TWEAK/Fn14 promotes the proliferation and collagen synthesis of rat cardiac fibroblasts via the NF-кB pathway.

We wished to elucidate a potential role of the tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible molecule 14 (Fn14) axis in myocardial fibrosis. Stimulation of neonatal rat cardiac fibroblasts (CFs) with TWEAK could increase CFs numbers and collagen synthesis. Conversely, when CFs were pretreated with siRNA against Fn14, induction of cell proliferation and collagen synthesis by TWEAK were inhibited. Pretreatment with TWEAK on CFs induced activation of the nuclear factor-kappaB (NF-кB) pathway and subsequently increased the production of metalloproteinase-9 (MMP-9). Cell treatment with siRNA against Fn14 led to inhibition of the NF-кB pathway. Additionally, after stimulation of cell with ammonium pyrrolidine dithiocarbamate, cell proliferation and collagen synthesis induced by NF-кB and the upregulation of MMP-9 production were inhibited. The present study suggested that the TWEAK/Fn14 axis increased cell proliferation and collagen synthesis by activating the NF-кB pathway and increasing MMP-9 activity. This axis may be important for regulating myocardial fibrosis.

Dissolvable layered microneedles with core-shell structures for transdermal drug delivery.

Microneedle (MN) systems for painless transdermal drug delivery have been developed in the past few years to overcome the issues of hypodermic injections. This study introduces a novel dissolvable layered microneedle (LMN) with core-shell structure for efficient transdermal drug delivery. Fabricated by three-step-casting method, the LMNs encapsulated the drug into the HA layer as a "shell", which is supported by PVA layer as core and base. When the LMNs are inserted into the skin, the drug would be released immediately once the HA layer were separated or dissolved. What's more, little drug would be wasted on the residual base after insertion. It is demonstrated that the mechanical property of LMNs is kept well with 100% insertion percentage at 60% relative humidity. Moreover, in the transdermal delivery in vivo test, almost 90% of drug in LMNs could be successful delivered into the skin with 10s, while the homogeneous HA MNs with wide drug distribution need more than 120s to reach the same efficiency. Owing to the advantages of stable mechanical property and rapid efficient drug delivery, the LMNs are more reliable and satisfied for the self-administration in the future.

Fabrication of coated polymer microneedles for transdermal drug delivery.

As an alternative to hypodermic needles, coated polymer microneedles (MNs) are able to deliver drugs to subcutaneous tissues after being inserted into the skin. The dip-coating process is a versatile, rapid fabricating method that can form coated MNs in a short time. However, it is still a challenge to fabricate coated MNs with homogeneous and precise drug doses in the dip-coating process. In this study, to fabricate coated polymer microneedles with controlled drug loading, an adjustable apparatus that can be lifted and lowered was designed to immerse a polylactic acid (PLA) MN patch in the coating solutions. Using the coating solution containing 0.5% (w/w) sulforhodamine B, the drug loadings were up to 12ng, 14ng, and 18ng per needle for the MNs with heights of 550µm, 650µm, and 750µm, respectively. Moreover, for the MNs with a 650-µm height, when increasing the viscosity of the coating solutions from 150mPa·s to 1360mPa·s, 2850mPa·s, and 8200mPa·s, the drug loading increased from 2.5ng to 5ng, 14ng, and 22ng per needle, respectively. Meanwhile, the drug delivery efficiencies of these MNs were approximately 90%. In the insertion experiments, the MNs could successfully penetrate the skin and deliver the coated drug with approximately 90% efficiency when the MN tips were exposed to the outer environment. In vivo studies in mice indicated that the coated polymer MNs continuously delivered drugs, and the skin recovered without any injuries. These results demonstrated that the coated polymer MN was a safe and effective method for transdermal drug delivery.

Rapidly separating microneedles for transdermal drug delivery.

UNLABELLED: The applications of polymer microneedles (MNs) into human skin emerged as an alternative of the conventional hypodermic needles. However, dissolving MNs require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin, which may lead to the low drug delivery efficiency. To address these issues, we introduce rapidly separating MNs that can rapidly deliver drugs into the skin in a minimally invasive way. For the rapidly separating MNs, drug loaded dissolving MNs are mounted on the top of solid MNs, which are made of biodegradable polylactic acid which eliminate the biohazardous waste. These MNs have sufficient mechanical strength to be inserted into the skin with the drug loaded tips fully embedded for subsequent dissolution. Compared with the traditional MNs, rapidly separating MNs achieve over 90% of drug delivery efficiency in 30s while the traditional MNs needs 2min to achieve the same efficiency. With the in vivo test in mice, the micro-holes caused by rapidly separating MNs can heal in 1h, indicating that the rapidly separating MNs are safe for future applications. These results indicate that the design of rapidly separating dissolvable MNs can offer a quick, high efficient, convenient, safe and potentially self-administered method of drug delivery. STATEMENT OF SIGNIFICANCE: Polymer microneedles offer an attractive, painless and minimally invasive approach for transdermal drug delivery. However, dissolving microneedles require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin due to the skin deformation, which may lead to the low drug delivery efficiency. In this work we proposed rapidly separating microneedles which can deliver over 90% of drug into the skin in 30s. The in vitro and in vivo results indicate that the new design of these microneedles can offer a quick, high efficient, convenient and safe method for transdermal drug delivery.

