Polymorphisms in Sorbitol-Aldose Reductase (Polyol) Pathway Genes and Their Influence on Risk of Diabetic Retinopathy Among Han Chinese.

BACKGROUND Sorbitol-aldose reductase (polyol) pathway genes have been strongly linked to diabetic retinopathy. Polymorphisms in these genes may affect their functions and influence the risk of retinopathy. In this work, we investigated the influence of the rs759853 polymorphism of ALR2 gene and rs2055858 and rs3759890 polymorphisms of SDH gene on risk of diabetic retinopathy among Han Chinese. MATERIAL AND METHODS We included 3,000 subjects in our study, of which 1,500 were patients with diabetic retinopathy and 1,500 were controls without the said condition. Among the cases, 750 had the non-proliferative diabetic retinopathy (NPDR) and 750 had proliferative diabetic retinopathy (PDR). The polymorphisms were genotyped using established methods and logistic regression analysis was used to determine whether the polymorphisms were associated with risk of diabetic retinopathy. RESULTS We found that variants of ALR2 rs759853 polymorphism were significantly associated with an increased risk of diabetic retinopathy, whereas variants of SDH rs2055858 polymorphism were significantly associated with a lower risk. For the former, an odds ratio (OR) of 1.46 were noted for the heterozygous genotype (95% CI=1.25-1.70, P<0.01) and the homozygous variant genotype (OR=1.90, 95% CI=1.40-2.60, P<0.01). For SDH rs2055858 polymorphism, an OR of 0.51 (95% CI=0.43-0.61, P<0.01) and 0.34 (95% CI=0.28-0.42, P<0.01) was observed for heterozygous and homozygous variant genotype respectively. Subgroup analysis based on NPDR and PDR showed a similar finding as the combined results. CONCLUSIONS ALR2 rs759853 and SDH rs2055858 polymorphisms were respectively associated with a higher and lower risk of diabetic retinopathy.

Turning Ineffective Transplatin into a Highly Potent Anticancer Drug via a Prodrug Strategy for Drug Delivery and Inhibiting Cisplatin Drug Resistance.

Clinically ineffective transplatin is highly potent against cancer cells when transformed into a transplatin(IV) prodrug nanoparticle. Herein, a hydrophobic transplatin(IV) was synthesized by H2O2-oxidization of transplatin and attachment of two hydrophobic aliphatic chains. Transplatin(IV) was subsequently encapsulated by a biodegradable amphiphilic copolymer, MPEG-PLA, forming a well-defined spherical micelles (M(TransPt)). Transplatin(IV) was protected efficiently and could be released under a simulated cancerous intracellular condition. Compared to the cisplatin and transplatin, M(TransPt) showed the highest Pt uptake and a clathrin-dependent endocytosis pathway. Most importantly, M(TransPt) displayed a nanomolar IC50 on A2780 cells and a great potency on cisplatin resistant A2780DDP cell line. Overall, this nanoplatform for delivering trans-geometry platinum(IV) drug exhibits excellent characteristics for enhancing efficacy and overcoming cisplatin drug resistance, and holds a strong promise for clinical use in the near future.

Nanoparticle-mediated delivery of multinuclear platinum(IV) prodrugs with enhanced drug uptake and the activity of overcoming drug resistance.

Here, a nanoparticle-mediated delivery of multinuclear platinum(IV) prodrugs [biodegradable polymer-di-cisPt(IV)] for overcoming cisplatin drug resistance is reported. From the MTT assays, lower IC50 values of polymer-di-cisPt(IV) on A2780DDP cells than A2780 were observed with the lowest resistance factor of 0.7. Inductively coupled plasma mass spectroscopy results showed that more drugs were delivered into cancer cells and greater number of Pt-DNA adducts were formed with the use of the polymer-di-cisPt(IV) conjugate nanoparticles. By a mechanistic study with endocytosis inhibitors to treat A2780 cells, we proved that polymer-di-cisPt(IV) conjugate nanoparticles were internalized by the cancer cells through endocytosis rather than through passive diffusion or copper transporter 1-mediated active transportation. This well illustrates the way how the polymer-di-cisPt(IV) micelles overcome cisplatin resistance.

Development and evaluation of a monoclonal antibody-based blocking ELISA to detect antibodies against the E2 protein of bovine viral diarrhea virus-1.

