Targeted sustained delivery of antineoplastic agent with multicomponent polylactide stereocomplex micelle.

A c(RGDfC)-decorated polylactide stereocomplex micelle (cRGD-SCM) was prepared through the stereocomplex and hydrophobic interactions among 4-arm poly(ethylene glycol)-block-poly(D-lactide) (4-arm PEG-b-PDLA), methoxy poly(ethylene glycol)-block-poly(L-lactide) (mPEG-b-PLLA), and c(RGDfC)-poly(ethylene glycol)-block-poly(L-lactide) (cRGD-PEG-b-PLLA) for targeted treatment of αvß3 integrin-positive C26 colon cancer. Doxorubicin (DOX), a model antitumor drug, was loaded into cRGD-SCM with a diameter of approximately 100nm, and the drug loading efficiency was 45.9wt.%. cRGD-SCM/DOX with a sustained release pattern exhibited prolonged circulation time, upregulated accumulation in tumor, enhanced tumor inhibition, and decreased side effects compared with free DOX and non-targeting SCM/DOX in vivo. More interestingly, the targeting ligand in the terminal of PEG can be easily replaced with other targeting groups according to the different types of malignancies. Therefore, the cRGD-decorated platform might be a promising targeted drug delivery system for personal chemotherapy clinically.

Removal and upgrading of lignocellulosic fermentation inhibitors by in situ biocatalysis and liquid-liquid extraction.

Hydroxycinnamic acids are known to inhibit microbial growth during fermentation of lignocellulosic biomass hydrolysates, and the ability to diminish hydroxycinnamic acid toxicity would allow for more effective biological conversion of biomass to fuels and other value-added products. In this work, we provide a proof-of-concept of an in situ approach to remove these fermentation inhibitors through constituent expression of a phenolic acid decarboxylase combined with liquid-liquid extraction of the vinyl phenol products. As a first step, we confirmed using simulated fermentation conditions in two model organisms, Escherichia coli and Saccharomyces cerevisiae, that the product 4-vinyl guaiacol is more inhibitory to growth than ferulic acid. Partition coefficients of ferulic acid, p-coumaric acid, 4-vinyl guaiacol, and 4-ethyl phenol were measured for long-chain primary alcohols and alkanes, and tetradecane was identified as a co-solvent that can preferentially extract vinyl phenols relative to the acid parent and additionally had no effect on microbial growth rates or ethanol yields. Finally, E. coli expressing an active phenolic acid decarboxylase retained near maximum anaerobic growth rates in the presence of ferulic acid if and only if tetradecane was added to the fermentation broth. This work confirms the feasibility of donating catabolic pathways into fermentative microorganisms in order to ameliorate the effects of hydroxycinnamic acids on growth rates, and suggests a general strategy of detoxification by simultaneous biological conversion and extraction.

Harnessing genetic diversity in Saccharomyces cerevisiae for fermentation of xylose in hydrolysates of alkaline hydrogen peroxide-pretreated biomass.

The fermentation of lignocellulose-derived sugars, particularly xylose, into ethanol by the yeast Saccharomyces cerevisiae is known to be inhibited by compounds produced during feedstock pretreatment. We devised a strategy that combined chemical profiling of pretreated feedstocks, high-throughput phenotyping of genetically diverse S. cerevisiae strains isolated from a range of ecological niches, and directed engineering and evolution against identified inhibitors to produce strains with improved fermentation properties. We identified and quantified for the first time the major inhibitory compounds in alkaline hydrogen peroxide (AHP)-pretreated lignocellulosic hydrolysates, including Na(+), acetate, and p-coumaric (pCA) and ferulic (FA) acids. By phenotyping these yeast strains for their abilities to grow in the presence of these AHP inhibitors, one heterozygous diploid strain tolerant to all four inhibitors was selected, engineered for xylose metabolism, and then allowed to evolve on xylose with increasing amounts of pCA and FA. After only 149 generations, one evolved isolate, GLBRCY87, exhibited faster xylose uptake rates in both laboratory media and AHP switchgrass hydrolysate than its ancestral GLBRCY73 strain and completely converted 115 g/liter of total sugars in undetoxified AHP hydrolysate into more than 40 g/liter ethanol. Strikingly, genome sequencing revealed that during the evolution from GLBRCY73, the GLBRCY87 strain acquired the conversion of heterozygous to homozygous alleles in chromosome VII and amplification of chromosome XIV. Our approach highlights that simultaneous selection on xylose and pCA or FA with a wild S. cerevisiae strain containing inherent tolerance to AHP pretreatment inhibitors has potential for rapid evolution of robust properties in lignocellulosic biofuel production.

