Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

Objective:To explore the prospective association between physical activity level and mor-tality risk in Chinese adults with chronic obstructive pulmonary disease(COPD).Methods:Based on the China Kadoorie Biobank(CKB)who had COPD at the baseline survey,this study employed the Cox proportional hazards regression model to estimate the prospective associations between the overall physical activity,different intensities(low-level,moderate-to-vigorous-level),and types(occupational,non-occupational)of physical activity level and the risks of all-cause and cause-specific mortality,such as vascular diseases,cancer,and respiratory diseases.Based on the quintiles of physical activity level,par-ticipants were divided into five groups(Q1-Q5),with the lowest quintile group(Q1)as the reference group.Hazard ratio(HR)and 95％confidence interval(95％CI)were calculated for the remaining.In our study,we also performed sensitivity and subgroup analyses,including age,gender,self-rated health status,severity of COPD,etc.Results:Among 33 588 COPD patients at the baseline survey,8 314(22.2％)deaths were documented during an average follow-up of(11.1±3.1)years.Negative linear associations between the overall physical activity level and mortality risk from all-cause,vascular,and respiratory diseases were observed(P trend for linear correlation being＜0.001,0.002,＜0.001).Compared with the lowest quintile group of total physical activity(Q1),the hazard ratios(HR)and 95％confidence intervals(CI)for all-cause mortality,vascular disease mortality,and respiratory disease mortality in the highest quintile group(Q5)were 0.77(0.70,0.85),0.77(0.65,0.91),and 0.58(0.48,0.71),respectively.The low-level and moderate-to-vigorous-level physical activity were nega-tively associated with all-cause mortality in the COPD patients(P trend for linear correlation:0.002,＜0.001,respectively).Compared with the lowest quintile group of low-intensity and moderate-to-vigorous intensity physical activity(Q1),the HRs(95％CI)for all-cause mortality in the highest quintile group(Q5)were 0.89(0.82,0.97)and 0.79(0.72,0.87),respectively.The occupational and non-occupational physical activity were also found to have a linear inverse association with all-cause mortality risk among the COPD patients(P trend＜0.001 and 0.015,respectively).Compared with the lowest quintile group of occupational and non-occupational physical activity(Q1),the HR(95％CI)for all-cause mortality in the highest quintile group(Q5)were 0.69(0.61,0.78)and 0.91(0.84,0.98),respectively.The associations between overall physical activity and all-cause mortality risk were stronger for patients aged 60 and above,female,and who reported poor health status(P for interaction:0.028,0.012,0.010).The protective effect of total physical activity was also applicable to the COPD patients of varying severity.Conclusion:Physical activity could reduce the mortality risk in a dose-response relationship among COPD patients,regardless of its intensity and type,especially among indi-viduals aged 60 and above,females,and those with poor self-report health status.

