A self-amplified nanocatalytic system for achieving "1 + 1 + 1 > 3" chemodynamic therapy on triple negative breast cancer.

BACKGROUND: Chemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H2O2) into toxic hydroxyl radicals (·OH) to kill cancer cells, holds great promise in tumor therapy due to its high selectivity. However, the therapeutic effect is significantly limited by insufficient intracellular H2O2 level in tumor cells. Fortunately, ß-Lapachone (Lapa) that can exert H2O2-supplementing functionality under the catalysis of nicotinamide adenine dinucleotide (phosphate) NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme offers a new idea to solve this problem. However, extensive DNA damage caused by high levels of reactive oxygen species can trigger the "hyperactivation" of poly(ADP-ribose) polymerase (PARP), which results in the severe interruption of H2O2 supply and further the reduced efficacy of CDT. Herein, we report a self-amplified nanocatalytic system (ZIF67/Ola/Lapa) to co-deliver the PARP inhibitor Olaparib (Ola) and NQO1-bioactivatable drug Lapa for sustainable H2O2 production and augmented CDT ("1 + 1 + 1 > 3"). RESULTS: The effective inhibition of PARP by Ola can synergize Lapa to enhance H2O2 formation due to the continuous NQO1 redox cycling. In turn, the high levels of H2O2 further react with Co2+ to produce the highly toxic ·OH by Fenton-like reaction, dramatically improving CDT. Both in vitro and in vivo studies demonstrate the excellent antitumor activity of ZIF67/Ola/Lapa in NQO1 overexpressed MDA-MB-231 tumor cells. Importantly, the nanocomposite presents minimal systemic toxicity in normal tissues due to the low NQO1 expression. CONCLUSIONS: This design of nanocatalytic system offers a new paradigm for combing PARP inhibitor, NQO1-bioactivatable drug and Fenton-reagents to obtain sustained H2O2 generation for tumor-specific self-amplified CDT.

[Ruifuping pectin protects against intestinal mucosal injury in the rat exertional heat stroke model].

OBJECTIVE: To evaluate the intestinal function in rats with exertional heat stroke (EHS) and explore the protective role of Ruifuping pectin (RFP) against heat related intestinal mucosal injury. METHODS: One hundred and twenty healthy special pathogen free (SPF) male Sprague-Dawley (SD) rats were randomly divided into normothermic control group, EHS model group, hyperthermic plus drinking water group (H2O+EHS group) and hyperthermic plus pectin group (RFP+EHS group) with 30 rats in each group. The rats in the H2O+EHS group and RFP+EHS group were given water 20 mL/kg or RFP 20 mL/kg orally for 5 days during adaptive training period. After 1 week, the temperature control range was adjusted to (37±1) centigrade using the temperature control treadmill, and the rat model of EHS was reproduced by one-time high temperature exhaustive exercise. No rehydration intervention was given during the training adaptation period in the EHS model group. The rats in the normothermic control group were maintained to room temperature (25±2) centigrade and humidity (55±5)% without other treatment. Behavior tests including withdraw response, righting, and muscle strength were performed immediately after onset of EHS. Blood of inferior vena cava was collected, and the serum inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukins (IL-6, IL-1ß, IL-10)] and activity of diamine oxidase (DAO) were detected by enzyme linked immunosorbent assay (ELISA). The intestinal mucosa was collected, after hematoxylin-eosin (HE) staining, and Chiu score was performed to assess EHS induced pathological changes under light microscope. RESULTS: The rats in the EHS model group had behavioral, inflammatory and pathological changes, such as delayed withdraw response and righting, decreased forelimb pulling, increased inflammatory index, and obvious intestinal mucosal injury, which indicated that the reproduction of the EHS model was successful. There was no significant difference in above parameters between the H2O+EHS group and the EHS model group except that the inflammatory index in the RFP+EHS group was improved. Compared with the EHS model group, the withdraw reflex to pain and righting after RFP pretreatment in the RFP+EHS group were significantly improved (righting score: 1.4±0.2 vs. 0.3±0.2, withdraw reflex to pain score: 1.0±0.1 vs. 0.2±0.1, both P < 0.05), the muscle strength was significantly increased (N: 13.0±0.5 vs. 8.2±0.6, P < 0.01). The levels of pro-inflammatory factors in the RFP+EHS group were significantly lower than those in the EHS model group [TNF-α (ng/L): 67.5±9.2 vs. 194.3±13.7, IL-6 (ng/L): 360.0±54.1 vs. 981.2±84.4, IL-1ß (ng/L): 33.7±9.0 vs. 88.7±6.1, all P < 0.01], while the level of anti-inflammatory factor IL-10 was higher than that in the EHS model group (ng/L: 208.7±10.5 vs. 103.7±7.0, P < 0.01). The degree of intestinal mucosal injury in the RFP+EHS group was less severe than that in the EHS model group, and the Chiu score and DAO were significantly lower than those in the EHS model group [Chiu score: 1.5±0.2 vs. 3.8±0.0, DAO (U/L): 83.7±6.7 vs. 128.7±10.5, both P < 0.05]. CONCLUSIONS: High temperature training can damage the intestinal barrier function, and induce endotoxemia and systemic inflammatory response syndrome (SIRS) in rats. Oral prophylactic RFP can protect the intestinal barrier function, alleviate SIRS, and promote the recovery of basic nerve reflex and muscle strength after the occurrence of EHS in rats.