Scale-up and integration of alkaline hydrogen peroxide pretreatment, enzymatic hydrolysis, and ethanolic fermentation.

Alkaline hydrogen peroxide (AHP) has several attractive features as a pretreatment in the lignocellulosic biomass-to-ethanol pipeline. Here, the feasibility of scaling-up the AHP process and integrating it with enzymatic hydrolysis and fermentation was studied. Corn stover (1 kg) was subjected to AHP pretreatment, hydrolyzed enzymatically, and the resulting sugars fermented to ethanol. The AHP pretreatment was performed at 0.125 g H(2) O(2) /g biomass, 22°C, and atmospheric pressure for 48 h with periodic pH readjustment. The enzymatic hydrolysis was performed in the same reactor following pH neutralization of the biomass slurry and without washing. After 48 h, glucose and xylose yields were 75% and 71% of the theoretical maximum. Sterility was maintained during pretreatment and enzymatic hydrolysis without the use of antibiotics. During fermentation using a glucose- and xylose-utilizing strain of Saccharomyces cerevisiae, all of the Glc and 67% of the Xyl were consumed in 120 h. The final ethanol titer was 13.7 g/L. Treatment of the enzymatic hydrolysate with activated carbon prior to fermentation had little effect on Glc fermentation but markedly improved utilization of Xyl, presumably due to the removal of soluble aromatic inhibitors. The results indicate that AHP is readily scalable and can be integrated with enzyme hydrolysis and fermentation. Compared to other leading pretreatments for lignocellulosic biomass, AHP has potential advantages with regard to capital costs, process simplicity, feedstock handling, and compatibility with enzymatic deconstruction and fermentation. Biotechnol. Bioeng. 2012; 109:922-931. © 2011 Wiley Periodicals, Inc.

Protective effects of silibinin on LPS-induced inflammation in human periodontal ligament cells.

Clinically, periodontitis is a chronic nonspecific inflammation that leads to damaged teeth and their supporting gum tissues. Although many studies on periodontitis have been conducted, therapy with natural products is still rare. Silibinin has been proven to have anti-inflammatory and antioxidant activities. However, the effects of silibinin on lipopolyssacharide (LPS)-induced inflammation in periodontal ligaments (PDLs) have not yet been investigated. In this study, the PDLs were treated with silibinin (10, 20, and 40 µM) in the presence of LPS. The results showed that silibinin treatment reduced the levels of NO, PGE2, IL-6, TNF-α, MMP-1, and MMP-3 and enhanced the activities of superoxide dismutase (SOD) and glutathione (GSH). Moreover, silibinin treatment downregulated RANKL levels and upregulated OPG and ALP levels. In summary, silibinin protected PDLs against LPS-induced inflammation, oxidative stress, and osteogenic differentiation.

Targeting cancer stem cells with polymer nanoparticles for gastrointestinal cancer treatment.

Nanomaterials are developing rapidly in the medical field, bringing new hope for treating various refractory diseases. Among them, polymer nanomaterials, with their excellent properties, have been used to treat various diseases, such as malignant tumors, diabetes, and nervous system diseases. Gastrointestinal cancer is among the cancers with the highest morbidity and mortality worldwide. Cancer stem cells are believed to play an important role in the occurrence and development of tumors. This article summarizes the characteristics of gastrointestinal cancer stem cells and reviews the latest research progress in treating gastrointestinal malignant tumors using polymer nanoparticles to target cancer stem cells. In addition, the review article highlights the potential of polymer nanoparticles in targeting gastrointestinal cancer stem cells.

