Design of in vitro biomimetic experimental system and simulation analysis for transvascular transport of nano-preparation.

Recently, the enhanced penetration and retention (EPR) effect of nano-preparations has been questioned. Whether the vascular endothelial cell gap (VECG) is the main transport pathway of nano-preparations has become a hot issue at present. Therefore, we propose an in vitro biomimetic experimental system that demonstrates the transvascular transport of nano-preparation. Based on the tumor growth process, the experimental system was used to simulate the change process of abnormal factors (vascular endothelial cell gap and interstitial fluid pressure (IFP)) in the tumor microenvironment. The influence of change in the abnormal factors on the enhanced penetration and retention effect of nano-preparation was explored, and simulation verification was performed. The results show that when the interstitial fluid pressure is close to the vascular fluid pressure (VFP), the transport of nano-preparation is obstructed, resulting in the disappearance of enhanced penetration and retention effect of the nano-preparation. This indicates that the pressure gradient between vascular fluid pressure and interstitial fluid pressure determines whether the enhanced penetration and retention effect of nano-preparations can exist.

The effects of soil intake on the growth performance, rumen microbial community and tissue mineral deposition of German Mutton Merino sheep.

Soil ingestion by livestock is common in grazing ecosystems, but few studies have been conducted to assess its effect on the animal organism. The topic is worthy of attention because these potential effects are likely to be enriched in the food chain and interfere with animal and human health. In this study, we present an indoor feeding trial conducted based on a completely randomized design to comprehensively evaluate the effects of simulated soil ingestion during grazing on nutrient digestibility, rumen fermentation, and microflora, and mineral deposition in the organs and tissues of sheep. Eighteen Mutton Merino crossbred sheep (42.7 ± 2.34 kg) were randomly allotted to three treatments and fed diets containing 0% (Control), 5% (SOIL5), and 10% (SOIL10) for 62 d, including a 7-d metabolism trial. It was found that soil intake altered the rumen fermentation in sheep, as evidenced by a decrease in total volatile fatty acids (VFA) and acetate concentrations in rumen fluid of 50.6% and 51.3%, respectively (p < 0.01), with soil proportion in the diet increased from 0% to 10%. Soil ingestion also reduced the species richness of rumen bacteria, with the relative abundance of Bacteroidetes decreasing significantly (p < 0.01), while that of Firmicutes and Proteobacteria increased considerably (p < 0.05). In terms of mineral elements deposition, higher levels of iron (Fe) were detected in the spleen and liver, and a higher concentration of copper (Cu) and zinc (Zn) in the liver were found in sheep fed a diet containing 5% soil compared to the other two groups (p < 0.05). Moreover, the concentrations of lead (Pb) in the liver and kidney, and arsenic (As) in the heart were also clearly increased after ingestion of soil (p < 0.05). Our findings indicate that although soil intake had no significant effect on the growth performance of sheep, it altered ruminal fermentation and increased the risk of excessive Fe, Pb, and As in their organism. This study supplies a theoretical basis for risk assessment of soil ingestion in grazing livestock.

Relaxin-Loaded Inhaled Porous Microspheres Inhibit Idiopathic Pulmonary Fibrosis and Improve Pulmonary Function Post-Bleomycin Challenges.

Idiopathic pulmonary fibrosis (IPF) causes worsening pulmonary function, and no effective treatment for the disease etiology is available now. Recombinant Human Relaxin-2 (RLX), a peptide agent with anti-remodeling and anti-fibrotic effects, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, due to its short circulating half-life, optimal efficacy requires continuous infusion or repeated injections. Here, we developed the porous microspheres loading RLX (RLX@PMs) and evaluated their therapeutic potential on IPF by aerosol inhalation. RLX@PMs have a large geometric diameter as RLX reservoirs for a long-term drug release, but smaller aerodynamic diameter due to their porous structures, which were beneficial for higher deposition in the deeper lungs. The results showed a prolonged release over 24 days, and the released drug maintained its peptide structure and activity. RLX@PMs protected mice from excessive collagen deposition, architectural distortion, and decreased compliance after a single inhalation administration in the bleomycin-induced pulmonary fibrosis model. Moreover, RLX@PMs showed better safety than frequent gavage administration of pirfenidone. We also found RLX-ameliorated human myofibroblast-induced collagen gel contraction and suppressed macrophage polarization to the M2 type, which may be the reason for reversing fibrosis. Hence, RLX@PMs represent a novel strategy for the treatment of IPF and suggest clinical translational potential.

Bioinspired Nanocomplexes Comprising Phenolic Acid Derivative and Human Serum Albumin for Cancer Therapy.

