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This study was designed to evaluate the subchronic toxicity of the compound of diphenhydramine hydrochloride (DH) and caffeine in Sprague-Dawley (SD) rats and beagle dogs. A total of 180 SD rats (15/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (51, 102, 204 mg/kg), DH group (60 mg/kg), caffeine group (144 mg/kg) and the vehicle control group. Sixty beagle dogs (5/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (male: 14.20, 28.30, 56.60 mg/kg, female: 5.66, 14.20, 28.30 mg/kg), DH group (male: 16.60 mg/kg, female: 8.30 mg/kg), caffeine group (male: 40.00 mg/kg, female: 20.00 mg/kg) and the vehicle control group. Rats and dogs were given continuous oral administration for 28 days following a 28-day recovery period. The adverse effects of the compound on rats and beagle dogs mainly included anorexia and liver function impairment. Most adverse effects induced by administration were reversible. Under the experimental conditions, the no-observed-adverse-effect level (NOAEL) of the compound of DH and caffeine was 51 mg/kg/day for SD rats and 28.30 mg/kg/day (male) and 5.66 mg/kg/day (female) for beagle dogs. [ABSTRACT FROM AUTHOR]

Antibody-mediated rejection (AMR) has a strongly negative impact on long-term renal allograft survival. Currently, no recognized effective treatments are available, especially for chronic antibody-mediated rejection (CAMR). Donor-specific antibodies (DSAs) secreted by long-lived plasma cells and memory B cells are acknowledged as biomarkers of AMR. Nevertheless, it may be too late for the DSA routine examination production since DSAs may have binded to graft vascular endothelial cells through complement-dependent or complement-independent pathways. Therefore, methods to effectively monitor memory B cells and long-lived plasma cells and subsequently prevent DSA production are key to reducing the adverse effects of AMR. Therefore, this review mainly summarizes the production pathways of memory B cells and long-lived plasma cells and provides suggestions for the prevention of AMR after transplantation. [ABSTRACT FROM AUTHOR]

The pollution of polycyclic aromatic hydrocarbons (PAHs) in food crops has been drawing worldwide attention due to their toxicity and carcinogenicity. However, the distribution process of PAHs in crop leaves is not clear. Here, we firstly study the distribution of phenanthrene in wheat, soybean and maize seedling leaves. High performance liquid chromatography was used to determine phenanthrene concentration in crop leaves. Over the exposure time, phenanthrene concentration in young and mature leaves of wheat and soybean increased to the maximum at 72 h, which were 8.25 and 1.47 mg kg−1, and 5.91 and 3.02 mg kg−1, respectively, and phenanthrene concentration of young leaves was higher. Inversely, phenanthrene concentration in maize mature leaves was the highest and that in the second leaves was the lowest. The distributions of phenanthrene concentration in leaf base, leaf medium and leaf apex of the three crops were as follows: it was leaf medium > leaf base > leaf apex in wheat; it was same for soybean and maize, with leaf apex > leaf medium > leaf base. Phenanthrene concentrations of leaf edge in wheat, soybean and maize were 10.55, 3.88 and 18.96 mg kg−1 at 72 h, which were higher than those of leaf middle (10.21, 3.39 and 10.47 mg kg−1), respectively. Phenanthrene concentrations of mesophylls and veins increased with time, and phenanthrene concentration of veins was higher. The observation of two-photon fluorescence microscopy showed that phenanthrene was mainly accumulated near the vascular bundles of major vein. Accordingly, distribution of phenanthrene in crop leaves depends on the type of crop, growth period, and contribution of xylem and phloem to acropetal transport. Our results are helpful not only for better understanding the distribution of PAHs in crop leaves, but also for effectively controlling the translocation of PAHs into the leaves to ensure the safety of agricultural products. [ABSTRACT FROM AUTHOR]

The blood–brain barrier represents an insurmountable obstacle for the therapy of central nervous system related diseases. Polymeric micelles have many desirable properties for brain targeting by oral delivery, but the stability and targeting efficiency needs to be improved. In this study, it was demonstrated that binary micelle system can compensate the drawbacks of mono system by preparing mixed micelles in combination with PEG-based copolymers. Here, we explored a brain targeting drug delivery system via facile approaches using P123 based mixed micelles in combination with a message guider from traditional Chinese medicine, borneol, for oral delivery. With higher drug-loading, improved stability, prolongedin vitrorelease profile, increased bioavailability and enhanced brain targeting effect was achieved after peroral delivery of the mixed micelles. More importantly, without extra structure modification for active targeting, it was demonstrated for the first time that oral delivery of vinpocetine loaded mixed micelles together with borneol is an effective way to increase drug concentration in the brain and the targeting efficiency is borneol dose dependent. Such a “simple but effective” modality may shed light on the potential use of polymeric micelles in combination with a message drug to achieve drug brain targeting or other targeting sites via oral delivery. [ABSTRACT FROM PUBLISHER]