Low-cost and highly efficient production of bacterial cellulose from sweet potato residues: Optimization, characterization, and application.

Bacterial cellulose (BC) is an emerging biological material with unique properties and structure, which has attracted more and more attention. In this study, Gluconacetobacter xylinus was used to convert sweet potato residues (SPR) hydrolysate to BC. SPR was directly used without pretreatment, and almost no inhibitors were generated, which was beneficial to subsequent glucan conversion and SPR-BC synthesis. SPR-BC production was 11.35 g/L under the optimized condition. The comprehensive structural characterization and mechanical analysis demonstrated that the crystallinity, maximum thermal degradation temperature, and tensile strength of SPR-BC were 87.39%, 263 °C, and 6.87 MPa, respectively, which were superior to those of BC produced with the synthetic medium. SPR-BC was added to rice straw pulp to enhance the bonding force between fibers and the indices of tensile, burst, and tear of rice straw paper. The indices were increased by 83.18%, 301.27%, and 169.58%, respectively. This research not only expanded the carbon source of BC synthesis, reduced BC production cost, but also improved the quality of rice straw paper.

Polymer nanotherapeutics to correct autoimmunity.

The immune system maintains homeostasis and protects the body from pathogens, mutated cells, and other harmful substances. When immune homeostasis is disrupted, excessive autoimmunity will lead to diseases. To inhibit the unexpected immune responses and reduce the impact of treatment on immunoprotective functions, polymer nanotherapeutics, such as nanomedicines, nanovaccines, and nanodecoys, were developed as part of an advanced strategy for precise immunomodulation. Nanomedicines transport cytotoxic drugs to target sites to reduce the occurrence of side effects and increase the stability and bioactivity of various immunomodulating agents, especially nucleic acids and cytokines. In addition, polymer nanomaterials carrying autoantigens used as nanovaccines can induce antigen-specific immune tolerance without interfering with protective immune responses. The precise immunomodulatory function of nanovaccines has broad prospects for the treatment of immune related-diseases. Besides, nanodecoys, which are designed to protect the body from various pathogenic substances by intravenous administration, are simple and relatively noninvasive treatments. Herein, we have discussed and predicted the application of polymer nanotherapeutics in the correction of autoimmunity, including treating autoimmune diseases, controlling hypersensitivity, and avoiding transplant rejection.

Porous fibrous bacterial cellulose/La(OH)3 membrane for superior phosphate removal from water.

Lanthanum (La)-based nanoparticles (NPs) are promising candidates for phosphate removal owing to their inherently high affinity towards phosphate. However, significant challenges remain to be addressed before their practical deployment, especially the problems associated with their aggregation. Herein, we fabricated a high-efficient sorbent for phosphate removal through in-situ synthesizing La(OH)3 NPs on a natural support, bacterial cellulose (BC), which is pre-modified with polyethyleneimine. The resultant La(OH)3 NPs-immobilized BC with different La contents (BPLa-X) exhibited a highly fibrous porous structure, in which BPLa-3 was selected for further phosphate adsorption studies. BPLa-3 demonstrated a high adsorption capacity of 125.5 mg P g-1, and high adsorption selectivity due to the large surface area and abundant exposed active adsorption sites for phosphate. Additionally, BPLa-3 also displayed high reusability and still possessed high adsorption capacity after four consecutive cycles of adsorption-desorption. Therefore, the present adsorbent is believed to be a promising candidate for practical phosphate removal.

[Progress in detoxification of inhibitors generated during lignocellulose pretreatment].