BACKGROUND:Acellular cartilage extracellular matrix is effective in the treatment of osteoarthritis,but its efficacy is limited when applied alone.Oxymatrine alleviates interleukin-1β-induced chondrocyte apoptosis and extracellular matrix degradation.OBJECTIVE:To observe the effect of different doses of oxymatrine combined with acellular cartilage extracellular matrix injection in knee cavity on osteoarthritis in rats.METHODS:The femoral cartilage of SD rats was obtained.The acellular cartilage extracellular matrix was prepared by physical,chemical and enzyme methods.Fifty SD rats were selected and divided into sham operation group,osteoarthritis group,simple material group,low-dose drug group,and high-dose drug group by random number table method,with 10 rats in each group.The latter four groups were treated with modified Hulth method to establish the rat model of osteoarthritis.After successful modeling,acellular cartilage extracellular matrix homogenate was injected into the knee cavity of rats in the simple material group.Acellular cartilage extracellular matrix homogenate containing 50,100 μg oxymatrine was injected into the knee cavity of rats in the low-dose drug group and the high-dose drug group,respectively.Samples were taken 4 weeks after injection for relevant detection.RESULTS AND CONCLUSION:(1) Compared with the sham operation group,the concentrations of interleukin 1β,tumor necrosis factor ɑ,and malondialdehyde in the joint effusion were increased (P<0.05),and the concentration of superoxide dismutase in the joint effusion was decreased (P<0.05) in the osteoarthritis group.Compared with osteoarthritis group,the levels of interleukin 1β,tumor necrosis factor ɑ,and malondialdehyde in joint effusion were decreased (P<0.05),while the level of superoxide dismutase was increased (P<0.05) in the low-dose drug group and high-dose drug group,and the changes were more significant in high-dose drug group.(2) TUNEL staining showed that compared with sham operation group,apoptotic chondrocytes increased in osteoarthritis group.Compared with the osteoarthritis group,the apoptotic chondrocytes decreased in the simple material group,the low-dose drug group,and the high-dose drug group,and the decrease was more significant in the high-dose drug group.(3) Hematoxylin-eosin staining and immunohistochemical staining showed that the knee cartilage was seriously degraded,the expression of type Ⅱ collagen was decreased (P<0.05),and the expression of matrix metalloproteinase-9 was increased (P<0.05) in the osteoarthritis group.Compared with the osteoarthritis group,the knee cartilage degeneration of rats in the simple material group,the low-dose drug group,and the high-dose drug group was significantly improved;the expression of type Ⅱ collagen was increased (P<0.05) and the expression of matrix metalloproteinase 9 was decreased (P<0.05),and the improvement was most significant in the high-dose drug group.(4) Western blot assay showed that compared with sham operation group,the expression of Nrf2,HO-1,and Bcl-2 protein in cartilage tissue decreased (P<0.05);expression levels of Cleaved-caspase-3,Cleaved-caspase-9,and Bax were increased (P<0.05) in the osteoarthritis group.Compared with the osteoarthritis group,the protein expression levels of Nrf2,HO-1,and Bcl-2 were increased (P<0.05),and the protein expressions of Cleaved-caspase-3,Cleaved-caspase-9,and Bax were decreased (P<0.05) in the low-dose and high-dose drug groups.The improvement was more significant in the high-dose drug group.(5) In conclusion,intracavicular injection of acellular cartilage extracellular matrix and oxymatrine can promote the synthesis of extracellular matrix,inhibit inflammation and oxidative stress,and suppress chondrocyte apoptosis,and play a therapeutic role in osteoarthritis,which may be related to the activation of Nrf2/HO-1 pathway.

Objective:To describe the prevalence of preserved ratio impaired spirometry (PRISm) in participants from the China Kadoorie Biobank (CKB) and explore the influencing factors.Methods:The CKB project conducted the baseline survey, the first and the second resurvey in 2004-2008, 2008, and 2013-2014, respectively. Based on the lung function tests, the participants were categorized into three groups: regular, PRISm, and airflow obstruction. The prevalence of PRISm was reported by gender, age, and region at the baseline survey. The secular trend in the prevalence of PRISm was described during the three surveys. Finally, we used the multiple logistic regression model to examine the factors related to PRISm in the baseline survey.Results:After standardization for gender, age, and region according to the sixth national census data in 2010, the overall prevalence of PRISm and airflow obstruction among the 434 760 participants at baseline was 24.8% and 6.1%, respectively. The prevalence of PRISm was higher in rural (25.4%) than that in urban areas (24.3%). Of the 10 study regions, Gansu had the highest prevalence of PRISm (56.0%), while Henan had the lowest (15.4%). After standardization for gender, age, and region according to the baseline population, the prevalence of PRISm decreased from 24.9% at baseline to 15.7% in the second resurvey, and the prevalence of airflow obstruction increased from 5.9% to 21.4%. Unmarried status, current smoking, using solid fuels for cooking, low body weight, being overweight, obesity, and central obesity were associated with an increased risk of PRISm. In contrast, higher education attainments, increased household income, and maintaining a specific degree of physical activity were associated with a reduced risk of PRISm.Conclusions:The prevalence of PRISm was high in adults aged 40 years and above in China, and it varied by sociodemographic and lifestyle factors.

