Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves multiple biological changes, including insulin resistance, oxidative stress, inflammation, as well as genetic and environmental factors. Liraglutide has been used to control blood sugar. But the impact of liraglutide on T2DM-associated NAFLD remains unclear. In this study, we investigated the impact and potential molecular mechanisms of inhibiting ferroptosis for liraglutide improves T2DM-associated NAFLD. METHODS: Mice were fed on high-fat-diet and injected with streptozotocin to mimic T2DM-associated NAFLD and gene expression in liver was analysed by RNA-seq. The fast blood glucose was measured during the period of liraglutide and ferrostatin-1 administration. Hematoxylin and eosin staining was used to evaluate the pathological changes in the liver. The occurrence of hepatic ferroptosis was measured by lipid peroxidation in vivo. The mechanism of liraglutide inhibition ferroptosis was investigated by in vitro cell culture. RESULTS: Liraglutide not only improved glucose metabolism, but also ameliorated tissue damage in the livers. Transcriptomic analysis indicated that liraglutide regulates lipid metabolism related signaling including AMPK and ACC. Furthermore, ferroptosis inhibitor rather than other cell death inhibitors rescued liver cell viability in the presence of high glucose. Mechanistically, liraglutide-induced activation of AMPK phosphorylated ACC, while AMPK inhibitor compound C blocked the liraglutide-mediated suppression of ferroptosis. Moreover, ferroptosis inhibitor restored liver function in T2DM mice in vivo. CONCLUSIONS: These findings indicate that liraglutide ameliorates the T2DM-associated NAFLD, which possibly through the activation of AMPK/ACC pathway and inhibition of ferroptosis.

Mollugin activates GLP-1R to improve cognitive dysfunction in type 2 diabetic mice.

AIMS: The incidence of diabetic cognitive dysfunction is increasing year by year, and it has gradually become a research hot spot. Studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists can improve cognitive dysfunction in diabetic patients. This study focuses on whether small molecule GLP-1R agonists from traditional Chinese medicine (TCM) can improve the diabetic cognitive dysfunction. MATERIALS AND METHODS: The small molecules from TCM were screened by cell membrane chromatography (CMC) with GLP-1R-HEK293 cell membrane column. MTT assay, flow cytometry, immunofluorescence cytochemistry and other methods were used to determine the effects of mollugin on the apoptosis rate and reactive oxygen species (ROS) level of high glucose (HG)/hydrogen peroxide (H2O2) induced PC12 cells. Real-Time PCR was used to detect mRNA expression in mouse cerebral cortex. Water maze test was further used to confirm the effect of mollugin on cognitive dysfunction in T2DM mice. KEY FINDINGS: Mollugin bound to GLP-1R, promoted Ca2+ influx, increased insulin secretion and cAMP content in ß-TC-6 cells. Mollugin enhanced the cell viability, ameliorated apoptosis, reduced intracellular ROS levels in HG/H2O2-injured PC12 cells. Mollugin reduced the T2DM mice's escape latency, improved neuronal cell damage, decreased the expression of Pik3ca, Akt1 and Mapk1 mRNA in the cerebral cortex tissue. SIGNIFICANCE: The results suggest that mollugin could improve cognitive dysfunction in T2DM mice through activating GLP-1R/cAMP/PKA signal pathway.

Schisandrin B, a potential GLP-1R agonist, exerts anti-diabetic effects by stimulating insulin secretion.

Diabetes mellitus is a metabolic disease that is characterized by elevated blood sugar. Although glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood glucose in a glucose-dependent manner, most of them are macromolecule polypeptides. Macromolecular peptides are relatively expensive and inconvenient compared with small molecules. Therefore, this study sought to identify the small molecules binding to GLP-1R via cell membrane chromatography (CMC), confirm their agonistic activity, and further study its beneficial effects in a mouse model of type 2 diabetes mellitus (T2DM) induced by a combination of high-fat diet and streptozotocin. We used CMC, calcium imaging and molecular docking techniques to screen and identify the potential small molecule Schisandrin B (Sch B), which exhibits a strong binding effect to GLP-1R, from the small molecule library of traditional Chinese medicine. Through in-vitro experiments, we found that Sch B stimulated insulin secretion in ß-TC-6 cells, while GLP-1R antagonist Exendin9-39, adenylate cyclase inhibitor SQ22536, and protein kinase A (PKA) inhibitor H89 could significantly inhibit the insulin secretion induced by Sch B. In vivo, Sch B significantly improved fasting blood glucose levels, intraperitoneal glucose tolerance test damage, and the status of pancreatic tissue damage, and reduced serum insulin levels, total cholesterol, triglyceride and low density lipoprotein in T2DM mice. These results indicate that Sch B alleviates T2DM by promoting insulin release through the GLP-1R/cAMP/PKA signaling pathway, suggesting that Sch B may be a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of T2DM.

Erythropoietin ameliorates cognitive dysfunction in mice with type 2 diabetes mellitus via inhibiting iron overload and ferroptosis.

