Lipid/Hyaluronic Acid-Coated Doxorubicin-Fe3O4 as a Dual-Targeting Nanoparticle for Enhanced Cancer Therapy.

Development of a delivery system to lower systemic toxicity and enhance doxorubicin (DOX) antitumor efficacy against multi-drug resistant (MDR) tumors is of great clinical significance. Here, lipid/hyaluronic acid (HA)-coated DOX-Fe3O4 was characterized to determine its optimal safety and efficacy on a tumor. DOX was first conjugated onto the Fe3O4 NPs surface, which was subsequently coated with phosphatidylcholine (PC) lipids, which consisted of a tumor cell-targeting HA ligand, to generate a dual-targeting nanoparticle (NP). DOX-Fe3O4 synthesis was validated by the Fourier-transform infrared (FT-IR) analysis results. Core-shell PC/HA@DOX-Fe3O4 formation, which had an average particle size of 48.2 nm, was observed based on the transmission electron microscopy (TEM) and dynamic laser light scattering (DLS) results. The saturation magnetization value of PC/HA@DOX-Fe3O4 was discovered to be 28 emu/g using vibrating-sample magnetometry. Furthermore, the designed PC/HA@DOX-Fe3O4 achieved greater MCF-7/ADR cellular uptake and cytotoxicity as compared with DOX. In addition, PC/HA@DOX-Fe3O4 exhibited significant DOX tumor-targeting capabilities and enhanced tumor growth inhibition activity in the xenograft MCF-7/ADR tumor-bearing nude mice following magnetic attraction and ligand-mediated targeting, with less cardiotoxicity. Therefore, PC/HA@DOX-Fe3O4 is a potential candidate for MDR tumor chemotherapy. Graphical abstract.

Efficacy and safety of sodium hyaluronate combined with celecoxib for knee osteoarthritis: A systematic review and meta-analysis.

Due to the large cost of joint replacement for surgical treatment of knee osteoarthritis, there are many complications in elderly patients, and there are many contraindications to surgery, and conservative treatment is still based on drugs. To further evaluate the efficacy and safety of sodium hyaluronate combined with celecoxib for the treatment of osteoarthritis of the knee. In total, 202 studies were screened, with a final selection of 9 RCTs involving 2339 participants; of these, 9 RCTs were included in the final meta-analysis. Treatment group reduces VAS (SMD = -1.61; 95 % CI [-2.25, -0.98]; I2 = 95 %; P < 0.00001) and adverse reactions (OR = 0.45; 95 % CI [0.22,0.94]; I2 = 0 %; P < 0.33); Meanwhile, improving Lysholm knee scores (SMD = 0.19; 95 % CI [-0.06, -0.44]; I2 = 76 %; P = 0.0004) and Clinical efficiency (OR = 0.31; 95 % CI [0.19,0.50]; I2 = 0 %; P < 0.00001). All indicators were superior to the control group. Our primary findings suggest that KOA treatment with celecoxib combined with sodium hyaluronate reduces VAS, while improving Lysholm scores and Clinical efficiency. In addition, we found that celecoxib combined with sodium hyaluronate treatment had fewer adverse effects than the control group, indicating that the combination is safe and effective in the treatment of KOA.

Stimulus-responsive hybrid nanoparticles based on multiple lipids for the co-delivery of doxorubicin and Sphk2-siRNA and breast cancer therapy.

The development of breast cancer is usually related to multiple pathways. A combinatory therapeutic system that combines drug/siRNA targeting several independent pathways has become an attractive approach to reduce the side effects and improve the efficiency of antitumor drugs. Herein, we designed a unique micelle-liposome hybrid nanoparticle platform for the combinatory administration of the cytotoxic drug DOX and Sphk2-siRNA for the treatment of multidrug-resistant (MDR) cancer. The synthesized lipid dioleoyl ethanolamine (DE) and pH-responsive DOPE were used to produce DOX/siRNA co-loaded hybrid nanoparticle (DOX-MC-siSphk2/ASLNP), with high drug-loading capacity and transfection efficacy. We demonstrated that simultaneous cellular endocytosis of DOX/siRNA induced by nanoparticles in MCF-7/ADR cells could acquire higher drug cytotoxicity and contribute to increasing the apoptosis of tumor cell. Furthermore, DOX-MC-siSphk2/ASLNP could significantly block the tumor growth of MDR breast cancer in xenograft mouse model with lower cardiotoxicity.

