Mannose-Integrated Nanoparticle Hitchhike Glucose Transporter 1 Recycling to Overcome Various Barriers of Oral Delivery for Alzheimer's Disease Therapy.

A brain-targeting nanodelivery system has been a hot topic and has undergone rapid progression. However, due to various obstacles such as the intestinal epithelial barrier (IEB) and the blood-brain barrier (BBB), few nanocarriers can achieve brain-targeting through oral administration. Herein, an intelligent oral brain-targeting nanoparticle (FTY@Man NP) constructed from a PLGA-PEG skeleton loaded with fingolimod (FTY) and externally modified with mannose was designed in combination with a glucose control strategy for the multitarget treatment of Alzheimer's disease (AD). The hydrophilic and electronegative properties of the nanoparticle facilitated its facile penetration through the mucus barrier, while the mannose ligand conferred IEB targeting abilities to the nanoparticle. Subsequently, glycemic control allowed the mannose-integrated nanoparticle to hitchhike the glucose transporter 1 (GLUT1) circulation across the BBB. Finally, the released FTY modulated the polarity of microglia from pro-inflammatory M1 to anti-inflammatory M2 and normalized the activated astrocyte, enhancing the clearance of toxic protein Amyloid-ß (Aß) while alleviating oxidative stress and neuroinflammation. Notably, both in vitro and in vivo results have consistently demonstrated that the oral administration of FTY@Man NP could effectively traverse the multiple barriers, thereby exerting significant therapeutic effects. This breakthrough holds the promise of realizing a highly effective orally administered treatment for AD.

Hollow copper sulfide nanoparticles carrying ISRIB for the sensitized photothermal therapy of breast cancer and brain metastases through inhibiting stress granule formation and reprogramming tumor-associated macrophages.

As known, the benefits of photothermal therapy (PTT) are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins (HSPs). Then HSPs further trigger the formation of stress granules (SGs) that regulate protein expression and cell viability under various stress conditions. Inhibition of SG formation can sensitize tumor cells to PTT. Herein, we developed PEGylated pH (low) insertion peptide (PEG-pHLIP)-modified hollow copper sulfide nanoparticles (HCuS NPs) encapsulating the SG inhibitor ISRIB, with the phase-change material lauric acid (LA) as a gate-keeper, to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system (IL@H-PP). The nanomedicine could specifically target slightly acidic tumor sites. Upon irradiation, IL@H-PP realized PTT, and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT, thereby increasing the antitumor effect and inducing potent immunogenic cell death (ICD). Moreover, IL@H-PP could promote the production of reactive oxygen species (ROS) by tumor-associated macrophages (TAMs), repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment. In vitro/vivo results revealed the potential of PTT combined with SG inhibitors, which provides a new paradigm for antitumor and anti-metastases.

Hsp70-Targeting and Size-Tunable Nanoparticles Combine with PD-1 Checkpoint Blockade to Treat Glioma.

Invasive glioma usually disrupts the integrity of the blood-brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting ability is still avidly needed to improve drug accumulation in glioma. Membrane-bound heat shock protein 70 (Hsp70) is expressed on the membrane of glioma cells rather than adjacent normal cells, therefore it can serve as a specific glioma target. Meanwhile, prolonging the retention in tumors is important for active-targeting nanoparticles to overcome receptor-binding barriers. Herein, the Hsp70-targeting and acid-triggered self-assembled gold nanoparticles (D-A-DA/TPP) are proposed to realize selective delivery of doxorubicin (DOX) to glioma. In the weakly acidic glioma matrix, D-A-DA/TPP formed aggregates to prolong retention, improve receptor-binding efficiency and facilitate acid-responsive DOX release. DOX accumulation in glioma induced immunogenic cell death (ICD) to promote antigen presentation. Meanwhile, combination with the PD-1 checkpoint blockade further activate T cells and provokes robust anti-tumor immunity. The results showed that D-A-DA/TPP can induce more glioma apoptosis. Furthermore, in vivo studies indicated D-A-DA/TPP plus PD-1 checkpoint blockade significantly improved median survival time. This study offeres a potential nanocarrier combining size-tunable strategy with active targeting ability to increase drug enrichment in glioma and synergizes with PD-1 checkpoint blockade to achieve chemo-immunotherapy.