A multifunctional SN38-conjugated nanosystem for defeating myelosuppression and diarrhea induced by irinotecan in esophageal cancer.

A combination of chemotherapy and phototherapy has been proposed as a promising treatment for esophageal cancer (EC). Irinotecan as a first-line treatment option is widely prescribed for metastatic EC, however, its clinical application is extremely restricted by the low conversion rate to SN38, severe myelosuppression and diarrhea. As a more potent active metabolite of irinotecan, SN38 is a better substitution for irinotecan, but the poor water solubility and the difficulty of encapsulation hindered its medical application. Herein, a multifunctional SN38-conjugated nanosystem (FA-PDA@PZM/SN38@BSA-MnO2, denoted as FA-PPSM) is designed for overcoming the above-mentioned drawbacks and achieving collaborative chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT). The tumor acidic microenvironment induces decomposition of BSA-MnO2 nanoparticles into O2 and Mn2+, thus enhancing oxygen-dependent PDT efficacy; meanwhile, Mn2+ can be employed as a magnetic resonance imaging (MRI) contrast agent. Under 650 and 808 nm laser irradiation, the FA-PPSM nanocomposites exhibit superior antitumor efficacy in Eca-109-tumor bearing mice. Notably, there is low gastrointestinal toxicity and myelosuppression in the FA-PPSM treated mice compared with those treated with irinotecan (alone). Taken together, this work highlights the great potential of the FA-PPSM nanocomposites for MRI-guided chemotherapy in combination with endoscopic light therapy for esophageal cancer.

Hepatoprotective Angelica sinensis silver nanoformulation against multidrug resistant bacteria and the integration of a multicomponent logic gate system.

The rampant usage of antibiotics has led to the emergence of toxicity, especially hepatotoxicity and the emergence of microbial drug resistance. Hence, a series of novel hepatoprotective, biocompatible, antibacterial silver nanoformulations (AS-AgNPs) were developed by using the important Chinese medicinal plant Angelica sinensis. The different size of AS-AgNPs were characterized by UV-Visible spectroscopy, transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). The size-dependent antibacterial properties of AS-AgNPs were investigated against Gram-positive, Gram-negative and multi-drug resistant bacteria. The minimum inhibitory concentration (MIC) of AS-AgNPs with different size against six bacteria was found to be in the range of 5-100 µg mL-1 with no resistance till 12 cycles. TEM and SEM results of bacteria after the treatment suggested that AS-AgNPs disrupted the cell membrane by creating pores. The cytocompatibility and cytoprotective effect of AS-AgNPs were evaluated against HepG2 cell lines, which showed that 85% of cells were viable up to 100 µg mL-1 of the concentration with almost no change in AST and ALT levels. Further, a logic combinatorial library, including basic logic gates (AND, OR, NOR, INHIBIT, IMPLICATION, and YES), three input logic gates (OR, and NOR) and combinatorial gates (INH-OR, INH-YES, INH-INH, AND-NOR, and NOT-AND-NOR) were designed by integrating multi-components based on the interaction between AS-AgNP1 and bacteria, where DiSC3(5) was used as the signal reporter. This system clearly demonstrates the ability of simple logic circuits to perform sophisticated analysis for the detection of multiple bacteria.

