instar larval eye–antennal disc to regulate adult eye development. This interaction is likely to limit the population of the eye precursor cells in the larval eye disc of Drosophila. Conclusions: The relative abundance of Tsh and CtBP in the third instar larval eye–antennal disc can dictate the outcome of their interaction on the Drosophila eye formation. Full article

The American cockroach (Periplaneta americana) serves as an exemplary model for regeneration research due to its exceptional regenerative capabilities, particularly in appendage regeneration. In this study, regenerated coxa tissue underwent histological analysis through H & E straining. Microscopic examination revealed the progression of regeneration. To elucidate the underlying mechanisms, a comparative transcriptomic analysis was conducted between regenerating legs and non-amputated control legs. This analysis identified 2343 differentially expressed genes (DEGs) between 0 days post-amputation (0 dpa) and 7 dpa, 2963 DEGs between 14 dpa and 0 dpa, and 3135 DEGs between 14 dpa and 7 dpa. Significantly, several DEGs are associated with growth- or regeneration-related processes, including extracellular matrix (different collagen, Pro-resilin isoforms, integrin beta (itgb) and matrix metalloproteinase (mmp)), immune-related genes (Toll-like receptor 13 (tlr13), defensin (def), drosomycin-like defensin (dld), Polyphenoloxidases2 (ppo2), cytochrome P450 (p450), peptidoglycan recognition protein (pgrp) and secreted C-type lectin (sClec)), insulin-like growth factor (IGF) and Epidermal Growth Factor Receptor (EGFR). Functional validation through RNA interference (RNAi) further suggested that EGFR and a specific C-type lectin (Regenectin) regulate leg regeneration in Periplaneta americana. These findings enhance our understanding of the molecular mechanisms governing regeneration in this species. Full article