Tohoku Journal of Experimental Medicine最新文献

Acute lung injury (ALI) is an acute bilateral pulmonary infiltration disease, which may finally cause impairment and even loss of lung function. This study aimed to investigate the therapeutic potential and the mechanism of the Xuanfei Huazhuo decoction (XFHZ) against ALI in mice. The ALI mice stimulated by lipopolysaccharide (LPS) were subjected to the treatment of saline, 0.06, 0.11, and 0.22 mg/kg of XFHZ, and 10 mg/kg of fasudil, respectively, for seven consecutive days. It was found that XFHZ significantly attenuated LPS-induced pathological injury and mitochondrial dysfunction of vascular endothelial cells in the lung and suppressed LPS-mediated lung pulmonary edema (lung wet/dry weight ratio), the elevation of vascular permeability (increased total protein and albumin content in bronchoalveolar lavage fluid) and neutrophil infiltration. Microtubule stabilization, a process that could be regulated by GEF-H1, MYPT-1, Tau, and MAP-4, is critical for maintaining the endothelial cell barrier, of which disruption is a pathological hallmark of ALI. XFHZ reduced the expression of GEF-H1 and MYPT-1 at mRNA and protein levels and decreased Tau and MAP-4 protein expression in LPS-induced ALI. XFHZ also suppressed the increase of monomeric tubulin and the decrease of polymeric tubulin in injured lung induced by LPS. This study demonstrated that XFHZ can improve LPS-induced ALI by promoting microtubule stabilization, providing a theoretical basis for the clinical treatment of patients with ALI induced by different factors, including SARS-CoV-2 infection.

Dexmedetomidine (DEX) exerts neuroprotective effects following ischemic stroke (IS) by regulating several pathways, such as extracellular signal-regulated kinase 1 and 2 pathway and Ca2⁺-stromal interaction molecule 1/Orai calcium release-activated calcium channel protein 1 pathway, according to previous studies. However, the underlying mechanisms are not entirely elucidated yet. The purpose of this study was to investigate the impact of DEX on inhibiting neuron damage during IS, and the potential mechanism. Hippocampal neurons (HT22 cells) were treated with oxygen-glucose deprivation/reoxygenation (OGD/R) in the presence of 1 _μM DEX, 10 _μM LY294002 [a protein kinase B (AKT) inhibitor], or their combination. DEX increased viability and reduced apoptosis in OGD/R-stimulated hippocampal neurons. DEX reduced lactate dehydrogenase (LDH) and reactive oxygen species (ROS), but increased superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) in OGD/R-stimulated hippocampal neurons. These discoveries indicated that DEX mitigated OGD/R-triggered oxidative stress in hippocampal neurons. DEX increased phosphorylated-AKT/AKT and phosphorylated-mammalian target of rapamycin (mTOR)/mTOR in OGD/R-stimulated hippocampal neurons, which suggested that DEX activated the AKT/mTOR pathway. LY294002 inhibited the AKT/mTOR pathway and viability, but enhanced apoptosis and oxidative stress in OGD/R-stimulated hippocampal neurons. Notably, LY294002 reversed the effect of DEX on the above-mentioned processes in OGD/R-stimulated hippocampal neurons. In conclusion, DEX inhibits OGD/R-triggered hippocampal neuron injury by activating the AKT/mTOR pathway, which is conducive to attenuating IS progression.