Poloxamer188-based nanoparticles improve the anti-oxidation and anti-degradation of curcumin.

Curcumin (CUR) is a food additive approved by World Health Organization. But the shortcomings, such as poor water solubility, easy oxidation and degradation, limit its application. In this study, the CUR-loaded poloxamer188-based nanoparticles (CUR/PTT NPs) were fabricated to improve the stability and water solubility of CUR. Studies found the spherical CUR/PTT NPs had an average size of 98.71 ± 0.64 nm. Stability experiments displayed CUR/PTT NPs were extremely stable in different conditions. XRD analysis indicated the changes of crystal structures of CUR might be the main cause of the improved water solubility. Reducing power and anti-degradation tests suggested CUR/PTT NPs could improve the anti-oxidation and anti-degradation of CUR. Additionally, the results of body weight gains, hematological examination, organ coefficients, hematoxylin and eosin staining demonstrated CUR/PTT NPs bearing the excellent in vivo bio-security. Therefore, this study may provide a new idea for the combination of food industry and nanoparticles.

NIR-Controlled Treatment of Multidrug-Resistant Tumor Cells by Mesoporous Silica Capsules Containing Gold Nanorods and Doxorubicin.

Multidrug resistance (MDR) is identified as a major impediment to the efficient chemotherapy of cancer, and considerable endeavors have been devoted to reverse MDR containing structuring varieties of multifunctional nanocarriers. Here, a specially light-activated hollow mesoporous silica nanocontainer with an in situ-synthesized Au nanorod (AuNR) core and a surface-modified hairpin structure DNA gatekeeper is reported for treating MDR tumor cells. In this system, the AuNR only fills part of the space in hollow mesoporous silica due to its controllable size, and the remaining space is used to load enough DOX. By controlling the near-infrared (NIR) laser intensity and exposure duration, the configuration of hairpin-structured DNA (Tm = 51.4 °C) can change reversibly and then trigger the controllable intracellular release of DOX, leading to a significantly enhanced chemotherapeutic efficacy and adjustable photothermal treatment for multidrug-resistant cancer cells. The in vitro experiments showed that this system could effectively overcome the MDR of HepG2-adm cells (a MDR cell line of human hepatocarcinoma cells) by the increased concentration of DOX intracellularly and the photothermal conversion of AuNRs, even at a low concentration (e.g., 30 µg mL-1). Therefore, this NIR-triggered chemo-photothermal synergistic treatment system can be used as a promising efficient strategy in reversing the multidrug resistance for cancer therapy.

Dynamic of Composition and Diversity of Gut Microbiota in Triatoma rubrofasciata in Different Developmental Stages and Environmental Conditions.

Triatoma rubrofasciata (T. rubrofasciata), one kind of triatomine insects, is the vector of Trypanosoma cruzi (T. cruzi), which lead to American trypanosomiasis. Although the gut microbiome may play an essential role in the development and susceptibility of triatomine, there is limited research on the gut microbiota of T. rubrofasciata. To elucidate the effect of the vector's developmental stages and environmental conditions on the gut microbiome, we employed 16S rRNA gene sequencing to profile the gut bacterial community diversity and composition of T. rubrofasciata. Significant shifts were observed in the overall gut microbe diversity and composition across the development of T. rubrofasciata and specific bacteria were detected in different stages. Serratia and Burkholderia-Caballeronia-Paraburkholderia were dominant in the 1st nymphal stage, while the abundance of Staphylococcus was low in the 1st nymphal stage. Oceanicaulis were undetectable in the adult stage and Odoribacter peaked in the 2nd nymphal stage. Moreover, Staphylococcus was correlated negatively with Serratia. Likewise, the total gut microbiota diversity and composition of T. rubrofasciata differentiated significantly by environmental conditions. The ingestion of a bloodmeal increased alpha diversity of gut bacterial communities, and Staphylococcus was more abundant in laboratory-reared bugs whereas Enterococcus enriched in wild-caught bugs. Furthermore, Pantoea was negatively correlated with Staphylococcus, and positively related to Bacillus only. The phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) algorithm showed obvious metagenomic functional differences by environmental conditions, and Chagas disease relevant pathway was enriched in wild-caught T. rubrofasciata.

