Composite Hydrogels of Ultrasound-Assisted-Digested Formic Acid-Decellularized Extracellular Matrix and Sacchachitin Nanofibers Incorporated with Platelet-Rich Plasma for Diabetic Wound Treatment.

In this study, an ultrasound-assisted digestion method of a formic acid-decellularized extracellular matrix (dECM) of porcine skin was developed and optimized to form UdECM hydrogels for diabetic wound healing. Results demonstrated that ultrasonication improved the extraction rate of collagen from dECM samples, preserved the collagen content of dECM, reduced residual cells, and extracted greater DNA contents. Scanning electron microscope (SEM) analyses were performed, which demonstrated the optimal porosity on the surface and density of the cross-section in the hydrogel structure, which could control the release of growth factors embedded in UdECM hydrogels at desirable rates to boost wound healing. A wound-healing study was conducted with six different composite hydrogels, both empty materials and materials enriched with rat platelet-rich plasma (R-PRP), sacchachitin nanofibers (SCNFs), and TEMPO-oxidized sacchachitin in diabetic rats. The assessment based on scars stained with hematoxylin and eosin (H&E), Masson's trichrome (MT), and a cluster of differentiation 31 (CD31) staining showed that the UdECM/SC/R-PRP treatment group had the most significant efficacy of promoting healing and even recovery of diabetic wounds to normal tissues. UdECM/R-PRP and UdECM/SCNFs demonstrated better healing rates than UdECM hydrogel scaffolds, which had only recovered 50% resemblance to normal skin. Treatment with both UdECM/TEMPO 050 and UdECM/TEMPO 050/R-PRP hydrogel scaffolds was ranked last, with even poorer efficacy than UdECM hydrogels. In summary, formulated UdECM and SCNF hydrogels loaded with PRP showed synergistic effects of accelerating wound healing and ultimately stimulating the wound to recover as functional tissues. This newly UdECM/SCNF composite hydrogel has promising potential for healing and regenerating diabetic wounds.

Distribution of Metallic Elements in Four Group Components of High-Temperature Coal Tar Pitch.

The metallic elements in high-temperature coal tar pitch (HCTP) will affect the properties of carbon materials produced from the HCTP. The study on the metallic elements in HCTP is essential for the quality improvement of its derived carbon materials. In this paper, the content of 15 metallic elements in HCTP and its four group components, including n-heptane-soluble substance (HS), n-heptane-insoluble-toluene-soluble substance (HI-TS), toluene-insoluble-quinoline-soluble substance (TI-QS), and quinoline-insoluble substance (QI), was determined. The results show that the content of Na, Ca, Fe, Mg, Zn, K, Pb, and Al is more than 100 ppm and is much higher than that of other metallic elements. The content of Ni, V, Cr, Mo, Sb, Cu, and Mn ranges from 0 to 50 ppm. By mass calculation of the contents of four group components in HCTP, it can be concluded that Na and Fe are randomly distributed in the group components. Al, Zn, Pb, V, and Mn are mainly distributed in the inorganic form in the QI component. Ca, Mg, K, Ni, Cr, Mo, Sb, and Cu are mainly distributed in the small molecular group components such as HS and HI-TS.

Poloxamer sols endowed with in-situ gelability and mucoadhesion by adding hypromellose and hyaluronan for prolonging corneal retention and drug delivery.

