Frontiers in bioscience (Landmark edition)最新文献

Background: Peritoneal fibrosis is a significant complication arising from long-term peritoneal dialysis (PD), primarily due to the loss of peritoneal mesothelial cells (PMCs). Recent studies have implicated periostin (POSTN) in the progression of various fibrotic diseases; however, its specific role in PD-induced peritoneal fibrosis remains unclear. Sodium alginate (SA) microgels have emerged as promising carriers for cell encapsulation in tissue engineering and regenerative medicine. This study investigated the therapeutic potential of PMCs encapsulated in SA microgels (SA/PMC) for reducing PD-induced peritoneal fibrosis, with a focus on the modulation by the periostin/nuclear factor kappa-B (NF-κB)/CXCL8 signaling pathway.

Methods: Primary human peritoneal mesothelial cells (PHPMCs) were isolated from the PD effluent of patients. The effect of SA encapsulation on PMCs proliferation was evaluated using a Cell Counting Kit 8 (CCK-8) assay. The expression levels of POSTN, NF-κB p65, and CXCL8, as well as fibrosis markers, including α-smooth muscle actin (α-SMA), collagen I, transforming growth factor-β (TGF-β), and fibronectin, were evaluated in patients undergoing PD and a PD mouse model.

Results: Patients undergoing PD for 1 year exhibited elevated levels of POSTN, NF-κB p65, CXCL8, and fibrosis markers compared with those undergoing PD for 1 week.

Conclusions: Consistent results from in vivo and in vitro models demonstrated that PD and hyperglycemic conditions upregulated the expression of POSTN, NF-κB p65, CXCL8, and profibrotic markers, leading to peritoneal thickening and fibrotic progression. Treatment with SA/PMC microgels ameliorated these effects. By modulating the POSTN/NF-κB/CXCL8 pathway and enhancing PMCs survival, SA/PMC microgels may have therapeutic potential in mitigating peritoneal fibrosis in PD patients.

Background: Cysteine and Glycine Rich Protein 1 (CSRP1) is a member of the cysteine-rich protein family, characterized by a unique double-zinc finger motif. It plays an important role in development and cellular differentiation. Aberrant expression of CSRP1 has been reported in several malignancies, including prostate cancer and acute myeloid leukemia. However, its function in renal cell carcinoma (RCC) remains unexplored. In this study, we investigated the role of CSRP1 in RCC for the first time.

Methods: CSRP1 and programmed death-ligand 1 (PD-L1) expression levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The effects of CSRP1 overexpression on cellular proliferation, migration, and apoptosis were assessed in vitro through CCK-8, wound healing, and flow cytometry assays. To evaluate the role of CSRP1 in immunotherapy, Balb/c mice were treated with anti-PD-L1 antibody, and tumor growth was monitored.

Results: In vitro, overexpression of CSRP1 significantly inhibited proliferation and migration of A498 cells while enhancing their sensitivity to sunitinib treatment. Mechanistically, CSRP1 overexpression downregulated PD-L1 expression in RCC cells. In BALB/c mice inoculated with Renca cells, CSRP1 overexpression led to reduced tumor growth and improved response to anti-PD-L1 therapy.

Conclusion: CSRP1 may play a role in regulating cell viability, migration, drug resistance, and possibly innate immunity in RCC. These findings suggest that CSRP1 could increase the efficacy of targeted drugs and immunotherapy in combination treatment strategies for RCC.

Background: Hepatocellular carcinoma (HCC) is as the most frequently observed histological subtype among primary liver malignancies. While quercetin (QT) shows potential antitumor activity, its preclinical anti-HCC effects and safety (especially in animals) remain unclear. Most existing studies use single methods (e.g., individual animal or in vitro assays), which compromises the reliability of the conclusions. This study's novelty lies in its use of a combined approach-integrating meta-analysis to quantify efficacy and network pharmacology to explore mechanisms, with experimental validation-to address this research gap. This work explores QT's preclinical anti-HCC effects and adverse effects using this integrated approach.

Methods: We collected literature on the treatment of HCC with QT from January 2000 to August 2024. Nine articles meeting the requirements were included in the current study. Subsequent to this, a meta-analysis was conducted, with further validation via network pharmacology approaches and experimental assays.