Sphk2 RNAi nanoparticles suppress tumor growth via downregulating cancer cell derived exosomal microRNA.

Exosomes secreted from cancer cells promote tumor progression through the transfection of containing microRNA (miRNA), mRNAs and proteins. Yet, little of this knowledge has translated into the therapeutic application. Herein, we propose a tumor therapeutic strategy via decreasing exosomal miRNA secretion. The study designed small interfering RNA (siRNA) loaded nanoparticles to downregulate sphingosine kinase 2 (Sphk2) and investigate their potential in decreasing exosomal oncogenic miRNA content and inhibiting tumor growth. The synthesized lipid (2E)-4-(dioleostearin)-amino-4­carbonyl-2-butenoic (DC) and chitosan were utilized to produce siRNA loaded nanoparticles (DC/CS-siRNA NPs), with optimal siRNA complexation and high transfection efficacy. We demonstrated that Sphk2 gene silencing induced by nanoparticles in hepatocellular carcinoma (HCC) cells could reduce miRNA-21 sorting into exosomes, contributing to the inhibition of tumor cell migration and tumorigenic function of exosomes to normal liver cells. Furthermore, in xenograft mouse model, Sphk2 siRNA loaded DC/CS NPs could significantly block tumor progression of malignancy HCC. These results suggest a new therapeutic approach for tumor treatment by ablating oncogenic miRNA in malicious exosomes.

Lipid-coated iron oxide nanoparticles for dual-modal imaging of hepatocellular carcinoma.

The development of noninvasive imaging techniques for the accurate diagnosis of progressive hepatocellular carcinoma (HCC) is of great clinical significance and has always been desired. Herein, a hepatocellular carcinoma cell-targeting fluorescent magnetic nanoparticle (NP) was obtained by conjugating near-infrared fluorescence to the surface of Fe3O4 (NIRF-Fe3O4) NPs, followed by coating the lipids consisting of tumoral hepatocytes-targeting polymer (Gal-P123). This magnetic NP (GPC@NIRF-Fe3O4) with superparamagnetic behavior showed high stability and safety in physiological conditions. In addition, GPC@NIRF-Fe3O4 achieved more specific uptake of human liver cancer cells than free Fe3O4 NPs. Importantly, with superpara-magnetic iron oxide and strong NIR absorbance, GPC@NIRF-Fe3O4 NPs demonstrate prominent tumor-contrasted imaging performance both on fluorescent and T2-weighted magnetic resonance (MR) imaging modalities in a living body. The relative MR signal enhancement of GPC@NIRF-Fe3O4 NPs achieved 5.4-fold improvement compared with NIR-Fe3O4 NPs. Therefore, GPC@ NIRF-Fe3O4 NPs may be potentially used as a candidate for dual-modal imaging of tumors with information covalidated and directly compared by combining fluorescence and MR imaging.

[Ultrabraid SUTURE WITH FOOTPRINT RIVET FOR ANTERIOR CRUCIATE LIGAMENT TIBIAL EMINENCE AVULSION FRACTURE IN ADOLESCENTS UNDER ARTHROSCOPY].