With the rapid development of cattle industry, bovine viral diarrhea virus (BVDV) is becoming widespread in China, which causes serious economic losses to the industry. Effective vaccination and viral surveillance are critical for the prevent and control of BVDV infection. In the present study, the immunogenic domain of E2 protein of BVDV-1 was expressed by prokaryotic pET-28a vector. Monoclonal antibodies (mAbs) against E2 protein were prepared and systemically examined by western blot, immunofluorescence assay, blocking ELISA (bELISA) and virus neutralization test (VNT). The mAb 1E2B3, which showed good reactivity and neutralizing activity to BVDV-1 strains, was selected for ELISA establishment. After a series of screening and optimization, a novel bELISA for highly sensitive and specific detection of BVDV-1 antibodies was established, using HRP-labeled 1E2B3 and recombinant E2 protein. ROC analysis of 91 positive and 84 negative reference bovine serum samples yielded the area under the curve (AUC) of 0.9903. A diagnostic specificity of 96.43 % and a sensitivity of 95.6 % were achieved when the cutoff value was set at 24.31 %. There was no cross reaction to the positive sera of classical swine fever virus (CSFV), BVDV-2, border disease virus (BDV), bovine parainfluenza virus type 3 (BPIV3), infectious bovine rhinotracheitis virus (IBRV), foot-and-mouth disease virus (FMDV), Mycoplasma bovis (M.bovis) and Brucella. The total agreement rate of bELISA with VNT was 93.96 % (249/265). In addition, the result of bELISA was positively correlated with neutralizing antibody titer, and the bELISA could well distinguish the serum samples before and after BVDV vaccination. These results indicate that the established bELISA in this study is specific, sensitive, simple and convenient, which provides technical support for the vaccine efficacy evaluation, prevention and control of BVD in the future.

A new earwig species of the genus Liparura Burr, 1907 (Dermaptera: Forficulidae) from China.

A new earwig species of the genus Liparura Burr, 1907 of the family Forficulidae, namely L. chongqingensis sp. nov., is described from Chongqing, southwestern China. The new species is characterized by the male forceps basally approached to each other, and each with a small tooth protruding dorsad. A key to the species of Liparura is provided.

Ultrathin two-dimensional polydopamine nanosheets for multiple free radical scavenging and wound healing.

Novel 2D polydopamine nanosheets were successfully prepared by using a simple but effective "bottom-up" synthesis method. The ultrathin polydopamine nanosheets exhibit excellent multiple free radical scavenging activities including DPPH˙ and ABTS˙+ free radicals, especially O2˙-. Full-thickness skin defect regeneration was accelerated by treatment with the nanosheets.

Magnesium oxide-crosslinked low-swelling citrate-based mussel-inspired tissue adhesives.

Tissue adhesives are commonly used in surgeries and regenerative engineering for the repair and regeneration of topical and internal wounds on tissues and organs such as skin, heart, blood vessels, and bone. However, achieving rapid crosslinking, strong wet adhesion and cohesion strengths, and minimal cytotoxicity remains a critical roadblock for clinical translation. Herein, in contrast to harsh and cytotoxic oxidants, magnesium oxide (MgO) particles were found to facilitate rapid crosslinking for injectable citrate-based mussel-inspired tissue bioadhesives synthesized by reacting citric acid, PEG-PPG-PEG diol and dopamine (iC-EPE). Our results confirmed the role of MgO particles as both crosslinkers and composite fillers to concurrently enhance bioadhesive cohesion and adhesion. iC-EPE crosslinked by MgO with/without sodium periodate (PI) exhibit enhanced mechanical strengths (1.0 Mpa < tensile strength ≤ 4.5 MPa) compared to that of iC-EPE crosslinked only by PI (~0.75 MPa), high adhesion strength (up to 125 kPa, 8 fold that of fibrin glue (~15 kPa)), tunable degradability (full degradation from <1 week to > 1 month), excellent in vitro and in vivo biocompatibility, encouraging anti-bacterial performance, and favorable wound closure efficacy. Thus, MgO crosslinked bioadhesives possess great potential for a wide range of applications in surgery and regenerative engineering.

Sterilization effects on the handling and degradation properties of calcium phosphate cements containing poly (D,L -lactic-co-glycolic acid) porogens and carboxymethyl cellulose.

Injectable, self-setting calcium phosphate cements (CPCs) are synthetic bone substitutes considered favorable for the repair and regeneration of bone due to their osteocompatibility and unique handling properties. However, their clinical applicability can be compromised due to insufficient cohesion upon injection into the body coupled with poor degradation rates that restricts new bone formation. Consequently, carboxymethyl cellulose (CMC) was incorporated into CPC formulations to improve their cohesion and injectability while poly (D,L -lactic-co-glycolic acid) (PLGA) porogens were added to introduce macroporosity and improve their biodegradation rate. Like most biomaterials, CPCs are gamma irradiated before clinical use to ensure sufficient sterilization. However, it is well known that gamma irradiation also reduces the molecular weight of CMC and PLGA via chain scission, which affects their material properties. Therefore, the aim of this study is to measure the effect that gamma irradiation has on the molecular weight of CMC at varying doses of 15, 40, or 80 kGy and investigate how this affects the handling (i.e., injectability, cohesion, washout, and setting times) and in vitro degradation behavior of CPC formulations. Results reveal that the molecular weight of CMC decreases with increasing gamma irradiation dose, thereby reducing the viscosifying capabilities of CMC, which causes CPCs to deteriorate more readily. Further, the addition of CMC seems to inhibit the degree of phase transformation during cement setting while the subsequent reduction in molecular weight of PLGA after gamma irradiation improves the in vitro degradation rate of CPCs due to the faster degradation rate of low molecular weight PLGA. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2216-2228, 2019.

