Journal of Molecular Histology最新文献

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.

Aims

Methotrexate (MTX), a commonly used chemotherapeutic and immunosuppressive agent, is known to induce significant ovarian toxicity through mechanisms involving oxidative stress, inflammation, and apoptosis. Vortioxetine (VTX), a novel antidepressant with proven neuroprotective and anti-inflammatory properties, has not yet been evaluated in the context of chemotherapy-induced gonadotoxicity. This study aimed to investigate the protective effects of VTX against MTX-induced ovarian injury in a rat model by employing comprehensive histopathological and immunohistochemical evaluations.

Methods and Results

Thirty-two adult female Wistar Albino rats (300–350 g) were randomly divided into four equal groups (n = 8): Control, MTX, MTX + VTX, and VTX. Ovarian damage was induced with a single intraperitoneal injection of MTX (20 mg/kg), while VTX was administered daily (10 mg/kg) by oral gavage for five days. Rats were sacrificed on day 5, and bilateral ovaries were collected. Histopathological evaluation included follicular degeneration, vascular congestion, hemorrhage, and inflammatory cell infiltration. Immunohistochemical analyses were performed for 8-Hydroxy-2'-deoxyguanosine (8-OHdG), nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), caspase 3 (Cas-3), and Anti-Müllerian hormone (AMH) to assess oxidative stress, inflammation, apoptosis, and ovarian reserve. MTX administration caused severe follicular atresia, hemorrhage, and dense neutrophil infiltration. Immunohistochemically, 8-OHdG, NF-κB, TNF-α, and Cas-3 expressions were significantly elevated, while AMH was markedly reduced. VTX co-treatment significantly attenuated histological damage and modulated the expression of all biomarkers, indicating potent protective effects. VTX alone did not induce deleterious changes.

Conclusion

VTX exhibits a robust protective effect against MTX-induced ovarian injury via suppression of oxidative stress, inflammatory response and apoptotic pathways, while simultaneously preserving ovarian reserve. These findings highlight a novel application for VTX in fertility preservation strategies during chemotherapeutic interventions.

Acute pancreatitis (AP) is a serious inflammatory condition of the pancreas often requiring hospitalisation and characterised by abdominal pain, nausea, and vomiting. Hyperin (HP), a natural flavonoid, possesses antioxidant and anti-inflammatory characteristics. However, the effect of HP on AP remains unclear. This study aimed to evaluate the protective effects of HP in a cerulein-induced AP model in rats, focusing on histopathological damage, inflammatory cytokines, and oxidative stress markers. All rats were randomly assigned into control (n = 8), AP (n = 8), and AP + HP (50 mg/kg) groups (n = 8). We created an AP rat model by intraperitoneal cerulein injections. We evaluated histopathologically pancreatic tissues using hematoxylin–eosin staining. NF-κB and TNF-α expressions were analysed using immunohistochemical method. Oxidative stress markers such as MDA, SOD, CAT, GPx as well as serum amylase and lipase levels were assessed using biochemical methods. IL-6 and IL-10 levels were measured using ELISA. HP treatment significantly reduced histological damage scores, including oedema, necrosis, and vacuolisation. Moreover, expression levels of NF-κB and TNF-α were markedly decreased in the AP + HP group. HP restored SOD activity and reduced MDA levels, indicating attenuated oxidative stress. HP decreased serum IL-6 and increased IL-10 levels, along with significant reductions in amylase and lipase. HP exerts both anti-inflammatory and antioxidant effects in cerulein-induced AP, primarily through NF-κB and TNF-α inhibition and SOD activation. These findings suggest that HP may be a promising natural compound for the adjunctive treatment of AP.

Background and Aims

Cancer cachexia is a paraneoplastic syndrome characterized by progressive muscle atrophy, which negatively impacts treatment efficacy, quality of life, and survival in individuals with cancer. Despite extensive research, no effective medical intervention has completely reversed cachexia, primarily due to an incomplete understanding of its pathogenesis. Toll-like receptor 4 (TLR4) plays an important role in inflammation and metabolic regulation. In this study, the role of TLR4 in muscle catabolism was investigated, with a focus on its regulation of the p38 mitogen-activated protein kinase (MAPK)-mediated activation of C/enhancer-binding protein beta (C/EBPβ) pathway.

Methods

TLR4 expression was silenced in C2C12 myotubes using specific small interfering RNAs (siRNAs). Conditioned medium derived from various cancer cell types was applied to C2C12 myotubes to simulate the tumor microenvironment. The pharmacological TLR4 inhibitor TAK-242 was administrated to C2C12 myotubes and C26 tumor-bearing mice to evaluate its effects on muscle atrophy. Western blot analysis and immunofluorescence microscopy were performed on C2C12 myotubes, while muscle tissues from C26 tumor-bearing mice, a model of cancer cachexia, were analyzed using western blot and histological examination.

Results

Exposure to conditioned medium from cachexia-associated cancer cell lines induced p38 MAPK–C/EBPβ in C2C12 myotubes, leading to upregulation of Ubr2 and Atrogin-1, myosin heavy chain degradation, and myotube atrophy. Silencing or inhibition of TLR4 using siRNA or TAK-242 prevented these catabolic effects in vitro. In C26 tumor-bearing mice, TAK-242 administration significantly attenuated cancer-associated muscle atrophy.

Conclusions

TLR4 plays a critical role in cancer-associated muscle atrophy through the p38β MAPK–C/EBPβ signaling pathway in both in vitro and in vivo models. Pharmacological inhibition of TLR4 with TAK-242 effectively attenuated muscle atrophy, highlighting its potential therapeutic value.