A Cu9S5 nanoparticle-based CpG delivery system for synergistic photothermal-, photodynamic- and immunotherapy.

Despite its great potential in cancer therapy, phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), often cause metastasis of tumors. Immunotherapy has revolutionized the cancer treatment owing to the capability of activating immune system to eliminate tumors. However, the integration of phototherapy and immunotherapy in a single nanoagent for cancer therapy is still a challenging task. Here, we fabricated (Cu9S5@mSiO2-PpIX@MnO2@CpG (CSPM@CpG)) as a synergistic therapeutic model for phototherapy enhanced immunotherapy. The intracellular uptake of cytosine-phosphate-guanine (CpG) promoted the infiltration of cytotoxic T lymphocytes (CTLs) in tumor tissue, further stimulating the production of interferon gamma (IFN-γ) and remarkably elevating the immune response level. Excellent anti-tumor effects have been achieved by synergistic PTT/PDT/immunotherapy. The metastasis of tumors was effectively inhibited by the immune response of CpG. Thus, our proposed work provides a strategy to combine phototherapy with immunotherapy to enhance the therapeutic efficiency and further inhibit metastasis of tumors.

Post-synthesis strategy to integrate porphyrinic metal-organic frameworks with CuS NPs for synergistic enhanced photo-therapy.

Multifunctional nanotheranostic systems with both therapeutic and imaging functions are highly desired for the development of more effective and less toxic anti-tumor drugs. Herein, a simple but effective method is reported to fabricate a novel PCN-CuS-FA-ICG-based nanoplatform for dual-modal imaging-guided synergistic photothermal/photodynamic therapy. Porphyrinic metal-organic frameworks with CuS NPs are obtained in aqueous solution via a simple post-synthesis strategy. Furthermore, to obtain a more effective therapy, indocyanine green (ICG) was incorporated into the multifunctional theranostic platform to promote the photothermal therapeutic effect. The as-prepared PCN-CuS-FA-ICG not only exhibits an excellent 1O2 generation efficiency under 650 nm irradiation to achieve remarkable photodynamic cell killing, but also presents outstanding photothermal conversion under 808 nm irradiation to destroy tumor tissues by hyperthermia. In particular, the nanotherapeutic agent realized fluorescence and thermal imaging dual-modal imaging-guided cancer treatment. Meanwhile, in vivo experiments confirmed the evident accumulation of nanoparticles (NPs) at local tumors, and tumor growth was inhibited obviously via synergistic photothermal/photodynamic therapy with negligible side effects.

Tumor-Targeted Drug and CpG Delivery System for Phototherapy and Docetaxel-Enhanced Immunotherapy with Polarization toward M1-Type Macrophages on Triple Negative Breast Cancers.

Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non-small-cell lung cancer because of its limited expression of PD-L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid-derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA-CuS/DTX@PEI-PpIX-CpG nanocomposites, denoted as FA-CD@PP-CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)-enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA-CD@PP-CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1-tumor-bearing mice modal. A low dosage of loaded DTX in FA-CD@PP-CpG can promote infiltration of CTLs to improve efficacy of anti-PD-L1 antibody (aPD-L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA-CD@PP-CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel-enhanced immunotherapy for clinical application of breast cancer.

Fabrication of a soluble crosslinked corn bran arabinoxylan matrix supports a shift to butyrogenic gut bacteria.

