The impacts of driving variables on energy-related carbon emissions reduction in the building sector based on an extended LMDI model: a case study in China.

As China's main contributor to energy-related carbon emissions, the building sector in Jiangsu Province generates around 13.58% of the national carbon emissions. However, the influential variables of the energy structure in Jiangsu Province have been little investigated during the past decade. With the increasing emphasis on China's investment in technological innovation and adjustment of its industrial structure, research and development (R&D) has become an inevitable area for carbon emissions reduction. Nevertheless, its role in carbon emissions has rarely been examined. In this research, based on the logarithmic mean Divisia index (LMDI) model, the variables affecting the fluctuation of carbon dioxide emissions in the building sector (CEBS) in Jiangsu Province during 2011-2019 were restructured by introducing technological factors related to the construction industry, including energy structure, energy intensity, R&D efficiency, R&D intensity, investment intensity, economic output, and population engaged in the construction industry. From the results, it can be inferred that (1) energy structure, energy intensity, R&D efficiency, and investment intensity operate as inhibitors in increasing CEBS, and investment intensity exerts a more prominent impact on suppressing the growth of CEBS; (2) R&D intensity, economic output, and population engaged have a promotional effect on the fluctuations of CEBS, among which the first factor most actively promoted the increase in carbon emissions, although its role was negligible for economic output and the population; and (3) R&D efficiency, R&D intensity, and investment intensity are the three most critical variables for influencing the CEBS, but they are volatile. The numerical fluctuation caused by the three factors might be correlated to national and local policy interventions. Finally, policy recommendations are put forward for strengthening the management and minimizing the CEBS in Jiangsu Province.

Strain differences in the drug transport capacity of intestinal glucose transporters in Sprague-Dawley versus Wistar rats, C57BL/6J versus Kunming mice.

Designing oral drug delivery systems using intestinal glucose transporters (IGTs) may be one of the strategies for improving oral bioavailability of drugs. However, little is known about the biological factors affecting the drug transport capacity of IGTs. Gastrodin is a sedative drug with a structure very similar to glucose. It is a highly water-soluble phenolic glucoside. It can hardly enter the intestine through simple diffusion but exhibits good oral bioavailability of over 80%. We confirmed that gastrodin is absorbed via the intestinal glucose transport pathway. It has the highest oral bioavailability among the reported glycosides' active ingredients through this pathway. Thus, gastrodin is the most selective drug substrate of IGTs and can be used to evaluate the drug transport capacity of IGTs. Obviously, strain is one of the main biological factors affecting drug absorption. This study firstly compared the drug transport capacity of IGTs between SD rats and Wistar rats and between C57 mice and KM mice by pharmacokinetic experiments and single-pass intestinal perfusion experiments of gastrodin. Then, the sodium-dependent glucose transporter type 1 (SGLT1) and sodium-independent glucose transporters type 2 (GLUT2) in the duodenum, jejunum, ileum and colon of these animals were quantified using RT-qPCR and Western blot. The results showed that the oral bioavailability of gastrodin in Wistar rats was significantly higher than in SD rats and significantly higher in KM mice than in C57 mice. Gastrodin absorption significantly differed among different intestinal segments in SD rats, C57 mice and KM mice, except Wistar rats. RT-qPCR and Western blot demonstrated that the intestinal expression distribution of SGLT1 and GLUT2 in SD rats and C57 mice was duodenum ≈ jejunum > ileum > colon. SGLT1 expression did not differ among different intestinal segments in KM mice, whereas the intestinal expression distribution of GLUT2 was duodenum ≈ jejunum ≈ ileum > colon. However, the expression of SGLT1 and GLUT2 did not differ among different intestinal segments in Wistar rats. It was reported that the intestinal expression distribution of SGLT1 and GLUT2 in humans is duodenum > jejunum > ileum > colon. Hence, the intestinal expression distribution of SGLT1 and GLUT2 of SD rats and C57 mice was more similar to that in humans. In conclusion, the drug transport capacity of IGTs differs in different strains of rats and mice. SD rats and C57 mice are more suitable for evaluating the pharmacokinetics of glycosides' active ingredients absorbed via the intestinal glucose transport pathway.

pH-Regulated Refinement of Pore Size in Carbon Spheres for Size-Sieving of Gaseous C8 , C6 and C3 Hydrocarbon Pairs.

