Tumor microenvironment-responsive size-changeable and biodegradable HA-CuS/MnO2 nanosheets for MR imaging and synergistic chemodynamic therapy/phototherapy.

Tumor microenvironment (TME)-responsive size-changeable and biodegradable nanoplatforms for multimodal therapy possess huge advantages in anti-tumor therapy. Hence, we developed a hyaluronic acid (HA) modified CuS/MnO2 nanosheets (HCMNs) as a multifunctional nanoplatform for synergistic chemodynamic therapy (CDT)/photothermal therapy (PTT)/photodynamic therapy (PDT). The prepared HCMNs exhibited significant NIR light absorption and photothermal conversion efficiency because of the densely deposited ultra-small sized CuS nanoparticles on the surface of MnO2 nanosheet. They could precisely target the tumor cells and rapidly decomposed into small sized nanostructures in the TME, and then efficiently promote intracellular ROS generation through a series of cascade reactions. Moreover, the local temperature elevation induced by photothermal effect also promote the PDT based on CuS nanoparticles and the Fenton-like reaction of Mn2+, thereby enhancing the therapeutic efficiency. Furthermore, the T1-weighted magnetic resonance (MR) imaging was significantly enhanced by the abundant Mn2+ ions from the decomposition process of HCMNs. In addition, the CDT/PTT/PDT synergistic therapy using a single NIR light source exhibited considerable anti-tumor effect via in vitro cell test. Therefore, the developed HCMNs will provide great potential for MR imaging and multimodal synergistic cancer therapy.

Self-adjuvant Astragalus polysaccharide-based nanovaccines for enhanced tumor immunotherapy: a novel delivery system candidate for tumor vaccines.

The study of tumor nanovaccines (NVs) has gained interest because they specifically recognize and eliminate tumor cells. However, the poor recognition and internalization by dendritic cells (DCs) and insufficient immunogenicity restricted the vaccine efficacy. Herein, we extracted two molecular-weight Astragalus polysaccharides (APS, 12.19 kD; APSHMw, 135.67 kD) from Radix Astragali and made them self-assemble with OVA257-264 directly forming OVA/APS integrated nanocomplexes through the microfluidic method. The nanocomplexes were wrapped with a sheddable calcium phosphate layer to improve stability. APS in the formed nanocomplexes served as drug carriers and immune adjuvants for potent tumor immunotherapy. The optimal APS-NVs were approximately 160 nm with uniform size distribution and could remain stable in physiological saline solution. The FITC-OVA in APS-NVs could be effectively taken up by DCs, and APS-NVs could stimulate the maturation of DCs, improving the antigen cross-presentation efficiency in vitro. The possible mechanism was that APS can induce DC activation via multiple receptors such as dectin-1 and Toll-like receptors 2 and 4. Enhanced accumulation of APS-NVs both in draining and distal lymph nodes were observed following s.c. injection. Smaller APS-NVs could easily access the lymph nodes. Furthermore, APS-NVs could markedly promote antigen delivery efficiency to DCs and activate cytotoxic T cells. In addition, APS-NVs achieve a better antitumor effect in established B16-OVA melanoma tumors compared with the OVA+Alum treatment group. The antitumor mechanism correlated with the increase in cytotoxic T cells in the tumor region. Subsequently, the poor tumor inhibitory effect of APS-NVs on the nude mouse model of melanoma also confirmed the participation of antitumor adaptive immune response induced by NVs. Therefore, this study developed a promising APS-based tumor NV that is an efficient tumor immunotherapy without systemic side effects.

Advances in herbal polysaccharides-based nano-drug delivery systems for cancer immunotherapy.