Lignocellulose can be hydrolyzed by cellulase into fermentable sugars to produce hydrogen, ethanol, butanol and other biofuels with added value. Pretreatment is a critical step in biomass conversion, but also generates inhibitors with negative impacts on subsequent enzymatic hydrolysis and fermentation. Hence, pretreatment and detoxification methods are the basis of efficient biomass conversion. Commonly used pretreatment methods of lignocellulose are chemical and physic-chemical processes. Here, we introduce different inhibitors and their inhibitory mechanisms, and summarize various detoxification methods. Moreover, we propose research directions for detoxification of inhibitors generated during lignocellulose pretreatment.

Features correlated to improved enzymatic digestibility of corn stover subjected to alkaline hydrogen peroxide pretreatment.

As one of the leading pretreatment approaches, alkaline hydrogen peroxide (AHP) pretreatment can enhance the enzymatic digestibility of lignocellulose significantly. In this study, the glucan conversion of AHP pretreated corn stover (CS) without and with water-wash were 28.4% and 50.0% higher than that of raw material, respectively. In order to systematically understand its mechanism, analyses of the features of AHP pretreated and raw CS, such as specific surface area, crystallinity, zeta potential, water holding capacity and swelling capacity and others were performed. The weight-average molecular weight (Mw) of the sugars in the hydrolysate and the particle size distribution of the hydrolysis residue were also analyzed. These results explained why AHP-CS was more conducive to enzymatic hydrolysis. The deeper reason was that the removal of lignin and the destruction of hydrogen bonds within cellulose and hemicellulose increased the accessibility of cellulose and reduced the non-productive adsorption of cellulase, which significantly improved the enzymatic digestibility.

Overexpression of microRNA-141 inhibits osteoporosis in the jawbones of ovariectomized rats by regulating the Wnt/ß-catenin pathway.

OBJECTIVE: This work was aimed to investigate the effect of microRNA-141 (miR-141) overexpression in the jawbones of ovariectomized-induced osteoporosis rats and investigate the role of miR-141 in the Wnt/ß-catenin pathway. METHODS: Twenty-four female rats were randomly divided into the sham group, ovariectomized osteoporosis group (OP), miR-141 agonist group (miR-141), and miR-141 scramble group (Scramble). Bone mineral density (BMD) and pathological changes of the jaw were detected. Serum receptor activator of nuclear factor-B ligand (RANKL), osteoprotegerin, tartrate-resistant acid phosphatase (TRAP), and bone gla protein (BGP) levels were tested by ELISA. The expression of Runt-related transcription factor 2 (Runx2), and Osterix measured by immunohistochemistry and the expression of Wnt, ß-catenin, and Dickkopf1 (DKK1) proteins was measured by Western blot. Furhter, the Wnt agonist DKK2-C2, Wnt inhibitor Endostar were used to verify the effect of miR-141 overexpression on the Wnt/ß-catenin pathway. RESULT: Compared with the OP group, the content of osteoprotegerin increased while the levels of RANKL, BGP, TRAP decreased in the miR-141 and DKK2-C2 groups (p < 0.05). The levels of Runx2 and Osterix increased significantly in the miR-141 and DKK2-C2 groups when compared to the OP group (p < 0.05). Interestingly, the protein expression of Wnt and ß-catenin increased while DKK1 was remarkably down-regulated in the miR-141 and DKK2-C2 groups when compared to the OP group (p < 0.05). In contrast to the miR-141 group, the above results were reversed after treatment with the Endostar (p < 0.05). CONCLUSION: Overexpression of miR-141 could inhibit the osteoporosis of jawbones in ovariectomized rats by activating the Wnt/ß-catenin pathway.

Enhanced enzymatic digestibility of poplar wood by quick hydrothermal treatment.

To elevate the glucose yield from the enzymatic hydrolysis of poplar wood for bio-ethanol production, quick hydrothermal treatment (QHT) was conducted at 200 °C for a short period of time from 5 min to 25 min. It was found that the QHT could remove >85% of the hemicelluloses and ~30% of the lignin in the poplar wood, and achieve 82% cellulose conversion at a low cellulase dosage of 10 FPU/g substrate. The enhancement digestibility of poplar wood was ascribed to the higher accessibility of cellulose, as the specific surface area of the substrate increased from 3.0 m2/g to 7.1 m2/g from the of untreated wood to the QHT-treated wood. The results demonstrate the improvements in digestibility and hydrolysis rates after QHT.

