While periodontitis is increasingly linked to systemic disorders through the oral–gut axis, the molecular mediators driving gut microbiota dysbiosis and barrier disruption remain elusive. Hepatocyte growth factor (HGF), a novel regulator of inflammatory bone loss in periodontitis, may serve as a critical communicator between oral infection and distal intestinal pathology. This study investigates how HGF overexpression modulates the gut microbial ecosystem and intestinal barrier integrity in a transgenic periodontitis model. In this study, we combined 16S rRNA sequencing of fecal microbiota with comprehensive gut barrier assessments, including systemic markers (D-lactate, LPS, and DAO ELISA), structural integrity (villous morphology), and molecular analysis (ZO-1, occludin, and NOD2 immunohistochemistry), using HGF-overexpressing transgenic (HGF-Tg) mice with periodontitis. The results demonstrated that HGF increased gut permeability in the context of periodontitis, as evidenced by elevated serum levels of D-lactate and LPS compared to wild type (WT) mice. In addition, gut villous morphology disorder was observed in HGF-Tg mice with periodontitis. HGF also diminished the protein level of occludin and upregulated NOD2 expression in mice with periodontitis. Moreover, HGF-Tg mice with periodontitis exhibited significant dysbiosis of gut microbiota, with reduced levels of probiotics (e.g., Faecalibaculum). Notably, HGF also increased the enrichment of the periodontitis-associated pathogens (e.g., Desulfovibrio and Streptococcus) in the gut. Microbial functions, particularly metabolic pathways, were significantly altered by HGF when periodontitis occurred. Some microorganisms like g_Desulfovibrio may play a role in gut barrier disorder in HGF-Tg mice with periodontitis. Overall, our findings position HGF as a novel orchestrator of oral–gut crosstalk, where its overexpression reshapes gut microbial ecology toward a “leaky gut” phenotype to compromise intestinal barrier integrity, further deepening our understanding of the oral–gut axis.

Background: Periodontitis is a chronic disease triggered by disturbed oral microbiota. We have previously reported that hepatocyte growth factor (HGF) could mitigate early-stage experimental periodontitis but exacerbate the condition in its late stage. Here, we investigated the impact of HGF on the periodontal microbiome during periodontitis progression. Methods: We established ligation-induced periodontitis in wild-type (WT) mice and HGF high-expression transgenic (HGF-Tg) mice. We quantified the levels of IL-6 and TNF-α in periodontal tissues, as well as the serum concentrations of CTXI and PINP. Ligatures were collected on days 0, 7, and 28 after ligation for 16S rRNA sequencing and microbial analysis. Results: HGF significantly altered the diversity of ligatures during periodontitis. Interestingly, specific microbial genera, such as Lactobacillus, exhibited opposing trends between the two disease stages of HGF-Tg mice, aligning with the different effects of HGF on periodontitis progression. We also identified some taxa, such as Sphingomonas, associated with IL-6, TNF-α, CTXI, and PINP. The predicted inflammatory pathways (e.g., IL-17 signaling pathways) were enriched in HGF-Tg mice on day 28 but decreased on day 7. Conclusions: HGF exerted different influences on the microbiota of ligatures during early and late stages of periodontitis, which may account for the divergent effects of HGF on periodontitis progression.

Background: Dynamic surveillance of vasculature is essential for evaluating the healing of oral ulcer. Existing techniques used in vascular imaging face limitations, such as inadequate spatial resolution, restricted diagnostic depth, and the necessity of exogenous contrast agents. Therefore, this study aimed to use robust photoacoustic imaging (PAI) for the dynamic monitoring of vascular response during healing and the associated treatment process of oral ulcer. Methods: Kunming mice (male, 8 weeks old, 31–41 g) were treated with 50% acetic acid for 90 s on the tongue mucosa for induction of oral traumatic ulcer. Mice were randomly divided into three groups (n=12): the control, compound chamomile and lidocaine hydrochloride gel (CCLH), and phycocyanin (PC) groups. PAI was then conducted on days 0, 2, 3, 5, and 7 to obtain vessel parameters of the ulcer area, including vessel intensity, density, mean diameter, maximum diameter, and curvature. Immunohistochemical and hematoxylin and eosin (HE) staining were performed on days 3 and 7 to assess microvessel density and inflammation score. The ulcer healing rate and body weight changes were evaluated for clinical observation. Results: Beginning on the second day after ulcer induction, there was a progressive increase over time in blood intensity and vessel parameters, including vascular density and diameter. On day 7, the CCLH and PC groups demonstrated significantly higher measures than did the control group in terms of blood intensity (P<0.05 and P<0.01), vascular density (both P values <0.05), mean diameter (both P values <0.01), and maximum diameter (P<0.01 and P0.05). The effects of vascular morphological changes were further supported by the histological and clinical outcomes. On day 7, compared to that of the control group, the level of microvessel density was significantly higher in both the CCLH (P<0.01) and PC (P<0.05) groups. The histopathological score in PC group was significantly lower than that of the control group on day 7 (P<0.05). Additionally, compared to that of the control group, the healing rates of the CCLH (P<0.01) and PC groups (P<0.05) were superior on day 7. On day 3, the control group showed more weight loss than did the CCLH (P<0.05) and PC (P<0.01) groups. Conclusions: These findings indicate that PAI is a valuable strategy for the dynamic and quantitative analysis of vascular alterations in oral traumatic ulcers and support its prospective application in improving clinical treatment.