Insoluble fermentable cell wall matrix fibers have been shown to support beneficial butyrogenic gut Clostridia, but have restricted use in food products. Here, a soluble fiber matrix was developed that exhibited a similar effect. A low arabinose/xylose ratio corn bran arabinoxylan (CAX) was extracted with two concentrations of sodium hydroxide, 0.25 M and 1.5 M, to give soluble polymers with relatively low (L) and high (H) residual levels of bound ferulic acid (FA) (CAX-LFA and CAX-HFA). After laccase treatment to make diferulate crosslinks, soluble matrices were formed with average 3.5 to 4.5 mer. In vitro human fecal fermentation of CAX-LFA, CAX-HFA, soluble crosslinked ∼3.5 mer CAX-LFA (SCCAX-LFA), and ∼4.5 mer SCCAX-HFA revealed that the SCCAX matrices had somewhat slower fermentation properties by measuring the gas production, total short chain fatty acids, and carbohydrate disappearance, with a higher butyrate proportion in SCCAX-HFA. 16S rRNA gene sequencing showed that SCCAX-HFA promoted OTUs associated with butyrate production including unassigned Ruminococcaceae, unassigned Blautia, Fecalibacterium prausnitzii, and unassigned Clostridium. Thus, when the physical form of an individual soluble polysaccharide was changed to a soluble crosslinked matrix, in vitro fermentation was shifted to Clostridial butyrate producers. This study shows that the physical form of the fiber influences the competition for substrate among the gut bacteria. Crosslinking of soluble fibers may be a strategy for developing soluble matrices with good physical functionalities for beverages and other foods to improve gut health.

Ultrasensitive and universal fluorescent aptasensor for the detection of biomolecules (ATP, adenosine and thrombin) based on DNA/Ag nanoclusters fluorescence light-up system.

We report here an ultrasensitive strategy based on the recognition-induced conformational alteration of aptamer and fluorescence turn-on abilities of guanine-rich (G-rich) DNA sequence in proximity to silver nanoclusters for adenosine triphosphate (ATP), adenosine (A) and thrombin (TB) detection. Herein, we designed two tailored DNA sequences noted as complementary DNA (abbreviated as c-DNA) and signal probe DNA (abbreviated as s-DNA), respectively. c-DNA is designed as a special structure consisting of a sequence complementary to aptamer at the 3'-end and a guanine-rich DNA sequence at the 5'-end; s-DNA contains a cytosine-rich sequence responsible for Ag NCs templated synthesis at the 3'-end and a link sequence (part of aptamer) complementary to partial of the c-DNA at the 5'-end. In the presence of target, the aptamer associated with the target, resulting in the formation of duplex DNA (dsDNA), the DNA-Ag NCs thereafter could close to the guanine-rich sequence, leading to enhanced fluorescence signal readout. The widespread application of the sensing system is achieved success in the detection of three biomolecules. ATP, adenosine and thrombin in the range of 0.5-8.0 µM, 0.5-7.0 µM and 50-900 nM could be linearly detected with the detection limits of 91.6 nM, 103.4 nM and 8.4 nM, respectively. This label-free and turn-on fluorescent sensing system employing the mechanism proposed here turns out to be sensitive, selective, and convenient for the detection of biomolecules without washing and separation steps.

Effects of heat-moisture treatment reaction conditions on the physicochemical and structural properties of maize starch: moisture and length of heating.

Changes in the properties of normal maize starch (NMS) and waxy maize starch (WMS) after heat-moisture treatment (HMT) under various reaction conditions were investigated. NMS and WMS were adjusted to moisture levels of 20%, 25% and 30% and heated at 100 °C for 2, 4, 8 and 16 h. The results showed that moisture content was the most important factor in determining pasting properties for NMS, whereas the heating length was more important for WMS. Swelling power decreased in NMS but increased in WMS, and while the solubility index decreased for both samples, the changes were largely determined by moisture content. The gelatinisation temperatures of both samples increased with increasing moisture content but remained unchanged with increasing heating length. The Fourier transform infrared (FT-IR) absorbance ratio was affected to different extents by the moisture levels but remained constant with increasing the heating length. The X-ray intensities increased but relative crystallinity decreased to a greater extent with increasing moisture content. This study showed that the levels of moisture content and length of heating had significant impacts on the structural and physicochemical properties of normal and waxy maize starches but to different extents.

