Hollow Mesoporous Silica Nanoparticles Gated by Chitosan-Copper Sulfide Composites as Theranostic Agents for the Treatment of Breast Cancer.

The combination of chemotherapy and photothermal therapy (PTT) into a single formulation has attracted increasing attention as a strategy for enhancing cancer treatment. Here, hollow mesoporous silica nanoparticles (HMSNs) were used as a base carrier material, loaded with the anti-cancer drug doxorubicin (DOX), and surface functionalized with chitosan (CS) and copper sulfide (CuS) nanodots to give HMSNs-CS-DOX@CuS. In this formulation, the CuS dots act as gatekeepers to seal the surface pores of the HMSNs, preventing a burst release of DOX into the systemic circulation. S-S bonds connect the CuS dots to the HMSNs; these are selectively cleaved under the reducing microenvironment of the tumor, permitting targeted drug release. This, coupled with the PTT properties of CuS, results in a potent chemo/PTT platform. The HMSNs-CS-DOX@CuS nanoparticles have a uniform size (150 ± 13 nm), potent photothermal properties (η = 36.4 %), and tumor-targeted and near infrared (NIR) laser irradiation-triggered DOX release. In vitro and in vivo experimental results confirmed that the material has good biocompatibility, but is effectively taken up by cancer cells. Moreover, the CuS nanodots permit simultaneous thermal/photoacoustic dual-modality imaging. Treatment with HMSNs-CS-DOX@CuS and NIR irradiation caused extensive apoptosis in cancer cells both in vitro and in vivo, and could dramatically extend the lifetimes of animals in a murine breast cancer model. The system developed in this work therefore merits further investigation as a potential nanotheranostic platform for cancer treatment. STATEMENT OF SIGNIFICANCE: Conventional cancer chemotherapy is accompanied by unavoidable off-target toxicity. Combination therapies, which can ameliorate these issues, are attracting significant attention. Here, the anticancer drug doxorubicin (DOX) was encapsulated in the central cavity of chitosan (CS)-modified hollow mesoporous silica nanoparticles (HMSNs). The prepared system can target drug release to the tumor microenvironment. When exposed to near infrared laser (NIR) irradiation, CuS nanodots located at the surface pores of the HMSNs generate energy, accelerating drug release. In addition, a systematic in vitro and in vivo evaluation confirmed the HMSNs-CS-DOX@CuS platform to give highly effective synergistic chemotherapeutic-photothermal therapy and have effective thermal/photoacoustic dual-imaging properties. This work may open up a new avenue for NIR-enhanced synergistic therapy with simultaneous thermal/photoacoustic dual imaging.

Functionalized boron nanosheets as an intelligent nanoplatform for synergistic low-temperature photothermal therapy and chemotherapy.

In this work, an innovative boron-based multifunctional nanoplatform was developed for synergistic chemotherapy/low temperature photothermal therapy (PTT). This platform is functionalized with a cRGD peptide to allow the targeting of αvß3 integrin, which is over-expressed in the cells of tumors. The nanoparticles were further loaded with the chemotherapeutic drug doxorubicin (DOX) and a heat shock protein inhibitor (17AAG), and high loading capacities for both DOX (603 mg g-1 B-PEG-cRGD) and 17AAG (417 mg g-1) were obtained. The resultant DOX-17AAG@B-PEG-cRGD system shows both pH-controlled and near-infrared (NIR)-induced DOX and 17AAG release. It also provides significantly enhanced cellular uptake in cancerous cells over healthy cells. The presence of 17AAG allows low-temperature PTT to be combined with chemotherapy with DOX, resulting in highly effective anti-cancer activity. This has been confirmed by both in vitro assays and using an in vivo murine cancer model. It is expected that such a multifunctional nanoplatform can serve as a promising candidate for cancer therapy.

Duan-Nai-An, A Yeast Probiotic, Improves Intestinal Mucosa Integrity and Immune Function in Weaned Piglets.

Post-weaning diarrhea commonly occurs in piglets and results in significant economic loss to swine producers. Non-antibiotic measures for managing post-weaning diarrhea are critically needed. Duan-Nai-An, a probiotic produced from the yeast fermentation of egg whites, was previously shown to optimize intestinal flora and reduce the incidence of clinical diarrhea in weaning piglets. To study the effects of Duan-Nai-An on mucosal integrity and immunity in pig intestine, we examined the microstructure and ultrastructure of the intestines of weaned pigs with or without Duan-Nai-An as a feed supplement. The piglets of the Duan-Nai-An-fed group developed intestines with intact columnar epithelia covered by tightly packed microvilli on the apical surface. However, piglets of the control group (no supplement) showed villous atrophy and thinning, microvillus slough, and in the severe cases, damage of intestinal epithelia and exposure of the underlying lamina propria. Moreover, piglets of the Duan-Nai-An-fed group showed apparent plasmocyte hyperplasia, increased lymphoid nodule numbers, well-developed Peyer's Patchs, and apparent germinal centers. The lymphoid tissues of the control group were far less developed, showing lymph node atrophy, lymphocyte reduction, degeneration, and necrosis. These results indicate that Duan-Nai-An improves the development of the intestinal structures and lymphoid tissues and promotes intestinal health in weaned piglets.

