Biochemical and molecular analysis of pediatric patients with metachromatic leukodystrophy in South China: functional characterization of five novel ARSA variants.

Metachromatic leukodystrophy (MLD) is a rare hereditary neurodegenerative disease caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA). This study described the clinical and molecular characteristics of 24 Chinese children with MLD and investigated functional characterization of five novel ARSA variants. A retrospective analysis was performed in 24 patients diagnosed with MLD at Guangzhou Women and Children's Medical Center in South China. Five novel mutations were further characterized by transient expression studies. We recruited 17 late-infantile, 3 early-juvenile, 4 late-juvenile MLD patients. In late-infantile patients, motor developmental delay and gait disturbance were the most frequent symptoms at onset. In juvenile patients, cognitive regression and gait disturbance were the most frequent chief complaints. Overall, 25 different ARSA mutations were identified with 5 novel mutations.The most frequent alleles were p.W320* and p.G449Rfs. The mutation p.W320*, p.Q155=, p.P91L, p.G156D, p.H208Mfs*46 and p.G449Rfs may link to late-infantile type. The novel missense mutations were predicted damaging in silico. The bioinformatic structural analysis of the novel missense mutations showed that these amino acid replacements would cause severe impairment of protein structure and function. In vitro functional analysis of the six mutants, showing a low ARSA enzyme activity, clearly demonstrated their pathogenic nature. The mutation p.D413N linked to R alleles. In western blotting analysis of the ARSA protein, the examined mutations retained reduced amounts of ARSA protein compared to the wild type. This study expands the spectrum of genotype of MLD. It helps to the future studies of genotype-phenotype correlations to estimate prognosis and develop new therapeutic approach.

Clinical manifestations and genetic mutation analysis of patients with mucopolysaccharidosis type VII in China.

OBJECTIVE: This study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection, disease management, and patient outcomes. METHODS: A retrospective review of medical records for five patients presenting with coarse facial features, rib protrusion, chest deformities, and scoliosis was conducted. Exome sequencing was employed to identify causative genetic mutations. RESULTS: The study comprised five patients (four males, one female) with disease onset at six months of age (range: 0-1.5 years). Common symptoms included coarse facial features, skeletal abnormalities, delayed motor and language development, and intellectual disability. Approximately 80% of the patients exhibited multiple skeletal dysplasias, enlarged adenoids or tonsils, and snoring; 60% had hernias; 40% reported hearing loss and hepatosplenomegaly. Less frequent manifestations were short stature, valvular heart disease, non-immune hydrops fetalis, and corneal opacity. All patients demonstrated elevated urine glycosaminoglycans levels and absent ß-glucuronidase activity in leukocytes. Exome sequencing identified compound heterozygous mutations in the GUSB gene in all four tested patients, uncovering seven mutations in total, three of which were novel (c.189G > A, c.869C > T, and c.1745 T > C). Furthermore, prenatal diagnosis through chorionic villus sampling in subsequent pregnancies of one patient's mother revealed both fetuses had normal ß-glucuronidase activity and no disease-causing mutations in the GUSB gene. CONCLUSION: The study's patients all presented with classic symptoms of MPS VII due to ß-glucuronidase deficiency, with three new pathogenic mutations identified in the GUSB gene. Genetic counseling and prenatal testing were highlighted as crucial for disease prevention.

Uric acid mediated the relationship between obesity and hypertension in children and adolescents: A population­based cohort study.