The purpose of this study was to develop poloxamer (P407)-based in-situ thermogellable hydrogels with reducing concentration of P407 by adding hypromellose (HPMC) and with enhancing mucoadhesion of resulting hydrogels by adding hyaluronic acid (HA) for prolonging ocular delivery of hydroxypropyl-ß-cyclodextrin (HPßCD)-solubilized testosterone (TES). Results demonstrated that 0.5% TES solution was successfully solubilized with adding 10% HPßCD. Non-gellable 13% P407 sol became in-situ gellable with adding 2.0-2.5% HPMC and mucoadhesibility was further imporved with adding 0.3% HA-L (low MW) or HA-H (high MW). Optimized 0.5% HPßCD-solubilized TES P407-based thermogellable hydrogels with enhancement of mucoadhesion for prolonging ocular delivery comprised 13% P407, 2.5% HPMC, and 0.3% HA-L or HA-H. Furthermore, rheological measurements under simulated eye blinking confirmed that non-thixotropic properties of optimized hydrogels could be spreaded evenly and retain a greater amount of drug-loaded hydrogels on the ocular surface for a longer period to prolong drug delivery. Compared with conventional eye drops, the prolonged residence time of optimized hydrogels from ex vivo and in vivo studies were observed, indicating relationships between rheological properties and in vivo performances. It was concluded that P407-based thermosensitive hydrogels with reducing concentration of P407 and enhancing mucoadhesion was successfully formulated by adding 2.5% HPMC and 0.3% HA in 13% P407 for potentially accomplishing effective clinical treatment of DED.

Combined Docetaxel/Pictilisib-Loaded mPEGylated Nanocarriers with Dual HER2 Targeting Antibodies for Synergistic Chemotherapy of Breast Cancer.

Introduction: Approximately 15%~30% of breast cancers have gene amplification or overexpression of the human epidermal growth factor receptor 2 (HER2), resulting in the chemotherapy resistance, a more-aggressive phenotype and poor prognosis. Methods: We propose a strategy of nanocarriers co-loaded with docetaxel (DTX) and pictilisib (PIC) at a synergistic ratio and non-covalently bound with dual anti-HER2 epitopes bispecific antibodies (BsAbs: anti-HER2-IV/methoxy-polyethylene glycol (mPEG) and anti-HER2-II/methoxy-PEG) for synergistic targeting to overcome the therapeutic dilemmas of the resistance for HER2-targetable chemodrugs. DTX/PIC-loaded nanocarriers (D/P_NCs) were prepared with single emulsion methods and characterized using dynamic light scattering analysis, and the drug content was assayed by high-performance liquid chromatographic method. The integrity and function of BsABs were evaluated using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA). The in vitro cell studies and in vivo breast tumor-bearing mice model were used to evaluate the anti-cancer effect and biosafety of formulations. Results: D/P_NCs optimally prepared exhibited a spherical morphology with small particle sizes (~140 nm), high drug loading (~5.5%), and good colloidal stability. The synergistic tumor cytotoxicity of loading DTX and PIC at 2:1 ratio in D/P_NCs was discovered. The BsAbs are successfully decorated on mPEGylated DTX/PIC-loaded nanocarriers via anti-mPEG moiety. In vitro studies revealed that non-covalent decoration with dual BsAbs on D_P-NCs significantly and synergistically increased cellular uptake, while with loading DTX and PIC at a synergistic ratio of 2:1 in D/P_NCs further resulted in synergistic cytotoxicity. In vivo tumor inhibition studies showed the comparable results for synergistic antitumor efficacy while minimizing systemic toxicity of chemodrugs. Conclusion: Non-covalent modification with dual distinct epitopes BsAbs on the nanocarriers loaded with dual chemodrugs at a synergistic ratio was expected to be a promising therapeutic platform to overcome the chemoresistance of various cancers and warrants further development for future therapy in the clinical.

Topochemical synthesis of Mn2O3/TiO2 and MnTiO3/TiO2 nanocomposites as lithium-ion battery anodes with fast Li+ migration and giant pseudocapacitance via the mesocrystalline effect.