Selective separation of industrial important C8 , C6 and C3 hydrocarbon pairs by physisorbents can greatly reduce the energy intensity related to the currently used cryogenic distillation techniques. The achievement of size-sieving based on carbonaceous materials is desirable, but commonly hindered by the random structure of carbons often with a broad pore size distribution. Herein, a pH-regulated pre-condensation strategy was introduced to control the carbon pore architecture by the sp2 /sp3 hybridization of precursor. The lower pH value during pre-condensation of glucose facilitates the growth of aromatic nanodomains, rearrangement of stacked layers and a concomitant transition from sp3 -C to sp2 -C. The subsequent pyrolysis endows the pore size manipulated from 6.8 to 4.8 Šand narrowly distributed over a range of 0.2 Å. The refined pores enable effective size-sieving of C8 , C6 and C3 hydrocarbon pairs with high separation factor of 1.9 and 4.9 for C8 xylene (X) isomers para-X/meta-X and para-X/ortho-X, respectively, 5.1 for C6 alkane isomers n-hexane/3-methylpentane, and 22.0 for C3 H6 /C3 H8 . The excellent separation performance based-on size exclusion effect is validated by static adsorption isotherms and dynamic breakthrough experiments. This synthesis strategy provides a means of exploring advanced carbonaceous materials with controlled hybridized structure and pore sizes for challenging separation needs.

Effects of Substitution Ratios of Zinc-Substituted Hydroxyapatite on Adsorption and Desorption Behaviors of Bone Morphogenetic Protein-2.

Understanding interactions between bone morphogenetic proteins (BMPs) and biomaterials is of great significance in preserving the structure and bioactivity of BMPs when utilized in clinical applications. Currently, bone morphogenetic protein-2 (BMP-2) is one of the most important growth factors in bone tissue engineering; however, atomistic interactions between BMP-2 and zinc-substituted hydroxyapatite (Zn-HAP, commonly used in artificial bone implants) have not been well clarified until now. Thus, in this work, the interaction energies, binding/debinding states, and molecular structures of BMP-2 upon a series of Zn-HAP surfaces (Zn-HAPs, 1 at%, 2.5 at%, 5 at%, and 10 at% substitution) were investigated by hybrid molecular dynamics (MD) and steered molecular dynamics (SMD) simulations. Meanwhile, cellular studies including alkaline phosphatase (ALP) activity and reverse transcription-polymerase chain reaction (RT-PCR) assay were performed to verify the theoretical modeling findings. It was found that, compared to pure HAP, Zn-HAPs exhibited a higher binding affinity of BMP-2 at the adsorption process; meanwhile, the detachment of BMP-2 upon Zn-HAPs was more difficult at the desorption process. In addition, molecular structures of BMP-2 could be well stabilized upon Zn-HAPs, especially for Zn10-HAP (with a 10 at% substitution), which showed both the higher stability of cystine-knots and less change in the secondary structures of BMP-2 than those upon HAP. Cellular studies confirmed that higher ALP activity and osteogenic marker gene expression were achieved upon BMP-2/Zn-HAPs than those upon BMP-2/HAP. These findings verified that Zn-HAPs favor the adsorption of BMP-2 and leverage the bioactivity of BMP-2. Together, this work clarified the interaction mechanisms between BMP-2 and Zn-HAPs at the atom level, which could provide new molecular-level insights into the design of BMP-2-loaded biomaterials for bone tissue engineering.

The WRKY10-VQ8 module safely and effectively regulates rice thermotolerance.

