Search Results (1,068)

Background/Objectives: Benign prostatic hyperplasia (BPH) is a prevalent urological disorder in aging men, characterized by the enlargement of prostate epithelial and stromal cells, which leads to lower urinary tract symptoms. Paeonol, a bioactive compound derived from Moutan Cortex (Paeonia suffruticosa), exhibits multiple pharmacological properties; however, its therapeutic potential in BPH remains unclear. This study aimed to elucidate the mechanisms of paeonol in BPH treatment using network pharmacology and in vivo experiments. Methods: Network pharmacology and molecular docking were conducted to identify potential targets of paeonol against BPH. For the in vivo study, testosterone-induced BPH rat models were employed, and efficacy was evaluated through prostate weight assessment, histological examination, and the quantitative real-time polymerase chain reaction (qRT-PCR) analysis of prostate tissues. Results: In silico analysis revealed key signaling pathways involved in apoptosis, proliferation, phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt), and inflammation. Paeonol administration significantly reduced prostate weight, volume, and histological hyperplasia in BPH rats. qRT-PCR analysis demonstrated that paeonol may suppress dihydrotestosterone production by inhibiting 5α-reductase 2 (5AR2) and the androgen receptor (AR), while also downregulating local growth factors, alpha serine/threonine-protein kinase (Akt1), nuclear factor-κB (NF-κB), and glutathione reductase (GR) expression. Conclusions: These findings provide novel insights into the multitargeted therapeutic potential of paeonol in BPH by inhibiting 5AR and AR and suppressing proliferation via NF-κB and Akt pathway modulation. Full article

Fiber fineness is a critical determinant of wool quality and is of great significance in enhancing the overall quality of wool. The aim of this research was to pinpoint the key proteins that participate in the regulation of wool fineness. To achieve this, we utilized Astral—DIA proteomics technology to examine the disparities in proteins, pathways, and GO terms among the wool tissues of Gansu alpine fine-wool sheep with varying mean fiber diameters (MFD). The experiment was divided into two groups: coarse (group C, MFD = 22.36 ± 0.75 μm, n = 4) and fine (group F, MFD = 16.89 ± 0.36 μm, n = 4). The results indicated that 67 differentially expressed proteins (DEPs) were identified from the wool tissues of Gansu alpine fine-wool sheep in groups C and F. Functional enrichment analysis demonstrated that several key differential proteins, including MGST3, KRT26, KRT72, KRT74, KRT71, etc., were mainly enriched in multiple functional pathways. These pathways included glutathione metabolism, oxidative phosphorylation, the degradation of valine, leucine, and isoleucine, intermediate filaments, serine protease activity, and cysteine protease activity (p < 0.05). Furthermore, protein–protein interaction (PPI) network analysis suggested that type II keratin and type I keratin (such as CTSF, PSAP, TMEM106B, LYPD3, KRT71, KRT72), along with glutathione metabolism (MGST3, W5QDB7), are closely related to hair follicle development and the regulation of wool fineness. In summary, this study enriches the existing sheep proteinome database and offers novel perspectives on the regulatory mechanisms of wool fineness. Full article

p53 protein is a nuclear phosphoprotein that is a critical tumor suppressor, playing a key role in regulating the cell cycle and initiating apoptosis in response to DNA damage. As a transcription factor, it also activates genes involved in DNA repair and cell cycle arrest. H2AX is a histone H2A variant, which is vital for detecting DNA double-strand breaks. When phosphorylated at Serine 139, it forms γH2AX, which recruits DNA repair proteins to damage sites. The interaction between p53 and γH2AX is central to the DNA damage response, where p53 activates repair pathways and γH2AX flags the DNA lesions. It is known that impairing γH2AX while preserving p53 activity may slow cancer progression. Towards understanding this, graphene quantum dots (GQDs) offer a promising solution for tracking γH2AX and analyzing DNA damage, where they can help visualize it by investigating how p53 contributes to DNA repair at sites marked by γH2AX. This study examines the interactions between γH2AX and p53 with three different-sized two-layered GQDs (2 × 3 nm, 5 × 6 nm, and 8 × 9 nm) using the Molecular Dynamics (MD) approach. Our analysis revealed that both proteins adsorbed strongly to the 5 × 6 nm and 8 × 9 nm GQDs, with 5 × 6 nm GQD having the highest stability, making it a key candidate for future biosensing and cancer research, whereas the 8 × 9 nm GQD has the greatest potential to denature the proteins. Full article