Feasibility of biodegradable PLGA common bile duct stents: an in vitro and in vivo study.

The current study investigates the feasibility of using a biodegradable polymeric stent in common bile duct (CBD) repair and reconstruction. Here, poly(L-lactide-co-glycolide) (PLGA, molar ratio LA/GA = 80/20) was processed into a circular tube- and dumbbell-shaped specimens to determine the in vitro degradation behavior in bile. The morphology, weight loss, and molecular weight changes were then investigated in conjunction with evaluations of the mechanical properties of the specimen. Circular tube-shaped PLGA stents with X-ray opacity were subsequently used in common bile duct exploration (CBDE) and primary suturing in canine models. Next, X-ray images of CBD stents in vivo were compared and levels of serum liver enzymes and a histological analysis were conducted after stent transplantation. The results showed that the PLGA stents exhibited the required biomedical properties and spontaneously disappeared from CBDs in 4-5 weeks. The degradation period and function match the requirements in repair and reconstruction of CBDs to support the duct, guide bile drainage, and reduce T-tube-related complications.

Electrospun polymer micro/nanofibers as pharmaceutical repositories for healthcare.

Electrospun polymer micro/nanofibers have been widely explored as platforms for controlled delivery of therapeutic agents. Electrospun fibers are featured by large surface area, high porosity, and tunable morphology, which can be manipulated to fabricate micro/nanofibers with appropriate physicochemical properties, degradation kinetics, and drug release profiles. Many therapeutic agents can be separately or simultaneously loaded by electrospun fibers in the application of cancer therapy, adhesion prevention, wound repair, and regeneration of bone and nerve. In this review, we mainly introduce the basic principles of electrospinning, and the mechanisms and applications of electrospun micro/nanofibers for delivery of small molecule drugs, proteins, and nucleic acids in the healthcare field.

Alkaline and Alkaline-Oxidative Pretreatment and Hydrolysis of Herbaceous Biomass for Growth of Oleaginous Microbes.

This chapter describes methods for generation of hydrolysates amenable to conversion to microbial lipids from herbaceous lignocellulosic biomass utilizing either mild alkali pretreatment with NaOH or alkaline hydrogen peroxide pretreatment with NaOH and H2O2. This pretreatment is followed by enzymatic hydrolysis of the plant cell wall polysaccharides to yield hydrolysates. These hydrolysates are composed primarily of the monosaccharides glucose and xylose as well as acetate and phenolic monomers that may all serve as a source of renewable carbon to produce microbial lipids. Application of these mild pretreatment conditions minimizes the generation of inhibitors, enabling microbial cultivations to often be performed without the need for detoxification.

High Mobility Group Box 1 Protein Level as a Novel Biomarker for the Development of Peri-Implant Disease.

Peri-implant disease is a chronic inflammation of the soft and hard tissues around a dental implant, resulting from bacterial infection. Recent evidence indicates that some pro-inflammatory cytokines and chemokines released by immunocytes are substantially responsible for the progress and consequence of inflammation. High mobility group box 1 (HMGB1) is released into the extracellular matrix and acts as a key pro-inflammatory factor during injury, necrosis and inflammation. A higher concentration of HMGB1 has been found in gingival crevicular fluid from inflammatory gingival tissue than from healthy sites. HMGB1 mRNA and protein are overexpressed in murine periodontal ligament fibroblasts stimulated with lipopolysaccharide (LPS) and IL-1ß. Thus, this study sought to assess HMGB1 expression in peri-implant crevicular fluid (PICF) at each stage of peri-implant disease and to investigate the correlation between HMGB1 and peri-implant disease progress. The results demonstrated that the HMGB1 expression level in PICF is indicative of the progress of peri-implant disease and hence may be a useful diagnostic and prognostic biomarker for peri-implant tissue.

