Down-regulation Of Related Genes Research Articles

Lincomycin as a growth-promoting antibiotic induces metabolic and immune dysregulation in animals

Since animal growth promoters (AGPs) are used in large quantities and commonly released to the environment from animal farms, it is necessary to determine whether such agents should be regarded as an environmental toxin that poses a threat to the ecosystem and health risk to wildlife. In this study, a multi-omics approach was employed to explore the effects of a representative AGP, lincomycin, on key metabolic and physiological functions of animals, using a mouse model. The results indicated that exposure to lincomycin resulted in a significant increase in growth rate of mice (50.11 %) over an 8 weeks period, during which significant decrease (61.94 %) and increase (68.64 %) in the relative abundance of Firmicutes and Escherichia coli, respectively, was observed in the gut microbiota, indicating that the gut microbiota structure has been altered. Moreover, the mice exhibited altered lipid profiles and liver damage suggestive of early-stage non-alcoholic fatty liver disease (NAFLD). Disruptions in blood glucose and insulin levels associated with type 2 diabetes mellitus (T2DM) were also observed. Furthermore, lincomycin was found to cause suppression in inflammatory responses, as evidenced by the downregulation of related genes and elevated inflammatory mediators, potentially resulting in increased susceptibility to microbial infection. Our findings underscore the detrimental effects of lincomycin on animal health and highlight the necessity for comprehensive toxicological assessments of lincomycin and other AGPs before their environmental release.

Decreased biofilm formation in Proteus mirabilis after short-term exposure to a simulated microgravity environment

BackgroundMicrobes threaten human health in space exploration. Studies have shown that Proteus mirabilis has been found in human space habitats. In addition, the biological characteristics of P. mirabilis in space have been studied unconditionally. The simulated microgravity environment provides a platform for understanding the changes in the biological characteristics of P. mirabilis.ObjectiveThis study intends to explore the effect of simulated microgravity on P. mirabilis, the formation of P. mirabilis biofilm, and its related mechanism.MethodsThe strange deformable rods were cultured continuously for 14 days under microgravity simulated in high-aspect rotating vessels (HARVs). The morphology, growth rate, metabolism, and biofilm formation of the strain were measured, and the phenotypic changes of P. mirabilis were evaluated. Transcriptome sequencing was used to detect differentially expressed genes under simulated microgravity and compared with phenotype.ResultsThe growth rate, metabolic ability, and biofilm forming ability of P. mirabilis were lower than those of normal gravity culture under the condition of simulated microgravity. Further analysis showed that the decrease of growth rate, metabolic ability, and biofilm forming ability may be caused by the downregulation of related genes (pstS, sodB, and fumC).ConclusionThe simulated microgravity condition enables us to explore the potential relationship between bacterial phenotype and molecular biology, thus opening up a suitable and constructive method for medical fields that have not been explored before. It provides a certain strategy for the treatment of P. mirabilis infectious diseases in space environment by exploring the microgravity of P. mirabilis.

The immune response of a warm water fish orange-spotted grouper (Epinephelus coioides) infected with a typical cold water bacterial pathogen Aeromonas salmonicida is AhR dependent

The present study reported the first pathogenic Aeromonas salmonicida (SRW-OG1) isolated from the warm water fish orange-spotted grouper (Epinephelus coioides), and investigated the function of Aryl hydrocarbon receptor (AhR), a ligand-dependent transcriptional factor which has been recently found to be closely associated with immune response in mammals and E. coioides. Our results showed that AhR was activated by an unknown ligand in the spleen, intestine and macrophages. Meanwhile, ahr1a and ahr1b were significantly increased in the spleen, intestine and macrophages, whereas ahr2 was only increased in the intestine, which indicated that the contribution of AhR2 to the immune response may be less than that of AhR1a and AhR1b. Some key genes involved in the macrophage inflammatory response, bacterial recognition, and intestinal immunity were significantly up-regulated in the SRW-OG1 infected E. coioides. Nevertheless, declining macrophage ROS production and down-regulation of related genes were also observed, suggesting that SRW-OG1 utilized its virulence mechanisms to prevent macrophage ROS production. Furthermore, AhR inhibitor 3′, 4′-DMF and the silence of ahr1a or ahr1b significantly rescued the increased IL-1β and IL-8 induced by SRW-OG1 infection, which proved that the induction of IL-1β and IL-8 in E. coioides macrophages was mediated by AhR. However, BPI/LBP, ROS production and related genes were not affected by AhR. The survival rate and immune escape rate of SRW-OG1 in the ahr1a/ahr1b knocked-down and 3′, 4′-DMF treated macrophages were significantly increased compared with those in wild type macrophages. Taken together, it was preliminarily confirmed that ahr1a and ahr1b played an important role in the immune response against A. salmonicida SRW-OG1.

Artemisia sphaerocephala Krasch polysaccharide mediates lipid metabolism and metabolic endotoxaemia in associated with the modulation of gut microbiota in diet-induced obese mice

Artemisia sphaerocephala Krasch polysaccharide (ASKP) has been proved to have many bioactivities. To determine the underlying mechanisms on anti-obesogenic effect of ASKP in mice, parameters related to obesity, gut microbiota composition, and the correlation between the parameters and specific bacterial taxa were investigated. The results showed that ASKP significantly alleviated high-fat-diet-induced obesity in mice with the amelioration of dyslipidemia, and metabolic endotoxaemia. Relative expression analyses of genes indicated that ASKP administration modulated hepatic lipid metabolism with the downregulation of related genes, including ACC-1, FAS, SREBP-1c, and PPARγ. 16S rRNA analysis showed that ASKP mediated the gut dysbiosis induced by high-fat diet, such as the reduction of Proteobacteria, AF12, and Helicobacter. Spearman’s correlation showed that some specific genera, such as Odoribacter, AF12, and Rikenella, were strongly associated with obesity-related parameters. Our results demonstrated that ASKP could serve as a potential prebiotic agent in the prevention of diet-induced obesity.