Emergence of two distinct subpopulations from Klebsiella pneumoniae grown in the stimulated microgravity environment.

AIM: To isolate and characterize the two phenotypically distinct subpopulations from Klebsiella pneumoniae clonal cultures grown in the simulate microgravity environment. MATERIALS & METHODS: Here clonal culture of K. pneumoniae strain ATCC BAA-1705 was grown within a vertically rotating wall vessel bioreactor. Microscopic, colony staining, biofilm assays and quantitative proteomics were used to define the features of subpopulations. RESULTS: Two subpopulations were isolated based on colony appearance and bacterial morphology and indicated the different capability of biofilm formation and antibiotics resistance. CONCLUSION: These findings would raise a possibility of understanding the adaptive roles of bacterial subpopulations formed under certain conditions from the viewpoint of population variation.

Synthesis and characterization of Eu(III) complexes of modified d-glucosamine and poly(N-isopropylacrylamide).

A series of chain-end functional polymers composed of poly(N-isopropylacrylamide) (PNIPAM) and 2-amino-2-deoxy-d-glucopyranose(d-glucosamine, GA) was synthesized via atom transfer radical polymerization (ATRP). Novel fluorescent complexes of glucosamine-PNI- PAM/Eu(III) were then formed by chelation of the polymers and europium(III) ions. The aqueous solutions of the polymers and its Eu(III) complexes exhibited a lower critical solution temperatures (LCSTs), and which were approximately equal to body temperature. Cell viability assays suggested that these thermosensitive polymers and Eu(III) complexes showed excellent biocompatibility in vitro.

Theoretical design and simulation of supramolecular polymer unit based on multiple hydrogen bonds.

The heterocyclic urea of deazapterin (DeAPa) and its protomeric conformers (b, c) with different substituents are selected as the building block for a series of dimers in different configurations. The stabilities of all dimers in various conditions have been investigated by density functional theory. Homodimer of b has more stability than other dimers. Topological analyses certify the coexistence of intermolecular with intramolecular H-bonds. Investigations into frequency demonstrate that all H-bonds show an evident red shift in their stretching vibrational frequencies. Electron donating substituents can provide favorable free energies of the dimer. Solvent effect computations suggest that the dimerization can be favored in weakly polar solvents, such as toluene and chloroform. UV-visible spectra exhibit obvious difference of maximum absorption wavelengths between monomers and dimers, thus may have potential applications for identifying intermolecular H-bonds and calculating association constant of DeAP equilibrium systems in experiments.

Necrosis of cervical carcinoma by dichloroacetate released from electrospun polylactide mats.

It is still a great challenge to apply therapeutic concentration of anti-cancer drugs to the tumor site with low system toxicity. An in situ administration strategy was applied to reverse the aerobic glycolysis of tumor in vivo for the first time. Controlled release of therapeutic concentration of dichloroacetate (DCA) from polylactide (PLA) electrospun mats covering the solid tumor locally was designed to suppress the cervical carcinoma in vivo. A dramatic decrease in the volume and weight of tumors was observed for 19 days in tumor-bearing mice, and a totally 96% of the tumor suppression degree was obtained even the initial tumor volume was around 200 mm(3). Half of the mice recovered in less than 3 weeks. Necrosis was examined rather than apoptosis on the tumor cells as the main process of cell death induced by the DCA-loaded electrospun mats. A proposed necroptosis mechanism was presented to explain the signal pathways that were induced by the metabolic remodeling of DCA. It provided support for this strategy that target the bio-energy metabolism of the cervical carcinoma locally is a quick and effective pathway to cure the advanced-carcinoma of cervical.

Co-delivery of daunomycin and oxaliplatin by biodegradable polymers for safer and more efficacious combination therapy.

An oxaliplatin pro-drug (Oxa(IV)-COOH) with an axial carboxyl group was synthesized and conjugated to biodegradable polymers with pendant hydroxyl groups to prepare polymer-Oxa(IV) conjugates. A hydrophobic anthracycline-based drug, daunorubicin (DRB) was conjugated to similar biodegradable polymers with carboxyl groups to synthesize polymer-DRB conjugates. The two drug conjugates have the similar polymer backbone and are amphiphilic; thus, they can co-assemble into composite micelles. In the composite micelles, the polymer-Oxa(IV) conjugates can release clinically widely used water soluble anticancer drug oxaliplatin (Oxa(II)) upon reduction, while polymer-DRB conjugate is thought to release DRB via acid hydrolysis in the cancer cells. In this way, combination of the hydrophilic platinum drug Oxa(II) and hydrophobic drug DRB can be realized by delivering them in one platform. Moreover, the composite micelles showed reduced systematic toxicity and greater synergistic effect than combination of small molecules of the two anticancer drugs both in vitro and in vivo; thus, this polymer based combination therapy can be useful in future clinic application.