Synthesis of Carboranylated Dihydropyrrolo[1,2-a]quinoxalines and Dihydroindolo[1,2-a]quinoxalines by BF3·OEt2-Catalyzed Heterocyclization of C-Formyl-o-carboranes and Investigation of Their Oxidation Stability.

A BF3·OEt2-catalyzed synthesis of carboranylated dihydropyrrolo[1,2-a]quinoxalines and dihydroindolo[1,2-a]quinoxalines in 30-99% yields is presented through the heterocyclization of various C-modified C-formyl-o-carboranes with 1-(2-aminophenyl)-pyrroles/indoles. A systematic comparative investigation of their oxidation stability in air confirmed that 4-carboranyl-4,5-dihydropyrrolo[1,2-a]quinoxaline had better stability than the 4-phenyl analogue. A cage-deboronation reaction for N-acetyl-substituted carboranylated dihydropyrrolo[1,2-a]quinoxaline produced the corresponding 7,8-nido-carborane cesium salt. A kinetic resolution was also realized to obtain an optically pure carboranylated N-heterocycle scaffold bearing a carborane cage carbon-bonded chiral stereocenter.

Bidirectional interactions between curcumin and gut microbiota in transgenic mice with Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with increasing prevalence worldwide, while there are no effective drugs at present. Curcumin, a natural polyphenolic substance isolated from turmeric, is a promising natural compound to combat AD, but its pharmacology remains to be fully understood for its poor in vivo bioavalibility. Inspired by the recently reported associations between gut microbiota and AD development, the present study investigated the interactions of curcumin with gut microbiota of APP/PS1 double transgenic mice from two directions: (i) curcumin influences gut microbiota, and (ii) gut microbiota biotransform curcumin. It was found that curcumin administration tended to improve the spatial learning and memory abilities and reduce the amyloid plaque burden in the hippocampus of APP/PS1 mice. On the one hand, curcumin administration altered significantly the relative abundances of bacterial taxa such as Bacteroidaceae, Prevotellaceae, Lactobacillaceae, and Rikenellaceae at family level, and Prevotella, Bacteroides, and Parabacteroides at genus level, several of which have been reported to be key bacterial species associated with AD development. On the other hand, a total of 8 metabolites of curcumin biotransformed by gut microbiota of AD mice through reduction, demethoxylation, demethylation and hydroxylation were identified by HPLC-Q-TOF/MS, and many of these metabolites have been reported to exhibit neuroprotective ability. The findings provided useful clues to understand the pharmacology of curcumin and microbiome-targeting therapies for AD.

Bone marrow mesenchymal stem cells regulate TGF-ß to adjust neuroinflammation in postoperative central inflammatory mice.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is one of the common postoperative complications, which is more common in aged patients. POCD mainly manifests as cognitive function changes after surgery, such as memory decline and inattention. In some severe cases, patients may suffer from personality changes and (or) social behavior decline. The aim of the current study is to confirm the effect and elucidate the mechanism of bone marrow mesenchymal stem cells (BMSCs) in postoperative central inflammatory mice. METHODS: Mice were randomly assigned to four groups: sham, sham+BMSCs, model, and BMSCs group. In the model group, mice were intraperitoneally injected 8 mg/kg per day lipopolysaccharide for 5 days. In sham+BMSCs and BMSCs group, BMSCs (1 × 10 7 ) in 100 µL saline were injected into sham mice and model mice, respectively. RESULTS: In the model group, transforming growth factor ß (TGF-ß) protein expression was significantly increased, compared with that in the sham group. BMSCs were treated into postoperative central inflammatory mice, which resulted in a decreased of TGF-ß protein expression. TGF-ß and smad2 protein expression were suppressed, and apoptosis rate and inflammation were inhibited in coculture with BMSCs. The suppression of TGF-ß inhibited the effects of BMSCs on apoptosis rate and inflammation in postoperative central inflammatory through a smad2 signaling pathway. The promotion of TGF-ß reduced the effects of BMSCs on apoptosis rate and inflammation in postoperative central inflammatory through a smad2 signaling pathway. CONCLUSION: The present study demonstrates that BMSCs regulates TGF-ß to adjust neuroinflammation in postoperative central inflammatory mice.

Effects of Metformin Combined with Lactoferrin on Lipid Accumulation and Metabolism in Mice Fed with High-Fat Diet.