OBJECTIVE: To investigate the clinical effects of the Ultrabraid suture with FOOTPRINT rivet by arthroscopic technique for the treatment of anterior cruciate ligament (ACL) tibial eminence avulsion fracture. METHODS: Between May 2011 and December 2013, 19 adolescent patients with ACL tibial eminence avulsion fracture were treated with arthroscopic reduction and fixation by Ultrabraid sutures with FOOTPRINT rivet. There were 13 males and 6 females with an average age of 15.8 years (range, 8-18 years). The left knees were involved in 10 cases and the right knees in 9 cases. The injury causes included traffic accident injury in 8 cases, sport injury in 6 cases, and sprain injury in 5 cases. Three patients had old fractures, and the others had fresh fractures. The results of Lachman test and anterior drawer test were both positive. The International Knee Documentation Committee (IKDC) subject score was 54.2 ± 4.0. Based on Meyers-McKeever classification, there were 3 cases of type II, 10 cases of type III, and 6 cases of type IV. RESULTS: The operation time was 50-60 minutes (mean, 55.2 minutes). X-ray film showed satisfactory fracture reduction at 1 day after operation. Primary healing of incision was obtained with no infection. Eighteen patients were followed up for 1-3 years (mean, 1.7 years). All fractures healed with smooth joint surface on the X-ray film at 3 months after operation. The results of Lachman test and anterior drawer test were both negative in 17 cases, and the results was negative for anterior drawer test and was weakly positive for Lachman test in 1 case. The IKDC subject score was significantly improved to 96.1 ± 2.1 at last follow-up (t = 34.600, P = 0.000). CONCLUSION: It could achieve early restoration of knee joint function to treat the ACL tibial eminence avulsion fracture by arthroscopic technique of the Ultrabraid suture with FOOTPRINT rivet because of satisfactory reduction, reliable fixation, small wound, and early rehabilitation.

Protective effect of Xingnaojia formulation on rats with brain and liver damage caused by chronic alcoholism.

The aim of this study was to observe the effect of a formulation of traditional Chinese medicine extracts known as Xingnaojia (XNJ) on the liver function, learning ability and memory of rats with chronic alcoholism and to verify the mechanism by which it protects the brain and liver. A rat model of chronic alcoholism was used in the study. The spatial learning ability and memory of the rats were tested. The rats were then sacrificed and their brains and hepatic tissues were isolated. The activity of superoxide dismutase (SOD) and levels of glutamate (Glu), N-methyl D-aspartate receptor subtype 2B (NR2B), cyclin-dependent kinase 5 (CDK5) and cannabinoid receptor 1 (CB1) in the hippocampus were analyzed. The ultrastructure of the hepatic tissue was observed by electron microscopy. In addition, the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in serum were tested and the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG) and total cholesterol (TCHOL) were analyzed. XNJ enhanced the learning and memory of rats with chronic alcoholism. Treatment with XNJ increased the activity of SOD, and decreased the expression levels of NR2B mRNA and NR2B, CB1 and CDK5 proteins in the brain tissues compared with those in the model rats. It also increased the activity of ALDH in the serum and liver, decreased the serum levels of LDL, TG and TCHOL and increased the serum level of HDL. These results indicate that XNJ exhibited a protective effect against brain and liver damage in rats with chronic alcoholism.

Oxytocin in the periaqueductal gray participates in pain modulation in the rat by influencing endogenous opiate peptides.

