Toll-like receptor 4, Toll-like receptor 7 and Toll-like receptor 9 agonists enhance immune responses against blood-stage Plasmodium chabaudi infection in BALB/c mice

BackgroundToll-like receptor (TLR) signals play vital roles during the blood-stage of malaria infections. However, the roles of TLR agonists in the regulation of immune responses and the development of protective immunity to malaria remain poorly understood.MethodBALB/c mice were pre-treated with TLR4, TLR7 and TLR9 agonists, followed by infection with Plasmodium chabaudi. After infection, splenic dendritic cells (DCs), Th1 cells and programmed death-1 (PD-1) expressed on Th1 cells, as well as regulatory T cells (Tregs) were analyzed by flow cytometry. The levels of IFN-γ, TNF-α, TGF-β and IL-10 in splenocytes and IgG1 and IgG2a in serum were measured by ELISA.ResultAdministration of TLR4, TLR7 and TLR9 agonists prior to infection improved disease outcomes. All TLR agonists promoted DC activation, and the proportions of Th1 cells increased. In TLR4, TLR7 and TLR9 agonist treated groups the levels of pro-inflammatory cytokines IFN-γ and TNF-α were elevated, and IgG1 and IgG2a serum levels were also significantly increased. TLR4, TLR7 and TLR9 agonists diminished the activation of Tregs and down-regulated the anti-inflammatory cytokines TGF-β and IL-10. Finally, PD-1 expressed on Th1 cells were decreased in TLR4, TLR7 and TLR9 agonist treated groups compared with control groups.ConclusionTLR4, TLR7 and TLR9 agonists activated DC-mediated innate immune responses and adaptive immune response, which against the blood-stage of Plasmodium and might be applied to malaria protection and treatment.     

A potent antiarrhythmic drug N-methyl berbamine extends the action potential through inhibiting both calcium and potassium currents

N-methyl berbamine (N-MB) is a berberine derivative. Its analogue berbamine has been reported to have remarkable antiarrhythmic and ischemic protective effects. However, the pharmacological effects of N-MB are ill-defined. In this study, molecular docking was used to evaluate the binding of N-MB to Ca_V1.2 Ca²⁺ and K_V11.1 K⁺ channels, and the effects of N-MB on action potential and ionic currents were observed in the ventricular myocytes of rabbits, HEK293 cells stably transfected with the hCa_V1.2 gene and CHO cells stably transfected with hERG (human ether-a-go-go related gene). The results showed that N-MB was able to bind to both Ca_V1.2 and K_V11.1 channels. Following a perfusion with N-MB, the durations of action potentials (APD₂₀, APD₅₀ and APD₉₀) were extended, and the outward tail current, I_tail, as well as the hERG current, I_hERG, were inhibited, while the amplitude of action potential (APA) was only slightly reduced. N-MB also decreased the peak amplitude of the L-type Ca²⁺ channel current, I_CaL, as well as the Ca_V1.2 current, I_CaV1.2; this may limit the prolongation of APD. In conclusion, N-MB is a potent and natural antiarrhythmic multitarget drug that may elicit its antiarrhythmic effect through blocking both Ca²⁺ and K⁺ channel currents.     

Modulating intestinal mucus barrier for nanoparticles penetration by surfactants

Improving peroral delivery efficiency is always a persistent goal for both small-molecule and macromolecular drug development. However, intestinal mucus barrier which greatly impedes drug-loaded nanoparticles penetration is commonly overlooked. Therefore, in this study, taking fluorescent labeled PLGA (poly (lactic-co-glycolic acid)) nanoparticles as a tool, the influence of anionic and nonionic surfactants on mucus penetration ability of nanoparticles and their mucus barrier regulating ability were studied. The movement of PLGA nanoparticles in mucus was tracked by multiple particles tracking method (MPT). Alteration of mucus properties by addition of surfactants was evaluated by rheology and morphology study. Rat intestinal villus penetration study was used to further evaluate penetration enhancement of nanoparticles. The effective diffusivities of the nanoparticles in surfactants pretreated mucus were increased by 2–3 times and the mucus barrier regulating capacity was also surfactant type dependent. Sodium dodecyl sulfate (SDS) increased the complex viscosity and viscoelastic properties of mucus, but poloxamer presented a decreased trend. Tween 80 maintained the rheological property of the mucus. With the mucus barrier regulated by surfactants, the penetration of nanoparticles in intestinal villus was obviously increased. In summary, the mucus penetration ability of nanoparticles could be enhanced by altering mucus microenvironment with surfactants. Tween 80 which largely retains the original mucus rheology and morphology properties may be a promising candidate for facilitating nanoparticle penetration through the mucus barrier with good safety profile.     