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis.

Erythropoietin Mitigates Diabetic Nephropathy by Restoring PINK1/Parkin-Mediated Mitophagy.

Diabetic nephropathy (DN), one of the most detrimental microvascular complications of diabetes, is the leading cause of end-stage renal disease. The pathogenesis of DN is complicated, including hemodynamic changes, inflammatory response, oxidative stress, among others. Recently, many studies have demonstrated that mitophagy, especially PINK1/Parkin-mediated mitophagy, plays an important role in the pathogenesis of DN. Erythropoietin (EPO), a glycoprotein hormone mainly secreted by the kidney, regulates the production of erythrocytes. This research intends to explore the beneficial effects of EPO on DN and investigate related mechanisms. In in vitro experiments, we found that EPO promoted autophagic flux and alleviated mitochondrial dysfunction in terms of mitochondrial fragmentation, elevated mitochondrial ROS as well as the loss of mitochondrial potential, and lowered the apoptosis level in high-glucose-treated mesangial cells. Moreover, EPO increased protein expressions of PINK1 and Parkin, enhanced the co-localization of LC3 with mitochondria, Parkin with mitochondria as well as LC3 with Parkin, and increased the number of GFP-LC3 puncta, resulting in increased level of PINK1/Parkin-mediated mitophagy in mesangial cells. The knockdown of PINK1 abrogated the effect of EPO on mitophagy. In addition, in vivo experiments demonstrated that EPO attenuated renal injury, reduced oxidative stress, and promoted expressions of genes related to PINK1/Parkin-mediated mitophagy in the kidneys of DN mice. In summary, these results suggest that PINK1/Parkin-mediated mitophagy is involved in the development of DN and EPO mitigates DN by restoring PINK1/Parkin-mediated mitophagy.

Low-Triggering-Potential Electrochemiluminescence from a Luminol Analogue Functionalized Semiconducting Polymer Dots for Imaging Detection of Blood Glucose.

In recent years, semiconducting polymer dots (Pdots) as environmentally friendly and high-brightness electrochemiluminescence (ECL) nanoemitters have attracted intense attention in ECL biosensing and imaging. However, most of the available Pdots have a high ECL excitation potential in the aqueous phase (>1.0 V vs Ag/AgCl), which causes poor selectivity in actual sample detection. Therefore, it is particularly important to construct a simple and universal strategy to lower the trigger potential of Pdots. This work has realized the ECL emission of Pdots at low-trigger-potential based on the electrochemiluminescence resonance energy transfer (ERET) strategy. By covalently coupling the Pdots with a luminol analogue, N-(4-aminobutyl)-N-ethylisoluminol (ABEI), the ABEI-Pdots showed an anodic ECL emission with a low onset potential of +0.34 V and a peak potential at +0.45 V (vs Ag/AgCl), which was the lowest trigger potential reported so far. We further explored this low-triggering-potential ECL for imaging detection of glucose in buffer and serum. By imaging the ABEI-Pdots-modified screen-printed electrodes (SPCE) at +0.45 V for 16 s, the ECL imaging method could quantify the glucose concentration in buffer from 10 to 200 µM with detection limits of 3.3 µM, while exhibiting excellent selectivity. When applied to real serum, the results of our method were highly consistent with a commercial blood glucose meter, with the relative errors ranging from 3.2 to 13%. This work provided a universal strategy for constructing low potential Pdots and demonstrated its application potential in complex biological sample analysis.

Characterization of the Transcriptome and Proteome of Brassica napus Reveals the Close Relation between DW871 Dwarfing Phenotype and Stalk Tissue.

Rapeseed is a significant oil-bearing cash crop. As a hybrid crop, Brassica napus L. produces a high yield, but it also has drawbacks such as a tall stalk, easy lodging, and is not suitable for mechanized production. To address these concerns, we created the DW871 rapeseed dwarf variety, which has a high yield, high oil content, and is suitable for mechanized production. To fully comprehend the dwarfing mechanism of DW871 and provide a theoretical foundation for future applications of the variety, we used transcriptome and proteome sequencing to identify genes and proteins associated with the dwarfing phenotype, using homologous high-stalk material HW871 as a control. By RNA-seq and iTRAQ, we discovered 8665 DEGs and 50 DAPs. Comprehensive transcription and translation level analysis revealed 25 correlations, 23 of which have the same expression trend, involving monolignin synthesis, pectin-lignin assembly, lignification, glucose modification, cell wall composition and architecture, cell morphology, vascular bundle development, and stalk tissue composition and architecture. As a result of these results, we can formulate a hypothesis about the DW871 dwarfing phenotype: plant hormone signal transduction, such as IAA and BRs, is linked to the formation of dwarf phenotypes, and metabolic pathways related to lignin synthesis, such as phenylpropane biosynthesis, also play a role. Our works will contribute to a better understanding of the genes and proteins involved in the rapeseed dwarf phenotype, and we will propose new insights into the dwarfing mechanism of Brassica napus L.