WRKY transcription factors (TFs) play crucial roles in biotic and abiotic stress responses. However, their roles in thermal response are still largely elusive, especially in rice. In this study, we revealed the functions of WRKY10 TF and VQ8 protein containing VQ motif in rice thermotolerance. Overexpression of WRKY10 or loss of VQ8 function increases thermosensitivity, whereas conversely, overexpression of VQ8 or loss of WRKY10 function enhances thermotolerance. Overexpression of WRKY10 accelerates reactive oxygen species (ROS) accumulation in chloroplasts and apoplasts, and it also induces the expression of heat shock TF and protein genes. We also found that WRKY10 regulates nuclear DNA fragmentation and hypersensitive response by modulating NAC4 TF expression. The balance between destructive and protective responses in WRKY10-overexpression plant is more fragile and more easily broken by heat stress compared with wild type. In vitro and in vivo assays revealed that VQ8 interacts with WRKY10 and inhibits the transcription activity via repressing its DNA-binding activity. Our study demonstrates that WRKY10 negatively regulates thermotolerance by modulating the ROS balance and the hypersensitive response and that VQ8 functions antagonistically to positively regulate thermotolerance. The functional module of WRKY10-VQ8 provides safe and effective regulatory mechanisms in the heat stress response.

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics.

With the widespread clinical use of drug combinations, the incidence of drug-drug interactions (DDI) has significantly increased, accompanied by a variety of adverse reactions. Drug transporters play an important role in the development of DDI by affecting the elimination process of drugs in vivo, especially in the pathological state. Tubulointerstitial fibrosis (TIF) is an inevitable pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease. Here, the dynamic expression changes of eleven drug transporters in TIF kidney have been systematically investigated. Among them, the mRNA expressions of Oat1, Oat2, Oct1, Oct2, Oatp4C1 and Mate1 were down-regulated, while Oat3, Mrp2, Mrp4, Mdr1-α, Bcrp were up-regulated. Pearson correlation analysis was used to analyze the correlation between transporters and Creatinine (Cr), OCT2 and MATE1 showed a strong negative correlation with Cr. In contrast, Mdr1-α exhibited a strong positive correlation with Cr. In addition, the pharmacokinetics of cimetidine, ganciclovir, and digoxin, which were the classical substrates for OCT2, MATE1 and P-glycoprotein (P-gp), respectively, have been studied. These results reveal that changes in serum creatinine can indicate changes in drug transporters in the kidney, and thus affect the pharmacokinetics of its substrates, providing useful information for clinical use.

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking.

The kidneys are a pair of important organs that excretes endogenous waste and exogenous biological agents from the body. Numerous transporters are involved in the excretion process. The levels of these transporters could affect the pharmacokinetics of many drugs, such as organic anion drugs, organic cationic drugs, and peptide drugs. Eleven drug transporters in the kidney (OAT1, OAT3, OATP4C1, OCT2, MDR1, BCRP, MATE1, MATE2-K, OAT4, MRP2, and MRP4) have become necessary research items in the development of innovative drugs. However, the levels of these transporters vary between different species, sex-genders, ages, and disease statuses, which may lead to different pharmacokinetics of drugs. Here, we review the differences of the important transports in the mentioned conditions, in order to help clinicians to improve clinical prescriptions for patients. To predict drug-drug interactions (DDIs) caused by renal drug transporters, the molecular docking method is used for rapid screening of substrates or inhibitors of the drug transporters. Here, we review a large number of natural products that represent potential substrates and/or inhibitors of transporters by the molecular docking method.

Preparation, Characterization, and Selection of Optimal Forms of (S)-Carvedilol Salts for the Development of Extended-Release Formulation.

(S)-carvedilol (S-CAR) is the dominant pharmacodynamic conformation of carvedilol, but its further development for extended-release formulation is restricted by its poor solubility. This study aimed to prepare and screen S-CAR salts that could be used to improve solubility and allow extended release. Five salts of S-CAR with well-known acid counterions (i.e., phosphate, hydrochloride, sulfate, fumarate, and tartrate) were produced using similar processes. However, these salts were obtained with water contents of 1.60-12.28%, and their physicochemical properties differed. The melting points of phosphate, hydrochloride, and tartrate were 1.1-1.5 times higher than that of the free base. The solubility of S-CAR salts was promoted to approximately 3-32 times higher than that of the free base at pH 5.0-8.0. Typical pH-dependent solubilities were evidently observed in S-CAR salts, but considerable differences in solubility properties among these salts were observed. S-CAR phosphate and hydrochloride possessed high melting points, considerable solubility, and excellent chemical and crystallographic stabilities. Accordingly, S-CAR phosphate and hydrochloride were chosen for further pharmacokinetic experiments and pharmaceutical study. S-CAR phosphate and hydrochloride extended-release capsules were prepared using HPMC K15 as the matrix and presented extended release in in vitro and in vivo evaluations. Results implied that water molecules in the hydrated salt were a potential threat to the achievement of crystal stability and thermostability. S-CAR phosphate and hydrochloride are suitable for further development of the extended-release formulation.

