Carfilzomib relieves pancreatitis-initiated pancreatic ductal adenocarcinoma by inhibiting high-temperature requirement protein A1.

Pancreatitis is a crucial risk factor for pancreatic ductal adenocarcinoma (PDAC), and our previous study had proved high-temperature requirement protein A1 (HTRA1) exacerbates pancreatitis insult; however, the function and mechanism of HTRA1 in pancreatitis-initiated PDAC is still unclear. In the present paper, we clarified the expression of HTRA1 in PDAC using bioinformatics and immunohistochemistry of tissue chip, and found that HTRA1 is significantly upregulated in PDAC. Moreover, the proliferation, migration, invasion and adhesion of PANC-1 and SW1990 cells were promoted by overexpression of HTRA1, but inhibited by knockdown of HTRA1. Meanwhile, we found that HTRA1 arrested PANC-1 and SW1990 cells at G2/M phase. Mechanistically, HTRA1 interacted with CDK1 protein, and CDK1 inhibitor reversed the malignant phenotype of PANC-1 and pancreatitis-initiated PDAC activated by HTRA1 overexpression. Finally, we discovered a small molecule drug that can inhibit HTRA1, carfilzomib, which has been proven to inhibit the biological functions of tumor cells in vitro and intercept the progression of pancreatitis-initiated PDAC in vivo. In conclusion, the activation of HTRA1-CDK1 pathway promotes the malignant phenotype of tumor cells by blocking the cell cycle at the G2/M phase, thereby accelerating pancreatitis-initiated PDAC. Carfilzomib is an innovative candidate drug that can inhibit pancreatitis-initiated PDAC through targeted inhibition of HTRA1.

Elevated first-trimester hepcidin level is associated with reduced risk of iron deficiency anemia in late pregnancy: a prospective cohort study.

Background: Iron deficiency (ID) and iron deficiency anemia (IDA) during pregnancy are highly prevalent worldwide. Hepcidin is considered an important biomarker of iron status. Currently, few longitudinal cohort studies have assessed the potential causal relationship between hepcidin and ID/IDA. Therefore, we aimed to investigate the association of first-trimester maternal serum hepcidin with third-trimester ID/IDA risk in a prospective cohort. Methods: Total of 353 non-ID/IDA pregnant women at 11-13 weeks' gestation were enrolled in Southern China and followed up to 38 weeks of gestation. Data on demography and anthropometry were obtained from a structured questionnaire at enrollment. Iron biomarkers including hepcidin were measured at enrollment and follow-up. Regression models were used to evaluate the association of first-trimester hepcidin with third-trimester ID/IDA risk. Results: Serum hepcidin levels substantially decreased from 19.39 ng/mL in the first trimester to 1.32 ng/mL in the third trimester. Incidences of third-trimester ID and IDA were 46.2 and 11.4%, respectively. Moreover, moderate and high levels of first-trimester hepcidin were positively related to third-trimester hepcidin (log-transformed ß = 0.51; 95% CI = 0.01, 1.00 and log-transformed ß = 0.66; 95% CI = 0.15, 1.17). Importantly, elevated first-trimester hepcidin was significantly associated with reduced risk of third-trimester IDA (OR = 0.38; 95% CI = 0.15, 0.99), but not with ID after adjustment with potential confounders. Conclusion: First-trimester hepcidin was negatively associated with IDA risk in late pregnancy, indicating higher first-trimester hepcidin level may predict reduced risk for developing IDA. Nonetheless, given the limited sample size, larger studies are still needed.

Machine Learning Techniques Applied to the Study of Drug Transporters.

With the advancement of computer technology, machine learning-based artificial intelligence technology has been increasingly integrated and applied in the fields of medicine, biology, and pharmacy, thereby facilitating their development. Transporters have important roles in influencing drug resistance, drug-drug interactions, and tissue-specific drug targeting. The investigation of drug transporter substrates and inhibitors is a crucial aspect of pharmaceutical development. However, long duration and high expenses pose significant challenges in the investigation of drug transporters. In this review, we discuss the present situation and challenges encountered in applying machine learning techniques to investigate drug transporters. The transporters involved include ABC transporters (P-gp, BCRP, MRPs, and BSEP) and SLC transporters (OAT, OATP, OCT, MATE1,2-K, and NET). The aim is to offer a point of reference for and assistance with the progression of drug transporter research, as well as the advancement of more efficient computer technology. Machine learning methods are valuable and attractive for helping with the study of drug transporter substrates and inhibitors, but continuous efforts are still needed to develop more accurate and reliable predictive models and to apply them in the screening process of drug development to improve efficiency and success rates.