Periaqueductal gray (PAG) plays a very important role in pain modulation through endogenous opiate peptides including leucine-enkephalin (L-Ek), methionine-enkephalin (M-Ek), ß-endorphin (ß-Ep) and dynorphin A(1-13) (DynA(1-13)). Our pervious study has demonstrated that intra-PAG injection of oxytocin (OXT) increases the pain threshold, and local administration of OXT receptor antagonist decreases the pain threshold, in which the antinociceptive role of OXT can be reversed by pre-PAG administration of OXT receptor antagonist. The experiment was designed to investigate the effect of OXT on endogenous opiate peptides in the rat PAG during the pain process. The results showed that (1) the concentrations of OXT, L-Ek, M-Ek and ß-Ep, not DynA(1-13) in the PAG perfusion liquid were increased after the pain stimulation; (2) the concentrations of L-Ek, M-Ek and ß-Ep, not DynA(1-13) in the PAG perfusion liquid were decreased by the OXT receptor antagonist; (3) the increased pain threshold induced by the OXT was attenuated by naloxone, an opiate receptor antagonist; and (4) the concentrations of L-Ek, M-Ek and ß-Ep, not DynA(1-13) in the PAG perfusion liquid were increased by exogenous OXT administration. The data suggested that OXT in the PAG could influence the L-Ek, M-Ek and ß-Ep rather than DynA(1-13) to participate in pain modulation, i.e. OXT in the PAG participate in pain modulation by influencing the L-Ek, M-Ek and ß-Ep rather than DynA(1-13).

Oxytocin, but not arginine vasopressin is involving in the antinociceptive role of hypothalamic supraoptic nucleus.

Our previous study has demonstrated that the hypothalamic supraoptic nucleus (SON) plays a role in pain modulation. Oxytocin (OXT) and arginine vasopressin (AVP) are the important hormones synthesized and secreted by the SON. The experiment was designed to investigate which hormone was relating with the antinociceptive role of the SON in the rat. The results showed that (1) microinjection of L-glutamate sodium into the SON increased OXT and AVP concentrations in the SON perfusion liquid, (2) pain stimulation induces OXT, but not AVP release in the SON, and (3) intraventricular injection (pre-treatment) with OXT antiserum could inhibit the pain threshold increase induced by SON injection of L-glutamate sodium, but administration of AVP antiserum did not influence the antinociceptive role of SON stimulation. The data suggested that the antinociceptive role of the SON relates to OXT rather than AVP.

Oxytocin in the periaqueductal grey regulates nociception in the rat.

Studies have demonstrated that oxytocin (OXT) plays important roles in pain modulation in the central nervous system, and there are OXT receptors in the periaqueductal grey (PAG). The experiment was designed to investigate the effect of OXT in the PAG on antinociception. The results showed that (1) intra-PAG injection of OXT increased the pain threshold, whereas the local administration of the high specific OXT receptor antagonist, desGly-NH(2), d(CH(2))(5)[D-Tyr(2), Thr-sup-4]OVT decreased the pain threshold in a dose-dependent manner; (2) Pain stimulation could elevate OXT concentration in the PAG perfusion liquid. The data suggested that OXT in the PAG was involved in the antinociceptive process through the OXT receptor.

Double-layer weekly sustained release transdermal patch containing gestodene and ethinylestradiol.

The combination therapy of gestodene (GEST) and ethinylestradiol (EE) has shown advanced contraception effect and lower side effect. The present study was designed to develop a weekly sustained release matrix type transdermal patch containing GEST and EE using blends of different polymeric combinations. The multiple-layer technique was adopted in order to maintain a steady permeation flux for 7 days. The effects of polymer types, polymer ratios, permeation enhancers, drug loadings and drug ratios in different layers on the skin permeations of the drugs were evaluated using excised mice skin. Polariscope examination was carried out to observe the drug distribution behavior. The formulation with the mixture of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) (7:1) was found to provide the regular release and propylene glycol (PG) could enhance the permeation fluxes of drugs. Double-layer transdermal drug delivery system (TDDS) could sustain the steady permeation flux of drugs for 7 days when the ratio of drug in drug release layer and drug reservoir layer was 1:4 with the identical total drug amount. The in vitro transdermal permeation fluxes were 0.377 microg/cm(2)/h and 0.092 microg/cm(2)/h, for GEST and EE respectively. The uniformity of dosage units test showed that the distribution of drugs in the matrix was homogeneous, which was further demonstrated by the polariscope result. The developed transdermal delivery system containing GEST and EE could be a promising non-oral contraceptive method.