Objective To investigate the relationship between platelet distribution width(PDW)and coronary artery calcification(CAC)in overweight and obese populations.Methods Clinical and chest CT data of 10 838 subjects with overweight or obesity(body mass index[BMI]≥24 kg/m2)were retrospectively analyzed.The subjects were divided into CAC group(n=4 237)and non-CAC group(n=6 601)based on CAC scores obtained from chest CT.The relationship between PDW and CAC in overweight and obese populations was analyzed after controlling confounding variables.A threshold effect analysis was conducted using a two-stage logistic model to find the non-linear inflection point.Subgroup analyses and interaction tests were conducted to validate the stability of the relationship between PDW and CAC.Results Non-linear relationship was observed between PDW and CAC risk in overweight and obese populations.The risk of CAC decreased with the increase of PDW which ≤17.80％(OR=0.82),but increased with the increase of PDW(OR=1.04)which＞17.80％.Subgroup analysis showed that the relationship between PDW and CAC remained stable in subgroups of different genders,BMI(＜28 kg/m2,≥28 kg/m2)and hypertension(all P＞0.05).Compared with aged＜40 years or ≥60 years subgroups,under the same PDW,aged≥40 and＜60 years subgroups had higher risk of CAC(interaction P=0.015).Conclusion Nonlinear relationship existed between PDW and CAC in overweight and obese populations.Both excessively high and low PDW were risk factors of CAC.

Objective:To explore the prospective association between physical activity level and mor-tality risk in Chinese adults with chronic obstructive pulmonary disease(COPD).Methods:Based on the China Kadoorie Biobank(CKB)who had COPD at the baseline survey,this study employed the Cox proportional hazards regression model to estimate the prospective associations between the overall physical activity,different intensities(low-level,moderate-to-vigorous-level),and types(occupational,non-occupational)of physical activity level and the risks of all-cause and cause-specific mortality,such as vascular diseases,cancer,and respiratory diseases.Based on the quintiles of physical activity level,par-ticipants were divided into five groups(Q1-Q5),with the lowest quintile group(Q1)as the reference group.Hazard ratio(HR)and 95％confidence interval(95％CI)were calculated for the remaining.In our study,we also performed sensitivity and subgroup analyses,including age,gender,self-rated health status,severity of COPD,etc.Results:Among 33 588 COPD patients at the baseline survey,8 314(22.2％)deaths were documented during an average follow-up of(11.1±3.1)years.Negative linear associations between the overall physical activity level and mortality risk from all-cause,vascular,and respiratory diseases were observed(P trend for linear correlation being＜0.001,0.002,＜0.001).Compared with the lowest quintile group of total physical activity(Q1),the hazard ratios(HR)and 95％confidence intervals(CI)for all-cause mortality,vascular disease mortality,and respiratory disease mortality in the highest quintile group(Q5)were 0.77(0.70,0.85),0.77(0.65,0.91),and 0.58(0.48,0.71),respectively.The low-level and moderate-to-vigorous-level physical activity were nega-tively associated with all-cause mortality in the COPD patients(P trend for linear correlation:0.002,＜0.001,respectively).Compared with the lowest quintile group of low-intensity and moderate-to-vigorous intensity physical activity(Q1),the HRs(95％CI)for all-cause mortality in the highest quintile group(Q5)were 0.89(0.82,0.97)and 0.79(0.72,0.87),respectively.The occupational and non-occupational physical activity were also found to have a linear inverse association with all-cause mortality risk among the COPD patients(P trend＜0.001 and 0.015,respectively).Compared with the lowest quintile group of occupational and non-occupational physical activity(Q1),the HR(95％CI)for all-cause mortality in the highest quintile group(Q5)were 0.69(0.61,0.78)and 0.91(0.84,0.98),respectively.The associations between overall physical activity and all-cause mortality risk were stronger for patients aged 60 and above,female,and who reported poor health status(P for interaction:0.028,0.012,0.010).The protective effect of total physical activity was also applicable to the COPD patients of varying severity.Conclusion:Physical activity could reduce the mortality risk in a dose-response relationship among COPD patients,regardless of its intensity and type,especially among indi-viduals aged 60 and above,females,and those with poor self-report health status.