Ovarian cancer has been regulated by microRNAs (miRNAs). Dysregulation of miR-487b-3p has been observed in several cancers. Present research was performed to explore the expression and function of miR-487b-3p in ovarian cancer. Differentially expressed miRNAs (DEmiRNAs) have been selected from GSE131790 dataset. miR-487b-3p level in epithelial ovarian cancer (EOC) patients has been verified by qRT-PCR. Effect of miR-487b-3p for EOC has been explored in SKOV3 and A2780 cells. Cell proliferation was assessed by Cell Counting Kit-8 conducted to assess the cell viability. Cell apoptosis rate was examined by flow cytometer. Transwell experiment was conducted to assess the migration and invasiveness of cells. Target gene of miR-487b-3p was predicted by databases. Target association was certified by double luciferase experiment. miR-487b-3p was upregulated in EOC patients. High miR-487b-3p could diagnose the onset of EOC (area under ROC curve (AUC) = 0.924, sensitivity = 88.79%, specificity = 84.8%). High FIGO stage (P = 0.023) and low differentiation grade (P = 0.044) were more frequently discovered in high miR-487b-3p group. miR-487b-3p could facilitate the cell viability, migration, invasiveness and inhibit the apoptosis of EOC cells. Ferrochelatase (FECH) is a direct target gene of miR-487b-3p. FECH was decreased in EOC tissues and passively related to miR-487b-3p. FECH could reverse the function of miR-487b-3p for EOC cells. Upregulated miR-487b-3p in EOC patients had high diagnostic value for EOC. miR-487b-3p facilitated EOC development via FECH.

Alcohol-induced osteoporosis (AOP) is a condition characterized by decreased bone mass and increased fracture risk due to excessive alcohol consumption. This study aimed to investigate the impact of ethanol on osteogenic differentiation through the KDM6B/BMP2 axis in AOP pathogenesis. Bone marrow mesenchymal stem cells (BMSCs) were cultured and exposed to ethanol to simulate AOP conditions. The expression levels of KDM6B, BMP2, and osteogenic markers were evaluated using RT-PCR, Western blotting, and immunohistochemistry. Osteogenic differentiation was assessed through alkaline phosphatase (ALP) activity assay and Alizarin Red staining experiment. The regulatory role of KDM6B in BMP2 demethylation was investigated using Chromatin Immunoprecipitation (ChIP) assay for H3K27me3 methylation levels. KDM6B and BMP2 expression was found decreased in AOP bone samples, and a positive correlation between KDM6B and BMP2 expression was observed. Ethanol treatment resulted in the downregulation of KDM6B, BMP2, and osteogenic markers in BMSCs, while upregulation of KDM6B rescued these phenomena. Moreover, ethanol treatment elevated the H3K27me3 methylation level of BMP2 promotor region, which was also reversed by KDM6B upregulation. Meanwhile, downregulation of BMP2 reversed the pro-osteogenic effects of KDM6B upregulation. KDM6B inhibits the H3K27me3 methylation of BMP2 to promote osteoblast differentiation and therefore ameliorates alcohol-induced osteoporosis.

Necrotizing enterocolitis (NEC) is a severe and damaging disorder of the gastrointestinal tract, primarily affecting premature babies. The study aimed to explore the clinical significance of miR-194-5p in NEC and elucidate its effect on lipopolysaccharides (LPS)-induced inflammatory response and oxidative stress. The expression level of miR-194-5p was detected by Real-time Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR), and the clinical value of miR-194-5p was analyzed by Receiver Operating Characteristic (ROC) analysis and logistic regression analysis. In addition, the levels of inflammatory factors and markers of oxidative stress were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA) kit. Cell viability was measured by Cell Counting Kit-8 (CCK-8) and the targeting relationship between miR-194-5p and TNF receptor associated factor 6 (TRAF6) was evaluated by dual luciferase reporter gene assay. miR-194-5p was down-regulated in the serum of premature infants with NEC and had a diagnostic value on NEC. Meanwhile, miR-194-5p regulated LPS-induced inflammation and oxidative stress responses by targeting TRAF6. In conclusion, miR-194-5p inhibited the progression of NEC, and miR-194-5p may be a biomarker for premature infants with NEC.

