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Background: The use of dexmedetomidine rather than midazolam may improve ICU outcomes. We summarized the available recent evidence to further verify this conclusion. Methods: An electronic search of PubMed, Medline, Embase, Cochrane Library, and Web of Science was conducted. Risk ratios (RR) were used for binary categorical variables, and for continuous variables, weighted mean differences (WMD) were calculated, the effect sizes are expressed as 95% confidence intervals (CI), and trial sequential analysis was performed. Results: 16 randomized controlled trials were enrolled 2035 patients in the study. Dexmedetomidine as opposed to midazolam achieved a shorter length of stay in ICU (MD = -2.25, 95%CI = -2.94, -1.57, p<0.0001), lower risk of delirium (RR = 0.63, 95%CI = 0.50, 0.81, p = 0.0002), and shorter duration of mechanical ventilation (MD = -0.83, 95%CI = -1.24, -0.43, p<0.0001). The association between dexmedetomidine and bradycardia was also found to be significant (RR 2.21, 95%CI 1.31, 3.73, p = 0.003). We found no difference in hypotension (RR = 1.44, 95%CI = 0.87, 2.38, P = 0.16), mortality (RR = 1.02, 95%CI = 0.83, 1.25, P = 0.87), neither in terms of adverse effects requiring intervention, hospital length of stay, or sedation effects. Conclusions: Combined with recent evidence, compared with midazolam, dexmedetomidine decreased the risk of delirium, mechanical ventilation, length of stay in the ICU, as well as reduced patient costs. But dexmedetomidine could not reduce mortality and increased the risk of bradycardia. [ABSTRACT FROM AUTHOR]

A switched Boolean network (SBN) is an important model for describing hybrid phenomena in gene regulatory networks, and it has received increasing attention since the development of the semi-tensor product of matrices. This paper aims to present a comprehensive survey on SBNs. First, the fundamental issues for SBNs with arbitrary switching signals are reviewed, including stability, stabilisation, controllability, observability, optimal control, and synchronisation. Next, a brief review of the stability analysis of SBNs with constrained switching, consisting of time-dependent switching, state-dependent switching, and logical switching, is given. In addition, some basic results on the SBNs under non-ideal conditions are also introduced comprehensively. [ABSTRACT FROM AUTHOR]

Stability analysis is the most basic and important problem of dynamic systems, which has been extensively studied in the last few decades. The research on finite-time stability and stability in distribution of k-valued logical networks (KVLNs) with Markov jump disturbances (MJDs) is considered in this paper. To begin with, we establish an equivalent Markov jump system for the considered KVLNs with MJDs via semi-tensor product (STP) of matrices, which can simplify the stability analysis of KVLNs with MJDs. Next, two criteria are proposed for finite-time stability and stability in distribution of KVLNs with MJDs, respectively. At last, the validity of the obtained results is illustrated by simulation on the apoptosis network. [ABSTRACT FROM AUTHOR]

This paper studies the optimal control of n-person random evolutionary Boolean games (REBGs). Firstly, the considered n-person REBG is converted to an equivalent stochastic control system by using the semi-tensor product of matrices. Secondly, based on the equivalent stochastic control system, an algorithm is proposed to solve the finite horizon optimal control problem of n-person REBGs, which is applied to the Mayer-type optimal control problem. Thirdly, using the receding horizon control method, the infinite horizon optimal control problem is considered, and an algorithm is established. Finally, an illustrate example is given to support the obtained results. [ABSTRACT FROM AUTHOR]

Background Clinical disagreement over antiplatelet (AP) resumption in patients with primary intracranial hemorrhage (ICH) has long existed. This meta-analysis aimed to evaluate the benefits of AP resumption on preventing ischemic or thromboembolic events against its risks of promoting ICH recurrence or hematoma expansion. Methods All relevant articles published in Pubmed, EMBASE, the Cochrane Library, and Science Direct from January 1950 to March 2017 were sourced, and the combined relative risk (RR) was calculated. Results A total of 3648 articles were found, and after screening, 6 cohort studies including 1916 patients were included in this meta-analysis. AP resumption was associated with a decreased risk of ischemic or thromboembolic events (RR, 0.61; 95% confidence interval (CI), 0.48–0.79; P < 0.01). There was no significant difference in the risk of ICH recurrence or hematoma expansion between patients with or without AP resumption (RR, 0.84; 95% CI, 0.47–1.51; P = 0.56). Conclusion AP resumption in patients with primary ICH reduced the risk of ischemic or thromboembolic events, without significant increase of risk of ICH recurrence or hematoma expansion. [ABSTRACT FROM AUTHOR]