The boom in cancer immunotherapy has provided many patients with a better chance of survival, but opportunities often come with challenges. Single immunotherapy is not good enough to eradicate tumours, and often fails to achieve the desired therapeutic effect because of the low targeting of immunotherapy drugs, and causes more side effects. As a solution to this problem, researchers have developed several nano Drug Delivery Systems (NDDS) to deliver immunotherapeutic agents to achieve good therapeutic outcomes. However, traditional drug delivery systems (DDS) have disadvantages such as poor bioavailability, high cytotoxicity, and difficulty in synthesis, etc. Herbal Polysaccharides (HPS), derived from natural Chinese herbs, inherently possess low toxicity. Furthermore, the biocompatibility, biodegradability, hydrophilicity, ease of modification, and immunomodulatory activities of HPS offer unique advantages in substituting traditional DDS. This review initially addresses the current developments and challenges in immunotherapy. Subsequently, it focuses on the immunomodulatory mechanisms of HPS and their design as nanomedicines for targeted drug delivery in tumour immunotherapy. Our findings reveal that HPS-based nanomedicines exhibit significant potential in enhancing the efficacy of cancer immunotherapy, providing crucial theoretical foundations and practical guidelines for future clinical applications.

Correlation between dietary theobromine intake and low cognitive performance in older adults in the United States: A cross-sectional study based on the National Health and Nutrition Examination Survey.

BACKGROUND AND OBJECTIVES: Few studies have investigated the effects of dietary theobromine intake on the cognitive performance of older adults. Therefore, we investigated these effects in older adults in the United States. METHODS AND STUDY DESIGN: In this cross-sectional study, we used data (2011-2014) from the National Health and Nutrition Examination Survey. Intake of theobromine intake was obtained through two 24-h dietary recall interviews and was adjusted by energy. Cognitive performance was assessed using the animal fluency test, Consortium to Establish a Registry for Alzheimer's Disease Word Learning subtest (CERAD), and Digit Symbol Substitution Test (DSST). Logistic regression and restricted cubic spline models were constructed to evaluate the correlation between the dietary intake of theobromine from different sources and the likelihood of low cognitive performance. RESULTS: The fully adjusted model revealed that compared with the lowest quintile, the odds ratios (with 95% confidence intervals) of cognitive performance in the CERAD test were 0.42 (0.28-0.64), 0.34 (0.14-0.83), 0.25 (0.07-0.87), and 0.35 (0.13-0.95) for the highest quintile of total theobromine intake and that from chocolate, coffee, and cream, respectively. Dose-response relationship analysis indicated nonlinear correlations between the likelihood of low cognitive performance and die-tary theobromine (total intake and that from chocolate, coffee, and cream). An L-shaped relationship was ob-served between total theobromine intake and cognitive performance in the CERAD test. CONCLUSIONS: The dietary intakes of theobromine (total and that from chocolate, coffee, and cream) may protect older adults, particularly men, against low cognitive performance.

Dietary Supplemental Chromium Yeast Improved the Antioxidant Capacity, Immunity and Liver Health in Broilers under High Stocking Density.

This study was conducted to investigate the effects of different levels of yeast chromium on growth performance, organ index, antioxidant capacity, immune performance and liver health of broilers under high stocking density. A total of 684 1-day-old Arbor Acres broilers were selected and fed a common diet from 1 to 22 days of age. At the end of 22 days, broilers with similar weight were randomly divided into six treatments, with six replications in each treatment. The broilers in control groups were fed with a control diet and raised at low stocking density of broilers (14 broilers/m2, LSD) and high stocking density (20 broilers/m2, HSD). The broilers in treatment groups were fed with diets supplemented with 200, 400, 800 and 1600 µg Cr/kg chromium yeast (Cr-yeast) under HSD, respectively. The experimental period was 23~42 days. Compared with the LSD group, the HSD group significantly decreased the liver index (ratio of liver weight to live weight of broilers) of broilers (p < 0.05), the HSD group significantly increased the content of corticosterone (CORT) and the activities of alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and decreased the prealbumin (PA) level in the serum (p < 0.05). HSD decreased the total antioxidant capacity (T-AOC) contents in the serum, liver and breast, serum glutathione peroxidase (GSH-Px) activities, breast total superoxide dismutase (T-SOD) activities and liver catalase (CAT) activities of broilers (p < 0.05). The HSD group significantly increased the total histopathological score (p < 0.05). Compared with the HSD group, adding 200, 400, and 1600 Cr-yeast significantly increased the liver index of broilers (p < 0.05), all HSD + Cr-yeast groups decreased the ALT activities (p < 0.05), and the HSD + 800 group significantly decreased the CORT contents and the ALP activities of the serum (p < 0.05); the HSD + 400, 800 and 1600 groups increased the PA contents of the serum (p < 0.05); HSD + 800 group significantly reduced the tumor necrosis factor-α (TNF-α) and Interleukin-1ß (IL-1ß) contents of the serum (p < 0.05); moreover, the HSD + 400 group increased the GSH-Px activities of the serum (p < 0.05), the T-AOC and the T-SOD activities of the breast (p < 0.05) and the T-AOC and CAT activities of the liver (p < 0.05). Adding 800 Cr-yeast significantly decreased the total histopathological score (degree of hepatocyte edema and inflammatory cell infiltration) under HSD (p < 0.05). In summary, Cr-yeast can improve the antioxidant capacity and immune traits, and liver health of broilers under HSD. Based on the results of the linear regression analysis, the optimal supplementation of Cr-yeast in antioxidant capacity, immunity ability and liver health were at the range of 425.00−665.00, 319.30−961.00, and 800.00−1531.60 µg Cr/kg, respectively.

