Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a "glycerol shunt", a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver. We generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PPfl/fl mice. Controls received AAV8-TBG-eGFP. Both groups were fed chow diet for 10 weeks. Hyperglycemia (16–20 mM) was induced by glucose infusion for 55 h. Hepatocytes were isolated from normoglycemic mice for ex vivo studies and targeted metabolomics were measured in mice liver after glucose infusion. LKO mice showed no change in body weight, food intake, fed and fasted glycemia but had increased fed plasma triglycerides. Hepatic glucose production from glycerol was increased in fasted LKO mice. LKO mouse hepatocytes displayed reduced glycerol production, elevated triglyceride and lactate production at high glucose concentration. Hyperglycemia in LKO mice led to increased liver weight and accumulation of triglycerides, glycogen and cholesterol together with elevated levels of Gro3P, dihydroxyacetone phosphate, acetyl-CoA and some Krebs cycle intermediates in liver. Hyperglycemic LKO mouse liver showed elevated expression of proinflammatory cytokines and M1-macrophage markers accompanied by increased plasma triglycerides, LDL/VLDL, urea and uric acid and myocardial triglycerides. The glycerol shunt orchestrated by G3PP acts as a glucose excess detoxification pathway in hepatocytes by preventing metabolic disturbances that contribute to enhanced liver fat, glycogen storage, inflammation and lipid build-up in the heart. We propose G3PP as a novel therapeutic target for hepatic disorders linked to nutrient excess.
Communicative language teaching (CLT) stresses communication as a medium and as the mainobjective of language education, a multilingual and international language teaching method.Communication is also a way to teach foreign languages and stresses communication as a means andprimary language learning goal. The aim of the study is to explore the impact of communicativelanguage teaching of BS students. It also recognizes the reasons why there are no proficient speakersof the English language even after the use of the communicative teaching method (Rababah, 2002).Afive-point Likert scale was used in the questionnaires that were filled by 183 students of The IslamiaUniversity and GSC women university of Bahawalpur. The findings reveal that communicativelanguage teaching is the completely suitable and perfect strategy to be applied in classrooms whenteaching a second or foreign language. Due to certain factors, it is unable to produce proficientspeakers of the English language.
In innate immune cells, TCA cycle components are not simply inert metabolites, but are key signaling molecules that can modulate inflammatory responses. Itaconate, an immunometabolite made by the enzyme aconitase decarboxylase (encoded by the gene Irg1), is highly upregulated in classically activated M1 macrophages and regulates immune responses by dampening inflammation. The role of itaconate in activation of alternative macrophage programs is of interest, as itaconate has recently been shown to be taken up by M2 macrophages. Here, we show that expression of Irg1 is specific to M1 macrophages and opposes regulators of IL-4 mediated alternative activation. Overexpression of Irg1 in murine M2 macrophages inhibited their program. Similarly, exogenous addition of a cell-permeable derivative of itaconate inhibited M2 gene expression and blocked activation of Stat6 and AKT in IL-4 activated macrophages. Itaconate-treated M2 macrophages also showed decreased oxidative phosphorylation, altogether suggesting that itaconate constrains IL-4-mediated alternative activation of macrophages. Mechanistically, this novel role of itaconate was not through previously reported pathways Nrf2 or Complex II (SDH), but rather via inhibition of the phosphorylation of Janus Kinase 1. We also show that an M2-specific microRNA, miR-378a, targets Irg1 to prevent itaconate production in these cells. Thus, we demonstrate that itaconate antagonizes M2 macrophage activation, suggesting a mechanism by which M1 macrophages inhibit alternative macrophage polarization. This may be useful in considering the therapeutic potential of itaconate as an inhibitor of M2 macrophages in such conditions as allergic asthma and fibrosis.