Results: A meta-analysis found that QT significantly inhibited HCC growth (reduced tumor volume/weight) and reduced mortality in tumor-bearing mice, with no significant effect on body weight. Network pharmacology identified protein kinase B alpha (AKT1) and the phosphoinositide 3-kinase (PI3K)/AKT pathway as potential therapeutic targets. Finally, the aforementioned conclusions were further verified through experimental validation.

Conclusion: Preclinically, QT effectively inhibited HCC growth and reduced mortality in tumor-bearing mice without affecting body weight, likely via the PI3K/AKT pathway (targeting AKT1). Our study results furnish preliminary evidence for QT as a promising candidate for HCC adjuvant treatment, supporting its further evaluation in clinical trials. Limitations include reliance on preclinical data; thus, the translational value needs clinical validation, and the underlying mechanisms require more in-depth investigation.

Background: Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Although dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, has demonstrated significant cardiovascular benefits in large clinical trials, the underlying mechanisms beyond glucose lowering remain incompletely understood. Increasing evidence suggests that gut microbiota and its metabolites may contribute to HF progression through gut-heart axis interactions.

Methods: In this study, a total of 135 individuals with HF were recruited, comprising 84 patients treated with dapagliflozin (Y group) and 51 receiving conventional therapy (N group). Gut microbial communities were characterized through 16S rRNA gene sequencing to evaluate compositional structure, diversity metrics, and taxa differences between groups. Untargeted metabolomic profiling of plasma samples was conducted to identify significantly altered metabolites and enriched metabolic pathways. Furthermore, the interrelationships between gut bacterial taxa and circulating metabolites were systematically explored to delineate potential microbiome-metabolome interactions.

Results: Dapagliflozin treatment significantly altered gut microbial composition (p < 0.05, permutational multivariate analysis of variance [PERMANOVA]), characterized by increased Prevotella, Akkermansia, Collinsella, and Fusobacterium, and reduced Bacteroides, Parabacteroides, Subdoligranulum, and Bifidobacterium in the dapagliflozin group, whereas control-enriched taxa included Lachnoclostridium and the Ruminococcus gauvreauii group. Fourteen plasma metabolites were differentially abundant between groups, including higher levels of O-phospho-L-threonine and epiandrosterone in the dapagliflozin group, while salicyluric acid and L- (+)-rhamnose were enriched in the control group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated alterations in amino acid and one-carbon metabolism, as well as carbohydrate and steroid-related pathways. Correlation analysis revealed that Collinsella was positively associated with fludarabine phosphate (p < 0.05), whereas Akkermansia and Paraprevotella showed negative correlations with maslinic acid and phospho-L-valine, respectively (p < 0.01 to p < 0.001).

Conclusion: Dapagliflozin modulates gut microbiota composition and circulating metabolic signatures in HF patients, supporting a potential gut-heart axis mechanism contributing to its cardioprotective effects.

Background: Hyperuricemic nephropathy is associated with mitochondrial dysfunction. Dynamin-related protein 1 (DRP1), a key regulator of mitochondrial fission, is activated under stress and translocates to the mitochondria, where it interacts with adapter proteins such as mitochondrial fission 1 protein (FIS1), thereby promoting excessive mitochondrial fission and apoptosis. Recent research has shown that inhibiting the DRP1/FIS1 interaction can reduce cellular injury in various disease models; however, its role in hyperuricemic nephropathy is unclear.

Methods: An in vitro model of hyperuricemic nephropathy was established by treating human renal tubular epithelial cells with uric acid (UA). Reverse transcription quantitative PCR and western blotting, and enzyme-linked immunosorbent assays were used to quantify the mRNA and protein levels of the target molecules. A specific peptide inhibitor, P110, was used to disrupt the binding between DRP1 and FIS1. Co-immunoprecipitation (Co-IP) was performed to confirm the interactions between DRP1 and FIS1. Cell viability was assessed using propidium iodide staining and the Cell Counting Kit-8 assay.