Objectives: To investigate the role of hepatocyte growth factor (HGF)/c-Met signaling in oral malignant transformation.Methods: We used immunohistochemistry to investigate HGF and c-Met expression in 53 oral squamous cell carcinoma (OSCC) specimens and 21 adjacent nontumor specimens and evaluated the associations between HGF and c-Met expression and clinicopathological parameters. Additionally, HGF-overexpression transgenic (HGF-Tg) and wild-type (Wt) mice were treated with 4-nitroquinoline-1-oxide (4NQO) to induce oral carcinogenesis for 16 weeks. At 16, 20, and 24 weeks, tongue lesions were collected for clinical observation; estimation of HGF, c-Met, and PCNA expression; apoptosis (TUNEL) assays; and RNA sequencing (RNA-seq).Results: HGF and c-Met were positively expressed in 92.5% and 64% of OSCC samples, respectively. High HGF expression was significantly associated with smaller tumor size (p = 0.006) and inferior TNM stage (p = 0.032). No correlation between HGF and c-Met levels and other clinical parameters or prognosis was noted. In addition, HGF and c-Met expression was elevated in 4NQO-induced lesions of Wt mice. Compared with Wt mice, HGF-Tg mice have lower tumor incidence, number, volume, and lesion grade. In addition, the percentage of PCNA-positive cells in Wt mice was significantly higher than that in HGF-Tg mice at different time points. At 16 weeks, HGF-Tg mice exhibited less apoptotic cells compared with Wt mice (p < 0.000), and these levels gradually increased until the levels were greater than that of Wt mice at 24 weeks (p < 0.000). RNA-seq data revealed that 140 genes were upregulated and 137 genes were downregulated in HGF-Tg mice. KEGG enrichment analysis showed that upregulated differentially expressed genes (DEGs) are highly correlated with oxidative and metabolic signaling and that downregulated DEGs are related to MAPK and PI3K-AKT signaling.Conclusions: HGF and c-Met expression is upregulated in OSCC tissues and is associated with the occurrence and development of OSCC. HGF overexpression in normal oral epithelial tissue can inhibit 4NQO-induced tumorigenesis potentially through inhibiting proliferation and accelerating apoptosis via MAPK and PI3K-AKT signaling.

Cuproptosis represents a promising strategy for cancer therapy. Generating copper diethyldithiocarbamate (Cu(DTC)₂) directly at tumor sites may enhance copper-dependent antitumor activity; however, inefficient precursor loading and premature release may limit local Cu(DTC)₂ formation and increase off-target toxicity. To overcome these challenges, a reactive oxygen species (ROS)-responsive, thioketal-linked dopamine dimer (DTD) and an H₂O₂-responsive DTC prodrug (DQ) were co-assembled and subsequently coated with a copper–tannic acid (Cu@TA) network to form CDD nanoparticles (CDD NPs). The DQ-loading capacity and stimulus responsiveness of CDD NPs were characterized, and their in vitro anticancer activity was evaluated in 4T1 cells. DTD promoted DQ loading and linked the core to the copper network through catechol coordination. DTD-free CD NPs contained only 57.3% of the DQ in CDD NPs and had a lower Cu(I) fraction. Copper release from the Cu@TA network was limited under physiological conditions but increased in an acidic environment, whereas H₂O₂ triggered DQ cleavage, supporting the proposed in situ formation of Cu(DTC)₂. In 4T1 cells, CDD NPs induced oxidative stress, glutathione depletion, and apoptosis. Intracellular copper accumulation, partial rescue by tetrathiomolybdate, and changes in ferredoxin 1 (FDX1) and dihydrolipoamide S-acetyltransferase (DLAT) suggested possible cuproptosis involvement. CDD NPs improved prodrug loading and controlled precursor release, inhibiting tumor cells in vitro.