Objective:To describe the prevalence of preserved ratio impaired spirometry (PRISm) in participants from the China Kadoorie Biobank (CKB) and explore the influencing factors.Methods:The CKB project conducted the baseline survey, the first and the second resurvey in 2004-2008, 2008, and 2013-2014, respectively. Based on the lung function tests, the participants were categorized into three groups: regular, PRISm, and airflow obstruction. The prevalence of PRISm was reported by gender, age, and region at the baseline survey. The secular trend in the prevalence of PRISm was described during the three surveys. Finally, we used the multiple logistic regression model to examine the factors related to PRISm in the baseline survey.Results:After standardization for gender, age, and region according to the sixth national census data in 2010, the overall prevalence of PRISm and airflow obstruction among the 434 760 participants at baseline was 24.8% and 6.1%, respectively. The prevalence of PRISm was higher in rural (25.4%) than that in urban areas (24.3%). Of the 10 study regions, Gansu had the highest prevalence of PRISm (56.0%), while Henan had the lowest (15.4%). After standardization for gender, age, and region according to the baseline population, the prevalence of PRISm decreased from 24.9% at baseline to 15.7% in the second resurvey, and the prevalence of airflow obstruction increased from 5.9% to 21.4%. Unmarried status, current smoking, using solid fuels for cooking, low body weight, being overweight, obesity, and central obesity were associated with an increased risk of PRISm. In contrast, higher education attainments, increased household income, and maintaining a specific degree of physical activity were associated with a reduced risk of PRISm.Conclusions:The prevalence of PRISm was high in adults aged 40 years and above in China, and it varied by sociodemographic and lifestyle factors.

BACKGROUND:Acellular cartilage extracellular matrix is effective in the treatment of osteoarthritis,but its efficacy is limited when applied alone.Oxymatrine alleviates interleukin-1β-induced chondrocyte apoptosis and extracellular matrix degradation.OBJECTIVE:To observe the effect of different doses of oxymatrine combined with acellular cartilage extracellular matrix injection in knee cavity on osteoarthritis in rats.METHODS:The femoral cartilage of SD rats was obtained.The acellular cartilage extracellular matrix was prepared by physical,chemical and enzyme methods.Fifty SD rats were selected and divided into sham operation group,osteoarthritis group,simple material group,low-dose drug group,and high-dose drug group by random number table method,with 10 rats in each group.The latter four groups were treated with modified Hulth method to establish the rat model of osteoarthritis.After successful modeling,acellular cartilage extracellular matrix homogenate was injected into the knee cavity of rats in the simple material group.Acellular cartilage extracellular matrix homogenate containing 50,100 μg oxymatrine was injected into the knee cavity of rats in the low-dose drug group and the high-dose drug group,respectively.Samples were taken 4 weeks after injection for relevant detection.RESULTS AND CONCLUSION:(1) Compared with the sham operation group,the concentrations of interleukin 1β,tumor necrosis factor ɑ,and malondialdehyde in the joint effusion were increased (P<0.05),and the concentration of superoxide dismutase in the joint effusion was decreased (P<0.05) in the osteoarthritis group.Compared with osteoarthritis group,the levels of interleukin 1β,tumor necrosis factor ɑ,and malondialdehyde in joint effusion were decreased (P<0.05),while the level of superoxide dismutase was increased (P<0.05) in the low-dose drug group and high-dose drug group,and the changes were more significant in high-dose drug group.(2) TUNEL staining showed that compared with sham operation group,apoptotic chondrocytes increased in osteoarthritis group.Compared with the osteoarthritis group,the apoptotic chondrocytes decreased in the simple material group,the low-dose drug group,and the high-dose drug group,and the decrease was more significant in the high-dose drug group.(3) Hematoxylin-eosin staining and immunohistochemical staining showed that the knee cartilage was seriously degraded,the expression of type Ⅱ collagen was decreased (P<0.05),and the expression of matrix metalloproteinase-9 was increased (P<0.05) in the osteoarthritis group.Compared with the osteoarthritis group,the knee cartilage degeneration of rats in the simple material group,the low-dose drug group,and the high-dose drug group was significantly improved;the expression of type Ⅱ collagen was increased (P<0.05) and the expression of matrix metalloproteinase 9 was decreased (P<0.05),and the improvement was most significant in the high-dose drug group.(4) Western blot assay showed that compared with sham operation group,the expression of Nrf2,HO-1,and Bcl-2 protein in cartilage tissue decreased (P<0.05);expression levels of Cleaved-caspase-3,Cleaved-caspase-9,and Bax were increased (P<0.05) in the osteoarthritis group.Compared with the osteoarthritis group,the protein expression levels of Nrf2,HO-1,and Bcl-2 were increased (P<0.05),and the protein expressions of Cleaved-caspase-3,Cleaved-caspase-9,and Bax were decreased (P<0.05) in the low-dose and high-dose drug groups.The improvement was more significant in the high-dose drug group.(5) In conclusion,intracavicular injection of acellular cartilage extracellular matrix and oxymatrine can promote the synthesis of extracellular matrix,inhibit inflammation and oxidative stress,and suppress chondrocyte apoptosis,and play a therapeutic role in osteoarthritis,which may be related to the activation of Nrf2/HO-1 pathway.