Transition metal compounds are a promising substitute for graphite as lithium-ion battery (LIB) anodes. In this study, mesocrystalline Mn2O3/TiO2 and MnTiO3/TiO2 nanocomposites were synthesized using a layered titanic acid H1.07Ti1.73O4 (HTO) precursor. The ß-MnOOH layer is intercalated into the interlayer of HTO by Mn2+-exchange treatment of H2O2-intercalated HTO, which includes ion-exchange of Mn2+ with H+ in the interlayer and oxidation of Mn2+ to the ß-MnOOH layer by H2O2 in the interlayer space. Mesocrystalline Mn2O3/TiO2 and MnTiO3/TiO2 nanocomposites with a platelike morphology were obtained by heat treatment of a sandwich layered HTO/ß-MnOOH under air and H2/Ar atmospheres, respectively. The electrochemical results suggest that the mesocrystalline Mn2O3/TiO2 and MnTiO3/TiO2 nanocomposites show a synergistic effect for enhanced cycling stability and a mesocrystalline effect for enhanced discharge-charge specific capacity by improving the Li+ mobility and enhancing the pseudocapacitance of the mesocrystalline nanocomposites as LIB anode materials. The discharge-charge specific capacity of the mesocrystalline Mn2O3/TiO2 nanocomposite is twice as high as that of the polycrystalline one caused by the mesocrystalline effect. Furthermore, the synergistic and mesocrystalline effects led to a stable large discharge-charge specific capacity of 710 mA h g-1 for the mesocrystalline Mn2O3/TiO2 nanocomposite. This work proposes a new concept to enhance the performance of anode materials for LIBs using mesocrystalline materials.

Bispecific T-cell engagers non-covalently decorated drug-loaded PEGylated nanocarriers for cancer immunochemotherapy.

Immunotherapy is blooming in recent years. However, this therapy needs to overcome off-target effects, cytokine release syndrome, and low responses in the 'cold' tumor environment. Herein, various combinations of immunotherapies and chemotherapies were proposed to transform 'cold' tumors into 'hot' tumors to enhance the efficacy of immunotherapies. In this study, we prepared a biocompatible ganetespib (GSP)-loaded PEGylated nanocarriers (NCs) with a thin-film method, which exhibited a small particle size (~220.6 nm), high drug loading (~5.8%), and good stability. We designed and produced the cluster of differentiation 3 (CD3)/programmed death ligand 1 (PD-L1)/methoxy-polyethylene glycol (mPEG) trispecific antibodies (TsAbs) as bispecific T-cell engagers (BiTEs) to non-covalently bind the GSP-NCs via anti-mPEG fragment and endowed the GSP-NCs with a targeting ability and immunotherapeutic potential to activate cytotoxic T cells. Decoration of the GSP-NCs with TsAbs (BiTEs-GSP-NCs) significantly promoted the cellular uptake and showed synergistic effects through respective anti-PD-L1 and anti-CD3 activation of T cell-mediated cytotoxicity. In vivo tumor-inhibition studies also showed that the BiTEs-GSP-NCs could inhibit tumor growth with the GSP chemodrug and increase T-cell infiltration. This study provides a promising drug delivery strategy for cancer immunochemotherapy.

CPT11 with P-glycoprotein/CYP 3A4 dual-function inhibitor by self-nanoemulsifying nanoemulsion combined with gastroretentive technology to enhance the oral bioavailability and therapeutic efficacy against pancreatic adenocarcinomas.

