Journal of Molecular Histology最新文献

Osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes such as articular cartilage degeneration and bone hyperplasia. Mitochondrial dysfunction in chondrocytes has been identified as a critical factor contributing to the progression of OA. Although Evodiamine (Evo) has been demonstrated effeicacy in inhibiting inflammatory responses and matrix degradation in OA chondrocytes, its effects and underlying mechanisms regarding mitochondrial dysfunction in these cells remain to be elucidated. IL-1β was utilized to stimulate chondrocytes in order to establish an in vitro OA model. Subsequently, the proliferation, lactate dehydrogenase (LDH) release, and apoptosis of chondrocytes were systematically evaluated. Mitochondrial function in chondrocytes was evaluated by quantifying of ATP content, ROS level, mitochondrial DNA (mtDNA) copy number, activities of mitochondrial respiratory chain Complexes I and III, as well as mitochondrial membrane potential change. Furthermore, the protein expression levels of the SIRT1/PGC-1α signaling pathway were examined, and an intervention involving the SIRT1 inhibitor EX527 was conducted to elucidate the potential mechanisms underlying the effects of Evo on chondrocytes. Evo treatment significantly elevated the proliferation activity of IL-1β-stimulated chondrocytes, inhibited LDH release and apoptosis, increased mtDNA copy number and ATP content, enhanced the enzymatic activities of Complexes I and III, and suppressed ROS production as well as mitochondrial membrane potential loss. Furthermore, Evo treatment activated the SIRT1/PGC-1α signaling pathway. However, the addition of the SIRT1 inhibitor EX-527 partially attenuated the protective effects of Evo against IL-1β-induced chondrocyte injury by exacerbating mitochondrial dysfunction. Evo promotes mitochondrial biosynthesis, reduces ROS production and improves mitochondrial function by activating SIRT1/PGC-1α pathway, thereby inhibiting IL-1β-induced chondrocyte injury.

Skin aging is a prominent manifestation of human aging, largely driven by oxidative stress and inflammation. D-limonene, a natural monoterpene, possesses strong antioxidant and anti-inflammatory properties that may help counteract these effects. This study aimed to explore the anti-aging and skin-rejuvenating potential of D-limonene in a mouse model of D-galactose-induced skin aging. 60 male mice were divided into 6 groups (n = 10). Group I served as the control. Group II received D-galactose (500 mg/kg) for 42 days to induce aging. Groups III and IV received vitamin C (100 mg/kg) either concurrently with D-galactose or after aging induction, respectively. Groups V and VI received D-limonene (100 mg/kg) either simultaneously with D-galactose or after induction. This design allowed comparison of protective versus therapeutic effects. Both concurrent and post-treatment with D-limonene substantially decreased pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and the oxidative stress marker MDA, while enhancing antioxidant components (SOD and GPx) and promoting the synthesis of collagen types I and III. Additionally, it improved skin thickness and histomorphological scores, restoring normal skin architecture. D-limonene exerts potent anti-aging and skin-rejuvenating effects by modulating oxidation and inflammatory markers, suggesting its potential as a preventive and curative anti-aging agent.

Graphical abstract

Hyperammonemia is a key pathological feature of hepatic encephalopathy (HE), yet its associated protein glycosylation remains incompletely understood. Here, we used whole mouse brain tissues from a hyperammonemia mouse model and astrocytes to conduct a comprehensive analysis of glycosylation changes and the corresponding enzyme associated with ammonia. The upregulation of O-linked N-acetylglucosamine (O-GlcNAc), mediated by O-GlcNAc transferase, was identified as a response to ammonia stimulation in astrocytes through a mechanism independent of glutamine synthesis and NADPH oxidase. These findings identify O-GlcNAc as an ammonia-sensitive post-translational modification that is associated with hyperammonemia. This study provides new insights into the molecular mechanisms of HE and suggests the potential role of O-GlcNAc as a therapeutic target warranting further investigation.

Costunolide (COS) is a bioactive sesquiterpene lactone compound extracted from Aucklandia lappa, known for its anticancer, anti-inflammatory, and antioxidant properties, aligning with the traditional Chinese medicine theory of "clearing heat and dispersing nodules" in the treatment of breast ailments. Network pharmacology identified EGFR as the core target of COS, with enrichment analysis revealing the EGFR/ERK/AKT axis as a key pathway. Molecular docking demonstrated strong binding affinity of COS to the EGFR kinase domain, relying on hydrogen bonds and hydrophobic interactions. In vitro experiments showed that COS inhibited TNBC cell proliferation and induced apoptosis. Mechanistically, COS increased EGFR ubiquitination, leading to a decrease in EGFR protein levels, thereby inhibiting EGFR phosphorylation and the activation of downstream ERK and Akt signaling pathways. EGF could partially reverse the growth inhibitory effects of COS, confirming the critical role of EGFR. This study elucidates that COS exerts its anti-TNBC effects by inducing EGFR ubiquitination and degradation, thereby inhibiting the ERK/AKT signaling pathway. This finding integrates traditional Chinese medicine theory with modern molecular oncology mechanisms, providing a reference for the development of plant-derived multi-target anticancer drugs.