Insight into mechanism of quality changes in tilapia fillets during salting from physicochemical and microstructural perspectives.

The effects and mechanisms of salting on quality properties of tilapia fillets were investigated in the present study. Salting under high NaCl concentrations (12 % and 15 %) resulted in low water content and decreased yields, due to the salting-out effects and low pH. Water in fillets increased in the later stage of salting in 3 % and 6 % NaCl solutions (p < 0.05). The released proteins accumulated with increasing time (p < 0.05). The TBARS value increased from 0.01 to 0.20 mg/kg after 10 h in 15 % NaCl solution (p < 0.05). The quality changes were mainly correlated to the shrinking or swelling of myofibers, extracellular spaces, and existential state of muscle proteins. In consideration of fish quality and increasing call for low sodium intake, it was recommended to prepare fillets below 9 % NaCl with short times. The finding provided instructions to obtain target quality properties from tilapia by controlling salting conditions.

Human cytomegalovirus-encoded microRNAs expression profile in plasma of patients with aortic dissection.

BACKGROUND: Aortic dissection (AD) is a rare disease with high mortality for which no effective diagnostic biomarkers are available. Human cytomegalovirus (HCMV) infection is an important cause of the occurrence and progression of many diseases, but the relationship between HCMV infection and AD is not clear. METHODS: In this study, we first used quantitative reverse transcription polymerase chain reaction (qRT-PCR) to determine the expression profile of 25 HCMV-encoded microRNAs (HCMV miRNAs) in the plasma within a training set consisting of 20 AD patients and 20 healthy controls. Then, abnormal expressed HCMV miRNAs were verified in a validation set of 12 AD patients and 12 healthy controls. In addition, HCMV infection was detected in the third cohort consisting of 20 AD patients and 20 healthy controls. RESULTS: The 95% quantile of the expression levels of HCMV miRNAs in the training set was used as the threshold for distinction between AD patients and healthy controls. The proportion of individuals with high level of five types of HCMV miRNAs was significantly different between AD patients and healthy controls. In the validation set, only the proportion of individuals with high levels of hcmv-miR-UL112-5p and hcmv-miR-UL22A-5p, two of the five HCMV miRNAs obtained in the preliminary screening, showed significant difference between AD patients and healthy controls. In the third cohort, there was no significant difference in HCMV DNA levels and anti-HCMV IgG concentrations between AD patients and healthy controls. CONCLUSIONS: The HCMV miRNAs levels in plasma differed in AD patients and healthy controls. This finding may contribute to a further understanding of the relationship between HCMV infection and AD and are worthy of future research on the diagnosis and etiology of AD.

Co-delivery of ibrutinib and hydroxychloroquine by albumin nanoparticles for enhanced chemotherapy of glioma.

Ibrutinib (IBR) is an oral covalent inhibitor of Bruton's tyrosine kinase (BTK) that has been approved for the treatment of hematological malignancies. It was reported that IBR exhibited great therapeutic potential for glioma. However, the poor water solubility and high hepatic first-pass effect restrict its anti-glioma application. Meanwhile, IBR induces cytoprotective autophagy through Akt/mTOR signaling pathway, thus leading to a compromised antitumor effect. Herein, we aimed to develop a human serum albumin (HSA) based co-delivery system (IBR&HCQ HSA NPs) encapsulating IBR and hydroxychloroquine (HCQ). The bioavailability of IBR was largely improved, and enhanced sensitivity of glioma to IBR was achieved due to inhibition effect of HCQ on IBR-induced pro-survival autophagy. The physicochemical properties of IBR&HCQ HSA NPs were characterized to optimize the formulation. Biodistribution investigation revealed that HSA NPs (20 mg/kg, i.v.) dramatically increased the accumulation of IBR in glioma, which was 5.59 times higher than that of free IBR (100 mg/kg, i.g.). CCK-8 and apoptosis assays demonstrated that IBR&HCQ HSA NPs showed maximal cytotoxicity to C6 cells. In vivo studies indicated that the survival time was significantly prolonged in IBR&HCQ HSA NPs treated mice compared to those treated with IBR HSA NPs. Taken together, the HSA-based drug delivery system of IBR and HCQ opens a new avenue for efficient treatment of glioma.