BACKGROUND AND AIM: Obesity and hyperuricemia (HUA) often coexist and have been widely accepted as risk factors for hypertension, but the role of uric acid (UA) in the relationship between obesity and hypertension remains unknown in children and adolescents. METHODS AND RESULTS: A total of 7525 subjects aged 6-16 years were from the School-based Cardiovascular and Bone Health Promotion Program (SCVBH) at baseline (2017) and followed up in 2019. Multivariable logistic regression with interaction terms, cross-lagged panel analysis, and causal mediation model were applied to delineate the joint impact of obesity and HUA on hypertension, including the interaction effect, the temporal association, and the mediating effect of UA in the relationship between obesity and hypertension. There were 10.8 % of the participants with normotension at baseline developed hypertension after two years of follow-up. Cross-lagged panel analysis showed that the two-time point association was significant only from baseline BMI to follow-up UA (ß1 = 0.302, P < 0.001), but not from baseline UA to follow-up BMI (ß2 = 0.002, P = 0.745). Multivariable logistic regression showed that both obesity and HUA increased the risk of hypertension, but no interaction effect between HUA and obesity. The causal mediation analysis found that UA partially mediated the association between BMI and SBP (mediate proportion: 20.3 %, 95 % CI: 17.4-22.9 %) or DBP (mediate proportion: 11.9 %, 95 % CI: 3.9-18.2 %). The results were consistent in the analysis of systolic hypertension rather than diastolic hypertension. CONCLUSIONS: It is mediating effect that UA played in the progress from obesity to hypertension, particularly systolic hypertension in children and adolescents.

Longitudinal association of serum 25-hydroxyvitamin D levels with metabolically healthy body size transition in children and adolescents: A prospective cohort study with 2 years of follow-up.

BACKGROUND AND AIMS: Although the associations of vitamin D with obesity and metabolic abnormalities have been reported, the role of vitamin D in the transition of obesity phenotype remains unclear but is highly desired since it is crucial to identify potential methods for obesity management. Therefore, we aimed to investigate the relationship between vitamin D and the risk for metabolically unhealthy obesity (MUO) or metabolically healthy obesity (MHO) in metabolically healthy children with 2 years of follow-up. METHODS: Data were collected from a population-based cohort consisting of 6424 metabolically healthy children aged 6-16 years at baseline. Metabolic abnormalities including hypertension, high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), hyperglycemia, and hyperuricemia were assessed both at baseline and follow-up. Baseline serum 25-hydroxyvitamin D (25[OH]D) concentrations were measured as exposure. The obesity phenotype transition was evaluated by weight status with the combination of metabolic health status from baseline to follow-up. RESULTS: During a 2-year follow-up, 889 (13.8 %) incident MUO cases occurred. For participants with obesity, each 10 nmol/L increment in 25(OH)D concentrations was associated with a 21 % (95%CI: 13 %∼43 %) and a 7 % (95%CI: 1 %∼14 %) decreased risk in high TG and hyperuricemia, respectively. A 51 % (95%CI: 22 %∼69 %) lower risk of MUO was observed in participants with sufficient vitamin D levels (≥50 nmol/L) compared to those with vitamin D deficiency (<30 nmol/L). Besides, among children who were MHO at baseline, those with sufficient vitamin D levels (≥50 nmol/L) were more likely to transition to metabolically healthy normal weight (MHNW) than vitamin D deficient individuals (<30 nmol/L). CONCLUSIONS: Vitamin D may prevent the development of MUO and help increase the transition from MHO to MHNW. The findings highlight that vitamin D might be an effective nutrient for obesity management.

Structure and Electron Configuration of Imidazole-2-carboxaldehyde and Its Excited Triplet: Resonance Raman and Transient Absorption Spectroscopy and DFT Calculation Investigations.

Imidazole-2-carboxaldehyde (IC) can be generated in atmospheric waters and absorbs solar radiation in the near UV region to produce its excited triplet state (3IC), which contributes to the formation of a secondary organic aerosol (SOA). The photoreactivity of IC is significantly influenced by its surroundings, such as water and acidic environment, because IC is capable of transforming into gem-diol under above conditions. Meanwhile, the electron configuration of 3IC is critical in elucidating the reaction mechanism of 3IC with other anthropogenic and biogenic volatile organic compounds (VOCs). In this study, steady-state and time-resolved resonance Raman as well as transient absorption spectroscopic experiments were conducted to provide vibrational and kinetic information on IC and 3IC in the presence of water and acid conditions. Using density functional theory (DFT) calculations, the H-bonding at the carbonyl O was confirmed and the hydrated structure of IC and 3IC was determined. 1,4-Cyclohexadiene is a good hydrogen donor, and it has a second-order rate constant of ∼107 M-1 s-1 toward 3IC. The results of CASSCF calculations suggest that the hydrogen abstraction may involve the transition from the ππ* to nπ* triplet state via the surface-crossing point.