Objective To investigate the relationship between platelet distribution width(PDW)and coronary artery calcification(CAC)in overweight and obese populations.Methods Clinical and chest CT data of 10 838 subjects with overweight or obesity(body mass index[BMI]≥24 kg/m2)were retrospectively analyzed.The subjects were divided into CAC group(n=4 237)and non-CAC group(n=6 601)based on CAC scores obtained from chest CT.The relationship between PDW and CAC in overweight and obese populations was analyzed after controlling confounding variables.A threshold effect analysis was conducted using a two-stage logistic model to find the non-linear inflection point.Subgroup analyses and interaction tests were conducted to validate the stability of the relationship between PDW and CAC.Results Non-linear relationship was observed between PDW and CAC risk in overweight and obese populations.The risk of CAC decreased with the increase of PDW which ≤17.80％(OR=0.82),but increased with the increase of PDW(OR=1.04)which＞17.80％.Subgroup analysis showed that the relationship between PDW and CAC remained stable in subgroups of different genders,BMI(＜28 kg/m2,≥28 kg/m2)and hypertension(all P＞0.05).Compared with aged＜40 years or ≥60 years subgroups,under the same PDW,aged≥40 and＜60 years subgroups had higher risk of CAC(interaction P=0.015).Conclusion Nonlinear relationship existed between PDW and CAC in overweight and obese populations.Both excessively high and low PDW were risk factors of CAC.

BACKGROUND: Biliary tract carcinomas (BTCs) are relatively rare but lethal primary malignant tumors derived from the biliary tract system. The burden of BTCs varies according to sex, age, region, and country, but limited attention has been paid to the burden of BTCs. We sought to explore the up-to-date data from the Global Burden of Disease Study (GBD) and expand findings by accessing the demographic features of BTC disease burden. METHODS: Using the latest data from the GBD 2021, we evaluated and analyzed the distributions and patterns of BTC disease burden in various age groups, sexes, regions, and countries. RESULTS: The number of incident cases, deaths, and disability-adjusted life-years (DALYs) tended to increase and peaked at 216,770 (95% uncertainty interval [UI]: 181,890-245,240), 171,960 (95% UI: 142,350-194,240), and 3,732,100 (95% UI: 3,102,900-4,317,000) person-years, respectively, in 2021. However, the average global age-standardized rates (ASRs) of incident cases, deaths, and DALYs shrunk by -11.46% (95% UI: -21.91 to 3.35%), -24.09% (95% UI: -33.19 to 16.88%), and -26.25% (95% UI: -35.53 to 18.36%), respectively, from 1990 to 2021. Meanwhile, the male/female ratio (male per 100 female) of incidence, deaths, and DALYs changed from 76.40, 75.41, and 74.72 to 86.89, 79.11, and 82.29, respectively. In 2021, the highest number of incident cases, deaths, and DALYs occurred in East Asia. The top three highest incidences, deaths, and DALYs were observed in China, India, and Japan, and the highest ASRs were observed in Chile in 2021. Analysis of the Human Development Index along with disease burden estimates of BTCs also suggests that the burden of the disease is related to the level of comprehensive development of the society. CONCLUSION This study provided a comprehensive comparison of differences in the burden of disease across populations and over time, and further presented evidence concerning the formulation of prevention and control policies and etiologic studies for BTCs and proposed logical hypotheses to investigate.
Humans ; Global Burden of Disease ; Biliary Tract Neoplasms/epidemiology* ; Male ; Female ; Disability-Adjusted Life Years ; Middle Aged ; Aged ; Adult ; Incidence ; Aged, 80 and over ; Quality-Adjusted Life Years ; Cost of Illness