Inspired by the natural phenomenon of phenolic-protein interactions, we translate this "naturally evolved interaction" to a "phenolic acid derivative based albumin bound" technology, through the synthesis of phenolic acid derivatives comprising a therapeutic cargo linked to a phenolic motif. Phenolic acid derivatives can bind to albumin and form nanocomplexes after microfluidic mixing. This strategy has been successfully applied to different types of anticancer drugs, including taxanes, anthraquinones, etoposides, and terpenoids. Paclitaxel was selected as a model drug for an in-depth study. Three novel paclitaxel-phenolic acid conjugates have been synthesized. Molecular dynamics simulations provide insights into the self-assembled mechanisms of phenolic-protein nanocomplexes. The nanocomplexes show improved pharmacokinetics, elevated tolerability, decreased neurotoxicity, and enhanced anticancer efficacies in multiple murine xenograft models of breast cancer, in comparison with two clinically approved formulations, Taxol (polyoxyethylated castor oil-formulated paclitaxel) and Abraxane (nab-paclitaxel). Such a robust system provides a broadly applicable platform for the development of albumin-based nanomedicines and has great potential for clinical translation.

Combination of oxaliplatin and POM-1 by nanoliposomes to reprogram the tumor immune microenvironment.

Some chemotherapy can damage tumor cells, releasing damage-related molecular patterns including ATP to improve immunological recognition against the tumor by immunogenic cell death (ICD). However, the immune-stimulating ATP may be rapidly degraded into immunosuppressive adenosine by highly expressed CD39 and CD73 in the tumor microenvironment, which leads to immune escape. Based on the above paradox, a liposome nanoplatform combined with ICD inducer (oxaliplatin) and CD39 inhibitor (POM-1) is designed for immunochemotherapy. The liposomes efficiently load the phospholipid-like oxaliplatin prodrug, and the cationic charged surface could adsorb POM-1. Rationally designed DSPE-PEGn-pep, on the one hand, could cover and hide POM-1 to avoid systematic toxicity and, on the other, achieve a response and charge reversal to favor POM-1 shedding and tumor deep penetration. This combination maximizes the ICD effect, and takes two-pronged advantage of stimulating the immune response and relieving immune suppression. The designed POL can effectively inhibit the growth of in situ, lung metastasis and postoperative recurrence melanoma model and form long-term immune memory. With the powerful clinical transformation potential of nanoliposome platforms, this new synergistic strategy is expected to enhance anticancer effects safely and effectively.

Response of the nuclear xenobiotic receptors to alleviate glyphosate-based herbicide-induced nephrotoxicity in weaned piglets.

Glyphosate-based herbicides (GBHs) are widely used worldwide. Glyphosate (GLP) is the main active component of GBHs. The presence of GBH residues in the environment has led to the exposure of animals to GBHs, but the mechanisms of GBH-induced nephrotoxicity are not clear. This study investigated the effects of GBHs on piglet kidneys. Twenty-eight healthy female hybrid weaned piglets (Duroc × Landrace × Yorkshire) with an average weight of 12.24 ± 0.61 kg were randomly divided into four treatment groups (n=7 piglets/group) that were supplemented with Roundup® (equivalent to GLP concentrations of 0, 10, 20, and 40 mg/kg) for a 35-day feeding trial. The results showed that the kidneys in the 40-mg/kg GLP group suffered slight damage. Roundup® significantly decreased the activity of catalase (CAT) (P=0.005) and increased the activity of superoxide dismutase (SOD) (P=0.029). Roundup® increased the level of cystatin-C (Cys-C) in the plasma (linear, P=0.002 and quadratic, P=0.015). The levels of neutrophil gelatinase-associated lipocalin (NGAL) in plasma increased linearly (P=0.007) and quadratically (P=0.003) as the dose of GLP increased. The mRNA expression of intercellular cell adhesion molecule-1 (ICAM-1) in the 20-mg/kg GLP group was increased significantly (P<0.05). There was a significant increase in the mRNA levels of pregnenolone X receptor (PXR), constitutive androstane receptor (CAR), and uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3) (P<0.05). Our findings found that kidney nuclear xenobiotic receptors (NXRs) may play an important role in defense against GBHs.

Effects of glyphosate-based herbicide-contaminated diets on reproductive organ toxicity and hypothalamic-pituitary-ovarian axis hormones in weaned piglets.