Using the algebraic state space representation, this paper studies the robust consensus of networked evolutionary games (NEGs) with attackers and forbidden profiles. Firstly, an algebraic form is established for NEGs with attackers and forbidden profiles. Secondly, based on the algebraic form, a necessary and sufficient condition is presented for the robust constrained reachability of NEGs. Thirdly, a series of robust reachable sets is constructed by using the robust constrained reachability, based on which a constructive procedure is proposed to design state feedback controls for the robust consensus of NEGs with attackers and forbidden profiles. Finally, an illustrative example is given to show that the main results are effective. [ABSTRACT FROM AUTHOR]

This study studies the stochastic set stabilisation of an n ‐person random evolutionary Boolean game (REBG). Firstly, the definition of stochastic set stabilisation has been proposed, and the n ‐person REBG is converted to an equivalent algebraic form by using the semi‐tensor product of matrices. Secondly, by defining a series of stochastic reachable sets, a necessary and sufficient condition is presented for the state feedback stochastic set stabilisation of n ‐person REBG. Thirdly, based on the concept of uniformly one‐step reachability with probability one, a constructive procedure is proposed for the calculation of stochastic reachable sets. Finally, as two applications of stochastic set stabilisation, the output tracking control and the strategy consensus of n ‐person REBG are investigated, respectively, and two necessary and sufficient conditions are presented. [ABSTRACT FROM AUTHOR]

Abstract: Thymopentin (TP5), a synthetic pentapeptide, has been used in clinic as a modulator for immunodeficiences through intramuscular administration. The purpose of this study was to design and evaluate dry powder inhalations (DPIs) for pulmonary delivery of TP5. Dry powder inhalations containing leucine (a dispersibility enhancer), mannitol, and lactose (bulking agents) were prepared by spray-drying from aqueous formulations. The formulation components on the aerosolisation characteristics of spray-dried powders were investigated through the use of various amount of leucine, lactose and mannitol. Following spray-drying, resultant powders were characterized using scanning electron microscopy, laser diffraction and tapped density measurements, and the aerosolisation performance was determined using Twin Stage Impinger. The immunosuppression Wistar rats model was constructed to evaluate the immunomodulating effects of TP5 DPIs in vivo. The results of T-lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+ ratio) analyses suggest that TP5 DPIs have modulating effects. On an overall evaluation, TP5 pulmonary delivery DPIs may be feasible for the future clinical application. [Copyright &y& Elsevier]

This article investigates the stability of probabilistic Boolean networks (PBNs) and switched Boolean networks (SBNs). To begin with, a unique Boolean network is presented with both stochastic signal and switching signal. It is then converted to algebraic form using semi-tensor product. An important concept named "existed path" is proposed, and further a novel method based on eigenvalue and trace-based method is used to derive some necessary and sufficient stability criteria for the first time. Moreover, these criteria are extended to include ordinary PBNs and SBNs. Finally, several examples are given to illustrate the main results. • A unique Boolean network is presented with both stochastic signal and switching signal. • Eigenvalue and trace-based method is used to derive stability criteria. • These criteria are extended to ordinary PBNs and SBNs. [ABSTRACT FROM AUTHOR]

