PEG length effect of peptide-functional liposome for blood brain barrier (BBB) penetration and brain targeting.

Nanoparticles, in particular PEGylated, show great potential for in vivo brain targeted drug delivery. Nevertheless, how polyethylene glycol (PEG) length of nanoparticles affects their blood brain barrier (BBB) penetration or brain targeting is still unclear. In this study, we investigated the power of PEG chain-lengths (2, 3.4, 5, 10 kDa) in BBB penetration and brain targeting using Angiopep-2 peptide decorated liposomes. We found that PEG chain-length is critical, where the shorter PEG enabled the Angiopep-2 decorated liposomes to display more potent in vitro cell uptake via endocytosis. In contrast, their in vitro BBB penetration via transcytosis was much weaker relative to the liposomes with longer PEG chains, which result from their ineffective BBB exocytosis. Interestingly, the in vivo brain targeting aligns with the in vitro BBB penetration, as the long chain PEG-modified liposomes exerted superior brain accumulation both in normal or orthotropic glioblastoma (GBM) bearing mice, which could be ascribed to the combinational effect of prolonged circulation and enhanced BBB penetration of long chain PEG attached liposomes. These results demonstrate the crucial role of PEG length of nanoparticles for BBB penetration and brain targeting, providing guidance for PEG length selection in the design of nanocarrier for brain diseases treatment.

Effective glioblastoma immune sonodynamic treatment mediated by macrophage cell membrane cloaked biomimetic nanomedicines.

Glioblastoma (GBM) as one of the most lethal brain tumours, remains poor therapeutic index due to its typical characters including heterogeneous, severe immune suppression as well as the existence of blood brain barrier (BBB). Immune sonodynamic (ISD) therapy combines noninvasive sonodynamic therapy with immunotherapy, which has great prospects for the combinational treatment of GBM. Herein, we develop macrophage cell membrane cloaked reactive oxygen species (ROS) responsive biomimetic nanoparticles, co-delivering of sonosensitizer Ce6 and JQ1 (a bromo-domain protein 4 (BRD4) inhibitor which can down-regulate PD-L1) and realizing potent GBM ISD therapy. The ApoE peptide decorated macrophage membrane coating endows these biomimetic nanoparticles with low immunogenicity, efficient BBB permeability, prolonged blood circulation half-live and good biocompatibility. The ROS responsive polymeric inner core could be readily degraded as triggered by excessive ROS under the ultrasound once they accumulated in tumour cells, fast release encapsulated drugs. The generation of ROS not only killed tumour cells via sonodynamic therapy, but also induced immunogenic cell death (ICD) and further activated the anti-tumour immune response. The released JQ1 inhibited tumour cell proliferation and augmented the immune activities by inhibiting the PD-L1 expression on the surface of tumour cells. The cascade sonodynamic and immune therapy resulted in significantly improved median survival time in both orthotopic GL261 and PTEN deficient immunosuppressive CT2A GBM mice models. Therefore, our developed biomimetic nanoparticle platform provides a promising combinational therapy strategy to treat immune suppressive GBM.

Bowel movement frequency and risks of major vascular and non-vascular diseases: a population-based cohort study among Chinese adults.

OBJECTIVE: The application of bowel movement frequency (BMF) in primary care is limited by the lack of solid evidence about the associations of BMF with health outcomes apart from Parkinson's disease and colorectal cancer. We examined the prospective associations of BMF with major vascular and non-vascular diseases outside the digestive system. DESIGN: Population-based prospective cohort study. SETTING: The China Kadoorie Biobank in which participants from 10 geographically diverse areas across China were enrolled between 2004 and 2008. PARTICIPANTS: 487 198 participants aged 30 to 79 years without cancer, heart disease or stroke at baseline were included and followed up for a median of 10 years. The usual BMF was self-reported once at baseline. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident events of predefined major vascular and non-vascular diseases. RESULTS: In multivariable-adjusted analyses, participants having bowel movements 'more than once a day' had higher risks of ischaemic heart disease (IHD), heart failure, chronic obstructive pulmonary disease, type 2 diabetes mellitus and chronic kidney disease (CKD) when compared with the reference group ('once a day'). The respective HRs (95% CIs) were 1.12 (1.09 to 1.16), 1.33 (1.22 to 1.46), 1.28 (1.22 to 1.36), 1.20 (1.15 to 1.26) and 1.15 (1.07 to 1.24). The lowest BMF ('less than three times a week') was also associated with higher risks of IHD, major coronary events, ischaemic stroke and CKD. The respective HRs were 1.07 (1.02 to 1.12), 1.22 (1.10 to 1.36), 1.11 (1.05 to 1.16) and 1.20 (1.07 to 1.35). CONCLUSION: BMF was associated with future risks of multiple vascular and non-vascular diseases. The integration of BMF assessment and health counselling into primary care should be considered.