Genetically proxied vitamin B12 and homocysteine in relation to life course adiposity and body composition.

OBJECTIVE: Observational studies explore the association between vitamin B12 and obesity. However, causality is not reflected by such observations. We performed a bi-directional Mendelian randomization (MR) study to elucidate the causal relationship of vitamin B12 and homocysteine (Hcy) with life course adiposity and body composition. METHODS: Two-sample MR analysis was conducted. Independent genetic variants associated with vitamin B12 and Hcy from large-scale genome-wide association studies (GWASs) were utilized as genetic instruments, and their causal effects on five life course adiposity phenotypes (birth weight, body mass index (BMI), childhood BMI, waist circumference, waist-to-hip ratio) and three body compositions (body fat mass, body fat-free mass, body fat percentage) were estimated from UK Biobank, other consortia, and large-scale GWASs. The inverse variance weighting (IVW, main analysis), bi-directional MR, and other six sensitivity MR analyses were performed. RESULTS: Genetically proxied higher vitamin B12 concentrations were robustly associated with reduced BMI (Beta = -0.01, 95% confidence interval (CI) -0.016 to -0.004, P = 7.60E-04), body fat mass (Beta = -0.012, 95%CI -0.018 to -0.007, P = 1.69E-05), and body fat percentage (Beta = -0.005, 95%CI -0.009 to -0.002, P = 4.12E-03) per SD unit by IVW and other sensitivity analyses. Stratification analysis showed that these results remained significant in females and at different body sites (all P < 0.05 after Bonferroni correction). Bi-directional analyses showed no reverse causation. CONCLUSIONS: This study provides strong evidence for the causal effect of vitamin B12 on adiposity. This gives novel clues for intervening obesity in public health and nutrition.

The 'invisible gorilla' during pedestrian-AV interaction: Effects of secondary tasks on pedestrians' reaction to eHMIs.

In road traffic, mental overload often leads to a failure to notice new and distinctive stimuli. Such phenomenon is known as 'inattentional blindness'. Safe and efficient interaction between automated vehicles (AVs) and pedestrians is expected to rely heavily on external human-machine interfaces (eHMIs), a tool AVs are equipped with to communicate their intentions to pedestrians. This study seeks to explore the phenomenon of 'inattentional blindness' in the context of pedestrian-AV interactions. Specifically, the aim is to understand the effects of a warning eHMI on pedestrians' crossing decisions when they are engaged in a secondary task. In an experiment study with videos of pedestrian crossing scenarios filmed from the perspective of the crossing pedestrian, participants had to decide the latest point at which they would be willing to cross the road in front of an AV with an eHMI vs. an AV without an eHMI. Participants were also asked to predict the future behavior of the AV. 125 female and 9 male participants aged between 18 and 25 completed the experiment and a follow-up questionnaire. It was found that the presence of a warning eHMI on AVs contributes to a clearer understanding of pedestrians' inferences about the intention of AVs and helps deter late and dangerous crossing decisions made by pedestrians. However, the eHMI fail to help pedestrians avoid such decisions when they face a high mental workload induced by secondary task engagement.

Prevalence of hypertension and its associations with body composition across Chinese and American children and adolescents.

