Journal of advanced research最新文献

Background: Homeostasis is a state of self-regulation and dynamic equilibrium, maintaining the good physiological functions of each system in living organisms. In the oral cavity, the interaction between the host and the oral microbiome forms oral microbial homeostasis. Physiological bone remodeling and renewal can occur under the maintenance of oral microbial homeostasis. The imbalance of bone homeostasis is a key mechanism leading to the occurrence of systemic bone-related diseases. Considering the importance of oral microbial homeostasis in the maintenance of bone homeostasis, it still lacks a complete understanding of the relationship between oral microbiome, periodontal disease and systemic bone-related diseases.

Aim of review: This review focuses on the homeostatic changes, pathogenic routes and potential mechanisms in the oral microbiome in periodontal disease and systemic bone-related diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis and osteomyelitis. Additionally, this review discusses oral microbiome-based diagnostic approaches and explores probiotics, mesenchymal stem cells, and oral microbiome transplantation as promising treatment strategies.

Key scientific concepts of review: This review highlights the association between oral microbial homeostasis imbalance and systemic bone-related diseases, and highlights the possibility of remodeling oral microbial homeostasis for the prevention and treatment of systemic bone-related diseases.

Introduction: Heterogeneous tissue stiffening promotes tumor progression and resistance, and predicts a poor clinical outcome in patients with hepatocellular carcinoma (HCC). Ferroptosis, a congenital tumor suppressive mechanism, mediates the anticancer activity of various tumor suppressors, including immune checkpoint inhibitors, and its induction is currently considered a promising treatment strategy. However, the role of extracellular matrix (ECM) stiffness in regulating ferroptosis and ferroptosis-targeted resistance in HCC remains unclear.

Objectives: This research aimed to explore how extracellular matrix stiffness affects ferroptosis and its treatment efficacy in HCC.

Methods: Ferroptosis analysis was confirmed via cell activity, intracellular ferrous irons, and mitochondrial pathology assays. Baseline PD-L2, SMYD3, and SLC7A11 (xCT) were evaluated in 67 sorafenib-treated patients with HCC (46 for non-responder and 21 for responder) from public data. The combined efficacy of shPD-L2, sorafenib, and anti-PD-1 antibody in HCC was investigated in vivo.

Results: Here, we revealed that matrix stiffness-induced PD-L2 functions as a suppressor of xCT-mediated ferroptosis to promote cancer growth and sorafenib resistance in patients with HCC. Mechanically, matrix stiffening induced the expression of PD-L2 by activating SMYD3/H3K4me3, which acts as an RNA binding protein to enhance the mRNA stability of FTL and elevate its protein level. Knockdown of PD-L2 significantly promoted xCT-mediated ferroptosis induced by RSL3 or sorafenib on stiff substrate via FTL, whereas its overexpression abolished these upward trends. Notably, PD-L2 deletion in combination with sorafenib and anti-PD-1 antibody significantly sensitized HCC cells and blunted cancer growth in vivo. Additionally, we found the ferroptosis- and immune checkpoint-related prognostic genes that combined PD-L2, SLC7A11 and SYMD3 well predict the clinical efficacy of sorafenib in patients with HCC.

Conclusion: These findings expand our understanding of the mechanics-dependent PD-L2 role in ferroptosis, cancer progression and resistance, providing a basis for the clinical translation of PD-L2 as a therapeutic target or diagnostic biomarker.

Introduction: Improving the rhizospheric HCO₃^- utilization of plant-soil ecosystem could increase the carbon sink effect of terrestrial ecosystem. However, to avoid its physiological stress on the crop growth, the dosage of HCO₃^- allowed to add into the rhizosphere soil was always low (i.e., <5-20 mol/m³).

Objectives: To facilitate the utilization of relatively high concentrations of HCO₃^- by plants in the pursuit of achieving terrestrial carbon sink enhancement.

Methods: In this study, the feasibility of directly supplementing a high concentration HCO₃^- carried by the biogas slurry to the plant rhizosphere was investigated using the tomato as a model plant.

