Protective role of fruits of Rosa odorata var. gigantea against WIRS-induced gastric mucosal injury in rats by modulating pathway related to inflammation, oxidative stress and apoptosis.

Objective: Rosa odorata var. gigantea is a popular medicinal plant. Some studies have demonstrated that ethanolic extract of the fruits of R. odorata var. gigantea (FOE) has gastroprotective properties. The aim of this study was to investigate the gastroprotective activity of FOE on water immersion restrained stress (WIRS)-induced gastric mucosal injury in a rat model and elucidate the possible molecular mechanisms involved. Methods: A rat stress ulcer model was established in this study using WIRS. After rats were treated with FOE orally for 7 d, the effect of FOE treatment was analyzed by hematoxylin and eosin (H&E) staining, and the changes of inflammatory factors, oxidative stress factors, and gastric-specific regulatory factors and pepsin in the blood and gastric tissues of rats were examined by ELISA assay. Molecular mechanism of FOE was investigated by immunohistochemical assay and Western blot. Results: Compared with the WIRS group, FOE could diminish both the macroscopic and microscopic pathological morphology of gastric mucosa. FOE significantly preserved the antioxidants glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and catalase (CAT) contents; anti-inflammatory cytokines interleukin-10 (IL-10) and prostaglandin E2 (PGE2) levels as well as regulatory factors tumor necrosis factor-α (TGF-α) and somatostatin (SS) contents, while decreasing malondialdehyde (MDA), nitric oxide synthase (iNOS), tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), gastrin (GAS) and endothelin (ET) levels. Moreover, FOE distinctly upregulated the expression of Nrf2, HO-1, Bcl2 and proliferating cell nuclear antigen (PCNA). In addition, FOE activated the expression of p-EGFR and downregulated the expression of NF-κB, Bax, Cleaved-caspase-3, Cyto-C and Cleaved-PARP1, thus promoting gastric mucosal cell survival. Conclusion: The current work demonstrated that FOE exerted a gastroprotective activity against gastric mucosal injury induced by WIRS. The underlying mechanism might be associated with the improvement of anti-inflammatory, anti-oxidation and anti-apoptosis systems.

Identification of chemical constituents of Qingjin Yiqi granules and comparative study on pharmacokinetics of 23 main bioactive components in normal and Lung-Qi deficiency rats by UPLC-MS/MS method.

Qingjin Yiqi granules (QJYQ granules) are hospital preparations derived from ancient prescriptions under the guidance of academician Zhang Boli; they have the effect of invigorating qi and nourishing yin, strengthening the spleen and harmonizing the middle, clearing heat, and drying dampness, and are mainly used for patients with coronavirus disease 2019 (COVID-19) during the recovery period. However, their chemical constituents and pharmacokinetic characteristics in vivo have not been systematically investigated. In this study, 110 chemical constituents of QJYQ granules were identified using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), and a fast and sensitive ultra-high-performance liquid chromatography-mass spectrometry method was developed and validated for the target analytes. A rat model of lung-qi deficiency was established by subjecting mice to passive smoking combined with cold baths, and 23 main bioactive components of QJYQ granules were analyzed in normal and model rats after oral administration. The results showed that, compared to the normal group, there were significant differences in the pharmacokinetics of baicalin, schisandrin, ginsenoside Rb1, naringin, hesperidin, liquiritin, liquiritigenin, glycyrrhizic acid, and hastatoside in the model rats (P < 0.05), indicating that the in vivo processes of the above components changed under pathological conditions, suggesting that they may have pharmacological effects as active components. This study has helped identify QJYQ particulate substances and further supports their clinical application..

ACE2 maybe serve as a prognostic biomarker in breast invasive carcinoma.

BACKGROUND: Breast cancer is a frequently occurring malignant tumor in women. Angiotensin-converting enzyme 2 (ACE2) is widely expressed in most organs; however, the association of ACE2 with prognosis and immune infiltration in breast invasive carcinoma (BRCA) remains elusive. METHODS: We explored the expression level and prognostic value of ACE2 in patients with BRCA using a series of online bioinformatics analysis databases encompassing Oncomine, UALCAN, Kaplan-Meier plotter, TIMER, LinkedOmics, and GEO. qRT-PCR was performed to verify our findings. RESULTS: Angiotensin-converting enzyme 2 mRNA and protein expression levels were decreased in BRCA tissues, and patients with low ACE2 expression levels had a poor prognosis. DNA promoter methylation of ACE2 significantly downregulated ACE2 expression in BRCA, while the expression of this protein was positively linked to immune infiltration of B cells, CD8+ and CD4+ T cells, neutrophils, and dendritic cells in BRCA tissues. The high expression level of ACE2 in enriched basophils, CD8+ T cells, and type-2 helper T cells, which showed decreasing levels, indicated a better prognosis for BRCA. Enrichment analyses revealed that NF-κB, IL-17, and TNF signaling pathways were highly correlated to ACE2 in BRCA. Verification study revealed that downregulation of ACE2 was associated with a better prognosis in BRCA. Univariate and multivariate analysis confirmed ACE2 expression and clinical stage as independent prognostic factors for breast cancer. CONCLUSIONS: Angiotensin-converting enzyme 2 may be a potential prognostic biomarker and target for BRCA. Nevertheless, future investigations are needed for validating our findings and promoting the clinical application of ACE2 in BRCA.