BACKGROUND: The age of onset of hypertension (HTN) is decreasing, and obesity is a significant risk factor. The prevalence and racial disparities in pediatric HTN and the association between body composition and blood pressure are insufficiently studied. This study aimed to evaluate the prevalence of HTN in Chinese and American children and adolescents and to assess the relationship between various body composition indices and HTN. METHODS: Seven thousand, five hundred and seventy-three Chinese and 6239 American children and adolescents aged 8-18 years from the 2013-2015 China Child and Adolescent Cardiovascular Health study and the 2011-2018 National Health and Nutrition Examination Surveys were analyzed. Blood pressure and body composition (fat and muscle) were measured by trained staff. The crude prevalence and age-standardized prevalence rate (ASPR) of primary HTN and its subtypes [isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH)] were calculated based on 2017 American Academy of Pediatrics guidelines. Multivariable-adjusted linear regression coefficients and odds ratios (ORs) were calculated to assess the associations of body composition indicators with HTN, ISH and IDH. RESULTS: The ASPR of HTN was 18.5% in China (CN) and 4.6% in the United States (US), whereas the obesity prevalence was 7.4% and 18.6%, and the population attributable risk of HTN caused by overweight and obesity was higher in the US than in CN. Increased fat mass, muscle mass and body fat percentage mass were associated with a higher risk of HTN in both countries. The percent of muscle body mass had a protective effect on HTN and ISH in both countries [HTN (CN: OR = 0.83, 95% CI = 0.78-0.88; US: OR = 0.72, 95% CI = 0.64-0.81); ISH (CN: OR = 0.87, 95% CI = 0.80-0.94; US: OR = 0.71, 95% CI = 0.62-0.81)], and the protective effect was more common among children and adolescents with high levels of physical activity. CONCLUSIONS: The burden of HTN in Chinese children and adolescents was substantial and much greater than that in the US, and the contribution of obesity to HTN was higher in the US than in CN. Augmenting the proportion of muscle mass in body composition has a protective effect against HTN in both populations. Optimizing body composition positively influences blood pressure in children and adolescents, particularly those with high-level physical activity. Video abstract (MP4 149982 KB).

Difference of glucose and lipid metabolism abnormalities and body fat between the Chinese and USA teenagers.

Background: Comparing body fat and the effect of body fat on metabolic abnormalities in Chinese and USA teenagers may provide clues for the early prevention and control of cardiovascular disease (CVD). We aimed to compare the prevalence of glucose and lipid metabolism abnormalities, body fat amount and distribution, and the effect of body fat on glucose and lipid metabolism in Chinese and US teenagers. Methods: We included 5424 Chinese teenagers (48.5% male) from the China Child and Adolescent Cardiovascular Health (CCACH) study and 8704 USA teenagers (55.6% male) from the USA National Health and Nutrition Examination Survey (NHANES). Blood lipid, blood glucose, and body fat indicators were obtained using the same standardised measurements. Results: The prevalence of dyslipidaemia in Chinese teenagers was of those in the USA (hypercholesterolaemia = 3.5% vs 7.4%; high low-density lipoprotein cholesterol (LDL-C) = 3.6% vs 5.0%; low high-density lipoprotein cholesterol (HDL-C) = 9.9% vs 14.3%; hypertriglyceridaemia = 3.7% vs 10.1%) (P < 0.05). However, with the increase in body mass index (BMI), the prevalence of high LDL-C increased more in Chinese than in US teenagers, even exceeding them in the obese group (2.7% in non-overweight to 9.7% in overweight group in China, P < 0.05; 3.5% in non-overweight to 6.5% in the obese group in the USA, P < 0.05). The prevalence of impaired fasting glucose was higher in China than in the USA (28.0% vs 17.5%, P < 0.05). Besides, Chinese adolescents are more likely to accumulate fat in the abdomen, and the per-unit fat increase would bring a higher risk of dyslipidaemia in Chinese boys than in USA boys. Conclusions: Dyslipidaemia was more prevalent in US teenagers than in Chinese teenagers, but with the increase in BMI, the prevalence of high LDL-C increased more in Chinese than in US teenagers. Impaired fasting glucose (IFG) was significantly more prevalent in China than in the USA. The unfavoured body fat and higher risk of body fat on metabolic disorders in Chinese teenagers suggest that Chinese teenagers should pay more attention to the adverse effect of body fat on metabolic abnormalities.