Context: Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. Objective: We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug in patients with inadequately controlled, eosinophilic asthma. Data sources: The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. Study selection: A literature review was performed to identify all published randomized double-blind, placebo-controlled trials of reslizumab for the treatment of inadequately controlled, eosinophilic asthma. Data extraction: Two reviewers independently extracted and verified pre-defined data fields. Results: Four publications including 5 RCTs that compared reslizumab with placebo. For the comparison of reslizumab with placebo, asthma exacerbation (odds ratio (OR) = 0.46, 95% confidence interval (CI) = 0.35 to 0.59, p <0.00001); a forced expiratory volume in 1 s (FEV1) (the standardized mean difference (SMD) = 0.16, 95%CI = 0.10 to 0.23, p <0.00001); Asthma Control Questionnaire (ACQ) score (the SMD = −0.26, 95%CI= −0.36 to −0.16, p <0.00001); blood eosinophil counts (the SMD = −475.62, 95%CI = −528.41 to −422.83, p <0.00001). Safety assessments included the proportion of individuals who withdrawn due to adverse event (AE) (OR = 0.60 95%CI = 0.38 to 1.17, p = 0.16) indicated that reslizumab was well tolerated. Limitations: The article didn't research the safety, efficacy of reslizumab with longer term. Conclusions: This meta-analysis indicates that reslizumab to be an effective and safe treatment for inadequately controlled, eosinophilic asthma. [ABSTRACT FROM AUTHOR]

Context:High-mobility group box 1 (HMGB1) protein is a highly abundant protein that can promote the pathogenesis of inflammatory. Some experiments have demonstrated a vital role for HMGB1 to modulate the immune function of regulatory T-cells (Tregs). Astragaloside IV (AST IV), an extract fromAstragalus membranaceusMoench (Leguminosae), has been shown to exert potent cardioprotective and anti-inflammatory effects. It is still unclear whether AST IV has a latent effect on the proinflammatory ability of HMGB1 with subsequent activation of Tregsin vivo. Objective:This research explores the antagonism of different doses of AST IV on the immunologic function of Tregs mediated by HMGB1. Materials and methods:Mouse models (BALB/c) were constructed by which normal saline or AST IV was administered i.p. at 2, 4 and 6 days after the administration i.p. of 20 μg recombinate HMGB1. Spleen was used to procure Treg and CD4 + CD25−T-cells which were co-cultured with Treg. Cell phenotypes of Tregs(Foxp3) were examined, and the cytokine levels in supernatants and the proliferation of T-cells were assayed. Gene expression was measured by RT-PCR. Results:(1) The expression levels of Foxp3 in Treg on post-stimulus days (PSD) 1–7 were significantly decreased in the HMGB1 group in comparison to those in the control group mice (p < 0.01). The Foxp3 expression was markedly increased in a dose-dependent manner in the AST group as compared with those in the HMGB1 group (p < 0.0 1–0.05). The same results were found in the contents of cytokines (IL-10 and TGF-β) released into supernatants by Treg. (2) When CD4 + CD25−T-cells were co-cultured with Treg stimulated by HMGB1, the cell proliferation and the levels of cytokines (IL-2 and IFN-γ) in supernatant were markedly increased as compared with those in the HMGB1 group. The level of IL-4 was markedly decreased as compared with that in the HMGB1 group. The same results were found when CD4 + CD25−T-cells were co-cultured with Treg in the NS group. Compared with those in the NS group, the contrary results were shown in a dose-dependent manner in the AST group. Discussion and conclusion:These results showed that AST IV has a therapeutic effect on inflammation promoted by HMGB1, and it should be studied as a new drug for the treatment of sepsis. [ABSTRACT FROM AUTHOR]

Objective: To explore the potential of non-ionic surfactants as novel intranasal absorption enhancers. Methods: Taking sumatriptan succinate (SMS) as a model drug, influence of different non-ionic surfactants, including laurate sucrose ester (SE), cremophor EL and poloxamer 188, on the intranasal absorption of SMS was investigated using anin situnasal perfusion technique in rats. Ciliotoxicity of the non-ionic surfactants was evaluated using anin situtoad palate model.In vivobehavior of the selected formulations was studied in rats. Results: All the non-ionic surfactants investigated increased the intranasal absorption of SMS remarkably but with varied extent and trend. Moreover, it was revealed that at the same concentration, laurate SE had better permeation-enhancing effect than that of cremophor EL and poloxamer 188. The ciliotoxicity results showed that all the non-ionic surfactants were regarded as safe at selected concentrations. Based on thein situabsorption data and ciliotoxicity results, the following three samples, 0.5% laurate SE, 0.1% cremophor EL and 0.5% poloxamer 188 were selected forin vivoabsorption studies in rats. Among them, 0.5% laurate SE group presented the highest enhancing effect, followed by 0.1% cremophor EL and 0.5% poloxamer 188 group, with absolute bioavailability 29.99%, 22.64% and 20.90%, respectively. Conclusions: Laurate SE is a promising intranasal absorption enhancer. [ABSTRACT FROM AUTHOR]