A fabrication method of microneedle molds with controlled microstructures.

Microneedle (MN) offers an attractive, painless and minimally invasive approach for transdermal drug delivery. Polymer microneedles are normally fabricated by using the micromolding method employing a MN mold, which is suitable for mass production due to high production efficiency and repeat-using of the mold. Most of the MN molds are prepared by pouring sylgard polymer over a MN master to make an inverse one after curing, which is limited in optimizing or controlling the MN structures and failing to keep the sharpness of MNs. In this work we describe a fabrication method of MN mold with controlled microstructures, which is meaningful for the fabrication of polymer MNs with different geometries. Laser micro-machining method was employed to drill on the surface of PDMS sheets to obtain MN molds. In the fabrication process, the microstructures of MN molds are precisely controlled by changing laser parameters and imported patterns. The MNs prepared from these molds are sharp enough to penetrate the skin. This scalable MN mold fabrication method is helpful for future applications of MNs.

[Absorption Spectral Characteristic Dynamics of Dissolved Organic Matter (DOM) from a Typical Reservoir Lake in Inland of Three Gorges Reservoir Areas: Implications for Hg Species in Waters].

Dissolved organic matter (DOM) is an important component in lake eco-systems. It plays a crucial role in the environmental fate of pollutants such as mercury(Hg), because of its specific characteristics and functional structures. In this study, a typical reservoir lake from inland of Three Gorges Reservoir areas, Changshou Lake was selected to track the changes of DOM geochemical properties for one year by using UV-Vis absorption spectroscopy technique. Meanwhile, based on observed Hg data in Changshou Lake, it further validated the key environmental implications of DOM for Hg distributions in lake. The results showed that as compared to January, other months including April, June and September had significantly higher CDOM, but also higher DOC with a slightly decreasing significance. Dynamics of chromphoric component is an important reason to explain the seasonal changes of DOM concentration in Changshou Lake. Chromphores of DOM were mainly derived from high molecular weight (MW) materials with high aromaticity. Also, three wavelengths fitting model of CDOM could be used for inversion of DOC concentration in annual monitoring. Meanwhile, seasonal differences of SUVA254 and S275-295 were significant. Lowest aromaticity and MW size were observed in January following an obvious increase from April. In contrast to other types of lakes, DOM aromaticity and MW size in Changshou Lake were lower than forest lakes, but higher than plateau lakes. Eco-system and land use types surrounding lakes could have a heavily impact on the heterogeneous properties of DOM. Importantly, no clear differences between concentrations of Hg species and SUVA254 and DOC respectively were observed, however chromphoric component and MW size controlled the dissolved Hg and reactive Hg in lake. Additionally, enrichment and migration of organic matter resulted from primary productivity in lake may be a substantial reason to explain the methylmercury changes.

Microneedles with Controlled Bubble Sizes and Drug Distributions for Efficient Transdermal Drug Delivery.

Drug loaded dissolving microneedles (DMNs) fabricated with water soluble polymers have received increasing attentions as a safe and efficient transdermal drug delivery system. Usually, to reach a high drug delivery efficiency, an ideal drug distribution is gathering more drugs in the tip or the top part of DMNs. In this work, we introduce an easy and new method to introduce a bubble with controlled size into the body of DMNs. The introduction of bubbles can prevent the drug diffusion into the whole body of the MNs. The heights of the bubbles are well controlled from 75 µm to 400 µm just by changing the mass concentrations of polymer casting solution from 30 wt% to 10 wt%. The drug-loaded bubble MNs show reliable mechanical properties and successful insertion into the skins. For the MNs prepared from 15 wt% PVA solution, bubble MNs achieve over 80% of drug delivery efficiency in 20 seconds, which is only 10% for the traditional solid MNs. Additionally, the bubble microstructures in the MNs are also demonstrated to be consistent and identical regardless the extension of MN arrays. These scalable bubble MNs may be a promising carrier for the transdermal delivery of various pharmaceuticals.

[Spectral Characteristics of Dissolved Organic Matter (DOM) Releases from Soils of Typical Water-Level Fluctuation Zones of Three Gorges Reservoir Areas:UV-Vis Spectrum].