The vasohibin (VASH) family includes vasohibin-1 (VASH1), whose expression is induced in vascular endothelial cells by angiogenic factors such as vascular endothelial growth factor (VEGF) to inhibit angiogenesis via a negative feedback loop, and vasohibin-2 (VASH2), a homolog of VASH1, which is mainly expressed in cancer cells and promotes angiogenesis. VASH proteins have been associated with tumor angiogenesis and prognosis in various tumor types, drawing attention to their role in tumor biology. To date, no studies have reported on the expression of VEGF, VASH1, and VASH2 in benign parotid gland tumors. Therefore, in this study, we aimed to investigate their expression in these tumors. Our cohort consisted of 28 patients with benign parotid gland tumors, aged 31-79 (mean age 60.0 ± 13.8) years. Tumors were histologically diagnosed as pleomorphic adenoma in 15 patients (15 specimens) and Warthin's tumor in 13 patients (15 specimens). Immunohistochemical staining for VEGF, VASH1, and VASH2 was assessed based on the percentage of stained cells per slide (0-100%) and staining intensity, quantified using the H score. Immunostaining for VEGF, VASH1, and VASH2 demonstrated that Warthin's tumors had statistically significantly higher H-scores compared to pleomorphic adenomas. In addition, CD31 immunostaining showed a higher mean microvessel density (MVD) in the tumor stroma in Warthin's tumors than in pleomorphic adenomas. Similarly, CD34 immunostaining showed a higher number of spindle cells in the tumor stroma in Warthin's tumors than in pleomorphic adenomas. These findings suggest that the overexpression of VEGF, VASH1, and VASH2 is likely involved in the pathogenesis of benign parotid gland tumors.

Chemotherapy options for patients with advanced esophageal cancer had been limited until immune checkpoint inhibitors (ICIs) were approved for this indication. In recent years, ICI alone and ICI-combined chemotherapy have been approved, which prolonged the overall survival (OS) of patients with advanced esophageal cancer. We retrospectively analyzed 265 patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) who received chemotherapy with and without ICIs at Tohoku University Hospital from January 2013 to March 2022. Cisplatin plus fluorouracil therapy was the most frequently administered regimen as first-line treatment, and their administration frequency did not significantly differ between before 2019 and after 2020. Nivolumab was the most frequently used treatment as second-line therapy since its first approval in 2020 (74%), whereas taxanes were the most frequently used regimen before 2019 (55%). The median OS was 13.9 months over the entire observation period. Among patients who received second-line therapy, those receiving ICIs at any line demonstrated significantly longer OS from the start of second-line treatment than the others (p = 0.03). Univariate analysis revealed that a G8 score of < 11 (hazard ratio: 1.62, p = 0.02) was a prognostic factor in patients aged ≥ 65 years. Among each components of the G8 score, a decrease in food intake, weight loss, impaired mobility, and self-perceived poor health status were shown to be particularly associated with shorter OS. Our real-world data demonstrated that ICI administration contributed to improved OS after initiating second-line treatment for unresectable, advanced, or recurrent ESCC. Additionally, we revealed that the G8 score could be a useful prognostic factor in elderly patients with advanced ESCC treated with chemotherapy.

We aimed to investigate the glaucoma-detecting ability of MEOCHECK, a novel and simple visual field measurement device based on retinal projection technology. This retrospective and observational study evaluated 94 glaucomatous eyes of 49 subjects and 31 non-glaucomatous eyes of 23 healthy subjects. We compared MEOCHECK's main output, Score 100, to visual acuity, intraocular pressure, optical coherence tomography-measured parameters (circumpapillary retinal nerve fiber layer thickness [cpRNFLT] and ganglion cell complex thickness [GCCT]), and automated perimetry-measured mean deviation (MD) in glaucomatous eyes. Score 100 showed significant correlations with age, visual acuity, cpRNFLT, GCCT, and MD (r = --0.38, p < 0.001; r = -0.42, p < 0.001; r = 0.65, p < 0.001; r = 0.59, p < 0.001; and r = 0.62, p < 0.001, respectively). Score 100 was statistically significantly lower in early- vs. moderate-stage glaucoma (p = 0.03) and in moderate- vs. severe-stage glaucoma (p = 0.002). A logistic regression analysis indicated that Score 100 could predict the presence of glaucoma, with an area under the receiver operating characteristic curve of 0.89. MEOCHECK, a novel device that uses retinal projection technology, effectively detected glaucomatous visual fields, demonstrating its potential as a reliable tool for glaucoma detection.