Comparative study on the intestinal absorption of three gastrodin analogues via the glucose transport pathway.

Gastrodin is the main active constituent of Tianma, a famous traditional Chinese herbal medicine. Our previous research has found that gastrodin is absorbed rapidly in the intestine by the sodium-dependent glucose transporter 1 (SGLT1). In the current report, gastrodin is the best glycoside compound absorbed via the glucose transport pathway. This study aimed to investigate the effect of the slight difference in chemical structure on the drug intestinal absorption via the glucose transport pathway. Traditional biopharmaceutical and computer-aided molecular docking methods were used to evaluate the intestinal absorption characteristics of three gastrodin analogues, namely, salicin, arbutin and 4-methoxyphenyl-ß-D-glucoside (4-MG). The oil-water partition coefficient (logP) experiments showed that the logP values of the gastrodin analogues followed the order: 4-MG > salicin > arbutin. In vitro Caco-2 cell transport experiments demonstrated that the apparent permeability coefficient (Papp) value of arbutin was higher than those of salicin and 4-MG. In situ single-pass intestinal perfusion experiments showed that the absorption of arbutin and 4-MG was better than that of salicin and that the absorption of the three compounds in the colon was lower than that in the small intestine. Quantitative real-time polymerase chain reaction results confirmed that the SGLT1 mRNA expression in the small intestine of rats was obviously higher than that in the colon of rats. In vivo pharmacokinetic experiments demonstrated that the oral bioavailability of salicin was lower than those of arbutin and 4-MG. In vitro and in vivo experiments showed that glucose or phlorizin (SGLT1 inhibitor) could decrease the intestinal absorption of the three compounds. Contrary to the above biopharmaceutical experiments, the computer-aided molecular docking test showed that the affinity of salicin to the vSGLT receptor was stronger than those of arbutin and 4-MG. In conclusion, the SGLT1 can facilitate the intestinal absorption of salicin, arbutin and 4-MG, and the slight difference in chemical structure can affect absorption.

Determination and Comparison of the Solubility, Oil-Water Partition Coefficient, Intestinal Absorption, and Biliary Excretion of Carvedilol Enantiomers.

Carvedilol is administered as a racemic mixture for the therapy of hypertension and heart failure. S-enantiomer is the dominant conformation of pharmacodynamics, but its further development was obstructed by its poor bioavailability. In this study, carvedilol and its enantiomers were compared in terms of solubility, permeability, and biliary excretion, and reasons for the poor bioavailability were discussed. Equilibrium solubility and log P were measured by a shake flask method at a wide pH range (1.2-8.0), and intestinal absorption and biliary excretion were evaluated using a single-pass rat intestinal perfusion model. According to BCS guidance, carvedilol and its R/S enantiomers are considered highly soluble at pH value less than 5.0 and low soluble at neutral or weak alkaline conditions. RS-carvedilol showed significantly lower solubilities at pH 1.2-5.0 and higher solubilities at pH 6.0-8.0 than its enantiomers. In addition, carvedilol and its enantiomers possessed similar log P values at pH 1.2-8.0. High intestinal permeabilities of carvedilol and its enantiomers were observed, and S-carvedilol showed higher absorption than R-carvedilol and RS-carvedilol. The biliary excretion about two major metabolites, 1-hydroxycarvedilol O-glucuronide and 8-hydroxycarvedilol O-glucuronide, of RS-carvedilol, S-carvedilol, and R-carvedilol were 66.4%, 73.5%, and 54.3%, respectively. In conclusion, there are significant differences amongst carvedilol and its R/S enantiomers in terms of solubility, intestine absorption, and biliary excretion abilities. The first pass effect is the primary reasons for the low bioavailability of S-carvedilol. Therefore, pharmaceutical strategies or parenteral routes should be considered to avoid the first pass metabolism.