Ceramide 1-phosphate (C1P) is a key regulator of cell proliferation and survival in both normal and transformed cells. Major pathways implicated in the mitogenic actions of C1P include activation of the mitogen-activated protein kinases (MAPKs) ERK1-2 and JNK, as well as stimulation of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, the product of retinoblastoma, or the sphingomyelin synthase (SMS)/diacylglycerol (DAG)/protein kinase C-alpha (PKC-α) pathway. C1P-stimulated cell proliferation can also be mediated through enhanced secretion of vascular endothelial growth factor (VEGF) in macrophages or by releasing lysophosphatidic acid (LPA) in myoblasts. Also, the production of low levels of reactive oxygen species (ROS) can mediate the stimulation of cell growth by C1P, particularly in macrophages. Upregulation of the PI3K/Akt/mTOR pathway is also involved in the inhibition of cell death by C1P, which can also contribute to cell survival by blocking the activity of the ceramide-generating enzymes acid sphingomyelinase (ASMase) and serine palmitoyl transferase (SPT). Moreover, C1P-promoted cell survival involves upregulation of inducible nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Using photosensitive C1P analogues, it could be concluded that promotion of cell growth and inhibition of cell death were elicited by intracellularly generated C1P in a receptor-independent manner. The aim of the present review is to evaluate in detail the implication of the CerK/C1P axis in controlling cell proliferation and survival in mammalian cells, as well as to discuss and update on the molecular mechanisms by which C1P can accomplish these actions. Full article

Gestational diabetes mellitus (GDM) is a growing global health concern, driving the need for novel diagnostic and prognostic approaches. The aim of this study was to analyze the amino acid profile in the mother–fetus system (maternal venous blood, umbilical cord blood, and amniotic fluid) and to identify specific biological markers of GDM and macrosomia. Using HPLC-MS/MS, we analyzed serum from maternal venous and umbilical cord blood, along with amniotic fluid, across 94 mother–fetus pairs (53 GDM, 41 controls). Machine learning and metabolic pathway analysis revealed significant alterations in 19 amino acids. In GDM, maternal serum showed elevated 5-OH-lysine and homocitrulline, while cord blood had higher isoleucine, serine, and threonine. Amniotic fluid exhibited increased leucine, isoleucine, threonine, serine, arginine, and ornithine. Conversely, histidine, glutamine, alanine, asparagine, β-/γ-aminobutyric acids, phenylalanine, ornithine, and citrulline were reduced. Histidine, glutamine, and asparagine inversely correlated with blood glucose (r = −0.26, r = −0.33, r = −0.30) and were lower in GDM. These findings highlight three key metabolic loci in GDM pathogenesis, with glutamine, histidine, and asparagine emerging as potential maternal blood biomarkers for early macrosomia prediction. However, given confounding factors in metabolomic studies, further large-scale validation is essential. Full article

Background: Prostate cancer (PCa) is the primary contributor to male cancer-related mortality and currently lacks effective treatment options. The Modified Guizhi Fuling Decoction (MGFD) is used in clinical practice to treat multiple tumors. This research focused on the mechanisms of action (MOA) in MGFD that inhibit PCa. Methods: The impact of MGFD on PCa cells (PC3 and DU145) was examined via Cell Counting Kit-8, wound healing assays, and transwell assays. To determine the MOA, high-throughput sequencing based high-throughput screening (HTS²) was utilized along with network pharmacology. Results: The findings indicated that MGFD suppressed the proliferation, migration, and invasion of PCa cells. We then utilized the HTS² assay to generate 270 gene expression profiles from PCa cells perturbed by MGFD. Large-scale transcriptional analysis highlighted three pathways closely associated with PCa: the TNF signaling pathway, cellular senescence, and FoxO signaling pathway. Through the combination of network pharmacology and bioinformatics, we discovered four primary targets through which MGFD acts on PCa: AKT serine/threonine kinase 1 (AKT1), Caspase-8 (CASP8), Cyclin-Dependent Kinase 1 (CDK1), and Cyclin D1 (CCND1). Finally, molecular docking demonstrated that the potential bioactive compounds baicalein, quercetin, and 5-[[5-(4-methoxyphenyl)-2-furyl] methylene] barbituric acid strongly bind to CDK1, AKT1, and CASP8, respectively. Conclusions: This research shows that MGFD displays encouraging anticancer effects via various mechanisms. Its multi-target activity profile underscores its promise as a potential therapeutic option for PCa treatment and encourages additional in vivo validation studies. Full article

