Journal of Zhejiang University SCIENCE B最新文献

Protein interacting with C kinase 1 (PICK1) interacts with a variety of membrane proteins and receptors involved in nervous system diseases and multiple cancers. However, the role of PICK1 in gastric cancer remains unclear. In the present work, we explored the expression and interactions of PICK1 with Toll-like receptor 4 (TLR4) in gastric cancer. Clinical data analysis showed that PICK1 expression decreases and is predictive of worse outcomes in patients with gastric cancer. High PICK1 levels attenuate the proliferation and migration of gastric cancer cells, which is dependent on the TLR4/myeloid differentiation primary response 88 (MyD88) signaling pathway. Furthermore, in vitro experiments demonstrated that PICK1 affects the trafficking and degradation of TLR4 and promotes TLR4 degradation via autophagy in gastric cancer cells. Molecular dynamics simulations highlighted the binding strength and stability of the TLR4-PICK1 complex. Our study provides new insights into the cellular and pathological functions of PICK1 in gastric cancer.

Oral squamous cell carcinoma (OSCC) poses significant challenges in terms of diagnosis and treatment, with high rates of morbidity and mortality. Emerging evidence highlights the critical involvement of Wingless/Int-1 (Wnt) ligands and receptors in OSCC pathogenesis. Dysregulated Wnt signaling pathways contribute to tumor initiation, progression, and therapy resistance by promoting cellular proliferation, epithelial‒mesenchymal transition (EMT), and the maintenance of cancer stem cells (CSCs). Targeting Wnt signaling presents a promising therapeutic avenue, yet its complex interplay with other signaling pathways requires a deeper understanding to implement effective intervention. This study sheds light on the current knowledge of the roles of Wnt ligands and receptors in OSCC, emphasizing their potential as diagnostic biomarkers and therapeutic targets. Future research directions involve elucidating context-specific Wnt signaling dynamics and exploring combination therapies to improve clinical outcomes for OSCC patients.

Osteosarcoma (OS), chondrosarcoma (CS), and Ewing sarcoma (ES) represent primary malignant bone tumors and pose significant challenges in oncology research and clinical management. Conventional research methods, such as two-dimensional (2D) cultured tumor cells and animal models, have limitations in recapitulating the complex tumor microenvironment (TME) and often fail to translate into effective clinical treatments. The advancement of three-dimensional (3D) culture technology has revolutionized the field by enabling the development of in vitro constructed bone tumor models that closely mimic the in vivo TME. These models provide powerful tools for investigating tumor biology, assessing therapeutic responses, and advancing personalized medicine. This comprehensive review summarizes the recent advancements in research on 3D tumor models constructed in vitro for OS, CS, and ES. We discuss the various techniques employed in model construction, their applications, and the challenges and future directions in this field. The integration of advanced technologies and the incorporation of additional cell types hold promise for the development of more sophisticated and physiologically relevant models. As research in this field continues to evolve, we anticipate that these models will play an increasingly crucial role in unraveling the complexities of malignant bone tumors and accelerating the development of novel therapeutic strategies.

Macrophages derived from the human THP-1 cell line have been widely used as substitutes for primary macrophages in various macrophage-related studies. However, difficulties still exist in establishing THP-1 macrophage models. This research presents techniques for generating different phenotypes of activated macrophages derived from THP-1 cells by introducing specific stimuli and provides some potential markers to confirm each type of activated macrophage. It is hoped to provide novel and useful methods for scientific research and to help researchers explore this field more intuitively and effectively.