Optimization of lipid materials in the formulation of S-carvedilol self-microemulsifying drug-delivery systems.

OBJECTIVES: The blocking effect of S-carvedilol (S-CAR) on the beta-adrenoceptor is about 100 times stronger than that of the right-handed conformation. However, further development is restricted because of its poor bioavailability caused by its low solubility and high first-pass effect. In the study, S-CAR self-microemulsifying drug-delivery systems (SMEDDSs) were established, and the effects of different lipid materials on the absorption and metabolism of S-CAR were investigated. METHODS: Six kinds of lipid materials with different chemical structures including oleic acid, glycerol monooleate, glycerol trioleate, oleoyl macrogol-6 glycerides, soybean lecithin, and α-tocopherol were selected to be the oil phase. The S-CAR SMEDDSs were prepared by the same ratio. In vitro characteristics, in vitro release, in situ intestine absorption, and bile excretion, as well as the in vivo characteristic of relative bioavailability, were determined. KEY FINDINGS: The lipid structure significantly affected physical characteristics, the absorption and excretion rates of S-CAR SMEDDSs. The findings of rat-intestine perfusion experiments showed that the S-CAR SMEDDSs decreased the bile-excretion rate of S-CAR. Compared with the S-CAR group, the oleic acid and soybean lecithin groups decreased the bile excretion to 32% and 45%, respectively. Pharmacokinetic studies showed that the AUCs of these two groups were about 1.9 and 1.7 times more than that of the S-CAR group, and the mean retention time was extended. CONCLUSION: The SMEDDS using ionic lipids (oleic acid or soybean lecithin) as oil phase can increase the oral bioavailability of S-CAR by increasing the solubility and reducing the first-pass effect.

Role of Glucose Transporters in Drug Membrane Transport.

BACKGROUND: Glucose is the main energy component of cellular activities. However, as a polar molecule, glucose cannot freely pass through the phospholipid bilayer structure of the cell membrane. Thus, glucose must rely on specific transporters in the membrane. Drugs with a similar chemical structure to glucose may also be transported through this pathway. METHODS: This review describes the structure, distribution, action mechanism and influencing factors of glucose transporters and introduces the natural drugs mediated by these transporters and drug design strategies on the basis of this pathway. RESULTS: The glucose transporters involved in glucose transport are of two major types, namely, Na+-dependent and Na+-independent transporters. Glucose transporters can help some glycoside drugs cross the biological membrane. The transmembrane potential is influenced by the chemical structure of drugs. Glucose can be used to modify drugs and improve their ability to cross biological barriers. CONCLUSION: The membrane transport mechanism of some glycoside drugs may be related to glucose transporters. Glucose modification may improve the oral bioavailability of drugs or achieve targeted drug delivery.

Molecular dynamics simulations of adsorption and desorption of bone morphogenetic protein-2 on textured hydroxyapatite surfaces.

Interactions between bone morphogenetic protein-2 (BMP-2) and biomaterial surfaces are of great significance in the fields of regenerative medicine and bone tissue engineering. In this work, the adsorption and desorption behaviors of BMP-2 on a series of nano-textured hydroxyapatite (HAP) surfaces were systematically investigated by combined molecular dynamic (MD) simulations and steered molecular dynamic (SMD) simulations. The textured HAP surfaces exhibited nanostructured topographies and played a critical role in the mediation of dynamic behaviors of BMP-2. Compared to the HAP-flat model, the HAP-1:1 group (means ridge vs groove = 1:1) showed the excellent ability to capture BMP-2, less conformation change of BMP-2 molecule, and high cysteine-knot stability during the adsorption and desorption processes. These findings suggest that nano-textured HAP surfaces are more capable of loading BMP-2 molecules, and most importantly, they can help maintain a higher biological activity of BMP-2 cargos. In the present study, for the first time, we have deeply clarified the adsorption and desorption dynamics of BMP-2 on various nano-textured HAP surfaces at the atomic level, which can provide significant guidelines for the future design of BMP-2-based tissue engineering implants/scaffolds. STATEMENT OF SIGNIFICANCE: By using combined molecular dynamic (MD) simulations and steered molecular dynamic (SMD) simulations, the adsorption and desorption dynamics of bone morphogenetic protein-2 (BMP-2) dimer on a series of nano-textured hydroxyapatite (HAP) surfaces at the atomic level were presented in details for the first time. We have proved that the HAP-1:1 model (means ridge vs groove = 1:1) possessed excellent ability to capture BMP-2, less conformation change, and high cysteine-knot stability. As a result, the nano-textured topography of HAP-1:1 could maintain a relatively high biological activity of BMP-2 cargos. This work could provide theoretical guidelines for the design of BMP-2-based implants/scaffolds for bone tissue engineering.