Therapeutic efficacies of orally administrated hydrophobic chemodrugs are decreased by poor water solubilities and reduced oral bioavailabilities by P-glycoprotein (P-gp) and CYP450. In this study, CPT11 alone or combined with dual-function inhibitors (baicalein (BA) silymarin (SM), glycyrrhizic acid (GA), and glycyrrhetinic acid (GLA)) of P-gp and CYP450 loaded in a lecithin-based self-nanoemulsifying nanoemulsion preconcentrate (LBSNENP) to improve the solubility and inhibit the elimination by P-gp and CYP450. Results revealed that the LBSNENP composed of Capryol 90, lecithin/Tween 80/Cremophor EL, and propylene glycol at a weight ratio of 18:58:24 (designated PC90C10P0) was optimally selected. Encapsulating CPT11 with PEO-7000K in PC90C10P10/30 further enhanced the resultant hydrogel to be gastro-retainable and to release CPT11 in a sustained manner. Pharmacokinetic study of CPT11-loaded PC90C10P0 administered orally revealed an absolute bioavailability (FAB, vs. intravenous CPT11) of 7.8 ± 1.01% and a relative bioavailability (FRB1, vs. oral solution of CPT11) of 70.7 ± 8.6% with a longer half-life (T1/2) and mean residence time (MRT). Among the dual-function inhibitors, SM was shown to be the most influential in increasing the oral bioavailability of CPT11. SM also increased the plasma concentration of the SN-38 active metabolite, which formed from the enhanced plasma concentration of CPT11. It is concluded that treatment with CPT11 loaded in PC90C10P0 with or without solubilization with SM could expose tumors to higher plasma concentrations of both CPT11 and SN-38 leading to enhancement of tumor growth inhibition with no signs of adverse effects.

Active Tumoral/Tumor Environmental Dual-Targeting by Non-Covalently Arming with Trispecific Antibodies or Dual-Bispecific Antibodies on Docetaxel-Loaded mPEGylated Nanocarriers to Enhance Chemotherapeutic Efficacy and Minimize Systemic Toxicity.

PURPOSE: This study was aimed at developing the trispecific antibodies (anti-EGFR/anti-FAP/anti-mPEG, TsAb) or dual bispecific antibodies (anti-EGFR/anti-mPEG and anti-FAP/anti-mPEG) docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micelles (mPEG-lsbPMs) for improving the targeting efficiency and therapeutic efficacy. METHODS: mPEG-lsbPMs were simply prepared via thin film method. The trispecific antibodies or bispecific antibodies bound the mPEG-lsbPMs by anti-mPEG Fab fragment. The formulations were characterized by DLS and TEM; in vitro and in vivo studies were also conducted to evaluate the cellular uptake, cell cytotoxicity and therapeutic efficacy. RESULTS: The particle sizes of mPEG-lsbPMs with or without the antibodies were around 100 nm; the formulations showed high encapsulation efficiencies of 97.12%. The TsAb and dual bispecific antibodies were fabricated and demonstrated their targeting ability. Two EGFR-overexpressed cell lines (HT-29 and MIA PaCa-2) were co-cultured with FAP-overexpressed WS1 cells (HT-29/WS1; MIA PaCa-2/WS1) to mimic a tumor coexisting in the tumor microenvironment. Cellular binding study revealed that the binding of anti-FAP micelles to three co-culture ratios (4:1, 1:1, and 1:4) of HT-29/EGFR to WS1/FAP was significantly higher than that for TsAb micelles and dual (1:1) micelles, and the binding of those targeting antibodies to WS1/FAP and MIA PaCa-2/EGFR was equally efficacious resulting in a similar binding amount of the TsAb and dual BsAbs (1:1) with the co-culture of MIA PaCa-2/EGFR and WS1/FAP at a 1:1 ratio. Antitumor efficacy study showed that treatment with DTX-loaded mPEG-lsbPMs modified with or without BsAbs, dual BsAbs (1:1), and TsAbs was enhanced in inhibiting tumor growth compared with that for Tynen® while showing fewer signs of adverse effects. CONCLUSION: Active targeting of both tumors and TAF-specific antigens was able to increase the affinity of DTX-loaded mPEG-lsbPMs toward tumor cells and TAFs leading to successive uptake by tumor cells or TAFs which enhanced their chemotherapeutic efficacy against antigen-positive cancer cells.

Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity.

Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, was recently identified as an important mechanism in radiotherapy (RT)-mediated tumor suppression and radioresistance, although the exact genetic contexts in which to target ferroptosis in RT remains to be defined. p53 is the most commonly mutated gene in human cancers and a major effector to RT. Here, we identify ferroptosis as a critical mechanism to mediate p53 function in tumor radiosensitivity. Mechanistically, RT-mediated p53 activation antagonizes RT-induced SLC7A11 expression and represses glutathione synthesis, thereby promoting RT-induced lipid peroxidation and ferroptosis. p53 deficiency promotes radioresistance in cancer cells or tumors at least partly through SLC7A11-mediated ferroptosis inhibition. Ferroptosis inducers (FINs) that inhibit SLC7A11 exert significant radiosensitizing effects in tumor organoids and patient-derived xenografts with p53 mutation or deficiency. Finally, we show that RT-induced ferroptosis correlates with p53 activation and better clinical outcomes to RT in cancer patients. Together, our study uncovers a previously unappreciated role of ferroptosis in p53-mediated radiosensitization and suggest using FINs in combination with RT to treat p53-mutant cancers.

mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation.

Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.

H2A Monoubiquitination Links Glucose Availability to Epigenetic Regulation of the Endoplasmic Reticulum Stress Response and Cancer Cell Death.

Epigenetic regulation of gene transcription has been shown to coordinate with nutrient availability, yet the mechanisms underlying this coordination remain incompletely understood. Here, we show that glucose starvation suppresses histone 2A K119 monoubiquitination (H2Aub), a histone modification that correlates with gene repression. Glucose starvation suppressed H2Aub levels independently of energy stress-mediated AMP-activated protein kinase activation and possibly through NADPH depletion and subsequent inhibition of BMI1, an integral component of polycomb-repressive complex 1 (PRC1) that catalyzes H2Aub on chromatin. Integrated transcriptomic and epigenomic analyses linked glucose starvation-mediated H2Aub repression to the activation of genes involved in the endoplasmic reticulum (ER) stress response. We further showed that this epigenetic mechanism has a role in glucose starvation-induced cell death and that pharmacologic inhibition of glucose transporter 1 and PRC1 synergistically promoted ER stress and suppressed tumor growth in vivo. Together, these results reveal a hitherto unrecognized epigenetic mechanism coupling glucose availability to the ER stress response. SIGNIFICANCE: These findings link glucose deprivation and H2A ubiquitination to regulation of the ER stress response in tumor growth and demonstrate pharmacologic susceptibility to inhibition of polycomb and glucose transporters.

Preparation and Characterization of a Novel Swellable and Floating Gastroretentive Drug Delivery System (sfGRDDS) for Enhanced Oral Bioavailability of Nilotinib.

Regarding compliance and minimization of side effects of nilotinib therapy, there is a medical need to have a gastroretentive drug delivery system (GRDDS) to enhance the oral bioavailability that is able to administer an optimal dose in a quaque die (QD) or daily manner. In this study, the influence on a swelling and floating (sf) GRDDS composed of a polymeric excipient (HPMC 90SH 100K, HEC 250HHX, or PEO 7000K) and Kollidon® SR was examined. Results demonstrated that PEO 7000K/Kollidon SR (P/K) at a 7/3 ratio was determined to be a basic GRDDS formulation with optimal swelling and floating abilities. MCC PH102 or HPCsssl,SFP was further added at a 50% content to this basic formulation to increase the tablet hardness and release all of the drug within 24 h. Also, the caplet form and capsule form containing the same formulation demonstrated higher hardness for the former and enhanced floating ability for the latter. A pharmacokinetic study on rabbits with pH values in stomach and intestine similar to human confirmed that the enhanced oral bioavailability ranged from 2.65-8.39-fold with respect to Tasigna, a commercially available form of nilotinib. In conclusion, the multiple of enhancement of the oral bioavailability of nilotinib with sfGRDDS could offer a pharmacokinetic profile with therapeutic effectiveness for the QD administration of a reasonable dose of nilotinib, thereby increasing compliance and minimizing side effects.