Results: The CO₂-rich biogas slurry was verified as a potential CO₂ carrier to increase the rhizospheric HCO₃^- concentration to 36 mol/m³ without causing a physiological stress. About 88.3 % of HCO₃^- carried by biogas slurry was successfully fixed by tomato-soil ecosystem, in which 43.8 % of HCO₃^- was assimilated by tomato roots for the metabolism, 0.5 ‰ of HCO₃^- was used by microorganisms for substances synthesis of cell structure through dark fixation, and 44.4 % of HCO₃^- was retained in the soil. The rest of HCO₃^- (∼11.7 %) might escape into the atmosphere through the reaction with H⁺. Correspondingly, the carbon fixation of tomato-soil ecosystem increased by 150.1 g-CO₂/m²-soil during a tomato growth cycle. As for the global countries that would adopt the strategy proposed in this study to cultivate the tomato, an extra carbon sink of soil with about 1031.1 kt-C per year (i.e., an additional 0.21 tons of carbon per hectare soil) could be obtained.

Conclusion: This would be consistent with the goal of soil carbon sink enhancement launched at COP21. Furthermore, the regions with low GDP per capita may easily achieve a high reduction potential of CO₂ emissions from the agricultural land after adopting the irrigation of CO₂-rich biogas slurry.

Introduction: Gut microbes and their metabolites play crucial roles in the pathogenesis of diabetic kidney disease (DKD). However, which one and how specific gut-derived metabolites affect the progression of DKD remain largely unknown.

Objectives: This study aimed to investigate the potential roles of indole-3-propionic acid (IPA), a microbial metabolite of tryptophan, in DKD.

Methods: Metagenomic sequencing was performed to analyze the microbiome structure in DKD. Metabolomics screening and validation were conducted to identify characteristic metabolites associated with DKD. The protective effect of IPA on DKD glomerular endothelial cells (GECs) was assessed through in vivo and in vitro experiments. Further validation via western blot, immunoprecipitation, gene knockout, and site-directed mutation elucidated the mechanism of IPA on mitochondrial injury.

Results: Alterations in gut microbial community structure and dysregulated tryptophan metabolism were evident in DKD mice. Serum IPA levels were significantly reduced in DKD patients and correlated with fasting blood glucose, HbA1c, urine albumin-to-creatinine ratio (UACR), and estimated glomerular filtration rate (eGFR). IPA supplementation ameliorated albuminuria, bolstered the integrity of the glomerular filtration barrier, and mitigated mitochondrial impairments in GECs. Mechanistically, IPA hindered SIRT1 phosphorylation-mediated ubiquitin-proteasome degradation, restoring SIRT1's role in promoting PGC-1α deacetylation and nuclear translocation, thereby upregulating genes associated with mitochondrial biosynthesis and antioxidant defense.

Conclusion: Our findings underscore the potential of the microbial metabolite IPA to attenuate DKD progression, offering novel insights and potential therapeutic strategies for its management.

Introduction: Intracerebral haemorrhage (ICH) is a devastating disease that leads to severe neurological deficits. Microglia are the first line of defence in the brain and play a crucial role in neurological recovery after ICH, whose activities are primarily driven by glucose metabolism. However, little is known regarding the status of glucose metabolism in microglia and its interactions with inflammatory responses after ICH.

Objectives: This study investigated microglial glycolysis and its mechanistic effects on microglial inflammation after ICH.

Methods: We explored the status of glucose metabolism in the ipsilateral region and in fluorescence-activated-cell-sorting-isolated (FACS-isolated) microglia via 2-deoxy-[¹⁸F]fluoro-D-glucose positron emission tomography (FDG-PET) analyses and gamma emission, respectively. Energy-related targeted metabolomics, along with ¹³C-glucose isotope tracing, was utilised to analyse glycolytic products in microglia. Mitochondrial membrane potential and mitochondrial reactive oxygen species (MitoROS) accumulation was assessed by flow cytometry. Behavioural, western blotting, gene regulation, and enzymatic activity analyses were conducted with a focus on microglia.

Results: Neurological dysfunction was strongly correlated with decreased FDG-PET signals in the perihaematomal region, where microglial uptake of FDG was reduced. The decreased quantity of glucose-6-phosphate (G-6-P) in microglia was attributed to the downregulation of glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Enhanced inflammatory responses were driven by HK2 suppression via decreased mitochondrial membrane potential, which could be rescued by MitoROS scavengers. HK inhibitors aggravated neurological injury by suppressing FDG uptake and enhancing microglial inflammation in ICH mice.

