Nomogram analysis of the influencing factors of rapid renal decline in patients with biopsy-proven diabetic nephropathy in type 2 diabetes.

BACKGROUND: HbA1c variability may be related to risk of poor prognoses in chronic kidney disease patients with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate whether HbA1c variability is associated with rapid renal function decline and the related risk factors in type 2 diabetic nephropathy (DN). MATERIALS AND METHODS: An observational analysis was performed on 387 DN patients who were diagnosed by kidney biopsy from January 2006 through January 2016 at the Department of Nephrology, Jinling Hospital Affiliated to Nanjing University. The rapid decliners were defined as an estimated glomerular filtration rate (eGFR) decline slope ≥ 5 mL/min/1.73m2/year. HbA1c variability and 24 baseline clinicopathologic parameters was evaluated using the least absolute shrinkage and selection operator regression (LASSO) and multivariate logistic regression. The nomogram method was applied to score the factors, and a scoring model was constructed. RESULTS: HbA1c variability positively correlated with the rate of renal function decline (r = 0.277; p < 0.001). Higher baseline eGFR, lower serum calcium concentration, glomerular lesions, arteriosclerosis, and interstitial fibrosis and tubular atrophy (IFTA) were selected into the nomogram. The calibration curve for the probability of survival showed good agreement between the prediction by nomogram and actual observation. The C-index for predicting survival was 0.811 (95% confidence interval (CI) 0.680 - 0.785). CONCLUSION: The proposed nomogram and score provide a useful risk estimate of fast renal function decline in patients with type 2 diabetic nephropathy.

Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual-acting glucokinase activator.

Dorzagliatin is a novel allosteric glucokinase activator targeting both pancreatic and hepatic glucokinase currently under clinical investigation for treatment of type 2 diabetes (T2D). This study aimed to investigate the effect of renal impairment (RI) on dorzagliatin's pharmacokinetics (PKs) and safety, and to guide appropriate clinical dosing in patients with diabetic kidney disease, including end-stage renal disease (ESRD). Based on the results from physiologically-based pharmacokinetic modeling, the predicted outcome of RI on dorzagliatin PK property would be minimum that the plasma exposure area under concentration (AUC) of dorzagliatin in patients with ESRD would increase at about 30% with minimal change in peak concentration (Cmax ) comparing to those in healthy volunteers (HVs). To definitively confirm the prediction, a two-part RI study was designed and conducted based on regulatory guidance starting with the patients with ESRD matched with HVs. Results of the RI study showed minimum difference between patients with ESRD and HVs with respect to dorzagliatin exposure with geometric mean ratio of ESRD to HV at 0.81 for Cmax and 1.11 for AUC. The elimination half-life, volume of distribution, and systemic clearance for dorzagliatin were similar between the two groups. Dorzagliatin was well-tolerated in patients with ESRD during the study. Therefore, RI showed no significant impact on dorzagliatin PK, suggesting that dorzagliatin can be readily used in patients with T2D at all stages of RI without need for dose adjustment.

Salt-Dependent Aggregation and Assembly of E coli-Expressed Ferritin.

Ferritin, with the primary function of iron storage, is a nearly ubiquitous protein found in most living organisms. Our recent investigations suggest that ferritin can assemble nanoparticles. So we use ferritin as a novel type of delivery vehicle for recombinant epitope vaccines. And, we found that ferritin form nonnative aggregates depended sensitively on NaCl concentrations. Here, we report that ferritin is an ion-sensitive protein and has the attribute of salt-dependent aggregation. Our results indicate that recombinant ferritin can be released as a soluble form from Escherichia coli at low NaCl concentrations (≤50 mmol/L). Moreover, this result affords us to confirm a proper self-assembling solution for soluble ferritin or other ferritin-based fusion proteins to assemble nanoparticles.

Influence of hydrophilic amino acids and GC-content on expression of recombinant proteins used in vaccines against foot-and-mouth disease virus in Escherichia coli.

Epitope-based protein expression in Escherichia coli can be improved by adjusting its amino acid composition and encoding genes. To that end, we analyzed 24 recombinant epitope proteins (rEPs) that carry multiple epitopes derived from VP1 protein of foot-and-mouth disease virus. High level expression of the rEPs was attributed to a high content of Arg, Asn, Asp and Thr, a low content of Gln, Pro and Lys, a high content of hydrophilic amino acids and a higher isoelectric point value resulting from abundant Arg. It is also attributed to the appropriate guanine and cytosine content in the encoding genes. The data provide a reference for adjusting the amino acid composition in designing epitope-based proteins used in vaccines and for adjusting the synonymous codons to improve their expressions in E. coli.

Preparation of bleomycin A2-PLGA microspheres and related in vitro and in vivo studies.

The goals of these studies were to prepare bleomycin (BLM) A(2)-poly(lactic-co-glycolic acid) (PLGA) microspheres and to investigate their in vitro release, pharmacokinetics, pharmacodynamics, and toxicology of this product. Long-acting BLM A(2)-PLGA microspheres were prepared using multiple emulsion solvent evaporation, and the related characteristics of the microspheres were investigated. The prepared microspheres were administered to dogs via intramuscular injection. The plasma concentration of BLM A(2) in dogs was detected using liquid chromatography-mass spectrometry. The pharmacodynamics of BLM A(2)-PLGA microspheres were investigated in a golden hamster model. The acute and chronic toxicities were investigated in a rat model. The inductive effects of BLM microspheres versus a conventional formulation on pulmonary injuries were compared in a mouse model. BLM A(2)-PLGA microspheres were released stably over 20 days and exhibited a significant inhibition of oral squamous carcinoma. The acute toxicity study suggested that doses up to 128 mg/kg were acceptable, and the chronic toxicity study showed no significant chronic toxicity. The study in mice showed less pulmonary toxicity with BLM microsphere formulation compared with the conventional formulation. As a novel microsphere drug formulation, BLM A(2)-PLGA microspheres showed a significant slow-release effect. These data may provide a new clinical medication option for patients with oral cancer.