Metformin (Met) and lactoferrin (Lf) both exhibit beneficial effects on body weight management and lipid accumulation. However, the synergistical action of Met and Lf remains unclear. In this study, 64 mice were divided into five groups, namely, the control group, high-fat diet (HFD group), HFD with Met (Met group), Lf (Lf group), and a combination of Met and Lf (Met + Lf group). Met (200 mg/kg body weight) and Lf (2 g/100 mL) were administrated in drinking water. The experiment lasted for 12 weeks. Body weight, serum, and hepatic lipids were determined. Histology of the liver and perirenal fat was observed. Protein expression related to hepatic lipid metabolism was also measured. HFD significantly increased body weight, visceral fat weight, and lipid profiles, which lead to obesity and dyslipidemia in mice. Compared with the HFD group, the treatments significantly decreased body weight and Lee's index (body mass index of mice) with the lowest values in the Met + Lf group. The treatments also decreased the weight of visceral fat, and improved circulating lipid profile and the ability for regulating glucose intake. The adipocyte size and serum TC level were significantly lower in the Met + Lf group as compared with those in the Met or Lf group. The treatments alleviated hepatic lipid accumulation, especially in the Met + Lf group. For protein expression, the p-AMPK/AMPK ratio, a key kinase-regulating cellular energy homeostasis, was significantly higher in the Met + Lf group than the ratio in the HFD group. Similarly, the treatments significantly downregulated the protein expression of lipogenic enzymes (FAS, ACC, and SREBP-1) and upregulated the protein expression of lipolytic enzyme (ATGL). The protein expression of HMGCoAR, which is an important rate limiting enzyme in cholesterol biosynthesis, was only significantly lower in the Met + Lf group than in the HFD group. In conclusion, Met and Lf, either alone or in combination, prevented HFD-induced obesity and improved lipid metabolism.

Mechanism of BDE209-induced impaired glucose homeostasis based on gene microarray analysis of adult rat liver.

Several persistent organic pollutants are reported to be potentially associated with the risk of human diabetes that has become rapidly epidemic in China currently. 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209) is commercially most important both in the production and in the use of polybrominated diphenyl ethers (PBDEs). It might bioaccumulate in wildlife and human and is the only PBDEs mixture still used today. In the present study, male adult rats treated with BDE209 (0, 0.05, 1, and 20 mg/kg) for 8 weeks were used to explore the effects of BDE209 on glucose homeostasis and possible mechanisms; 0.05 mg/kg of BDE209 induced dose-related hyperglycemia. Then, we performed the full-genome gene expression microarrays, gene ontology analysis, and pathway analysis in this group and control. BDE209 induced 1,257 liver gene transcript changes, and 18 canonical pathways were significantly enriched. Four of them were involved in immune diseases, including autoimmune thyroid disease, graft-versus-host disease, allograft rejection, and type I diabetes mellitus (T1MD), which was confirmed by the decrease in serum insulin. Subsequently, gene act network and gene co-expression network found that some MHC molecules and TNF-α were involved in T1DM pathway, which was then confirmed by the increase in serum TNF-α. Additionally, reduced glutathione and superoxide dismutase in plasma indicated that oxidative damage might partly contribute to BDE209-induced hyperglycemia. The results of this study provide some new experimental evidence that the exposure to high levels of BDE209 may contribute to the onset of diabetes in human populations. Further work needs to be done to confirm this link.

In vitro degradation of three-dimensional chitosan/apatite composite rods prepared via in situ precipitation.

Three-dimensional (3D) compact rods with multilayer structure made from chitosan (CHI) and apatite (Ap) have been prepared. The cytocompatibility assay revealed that the CHI/Ap composite could promote cell proliferation. In vitro degradation behaviors of the rods have been systematically investigated for up to 6 weeks in phosphate buffer saline (PBS) solution at 37°C. The properties of the composite rods were measured by means of weight loss, swelling ratio, and the changes in mechanical properties, etc. The pH of the PBS solution during the first 2 weeks of degradation was also detected. Results showed that the medium of CHI/Ap composite rods exhibited more stable pH change compared with that of CHI rods. Weight loss as well as the changes in mechanical properties happened more often to CHI rods than CHI/Ap rods. The presence of Ap could effectively reduce the degradation rate of the composite rods. All the results suggested that the composite rods could keep the initial shapes and mechanical properties longer than the pure CHI rods.

Fabrication of chitosan/hydroxylapatite composite rods with a layer-by-layer structure for fracture fixation.

A composite rod for fracture fixation using chitosan (CHI)/hydroxylapatite (HA) was prepared by means of in situ precipitation, which had a layer-by-layer structure, good mechanical properties, and cell compatibilities. The CHI/HA composite rods were precipitated from the chitosan solution with calcium and phosphorus precursors, followed by treatment with a tripolyphosphate-trisodium phosphate solution (pH >13) to crosslink the CHI and to hydrolyze the calcium phosphates to nanocrystalline HA. The results of FTIR, XRD, and TEM measurements confirmed that HA had been formed within the CHI matrix. The effects of the CHI/HA ratios (20/0, 20/1, 20/2, 20/4, and 20/5, w/w) on the mechanical properties were investigated. At the CHI/HA ratio of 20/4 (w/w), the bending strength and modulus of the rods were 133 MPa and 6.8 GPa, respectively. Pre-osteoblast MC3T3-E1 cells were cultured in an extract of the CHI/HA rods (20/4, w/w) to study the cell compatibilities of the composite. The observations indicated that the CHI/HA composite could promote the growth of MC3T3-E1 cells better than the composite without HA (p < 0.05). Furthermore, the co-cultivation of the cells and the CHI/HA composite showed that cells fully spread on the surface of the composite with an obvious cytoskeleton organization, which also revealed that the CHI/HA composite had a good biocompatibility.