Conclusion: These findings indicate an unexpected metabolic status in pro-inflammatory microglia after ICH, consisting of glycolysis impairment caused by the downregulation of GLUT1 and HK2. Additionally, HK2 suppression promotes inflammatory responses by disrupting mitochondrial function, providing insight into the mechanisms by which inflammation may be facilitated after ICH and indicating that metabolic enzymes as potential targets for ICH treatment.

Introduction: Endometriosis is a chronic inflammatory disease that affects ∼10 % of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis.

Objectives: We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice.

Methods: Peritoneal fluid was collected from endometriosis patients undergoing surgery and the levels of NGF and VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA. VEGFR1 regulator concentrations were used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibodies, and pharmacological approaches to specifically block neurotrophic ligands (NGF or BDNF) or receptors (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was measured using von Frey filaments, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Disease parameters were evaluated by lesion size and prevalence. To evaluate potential toxicity, we measured the effect of entrectinib dose and schedule on body weight, liver and kidney function, and bone structure (via micro-CT).

Results: We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though calculated receptor occupancy revealed that VEGFR1 agonist levels are sufficient to support signaling, blocking VEGFR1 via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Notably, changing dosing schedule to once weekly eliminated entrectinib-induced bone-loss without decreasing efficacy against pain.

Conclusions: This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment.

Introduction: Homologous recombination repair during meiosis is essential for the exchange of genetic information between sister chromosomes, underpinning spermatogenesis and, consequently, fertility. The disruption of this process can lead to infertility, highlighting the importance of identifying the molecular actors involved.

Objectives: This study aims to elucidate the role of the E3 ubiquitin ligase Rnf126 in spermatogenesis and its impact on fertility, particularly through its involvement in meiotic homologous recombination repair.

Methods: We used heterozygous and homozygous Rnf126 deletion models in mouse testes to examine the consequences on testicular health, sperm count, and the process of spermatogenesis. Additionally, we explored the association between RNF126 gene missense variants and nonobstructive male infertility in patients, with a focus on their functional impact on the protein's ubiquitin ligase activity.

Results: Rnf126 deletion led to testicular atrophy, disrupted seminiferous tubule structure, reduced sperm count, and spermatogenesis arrest at meiotic prophase I. Furthermore, male mice exhibited impaired homologous recombination repair and increased apoptosis within the seminiferous tubules. We identified four missense variants of the RNF126 (V68M, R241H, E261A, D253N) associated with male infertility. Specifically, the E261A and D253N variants, located in the RING domain, directly compromised the E3 ubiquitin ligase activity of RNF126.

Conclusion: Our findings demonstrate the pivotal role of RNF126 in maintaining spermatogenesis and fertility, offering insights into the molecular mechanisms underlying male infertility. The identified RNF126 variants present novel targets for diagnostic and therapeutic strategies in treating nonobstructive male infertility.

Introduction: Breast cancer, a heterogeneous disease, is influenced by multiple genetic and epigenetic factors. The majority of prognostic models for breast cancer focus merely on the main effects of predictors, disregarding the crucial impacts of gene-gene interactions on prognosis.

Objectives: Using DNA methylation data derived from nine independent breast cancer cohorts, we developed an independently validated prognostic prediction model of breast cancer incorporating epigenetic biomarkers with main effects and gene-gene interactions (ARTEMIS) with an innovative 3-D modeling strategy. ARTEMIS was evaluated for discrimination ability using area under the receiver operating characteristics curve (AUC), and calibration using expected and observed (E/O) ratio. Additionally, we conducted decision curve analysis to evaluate its clinical efficacy by net benefit (NB) and net reduction (NR). Furthermore, we conducted a systematic review to compare its performance with existing models.

Results: ARTEMIS exhibited excellent risk stratification ability in identifying patients at high risk of mortality. Compared to those below the 25th percentile of ARTEMIS scores, patients with above the 90th percentile had significantly lower overall survival time (HR = 15.43, 95% CI: 9.57-24.88, P = 3.06 × 10^-29). ARTEMIS demonstrated satisfactory discrimination ability across four independent populations, with pooled AUC_3-year = 0.844 (95% CI: 0.805-0.883), AUC_5-year = 0.816 (95% CI: 0.775-0.857), and C-index = 0.803 (95% CI: 0.776-0.830). Meanwhile, ARTEMIS had well calibration performance with pooled E/O ratio 1.060 (95% CI: 1.038-1.083) and 1.090 (95% CI: 1.057-1.122) for 3- and 5-year survival prediction, respectively. Additionally, ARTEMIS is a clinical instrument with acceptable cost-effectiveness for detecting breast cancer patients at high risk of mortality (P_t = 0.4: NB_3-year = 19‰, NB_5-year = 62‰; NR_3-year = 69.21%, NR_5-year = 56.01%). ARTEMIS has superior performance compared to existing models in terms of accuracy, extrapolation, and sample size, as indicated by the systematic review. ARTEMIS is implemented as an interactive online tool available at http://bigdata.njmu.edu.cn/ARTEMIS/.