The pharmacodynamics in patients with high body fat percentage might be similar to those in obese patients. This randomised controlled clinical trial observed the effects of rocuronium in patients with different percent body fats (PBFs). Fifty‐four patients who underwent elective urological or pelvic surgery under general anaesthesia at Shanghai General Hospital were included in the present study; 51 patients were included for data analysis. Patients with normal PBF (<25%) were given a single dose of rocuronium calculated based on total body weight (N‐TBW, control group). Patients with a higher PBF (≥25%) were given a single dose of rocuronium calculated based on total body weight (H‐TBW). Patients with higher PBF and rocuronium were dosed based on fat‐free mass (H‐FFM). A train of four (TOF)‐Watch acceleromyography monitor was used to measure the effects of the rocuronium. H‐TBW (91.9 ± 28.8 s) had significantly shorter onset time than N‐TBW and H‐FFM (p = 0.003). H‐TBW had significantly longer clinical duration time and pharmacological duration time than the other groups (p = 0.000 and 0.000, respectively); the TOF ratio0.25–0.9 time was significantly different among the three groups (p = 0.005). There were no significant differences in the recovery time (p = 0.103) or recovery index (p = 0.159) among the three groups. The effects of rocuronium dosed based on FFM in patients with high PBFs are similar to those in normal patients. A single dose of rocuronium calculated based on TBW might shorten the onset time, prolong the clinical and pharmacological duration times, and prolong the recovery time. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is the most common cause of cardiovascular morbidity and mortality worldwide. Despite the identification of many pathogenic genes associated with MI, the underlying molecular mechanisms remain poorly understood. MicroRNAs (miRNAs, miRs), which regulate target genes at the post-transcriptional level, play a significant role in the regulation of cardiovascular diseases such as MI. Pyroptosis is a caspase-1-dependent pro-inflammatory programmed cell death (PCD) mechanism. The role of pyroptosis in several diseases associated with various miRNAs has been studied extensively. Meanwhile, the role of NOD-like receptor-containing pyrin 3 (NLRP3)/caspase-1/interleukin-1β (IL-1β) pathway in cardiac diseases has also been more recognized. We established a mice MI model which ligated with the left anterior descending coronary artery and a cardiomyocytes injury model treated by hydrogen peroxide (H 2 O 2) to detect the expressions of miR-135b and NLRP3/caspase-1/IL-1β pathway. Then miR-135b mimic, agomir-135b, and α-MHC-miR-135b transgenic mice were used to evaluate the effects of miR-135b overexpression. We demonstrated that miR-135b was downregulated after cardiomyocytes injury both in vivo and in vitro. Pyroptosis pathway was also activated. MiR-135b overexpression remarkably restored impaired cardiac function and attenuated the upregulation of NLRP3/caspase-1/IL-1β pathway. The present findings shed light on the protective role of miR-135b in MI mediated by the inhibition of the NLRP3/caspase-1/IL-1β pathway. • NLRP3/caspase-1/IL-1β pathway is activated in MI model. • MiR-135b could inhibit pyroptosis by targeting caspase-1 during MI. • MiR-135b plays a protective role in MI. • MiR-135b alleviates MI injury by inhibiting the NLRP3/caspase-1/IL-1β pathway. [ABSTRACT FROM AUTHOR]

Abstract This paper analyzes the finite-time stability of stochastic switched Boolean networks (SBNs) with impulsive effect. Using the algebraic state space representation (ASSR) approach, the dynamics of SBNs with impulsive effect is converted to an algebraic form. Based on the algebraic form, some necessary and sufficient conditions are presented for the finite-time stability of stochastic SBNs with impulsive effect, including probabilistic switching signal case and Markov jump switching signal case. The study of an illustrative example shows that the obtained new results are effective. [ABSTRACT FROM AUTHOR]

• Pre-transplantation of hUCMSCs had a better therapeutic effect on ALF rats, providing empirical evidence for preclinical studies. • hUCMSCs ameliorated ALF by anti-inflammation, promoting hepatocyte regeneration, and suppressing liver injury in rats. • The timing of hUCMSCs administration should be considered a critical parameter in the application of hUCMSCs therapy in ALF patients. Acute liver failure (ALF) is characterized by an intense systemic inflammatory response, single or multiple organ system failure and high mortality. However, specific and effective treatments for ALF patients are still lacking. According to the current investigation, human umbilical cord mesenchymal stem cells (hUCMSCs) have shown remarkable potential to enhance the functional recovery of injured livers. We aimed to investigate the therapeutic effects of time-differentiated hUCMSCs administration regimens on ALF. The rat model of ALF was induced by D-galactosamine (D-gal), and hUCMSCs were administered via the tail vein 12 h before or 2 h after induction. The potential mechanisms of hUCMSCs in treatment of ALF, regulation cell subset and secretion of inflammatory factors, were verified by co-culturing with PBMCs in vitro. Liver function indicators were detected by an automatic biochemistry analyzer and inflammatory factors were obtained by ELISA detection. The distribution of hUCMSCs in rats after administration was followed by quantitative real-time fluorescence PCR. The findings of the study discovered that administration of hUCMSCs 12 h prior to surgery could significantly improve the survival rate of rats, stabilize various liver function indicators in serum levels of ALT, AST, T-BIL, or ALB diminish inflammatory infiltration in liver tissue, and inhibit the secretion of inflammatory factors. Our data showed that pre-transplantation of hUCMSCs had a better therapeutic effect on ALF rats, providing empirical evidence for preclinical studies. Thus, the timing of hUCMSCs transplantation is necessary for the optimal clinical treatment effect. [ABSTRACT FROM AUTHOR]