Low Level of Dietary Organic Trace Minerals Improved Egg Quality and Modulated the Status of Eggshell Gland and Intestinal Microflora of Laying Hens During the Late Production Stage.

This study aimed to investigate the effects of dietary organic trace minerals on egg quality and intestinal microflora of laying hens during the late production stage. In total, 1,080 Jinghong-1 laying hens aged 57 weeks were randomly assigned to five treatment groups: CON, basal diet containing about 6, 29, 49, and 308 mg·kg-1 of Cu, Mn, Zn, and Fe; IT100, basal diet supplemented with 10, 80, 80, and 60 mg·kg-1 of Cu, Mn, Zn, and Fe (each as inorganic sulfates), respectively; OT20, basal diet supplemented with 2, 16, 16, and 12 mg·kg-1 of Cu, Mn, Zn, and Fe (each as organic trace minerals chelated with lysine and methionine in the ratio of 2:1 amino acid: organic trace minerals), respectively; OT30, basal diet supplemented with 3, 24, 24, and 18 mg·kg-1 of organic Cu, Mn, Zn, and Fe, respectively; and OT50, basal diet supplemented with 5, 40, 40, and 30 mg·kg-1 of organic Cu, Mn, Zn, and Fe, respectively. Overall, OT20, OT30, and OT50 had equal or higher potential to promote Cu, Mn, Zn, and Fe deposition in egg yolks compared with IT100. In addition, OT50 enhanced the eggshell breaking strength and the antioxidant status of the eggshell gland. Cecal microbiota, including Barnesiellaceae and Clostridia, were significantly decreased in IT100- and OT50-treated hens compared with the CON group. Clostridia UCG-014 was negatively correlated with eggshell weight and OCX-32. In conclusion, reduced supplementation of organic trace minerals can improve the eggshell quality and trace mineral deposition, possibly by modulating genes involved in the eggshell formation in the eggshell gland and by controling of the potentially harmful bacteria Barnesiellaceae and Clostridiales in the cecum. Inorganic trace minerals may be effectively replaced by low level of complex organic trace minerals in laying hens during the late production stage.

High Dietary Organic Iron Supplementation Decreases Growth Performance and Induces Oxidative Stress in Broilers.