At present, glyphosate (GLP) is the most produced and used herbicide in the world. With the large-scale use of glyphosate-based herbicides (GBHs), their toxic effects on animals and plants have increasingly become a concern. Based on the Codex Alimentarius Commission (CODEX) dose (20 mg kg-1) and the dose set by the government (40 mg kg-1), four experimental groups in which Roundup® (R) herbicide was added to the feed of weaned piglets at GLP concentrations of 0, 10, 20, and 40 mg kg-1 were designed. The results showed that R had no significant effect on the vulvar size or index of reproductive organs but that it could affect the tissue morphology and ultrastructure of the uterus and ovary. With the increase in GLP concentration, the activities of antioxidant enzymes [SOD (P < 0.05) and GPx (P = 0.002)] in the uterus showed significant increases. Compared with the control group, the content of hydrogen peroxide (H2O2) in the treatment groups increased significantly (P < 0.05), the malondialdehyde (MDA) content in the 10 mg kg-1 treatment group was significantly higher than that in the control group. We measured hypothalamic-pituitary-ovarian axis (HPOA) hormones and also found that GLP significantly increased luteinizing hormone-releasing hormone (LHRH), gonadotropin-releasing hormone (GnRH) and testosterone (T) content (P < 0.05) and decreased follicle-stimulating hormone (FSH) content (P < 0.05). In summary, although R does not affect the vulvar size or reproductive organ index of weaned piglets, it changes the morphology and ultrastructure of the uterus and ovaries, interferes with the synthesis and secretion of HPOA hormones, and causes changes in the balance of the antioxidant system of uterus. This study provided a theoretical basis for preventing reproductive system harm caused by GBHs.

Precise design strategies of nanomedicine for improving cancer therapeutic efficacy using subcellular targeting.

Therapeutic efficacy against cancer relies heavily on the ability of the therapeutic agents to reach their final targets. The optimal targets of most cancer therapeutic agents are usually biological macromolecules at the subcellular level, which play a key role in carcinogenesis. Therefore, to improve the therapeutic efficiency of drugs, researchers need to focus on delivering not only the therapeutic agents to the target tissues and cells but also the drugs to the relevant subcellular structures. In this review, we discuss the most recent construction strategies and release patterns of various cancer cell subcellular-targeting nanoformulations, aiming at providing guidance in the overall design of precise nanomedicine. Additionally, future challenges and potential perspectives are illustrated in the hope of enhancing anticancer efficacy and accelerating the translational progress of precise nanomedicine.

The role of antibody delivery formation in cancer therapy.

Cancer has become one of the major threats to human survival. Because of antibodies specificity and low toxicity, it is the primary choice to diagnose and treat cancer. It is easy to be cleared from the blood circulation or distributing throughout the body and causes unnecessary side effects. It is necessary to delivery antibodies to the tumour region in a stable, safe and effective manner. In this review, we discuss the latest studies that aimed to delivery antibodies to tumour sites via several vector forms, such as liposomes, carbon nanomaterials, and gold nanomaterials. How to deliver antibodies to the target site is a difficulty for antibody therapy. This review summarises the antibody's therapeutic forms and carrier materials in recent years, and to explore how antibodies can be safely and stably delivered to the target site.

Toxic effects of glyphosate on intestinal morphology, antioxidant capacity and barrier function in weaned piglets.

At present, the public is paying more attention to the adverse effects of pesticides on human and animal health and the environment. Glyphosate is a broad-spectrum pesticide that is widely used in agricultural production. In this manuscript, the effects of diets containing glyphosate on intestinal morphology, intestinal immune factors, intestinal antioxidant capacity and the mRNA expression associated with the Nrf2 signaling pathway were investigated in weaned piglets. Twenty-eight healthy female hybrid weaned piglets (Duroc × Landrace × Yorkshire) were randomly selected with an average weight of 12.24 ±â€¯0.61 kg. Weaned piglets were randomly assigned into 4 treatment groups and fed a basal diet supplemented with 0, 10, 20, and 40 mg/kg glyphosate for a 35-day feeding trial. We found that glyphosate had no effect on intestinal morphology. In the duodenum, glyphosate increased the activities of CAT and SOD (linear, P < 0.05) and increased the levels of MDA (linear and quadratic, P < 0.05). In the duodenum, glyphosate remarkably increased the relative mRNA expression levels of Nrf2 (linear and quadratic, P < 0.05) and NQO1 (linear and quadratic, P < 0.05) and reduced the relative mRNA expression levels of GPx1, HO-1 and GCLM (linear and quadratic, P < 0.05). In the jejunum, glyphosate remarkably increased the relative mRNA expression levels of Nrf2 (linear and quadratic, P < 0.05) and decreased the relative mRNA expression levels of GCLM (linear and quadratic, P < 0.05). Glyphosate increased the mRNA expression levels of IL-6 in the duodenum (linear and quadratic, P < 0.05) and the mRNA expression levels of IL-6 in the jejunum (linear, P < 0.05). Glyphosate increased the mRNA expression of NF-κB in the jejunum (linear, P = 0.05). Additionally, the results demonstrated that glyphosate linearly decreased the ZO-1 mRNA expression levels in the jejunum and the mRNA expression of claudin-1 in the duodenum (P < 0.05). In the duodenum, glyphosate increased the protein expression levels of Nrf2 (linear, P = 0.025). Overall, glyphosate exposure may result in oxidative stress in the intestines of piglets, which can be alleviated by enhancing the activities of antioxidant enzymes and self-detoxification.