Improving burn surgery education for medical students in China

IntroductionIn China, although burn treatment develops rapidly, and ranks in the forefront of the world, there is a relative shortage of burn specialists, which limits the development of burn education. In traditional curriculum of surgery education, burn surgery education accounts for few proportions, which results in the indifference to the burn surgery among medical students. To date, few research reported the application of Clinical pathway- Problem based Learning (CP-PBL) in burn surgery education. The objective of the study is to explore the teaching effect of this novel teaching method in burn surgery education.MethodsA pilot study was performed. One hundred and six students were randomly divided into a Lecture based Learning (LBL) only group (control group) and a LBL combined Clinical pathway- Problem based Learning group (observation group). A set of test was designed as evaluation criteria based on questions of burn surgery in National Medical Licensing Examination (NMLE) from 2011 to 2018.ResultsThe students with Clinical pathway- Problem based Learning had better academic performances in profession theory. Type A2 and Type A3/A4 scores in the observation group were higher than those in the control group (p < 0.05). The scores of the observation group were higher than those of control group in the domains of understanding and application (p < 0.05). They also have higher favorable impressions of learning experience.ConclusionsMore active approaches yield more learning and are viewed more favorable, which provides a vital message for the evolution of curriculum in Chinese medical schools.     

童年期不良经历对个体健康影响的研究进展

童年期不良经历(ACEs)作为一项全球性的严峻公共卫生挑战,其对全生命周期的健康影响不容小觑。因此本文从心理健康、生理健康、性传播疾病及危险性行为、健康危险行为4个方面对ACEs的健康影响进行综述,为ACEs及其可能健康结局提供参考。     

Methionine enkephalin,its role in immunoregulation and cancer therapy

Methionine enkephalin (MENK), an endogenous neuropeptide has a crucial role in both neuroendocrine and immune systems. MENK is believed to have an immunoregulatory activity to have cancer biotherapy activity by binding to the opioid receptors on immune and cancer cells. Clinical trial studies in cancer patients have shown that MENK activates immune cells directly and by inhibiting regulatory T-cells (Tregs). MENK may also change the tumor microenvironment by binding to opioid receptor on or in cancer cells. All of these mechanisms of action have biologic significance and potential for use in cancer immunotherapy. Furthermore, they reveal a relationship between the endocrine and immune systems. Due to the apparent role of MENK in cancer therapy we reviewed herein, the research undertaken with MENK in recent years; which has advanced our understanding of the role MENK has in cancer progression and its relationship to immunity, supporting MENK as a new strategy for cancer immunotherapy.     

Low-dose naltrexone inhibits the epithelial-mesenchymal transition of cervical cancer cells in vitro and effects indirectly on tumor-associated macrophages in vivo

The metastasis of cervical cancer has always been a clinical challenge. We investigated the effects of low-dose naltrexone (LDN) on the epithelial mesenchymal transition of cervical cancer cells in vitro as well as its influence on macrophage polarization and associated cytokines in vivo. The results suggested that LDN supressed the proliferation, migration and invasion abilities and promote their apoptosis in Hela cells, whereas the opioid growth factor receptor (OGFr) silenced significantly reversed these effects in vitro. Knockdown the expression of OGFr, the inhibitory of LDN on EMT was weakened. LDN could inhibit cervical cancer progression in nude mice. In additon, LDN indirectly reduced the number of tumor-associated macrophages (TAMs), mainly M2 macrophages, and decreased expression of anti-inflammatory factor IL-10 in the serum of nude mice. These findings demonstrate that LDN could be a potential treatment for cervical cancer.