Cardioprotective effects of Guanxinshutong (GXST) against myocardial ischemia/ reperfusion injury in rats.

BACKGROUND: The protective effects against reperfusion injury of cardioprotective drugs have recently been evaluated and found to be inadequate. Guanxinshutong (GXST), a combination of the traditional herb and Mongolian medicine, is effective and safe in treating angina pectoris in clinical trials. We assess the cardioprotective effects of GXST against myocardial ischemia and reperfusion (MI/R) injury in rats and explore its possible mechanism. METHODS: Forty-five male Sprague Dawley rats were randomized into three groups: non-MI/R group (Sham, n = 15), MI/R group treated with vehicle (Control, n = 15) and MI/R group treated with GXST (Drug, n = 15). MI/R was induced by ligation of the left anterior descending coronary artery (LAD) for 30 minutes, followed by 2/24 hour reperfusion in the Control and Drug groups. In the Sham group, the LAD was exposed without occlusion. GXST powder (in the Drug group) or saline (in the Control and Sham groups) were administered via direct gastric gavage from 7 day prior to surgery. Blood samples were collected from the carotid artery (10 rats each group) after 2 hours of reperfusion, to determine the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) using enzyme-linked immunosorbent assays. The animals were then sacrificed and the hearts were harvested for histopathology and western blot analysis. Infarct size was measured in the remaining five rats in each group after 24 hours reperfusion. RESULTS: GXST significantly decreased levels of TNF-α, IL-1ß, IL-6, ICAM-1, apoptosis index (AI) and infarct size. GXST also obviously inhibited nuclear factor kappa B (NF-κB) activity when compared with the Control group (all P < 0.05). CONCLUSIONS: GXST is effective in protecting the myocardium against MI/R injury in rats. Its possible cardioprotective mechanism involves inhibition of the inflammatory response and apoptosis following MI/R injury.

[The effects of Guanxinshutong on protection of left ventricular function after acute myocardial infarction in rats].

OBJECTIVE: To assess the effects of Guanxinshutong capsule (GXST) on protection of left ventricular (LV) function after acute myocardial infarction (AMI) in rats. METHODS: Twenty-eight male Sprague Dawley rats were randomized to Model group, Drug group and Sham-operated group, with acute myocardial infarction (AMI) achieved by ligating coronary artery in Model and Drug groups. From one week before surgery to four weeks after surgery, GXST for Drug group (1.5 g/kg, 2 times/day) or saline for Model and Sham-operated groups was administered via direct gastric gavage. After four weeks of treatment following surgery, measurement of LV function, pathohistological observation and analysis were performed. RESULTS: Compared with rats in the Model group, LV systolic pressure (LVSP) [(97.7 ± 9.0) mm Hg (1 mm Hg = 0.133 kPa) vs (85.9 ± 9.4) mm Hg], the maximum rising rate of LV pressure (+dp/dtmax) [(4810.2 ± 595.0) mm Hg/s vs (3786.2 ± 723.0) mm Hg/s] and the maximum dropping rate of LV pressure (-dp/dtmax) [(3781.6 ± 573.6) mm Hg/s vs (2774.4 ± 633.5)mm Hg/s] in the Drug group were significantly increased, while LV end-diastolic pressure (LVEDP) [(10.3 ± 0.7) mm Hg vs (12.7 ± 2.4) mm Hg] in the Drug group was significantly decreased (all P < 0.05). Myocardial pathohistological morphology was improved in the Drug group with fibrosis alleviated [(5.13 ± 1.37)% vs (7.27 ± 1.01)%] and infarct size reduced [(20.14 ± 8.49)% vs (31.90 ± 4.98)%]. Apoptosis index (AI) was decreased [(14.05 ± 4.04)% vs (20.87 ± 6.03)%] and vessel density was significantly increased by 1.48-fold in the Drug group (all P < 0.05). CONCLUSIONS: GXST is effective in protecting LV function after AMI in rats, which may be affect through increasing vessel density of infarction area, improving myocardial pathohistological morphology, alleviating fibrosis, reducing infarct size and decreasing AI.