Hepcidin expression in patients with acute leukaemia.

BACKGROUND: Hepcidin plays a central role in iron homeostasis, which is regulated by iron stores, the rate of erythropoiesis, inflammation, and hypoxia. Aberrant expression of hepcidin was found in many diseases, however, there is scant information on hepcidin expression in acute leukemia (AL). MATERIALS AND METHODS: 32 patients with AL which diagnosis according to FAB criteria were studied. Serum hepcidin levels, erythropoietin (EPO), interleukin-6 (IL-6), hematological parameters, intracellular and extracellular iron store were evaluated. RESULTS: Hepcidin was elevated significantly with increased iron storage in patients at onset of AL when erythropoiesis was depressed by blast cells, then decreased significantly with AL remission, while soluble transferrin receptor (sTfR) concentration was elevated. Negative correlations were found between serum hepcidin and erythropoietic markers including RBC, Hb, Ret and sTfR. Positive correlations were shown between hepcidin and ferritin, between hepcidin and ratio of sideroblasts, as well as between hepcidin and IL-6. CONCLUSIONS: Hepcidin production was regulated by iron stores, inflammation and erythropoietic activity in AL patients. Erythropoietic activity may play the main role among the regulators of hepcidin expresssion.

Hepcidin expression and iron parameters change in Type 2 diabetic patients.

AIM: Iron may contribute to the pathogenesis of Type 2 diabetes mellitus (DM). The aim of this study was to determine iron regulator hepcidin and iron metabolic parameters in Type 2 DM patients, the relationships among them were evaluated in this specific sub-groups. MATERIALS AND METHODS: The study included sixty-four people: 34 cases of diabetes and 30 age-matched controls. Serum hepcidin, IL-6, hsCRP, ferritin, sTfR, EPO as well as other clinical parameters were detected, and the associations between hepcidin levels and iron/inflammatory parameters were analyzed in diabetes and the controls. RESULTS: Serum ferritin and hepcidin levels in diabetic patients were significant higher than the controls (p<0.001 respectively). A positive correlation between hepcidin and ferritin, as well as between ferritin and IL-6 levels was existed in diabetes and the control groups (p<0.001 respectively). CONCLUSION: All of these data demonstrated that the higher hepcidin levels in diabetic patients may be due to those higher ferritin and IL-6 levels, the elevated hepcidin might have adaptive value through down-regulated iron absorb and play an important role in pathogenesis of Type 2 DM.

Association between inflammatory genetic polymorphism and acute lung injury after cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Recently, single nucleotide polymorphisms were proposed as potentially new predictors for perioperative risks, such as myocardial infarction and organ dysfunction. The objectives of this study were to investigate whether IL-6 -572C/G, IL-10 -1082A/G, and TNF-alpha -308G/A were associated with acute lung injury after cardiac surgery with cardiopulmonary bypass. MATERIAL/METHODS: One hundred patients with acute lung injury at 24 hours after cardiac surgery with cardiopulmonary bypass and 112 patients without acute lung injury as controls were included. Genotyping assay was performed with real-time fluorescence-based allele-specific PCR. Serum levels of IL-6, IL-10, and TNF-alpha were also determined by ELISA. Associations between these polymorphisms and acute lung injury, as well as serum cytokine levels, were analyzed. All patients were genotyped for IL-6 -572C/G, IL-10 -1082A/G, and TNF-alpha -308G/A. Circulating level of these cytokines were also determined. RESULTS: Acute lung injury after cardiac surgery with cardiopulmonary bypass was associated with IL-6 -572C/G polymorphism, but not IL-10 -1082A/G or TNF-alpha -308G/A. This functional polymorphism was further confirmed by multivariate analyses. The ratio of circulating concentrations of IL-10/IL-6 was associated with IL-6 genotypes and incidence of acute lung injury as well. CONCLUSIONS: The IL-6 -572 polymorphism was associated with acute lung injury after cardiac surgery with cardiopulmonary bypass. Proinflammatory and anti-inflammatory imbalance might be the clinical significance of IL-6 polymorphism (ClinicalTrials.gov number, NCT00826072).