Association Between Active Commuting and Incident Cardiovascular Diseases in Chinese: A Prospective Cohort Study.

Background Active commuting is related to a higher level of physical activity but more exposure to ambient air pollutants. With the rather serious air pollution in urban China, we aimed to examine the association between active commuting and risk of incident cardiovascular disease in the Chinese population. Methods and Results A total of 104 170 urban commuters without major chronic diseases at baseline were included from China Kadoorie Biobank. Self-reported commuting mode was defined as nonactive commuting, work at home or near home, walking, and cycling. Multivariable Cox regression was used to examine associations between commuting mode and cardiovascular disease. Overall, 47.2% of the participants reported nonactive commuting, 13.4% reported work at home or work near home, 20.1% reported walking, and 19.4% reported cycling. During a median follow-up of 10 years, we identified 5374 incidents of ischemic heart disease, 664 events of hemorrhagic stroke, and 4834 events of ischemic stroke. After adjusting for sex, socioeconomic status, lifestyle factors, sedentary time, body mass index, comorbidities, household air pollution, passive smoking, and other domain physical activity, walking (hazard ratio, 0.90; 95% CI, 0.84-0.96) and cycling (hazard ratio, 0.81; 95% CI, 0.74-0.88) were associated with a lower risk of ischemic heart disease than nonactive commuting. Cycling was associated with a lower risk of ischemic stroke (hazard ratio, 0.92; 95% CI, 0.84-1.00). No significant association was found of walking or cycling with hemorrhagic stroke. The associations of commuting mode with major cardiovascular disease were consistent among men and women and across different levels of other domain physical activity. Conclusions In urban China, cycling was associated with a lower risk of ischemic heart disease and ischemic stroke. Walking was associated with a lower risk of ischemic heart disease.

Family History, Tobacco Smoking, and Risk of Ischemic Stroke.

BACKGROUND AND PURPOSE: Both genetic factors and smoking are associated with ischemic stroke (IS) risk. However, little is known about the potential interaction of these factors. We aimed to assess whether smoking and a positive family history interact to increase the risk of IS. METHODS: The nationwide prospective study recruited 210,000 men and 300,000 women in 2004 to 2008 at ages 30 to 79 years. During 9.7 years of follow-up, we documented 16,923 and 20,656 incident IS cases in men and women without major chronic diseases at baseline, respectively. Multivariable Cox regression models were used to examine associations between family history and IS. Likelihood ratio tests were used to test the smoking-family history interactions on IS. RESULTS: About 67.8% (n=135,168) of men ever smoked regularly compared with 2.7% (n=7,775) of women. Among men, a significant interaction between family history and smoking on IS was observed (P for interaction=0.03), with more pronounced association between family history and IS among ever-regular smokers (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.16 to 1.27) than among never-smokers (HR, 1.11; 95% CI, 1.01 to 1.23). The association between family history and IS among ex-smokers after more than 10 years of cessation (HR, 1.01; 95% CI, 0.85 to 1.20) appeared similar to that among never-smokers. Among women, a similar but not significant interaction between family history and smoking on IS was observed. Ever-regular smokers who had a family history of stroke had the highest risk of IS. CONCLUSIONS: Among Chinese men, the association of family history with IS was accentuated by smoking, and such accentuation tended to be lowered by cessation.

Effect of total, domain-specific, and intensity-specific physical activity on all-cause and cardiovascular mortality among hypertensive adults in China.