Although Iron (Fe) is an essential nutrient that plays a vital role in respiratory processes, excessive Fe in the diet can affect the health of broilers. We investigated the effects of diet supplemented with high levels of iron chelates with lysine and glutamic acid (Fe−LG) on the growth performance, serum biochemical parameters, antioxidant status, and duodenal mRNA expression of Fe transporters in broilers. A total of 800 1-day-old male Arbor Acres broilers were assigned to 5 groups, with 8 replicates each. Broilers were fed a corn−soybean meal basal diet or basal diets supplemented with 40, 80, 400, or 800 mg Fe/kg as Fe−LG for 6 weeks. The body weight (BW) was increased in the 80 mg Fe/kg treatment group, but decreased in the 800 mg Fe/kg treatment group on day 21. During days 1−21, compared with the control group, the supplementation of the 80 mg Fe/kg increased the average daily gain (ADG) and average daily feed intake (ADFI); however, the supplementation of the 800 mg Fe/kg group decreased the ADG and increased the FCR in broilers (p < 0.05). The heart, liver, spleen, and kidney indices were reduced in the 800 mg Fe/kg treatment group (p < 0.05). The supplementation of the 800 mg Fe/kg group increased the serum aspartate aminotransferase activity and the levels of creatinine and urea nitrogen on day 42 (p < 0.05). The broilers had considerably low liver total superoxide dismutase activity and total antioxidant capacity in the 800 mg Fe/kg treatment group (p < 0.05). Serum and liver Fe concentrations were elevated in the 400 and 800 mg Fe/kg treatment groups, but were not affected in the 40 and 80 mg Fe/kg treatment groups. The duodenal Fe transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) were downregulated in the Fe−LG treatment groups (p < 0.05). We conclude that a high dietary supplement of 800 mg Fe/kg in broilers leads to detrimental health effects, causing kidney function injury and liver oxidative stress.

Amyloid Protein-Biofunctionalized Polydopamine Nanoparticles Demonstrate Minimal Plasma Protein Fouling and Efficient Photothermal Therapy.

Polydopamine (PDA) shows great application potential in photothermal therapy (PTT) of tumors due to its excellent photothermal performance. However, PDA rich in a large number of catechin structures, with strong adhesion, can readily attach to plasma proteins in blood to form protein corona, which greatly hinders the transfer efficiency to tumors and reduces the bioavailability. In this paper, a simple, rapid phase-transitioned albumin biomimetic nanocorona (TBSA) is used for the surface camouflage of PDA nanoparticles for minimal plasma protein fouling and efficient PTT. TBSA coating is formed by the BSA-derived amyloid through the hydrophobic aggregation near the isoelectric point and the rupture of disulfide bonds by tris(2-carboxyethyl) phosphine. The stable PDA@TBSA complexes are formed by camouflaging TBSA onto the surface of PDA through hydrophobic, electrostatic, and covalent binding between TBSA and PDA, which showed excellent anti-plasma protein adsorption properties profited from the surface charge of PDA@TBSA approaching equilibrium and the surface passivation of BSA. The plasma protein thickness of the PDA@TBSA surface is 6 times lower than that of PDA at adsorption saturation. In vitro and in vivo experiments have revealed that PDA@TBSA has an excellent photothermal antitumor effect compared to PDA. Both PDA and PDA@TBSA treatment plus 808 nm laser irradiation result in more than 70% inhibition on tumor cell proliferation. In addition, PDA@TBSA does not cause a significant inflammatory response and tissue damage. Taken together, the TBSA coating endows PDA with low-fouling functions in blood and improves the residence time of PDA in blood and enrichment in the tumor tissue. This work offers a novel and efficient strategy for the design of functional nanosystems exploiting the speciality of the biomolecular corona formation around nanomaterials.

Effects of organic chromium sources on growth performance, lipid metabolism, antioxidant status, breast amino acid and fatty acid profiles in broilers.

BACKGROUND: Trivalent chromium (Cr) is involved in carbohydrate, lipid, protein and nucleic acid metabolism in animals. This study evaluated the effects of different organic Cr forms with Cr methionine (CrMet), Cr picolinate (CrPic), Cr nicotinate (CrNic), and Cr yeast (Cr-yeast) at the level of 400 µg kg-1 Cr, on growth performance, lipid metabolism, antioxidant status, breast amino acid and fatty acid profiles of broilers. In total, 540 one-day-old Arbor Acres male broilers were randomly assigned to five treatments with six replicates (18 broilers per replicate) until day 42. RESULTS: The results showed growth performance was not affected by Cr sources. The Cr-yeast group had lower serum cortisol levels than the CrNic group (P < 0.05). Besides, Cr-yeast increased methionine and cysteine content in breast compared with the control group. Liver malondialdehyde content was lower in the CrMet group than the CrPic group on day 42 (P < 0.05). The n-3 polyunsaturated fatty acid (PUFA) values were increased, but the n-6/n-3 PUFA ratio was decreased in both CrMet and CrNic groups (P < 0.05). There were no significant effects on broilers' serum antioxidant status and breast total essential amino acid content among all treatments. CONCLUSIONS: Diets supplemented with organic Cr could regulate lipid metabolism, and improve amino acid and fatty acid profiles in broiler breast. Moreover, Cr-yeast was the most effective source in improving methionine and cysteine content, whereas CrMet was more effective than CrNic in increasing n-3 PUFA value and decreasing n-6/n-3 PUFA ratio in breast meat and effectively strengthened liver antioxidant ability than CrPic. © 2020 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Effect of Zuoguiwan on osteoporosis in ovariectomized rats through RANKL/OPG pathway mediated by ß2AR.

