Design, synthesis, and evaluation of Leu*Ala hydroxyethylene-based non-peptide beta-secretase (BACE) inhibitors

With the aim of developing small molecular non-peptide beta-secretase (BACE) inhibitors, Leu*Ala hydroxyethylene (HE) was investigated as a scaffold to design and synthesize a series of compounds. Taking advantage of efficient combinatorial synthesis approaches and molecular modeling, extensive structure-activity relationship (SAR) studies were carried out on the N- and C-terminal residues of the Leu*Ala HE scaffold. Isobutyl amine was found to be an optimal C-cap, and suitable hydroxylalkylamines at the 3-position and nitro or methyl(methylsulfonyl)amine at the 5-position of isophthalamide as the N-terminus could form additional hydrogen bonds with BACE active sites and help improve potency. Many new potent non-peptide BACE inhibitors were identified in this study. Among them, compounds 37 and 44 exhibited excellent enzyme-inhibiting potency, comparable to that of OM99-2, and obvious inhibitory effects in cell-based assay with low molecular weights (<600).     

Enhancement of rhizosphere citric acid and decrease of NO3−/NH4+ ratio by root interactions facilitate N fixation and transfer

Plant and Soil - Plant growth is often limited by low soil phosphorus (P) availability, soil nitrogen (N) availability may affect plants’ responses to P supply. We studied the growth and...     

Decreasing Nitrogen Fertilizer Input Had Little Effect on Microbial Communities in Three Types of Soils

In this study, we examined the influence of different nitrogen (N) application rates (0, 168, 240, 270 and 312 kg N ha^-1) on soil properties, maize (Zea mays L.) yields and microbial communities of three types of soils (clay, alluvial and sandy soils). Phospholipid fatty acid analysis was used to characterize soil microbial communities. Results indicated that N fertilization significantly decreased microbial biomass in both clay and sandy soils regardless of application rate. These decreases were more likely a result of soil pH decreases induced by N fertilization, especially in the sandy soils. This is supported by structural equation modeling and redundancy analysis results. Nitrogen fertilization also led to significant changes in soil microbial community composition. However, the change differences were gradually dismissed with increase in N application rate. We also observed that N fertilization increased maize yields to the same level regardless of application rate. This suggests that farmers could apply N fertilizers at a lower rate (i.e. 168 kg N ha^-1), which could achieve high maize yield on one hand while maintain soil microbial functions on the other hand.     

Triglyceride Levels Are Closely Associated with Mild Declines in Estimated Glomerular Filtration Rates in Middle-Aged and Elderly Chinese with Normal Serum Lipid Levels

Objective

To investigate the relationship between lipid profiles [including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)] and a mild decline in the estimated glomerular filtration rate (eGFR) in subjects with normal serum lipid levels.

Design and Methods

In this study, we included 2647 participants who were ≥40 years old and had normal serum lipid levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the GFR. A mildly reduced eGFR was defined as 60–90 mL/min/1.73 m². First, multiple linear regression analysis was used to estimate the association of lipid profiles with the eGFR. Then, the levels of each lipid component were divided into four groups, using the 25th, 50th and 75th percentiles as cut-off points. Finally, multiple logistic regression analysis was used to investigate the association of different lipid components with the risk of mildly reduced eGFR.

Results

In the group with a mildly reduced eGFR, TG and LDL-C levels were significantly increased, but HDL-C levels were significantly decreased. After adjusting for age, gender, body mass index (BMI), systolic blood pressure (SBP), glycated hemoglobin (HbA_1c), smoking and drinking, only TC and TG were independently related to the eGFR. Additionally, only TG showed a linear relationship with an increased risk of a mildly reduced eGFR, with the highest quartile group (TG: 108–150 mg/dl [1.22–1.70 mmol/L]) having a significantly increased risk after adjusting for the above factors.

Conclusions

Triglyceride levels are closely associated with a mildly reduced eGFR in subjects with normal serum lipid levels. Dyslipidemia with lower TG levels could be used as new diagnostic criteria for subjects with mildly reduced renal function.     

Fluctuation between Fasting and 2-H Postload Glucose State Is Associated with Chronic Kidney Disease in Previously Diagnosed Type 2 Diabetes Patients with HbA1c ≥ 7%

Objective

To investigate how the glucose variability between fasting and a 2-h postload glucose state (2-h postload plasma glucose [2hPG]-fasting plasma glucose [FPG]) is associated with chronic kidney disease (CKD) in middle-aged and elderly Chinese patients previously diagnosed with type 2 diabetes.