Objective: Lithospermum erythrorhizon has been extensively used for the clinical treatment of skin diseases, but its material basis and mechanism of action remain unclear. This study integrates network pharmacology, untargeted metabolomics, and in vitro experimental validation to elucidate the anti-inflammatory effects and underlying mechanisms of β-acetoxyisovalerylalkannin, a bioactive naphthoquinone compound isolated from Arnebiae Radix, using inflammatory skin disease models. Methods: Core targets for β-Acetoxyisovalerylalkannin and skin inflammation were identified via network pharmacology and validated through molecular docking. In vitro assays assessed β-Acetoxyisovalerylalkannin’s impact on keratinocyte proliferation, migration, apoptosis, and inflammatory factors (CXCL1, CXCL2, CXCL8, CCL20, IFN-γ, MCP-1, TNF-α, NF-κB). Non-targeted metabolomics identified differential metabolites and pathways. Results: Network pharmacology revealed 66 common targets significantly enriched in the MAPK/STAT3 signaling pathway. In vitro, β-Acetoxyisovalerylalkannin suppressed proliferative viability and hypermigration and induced apoptosis in HaCaTs. Moreover, it downregulated the mRNA levels of inflammatory markers (CXCL1, CXCL2, CXCL8, CCL20, IFN-γ, MCP-1, TNF-α, and NF-κB) by inhibiting the activation of the MAPK/STAT3 signaling pathway. Metabolomics identified 177 modified metabolites, associating them with the arginine/proline, glycine/serine/threonine, glutathione, and nitrogen metabolic pathways. Conclusions: β-Acetoxyisovalerylalkannin exerts protective effects against skin inflammation by reducing abnormal cell proliferation and inflammatory responses, promoting apoptosis, and effectively improving the metabolic abnormalities of HaCaTs. β-Acetoxyisovalerylalkannin is, therefore, a potential therapeutic option for mitigating skin inflammation-related damage. Full article

The internal mammary arteries (IMAs) and coronary arteries share many common characteristics. The inner layer (tunica intima, or intima) of both arteries is lined with a smooth, longitudinally orientated monolayer of endothelial cells (ECs), connective tissue, and an internal elastic lamina that separates the tunica intima from the tunica media (middle layer). The intima of IMAs is lined with an additional protective layer, the neointima, containing vascular smooth muscle cells (VSMCs). The neointima, located between the intima and internal elastic lamina, protects IMAs from damage by assisting in the remodeling of VSMCs. Coarse longitudinal folds in the internal elastic lamina of IMAs partially prevent the infiltration of VSMCs into damaged IMAs, and intimal thickening is thus less likely to occur. Inflamed IMAs resist the migration of monocytes across the endothelial layer and prevent the formation of lipid-rich macrophages (foam cells) within the subintimal or medial layers of arteries. IMAs are thus less likely to form plaques and develop atherosclerosis (AS). Higher levels of prostacyclin (PGI2) in IMAs prevent blood clotting. The anti-thrombotic agents, and production of tumor necrosis factor α (TNF-α), interferon-γ (INF-γ), and visfatin render IMAs more resistant to inflammation. An increase in the production of nitric oxide (NO) by ECs of IMAs may be due to small ubiquitin-like modifier (SUMO) proteins that alter the nuclear factor kappa B (NF-κB) and TLR pathways. The production of reactive oxygen species (ROS) in IMAs is suppressed due to the inhibition of NADPH oxidase (NOX) by a pigment epithelium-derived factor (PEDF), which is a serine protease inhibitor (SERPIN). In this review, a comparison is drawn between the anatomy of IMAs and coronary arteries, with an emphasis on how ECs of IMAs react to immunological changes, rendering them more suited for coronary artery bypass grafts (CABGs). This narrative review covers the most recent findings published in PubMed and Crossref databases. Full article

Background: IgA vasculitis (IgAV) represents the most frequently seen form of vasculitis among children. Although it often resolves without intervention, renal involvement (IgAV nephritis) poses a risk for long-term complications. Although the lectin and alternative complement pathways are possible causes in its development, dependable serum biomarkers for the early identification of nephritis remain unavailable. Methods: In this prospective case-control study, we examined how the serum levels of a membrane attack complex (sC5b-9), complement factor H (CFH), mannose-binding lectin (MBL), and mannose-binding lectin-associated serine protease-1 (MASP-1) relate to renal involvement in IgAV. These complement proteins were measured in children diagnosed with IgAV and compared to levels in healthy controls (HCs) matched for age and sex. Results: The study cohort comprised 44 IgAV patients with a median age of 8 years and 34 HCs. The CFH levels were reduced significantly in the patient group (median: 357.31 ng/mL; IQR: 228.32) relative to the controls (median: 543.08 ng/mL; IQR: 504.05) (p < 0.001). This decrease was observed irrespective of the presence of nephritis. There were no significant differences in serum sC5b-9, MBL, or MASP-1 levels between the patients and controls. Furthermore, no correlation emerged between these complement components and renal involvement. Conclusion: The data suggest that lower CFH levels may signal systemic dysregulation of the alternative pathway in IgAV. In contrast, the serum levels of sC5b-9, MBL, and MASP-1 appear inadequate as markers for predicting renal involvement. Further research with larger cohorts that includes genetic analyses and examination of kidney tissue is needed to better define the contribution of complement activation in IgAV-related nephritis. Full article