Background: Seven ideal health metrics were defined by AHA to monitor cardiovascular health. This study aimed to investigate the impact of ideal cardiovascular health behaviors and factors on the development of hypertension in prehypertensive subjects.Methods: Thirty-two thousand eight-hundred and eighty-seven participants with prehypertension were included in the study after excluding for preexisting stroke, myocardial infarction or malignancy. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals [CI] for the development of hypertension.Results: During a follow-up of 52.2 months, 15 500 prehypertensive participants developed hypertension. The cumulative incidence of hypertension decreased with the number of ideal health metrics increased. It was 78.61%, 71.08%, 63.15%, 56.07% and 61.62% in prehypertensive individuals carrying ≤1, 2, 3, 4 and ≥5 ideal health behaviors or factors, respectively. After adjustment for age, gender, family history of hypertension, alcohol consumption, resting heart rate, plasma triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein, the risk ratios of incident hypertension in the subjects who carried 2, 3, 4, and ≥5 ideal health metrics were 0.833 (95%CI: 0.789–0.880), 0.710 (95%CI: 0.672–0.749), 0.604 (95%CI: 0.568–0.642), and 0.581 (95%CI: 0.524–0.643), respectively, in comparison to those with ≤1 ideal health metric. A similar trend was also observed in male and female populations. Poor health metrics, including body mass index, diet (salt intake), physical activity, total cholesterol, and smoking, were predictors for the development of hypertension in prehypertensive individuals.Conclusion: Ideal cardiovascular health behaviors and factors are protective factors to prevent the progression from prehypertension to hypertension. [ABSTRACT FROM PUBLISHER]

Purposes/Aim: Glucocorticoid steroids can induce expression of PPARγ gene and enhance adipogenesis by bone marrow mesenchymal stem cells (BMSCs), which may result in osteonecrosis of the femoral head. Currently, there are no medications available to prevent steroid-induced osteonecrosis. We hypothesized that siRNA targeting PPARγ gene may prevent steroid-induced adipogenesis and osteonecrosis in rabbit. The purpose of this study was to evaluate the preventive effects of siRNA targeting PPARγ gene on steroid-induced adipogenesis and osteonecrosis. Methods: Forty-eight healthy New Zealand rabbits were randomized into four groups with Group M treated with dexamethasone only, Group S with dexamethasone and a recombinant adenovirus shuttle vector carrying siRNA targeting PPARγ gene, Group Con with dexamethasone and a vector carrying irrelative sequence, and Group N with no treatment serving as control. Expressions of the PPARγ, osteocalcin and Runx2 genes, as well as histopathologic changes were evaluated. Results: The levels of PPARγ gene expression were decreased while the levels of osteocalcin and Runx2 gene expression were increased in rabbits treated with dexamethasone and recombinant adenovirus shuttle vector carrying siRNA targeting PPARγ gene (Group S), compared to rabbits treated either with dexamethasone alone (Group M) or with both dexamethasone and a vector carrying irrelative sequence (Group Con). The marrow necrosis, adipocyte hypertrophy and proliferation, diminished hematopoiesis, thinner and sparse trabeculae, and increased empty osteocyte lacunae in the femoral head were observed in Group M and Group Con rabbits. However, no such changes were seen in Group S rabbits that were treated with dexamethasone and a recombinant adenovirus shuttle vector carrying siRNA targeting PPARγ gene. Conclusion: siRNA targeting PPARγ gene can inhibit adipogenic differentiation of BMSCs and prevent steroid-induced osteonecrosis in rabbit. The inhibition of bone-marrow adipogenesis and concomitant enhancement of osteogenesis with RNAi may provide a novel approach to the prevention of steroid-induced osteonecrosis. [ABSTRACT FROM AUTHOR]

AbstractAdsorption is widely regarded as the most promising method for uranium extraction. Among the various materials that have been studied, graphene oxide (GO) has attracted intensive interest because of its large specific surface area and abundant oxygen-containing functional groups. However, the layers tend to aggregate owing to pronounced Van der Waals forces, which reduce the surface area and diminish the likelihood of contact between uranyl ions and adsorption sites. Graphite oxide is an intermediate product of GO, with a simple preparation process and low cost. In this study, graphite oxide nanosheets (GONs) were synthesized using graphite oxide powder as the raw material and the NaOH activation method. GONs possessed a larger specific surface area and more carboxyl groups, which resulted in an excellent uranium adsorption capacity. The maximum adsorption capacity was found to be 578.0 mg·g−1, and the adsorption rate was 90.8% within 30 min. The adsorption process closely resembled the pseudo-second-order model and the Langmuir model. The mechanism of uranium adsorption by GONs was the synergistic coordination of -COOH and -OH with U(VI). This research suggests that the novel uranium adsorbent GONs can be applied to efficiently capture U(VI) from radioactive wastewater. [ABSTRACT FROM AUTHOR]