Stearyl polyethylenimine complexed with plasmids as the core of human serum albumin nanoparticles noncovalently bound to CRISPR/Cas9 plasmids or siRNA for disrupting or silencing PD-L1 expression for immunotherapy.

PURPOSE: In this study, a double emulsion method for complexing plasmids with stearyl poly-ethylenimine (stPEI) as the core to form human serum albumin (HSA) (plasmid/stPEI/HSA) nanoparticles (NPs) was developed for gene delivery by non-covalently binding onto plasmid/stPEI/HSA nanoparticles with CRISPR/Cas9 or siRNA, which disrupts or silences the expression of programmed cell death ligand-1 (PD-L1) for immunotherapy. MATERIALS AND METHODS: Chemically synthesized stearyl-polyethyenimine (stPEI)/plasmids/HSA nanoparticles were maded by double emulsion method. They were characterized by dynamic light scattering (DLS), transmission electron microscope and also evaluated by in vitro study on CT 26 cells. RESULTS: stPEI was synthesized by an N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC)-N-hydroxysuccinimide (NHS) reaction, and we found that the degree of substitution was ~1.0 when the ratio of PEI to stearic acid was 1:7 in the reaction. Then, two sgRNA sequences were selected and evaluated for their ability to knock out PD-L1 by decreasing its expression by about 20%. Based on the trend of particle size/zeta potential values as a function of ratio, F25P1 containing 25 µg of plasmid/stPEI/HSA NPs noncovalently bound to 1 µg plasmids via charge-charge interactions was found to be optimal. Its particle size was about 202.7±4.5 nm, and zeta potential was 12.60±0.15 mV. In an in vitro study, these NPs showed little cytotoxicity but high cellular uptake. Moreover, they revealed the potential for transfection and PD-L1 knockout in an in vitro cell model. Furthermore, F25P1S0.5 containing 25 µg of plasmid/stPEI/HSA NPs noncovalently bound to 1 µg of plasmids and 0.5 µg siRNA was prepared to simultaneously deliver plasmids and siRNA. An in vitro study demonstrated that the siRNA did not interfere with the transfection of plasmids and showed a high-transfection efficiency with a synergistic effect on inhibition of PD-L1 expression by 21.95%. CONCLUSION: The plasmids/stPEI/HSA NPs could be a promising tool for gene delivery and improved immunotherapy.

MicroRNA-144-3p inhibits cell proliferation and induces cell apoptosis in prostate cancer by targeting CEP55.

Previous research reported that miR-144-3p functions as tumor suppressor in several tumors, including glioblastoma and hepatocelluar carcinoma, but the role of miR-144-3p in prostate cancer (PCa) remains unclear. In this study, we aimed to analyze the role of miR-144-3p in PCa. By RT-qPCR, we found that expression of miR-144-3p was markedly down-regulated in PCa tissues and cell lines compared with that in paired adjacent normal tissues and normal cell lines. Moreover, miR-144-3p overexpression in PC-3 and DU145 cells by transfection with miR-144-3p mimics significantly inhibited cell proliferation and in vitro by MTT, colony formation assays and suppressed tumor growth in vivo by nude mice model. Flow cytometry analysis further demonstrated that forced expression of miR-144-3p induced cell cycle G1/S phase arrest and apoptosis. Moreover, centrosomal protein of 55 (CEP55) was confirmed as a direct target of miR-144-3p by bioinformatics analysis and luciferase reporter assays. Overexpression of miR-144-3p decreased the CEP5 mRNA and protein levels in PC-3 and DU145 cells. Using Oncomine database analysis, we further found the expression of CEP55 was significantly upregulated in PCa tissues. In addition, knockdown of CEP55 elicited similar effects with miR-144-3p overexpression in PCa cells. Taken together, our results demonstrate that miR-144-3p functions as a tumor suppressor in PCa by downregulating CEP55, supporting the targeting miR-144-3p might be a potentially effective therapeutic approach for PCa.