ETHNOPHARMACOLOGICAL RELEVANCE: The deficiency of kidney Yin is the main pathogenesis of postmenopausal osteoporosis (PMOP) according to traditional Chinese medicine (TCM). Zuoguiwan (ZGW) is among the classical prescriptions in TCM and has been applied to various diseases that are due to deficiency of kidney Yin, including osteoporosis, fractures, menopausal syndromes. However, the underlying mechanism of ZGW in treating PMOP remains poorly understood. AIM OF THE STUDY: ZGW, a traditional Chinese prescription, has been used to nourish Yin and reinforce the kidney since ancient times. The investigation aimed to explore the mechanism of ZGW via the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling pathway as mediated by the ß2-adrenergic receptor (ß2AR) in an osteoporosis rat model. MATERIALS AND METHODS: An osteoporosis model induced by ovariectomy was established in rats. A total of 40 female Sprague-Dawley rats were randomly assigned into bilateral ovariectomy group (OVX), sham operated group (Sham), 17ß-estradiol-treated positive group (E2, 25 µg/kg/d), ZGW low-dose group (ZGW-L, 2.3 g/kg/d lyophilized powder) and ZGW high-dose group (ZGW-H, 4.6 g/kg/d lyophilized powder). The serum markers of bone turnover were measured using enzyme-linked immunosorbent assay (ELISA). The morphological structure changes in bones were detected through H&E staining. Local bone mineral density (BMD) and trabecular bone microarchitecture of the right distal femur were measured and evaluated by using micro-CT. Furthermore, the mRNA and protein expressions levels of ß2AR, OPG and RANKL were measured by qPCR and Western blot analysis. RESULTS: Compared with the OVX group, ZGW groups showed significantly reduced levels of serum tartrate-resistant acid phosphatase 5b (TRACP-5b) and ß-cross-linked c-telopeptide of type I collagen (ß-CTX) (P ＜ 0.01), increased levels of serum bone-specific alkaline phosphatase (BALP) (P ＜ 0.01) and OPG (P ＜ 0.05), prevention of OVX-induced bone loss, and improved microarchitecture of the trabecular bone of distal femur. Moreover, ZGW mediated the osteoporosis syndrome by reducing the empty bone lacunae, promoting the ordered arrangement of trabeculae structure, and increasing the trabeculae structure thickness. Furthermore, in ZGW groups, the protein expression of OPG in the tibia was notably up-regulated (P ＜ 0.01), whereas the mRNA and protein expression of ß2AR in the hippocampus (P ＜ 0.01), and the protein expressions levels of ß2AR (P ＜ 0.01) and RANKL (P ＜ 0.05) in the tibia were down-regulated compared with OVX group. CONCLUSIONS: ZGW through its protective effects, stimulates bone formation and suppresses bone resorption. The underlying mechanism of ZGW in improving perimenopausal syndrome and increasing bone mass might be attributed to the regulation of RANKL/OPG, as mediated by ß2AR. Therefore, ZGW may be used as an alternative treatment for PMOP.

Dietary ZnO nanoparticles alters intestinal microbiota and inflammation response in weaned piglets.