Relationships for vitamin D with childhood height growth velocity and low bone mineral density risk.

Objective: To investigate how serum 25-hydroxyvitamin D (25[OH]D) affects height growth velocity and the risk of low bone mineral density (BMD) in children. Design: A population-based prospective cohort study. Patients and methods: A total of 10 450 participants with complete follow-up records from a cohort were included in the current study. Serum 25(OH)D concentrations were measured at baseline and 2-year follow-up, and the average of 2-time measurements was used for analysis. Low BMD was defined as calcaneus speed of sound Z-score ≤ -1. The associations of vitamin D with height growth velocity and the risks of incident low BMD were evaluated using adjusted ß and risk ratio (RR). Results: After multivariable adjustment, an inverse L-shaped association between serum 25(OH)D concentrations and height growth velocity was observed, leveling off up to 40-60 nmol/L. Overall, each 10 nmol/L higher serum 25(OH)D concentration was associated with a 0.15 cm/year higher height growth velocity (P < 0.001) and a 7% decreased risk of low BMD [RR (95%CI): 0.93 (0.87~0.98)]. Compared to those with vitamin D deficiency, participants who had sufficient vitamin D had a 22% lower risk for low BMD [RR(95%CI): 0.78 (0.62~0.98)]. However, no significant associations between vitamin D and the risk of low BMD were found in overweight and obese children. Conclusion: These findings highlight the importance of maintenance of sufficient 25(OH)D concentrations and healthy body weight during childhood in height growth and bone health promotion.

Overfat cutoffs and the optimal combination of body fat indices for detecting cardiometabolic risk among school-aged children.

OBJECTIVE: This study aimed to develop cutoffs and the optimal combination for body fat indices for screening cardiometabolic risk (CMR) among the pediatric population. METHODS: This cross-sectional study consisted of 8710 (50.3% boys) Chinese children aged 6 to 18 years. Body fat indices, including fat mass index (FMI), body fat percentage, trunk to leg fat ratio (TLR), and android to gynoid fat ratio, were derived from dual-energy x-ray absorptiometry scans. The area under the receiver operating characteristic curve was used to determine the best combination and optimal cutoffs of body fat indices to identify CMR. RESULTS: Compared with anthropometry-based obesity measures, i.e., BMI and waist circumference, the FMI + TLR combination presented statistically higher area under the receiver operating characteristic curve values for discriminating CMR and its clustering. The optimal overfat cutoffs of FMI and TLR were respectively determined at the 75th percentile in boys and at the 80th percentile of FMI and the 75th percentile of TLR in girls. Moreover, simplified thresholds derived from age-group-merged cutoffs showed similar performance as optimal cutoffs in detecting CMR. CONCLUSIONS: Both the optimal and simplified overfat cutoffs were provided for the Chinese pediatric population. The use of FMI and TLR together allows for adequate screening of CMR and its clustering.

DUCNP@Mn-MOF/FOE as a Highly Selective and Bioavailable Drug Delivery System for Synergistic Combination Cancer Therapy.

Heterostructures comprising lanthanide-doped upconversion nanoparticles (DUCNPs) and metal-organic frameworks (MOFs) are emerging as promising nanosystems for integrating medical diagnosis and treatment. Here, the DUCNP@Mn-MOF nanocarrier was developed, which showed good efficiency for loading and delivering a cytotoxic antitumor agent (3-F-10-OH-evodiamine, FOE). The combined advantages of the pH-responsive and peroxidase-like properties of Mn-MOF and the unique optical features of DUCNPs granted the DUCNP@Mn-MOF/FOE system synergistic chemodynamic and chemotherapeutic effects. The DUCNP@Mn-MOF nanocarrier effectively overcame the intrinsic limitations of FOE, such as its unfavorable physicochemical properties and limited in vivo potency. This complexed nanosystem was responsive to the tumor microenvironment and showed excellent tumor targeting capability. Thus, DUCNP@Mn-MOF/FOE exhibited highly selective and bioavailable drug delivery properties and is promising for cancer therapy. In a mouse breast cancer model, DUCNP@Mn-MOF/FOE inhibited tumor growth without significant toxicity. Therefore, the proposed nanosystem represents a promising theragnostic platform for multimodal combination diagnosis and therapy of tumors.