To improve gene therapeutic delivery to the central nervous system, PEG- b -PAsp(TEP)-cholesterol cationic copolymer was synthesized, then RVG29 and Tet1 peptides were exploited as ligands to construct a dual-target brain gene delivery polyion complex (Tet1/RVG29-PIC). Tet1/RVG29-PIC improved behavioral deficits in the APP/PS1 mouse model through siRNA‑mediated BACE1 silencing. Our results suggested the nanoformulation has the potential to be exploited as a multistage gene vectors for the CNS disease therapy. [Display omitted] Cleavage of Amyloid precursor protein (APP) by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting step in the production of amyloid-β (Aβ) synaptotoxins. The siRNA-mediated silencing to attenuate the expression of BACE1 to ameliorate cognitive dysfunction in mice had been investigated. To improve therapeutic gene delivery to the central nervous system, cationic copolymer poly(ethylene glycol)- b -poly[N-(N′-{N′′-[N′′′-(2-aminoethyl)-2-aminoethyl]-2-aminoethyl}-2-aminoethyl)aspartamide]-cholesterol was synthesized, then RVG29 and Tet1 peptides were exploited as ligands to construct a dual-targeting brain gene delivery polyion complex (Tet1/RVG29-PIC). The cell uptake of a coculture cell model showed that the Tet1/RVG29-PIC exhibited notable transport characteristics and possessed affinity towards nerve cells. In vivo transfection, Tet1/RVG29-PIC possessed the highest expression of luciferase in brain compared with that of RVG29-PIC or Tet1-PIC, which were 1.25 and 1.22 times respectively. Silence BACE1 expression using siRNA-expressing plasmid loaded Tet1/RVG29-PIC that improved behavioral deficits in the APP/PS1 mouse model, demonstrating the favorable brain delivery properties of Tet1/RVG29-PIC by synergistical engagement of GT1B and nicotinic acetylcholine receptors. Our results suggested that the nanoformulation has the potential to be exploited as a multistage-targeting gene vector for the CNS disease therapy. [ABSTRACT FROM AUTHOR]

This paper investigates the set stability of switched delayed logical networks (SDLNs) by using the semi-tensor product of matrices. The equivalent algebraic form of SDLNs is established, and it is proved that the set stability of SDLNs is equivalent to the set stability of the algebraic form with respect to trajectory. Based on the switching point reachability, a necessary and sufficient condition is proposed for the set stability of the algebraic form, which is also the criterion for the set stability of SDLNs. The obtained results on the set stability of SDLNs are applied to the consensus of finite-field networks (FFNs) with switching topology and time delays, and a new necessary and sufficient condition is presented for the finite-field consensus. [ABSTRACT FROM AUTHOR]

Herein we report the controllable synthesis of NaYF4:Yb3+/Er3+via mesoscale regulation through the introduction of Li+/K+ into a hydrothermal system. The crystal evolution process of β-NaYF4:Yb3+/Er3+ is investigated based on the reaction parameters. The mesoscale growth process includes four stages: (1) nucleation, (2) aggregation, (3) orientation growth, and (4) ripening. Through the introduction of Li+/K+ into the hydrothermal environment, super-small β-NaYF4:Yb3+/Er3+ upconversion nanoparticles can be obtained. [ABSTRACT FROM AUTHOR]