Localization and promotion of recombinant human bone morphogenetic protein-2 bioactivity on extracellular matrix mimetic chondroitin sulfate-functionalized calcium phosphate cement scaffolds.

Localization of recombinant human bone morphogenetic protein-2 (rhBMP-2) with continuous and effective osteogenic stimulation is still a great challenge in the field of bone regeneration. To achieve this aim, rhBMP-2 was tethered on chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) scaffolds through specific noncovalent interactions. CS, one of the core glycosaminoglycans, was covalently conjugated onto CPC scaffolds with the assistance of polydopamine (PDA) and further immobilized rhBMP-2 in a biomimetic form. The CPC-PDA-CS scaffolds not only controlled the release kinetics and presentation state of rhBMP-2 but also effectively increased the expression levels of bone morphogenetic protein receptors (BMPRs) and enhanced the recognitions of the remaining rhBMP-2 to BMPRs. Strikingly, the rhBMP-2-loaded CPC-PDA-CS significantly promoted the cellular surface translocation of BMPRs (especially BMPR-IA). In vivo studies demonstrated that, compared with the rhBMP-2 upon CPC and CPC-PDA, the rhBMP-2 upon CPC-PDA-CS exhibited sustained release and induced high quality and more ectopic bone formation. Collectively, these results suggest that rhBMP-2 can be localized within CS-functionalized CPC scaffolds and exert continuous, long-term, and effective osteogenic stimulation. Thus, this work could provide new avenues in mimicking bone extracellular matrix microenvironment and localizing growth factor activity for enhanced bone regeneration. STATEMENT OF SIGNIFICANCE: A bioinspired chondroitin sulfate (CS)-functionalized calcium phosphate cement (CPC) platform was developed to tether recombinant human bone morphogenetic protein-2 (rhBMP-2), which could exhibit continuous, long-term, and effective osteogenic stimulation in bone tissue engineering. Compared with rhBMP-2-loaded CPC, the rhBMP-2-loaded CPC-polydopamine-CS scaffolds induced higher expression of bone morphogenetic protein receptors (BMPRs), greater cellular surface translocation of bone morphogenetic protein receptor-IA, higher binding affinity of BMPRs/rhBMP-2, and thus higher activation of the drosophila gene mothers against decapentaplegic protein-1/5/8 (Smad1/5/8) and extracellular-regulated protein kinases-1/2 (ERK1/2) signaling. This work can provide new guidelines for the design of BMP-2-based bioactive materials for bone regeneration.

Dual-generation dendritic mesoporous silica nanoparticles for co-delivery and kinetically sequential drug release.

Although multi-drug synergetic therapy is increasingly important in clinical application, sophisticated delivery systems with the ability to deliver multiple drugs and realize sequential release with independently tunable kinetics at different stages are highly desirable. In this study, a dual-generation mesoporous silica nanoparticle (DAMSN) with three-dimensional dendrimer-like structure as an adaptable dual drug delivery system is developed. The DAMSN was synthesized via a heterogeneous interfacial reaction and was of uniformly spherical morphology (150-170 nm) with dendritic structures and hierarchical pores (inner pore, 3.5 nm; outer pore, 8.3 nm). And the inner generation of DAMSN was modified with 3-aminopropyltriethoxysilane (APTMS). The IBU and BSA as model drugs were loaded into the inner generation via covalent conjugation and the outer generation by electrostatic adsorption, respectively. Intriguingly, DAMSN underwent a rapid bio-degradation for about 4 days, partly due to its center-radial dendritic channel structure. The release results showed that IBU was of a typical two-phase release profile with almost zero release in the first 12 h and more sustained release for the following 88 h, while BSA was sustained over a long period of 100 h. Notably, the release behaviors of both drugs can be independently tailored by changing the intrinsic properties of the DAMSN. In addition, DAMSN exhibited good bio-compatibility. These results indicated that the dual-generation, dendrimer-like MSN structure could spatiotemporally present different drugs to realize sequential drug release, and has potential use in the field of tissue engineering and regenerative medicine.