Analysis of the typing of adenovirus and its clinical characteristics in children with acute respiratory tract infection.

BACKGROUND: The purpose of this study was to investigate the typing of adenovirus (AdV) infection in children hospitalized with acute respiratory tract infection (ARTI) and its clinical characteristics. METHODS: Samples from 7832 hospitalized children with ARTIs from January 2021 to June 2022 were tested by multiplex PCR for AdV. AdV hex neighborhood genes were amplified and sequenced for typing by nested PCR. RESULTS: Three hundred twenty-eight cases were positive for AdV with rate of 4.48% (328/7832). No statistical difference in the rate of AdV detection was observed in different ages (P > 0.05). Among the 328 cases, 305 cases underwent amplification and sequence determination of AdV five-neighborhood, six-neighborhood and fibronectin genes. Only 237 cases were sequenced successfully for all 3 genetic fragments. The typing results of 231 cases with 3 genes were consistent, with 49.78% (115/231) of type 3, 41.56% (96/231) of type 7 and 8.66% (20/231) of other types identified. The main clinical symptoms in 231 children hospitalized with ARTI who were AdV positive were cough, sputum not easily coughable, Wheezing or shortness of breath and fever. Clinical diagnoses of 231 cases included: acute bronchitis 3.03% (7/231), capillary bronchitis 16.45% (38/231), pneumonia (mild/severe) 76.62% (177/231) (68.40% (158/231) in mild and 8.23% (19/231) in severe cases), bronchial asthma combined with pulmonary infection 3.46% (8/231). Higher percentage of shortness of breath, multilobar infiltration, and pleural effusion were found in type 7. Calcitoninogen in type 7 were significantly higher than those of type 3 and other types, and the white blood cell count was lower than those of type 3 and other types, and the difference was statistically significant (P < 0.05). CONCLUSION: AdV type 3 and 7 were frequently found in hospitalized children with acute lower respiratory tract involvement. AdV type 7 seems to be associated with more severe outcome.

Differences in air displacement plethysmography, bioelectrical impedance analysis and dual-energy X-ray absorptiometry for estimating body composition in Chinese children and adolescents.

AIM: This study aimed to compare body composition (BC) measurements obtained by three widely used BC measuring methods, air displacement plethysmography (ADP), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA), in Chinese children and adolescents by sex and different BMI categories. METHODS: We used three BC measuring methods to evaluate healthy Chinese children and adolescents aged 5-17 years with BMI categories ranging from underweight to obese. Fat mass (FM, kg), fat mass percentage (FMP, %), fat-free mass (FFM, kg) and appendicular skeletal muscle mass (ASM, kg) were measured by DXA, BIA and ADP on the same day within 1 h. RESULTS: A total of 172 Chinese children and adolescents were included in this study. The agreements for FM, FFM and ASM estimated by the three methods were excellent or good at the population level (intraclass correlation coefficient > 0.850, P < 0.05). However, ADP or BIA estimated lower body fat content and higher FFM than DXA (P < 0.001 for all). Moreover, the precise estimates significantly varied across BMI categories. In addition, the limit of agreements was wide, and the differences might not be clinically acceptable at the individual level. CONCLUSIONS: Body fat and FFM obtained by the three commonly used methods were highly correlated, but systematically different and influenced by BMI. This study provided a basis for mutual reference of measurements between three widely used methods.

Temporal trends in cardiovascular health among Chinese urban children and adolescents, 2004-2019 pre-pandemic COVID-19.