Results: UA significantly upregulated DRP1 expression, activated DRP1, and promoted mitochondrial translocation. P110 inhibited DRP1/FIS1 binding, preventing DRP1 UA-induced mitochondrial translocation. Excessive mitochondrial fission, reactive oxygen species generation, release of inflammatory factors, and apoptosis were significantly alleviated. In addition, inhibition of DRP1 mitochondrial translocation decreased the expression of apoptosis-related markers and apoptosis.

Conclusions: The overactivation of DRP1 is crucial for UA-induced renal tubular epithelial cell injury. P110 exerts a cytoprotective effect by inhibiting the DRP1/FIS1 interaction and modulating the mitochondrial apoptotic pathway. This study proposes a possible target for therapeutic intervention in the treatment of hyperuricemic nephropathy.

Background: Klebsiella pneumoniae is one of the most critical Gram-negative bacteria according to the World Health Organization (WHO). Due to the ability of this bacterium to evade antibiotics, phage therapy is becoming a promising tool. However, the use of isolated proteins rather than entire phages could reduce several risks associated with phage replication. Thus, understanding the protein composition and structural organization of bacteriophages is crucial for unlocking their biology and holds great potential for medicine and biotechnology.

Methods: In this study, artificial intelligence with AlphaFold 3.0 (AF3) and bioinformatic analysis were used to model the hitherto unknown structure of the Klebsiella phage KP32 (KP32), a complex and selective phage that targets K. pneumoniae strains with the K3 and K21/KL163 capsular serotypes.

Results: By combining AF3 with sequence and structure analysis, we reconstructed the entire phage KP32. This complex phage is composed of over 500 protein chains, of which 415 compose its capsid and 104 its core-portal-tail complex, a platform that allows the phage to adhere to K. pneumoniae, hydrolyze its capsular sugars and finally inject its genetic code into the bacterium.

Conclusions: Phage therapy is a potentially promising tool for controlling antimicrobial resistance (AMR). However, one limitation arises from the limited knowledge of their nature and mechanisms of action, as only a few phages have been structurally characterized. The reconstruction of entire phages is currently a viable strategy for elucidating their mechanistic properties, knowledge that will enhance their potential applications as therapeutic alternatives.

Background: Although epirubicin is used among therapeutic options for multiple myeloma (MM), its clinical use remains limited, in part because the subgroup of patients most likely to benefit has not been clearly defined. Identifying robust biomarkers capable of predicting chemosensitivity is therefore essential to aimed personalized treatment strategies and enhance therapeutic outcomes. This study sought to characterize the molecular effects of epirubicin in MM cells, elucidate its tumor-suppressive mechanisms, and determine potential indicators for patient stratification.

Materials and methods: The half-maximal inhibitory concentration (IC50) for epirubicin was quantified using the Cell Counting Kit-8 (CCK-8) viability assay. Gene expression alterations before and after epirubicin exposure were investigated via microarray profiling, followed by bioinformatic interrogation of publicly available datasets to examine the prognostic value of CDC20 expression in MM. Subsequently, functional validation was performed through in vitro assays and in vivo xenograft models to evaluate the impact of epirubicin on cell-cycle progression and tumor growth.

Results: Epirubicin exhibited an IC50 of 23.85 μM in MM.1R cells. Transcriptome analysis revealed 115 genes upregulated and 25 genes downregulated post-treatment. Among the significantly altered genes were CDC20 (log FC = -2.409), KIF20A (log FC = -1.693), FAM72A (log FC = -1.742), CCNB1 (log FC = -1.787), PIF1 (log FC = -2.201), and LMNB1 (log FC = -1.589). Higher CDC20 expression was associated with shorter overall survival (OS), event-free survival (EFS), and post-progression survival (PPS). Mechanistic studies demonstrated that epirubicin triggers G2/M arrest in MM cells by suppressing CDC20, and in vivo experiments corroborated that decreased CDC20 expression contributes to reduced tumor proliferation via cell-cycle blockade.

Conclusion: Epirubicin exerts anti-myeloma effects by downregulating CDC20 and inducing cell-cycle arrest in MM, highlighting CDC20 as a potential biomarker for identifying MM patients likely to benefit from epirubicin.