Strontium doping promotes bioactivity of rhBMP-2 upon calcium phosphate cement via elevated recognition and expression of BMPR-IA.

Preserving and improving osteogenic activity of bone morphogenetic protein-2 (BMP-2) upon implants remains one of the key limitations in bone regeneration. With calcium phosphate cement (CPC) as model, we have developed a series of strontium (Sr)-doped CPC (SCPC) to address this issue. The effects of fixed Sr on the bioactivity of recombinant human BMP-2 (rhBMP-2) as well as the underlying mechanism were investigated. The results suggested that the rhBMP-2-induced osteogenic activity was significantly promoted upon SCPCs, especially with a low amount of fixed Sr (SrCO3 content <10wt%). Further studies demonstrated that the Sr-induced enhancement of bioactivity of rhBMP-2 was related to an elevated recognition of bone morphogenetic protein receptor-IA (BMPR-IA) to rhBMP-2 and an increased expression of BMPR-IA in C2C12 model cells. As a result, the activations of BMP-induced signaling pathways were different in C2C12 cells incubated upon CPC/rhBMP-2 and SCPCs/rhBMP-2. These findings explicitly decipher the mechanism of SCPCs promoting osteogenic bioactivity of rhBMP-2 and signify the promising application of the SCPCs/rhBMP-2 matrix in bone regeneration implants.

Magnesium modification up-regulates the bioactivity of bone morphogenetic protein-2 upon calcium phosphate cement via enhanced BMP receptor recognition and Smad signaling pathway.

Efficient presentation of growth factors is one of the great challenges in tissue engineering. In living systems, bioactive factors exist in soluble as well as in matrix-bound forms, both of which play an integral role in regulating cell behaviors. Herein, effect of magnesium on osteogenic bioactivity of recombinant human bone morphogenetic protein-2 (rhBMP-2) was investigated systematically with a series of Mg modified calcium phosphate cements (xMCPCs, x means the content of magnesium phosphate cement wt%) as matrix model. The results indicated that the MCPC, especially 5MCPC, could promote the rhBMP-2-induced in vitro osteogenic differentiation via Smad signaling of C2C12 cells. Further studies demonstrated that all MCPC substrates exhibited similar rhBMP-2 release rate and preserved comparable conformation and biological activity of the released rhBMP-2. Also, the ionic extracts of MCPC made little difference to the bioactivity of rhBMP-2, either in soluble or in matrix-bound forms. However, with the quartz crystal microbalance (QCM), we observed a noticeable enhancement of rhBMP-2 mass-uptake on 5MCPC as well as a better recognition of the bound rhBMP-2 to BMPR IA and BMPR II. In vivo results demonstrated a better bone regeneration capacity of 5MCPC/rhBMP-2. From the above, our results demonstrated that it was the Mg anchored on the underlying substrates that tailored the way of rhBMP-2 bound on MCPC, and thus facilitated the recognition of BMPRs to stimulate osteogenic differentiation. The study will guide the development of Mg-doped bioactive bone implants for tissue regeneration.

Facilitated receptor-recognition and enhanced bioactivity of bone morphogenetic protein-2 on magnesium-substituted hydroxyapatite surface.