Novel nortriterpenoids with new skeletons and limonoids from the fruits of Evodia rutaecarpa and their bioactivities.

Two novel nortriterpenoids together with 7 known compounds were isolated from the fruits of Evodia rutaecarpa. The structures of the new compounds were elucidated by spectroscopic analysis, X-ray, and electronic circular dichroism (ECD) calculations. Compound 1 is the first example of triterpenoid with a 27 (17 â†’ 12)-abeo-five-ring skeleton. In turn, compound 2 possesses a unique C/D/E linear fused ring system and a methyl on C-21. Plausible biogenetic pathway for the new compounds 1 and 2 are also proposed. Compound 1 exhibited significantly antitumor activity against A549 and LoVo cells with IC50 values of 2.0 µM and 1.9 µM, respectively. Colony formation inhibition, cell cycle arrest and cell apoptosis of compound 1 were also evaluated. Compound 2, 6, 7 and 9 showed potent neuroprotective activities against serum-deprivation induced P12 cell damage.

A multifunctional nanoplatform based on MoS2-nanosheets for targeted drug delivery and chemo-photothermal therapy.

Synergistic tumor treatment has recently attracted more and more attention due to its remarkable therapeutic effect. Herein, a multifunctional drug delivery system based on hyaluronic acid (HA) targeted dual stimulation responsive MoS2 nanosheets (HA-PEI-LA-MoS2-PEG, HPMP) for active interaction with CD44 receptor positive MCF-7 cells is reported. Melanin (Mel), a new type of photothermal agent and doxorubicin (DOX) are both loaded onto the HPMP nanocomposite and can be released by mild acid or hyperthermia. The prepared HPMP nanocomposite has a uniform hydrodynamic diameter (104 nm), a high drug loading (944.3 mg.g-1 HPMP), a remarkable photothermal effect (photothermal conversion efficiency: 55.3%) and excellent biocompatibility. The DOX release from HPMP@(DOX/Mel) can be precisely controlled by the dual stimuli of utilizing the acidic environment in the tumor cells and external laser irradiation. Meanwhile, loading of Mel onto the surface can enhance the photothermal effect of the MoS2 nanosheets. In vitro experiments showed that the HPMP@(DOX/Mel) nanoplatform could efficiently deliver DOX into MCF-7 cells and demonstrated enhanced cytotoxicity compared to that of the non-targeted nanoplatform. In vivo experiments in a breast cancer model of nude mice further confirmed that the HPMP@(DOX/Mel) significantly inhibited tumor growth under near infrared (NIR) laser irradiation, which is superior to any single therapy. In summary, this flexible nanoplatform, based on multi-faceted loaded MoS2 nanosheets, exhibits considerable potential for efficient pH/NIR-responsive targeted drug delivery and chemo-photothermal synergistic tumor therapy.

Nanoliposomes containing Eucalyptus citriodora as antibiotic with specific antimicrobial activity.

Bacterial infections are a serious issue for public health and represent one of the major challenges of modern medicine. In this work, a selective antimicrobial strategy based on triggering of pore-forming toxin, which is secreted by infective bacteria, was designed to fight Staphylococcus aureus. The antimicrobial activity is realized by employing Eucalyptus citriodora oil as antibiotic which in this study is encapsulated in nanoliposomes.

[Effect of electroacupuncture intervention at different time-points of post-modeling on hippocampal monoamine neurotransmitter levels in mice with vascular dementia].

OBJECTIVE: To observe the effect of electrocupuncture (EA) intervention at different time-points of post-modeling on behavior and hippocampal monoamine neurotransmitter noradrenalin (NE), dopamine (DA) and 5-hydroxytrypamine (5-HT) contents in vascular dementia (VD) mice, so as to study its mechanism underlying improvement of VD. METHODS: A total of 60 Kunming mice were randomized into sham-operation control (n = 20), VD model (n = 20), EA-day (D)-1 (EA treatment was given from the 1st day on after modeling, n = 10), EA-D-3 (EA was given from the 3rd day on after modeling, n = 10) groups. VD model was established by occlusion of the bilateral cervical common arteries and reperfusion. EA (2 Hz/80 Hz) was applied to "Baihui" (GV 20), "Dazhui" (GV 14),"Zusanli" (ST 36) and "Geshu"(BL 17) for 10 min, once daily for 15 days. Hippocampal NE, DA and 5-HT contents were assayed by fluorospectrophotometry. The mouse's learning-memory ability was assessed by step-down tests. RESULTS: In comparison with the sham-operation control group, the learning-memory ability (marked increase of reaction time and error times, decrease of step-down latency) was apparently lowered in the model group (P < 0.01). The hippocampal NE, DA and 5-HT contents were significantly lower in the model group than in the sham-operation group (P < 0.01). Compared with the model group, the mice's learning-memory ability (marked decrease of reaction time and error times, increase of step-down latency) was significantly increased in EA intervention groups (P < 0.01), and hippocampal NE, DA and 5-HT levels were significantly increased (P < 0.01), and the effect of EA-D-3 group was obviously better than that of the EA-D-1 group (P < 0.05, P < 0.01). CONCLUSION: EA can improve the VD mice's learning-memory ability, which is closely related to its effects in up-regulating hippocampal NE, DA and 5-HT contents, and the effect of later EA intervention after modeling is better.