Microorganisms inhabiting soils contaminated with heavy metals produce melanin, a dark brown pigment, as a survival strategy. In this study, a melanin-producing bacterium, Acinetobacter sp. ME1, with heavy metal tolerance and plant growth-promoting traits, was isolated from abandoned mine soil. Strain ME1 exhibited growth at concentrations of Zn up to 250 mg/L, Cd and Pb up to 100 mg/L, and Cr up to 50 mg/L. It had the ability to produce the plant hormone indole-3-acetic acid and siderophores along with 1-aminocyclopropane-1-carboxylic acid deaminase and protease activities. Additionally, it showed antioxidant activity, including catalase and 2,2-diphenyl-1-picryhydrazyl (DPPH) scavenging activities. The optimal conditions for melanin production by ME1 were a pH of 7 and a temperature of 35 ℃. At 1000 mg/L, ME1-extracted melanin exhibited DPPH radical scavenging activity of (25.040±0.007)%, a sun protection factor of 15.200±0.260, and 19.6% antibacterial activity against the plant pathogen Xanthomonas campestris. Furthermore, its adsorption capacity was (0.235±0.073) mg/g melanin for Zn and (0.277±0.008) mg/g melanin for Ni. In plants of Brassica chinensis grown under conditions of hydroponic cultivation with single heavy metal contamination of Cd, Zn, Pb, or Cr, the removal efficiency of each heavy metal was improved by 0.1‒1.8 times after 3 d following inoculation with the strain ME1 compared to the plants grown under the same conditions without inoculation. In addition, ME1 inoculation improved the removal efficiency of each heavy metal by 0.1‒1.0 times under multiple heavy metal contamination conditions. These findings suggest that Acinetobacter sp. ME1 could be used to enhance phytoremediation efficiency in heavy metal-contaminated soils. Moreover, the melanin it produces also holds promise in cosmetics, household products, and medical applications due to its photoprotective, antioxidant, and antimicrobial properties.

The most common medications for the treatment of zoonotic toxoplasmosis are pyrimethamine and sulfadiazine, which may cause serious undesirable side effects. Thus, there is an urgent need to develop novel therapeutics. Baicalein (BAI, C₁₅H₁₀O₅) has been shown to perform well against protozoan parasites including Leishmania and Cryptosporidium. In this study, the inhibition efficacy of BAI on Toxoplasma gondii was evaluated using plaque, invasion, and intracellular proliferation assays. BAI effectively inhibited T. gondii (half-maximum inhibitory concentration (IC₅₀)=6.457×10^-5 mol/L), with a reduced invasion rate (33.56%) and intracellular proliferation, and exhibited low cytotoxicity (half-maximum toxicity concentration (TC₅₀)=5.929×10^-4 mol/L). Further investigation using a mouse model shed light on the inhibitory efficacy of BAI against T. gondii, as well as the potential mechanisms underlying its anti-parasitic effects. The survival time of T. gondii-infected ICR mice treated with BAI was remarkably extended, and their parasite burdens in the liver and spleen were greatly reduced compared with those of the negative control group. Histopathological examination of live sections revealed effective therapeutic outcomes in the treatment groups, with no notable pathological alterations observed. Furthermore, alterations in cytokine levels indicated that BAI not only effectively suppressed the growth of T. gondii but also prevented excessive inflammation in mice. Collectively, these findings underscore the significant inhibitory efficacy of BAI against T. gondii, positioning it as a promising alternative therapeutic agent for toxoplasmosis.

Chemical communication in plant-microbiome and intra-microbiome interactions weaves a complex network, critically shaping ecosystem stability and agricultural productivity. This non-contact interaction is driven by small-molecule signals that orchestrate crosstalk dynamics and beneficial association. Plants leverage these signals to distinguish between pathogens and beneficial microbes, dynamically modulate immune responses, and secrete exudates to recruit a beneficial microbiome, while microbes in turn influence plant nutrient acquisition and stress resilience. Such bidirectional chemical dialogues underpin nutrient cycling, co-evolution, microbiome assembly, and plant resistance. However, knowledge gaps persist regarding validating the key molecules involved in plant-microbe interactions. Interpreting chemical communication requires multi-omics integration to predict key information, genome editing and click chemistry to verify the function of biomolecules, and artificial intelligence (AI) models to improve resolution and accuracy. This review helps advance the understanding of chemical communication and provides theoretical support for agriculture to cope with food insecurity and climate challenges.