Water-level fluctuation zone is an important area in Three Gorges Reservoir areas, because dissolved organic matter (DOM) releases from submerged soils is a crucial source of DOM in overlying waters when flooding occurs. But there was little qualitative and quantitative analysis for DOM. In this study, soils of four typical water-level fluctuation zones were selected to conduct simulated flooding experiment. Also, UV-Vis spectroscopy was utilized to investigate the DOM spectral characteristics in two individual flooding sets including ambient (open air) and anoxic conditions. The results showed, for all soils, the DOM release patterns all showed a "rapid release, then decrease, and final dynamic equilibrium" trend. Also, through calculations of DOM releasing rates and fluxes, DOM releases clearly showed a feature of "source-sink dynamic exchange". By comparison between two flooding treatments, although DOC and CDOM didn't show any significant differences, but higher aromaticity (SUVA280) was observed in anoxic experiment. In contrast, spectra slope ratio (SR) was insensitive to redox conditions of different flooding. Meanwhile, correlation between DOC and CDOM in anoxic was also higher than that in ambient flooding. Additionally, obvious differences among soils from different sampling sites were observed, Shibao Zhai (SB) of which showed the greatest releasing potential. Considering the various soil properties, soil organic matter amounts in soils is one of the key factors to explain the differences among sampling sites, but other geochemical factors should also be considered in the processes of DOM releases. Summarily, only focusing on the changes of DOC concentrations in submerging process is not enough to comprehensively describe the DOM release characteristics.

[Spectral Characteristics of Dissolved Organic Matter (DOM) Releases from Soils of Typical Water-Level Fluctuation Zones of Three Gorges Reservoir Areas:Fluorescence Spectra].

As an important sources of dissolved organic matter (DOM) in aquatic system, DOM releases from flooding or submerged soils is a key process in water-level fluctuation zones. In this study, four typical sites in water-level fluctuation zones of Three Gorges Reservoir areas were selected to conduct simulated soil flooding experiments, under ambient (open air) and anoxic conditions. By using fluorescence spectrum technique, the dynamic and geochemical characteristics of DOM releases from flooding soils were investigated. Results showed that the trend or model of DOM releases observed by fluorescence spectrum in all soils from four sampling sites was similar to the observation by UV-Vis spectrum. Fluorescence property of DOM releases showed an important contribution to DOM fluorescence in overlying waters. The rapid releases at initial stage and removal mechanism for later dynamic equilibrium were crucial to explain the dynamic "source-sink" equilibrium in whole flooding period. Effect of inorganic mineral adsorption-desorption on humic-like components (A and C peaks) was significant. Also, impact of microbial utilization on protein-like components (B and T peaks) was confirmative. Additionally, all DOM samples had "autochthonousness plus allochthonousness" property. Except Shibaozhai (SB) site in Zhongxian county, during the whole flooding period, all three other sites didn't show any significant difference between ambient and anoxic conditions. They could be explained by the high heterogeneity of soil property including minerals and organic components. Meanwhile, both the UV-Vis and fluorescence spectra were complementary for each other, and they evidentially showed that the "source-sink" (release and removal) mechanism in DOM releases from submerged soils was the core to decide the dynamics of DOM in overlying waters. Importantly, DOM showed higher aromaticity and humification at the initial release stage when flooding occurred, as well as the greater terrestrial source characteristics, which further helped to explain the environmental fates of pollutants in these environmental sensitive areas. It would also be useful for unveiling the role of DOM in environmental system in future.

[Spectral Characteristics of Dissolved Organic Matter (DOM) in Waters of Typical Agricultural Watershed of Three Gorges Reservoir Areas].

As a key geochemical factor in earth system, dissolved organic matter (DOM) plays an important role in controlling environmental quality of watersheds. In this study, a typical agricultural watershed of Three Gorges reservoir areas, Wangjiagou watershed in Fuling district of Chongqing, was selected to characterize DOM in waters through fluorescence and UV-Vis spectroscopy, while the effect of land-use types in this watershed was discussed. The results showed large spatial variances of aquatic DOM in this watershed, with significant differences in compositions and sources. After calculation of ag*(355) for indicating proportion of chromophoric DOM in bulk DOM, the order of DOM was paddy rice field> ditch> pond> well> outlet point. DOM samples from paddy rice field and ditch showed higher SUVA254 suggesting higher aromaticity. DOM from this watershed showed 2 typical types (4 peaks A, C, B and T) of fluorescent components including humic-like and protein-like components. Dual contributions from autochthonous (e.g., microbial or alga production) and allochthonous both heavily affected the DOM characteristics. Besides active microbial activities due to high organic and nutrients inputs from agricultures, discharge of sewage and water used in agricultural production could contribute proteins possibly inducing ascending proportion of protein-like component as shown in fluorescence analysis. DOM samples from the same sampling points but in different crop plantation seasons were collected to compare, for understanding the differences between two planting seasons. It clearly suggested protein-like component was the key variable to control the DOM dynamics. After land-use changing from rice/corn into mustard plantation, all of DOC, CDOM and r(T/C)showed significant differences, but no such observations were observed in FI, BIX and r(A/C).