Collaborative Filtering Recommendation on Users' Interest Sequences.

As an important factor for improving recommendations, time information has been introduced to model users' dynamic preferences in many papers. However, the sequence of users' behaviour is rarely studied in recommender systems. Due to the users' unique behavior evolution patterns and personalized interest transitions among items, users' similarity in sequential dimension should be introduced to further distinguish users' preferences and interests. In this paper, we propose a new collaborative filtering recommendation method based on users' interest sequences (IS) that rank users' ratings or other online behaviors according to the timestamps when they occurred. This method extracts the semantics hidden in the interest sequences by the length of users' longest common sub-IS (LCSIS) and the count of users' total common sub-IS (ACSIS). Then, these semantics are utilized to obtain users' IS-based similarities and, further, to refine the similarities acquired from traditional collaborative filtering approaches. With these updated similarities, transition characteristics and dynamic evolution patterns of users' preferences are considered. Our new proposed method was compared with state-of-the-art time-aware collaborative filtering algorithms on datasets MovieLens, Flixster and Ciao. The experimental results validate that the proposed recommendation method is effective and outperforms several existing algorithms in the accuracy of rating prediction.

Enhanced photoelectrocatalytic performance of α-Fe2O3 thin films by surface plasmon resonance of Au nanoparticles coupled with surface passivation by atom layer deposition of Al2O3.

The short lifetime of photogenerated charge carriers of hematite (α-Fe2O3) thin films strongly hindered the PEC performances. Herein, α-Fe2O3 thin films with surface nanowire were synthesized by electrodeposition and post annealing method for photoelectrocatalytic (PEC) water splitting. The thickness of the α-Fe2O3 films can be precisely controlled by adjusting the duration of the electrodeposition. The Au nanoparticles (NPs) and Al2O3 shell by atom layer deposition were further introduced to modify the photoelectrodes. Different constructions were made with different deposition orders of Au and Al2O3 on Fe2O3 films. The Fe2O3-Au-Al2O3 construction shows the best PEC performance with 1.78 times enhancement by localized surface plasmon resonance (LSPR) of NPs in conjunction with surface passivation of Al2O3 shells. Numerical simulation was carried out to investigate the promotion mechanisms. The high PEC performance for Fe2O3-Au-Al2O3 construction electrode could be attributed to the Al2O3 intensified LSPR, effective surface passivation by Al2O3 coating, and the efficient charge transfer due to the Fe2O3-Au Schottky junctions.

Metformin Induced AMPK Activation, G0/G1 Phase Cell Cycle Arrest and the Inhibition of Growth of Esophageal Squamous Cell Carcinomas In Vitro and In Vivo.

Esophageal squamous cell carcinomas (ESCC) have become a severe threat to health and the current treatments for ESCC are frequently not effective. Recent epidemiological studies suggest that the anti-hyperglycemic agent metformin may reduce the risk of developing cancer, including ESCC, among diabetic patients. However, the antitumor effects of metformin on ESCC and the mechanisms underlying its cell cycle regulation remain elusive. The findings reported herein show that the anti-proliferative action of metformin on ESCC cell lines is partially mediated by AMPK. Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1. In vivo experiments further showed that metformin inhibited tumor growth in a ESCC xenograft model. Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo. In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model. AMPK, p53, p21CIP1, p27KIP1 and cyclinD1 are involved in the inhibition of tumor growth that is induced by metformin and cell cycle arrest in ESCC. These findings indicate that metformin has the potential for use in the treatment of ESCC.

AMP-activated protein kinase suppresses the in vitro and in vivo proliferation of hepatocellular carcinoma.