Polymer materials for prevention of postoperative adhesion.

Postoperative adhesion (POA) is a common complication that often occurs after a variety of surgeries, such as plastic surgery, repair operations of abdominal, pelvic, and tendon, and so forth. Moreover, POA leads to chronic abdominal pain, secondary infertility in women, intestinal obstruction, and other severe complications, which significantly reduce the life quality of patients. In order to prevent the formation of POA, a number of strategies have been developed, among which an emerging method is physical barriers consisting of polymer materials. This review highlights the most commonly used natural and synthetic polymer materials in anti-adhesion physical barriers. The specific features of polymer materials are analyzed and compared, and the possible prospect is also predicted. STATEMENT OF SIGNIFICANCE: Postoperative adhesion (POA) is a serious complication accompanied with various surgeries. Polymer material-based physical barriers have attracted a large amount of attention in POA prevention. The polymer barriers can effectively avoid the formation of fibrous tissues among normal organs by reducing the interconnection of injured tissues. In this review, specific features of the natural and synthetic polymer materials for application in POA prevention were presented, and the possible prospects were predicted. All in all, our work can provide inspiration for researchers to choose proper polymer materials for preclinical and even clinical anti-adhesion studies.

Antitumor activity of electrospun polylactide nanofibers loaded with 5-fluorouracil and oxaliplatin against colorectal cancer.

The purpose of this study was to evaluate both in vitro and in vivo anticancer activities against colorectal cancer (CRC) of electrospun polylactide (PLA) nanofibers loaded with 5-fluorouracil (5-Flu) and oxaliplatin. For in vitro evaluation, human CRC HCT8 cells were directly exposed to the drug-loaded fiber mats, followed with MTT and flow cytometry (FCM) assay. For in vivo evaluation, the drug-loaded fiber mats were locally implanted into mouse colorectal CT26 tumor-bearing mice, followed with histological analysis and detection of survival rate. The results showed that the drug-loaded fiber mats was similar to that of the combination of free 5-Flu and oxaliplatin in vitro cytotoxicity but was much superior to intravenous injection of free drug in vivo anticancer activities, presenting with suppressed tumor growth rate and prolonged survival time of mice. In conclusion, anticancer activities of 5-Flu and oxaliplatin against CRC can be significantly improved by using PLA electrospun nanofibers as local drug delivery system.

Engineering and two-stage evolution of a lignocellulosic hydrolysate-tolerant Saccharomyces cerevisiae strain for anaerobic fermentation of xylose from AFEX pretreated corn stover.

The inability of the yeast Saccharomyces cerevisiae to ferment xylose effectively under anaerobic conditions is a major barrier to economical production of lignocellulosic biofuels. Although genetic approaches have enabled engineering of S. cerevisiae to convert xylose efficiently into ethanol in defined lab medium, few strains are able to ferment xylose from lignocellulosic hydrolysates in the absence of oxygen. This limited xylose conversion is believed to result from small molecules generated during biomass pretreatment and hydrolysis, which induce cellular stress and impair metabolism. Here, we describe the development of a xylose-fermenting S. cerevisiae strain with tolerance to a range of pretreated and hydrolyzed lignocellulose, including Ammonia Fiber Expansion (AFEX)-pretreated corn stover hydrolysate (ACSH). We genetically engineered a hydrolysate-resistant yeast strain with bacterial xylose isomerase and then applied two separate stages of aerobic and anaerobic directed evolution. The emergent S. cerevisiae strain rapidly converted xylose from lab medium and ACSH to ethanol under strict anaerobic conditions. Metabolomic, genetic and biochemical analyses suggested that a missense mutation in GRE3, which was acquired during the anaerobic evolution, contributed toward improved xylose conversion by reducing intracellular production of xylitol, an inhibitor of xylose isomerase. These results validate our combinatorial approach, which utilized phenotypic strain selection, rational engineering and directed evolution for the generation of a robust S. cerevisiae strain with the ability to ferment xylose anaerobically from ACSH.