This paper studies the structural monostability and structural cycle‐stability of Boolean networks (BNs). Firstly, the structural‐equivalent Boolean networks are converted to the algebraic forms by using the semitensor product of matrices. Secondly, the concepts of structural monostability and structural cycle‐stability for Boolean networks are proposed. On the basis of the algebraic forms of structural‐equivalent Boolean networks, some necessary and sufficient conditions are presented for the structural monostability and structural cycle‐stability of Boolean networks. Finally, an illustrative example is worked out to show the effectiveness of the obtained results. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiac hypertrophy is a serious factor underlying heart failure. Although a large number of pathogenic genes have been identified, the underlying molecular mechanisms of cardiac hypertrophy are still poorly understood. MicroRNAs are a class of small non-coding RNAs which regulate their target genes at the post-transcriptional level. L-type calcium channels play important role in hypertrophic signaling pathways, and CACNA1C is encoded by L-type calcium channels. Here, we hypothesize that the overexpression of miR-135b can attenuate hypertrophy by targeting CACNA1C. Methods We test the functional involvement of miR-135b in cardiac hypertrophy model. In order to evaluate the effect of miR-135b in cardiac hypertrophy, miR-135b mimic, miR-135b agomir and α-MHC-miR-135b transgenic mice were used for the overexpression of miR-135b. Luciferase reporter assays were used to testify the binding of miR-135b to the CACNA1C 3′UTR. Results Our results revealed that in a pathological cardiac hypertrophy model, the expression of miR-135b was clearly downregulated. Hypertrophic marker genes were upregulated after the knockdown of miR-135b in vitro , while the overexpression of miR-135b attenuated hypertrophy. These results suggested that miR-135b may weaken hypertrophic signals. We then explored the mechanism of miR-135b in hypertrophy and identified that CACNA1C was a target gene for miR-135b. The overexpression of miR-135b attenuated cardiac hypertrophy by targeting CACNA1C. Conclusions Our studies revealed that miR-135b is a critical regulator of cardiomyocyte hypertrophy. Our findings may provide a novel strategy for the treatment of cardiac hypertrophy. Highlights • Loss expression of miR-135b was found in pathological cardiac hypertrophy models both in vivo and in vitro. • CACNA1C was a direct target gene of miR-135b. • The overexpression of miR-135b could attenuate pathological cardiac hypertrophy by targeting CACNA1C. [ABSTRACT FROM AUTHOR]

Background: Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein reported as an anti-inflammatory adipocytokine. Evidences from clinical and experimental studies revealed that brain inflammation plays important roles in epileptogenesis and seizure. Interestingly, closely relationship between ZAG and many important inflammatory mediators has been proven. Our previous study identified ZAG in neurons and found that ZAG is decreased in epilepsy and interacts with TGFβ and ERK. This study aimed to investigate the role of ZAG in seizure and explore its effect on seizure-related neuroinflammation.Methods: We overexpressed AZGP1 in the hippocampus of rats via adeno-associated virus vector injection and observed their seizure behavior and EEG after pentylenetetrazol (PTZ) kindling. The level of typical inflammation mediators including TNFα, IL-6, TGFβ, ERK, and ERK phosphorylation were determined.Results: The overexpression of AZGP1 reduced the seizure severity, prolonged the latency of kindling, and alleviated epileptiform discharges in EEG changes induced by PTZ. Overexpression of AZGP1 also suppressed the expression of TNFα, IL-6, TGFβ, and ERK phosphorylaton in PTZ-kindled rats.Conclusions: ZAG may inhibit TGFβ-mediated ERK phosphorylation and inhibit neuroinflammation mediated by TNFα and IL-6, suggesting ZAG may suppress seizure via inhibiting neuroinflammation. ZAG may be a potential and novel therapeutic target for epilepsy. [ABSTRACT FROM AUTHOR]

Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein encoded by the AZGP1 gene that is known as a lipid mobilizing factor and is highly homologous to major histocompatibility complex class I family molecules. Recently, transcriptomic research has shown that AZGP1 expression is reduced in the brain tissue of epilepsy patients. However, the cellular distribution and biological role of ZAG in the brain and epilepsy are unclear. Patients with refractory temporal lobe epilepsy (TLE) and brain trauma were included in this study, and pentylenetetrazole (PTZ)-kindled rats were also used. The existence and level of ZAG in the brain were identified using immunohistochemistry, double-labeled immunofluorescence and western blot, and the expression level of AZGP1 mRNA was determined with quantitative real-time polymerase chain reaction (qrt-PCR). To explore the potential biological role of ZAG in the brain, co-immunoprecipitation (Co-IP) of phosphorylated ERK (p-ERK), TGF-β1 and ZAG was also performed. ZAG was found in the cytoplasm of neurons in brain tissue from both patients and rats. The levels of AZGP1 mRNA and ZAG were lower in refractory TLE patients and PTZ-kindled rats than in controls. In addition, the ZAG level decreased as PTZ kindling continued. Co-IP identified direct binding between p-ERK, TGF-β1 and ZAG. ZAG was found to be synthesized in neurons, and both the AZGP1 mRNA and ZAG protein levels were decreased in epilepsy patients and rat models. The reduction in ZAG may participate in the pathogenesis and pathophysiology of epilepsy by interacting with p-ERK and TGF-β1, promoting inflammation, regulating the metabolism of ketone bodies, or affecting other epilepsy-related molecules. [ABSTRACT FROM AUTHOR]