AMP-activated protein kinase (AMPK) is a central metabolic sensor and plays an important role in regulating glucose, lipid and cholesterol metabolism. Therefore, AMPK is a key therapeutic target in diabetes. Recent pilot studies have suggested that diabetes drugs may reduce the risk of cancer by affecting the AMPK pathway. However, the association between AMPK and the proliferation of hepatocellular carcinoma (HCC) is unknown. In this study, we investigated the relationship between AMPK activity and the proliferation of HCC in cell lines, nude mice and human clinic samples. We first investigated the relationship between AMPK activity and cell proliferation in two HCC cell lines, PLC/PRF/5 and HepG2, by two AMPK activators, 5-aminoimidazole-4-carboxamide-1-h-D-ribofuranoside (AICAR) and metformain. AICAR and metformin treatment significantly inhibited the proliferation of HCC cells and induced cell cycle arrest at G1-S checkpoint. We then observed that metformin abrogated the growth of HCC xenografts in nude mice. The clinical pathology of AMPK activity in HCC, including cell proliferation, differential grade, tumor size and microvessel density, was studied by using 30 clinical tissue samples. In HCC tissue samples, phosphorylated AMPK was expressed mainly in cytoplasm. AMPK activity decreased significantly in HCC in comparison with paracancerous liver tissues (P<0.05). AMPK activity was negatively correlated with the level of Ki-67 (a marker of cell proliferation), differential degradation and tumor size (P<0.05), but not with microvessel density, hemorrhage or necrosis in HCC. Our findings suggest that AMPK activity inhibits the proliferation of HCC and AMPK might be an effective target for prevention and treatment of HCC.

Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic ß cells.

Hyperuricaemia is a disorder of purine metabolism, and is strongly associated with insulin resistance and abnormal glucose metabolism. As the producer of insulin, pancreatic ß cells might be affected by elevated serum uric acid levels and contribute to the disregulated glucose metabolism. In this study, we investigated the effect of high uric acid on rat pancreatic ß cell function. Under high uric acid condition, proliferation of pancreatic ß cells was inhibited, production of reactive oxygen species increased, and glucose stimulated insulin secretion was also compromised. Further examination on signal transduction pathways revealed that uric acid-induced ROS is involved in the activation of adenosine monophosphate-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK). Pharmacological inhibition of ERK activation rescued ß cells from growth inhibition. More importantly, activation of ERK induced by uric acid is significantly diminished by AMPK inhibitor, indicating ERK as a downstream target of AMPK in response to high uric acid condition. We also investigated the transportation channel for uric acid into pancreatic ß cells. While major urate transporter URAT1 is not expressed in ß cells, organic anion transporter (OAT) inhibitor successfully blocked the activation of ERK by uric acid. Our data indicate that high uric acid levels induce oxidative damage and inhibit growth of rat pancreatic ß cells by activating the AMPK and ERK signal pathways. Hyperuricemia may contribute to abnormal glucose metabolism by causing oxidative damage and function inhibition of pancreatic ß cells.

[Genetic polymorphism of HSP70-1 gene and its correlation with resistance to mastitis in Chinese Holstein].

The polymorphisms of HSP70-1 gene in 253 Chinese Holstein dairy cows were studied, and the association between the polymorphisms and somatic cell score (SCS) were analyzed. PCR-SSCP, PCR-RFLP and DNA sequencing were used to investigate mutations in the coding region of HSP70-1 gene. The G-->A-->C mutation at 1 623 bp and G-->A mutation at 2 409 bp were found and both of them were silence mutations that caused no alteration in amino acid sequence. Chi-square test showed both loci were'nt at Hardy-Weinberg disequilibrium in Chinese Holstein. In the meanwhile, the association of 2 409 locus and SCS was not significant. However, the polymorphism at 1623 locus affected SCS significantly (P<0.05). The SCS of genotype CC was significantly lower than that of genotype AG and GG (P<0.05), so genotype CC was mastitis resistant. These results suggest that genotype CC of HSP70-1 gene may be used as a molecular and genetic marker to improve the phenotype of anti-mastitis in Chinese Holstein dairy cows.