Design and Methods

This cross-sectional study included 1054 previously diagnosed type 2 diabetes patients who were 40 years of age and older. First, the subjects were divided into two groups based on a glycated hemoglobin (HbA1c) value of 7%. Each group was divided into two subgroups, with or without CKD. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the glomerular filtration rate (GFR). CKD was defined as eGFR<60 mL/min/1.73 m². Multiple linear regression analysis was used to estimate the association between the 2hPG-FPG and eGFR. The 2hPG-FPG value was divided into four groups increasing in increments of 36 mg/dl (2.0 mmol/L): 0–72, 72–108, 108–144 and ≥144 mg/dl, based on the quartiles of patients with HbA1c levels ≥7%; then, binary logistic regression analysis was used to investigate the association between 2hPG-FPG and the risk of CKD.

Results

In the patients with HbA1c levels ≥7%, the 2hPG-FPG was significantly associated with decreased eGFR and an increased risk of CKD independent of age, gender, body mass index (BMI), systolic blood pressure (BP), diastolic BP, smoking, and drinking, as well as fasting insulin, cholesterol, triglyceride, and HbA1c levels. The patients with 2hPG-FPG values ≥144 mg/dl showed an increased odds ratio (OR) of 2.640 (P = 0.033). Additionally, HbA1c was associated with an increased risk of CKD in patients with HbA1c values ≥7%.

Conclusions

The short-term glucose variability expressed by 2hPG-FPG is closely associated with decreased eGFR and an increased risk of CKD in patients with poor glycemic control (HbA1c≥7%).     

Fluctuation between Fasting and 2-H Postload Glucose State Is Associated with Glomerular Hyperfiltration in Newly Diagnosed Diabetes Patients with HbA1c < 7%

Objective

To investigate whether fluctuations between the fasting and 2-h postload glucose ([2-hPBG]-fasting blood glucose [FBG]) states are associated with glomerular hyperfiltration (GHF) in middle-aged and elderly Chinese patients with newly diagnosed diabetes.

Design and Methods

In this study, we included 679 newly diagnosed diabetes patients who were ≥40 years old. All the subjects were divided into two groups; those with HbA1c<7% and ≥7%. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the glomerular filtration rate (GFR). GHF was defined as an eGFR ≥ the 90th percentile. First, a multiple linear regression analysis was used to estimate the association of 2-hPBG-FBG with eGFR. Then, a generalized additive model was used to explore the possible nonlinear relationship between 2-hPBG-FBG and eGFR. Next, the 2-hPBG-FBG values were divided into four groups as follows: 0–36, 36–72, 72–108 and ≥108 mg/dl. Finally, a multiple logistic regression analysis was used to investigate the association of 2-hPBG-FBG with the risk of GHF.

Results

For the group with HbA1c<7%, the eGFR and the percentage of GHF were significantly higher compared with the group with HbA1c≥7%. After adjusting for age, gender, body mass index (BMI), systolic blood pressure (BP), diastolic BP, fasting insulin, cholesterol, triglycerides, smoking, drinking and glycated hemoglobin (HbA1c), 2-hPBG-FBG was significantly associated with increased eGFR and an increased risk of GHF (the GHF risk increased by 64.9% for every 36.0 mg/dl [2.0 mmol/L] 2-hPBG-FBG increase) only in those patients with HbA1c<7%. Additionally, 2-hPBG-FBG and eGFR showed a nonlinear association (P<0.001).

Conclusions

Increased fluctuations between the fasting and 2-h postload glucose states are closely associated with increased eGFR and an increased risk of GHF in newly diagnosed diabetes patients with HbA1c<7%.     

Combination use of ultrasound irradiation and ionic liquid in enzymatic isomerization of glucose to fructose

The synthetic effect of the combination use of ultrasound irradiation (UI) and ionic liquid (IL) on improving enzyme activity was studied when they were employed in isomerization of glucose to fructose by immobilized glucose isomerase (IGI, produced from streptomyces murinus and immobilized on silica). Both of UI and IL [EMIM][Cl], which was screened as the best medium for this reaction, were found to increase the enzyme activity in isomerization reaction. And a further increase of enzyme activity was observed by combination use of UI and IL. A systematic screening and optimization of the reaction parameters in ILs under UI on the IGI activity were performed. Under the optimum reaction conditions, 45.3% yield of fructose was achieved in 10 h under UI in [EMIM][Cl], compared to only 41.5% yield under stirring in [EMIM][Cl], 44.2% under UI without [EMIM][Cl] and 38.9% under stirring without [EMIM][Cl] in 12 h, respectively. High thermal stability and reusability of IGI was also observed under UI in [EMIM][Cl]. These results indicated that the combination use of UI and IL might be a fast and efficient method for enzymatic isomerization of glucose to fructose.