Objective: Little is known about pre-pandemic cardiovascular health (CVH) status and its temporal variation in Chinese children. Thus, we aimed to evaluate the secular trends and associated factors of CVH in Chinese urban children from 2004 to 2019. Methods: We identified 32,586 individuals in Beijing, aged 6 to 18 years, from three independent cross-sectional studies conducted in 2004, 2014, and 2019, respectively. CVH was assessed by 7 metrics according to modified American Heart Association criteria, including smoking, physical activity, diet, body mass index, total cholesterol, blood pressure, and fasting glucose. Multivariable logistic regression was used to assess the associations between sociodemographic characteristics and the ideal CVH status. Results: The proportion of ideal CVH decreased from 27.7% (boys 26.6%, girls 28.9%) in 2004 to 4.2% (boys 3.8%, girls 4.8%) in 2014, and then increased to 16.2% (boys 13.5%, girls 18.9%) in 2019. Overall, ideal smoking was the most prevalent CVH component during 2004-2019 (2004, 97.5%; 2014, 92.9%; 2019, 98.0%), while ideal physical activity (2004, 27.6%; 2014, 14.4%; 2019, 28.0%) and dietary intake (2004, 26.0%; 2014, 10.7%; 2019, 23.5%) were the least prevalent components. Notably, the proportion of ideal body mass index (2004, 77.5%; 2019, 59.7%) and blood pressure (2004, 73.6%; 2019, 67.3%) continuously decreased from 2004 to 2019. Girls, parental normal weight status, free of family CVD history, and lower levels in fat mass were associated with higher odds of ideal CVH. Conclusion: The cardiovascular health in Chinese urban children deteriorated during 2004-2019. Distinct strategies are required to mitigate socioeconomic inequity in the intervention of CVH promotion.

Role and Mechanism of Keap1/Nrf2 Signaling Pathway in the Regulation of Autophagy in Alleviating Pulmonary Fibrosis.

A variety of internal and external lung diseases may eventually lead to pulmonary fibrosis, and insufficient autophagy is closely related to pulmonary fibrosis. This research is aimed to explore the mechanism of autophagy to alleviate pulmonary fibrosis. Then, a mouse model of pulmonary fibrosis induced by boromycin and histopathological lesions of the lungs of mice were observed by HE staining, which Masson staining assessed the degree of fibrosis in the lung tissue by detecting the expression of hydroxyproline in the tissue. RT-qPCR and western blotting were used to detect the levels of autophagy and Keap1/Nrf2 signaling pathway-related proteins. It was proved that autophagy-related proteins MAP1LC3(LC3) and Beclin 1 were decreased in mice with pulmonary fibrosis, while the expression of p62 was increased. Mice with pulmonary fibrosis worsened after injection of a 3-MA autophagy inhibitor, while injection of autophagy activation of rapamycin agent promoted Nrf2 nuclear mobilization. In a word, autophagy relieves pulmonary fibrosis through the activation of the Keap1/Nrf2 signaling pathway.

Preclinical Drug Pharmacokinetic, Tissue Distribution and Excretion Profiles of the Novel Limonin Derivate HY-071085 as an Anti-Inflammatory and Analgesic Candidate in Rats and Beagle Dogs.

Limonin is one of the research hotspots in natural drug development. However, its low solubility in water leads to poor oral bioavailability, discouraging the further study of its potential as a candidate compound. In order to overcome this limitation, and to enhance its biological activities, a novel limonin derivative-HY-071085-was synthesized by structural modification, and has exhibited strong anti-inflammatory and analgesic activity. In order to achieve a thorough understanding of the biological actions of HY-071085 in vivo, this study evaluated the pharmacokinetics and bioavailability of HY-071085 in rats and beagle dogs, and the distribution and excretion in rats. Using ultra-high-performance liquid chromatography-tandem mass spectrometry, the kinetic profiles of HY-071085 in the plasma of healthy rats and beagle dogs after a single gavage, repeated gavages and the intravenous injection of HY-071085 were studied. The tissue distribution (heart, liver, spleen, lung, kidney, gastric tissue, intestine, brain, skin, testis, ovary and womb) and excretion of HY-071085 were also studied. These results showed that HY-071085 has nonlinear dynamic characteristics in rat and beagle dog plasma. It was found that the plasma concentrations of HY-071085 in female rats were significantly higher than those in male rats after a single oral administration. There were gender differences in the kinetic behavior of HY-071085 in rats; however, there was no difference identified in dogs. HY-071085 was mainly eliminated as metabolites in rats, and was distributed in most of the tissues except the brain, with the highest content being in the gastric tissue and intestinal arease, followed by the liver, spleen, fat, lung, kidney, ovary and heart. The bioavailability of HY-071085 in male and female rats was 2.8% and 10.8%, respectively, and was about 13.1% in beagle dogs. The plasma protein binding rate of HY-071085 in rats, beagle dogs and humans ranged from 32.9% to 100%, with obvious species differences. In conclusion, our study provides useful information regarding the absorption, distribution and excretion of HY-071085, which will provide a good base for the study of the mechanism of its biological effects.