Physicochemical and microstructural mechanisms for quality changes in lightly salted tilapia (Oreochromis niloticus) fillets during frozen storage.

BACKGROUND: Frozen tilapia fillet has become a leading aquatic product. High drip loss, dry and fibrous mouthfeel, and an unappealing appearance are its main problems. It was hypothesized that light salting could improve the quality, and that the preparation conditions would affect the storage stability of frozen tilapia fillets. RESULTS: The quality changes of lightly salted tilapia fillets were evaluated during frozen storage, and the underlying mechanisms were studied from the physicochemicaland microstructural perspectives. Though the salt content was 1.5% in all samples,the amount of ice crystals in frozen tissues decreased with the descending water content and freezing point (P < 0.05). No intracellular voids were observed in the samples prepared under proper salting conditions, and the myofibers were plump and smooth after freezing-thawing, which contributed to the high water-holding capacity of lightly salted fillets. After 28 days,the water-binding capacity of the salted groups was 14.69%-18.62% higher than that of their unsalted counterparts (P < 0.05). The reduced protein solubility in the salted fillets was likely to have occurred because the solubilized and unfolded proteins interacted more easily during frozen storage. The oxidation degree of myofibrillar proteins was also affected by salting condition, and the fillets with less oxidized sulfhydryl groups maintained high springiness after 28 days of frozen storage. CONCLUSION: The salting condition of 9% NaCl solution for 1 h was recommended for the preparation of lightly salted fillets from freshwater fish, taking into account quality, processing efficiency, and storage stability. The enhanced water-holding capacity and texture of lightly salted tilapia fillets were attributed to modified physicochemical and microstructural properties. These results could provide a scientific basis for the processing and storage of high-quality, frozen, lightly salted fillets from freshwater fish. © 2022 Society of Chemical Industry.

Diminazene aceturate mitigates cardiomyopathy by interfering with renin-angiotensin system in a septic rat model.

BACKGROUND: There were limited studies investigating treatments of septic cardiomyopathy (SCM), which is a common complication during sepsis. A septic rat model created by cecal ligation and puncture (CLP) was used to investigate the effects of diminazene aceturate (DIZE) in SCM. METHODS: A total of 151 Wistar rats were randomly assigned into the sham, CLP, or CLP + DIZE group. Data evaluated postoperatively at 6, 12, 24, and 48 hours included: cardiac function; plasma concentrations of tumor necrosis factor-alpha (TNF-α), interleukin-6, angiotensin-(1-7) [Ang-(1-7)], angiotensin II (AngII), troponin I, and brain natriuretic peptide; expression levels of myocardial Ang-(1-7), angiotensin-converting enzyme (ACE), ACE2, and angiotensin type 1 and Mas receptors; and histological changes. RESULTS: We found that the CLP + DIZE group had a lower mortality compared to the CLP group (38.5% versus 61.5%) within 48 h postoperatively, although without statistical significance. In contrast to the sham group, the CLP group had decreased cardiac functions, increased myocardial injuries, and higher TNF-α levels, which were ameliorated in the CLP + DIZE group. Furthermore, administration of DIZE could reverse the decreases of myocardial Ang-(1-7) and ACE2 expressions in the CLP group, which finally minimized the myocardial microstructure disruptions. CONCLUSIONS: It was concluded that DIZE could mitigate the development of SCM and preserve cardiac function during sepsis possibly by interfering with the renin-angiotensin system through promoting myocardial ACE2 expression and restoring local Ang-(1-7) levels.

Selective detection of sulfasalazine antibiotic and its controllable photodegradation into 5-aminosalicylic acid by visible-light-responsive metal-organic framework.