This manuscript presents a letter to the editor addressing the study by Lv et al. (J Mol Histol 56(2):129, 2025), which identifies PDZ-binding kinase (PBK) as a diagnostic and prognostic biomarker for hepatocellular carcinoma (HCC). While commending the article’s comprehensive approach—including bioinformatics integration and validation of PBK's role in immune infiltration and methylation—the authors highlight three critical areas for improvement to enhance the study's rigor and clarity. First, they identify methodological issues in differential gene analysis, recommending RNA-seq-specific tools (e.g., DESeq2) over misapplied microarray frameworks like limma. Second, they critique the presentation of statistical significance, urging clearer reporting of P-values (e.g., P < 0.001) instead of P < 0.000. Third, they dispute the unrealistic survival curve in Fig. 2, suggesting evidence-based adjustments to reflect clinical plausibility. The letter emphasizes that addressing these concerns would strengthen the findings' impact on HCC research.

Objective

Candida albicans represents one of the most prevalent species of fungi in the human mycobiome. which colonize the multiple sites of the body, like the oral cavity. This study aimed to investigate the antifungal and tissue-protective effects of artemisinin against Candida albicans in mouse models.

Methods

We collected 120 oral swabs from patients and healthy individuals. Chromogenic Candida differential agar was applied to diagnose Candida isolates. The Vitek2 system is used to confirm Candida spp. diagnosis for patient samples. Moreover, in vitro and in vivo experimentation were applied to evaluate Artemisinin's effects on Candida albicans and animal tissue.

Results

The results indicate that the number of positive samples for Candida albicans growth among patients was 54 (90%), compared to healthy individuals that was recorded 17 (28.3%). The distribution results of those infected with oral candidiasis according to age groups showed that the age group older than 50 years accounted for 20%. Regarding the effect of Artemisinin on C. albicans, it was shown that after treating C. albicans with Artemisinin (0.2 mg/gram) for 3 h, the number of C. albicans decreased and affected the morphology of hyphae and growth of Candida compared with Fluconazole (0.53 mg/20 g) and the control. The results of the survival rate were lowest in the mice group treated with (Neoral + Fungi + artemisinin + fluconazole). While the survival rate was highest in mice groups treated with (Neoral), (Fungi), (Neoral + Fungi + fluconazole), (Neoral + Fungi + Artemisinin), (Fungi + fluconazole), (Fungi + Artemisinin), (Fungi + fluconazole + Artemisinin), respectively. These groups recorded less mortality. Concerning the histological examination of the tongue in infected mice, it was observed that there was epithelial ulceration with infiltration of inflammatory cells and epithelial sloughing, along with degeneration and necrosis of gastric glandular cells in the stomach. Additionally, the duodenum tissue showed mild inflammation of the intestinal mucosa, with thickening of the villi due to epithelial hyperplasia and infiltration. Meanwhile, mice treated with Artemisinin displayed normal tissue appearance.

Conclusion

Artemisinin demonstrated significant antifungal effectiveness against Candida albicans in both in vitro and in vivo. It diminished fungal load, impeded hyphal development, and preserved gastrointestinal tissue integrity in infected mice.

Distant metastasis remains the primary cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). Thus, it is essential to explore the regulatory mechanisms underlying NPC metastasis. Ets variant 5 (ETV5) is a transcription factor demonstrated to be overexpressed in various malignancies. However, the function of ETV5 in NPC is poorly characterized. We aim to investigate the function and mechanisms of ETV5 in NPC development. We assessed ETV5 expression in nasopharyngeal carcinoma tissues from 99 patients using quantitative immunohistochemistry. ETV5 levels in the cell lines 6-10B, CNE2, 5-8F, and S18 were determined using Western blotting. Cell proliferation, migration, and invasion capabilities were assessed using colony formation, scratch, and Transwell assays. The binding of ETV5 to promoter of leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) was detected by dual luciferase reporter gene detection system. We found that ETV5 overexpression was significantly correlated with poorer prognosis in NPC patients. Based on endogenous ETV5 expression, ETV5 overexpressing and downregulation cell lines were established. Functional analyses were conducted using CCK-8, colony formation, wound healing, and transwell assays. Elevated ETV5 expression promotes NPC cell proliferation and invasion migration, while knocking down ETV5 has the opposite effect. Mechanistically, ETV5 transcriptionally activates of LGR4 by directly binding to its promoter region. Our study revealed that ETV5 induces cell proliferation, invasion and migration by upregulating LGR4 in NPC. ETV5/LGR4 signaling may serve as a therapeutic target for NPC patients.