Rupture of carotid atherosclerotic plaque may cause stroke, while few biomarker in clinic can evaluate carotid plaque vulnerability. In this study, we divided the recruited participants into no plaque, stable plaque, and vulnerable plaque group according to carotid ultrasonography, and screened the differentially expressed proteins in plasma of these participants using isobaric tags for relative and absolute quantitation labeling coupled with liquid chromatography-tandem mass spectrometry. 28 proteins were identified differentially expressed, among which alpha-2-macroglobulin (α2M) and heparin cofactor II (HCII) were found to be at hub position in the interactions of these proteins by STRING analysis and were selected for enzyme-linked immunosorbent assay measurement to assess their relevance with carotid plaques vulnerability and diagnostic efficiency. The plasma level of α2M was found positively correlated, while HCII level was negatively correlated with higher vulnerability of carotid plaques. Both proteins were efficient in differentiating stable and vulnerable carotid plaques. These findings provide potential new targets for the research of carotid plaque vulnerability. Plasma α2M and HCII may be potential biomarkers for evaluation of the vulnerability of carotid plaques if further studied. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the suitability of poly-( d,l-lactic acid-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA triblock copolymer as a matrix material for a sustained-release system for docetaxel (DTX). The copolymers were synthesized by ring-opening polymerization reaction and characterized by 1H-NMR and gel permeation chromatography. The DTX-loaded formulations were prepared, characterized. And the antitumor efficacy and the pharmacokinetics of DTX-loaded copolymer on A-549 lung tumor-bearing BALB/cA mice were investigated. The results showed that DTX-loaded copolymer highly increased the solubility of DTX by more than 3000-fold. And copolymer concentration as well as drug loading level exerted appreciable influence on the drug release behavior. Further, the pharmacokinetic test showed that DTX-loaded copolymer could be with the sustained-release nature for over 3 weeks, which correlated well with the in vitro release. Additionally, one intratumoral injection of the thermo-sensitive hydrogel containing DTX was comparable to three intravenous injections of DTX injection in inhibiting the tumor growth in A-549 lung tumor-bearing BALB/cA mice with a less toxic manner. PLGA-PEG-PLGA could thus provide a promising alternate locally delivered vehicle for DTX to achieve prolonged exposure having greater efficacy in inhibiting tumor growth with lower toxicity. [ABSTRACT FROM AUTHOR]

Abstract: This study was designed to investigate the penetration and the distribution of poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles in the human skin treated with microneedles. Fluorescent nanoparticles were prepared to indicate the transdermal transport process of the nanoparticles. Permeation study was performed on Franz-type diffusion cells in vitro. The distribution of nanoparticles was visualized by confocal laser scanning microscopy (CLSM) and quantified by high performance liquid chromatography (HPLC). CLSM images showed that nanoparticles were delivered into the microconduits created by microneedles and permeated into the epidermis and the dermis. The quantitative determination showed that (i) the permeation of nanoparticles into the skin was enhanced by microneedles, but no nanoparticle reached the receptor solution; (ii) much more nanoparticles deposited in the epidermis than those in the dermis; (iii) the permeation was in a particle size-dependent manner; and (iv) the permeation increased with the nanoparticle concentration increasing until a limit value was reached. These results suggested that microneedles could enhance the intradermal delivery of PLGA nanoparticles. The biodegradable nanoparticles would sustain drug release in the skin and supply the skin with drug over a prolonged period. This strategy would prove to be useful for topical drug administration. [ABSTRACT FROM AUTHOR]

Abstract: The purposes of this study were to improve the transdermal permeation of the Shangwu traumatic formula by chemical penetration enhancers and to investigate the pharmacodynamic changes of the formula caused by incorporated enhancers. The effects of different enhancers on the transdermal absorption of piperine, the representative component of formula, were investigated by in vitro permeation studies. The tests showed an increasing enhancement effect in the following order: Azone/N-methylpyrrolidone (NMP)>oleic acid>Azone/peppermint oil>Azone/oleic acid>Azone/propylene glycol>Azone>peppermint oil>NMP>propylene glycol. The ratio and the content of the most effective enhancer Azone/NMP were determined subsequently. The results suggested that the most significant penetration enhancement was achieved by 3% (w/w) Azone/NMP (3:7). Furthermore, the in vivo pharmacodynamic responses of the formula suspension with or without Azone/NMP were compared using hot-plate assay and xylene-induced ears edema test as models. The data indicated that the formula had positive effect on analgesis and anti-inflammatory, which can be enhanced with the addition of enhancers. [Copyright &y& Elsevier]

Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin αvβ3. Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy. [ABSTRACT FROM AUTHOR]