The circadian clock is a highly conserved timekeeping system in organisms, which maintains physiological homeostasis by precisely regulating periodic fluctuations in gene expression. Substantial clinical and experimental evidence has established a close association between circadian rhythm disruption and the development of various malignancies. Research has revealed characteristic alterations in the circadian gene expression profiles in tumor tissues, primarily manifested as a dysfunction of core clock components (particularly circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1)) and the widespread dysregulation of their downstream target genes. Notably, CLOCK demonstrates non-canonical oncogenic functions, including epigenetic regulation via histone acetyltransferase activity and the circadian-independent modulation of cancer pathways. This review systematically elaborates on the oncogenic mechanisms mediated by CLOCK/BMAL1, encompassing multidimensional effects such as cell cycle control, DNA damage response, metabolic reprogramming, and tumor microenvironment (TME) remodeling. Regarding the therapeutic strategies, we focus on cutting-edge approaches such as chrononutritional interventions, chronopharmacological modulation, and treatment regimen optimization, along with a discussion of future perspectives. The research breakthroughs highlighted in this work not only deepen our understanding of the crucial role of circadian regulation in cancer biology but also provide novel insights for the development of chronotherapeutic oncology, particularly through targeting the non-canonical functions of circadian proteins to develop innovative anti-cancer strategies.

Retinopathy of prematurity (ROP) is a vision-threatening disorder that leads to pathological growth of the retinal vasculature due to hypoxia. Here, we investigated the potential effects of alamandine, a novel heptapeptide in the renin-angiotensin system (RAS), on hypoxia-induced retinal neovascularization and its underlying mechanisms. In vivo, the C57BL/6J mice with oxygen-induced retinopathy (OIR) were injected intravitreally with alamandine (1.0 μmol/kg per eye). In vitro, human retinal microvascular endothelial cells (HRMECs) were utilized to investigate the effects of alamandine (10 μg/mL) on proliferation, apoptosis, migration, and tubular formation under vascular endothelial growth factor (VEGF) stimulation. Single-cell RNA sequencing (scRNA-seq) matrix data from the Gene Expression Omnibus (GEO) database and RAS-related genes from the Molecular Signatures Database (MSigDB) were sourced for subsequent analyses. By integrating scRNA-seq data across multiple species, we identified that RAS-associated endothelial cell populations were highly related to retinal neovascularization. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed a significant decrease in alamandine levels in both the serum and retina of OIR mice compared to those in the control group. Next, alamandine ameliorated hypoxia-induced retinal pathological neovascularization and physiologic revascularization in OIR mice. In vitro, alamandine effectively mitigated VEGF-induced proliferation, scratch wound healing, and tube formation of HRMECs primarily by inhibiting the hypoxia-inducible factor-1α (HIF-1α)/VEGF pathway. Further, coincubation with D-Pro⁷ (Mas-related G protein-coupled receptor D (MrgD) antagonist) hindered the beneficial impacts of alamandine on hypoxia-induced pathological angiogenesis both in vivo and in vitro. Our findings suggested that alamandine could mitigate retinal neovascularization by targeting the MrgD-mediated HIF-1α/VEGF pathway, providing a potential therapeutic agent for OIR prevention and treatment.

Objectives: The risk factors and role of mother‒child gut microbiota in pediatric inflammatory bowel disease (PIBD) remain unclear. We aimed to explore the clinical risk factors associated with PIBD, analyze the characteristics of gut microbiota of children and their mothers, and examine the correlation of the microbial composition in mother‒child pairs.

Methods: We conducted a case-control study including children with PIBD and their mothers as the case group, as well as healthy children and their mothers as the control group. Questionnaires were used to collect information such as family illness history and maternal and early-life events. Fecal samples were collected from the children and mothers for microbiota 16S ribosomal RNA (rRNA) sequencing to analyze the composition and its potential association with PIBD.

Results: A total of 54 pairs of cases and 122 pairs of controls were recruited. A family history of autoimmune disease and antibiotic use during pregnancy were associated with an increased risk of PIBD, and a higher education level of the father was associated with a decreased risk of PIBD. Children with PIBD and mothers exhibited different gut microbiota compared to healthy children and mothers. Similarities were observed in the gut microbiota of mothers and children in the same groups. Some bacterial biomarkers of mothers discovered in this study had the power to predict PIBD in their offspring.

Conclusions: PIBD is influenced by maternal risk factors and has unique gut microbiota characteristics. The mother‒child gut microbiota is closely related, suggesting the transmission and influence of the gut microbiota between mothers and children. This study highlights the potential pathogenesis of PIBD and provides a basis for developing targeted interventions.