Biomaterial surface functionalized with bone morphogenetic protein-2 (BMP-2) is a promising approach to fabricating successful orthopedic implants/scaffolds. However, the bioactivity of BMP-2 on material surfaces is still far from satisfactory and the mechanism of related protein-surface interaction remains elusive. Based on the most widely used bone-implants/scaffolds material, hydroxyapatite (HAP), we developed a matrix of magnesium-substituted HAP (Mg-HAP, 2.2 at% substitution) to address these issues. Further, we investigated the adsorption dynamics, BMPRs-recruitment, and bioactivity of recombinant human BMP-2 (rhBMP-2) on the HAP and Mg-HAP surfaces. To elucidate the mechanism, molecular dynamic simulations were performed to calculate the preferred orientations, conformation changes, and cysteine-knot stabilities of adsorbed BMP-2 molecules. The results showed that rhBMP-2 on the Mg-HAP surface exhibited greater bioactivity, evidenced by more facilitated BMPRs-recognition and higher ALP activity than on the HAP surface. Moreover, molecular simulations indicated that BMP-2 favoured distinct side-on orientations on the HAP and Mg-HAP surfaces. Intriguingly, BMP-2 on the Mg-HAP surface largely preserved the active protein structure evidenced by more stable cysteine-knots than on the HAP surface. These findings explicitly clarify the mechanism of BMP-2-HAP/Mg-HAP interactions and highlight the promising application of Mg-HAP/BMP-2 matrixes in bone regeneration implants/scaffolds.

Nanostructured hydroxyapatite surfaces-mediated adsorption alters recognition of BMP receptor IA and bioactivity of bone morphogenetic protein-2.

Highly efficient loading of bone morphogenetic protein-2 (BMP-2) onto carriers with desirable performance is still a major challenge in the field of bone regeneration. Till now, the nanoscaled surface-induced changes of the structure and bioactivity of BMP-2 remains poorly understood. Here, the effect of nanoscaled surface on the adsorption and bioactivity of BMP-2 was investigated with a series of hydroxyapatite surfaces (HAPs): HAP crystal-coated surface (HAP), HAP crystal-coated polished surface (HAP-Pol), and sintered HAP crystal-coated surface (HAP-Sin). The adsorption dynamics of recombinant human BMP-2 (rhBMP-2) and the accessibility of the binding epitopes of adsorbed rhBMP-2 for BMP receptors (BMPRs) were examined by a quartz crystal microbalance with dissipation. Moreover, the bioactivity of adsorbed rhBMP-2 and the BMP-induced Smad signaling were investigated with C2C12 model cells. A noticeably high mass-uptake of rhBMP-2 and enhanced recognition of BMPR-IA to adsorbed rhBMP-2 were found on the HAP-Pol surface. For the rhBMP-2-adsorbed HAPs, both ALP activity and Smad signaling increased in the order of HAP-Sin

Controlled preparation and antitumor efficacy of vitamin E TPGS-functionalized PLGA nanoparticles for delivery of paclitaxel.

Vitamin E TPGS-functionalized polymeric nanoparticles have been developed as a promising drug delivery platform in recent years. Obtaining reproducible monodisperse TPGS/polymeric nanoparticles with high encapsulation efficiency (EE%) still remains a big challenge. In this study, an inverse-phase nanoprecipitation method was developed to synthesize TPGS-functionalized PLGA nanoparticles (TPNs) for controlled release of paclitaxel (PTX). To take advantages of lipids, a part of TPGS in the TPNs was replaced by lipids. The results showed that with weight ratio of TPGS-to-PLGA of 2-3 and a molar replacement of lecithin ratio of 30%, the PTX-loaded TPNs (PTPNs) and PTX-loaded lipid-containing TPNs (PLTPNs) exhibited controllable and nearly uniform size of 130-150nm and EE% of over 80%. Compared to Taxol(®), both the PTPNs and PLTPNs significantly increased the intracellular uptake and exerted strong inhibitory effect on human lung cancer A549 model cells. Furthermore, a selective accumulation to tumor site and significant antitumor efficacy of TPNs in the A549 lung cancer xenografted nude mice were observed by intravenous administration, especially for the PTPNs group. Our data suggested that the inverse-phase nanoprecipitation method holds great potential for the fabrication of the paclitaxel-loaded TPNs and the TPNs prepared here is a promising controllable delivery system for paclitaxel.