Background/Aims: We investigated the unknown molecular mechanisms of Interleukin-1 (IL-1β)-induced cartilage aggrecan degeneration by aggrecanase (ADAMTS-A Disintegrin And Metalloproteinase with ThromboSpondin motifs) in human articular chondrocytes, a model mimicking human arthritis. Methods: Chondrocytes were pretreated with various pharmacological inhibitors and then stimulated with IL-1β for 24 h. ADAMTS-4 expression or activity was studied by RT-PCR or ELISA and other proteins measured by Western blotting. Results: MAP kinase kinase-specific inhibitor, U0126 inhibited IL-1-induced phosphorylation of ERK1/2 and down-regulated ADAMTS-4 expression and activity. Protein 38 inhibitor, SB203580 down-regulated the phosphorylation of p38 and its target, activating transcription factor-2 (ATF-2), ADAMTS-4 mRNA and activity. C-Jun N-terminal kinase (JNK) inhibitor, SP600125 diminished IL-1-stimulated JNK phosphorylation, ADAMTS-4 mRNA expression and enzyme activity. A c-fos/lipoxygenase pathway inhibitor and antioxidant, nordihydroguaiaretic acid (NDGA) significantly suppressed ADAMTS-4 mRNA induction and activity. Activating protein (AP-1) and nuclear factor kappa B (NF-ĸB) transcription factor inhibitors, curcumin and pyrrolidine dithiocarbamate (PDTC) partially inhibited ADAMTS-4 induction and activity. Conclusion: These results suggest partial involvement of ERK-, p38-and JNK-MAPKs as well as AP-1, ATF-2 and NF-ĸB transcription factors in IL-1-induced ADAMTS-4 in chondrocytes. Inhibition of these targets by the specific pharmacological agents could be useful for reducing aggrecanase-driven cartilage resorption in arthritis.
In the present study, the response of primary attributes (seedling growth, percent emergence, seedling fresh and dry biomass, and seedling moisture contents) and nutrient contents (Calcium, Magneisum, Iron, Manganese, Zinc, Copper) of Brassica napus L. was evaluated as a function of glucose-induced priming and salinity. The priming comprised 30 minutes, 60 minutes and 90 minutes of seeds soaking in glucose solution (0.50 M) and salinity stress was simulated by the solutions of 0, 15, 18, 21, and 24 milli Molar (mM) NaCl. The results revealed that doses of salinity induced significant changes in the fresh weight of Brassica napus L. The response of selected nutrients (except Magnesium) as a function of salinity was also highly significant (P≤0.05 %). The salinity doses reduced plants' mineral contents (except Mn) compared to control. The priming of seeds for 90 minutes significantly (P≤0.05 %) enhanced certain early growth traits (plumule growth, radical growth, fresh weight and dry weight) of Brassica napus. On the other hand, for improving germination (%) and moisture contents (%) of Brassica napus, soaking durations of 30 minutes and 60 minutes are more suitable. The pre-soaking of seeds for 60 minutes increased the Calcium, Magnesium and Manganese contents (mg/litre) of Brassica napus. The Iron and Zinc contents (mg/litre) showed hype in seedlings raised from seeds primed for 30 minutes. The priming of seeds for 90 minutes was found to be stimulatory for Copper (mg/litre) only. The influence of factors interaction (treatments × priming durations) on the initial growth attributes and the studied minerals of Brassica napus L. was highly significant (P≤0.05 %). From the gathered evidence, the present study concludes glucose as a potent priming agent that can boost oil-yielding plants' performance under saline conditions.
Abstract The flocculation process aggregates destabilized particles into larger and more easily settleable flocs. The coagulation process destabilizes particles through chemical reactions between the coagulant and the suspended colloids, but flocculation is the transport step that causes the necessary collision between destabilized particles. The purpose of the flocculation process is to promote the interaction of particles and to form aggregates that can be efficiently removed in the subsequent separation processes such as sedimentation, flotation, and coarse bed filtration. In practice, flocculation is accomplished by providing a gentle mixing phase that follows the rapid dispersion of coagulants.
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