OBJECTIVES: We aimed to prospectively examine the associations of total, domain-specific, and intensity-specific physical activity with all-cause and cardiovascular mortality among Chinese hypertensive adults. METHODS: We performed a prospective cohort study in 150 391 hypertensive participants aged 30-79 years from the China Kadoorie Biobank study of 512 891 participants recruited from 10 diverse areas across China during 2004-2008. Participants with heart disease, stroke, chronic obstructive pulmonary disease, and cancer at baseline were excluded. RESULTS: During 1069 863 person-years of follow-up (median 7.1 years), a total of 5332 men and 4384 women died. Compared with hypertensive participants in the lowest level of total physical activity, the hazard ratios for all-cause mortality were 0.80 (0.76-0.84), 0.69 (0.65-0.73), and 0.67 (0.62-0.72) for those in quartiles 2-4 (Ptrend < 0.001), respectively. Inverse associations were also observed for cardiovascular mortality. Being active in occupational, domestic, and leisure time were associated with lower risk of all-cause and cardiovascular mortality. However, the adjusted ratio for active commuting was 1.08 (1.02-1.15) for all-cause mortality. High levels of low-intensity, moderate-intensity, and vigorous-intensity physical activity were consistently associated with lower risks of all-cause and cardiovascular mortality. CONCLUSION: Among Chinese hypertensive adults, a higher level of physical activity reduces all-cause and cardiovascular mortality, independent of intensities of physical activity. Not only leisure-time but also occupational and domestic physical activities were benefited.

Novel T-cell epitopes on Schistosoma japonicum SjP40 protein and their preventive effect on allergic asthma in mice.

Allergic asthma is a chronic inflammatory disease mediated by Th2 cell immune responses. Currently, immunotherapies based on immune deviation are attractive, preventive, and therapeutic strategies for asthma. Many studies have shown that intracellular bacterial infections such as mycobacteria and their components can suppress asthmatic reactions by enhancing Th1 responses, while helminth infections and their proteins can inhibit allergic asthma via immune regulation. However, some helminth proteins such as SmP40, the major egg antigen of Schistosoma mansoni, are found as Th1 type antigens. Using a panel of overlapping peptides, we identified T-cell epitopes on SjP40 protein of Schistosoma japonicum, which can induce Th1 cytokine and inhibit the production of Th2 cytokines and airway inflammation in a mouse model of allergic asthma. These results reveal a novel form of immune protective mechanism, which may play an important role in the modulating effect of helminth infection on allergic asthmatic reactions.

[Regional differences on patterns of physical activity and leisure sedentary time: findings from the China Kadoorie Biobank study, including a million people from 10 regions].

OBJECTIVE: To describe the gender and regional differences in patterns of physical activity and sedentary behavior across 10 study areas through data from the China Kadoorie Biobank (CKB) that involving half a million adults. METHODS: The baseline survey of CKB took place in 5 urban and 5 rural areas across China during 2004-2008. After excluding those who had a prior history of heart disease, stroke and/or cancer, 486 514 participants (age: 30-79 y) were included in the analyses. MET-h/d was calculated for each one of the participant, based on the type, duration and intensity of self-reported physical activity, along with time spent on sedentary activity. These data were compared, after standardization for age between sex and study areas. RESULTS: The mean total physical activity was 22.9 MET-h/d among men, 20.6 MET-h/d among women, and the mean sedentary leisure time appeared 3.1 h/d in men and 2.9 h/d in women. In men, the total physical activity ranged from 13.3 MET-h/d in Haikou to 31.3 MET-h/d in Zhejiang, while in women it ranged from 14.7 MET-h/d to 30.2 MET-h/d across the 10 areas. For sedentary leisure time, it ranged from 2.0 h/d in Zhejiang to 3.8 h/d in Sichuan in men and 1.6 h/d to 3.7 h/d in women. In both men and women, occupational physical activities (77.6% and 59.8% respectively) accounted for most of the daily activities, while leisure time physical activities accounted for the least (3.1% in both men and women). Among men, the proportion of occupational physical activity ranged from 86.5% in Zhejiang to 69.4% in Haikou (69.4%), while in women it ranged from 74.8% in Zhejiang to 40.9% in Henan. Gansu (men 17.8%, women 18.1%) reported the highest proportion of transportation physical activities. Among women, areas reporting the highest proportion of physical activity at home would include Henan (54.0%) and Hunan (39.1%), whereas adults in Zhejiang (20.0%) reported the lowest proportion. Among men, Hunan (18.0%) reported the highest proportion of physical activity at home. Compared with rural areas, male and female participants from urban areas tended to have more leisure time for physical activity and less vigorous-intensity physical activity. CONCLUSION: The patterns of physical activity and sedentary behavior including the levels of physical activity, domains and intensity of physical activities. Sedentary leisure time appeared all various greatly across different regions in China.