[Ultraviolet-visible (UV-Vis) and fluorescence spectral characteristics of soil dissolved organic matter (DOM) in typical agricultural watershed of Three Gorges Reservoir Region].

As an important geo-factor to decide the environmental fate of pollutants in watershed, soil dissolved organic matter (DOM) sampled from a typical agricultural watershed in the Three Gorges Reservoir area was investigated using ultraviolet-visible (UV-Vis) and fluorescence spectroscopies, to analyze and discuss the effect of different land uses including forest, cropland, vegetable field and residence, on soil DOM geochemical characteristics. The results showed that significant differences in DOM samples amongst different land uses were observed, and DOM from forest had the highest aromaticity and humification degree, followed by DOM from cropland. Although DOM from vegetable field and residence showed the highest dissolved organic carbon (DOC) concentration (average values 0.81 g x kg(-1) and 0.89 g x kg(-1), respectively), but the aromaticity was lower indicating lower humification, which further suggested that the non-chromophoric component in these DOM samples contributed significantly to total DOM compositions. Additionally, in all DOM samples that were independent of land uses, fluorescence index (FI) values were between 1.4 (terrigenous) and 1.9 (authigenic) , evidently indicating both the allochthonous and autochthonous sources contributed to DOM characteristics. Meanwhile, r(T/C) values in most of samples were higher than 2.0, suggesting that soil DOM in this agricultural watershed was heavily affected by anthropogenic activities such as agricultural cultivation, especially, vegetable field was a good example. Additionally, sensitivities of different special spectral parameters for reflecting the differences of DOM characteristics amongst different land uses were not identical. For example, neither spectral slope ratio (S(R)) nor humification index (HIX) could clearly unveil the various geochemical characteristics of soil DOM from different sources. Thus, simple and single special spectral parameter cannot comprehensively provide the detailed information of DOM, and combined application of UV-Vis and fluorescence spectroscopies is highly recommended.

[Absorption and fluorescence characteristics of dissolved organic matter (DOM) in rainwater and sources analysis in summer and winter season].

This study aimed at evaluating the variability of the optical properties including UV-Vis and fluorescence characteristics of dissolved organic matter (DOM) from rainwater in summer and winter seasons. UV-Vis and fluorescence spectroscopy, together with Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model and fire events map, were conducted to characterize DOM and investigate its sources and contributions. The results showed that as compared with aquatic and soil DOM, rainwater DOM showed similar spectral characteristics, suggesting DOM in precipitation was also an important contributor to DOM pool in terrestrial and aquatic systems. The concentrations of DOC in rainwater were 0.88-12.80 mg x L(-1), and the CDOM concentrations were 3.17-21.11 mg x L(-1). Differences of DOM samples between summer and winter were significant (P < 0.05). In comparison to summer, DOM samples in winter had lower molecular weight and aromaticity, and also lower humification. Input of DOM in winter was predominantly derived from local and short-distance distances, while non-special scattering sources were identified as the main contributors in summer. Although absorption and fluorescence spectroscopy could be used to identify DOM composition and sources, there were obvious differences in spectra and sources analysis between rainwater DOM and the others from other sources. Thus, the classic differentiation method by "allochthonous (terrigenous) and autochthonous (authigenic)" is possibly too simple and arbitrary for characterization of DOM in rainwater.

Mesoscopic simulation studies on the formation mechanism of drug loaded polymeric micelles.

In this work, the formation of polymeric micelles as drug delivery vehicles in an aqueous environment is investigated by dissipative particle dynamics (DPD) simulations. Doxorubicin (DOX) is selected as the model drug, whereas docosahexaenoic acid (DHA) conjugated His10Lys10 (DHA-His10Lys10) as the drug carrier. It is shown from DPD simulation that drug molecules and DHA-His10Lys10 molecules could aggregate and form micelles under a defined composition recipe; drug molecules are homogeneously distributed inside the carrier matrix, on whose surface the stabilizer lysine segments are absorbed. Under different compositions of drug and water, aggregate morphologies of polymeric micelles are observed as spherical, columnar, and lamellar structures. We finally proposed the formation mechanism of drug loaded polymeric micelles and apply it in practice by analyzing the simulated phenomena. All the results can effectively guide the experimental preparation of drug delivery system with desired properties or explore a novel polymeric micelle with high performance.