Comparative Transcriptome Analysis Revealed Genes Involved in Sexual and Polyploid Growth Dimorphisms in Loach (Misgurnus anguillicaudatus).

Sexual and polyploidy size dimorphisms are widespread phenomena in fish, but the molecular mechanisms remain unclear. Loach (Misgurnus anguillicaudatus) displays both sexual and polyploid growth dimorphism phenomena, and are therefore ideal models to study these two phenomena. In this study, RNA-seq was used for the first time to explore the differentially expressed genes (DEGs) between both sexes of diploid and tetraploid loaches in four tissues (brain, gonad, liver, and muscle). Results showed that 21,003, 17, and 1 DEGs were identified in gonad, liver, and muscle tissues, respectively, between females and males in both diploids and tetraploids. Regarding the ploidy levels, 4956, 1496, 2187, and 1726 DEGs were identified in the brain, gonad, liver, and muscle tissues, respectively, between tetraploids and diploids of the same sex. When both sexual and polyploid size dimorphisms were considered simultaneously in the four tissues, only 424 DEGs were found in the gonads, indicating that these gonadal DEGs may play an important regulatory role in regulating sexual and polyploid size dimorphisms. Regardless of the sex or ploidy comparison, the significant DEGs involved in glycolysis/gluconeogenesis and oxidative phosphorylation pathways were upregulated in faster-growing individuals, while steroid hormone biosynthesis-related genes and fatty acid degradation and elongation-related genes were downregulated. This suggests that fast-growing loaches (tetraploids, females) have higher energy metabolism levels and lower steroid hormone synthesis and fatty acid degradation abilities than slow-growing loaches (diploids, males). Our findings provide an archive for future systematic research on fish sexual and polyploid dimorphisms.

Huperzine A, reduces brain iron overload and alleviates cognitive deficit in mice exposed to chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) is a consequence of obstructive sleep apnea (OSA), which increases reactive oxygen species (ROS) generation, resulting in oxidative damage and neurocognitive impairment. This study was designed to determine whether abnormal iron metabolism occurs in the brain under conditions of CIH and whether Huperzine A (HuA) could improve abnormal iron metabolism and neurological damage. The mouse model of CIH was established by reducing the percentage of inspired O2 (FiO2) from 21% to 9% 20 times/h for 8 h/day, and Huperzine A (HuA, 0.1 mg/kg, i.p.) was administered during CIH exposure for 21 days. HuA significantly improved cognitive impairment and neuronal damage in the hippocampus of CIH mice via increasing the ratio of Bcl-2/Bax and inhibiting caspase-3 cleavage. HuA considerably decreased ROS levels by downregulating the high levels of NADPH oxidase (NOX 2, NOX 4) mediated by CIH. There was an overload of iron, which was characterized by high levels of ferritin (FTL and FTH) and transferrin receptor 1 (TfR1) and low levels of ferroportin 1 (FPN1) in the hippocampus of CIH mice. Decreased levels of TfR1 and FTL proteins observed in HuA treated CIH group, could reduce iron overload in hippocampus. HuA increased PSD 95 protein expression, CREB activation and BDNF protein expression to protect against synaptic plasticity impairment induced by CIH. HuA acts as an effective iron chelator to attenuate apoptosis, oxidative stress and synaptic plasticity mediated by CIH.

Resveratrol prevents chronic intermittent hypoxia-induced cardiac hypertrophy by targeting the PI3K/AKT/mTOR pathway.