The present study was carried out to determine whether low dose of zinc oxide nanoparticles (Nano-ZnO) could serve as a potential substitute of pharmacological dose of traditional ZnO in weaned piglets. 180 crossbred weaning piglets were randomly assigned to 3 treatments. Experimental animals were fed basal diet supplemented with 0 mg Zn/kg (Control), 600 mg Zn/kg (Nano-ZnO) and 2000 mg Zn/kg (ZnO) for 14 days. On day 14 after weaning, the piglets fed Nano-ZnO did not differ from those fed traditional ZnO in growth performance and jejunal morphology, while Nano-ZnO treatment could significantly alleviate the incidence of diarrhea (P < 0.05). In jejunum, the mRNA expressions of intestinal antioxidant enzymes and tight junction proteins were increased (P < 0.05) in Nano-ZnO treatment. In ileum, the expression levels of IFN-γ, IL-1ß, TNF-α and NF-κB were decreased (P < 0.05). Gene sequencing analysis of 16S rRNA revealed that dietary Nano-ZnO increased the bacterial richness and diversity in ileum, while decreased both of them in cecum and colon. Specifically, the relative abundances of Streptococcus in ileum, Lactobacillus in colon were increased, while the relative abundances of Lactobacillus in ileum, Oscillospira and Prevotella in colon were decreased (P < 0.05). In conclusion, our data reveal that low dose of Nano-ZnO (600 mg Zn/kg) can effectively reduce piglet diarrhea incidence, similar to high dose of traditional ZnO (2000 mg Zn/kg), which may be mediated by improving intestinal microbiota and inflammation response in piglets, and help to reduce zinc environmental pollution.

Acupuncture for the treatment of allergic rhinitis: a systematic review and meta-analysis.

BACKGROUND: Because acupuncture may modulate the immune system, it has been proposed as a useful treatment for patients with allergic rhinitis (AR). Here, we assessed the evidence for the clinical efficacy of acupuncture for the management of AR patients by performing a systematic review and meta-analysis of the published literatures. METHODS: By searching PubMed, EMBASE, the Cochrane clinical trials database, and the China National Knowledge Infrastructure from 1980 through July 11, 2013, we collected and analyzed the randomized controlled trials (RCTs) of acupuncture for the treatment of AR patients to assess its efficacy and safety. RESULTS: Thirteen full papers that met our inclusion criteria were included, and a total of 2365 participants, including 1126 as treatment group and 1239 as control group, were enrolled. Compared with control group, acupuncture treatment group exerted a significant reduction in nasal symptom scores (weighted mean difference [WMD]: -4.42, 95% confidence interval [CI]: -8.42 to -0.43, p = 0.03), medication scores (WMD: 1.39, 95% CI: -2.18 to -0.61, p = .0005), and serum IgE (WMD: -75.00, 95% CI: -91.17 to -58.83, p < 0.00001). Data relating to Rhinitis Quality of Life Questionnaire (RQLQ) and 36-Item Short-Form (SF-36) component score in included studies were analyzed, which ultimately point to the efficacy of acupuncture treatment in improving quality of life in AR patients. No fatal events were reported in any of the included studies, and no serious systemic reaction, which needed treatment in the hospital, was related to the acupuncture treatment. CONCLUSION: Our meta-analysis suggests that that acupuncture could be a safe and valid treatment option for AR patients.

Semiclassical treatment of thermally activated electron transfer in the inverted region under the fast dielectric relaxation.

The previously formulated semiclassical theory (Zhao, Liang, and Nakamura, J. Phys. Chem. A 2006, 110, 8204) is used to study electron transfer in the Marcus inverted case by considering multidimensional potential energy surfaces of donor and acceptor. The Zhu-Nakamura formulas of nonadiabatic transition in the case of Landau-Zener type are incorporated into the approach. The theory properly takes into account the nonadiabatic transition coupled with the nuclear tunneling and can cover the whole range from weak to strong coupling regime uniformly under the assumption of fast solvent relaxation. The numerical calculations are performed for the 12-dimensional model of shifted harmonic oscillators and demonstrate that the reaction rate with respect to the electronic coupling shows a maximum, confirming the adiabatic suppression in the strong coupling limit. The adiabatic suppression is dramatically reduced by the effect of nuclear tunneling compared to the case that the Landau-Zener formula is used. The possible extension and applications to the case of the slow solvent dynamics are discussed.