Background: Natural killer (NK) cells are crucial in inflammatory skin diseases, but their diverse functions and lack of a standardized classification system across diseases have limited deeper insights into their roles.

Methodology: We merged single-cell transcriptomic data from 40 skin samples to create a comprehensive atlas of NK cells across various skin diseases, identifying nine distinct NK cell subsets with unique functions.

Results: Our analysis revealed a conserved Aryl Hydrocarbon Receptor (AHR)⁺ NK cell subset that is broadly present across multiple skin diseases. Notably, the Granzyme B (GZMB)⁺ NK cell subset may be associated with the pathogenesis of psoriasis (PSO) and appears to undergo a differentiation trajectory toward IL13⁺ NK cells in the pseudotime analysis. This finding suggests a potential role for these cells in mediating paradoxical cutaneous inflammation. Our analysis identified NK cells expressing GZMB in a variety of skin diseases. Notably, the NK cell subpopulation expressing GZMB appears to be associated with the pathogenesis of PSO and ultimately exhibits the expression of IL13 in pseudotime analysis, suggesting that it may play a role in regulating contradictory skin inflammation.

Conclusion: This study offers a comprehensive overview of skin NK cells, identifies pathogenic subsets that may drive skin disease progression, and provides novel insights for future targeted therapies.

Background: Premature ovarian insufficiency (POI) is a condition marked by diminished ovarian function and reduced fertility, caused by the chemotherapy drug cyclophosphamide (CTX) used to treat gynecologic cancers. The abnormal inflammation of ovarian tissue induced by CTX represents a key factor that impairs follicular cells and disrupts fertility. Therefore, the present study aims to investigate the underlying mechanisms of CTX-induced abnormal ovarian inflammation and identify potential therapeutic agents.

Methods: RNA sequencing data derived from CTX-induced mouse ovarian tissues were first intersected with inflammation-related genes retrieved from the Gene Ontology (GO) database. This was followed by functional enrichments analysis and protein-protein interaction (PPI) analyses to identify target genes. Subsequently, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was screened to obtain corresponding candidate therapeutic agents. Finally, a CTX-induced mouse model was established to verify the therapeutic efficacy of the candidate drug and elucidates its underlying mechanisms.

Results: A total of 25 candidate genes were identified, with interleukin 1β (IL1β) confirmed as the core gene. Subsequent screening resulted in the identification of Irisolidone as a potential therapeutic agent. The present study demonstrated that Irisolidone ameliorates CTX-induced follicular cell developmental impairment and improves fertility in mice with POI. Mechanistically, it was found that Irisolidone suppressed abnormal ovarian inflammation by inhibiting the CTX-disrupted nuclear factor kappa B (NFκB)/NOD-like receptor pyrin domain-containing 3 (NLRP3)/Caspase1 signaling pathway.

Conclusion: The present study demonstrates that Irisolidone can effectively alleviate CTX-induced POI by inhibiting abnormal inflammation. These findings suggest that Irisolidone holds promise as a novel therapeutic candidate for POI, thereby providing a potential new treatment strategy for clinical management of this condition.

Background: Genes belonging to the adenylate cyclase (ADCY) family regulate various biological processes, including tumor metabolism, metastasis, angiogenesis, and immune escape. However, the functions of these genes in multiple cancers unclear.

Methods: This study analyzed the expression, prognostic value, correlation, mutation, and methylation patterns of ten genes belonging to the ADCY family across multiple cancers using multi-omics data. Additionally, the correlation between ADCY5 and immune cells, as well as the function of ADCY5 in multiple cancers were examined using single-cell data and spatial transcriptomic data.

Results: Ten ADCY family genes were differentially expressed in most tumors and normal tissues, and their aberrant expression in multiple cancers significantly reduced patient survival. The expression level of ADCY5 was significantly correlated with the immune microenvironment. We also identified and validated the potential of ADCY5 as a potential biomarker for gastric cancer.

Conclusion: Our pan-cancer analysis nominates the ADCY family as a source of potential cancer biomarkers. We specifically validated ADCY5 in gastric cancer, establishing it as a promising prognostic biomarker with clinical and functional relevance, with significant implications for optimizing immunotherapy strategies and prognostic assessment in this malignancy.