AIMS: Resveratrol is a polyphenolic compound that has received much attention for its use in ameliorating various systemic pathological conditions. The present study was performed to investigate whether the resveratrol alleviated cardiac hypertrophy and functional remodelling by regulating autophagy. MATERIALS AND METHODS: Male rats were exposed to CIH 8 h/day for five weeks and/or intragastric administration of resveratrol daily. The morphological and echocardiography were used to evaluate the cardiac protective effects. The apoptosis was detected by TUNEL staining. The biochemical assessments were used to evaluate oxidative stress. Further, the effect of resveratrol on autophagy and PI3K/AKT/mTOR pathway was investigated. KEY FINDINGS: The CIH group exhibited increased heart weight/body weight and left ventricle weight/body weight ratios, which was accompanied by left ventricular remodelling. Echocardiography analysis showed that CIH-treated rats had significantly higher left ventricular posterior wall thickness, ejection fraction and fractional shortening than those of controls. In addition, the apoptosis index and oxidative markers were significantly elevated in the CIH group versus the control. The autophagy marker Beclin-1 was elevated, while p62 was decreased by CIH treatment. Resveratrol treatment significantly improved cardiac function and alleviated cardiac hypertrophy, oxidative stress, and apoptosis in CIH rats. Further results indicated that PI3K/AKT pathway-mediated inhibition of the mammalian target of rapamycin (mTOR) pathway played a role in the activation of autophagy by resveratrol after CIH stimulation. SIGNIFICANCE: In conclusion, resveratrol supplementation during CIH upregulates autophagy by targeting the PI3K/AKT/mTOR pathway, which appears to be beneficial for resisting cardiac hypertrophy.

Hydrogen Gas Alleviates Chronic Intermittent Hypoxia-Induced Renal Injury through Reducing Iron Overload.

Iron-induced oxidative stress has been found to be a central player in the pathogenesis of kidney injury. Recent studies have indicated H2 can be used as a novel antioxidant to protect cells. The present study was designed to investigate the protective effects of H2 against chronic intermittent hypoxia (CIH)-induced renal injury and its correlation mechanism involved in iron metabolism. We found that CIH-induced renal iron overloaded along with increased apoptosis and oxidative stress. Iron accumulates mainly occurred in the proximal tubule epithelial cells of rats as showed by Perl's stain. Moreover, we found that CIH could promote renal transferrin receptor and divalent metal transporter-1 expression, inhibit ceruloplasmin expression. Renal injury, apoptosis and oxidative stress induced by CIH were strikingly attenuated in H2 treated rats. In conclusion, hydrogen may attenuate CIH-induced renal injury at least partially via inhibiting renal iron overload.

MiR-124-3p suppresses glioma aggressiveness via targeting of Fra-2.

Malignant glioma is the most common and deadly primary brain tumor in adults. However, the mechanisms underlying the malignancy of glioma remain unclear. In the present study, we found that Fos-related antigen-2 (Fra-2) was overexpressed in most glioma cells, and knockdown of Fra-2 prevented cell proliferation, migration, and invasion. Mechanistically, Fra-2 silencing led to a significant reduction in cell-cycle drivers (Cyclin D1 and Cyclin E1), one invasion-associated gene (MMP9), the mesenchymal marker (Vimentin), and induction of the epithelial marker (E-cadherin). Further study confirmed that miR-124-3p decreased the expression of Fra-2 via directly targeting the 3'-UTR, and transfection with miR-124-3p in glioma cells inhibited expression of the above cell-cycle and EMT promoters. Phenotypic experiments also showed that overexpression of Fra-2 weakened the inhibitory effects of miR-124-3p on the proliferation, migration, and invasion of glioma cells. In addition, Fra-2 knockdown impaired the malignant phenotypes enhanced by miR-124-3p inhibition, which suggested a crucial role for the miR-124-3p/Fra-2 pathway in glioma development. Consistently, high expression of Fra-2 was closely associated with low miR-124-3p level and indicated a poor prognosis in patients with glioma. In conclusion, this study indicates the existence of an aberrant miR-124-3p/Fra-2 pathway that results in glioma aggressiveness, which suggests novel therapeutic opportunities for this fatal disease.

Global and Complement Gene-Specific DNA Methylation in Grass Carp after Grass Carp Reovirus (GCRV) Infection.

Grass carp reovirus (GCRV) causes huge economic loss to the grass carp cultivation industry but the mechanism remains largely unknown. In this study, we investigated the global and complement gene-specific DNA methylation in grass carp after GCRV infection aimed to uncover the mechanism underlying GCRV infection. The global DNA methylation level was increased after GCRV infection. Expression levels of enzymes involved in DNA methylation including DNA methyltransferase (DNMT), ten-eleven translocation proteins (TETs), and glycine N-methyltransferase (GNMT) were significantly altered after GCRV infection. In order to investigate the relationship between the gene expression level and DNA methylation level, two representative complement genes, complement component 3 (C3) and kininogen-1 (KNG1), were selected for further analysis. mRNA expression levels of the two genes were significantly increased at 5 and 7 days after GCRV infection, whereas the DNA methylation level at the 5' flanking regions of the two genes were down-regulated at the same time-points. Moreover, a negative correlation was detected between gene expression levels and DNA methylation levels of the two genes. Therefore, the current data revealed a global and complement gene-specific DNA methylation profile after GCRV infection. Our study would provide new insights into understanding the mechanism underlying GCRV infection.