Liraglutide ameliorates diabetes-associated cognitive dysfunction via rescuing autophagic flux.

The incidence of diabetes-associated cognitive dysfunction is increasing. However, few clinical interventions are available to prevent the disorder. Several researches have shown that liraglutide, as a glucagon-like peptide-1 analog, has protective effects on various neurodegenerative diseases, but its roles in diabetic cognitive dysfunction are rarely reported. This study aims to investigate the protective effects of liraglutide on diabetic cognitive dysfunction and its underlying mechanisms. In vivo, the effects of liraglutide treatment were investigated in a mouse model of type 2 diabetes mellitus (T2DM). In vitro, we investigated the effects of liraglutide on the high-glucose-induced rat primary neurons. The results showed that liraglutide reduced the escape latency and increased the time in effective area in the Morris water maze test, improved the damage of hippocampal and synaptic ultrastructure, and decreased the accumulation of amyloid ß protein in hippocampus of T2DM mice. Furthermore, liraglutide increased the ratio of microtubule-associated protein light 1 chain Ⅱ/Ⅰ, the expression of Beclin1 protein and Lysosome-associated membrane protein 2 in vivo and vitro. Additionally, Bafilomycin A1 which can inhibit the fusion of autophagosome and lysosome partially abolished the effects of liraglutide. These findings indicate liraglutide ameliorates diabetes-associated cognitive dysfunction by rescuing autophagic flux.

[Efficacy and safety of levetiracetam versus phenytoin as second-line drugs for the treatment of children with convulsive status epilepticus: a Meta analysis].

OBJECTIVE: To systematically evaluate the efficacy and safety of levetiracetam (LEV) versus phenytoin (PHT) as second-line drugs for the treatment of convulsive status epilepticus (CSE) in children. METHODS: English and Chinese electronic databases were searched for the randomized controlled trials comparing the efficacy and safety of LEV and PHT as second-line drugs for the treatment of childhood CSE. RevMan 5.3 software was used for data analysis. RESULTS: Seven studies with 1 434 children were included. The Meta analysis showed that compared with the PHT group, the LEV group achieved a significantly higher control rate of CSE (RR=1.12, 95%CI:1.00-1.24, P=0.05), but there was no significant difference between the two groups in the recurrence rate of epilepsy within 24 hours (RR=0.82, 95%CI:0.22-3.11, P=0.77) and the rate of further antiepileptic drug therapy (RR=0.97, 95%CI:0.64-1.45, P=0.87). There was no significant difference in the incidence rate of adverse events between the two groups (RR=0.77, 95%CI:0.55-1.09, P=0.15). CONCLUSIONS: LEV has a better clinical effect than PHT in the treatment of children with CSE and does not increase the incidence rate of adverse events.

The Effectiveness of Mating Induction on Men's Financial Risk-Taking: Relationship Experience Matters.

Substantial evidence from experimental studies has shown that mating motivation increases men's financial risk-taking behaviors. The present study proposed a new moderator, men's past relationship experience, for this well-accepted link between mating motivation and financial risk-taking tendency. Heterosexual young men were randomly assigned to the mating condition and control condition, and they completed a set of financial risk-taking tasks and reported their past relationship experience. A significant main effect of mating motivation and a significant interaction effect between experimental conditions (mating group and control group) and relationship experience emerged, suggesting that mating motivation increased financial risk-taking tendency only among men who have never been committed in a romantic relationship, rather than those who have had such experience. This moderating effect was replicated in two experiments. The present study contributed to the understanding of individual differences in the relationship between mating motivation and male financial risk-taking. The present findings also have important implications for financial industry and gambling companies to better target clients and advertise their high-risk products.

catena-Poly[[[aqua-(1,10-phenan-throline)cadmium(II)]-µ-benzene-1,4-dicarboxyl-ato] benzene-1,4-dicarboxylic acid hemisolvate].

A new cadmium(II) coordination polymer, {[Cd(C(8)H(4)O(4))(C(12)H(8)N(2))(H(2)O)]·0.5C(8)H(6)O(4)}(n), has been synthesized under hydro-thermal conditions. The asymmetric unit contains one Cd(II) atom, one benzene-1,4-dicarboxyl-ate anion, one 1,10-phenanthroline ligand, one coordinated water mol-ecule and half of an uncoordinated benzene-1,4-dicaboxylic acid solvent mol-ecule. The Cd(II) atom is in the centre of a monocapped distorted octa-hedron made up of four O atoms of two chelating benzene-1,4-dicarboxyl-ate anions, one water O atom and two 1,10-phenanthroline N atoms. The metal centres are connected via bis-chelating benzene-1,4-dicarboxyl-ate anions into a zigzag chain structure along [001]. These chains are further connected by O-H⋯O hydrogen bonds between the water mol-ecules and adjacent carboxyl-ate O atoms. Additional O-H⋯O hydrogen bonding between the uncoordinated benzene-1,4-dicaboxylic acid mol-ecules along [010] consolidates the structure.