The extensive use of sulfasalazine (SSZ) antibiotics has brought potential threats to aquatic ecosystems and human health. Thus, necessary measures for the removal of SSZ must be taken to prevent arbitrary antibiotic exposure to the aquatic environment. However, not all the recent photocatalysts that have been used for the degradation of SSZ could not achieve the controlled release of SSZ and hence are losing their medicinal values. Herein, by utilizing an Eosin Y moiety as an efficient light-harvesting and emission site, an Eosin Y-based visible-light-responsive metal-organic framework has been synthesized and characterized, which exhibits high selectivity for detecting the antibiotic SSZ in water and simulated physiological conditions, with a detection limit of below 1 µM (0.4 µg mL-1). It also represents the first example of a MOF-based photocatalyst for the controllable degradation of SSZ into 5-aminosalicylic acid with excellent catalytic activity and recyclability.

Toxicity assessment and microbial response to soil antibiotic exposure: differences between individual and mixed antibiotics.

Increasing amounts of antibiotics are introduced into soils, raising great concerns on their ecotoxicological impacts on the soil environment. This work investigated the individual and joint toxicity of three antibiotics, tetracycline (TC), sulfonamide (SD) and erythromycin (EM) via a whole-cell bioreporter assay. TC, SD and EM in aqueous solution demonstrated cytotoxicity, whilst soil exposure showed genotoxicity, indicating that soil particles possibly affected the bioavailability of antibiotics. Toxicity of soils exposed to TC, SD and EM changed over time, demonstrating cytotoxic effects within 14-d exposure and genotoxic effects after 30 days. Joint toxicity of TC, SD and EM in soils instead showed cytotoxicity, suggesting a synergetic effect. High-throughput sequencing suggested that the soil microbial response to individual antibiotics and their mixtures showed a different pattern. Soil microbial community composition was more sensitive to TC, in which the abundance of Pseudomonas, Pirellula, Subdivision3_genera_incertae_sedis and Gemmata varied significantly. Microbial community functions were significantly shifted by EM amendments, including signal transduction mechanisms, cytoskeleton, cell wall/membrane/envelope biogenesis, transcription, chromatin structure and dynamics, and carbohydrate transport and metabolism. This work contributes to a better understanding of the ecological effects and potential risks of individual and joint antibiotics on the soil environment.

The impact of Flavourzyme on flavor, antioxidant activity, and sensory attributes of salted grass carp by brine injection and brining.

BACKGROUND: Enzyme injection is vital for improving the sensory attributes and processing characteristics of meat products by enhancing proteolysis. However, studies regarding the appropriate dose addition for accelerating protein degradation in grass carp are minimal. This study aimed to investigate the impact of Flavourzyme® on the flavor quality and antioxidant activity of salted grass carp via brine injection and brining. RESULTS: Flavourzyme was added at doses of 0, 5, 10, 20, and 30 leucine aminopeptidase units (LAPU) per kilogram of raw meat. The results indicated that adding Flavourzyme promoted proteolysis, which was reflected by the enhanced total free amino acid content (from 3.7414 g kg-1 to 4.9160 g kg-1 in the brining group and from 3.8039 g kg-1 to 5.4061 g kg-1 in the injection group) and a decrease in salt soluble and insoluble protein (P < 0.05). The antioxidant activity was improved, and the thiobarbituric acid reactive substance value in salted carp decreased due to the higher content of the protein hydrolysis product (P < 0.05). All sensory attributes were improved significantly, especially when using brine injection (P < 0.05). Brine injection was helpful to diffuse the Flavourzyme, resulting in stronger proteolysis. CONCLUSION: The appropriate Flavourzyme dose was 10 LAPU kg-1 in the injection group and 20 LAPU kg-1 in the brining group. Therefore, moderate Flavourzyme addition was excellent in improving sensory attributes and storage characteristics, whereas injection represented a novel method to obtain a similar fish meat quality in a shorter time and with less added Flavourzyme. © 2021 Society of Chemical Industry.

Changes in Gel Structure and Chemical Interactions of Hypophthalmichthys molitrix Surimi Gels: Effect of Setting Process and Different Starch Addition.