Molecular cloning, expression analysis and localization pattern of the MST family in grass carp (Ctenopharyngodon idella).

The mammalian sterile 20-like (MST) family, which belongs to the serine/threonine protein kinase superfamily, has five members that can be found in mammals: STK3 (also called MST2), STK4 (MST1), STK24 (MST3), STK25 (YSK1 or SOK1), and STK26 (MST4). The MST kinases have key roles in apoptosis, immune regulation, inflammatory responses, cancer, and cell proliferation in mammals, whereas the roles and transcriptional regulatory mechanism of these kinases in teleost fish are still unclear. In this study, four STK genes (CiSTK3, CiSTK24, CiSTK25, and CiSTK26) were cloned and analyzed in grass carp (Ctenopharyngodon idella). All four STK genes were broadly expressed in the examined tissues, while their relative expression levels differed. In addition, after exposure to the grass carp reovirus, mRNA expression levels of the four STK genes were altered to different levels in the immune organs, and the levels were dramatically altered in the blood. Subcellular localization indicated that all four STK proteins were localized in the cytoplasm of transfected cells. Moreover, bimolecular fluorescence complementation analysis revealed that mouse protein-25 could interact with CiSTK3, CiSTK24, CiSTK25, and CiSTK26 independently in grass carp. Thus, our findings provide new insights for understanding the functions of the MST family in teleosts.

Relationship of oestrogen receptor alpha gene polymorphisms with risk for benign prostatic hyperplasia and prostate cancer in Chinese men.

The relationship of oestrogen receptor with benign prostatic hyperplasia (BPH) and prostate cancer (PC) is not clear at present. This study aimed to investigate the molecular mechanism underlying the occurrence and development of BPH and prostate.Two hundred forty-four PC cases, 260 BPH patients, and 222 healthy men were recruited from Han people in China, and the oestrogen receptor alpha (ESRα) gene polymorphism (rs2234693 [PvuII] and rs9340799 [XbaI]) on intron 1 was determined. The relationship of gene polymorphism with PC and BPH was evaluated with Logistic regression, and the linkage disequilibrium and haplotyping were assessed with SHEsis software.The risk for PC in BPH patients with PvuII C allele was higher (OR = 1.437, 95% CI: 1.110-1.859), but the differentiation degree of cancer cells was relatively better in PC patients with PvuII C allele (OR = 0.419, 95% CI: 0.285-0.616), and most of them are circumscribed (OR = 0.706, 95% CI: 0.485-1.02). There was significant linkage disequilibrium between PvuII and XbaI. The genotype TTAG not only induced BPH (OR = 6.260, 95% CI: 1.407-27.852), but increased the risk for PC (OR = 6.696, 95% CI: 1.504-29.801). However, the genotype TTAG in BPH patients had no relationship with the risk for PC (P > 0.05). Furthermore, men with haplotype TG were more likely to suffer PC (OR = 9.168, 95% CI: 2.393-35.119), but men with haplotype TA and enlarged prostate had a low risk for PC (OR = 0.708, 95% CI: 0.551-0.912).These results show the relationship between ESRα gene polymorphism and susceptibility to PC and BPH in Chinese men, and the ethnic and regional difference as well.

Over-expression of CD200 predicts poor prognosis in MDS.

BACKGROUND: We studied the expression of CD200 in a series of 101 patients with diagnosis of myelodysplastic syndrome (MDS), to evaluate its impact on outcome and its possible association with other known prognostic factors. MATERIAL/METHODS: The CD200 was detected by flow cytometry, and the chromosome karyotypes were determined by G banding respectively. The Mann-Whitney U test was used to analyze the association among CD200 expression and clinical features. In addition, the overall survival and AML transformation of the MDS patients according to the expression level of CD200 was also explored. RESULTS: Overall, the flow cytometric analyses confirmed that expression of CD200 was high in this patient cohort compared to normal BM (p<0.01). The levels of CD200 in RCUD (20.3%±4.3%), RCMD (25.0%±4.5%), RAEB-1 (39.2%±4.9%), and RAEB-2 (43.2%±5.8%) groups were obviously higher than that of RARS group (6.8%±1.7%, P<0.05). Significant differences of CD200 expression were observed in the 4 groups of MDS according to IPSS risk(P<0.01). After 45-month follow-up, Kaplan-Meier analysis of patients with MDS in our study indicated that patients with high expression level of CD200 had a shorter overall survival and a high Leukemic transformation than those with low expression (p<0.01). CONCLUSIONS: In conclusion, our findings provide firstly the evidence that CD200 is up-regulated and emerging as both a prognostic factor and a potential target of novel therapeutic approaches for MDS.