Soil salinity severely impairs plant growth, and polyamines such as spermidine (Spd) are known to bolster stress tolerance by acting as osmoprotectants and signaling molecules. Using TiO₂ enrichment, iTRAQ quantification, and bioinformatics analysis, we identified 870 proteins and 157 differentially phosphorylated proteins. Functional annotation showed that salt stress activated key components of the Salt Overly Sensitive pathway, particularly serine threonine kinases (SOS2) and Ca²⁺ binding sensors (SOS3). Among thirty-six SOS-associated kinases detected, eight SOS2 isoforms, four MAPKs, and two SOS3 homologs were significantly upregulated by NaCl, and Spd further increased the phosphorylation of six SOS2 proteins and one SOS3 protein under salt stress, with no detectable effect on SOS1. qRT PCR revealed enhanced expression of MAPKs and calcium-dependent protein kinases, suggesting a phosphorylation-centered model in which Spd amplifies Ca²⁺-mediated SOS signaling and reinforces ion homeostasis through coordinated transcriptional priming and post-translational control. Additional, proteins involved in protein synthesis and turnover (ribosomal subunits, translation initiation factors, ubiquitin–proteasome components), DNA replication and transcription, and RNA processing showed differential expression under salt or Spd treatment. Central metabolic pathways were reprogrammed, involving glycolysis, the TCA cycle, the pentose phosphate pathway, as well as ammonium transporters and amino acid biosynthetic enzymes. These findings indicate that exogenous Spd regulated phosphorylation-mediated networks involving the SOS signaling pathway, protein homeostasis, and metabolism, thereby enhancing cucumber salt tolerance. Full article

COVID affects around 400 million individuals today with a strong economic impact on the global economy. The list of long COVID symptoms is extremely broad because it is derived from neurological, cardiovascular, respiratory, immune, and renal dysfunctions and damages. We review here these pathophysiological manifestations and the predictors of this multi-organ pathology like the persistence of the virus, altered endothelial function, unrepaired tissue damage, immune dysregulation, and gut dysbiosis. We also discuss the similarities between long COVID and vaccine side effects together with possible common immuno-inflammatory pathways. Since the spike protein is present in SARS-CoV-2 (and its variants) but also produced by the COVID vaccines, its toxicity may also apply to all mRNA or adenoviral DNA vaccines as they are based on the production of a very similar spike protein to the virus. After COVID infection or vaccination, the spike protein can last for months in the body and may interact with ACE2 receptors and mannan-binding lectin (MBL)/mannan-binding lectin serine protease 2 (MASP-2), which are present almost everywhere in the organism. As a result, the spike protein may be able to trigger inflammation in a lot of organs and systems similar to COVID infection. We suggest that three immuno-inflammatory pathways are particularly key and responsible for long COVID and COVID vaccine side effects, as it has been shown for COVID, which may explain in large part their strong similarities: the renin–angiotensin–aldosterone system (RAAS), the kininogen–kinin–kallikrein system (KKS), and the lectin complement pathway. We propose that therapeutic studies should focus on these pathways to propose better cures for both long COVID as well as for COVID vaccine side effects. Full article

The serine protease kazal-type inhibitor (SPINK) family is central to the regulation of proteolytic function, the establishment of physiological homeostasis, and the development of many disease states, including cancer. Emerging research has identified that members of the SPINK family are commonly overexpressed in most malignancies and are deeply implicated in pivotal oncogenic pathways like cell growth, epithelial-to-mesenchymal transition (EMT), metastasis, and drug resistance. This review provides an in-depth examination of structural and functional characteristics of SPINK proteins and their involvement in the onset and development of multiple cancers, which include prostrate, pancreatic, and colorectal carcinomas. Significantly, SPINK proteins regulate major signalling pathways, including EGFR, NF-κB, and MAPK, highlighting their role as prognostic biomarkers and therapeutic targets. The review underscores the most recent advancements in therapeutic strategies for SPINK-related pathways and outlines the bottlenecks that have restricted their use in the clinic. By integrating current evidence, this work signals the potential of SPINK proteins as good precision oncology candidates with novel options for cancer prognosis, treatment, and management. Full article