Conclusion: ARTEMIS is an efficient and practical tool for breast cancer prognostic prediction.

Introduction: The efficiency of zinc oxide (ZnO) nanoparticles for environmental decontamination is limited by their reliance on ultraviolet (UV) light and rapid charge carrier recombination. Carbon doping has been proposed to address these challenges by potentially enhancing visible light absorption and charge separation.

Objectives: This study aims to introduce a novel, single-step synthesis method for carbon-doped ZnO (C-Z) nanoparticles, leveraging the decomposition of zinc nitrate hexahydrate and furfural under a nitrogen atmosphere to improve photocatalytic activity under visible light.

Methods: A series of C-Z variants (C-Z-1 to C-Z-5) and an undoped sample (ZnO-0) were synthesized. The influence of furfural on the synthesis process and doping mechanism was analyzed by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and UV-visible diffuse reflectance spectroscopy (DRS).

Results: XPS confirmed the integration of carbon within the ZnO matrix, and XRD indicated increased lattice dimensions owing to doping. DRS revealed bandgap narrowing, suggesting enhanced charge separation. Among the variants, C-Z-3 significantly outperformed the others, showing a 12-fold increase in the photocatalytic degradation rate of Rhodamine B compared to undoped ZnO.

Conclusion: The developed single-step synthesis method for C-Z nanoparticles represents a major advancement in materials engineering for ecological applications. The enhanced photocatalytic activity under visible light, as demonstrated by C-Z-3, underscores the potential of these nanoparticles for environmental decontamination.

Introduction: Cetuximab (CTX) is an effective targeted drug for the treatment of metastatic colorectal cancer, but it is effective only in patients with wild-type KRAS genes. Even in this subset of patients, the sensitivity of CTX in patients with right hemi-colon cancer is much lower than that in patients with left hemi-colon cancer. This significantly limits its clinical application. Therefore, further elucidation of the underlying molecular mechanisms is needed. N-myc downstream-regulated gene 1 (NDRG1) plays an important role in solid tumor invasion and metastasis, but whether it can influence CTX sensitivity has not been thoroughly investigated.

Objective: Our study aimed to identify a novel mechanism by which NDRG1 affects CTX sensitivity.

Methods: Through mass spectrometry analysis of our previously constructed CTX-resistant RKO and HCT116 cells, we found that the signal transducer and activator of transcription-1 (Stat1) might be a potential target of NDRG1. By knocking out NDRG1 or/and Stat1 genes, we then applied the loss-of-function experiments to explore the regulatory relationship between NDRG1 and Stat1 and their roles in the cell cycle, epithelial-mesenchymal transition (EMT), and the sensitivity to CTX in these two colorectal cancer (CRC) cells. Finally, we used the nude-mouse transplanted tumor model and human CRC samples to verify the expression of NDRG1 and Stat1 and their impact on CTX sensitivity in vivo.

Results: Stat1 was upregulated in CTX-resistant cells, whereas NDRG1 was downregulated. Mechanically, NDRG1 was inversely correlated with Stat1 expression. It suppressed CRC cell proliferation, migration, and invasion, and promoted apoptosis and epithelial-mesenchymal transition (EMT) by inhibiting Stat1. In addition, NDRG1 directly interacted with Stat1 and promoted Smurf1-induced Stat1 ubiquitination. Importantly, this novel NDRG1-dependent regulatory loop also enhanced CTX sensitivity both in vitro and in vivo.

Conclusion: Our study revealed that NDRG1 enhanced the sensitivity to Cetuximab by inhibiting Stat1 expression and promoting its ubiquitination in colorectal cancer, elucidating NDRG1 might be a potential therapeutic target for refractory CTX-resistant CRC tumors. But its clinical value still needs to be validated in a larger sample size as well as a different genetic background.