The modifications of histological properties and chemical forces on heated surimi gels with starch addition (0-12 g/100 g surimi) were investigated. Two types of heating processes (direct heating and two-step heating) were carried out on surimi gels in order to reveal the effect of setting on mixed matrices. The results of transverse relaxation time showed less immobile water and free water converted into bound water in a matrix subjected to the setting process. Scanning electron microscope and light microscopy images revealed inefficient starch-swelling in two-step heated gels. Chemical interactions and forces in direct cooking gels were more vulnerable to starch addition, resulting in significant decreases in hydrophobic interaction and sulfhydryl content (p < 0.05). With the increment of starch, the disulfide stretching vibrations of the gauche-gauche-gauche conformation were reduced in both gel matrices. The structural variations of different components collectively resulted in changes in texture profile analysis and water holding capacity. Overall, the results demonstrated that starch addition had a great and positive effect on the weak gel matrix by direct heating.

The effect of speech material on the band importance function for Mandarin Chinese.

Speech material influences the relative contributions of different frequency regions to intelligibility for English. In the current study, whether a similar effect of speech material is present for Mandarin Chinese was investigated. Speech recognition was measured using three speech materials in Mandarin, including disyllabic words, nonsense sentences, and meaningful sentences. These materials differed from one another in terms of the amount of contextual information and word frequency. The band importance function (BIF), as defined under the Speech Intelligibility Index (SII) framework, was used to quantify the contributions across frequency regions. The BIFs for the three speech materials were estimated from 16 adults who were native speakers of Mandarin. A Bayesian adaptive procedure was used to efficiently estimate the octave-frequency BIFs for the three materials for each listener. As the amount of contextual information increased, low-frequency bands (e.g., 250 and 500 Hz) became more important for speech recognition, consistent with English. The BIF was flatter for Mandarin than for comparable English speech materials. Introducing the language- and material-specific BIFs to the SII model led to improved predictions of Mandarin speech-recognition performance. Results suggested the necessity of developing material-specific BIFs for Mandarin.

Evaluation of feedforward and feedback contributions to hand stiffness and variability in multijoint arm control.

The purpose of this study is to validate a neuromechanical model of the virtual arm (VA) by comparing emerging behaviors of the model to those of experimental observations. Hand stiffness of the VA model was obtained by either theoretical computation or simulated perturbations. Variability in hand position of the VA was generated by adding signal dependent noise (SDN) to the motoneuron pools of muscles. Reflex circuits of Ia, Ib and Renshaw cells were included to regulate the motoneuron pool outputs. Evaluation of hand stiffness and variability was conducted in simulations with and without afferent feedback under different patterns of muscle activations during postural maintenance. The simulated hand stiffness and variability ellipses captured the experimentally observed features in shape, magnitude and orientation. Steady state afferent feedback contributed significantly to the increase in hand stiffness by 35.75±16.99% in area, 18.37±7.80% and 16.15±7.15% in major and minor axes; and to the reduction of hand variability by 49.41±21.19% in area, 36.89±12.78% and 18.87±23.32% in major and minor axes. The VA model reproduced the neuromechanical behaviors that were consistent with experimental data, and it could be a useful tool for study of neural control of posture and movement, as well as for application to rehabilitation.

Dynamic simulation of perturbation responses in a closed-loop virtual arm model.

A closed-loop virtual arm (VA) model has been developed in SIMULINK environment by adding spinal reflex circuits and propriospinal neural networks to the open-loop VA model developed in early study [1]. An improved virtual muscle model (VM4.0) is used to speed up simulation and to generate more precise recruitment of muscle force at low levels of muscle activation. Time delays in the reflex loops are determined by their synaptic connections and afferent transmission back to the spinal cord. Reflex gains are properly selected so that closed-loop responses are stable. With the closed-loop VA model, we are developing an approach to evaluate system behaviors by dynamic simulation of perturbation responses. Joint stiffness is calculated based on simulated perturbation responses by a least-squares algorithm in MATLAB. This method of dynamic simulation will be essential for further evaluation of feedforward and reflex control of arm movement and position.