Protein Kinase B and Extracellular Signal-Regulated Kinase Inactivation is Associated with Regorafenib-Induced Inhibition of Osteosarcoma Progression In Vitro and In Vivo.

Osteosarcoma is the most common type of bone cancer. Multimodality treatment involving chemotherapy, radiotherapy and surgery is not effective enough to control osteosarcoma. Regorafenib, the oral multi-kinase inhibitor, has been shown to have positive efficacy on disease progression delay in chemotherapy resistant osteosarcoma patients. However anti-cancer effect and mechanism of regorafenib in osteosarcoma is ambiguous. Thus, the aim of this study is to investigate the efficacy and molecular mechanism of regorafenib on osteosarcoma in vitro and in vivo. Human osteosarcomas U-2 OS or MG-63 were treated with regorafenib, miltefosine (protein kinase B (AKT) inhibitor), or PD98059 (mitogen-activated protein/extracellular signal-regulated kinase (MEK) pathway inhibitor) for 24 or 48 h. Cell viability, apoptotic signaling transduction, tumor invasion, expression of tumor progression-associated proteins and tumor growth after regorafenib treatment were assayed by MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, transwell assay, Western blotting assay and in vivo animal experiment, respectively. In these studies, we also indicated that regorafenib suppressed cell growth by prompting apoptosis of osteosarcoma cells, which is mediated through inactivation of ERK and AKT signaling pathways. After regorafenib treatment, downregulation of related genes in invasion (vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9)), proliferation (CyclinD1) and anti-apoptosis (X-linked inhibitor of apoptosis protein (XIAP), myeloid cell leukemia-1 (MCL-1), and cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (C-FLIP)) were found. Moreover, upregulation of caspase-3 and caspase-8 cleavage were also observed. In sum, we suggest that regorafenib has potential to suppress osteosarcoma progression via inactivation of AKT and ERK mediated signaling pathway.

Upregulation of Nrf2–p300 mediates anti-inflammatory effects of curcumin in microglia by downregulating p65–p300

ABSTRACTCurcumin (CUR) is a hydrophobic polyphenol derived from the rhizome of Curcuma longa. CUR confers protection in various pathological conditions, including many brain-related diseases, such as cerebral ischemia, intracerebral hemorrhage, or Alzheimer’s disease, and these effects have been attributed to its anti-inflammatory and anti-oxidative properties. In the present study, we found CUR induced the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in microglia, brain macrophage, and thus upregulated genes downstream of antioxidant response element, such as heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, glutamate-cysteine ligase modifier subunit, and ferritin light chain, and simultaneously downregulated lipopolysaccharide-induced inducible nitric oxide synthase expression. We showed that the anti-inflammatory effect of CUR in microglia is connected with its anti-oxidative effect in that CUR promotes Nrf2–p300 binding at the expense of p65–p300 binding. Since CUR is a dietary spice that is eaten on a daily basis, it appears that CUR could be used therapeutically to induce anti-oxidative effect and simultaneously ameliorate inflammatory conditions via up–downregulation of related genes.

Effects of overexpression of a bHLH transcription factor on biomass and lipid production in Nannochloropsis salina.

BackgroundMicroalgae are considered promising alternative energy sources because they consume CO2 and accumulate large amounts of lipids that can be used as biofuel. Nannochloropsis is a particularly promising microalga due to its high growth rate and lipid content, and the availability of genomic information. Transcription factors (TFs) are global regulators of biological pathways by up- or down-regulation of related genes. Among these, basic helix-loop-helix (bHLH) TFs regulate growth, development, and stress responses in plants and animals, and have been identified in microalgae. We identified two bHLH TFs in the genome of N. salina CCMP1776, NsbHLH1, and NsbHLH2, and characterized functions of NsbHLH2 that may be involved in growth and nutrient uptake.ResultsWe obtained NsbHLH2 overexpressing transformants of N. salina CCMP1776 by particle bombardment and confirmed that these were stable transformants. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting using antibodies against the FLAG tag that was attached at the end of the coding sequence confirmed the expression of the NsbHLH2 protein under various culture conditions. The qRT-PCR results also indicated that the endogenous and transgenic expression of NsbHLH2 was reduced under stressed conditions. Overexpression of NsbHLH2 led to increased growth rate in the early growth period, and concomitantly higher nutrient uptake, than wild type (WT). These enhanced growth and nutrient uptake resulted in increased productivities of biomass and FAME. For example, one of the transformants, NsbHLH2 3–6, showed increased biomass productivity by 36 % under the normal condition, and FAME productivity by 33 % under nitrogen limitation condition. Conclusively, the improved growth in the transformants can be associated with the enhanced nutrient uptake. We are currently assessing their potential for scale-up cultivation with positive outcomes.ConclusionOverexpression of NsbHLH2 led to enhanced growth rate and nutrient uptake during the early growth phase, and increased biomass and FAME productivity, especially in the later period under normal and stressed conditions. Based on these results, we postulate that NsbHLH2 can be employed for the industrial production of biodiesel from N. salina.Electronic supplementary materialThe online version of this article (doi:10.1186/s13068-015-0386-9) contains supplementary material, which is available to authorized users.