Background/Objectives: Colorectal cancer (CRC) is one of the most common malignancies worldwide. microRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally and have emerged as important regulators in cancer biology. This study aimed to investigate the roles of miR-379-5p and miR-519a-3p in CRC using Quantitative Real-Time PCR (RT-qPCR) and comprehensive bioinformatic analyses. Methods: Tumor tissues and matched adjacent normal tissues were collected from 54 patients with CRC. The expression levels of miR-379-5p and miR-519a-3p in these tissues were determined using the RT-qPCR method. To investigate the functional roles of differently expressed miRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to construct miRNA–transcription factor (TF)–target gene–disease interaction networks. Results: It was found that the expression level of miR-379-5p was statistically significantly increased in tumor tissues compared to normal tissues, while miR-519a-3p was decreased (p < 0.05). GO analysis revealed enrichment in several important biological processes, including cellular protein metabolic processes, biosynthetic processes, response to stress, and nucleic acid binding TF activity. KEGG analysis exhibited that dysregulated miRNAs were associated with important pathways related to carcinogenesis, such as p53 signaling, TGF-beta signaling, and FoxO signaling pathways. Additionally, the miRNAs-TFs-Genes-Diseases Networks analysis identified ESR1 and FOXA1 as common target TFs of dysregulated miRNAs. Network analyses showed that dysregulated miRNAs interact with CRC-associated genes (Caspase 3 (CASP3), Adenomatous polyposis coli (APC), and AKT serine/threonine kinase 3 (AKT3)). Conclusions: The present study indicates that miR-379-5p and miR-519a-3p may be involved in CRC progression, with miR-379-5p being upregulated and miR-519a-3p being downregulated in tumor tissues. However, further functional studies are required to clarify their potential roles in tumor biology. The findings of the study suggest that miR-379-5p and miR-519a-3p may be associated with regulatory pathways related to CRC. These miRNAs have the potential to serve as diagnostic biomarkers or therapeutic targets in CRC. Full article

Sulforaphane, a natural isothiocyanate predominantly found in cruciferous vegetables, has shown potential in preventing and treating Helicobacter pylori infection. However, the underlying metabolic mechanisms remain largely unclear. This study employed high-coverage metabolomics and lipidomics methods to comprehensively investigate the effects of sulforaphane on the serum and liver metabolic profiles of H. pylori-infected mice. Metabolomics and lipidomics analysis revealed that H. pylori infection disrupted multiple metabolic pathways, leading to perturbations in amino acids, fatty acids, bile acids, and various lipid species. Sulforaphane treatment can ameliorate these disruptions, notably reversing alterations in serum glycerophospholipids and restoring hepatic levels of amino acids, bile acids, glycerophospholipids, ceramides, and peptides. Key metabolic pathways implicated included glutathione metabolism and glycine and serine metabolism, which are associated with antioxidant defense and host resistance to pathogenic infections. These findings offer a comprehensive metabolic basis for understanding the therapeutic effects of sulforaphane against H. pylori infection. Full article

Normal proliferation of ovarian granulosa cells is essential for follicular development. The results of this study showed that ADAMTS1 was primarily localized in the cytoplasm of granulosa cells in sheep ovarian follicles, as revealed by immunohistochemistry and immunofluorescence staining. Knockdown and overexpression experiments of ADAMTS1 in granulosa cells demonstrated that the number of EdU-positive cells significantly decreased in the knockdown group (p < 0.05), while the expression levels of Bax (p < 0.05), Bax/Bcl2 (p < 0.01), and caspase3 (p < 0.05) were significantly upregulated, indicating that knockdown of ADAMTS1 markedly inhibited granulosa cell proliferation. In contrast, overexpression of ADAMTS1 significantly promoted cell proliferation. Transcriptome sequencing revealed that PSAT1 and SLC6A9 were significantly downregulated in the knockdown group and significantly upregulated in the overexpression group, which was confirmed by Quantitative Polymerase Chain Reaction (Q-PCR) (p < 0.05). KEGG enrichment analysis showed that PSAT1 was significantly enriched in the glycine, serine and threonine metabolism and vitamin B6 metabolism pathways. Molecular docking analysis indicated a stable binding interface between ADAMTS1 and PSAT1. Based on these findings, we speculate that ADAMTS1 may regulate amino acid metabolism in ovarian granulosa cells by modulating the expression of SLC6A9, which in turn affects PSAT1 in the glycine, serine, and threonine metabolism and vitamin B6 metabolism pathways, thereby influencing granulosa cell proliferation. Full article