Glial cells, including astrocytes, microglia, and oligodendrocytes, play an important role in the repair of damaged central nervous system tissue. In our previous study, we showed that transforming growth factor-beta (TGF-β) signaling occurs in glial cells in the hippocampus after ischemia. However, the functional significance of TGF-β signaling in the hippocampus after ischemia remains unclear. In the present study, transcriptome analysis was performed to comprehensively examine the TGF-β signaling-induced gene expression changes in primary cultured rat mixed glial cells. TGF-β1 upregulated 287 genes and downregulated 272 genes. Representative genes upregulated by TGF-β1 included genes encoding extracellular matrix-related proteins. Conversely, representative genes downregulated by TGF-β1 included genes encoding proteins related to immune response. These results suggest the diverse effects of TGF-β1 on gene expression. Since genes downregulated by TGF-β1 included genes involved in cell phagocytosis, proliferation, and survival, the effects of TGF-β1 and -β2 on cell phagocytosis, proliferation, and survival were investigated in mixed glial cells. TGF-β1 and -β2 suppressed astrocyte and microglial proliferation, and promoted and suppressed astrocyte and microglial phagocytosis, respectively. Additionally, TGF-β1 or -β2 canceled the serum-free culture−induced increase in the ratio of TUNEL-labeled microglia and oligodendrocytes. Furthermore, the culture in a medium containing the TGF-β signaling inhibitor SB525334 reduced glial cell survival and increased the expressions of genes encoding cell death-related molecules. Our study results suggest that TGF-β contributes to postischemic brain tissue repair by regulating glial cell gene expression, phagocytosis, and proliferation, and supporting glial cell survival.

Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and is commonly observed in elderly, diabetic, hypertensive, and obese patients. Accumulating evidence suggests a close relationship between sirtuins and myocardial damage in HFpEF. This study aimed to explore whether sirtuin 3 (Sirt3) is involved in HFpEF. Wistar-Kyoto (WKY) rats served as the controls, while spontaneously hypertensive rats (SHRs) were randomly divided into three groups: the SHR group, HFpEF group, and HFpEF + 3-TYP group. Except for rats in the WKY and SHR groups, rats in the other groups were subjected to a high-fat diet (45%) and an intraperitoneal (i.p.) injection of streptozotocin (35 mg/kg) to establish the HFpEF model. Moreover, Sirt3 was inhibited using 3-TYP to further explore the regulatory mechanism of key molecules in this process. Cardiac function was evaluated by echocardiography, histological changes were examined by microscopy, and the morphology of the ER and mitochondria was observed through transmission electron microscopy. Western blotting was used to measure the levels of endoplasmic reticulum stress (ERS) and mitophagy-related proteins. Following high-fat feeding and i.p. injection of streptozotocin, SHRs presented markedly impaired diastolic function, decreased exercise tolerance, increased cardiac hypertrophy and fibrosis, and increased Sirt3 protein expression. Treatment with 3-TYP led to a significant reversal of these changes. When Sirt3 expression increased, endoplasmic reticulum stress and mitochondrial autophagy increased. Sirt3 silencing markedly reduced the excessive ERS and mitophagy levels induced by metabolic stress. 3-TYP can mitigate cardiac hypertrophy and improve function in HFpEF patients by inhibiting Sirt3, thereby protecting against metabolic disorders and excessive endoplasmic reticulum stress. These findings suggest that 3-TYP may be a promising therapeutic candidate for patients with metabolic syndrome-related HFpEF.

Despite the discoveries of new and promising therapeutics, effective treatments for advanced and metastatic thyroid cancer (THCA) are still lacking. Epithelial-to-mesenchymal transition (EMT) is crucial for developing an invasive phenotype in tumor cells and, therefore, a hallmark of metastatic disease. We here investigate the effect of EGF-like repeat and discoidin I-like domain-containing protein 3 (EDIL3) on EMT in THCA and the mechanism involved. THCA cells with EDIL3 knockdown were generated to analyze the effect on EMT, proliferation, migration, invasion, and angiogenesis. THCA cells with knockdown of EDIL3 had increased expression of E-cadherin and decreased expression of Vimentin and Slug, proliferation, migration, invasion, and angiogenesis. GLI-similar 2 (GLIS2) bound to the EDIL3 promoter to activate its expression. Knockdown of GLIS2 promoted the killing activity of CD8⁺ T cells, while overexpression of EDIL3 reversed phenotypic changes and suppressed the anti-tumor responses of T cells. Overexpression of EDIL3 also reversed the inhibitory effects of knocking down GLIS2 alone on tumor metastasis in BALB/c nude mice. Together, our results demonstrate that EDIL3 induced by GLIS2 inhibits the anti-tumor activity of CD8⁺ T cells and promotes EMT in THCA.