Mechanism of protective effects of Danshen against iron overload-induced injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen (Salvia miltiorrhiza) has been widely prescribed in traditional folk medicine for treatment of hepatic and cardiovascular diseases in China and other Asian countries for several hundred years. MATERIALS AND METHODS: Sixty male mice were randomly divided into five groups: control, iron overload, low-dose Danshen (L-Danshen, 3g/kg/day), high-dose Danshen (H-Danshen, 6g/kg/day) and deferoxamine (DFO) groups (n=12 per group). Iron dextran was injected intraperitoneally (i.p.) at 50mg/kg body weight/day to establish the iron overload model. While control mice received saline, mice of the treated groups simultaneously received (i.p.) injections of L-Danshen, H-Danshen or DFO daily for 2 weeks. At the end of the experiment, changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), glutathione peroxidase (GSH-Px), superoxide desmutase (SOD) and malondialdehyde (MDA) were measured, and histological changes were observed by Prussian blue or hematoxylin and eosin staining of the liver. Apoptosis was detected by terminal-deoxynucleotidyl transferase mediated nick end labeling. RESULTS: Treatment of iron overloaded mice with either low or high doses of Danshen not only significantly attenuated the hepatic dysfunction (ALT/AST levels), decreased the content of MDA and increased the activities of GSH-Px and SOD, it also suppressed apoptosis in hepatocytes. Histopathological examination showed that treatment with Danshen reduced iron deposition and ameliorated pathological changes in the liver of iron overloaded mice. CONCLUSIONS: Danshen demonstrated significant protective effects in the liver of iron overloaded mice, which were at least partly due to the decrease of iron deposition and inhibition of lipid peroxidation and hepatocyte apoptosis.

[Effect of electroacupuncture on apoptosis of hippocampus tissue in mice with vascular dementia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on hippocampal apoptosis and learning-memory ability in vascular dementia (VD) mice so as to investigate its underlying mechanism in the treatment of VD patients. METHODS: Kunming mice were randomly divided into sham-operation (sham, n = 13), model (n = 15), EA (n = 16) and Nimodipine (intragastric gavage, 30 mg/kg for 15 days, n = 15) groups. VD model was duplicated by occlusion of bilateral carotid arteries and reperfusion. EA (2-80 Hz, 2 mA) was applied to "Dazhui" (GV 14), "Baihui" (GV 20), "Geshu" (BL 17) and "Zusanli" (ST 36) for 10 min, once daily for 15 days. Step-down and step-up tests were performed to assess the animal's memory and learning abilities separately; and the terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling (TUNEL) method was used to display the apoptotic cells of the hippocampus tissue. RESULTS: In comparison with sham group, the animals' reaction time upon electric shock stimulation, both step-up and step-down error times, and hippocampal apoptosis number in model, EA and Nimodipine groups increased significantly (P<0.01), while the reaction latency upon electric shock of model, EA and Nimodipine groups decreased significantly (P<0.01). Compared with model group, the reaction time, both step-up and step-down error times and hippocampal apoptosis number of both EA and Nimodipine groups decreased significantly (P<0.05, P<0.01); while the reaction latency of EA and Nimodipine groups increased considerably (P<0.01). Comparison between EA and Nimodipine groups showed that the reaction latency of EA group was obviously longer than that of the later group (P<0.01), and the step-down error times of EA group was markedly lower than that of Nimodipine group (P<0.05). No significant differences were found between these two groups in other indexes (P>0.05). CONCLUSION: EA can ameliorate VD mice's learning-memory ability, which may be closely related to its effect in reducing hippocampal apoptosis.

[Effect of icariin on hypoxia induced vascular endothelial cells injury].

OBJECTIVE: To study the effect of icariin on vascular endothelial cells (VECs) injury induced by hypoxia. METHODS: The hypoxia-ischemia model was established. The effect of icariin on injury of VECs activity induced by hypoxia was determined by MTT assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and lactate dehydrogenase (LDH) activity in cell homogenate were measured with corresponding kit. Effect of icariin on cells apoptosis induced by hypoxia was determined by Hoechst 33342 fluorescent staining, cell ultrastructure observation under transmission electron microscopy and analysis on gene fragmentation by flow cytometry and DNA gel electrophoresis. RESULTS: ICA could inhibit the hypoxia induced VECs reduction, suppress LDH activity, reduce the MDA production, and enhance SOD activity under hypoxia. Hypoxia could induce VECs apoptosis, revealed chromation condensed in nuclei with the fragments arranged along the nuclear membrane. DNA gel electrophoresis showed typical ladder strands of DNA. Cells displayed a typical sub-diploid peak in flow cytometry. ICA could significantly inhibit the hypoxia induced apoptosis of VECs. CONCLUSION: ICA has the protective effect on hypoxia injured VECs, which may be related to its effect of anti-apoptosis, anti-lipid peroxidation and SOD activity enhancing.