Toxicity of glyphosate in feed for weanling piglets and the mechanism of glyphosate detoxification by the liver nuclear receptor CAR/PXR pathway.

Glyphosate (GLP), the most widely used and productive pesticide worldwide, which safety and reliability gradually become a social concern. It is important to explore the toxic of GLP on the limitation level by governments on piglets and the potential role of hepatic CAR/PXR and Keap1-Nrf2 pathways in low levels of glyphosate detoxification. Compared with the control group, the production performance and organ index of GLP group showed no significant change. However, the liver GLP residue of 40 mg/kg group was significantly higher than the control group. We also found that the activity of ALP increased linearly and DBIL content increased quadratically. Furthermore, GLP could significantly increase SOD and GSH-Px and decrease T-AOC and CAT activities and significantly increase MDA and H2O2 contents (P < 0.05); however, the genes expression of Keap1/Nrf2 pathway was not affected. Gene expression of CAR/PXR pathway showed that GLP could significantly stimulate the expression of CAR, but it could not affect the expression of phase Ⅰ (CYP1A1, CYP1A2, CYP2E1, CYP2A19, CYP3A29), phase Ⅱ (UGT1A6, GSTA1, GSTA2) detoxification enzymes and transporters (MDR1, MRP2, P-gp). Our study showed that although 10-40 mg/kg GLP would inevitably cause some liver damage and dysfunction, it can self-alleviating the toxic effect of GLP.

Effects of different emulsifiers on growth performance, nutrient digestibility, and digestive enzyme activity in weanling pigs1.

The objective of this study was to investigate the effects of diets supplemented with sodium stearoyl-2-lactylate (SSL), polyglycerol fatty acid ester (PGFE), and combined emulsifiers (0.02% SSL and 0.08% PGFE) on growth performance, nutrient digestibility, and plasma lipid profiles in weaned piglets and to further evaluate the possible effects of feeding exogenous emulsifiers on digestive enzyme activities and liver bile acid (BA) metabolism. Twenty-eight barrows (age at 35 d, Duroc × Landrace × Yorkshire) with an initial BW of 10.13 ± 0.16 kg were randomly assigned to 4 dietary treatment groups (7 pigs/treatment). Dietary treatment groups included the following: 1) basal diet (Control, CTR); 2) basal diet with 0.1% SSL (SSL); 3) basal diet with 0.1% PGFE (PGFE); and 4) basal diet with 0.08% PGFE+0.02% SSL (PG-SL). SSL diet increased ADG and ADFI of piglets during day 0 to 17 (P < 0.05) compared with the CTR treatment. Piglets fed emulsifier diets experienced a significant improvement in the digestibility of nutrients (DM, CP, ether extract, energy, calcium, and phosphorus) during the first 17 d (P < 0.05). The level of low-density lipoprotein cholesterol (LDL-C) was lower in the PGFE and PG-SL treatment groups than in the CTR treatment group (P < 0.05). Feeding emulsifier diets increased the lipase activity of the pancreas when compared with the CTR diet (P < 0.05). Moreover, the emulsifier diets significantly increased the mRNA expression of FXR (P < 0.05) and decreased the mRNA expression of CYP27A1 (P < 0.05) in the liver. In conclusion, the addition of emulsifiers improved nutrient digestibility and increased the mRNA expression of FXR BA receptors while inhibiting the mRNA expression of BA biosynthesis by CYP27A1 in weanling piglets.

Mechanisms of Accountability for the Realization of the Right to Health in China.

China ratified the International Covenant on Economic, Social and Cultural Rights in 2001. It thus bears obligations under Article 12 of the covenant to take appropriate measures at the domestic level to realize the right to health in China. Accountability is an important component of the right to health. This article examines whether the Western concept of accountability, recently imported into China, has the potential to improve the protection of the right to health within China's existing political, legal, and cultural framework. In so doing, it reviews current Chinese institutional mechanisms and considers the use of less formal mechanisms by which duty-bearers might be held accountable in China. More specifically, this article provides an overview of a range of health-related accountability mechanisms, including judicial, political, administrative, professional, and social accountability arrangements. It concludes that although there is the basis of an accountability framework for the right to health in China, the effective operation of accountability mechanisms is hindered by longstanding cultural and political barriers.