Distinct causal effects of body fat distribution on cardiometabolic traits among children: Findings from the BCAMS study.

BACKGROUND AND AIMS: Observational studies reveal that different body fat measures are associated with cardiometabolic disease with different effects. However, causality is not reflected by such observations. To explore and compare the causal relationships of general obesity (measured by body mass index (BMI)), adipose obesity (measured by fat mass percentage (FMP)) and central obesity (measured by waist-to-height ratio (WHtR)) with cardiometabolic traits among children. METHODS AND RESULTS: We conducted one sample Mendelian randomization (MR) analysis in 3266 children from Beijing Children and Adolescents Metabolic Syndrome Study. Genetic instruments based on 28 SNPs were performed to explore and compare the causal associations of genetically BMI, FMP and WHtR with cardiometabolic traits. The genetic instruments were robustly correlated with observed BMI, FMP and WHtR. Each genetically 1-SD increment in BMI, FMP and WHtR were causally associated with increment in systolic blood pressure (SBP), diastolic blood pressure (DBP), log-transformed fasting plasma glucose (FPG), log-transformed HOMA-ß, and decrease in log-transformed high-density lipoprotein cholesterol (HDL), respectively (all P < 0.05 after Bonferroni correction). The receiver operating characteristic curve indicated that BMI and FMP showed stronger effects on SBP, DBP, HOMA-ß and HDL than WHtR (all P < 0.05). We also observed causal associations of BMI and FMP with log-transformed fasting insulin and HOMA-IR. CONCLUSIONS: The MR analysis based on population-based cohort indicated a causal relationship of adiposity and body fat distribution with cardiometabolic traits. When compared with central obesity, general obesity and adipose obesity might own stronger effects on blood pressure and blood lipids among children.

Central body fat deposits are associated with poor vitamin D status in Chinese children and adolescents.

OBJECTIVES: To examine the association between regional fat deposits and vitamin D levels in Chinese children. Whether regional fat distribution contributes to vitamin D deficiency remains uncertain. METHODS: A population-based, nationwide and multicenter cross-sectional study involving 6,589 pediatric participants (49.9% boys) ages 6 to 18 y. The regional fat mass index (FMI) variables were calculated as regional fat mass (kg) divided by the square of height (m2), and plasma 25-hydroxyvitamin D (25[OH]D) levels were measured. RESULTS: Among boys, after adjustment for multiple variables (including opposite regional fat), higher values for trunk FMI and android FMI were associated with a greater likelihood of vitamin D inadequacy (odds ratios [ORs], 2.14 and 1.87, respectively), whereas the extremity FMI and gynoid FMI were associated with protection from vitamin D inadequacy (ORs, 0.63 and 0.71, respectively). Consistently, increased central fat distribution (e.g., trunk or android to total fat ratio) and decreased peripheral fat distribution (e.g., extremity or gynoid to total fat ratio) were associated with greater odds of vitamin D inadequacy. Among girls, the associations of regional fat with vitamin D were weaker than those in boys, and most analyses did not reach statistical significance. CONCLUSIONS: Regional fat deposits were associated with vitamin D status in Chinese school-aged children and more pronounced among boys.