Magnetically responsive phase-change microspheres with large magnetization using ferrite nanoparticles.

Magnetically responsive phase-change microspheres were prepared and studied in this article. In the synthetic process, oleic acid was used to modify the iron oxide nanoparticles. The ferrite nanoparticles, about 10 nm in diameter, were highly dispersed due to the oleic acid on the surface of the particles, and they were encapsulated in polymethyl methacrylate (PMMA) by microemulsion polymerization with paraffin, which could be presumed from the differential scanning calorimetry (DSC) curves. According to the morphology in the scanning electron microscopy (SEM) image, the average diameter of the microspheres was about 200 nm, a large amount of nano-sized ferrite can be observed in a transmission electron microscope (TEM) image showing the structure of the microspheres. Finally, in the magnetization curve from a vibrating sample magnetometer, the saturation magnetization of microspheres was 12.2 emu/g, which was effective in the compatibility of infrared simulation and microwave absorption.

[Effect of Ce3+ implantation on photoluminescence intensity of Si nanocrystals embedded in superlattices].

In the present paper, SiO/SiO2 superlattices samples were prepared on Si substrates by electron beam evaporation. The samples were annealed in nitrogen atmosphere at high temperature subsequently. And then, Ce3+ ions with a dose of 2.0 x 10(14) and 2.0 x 10(15) cm(-2) respectively were implanted into these samples with formed Si nanocrystals. The photoluminescence (PL) spectra showed that the PL intensities of samples with Ce3+ implanting dropped sharply compared with the samples without Ce3+ implanting. The PL intensity increased gradually with increasing re-annealing temperature, but dropped again when the temperature exceeded 600 degrees C. The PL intensity even could be higher than that of samples without Ce3+ implanting if only the dose of Ce3+ was 2.0 x 10(14) cm(-2). When the dose of Ce3+ was 2.0 x 10(15) cm(-2), the PL intensity couldn't exceed that of samples without Ce3+ implanting even when the re-annealing temperature was 600 degrees C. Further investigations showed that the varieties of the PL intensities were mainly dependent on the re-annealing temperature, which had the best point at 600 degrees C, and the dose of Ce3+ had the right value. Furthermore, the experiment results proved that there was energy transfer from Ce3+ to Si nanocrystals in this kind of structure.

[Deposition and structures analysis of amorphous SiNx films prepared by magnetron sputtering].

Amorphous SiNx films were deposited on p-type Si(100)substrates by magnetron sputtering technology. The samples were then detected by a Bruker Tennsor 27 Fourier transform spectrometer. One intense absorption band of the SiNx films (from 812 to 892 cm(-1)) which was assigned to the stretching vibration mode of Si--N--Si bond was detected by Fourier transform infrared (FTIR) spectroscopy. Obviously, it was showed that a red shift of the absorption peak occurred in the FTIR spectrum with the sputtering power increasing; nevertheless, a blue shift of the absorption peak occurred after annealing with the temperature increasing. In the present paper, the deposition process and inner structures of the SiNx films were studied according to RBM (random bonding model)and CFM (central force model). With the increase in the ratio of N(Si)to N(N), the angle of the Si--N--Si changed and the different structures were formed correspondingly. Therefore the Si--Ny--Si(4-y) (0 < or = y < or = 4) models were set up to explain the inner structure of the SiNx films. The investigation showed that Si--N4 tetrahedron, Si--N--Si3, Si--N2--Si2, Si--N3--Si and Si--Si modes were formed accordingly in the SiNx films with the sputtering power increasing. And five models in total were formed during the deposition process. Different stretching vibration modes of Si--N--Si bond were corresponding to the different inner structures of thin films prepared by different sputtering power. With the temperature increasing, the activity of atoms increased which would let the angle of the Si--N--Si go to identical. As a result, Si3N4 and Si nanocrystals were formed with the phase separation of SiNx films during the annealing process with higher temperature, which would result in a blue shift to 870 cm(-1) (the standard absorption peak of Si3N4).