Effect of berberine on hyperglycaemia and gut microbiota composition in type 2 diabetic Goto-Kakizaki rats

BACKGROUND A recent investigation showed that the prevalence of type 2 diabetes mellitus(T2DM)is 12.8%among individuals of Han ethnicity.Gut microbiota has been reported to play a central role in T2DM.Goto-Kakizaki(GK)rats show differences in gut microbiota compared to non-diabetic rats.Previous studies have indicated that berberine could be successfully used to manage T2DM.We sought to understand its hypoglycaemic effect and role in the regulation of the gut microbiota.AIM To determine whether berberine can regulate glucose metabolism in GK rats via the gut microbiota.METHODS GK rats were acclimatized for 1 wk.The GK rats were randomly divided into three groups and administered saline(Mo),metformin(Me),or berberine(Be).The observation time was 8 wk,and weight,fasting blood glucose(FBG),insulin,and glucagon-like peptide-1(GLP-1)were measured.Pancreatic tissue was observed for pathological changes.Additionally,we sequenced the 16S rRNA V3-V4 region of the gut microbiota and analysed the structure.RESULTS Compared with the Mo group,the Me and Be groups displayed significant differences in FBG(P<0.01)and GLP-1(P<0.05).A significant decrease in weight and homeostatic model assessment-insulin resistance was noted in the Be group compared with those in the Me group(P<0.01).The pancreatic islets of the Me-and Be-treated rats showed improvement in number,shape,and necrosis compared with those of Mo-treated rats.A total of 580 operational taxonomic units were obtained in the three groups.Compared to the Mo group,the Me and Be groups showed a shift in the structure of the gut microbiota.Correlation analysis indicated that FBG was strongly positively correlated with Clostridia_UCG-014(P<0.01)and negatively correlated with Allobaculum(P<0.01).Body weight showed a positive correlation with Desulfovibrionaceae(P<0.01)and a negative correlation with Akkermansia(P<0.01).Importantly,our results demonstrated that Me and Be could significantly decrease Bacteroidetes(P<0.01)and the Bacteroidetes/Firmicutes ratio(P<0.01).Furthermore,Muribaculaceae(P<0.01;P<0.05)was significantly decreased in the Me and Be groups,and Allobaculum(P<0.01)was significantly increased.CONCLUSION Berberine has a substantial effect in improving metabolic parameters and modulating the gut microbiota composition in T2DM rats.

TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro

Brucella abortus is a zoonotic Gram-negative pathogen that causes brucelosis in ruminants and humans. Toll-like receptors （TLRs） recognize Brucella abortus and initiate antigen-presenting cell activities that affect both innate and adaptive immunity. In this study, we focused on recombinant Brucella cell-surface protein 31 （rBCSP31） to determine its effects on mouse macrophages. Our results demonstrated that rBCSP31 induced TNF-α, IL-6 and IL-12p40 production, which depended on the activation of mitogen-activated protein kinases （MAPKs） by stimulating the rapid phosphorylation of p38 and JNK and the activation of transcription factor NF-KB in macrophages. In addition, continuous exposure （〉24 h） of RAW264.7 cells to rBCSP31 significantly enhanced I FN-y-induced expression of MHC-II and the ability to present rBCSP31 peptide to CD4＋ T cells. Furthermore, we found that rBCSP31 could interact with both TLR2 and TLR4. The rBCSP31-induced cytokine production by macrophages from TLR2-/- and TLR4-/- mice was lower than that from C57BL/6 macrophages, and the activation of NF-KB and MAPKs was attenuated in macrophages from TLR2-/- and TLR4-/- mice. In addition, CD4＋ T cells from C57BL/6 mice immunized with rBCSP31 produced higher levels of IFN-y and IL-2 compared with CD4＋ T cells from TLR2-/- and TLR4-/- mice. Macrophages from immunized C57BL/6 mice produced higher levels of IL-12p40 than those from TLR2-/- and TLR4-/- mice. Furthermore, immunization with rBCSP31 provided better protection in C57BL/6 mice than in TLR2-/- and TLR4-/- mice after B. abortus 2308 challenge. These results indicate that rBCSP31 is a TLR2 and TLR4 agonist that induces cytokine production, upregulates macrophage function and induces the Thl immune response.

The rLrp of Mycobacterium tuberculosis inhibits proinflammatory cytokine production and downregulates APC function in mouse macrophages via a TLR2-mediated PI3K/Akt pathway activation-dependent mechanism

We demonstrate that Mycobacterium tuberculosis recombinant leucine-responsive regulatory protein （rLrp） inhibits lipopolysaccharide （LPS）-induced tumor necrosis factor alpha （TNF-a）, interleukin-6, and interleukin-12 production and blocks the nuclear translocation of subunits of the nuclear-receptor transcription factor NF-KB （Nuclear factor-kappa B）. Moreover, rLrp attenuated LPS-induced DNA binding and NF-κB transcriptional activity, which was accompanied by the degradation of inhibitory IκBα and a consequent decrease in the nuclear translocation of the NF-κB p65 subunit. RLrp interfered with the LPS-induced clustering of TNF receptor-associated factor 6 and with interleukin-1 receptor-associated kinase 1 binding to TAKI. Furthermore, rLrp did not attenuate proinflammatory cytokines or the expression of CD86 and major histocompatibility complex class-II induced by interferon-gamma in the macrophages of Toll-like receptor 2 deletion （TLR2-/-） mice and in protein kinase b （Akt）-depleted mouse cells, indicating that the inhibitory effects of rLrp were dependent on TLR2-mediated activation of the phosphatidylinositol 3-OH kinase （PI3K）/ Akt pathway. RLrp could also activate the PI3K/Akt pathway by stimulating the rapid phosphorylation of PI3K, Akt, and glycogen synthase kinase 3 beta in macrophages. In addition, 19 amino acid residues in the N-terminus of rLrp were determined to be important and required for the inhibitory effects mediated by TLR2. The inhibitory function of these 19 amino acids of rLrp raises the possibility that mimetic inhibitory peptides could be used to restrict innate immune responses in situations in which prolonged TLR signaling has deleterious effects. Our study offers new insight into the inhibitory mechanisms by which the TLR2-mediated PI3K/Akt pathway ensures the transient expression of potent inflammatory mediators.

Temperature-induced resistance transition behaviors of melamine sponge composites wrapped with different graphene oxide derivatives

Temperature-re s ponsive resistance transition behaviors of the melamine sponges wrapped with different graphene oxide derivatives(i.e.nanoribbon,wide-ribbon and sheet)were investigated.Melamine sponge composites coated by three types of GO derivatives were prepared by a simple dip-coating approach.All these composites show good mechanical flexibility and reliability(almost unchanged compressive stress at 70%strain after 100 cycles),high hydrophobicity(water contact angle>120°),excellent flame resistance(self-extinguishing)and structural stability even after burning,which was used to construct the resistance-based fire alarm/warning sensor.Notably,the different resistance response behaviors of such sensors are strongly dependent on the GO size and network formed on the MF skeleton surface.Typically,at a fixed high temperature of~350℃,the three fire alarm sensors show different response time(to trigger the alarm light)of 6.3,8.4 and 11.1 s for nanoribbon,wide-ribbon and sheet at the same concentration,respectively.The structural observation and chemical analysis demonstrated that the discrepancy of temperature-responsive resistance transition behaviors of various GO derivatives was strongly determined by their different thermal reduction degrees during the high-tempe rature or flame treating process.This work offers a design and development for construction of smart fire alarm device for potential fire prevention and safety applications.