Effects of a school-based lifestyle intervention on ideal cardiovascular health in Chinese children and adolescents: a national, multicentre, cluster-randomised controlled trial.

BACKGROUND: The prevalence of ideal cardiovascular health among Chinese children and adolescents is alarmingly low. We aimed to examine whether a school-based lifestyle intervention against obesity would improve ideal cardiovascular health. METHODS: In this cluster-randomised controlled trial, we included and randomly assigned schools from the seven regions of China to intervention or control (1:1), stratified by province and school grade (grades 1-11; ages 7-17 years). Randomisation was done by an independent statistician. The 9-month intervention consisted of school promotion for diet, exercise, and self-monitor of obesity-related behaviours and the control group was no promotion. The primary outcome, assessed at both baseline and 9 months, was ideal cardiovascular health (six or more ideal cardiovascular health behaviours [non-smoking, BMI, physical activity, and diet] and factors [total cholesterol, blood pressure, and fasting plasma glucose]). We did intention-to-treat analysis and multilevel modelling. This study was approved by the ethics committee of Peking University, Beijing, China (ClinicalTrials.gov, NCT02343588). FINDINGS: 30 629 students in the intervention group and 26 581 students in the control group from 94 schools with any follow-up cardiovascular health measures were analysed. At follow-up, 22·0% (1139/5186) of the intervention group and 17·5% (601/3437) in the control group met ideal cardiovascular health. Overall, the intervention was associated with ideal cardiovascular health behaviours (three or more; odds ratio 1·15; 95% CI 1·02-1·29), but not other ideal cardiovascular health metrics after adjusting for covariates. The intervention had higher effects on ideal cardiovascular health behaviours in primary school students aged 7-12 years (1·19; 1·05-1·34) than secondary school students aged 13-17 years (p<0·0001), with no apparent sex difference (p=0·58). The intervention protected senior students aged 16-17 years from smoking (1·23; 1·10-1·37) and improved ideal physical activity in primary school students (1·14; 1·00-1·30) but was associated with lower odds of ideal total cholesterol in primary school boys (0·73; 0·57-0·94). INTERPRETATION: This school-based intervention, focused on diet and exercise, was effective in improving ideal cardiovascular health behaviours in Chinese children and adolescents. Early intervention might benefit cardiovascular health over the life course. FUNDING: The Special Research Grant for Non-profit Public Service of the Ministry of Health of China (201202010) and Guangdong Provincial Natural Science Foundation (2021A1515010439).

Application of aptamer-drug delivery system in the therapy of breast cancer.

Despite significant treatment advances, breast cancer remains the leading cause of cancer death in women. From the current treatment situation, in addition to developing chemoresistant tumours, distant organ metastasis, and recurrences, patients with breast cancer often have a poor prognosis. Aptamers as "chemical antibodies" may be a way to resolve this dilemma. Aptamers are single-stranded, non-coding oligonucleotides (DNA or RNA), resulting their many advantages, including stability for long-term storage, simplicity of synthesis and function, and low immunogenicity, a high degree of specificity and antidote. Aptamers have gained popularity as a method for diagnosing and treating specific tumors in recent years. This article introduces the application of ten different aptamer delivery systems in the treatment and diagnosis of breast cancer, and systematically reviews their latest research progress in breast cancer treatment and diagnosis. It provides a new direction for the clinical treatment of breast cancer.

Metabolic reprogramming of immune cells in pancreatic cancer progression.

Abnormal intracellular metabolism not only provides nutrition for tumor occurrence and development, but also sensitizes the function of various immune cells in the immune microenvironment to promote tumor immune escape. This review discusses the emerging role of immune cells in the progress of pancreatic cancer, acrossing metabolic reprogramming and key metabolic pathways present in different immune cell types. At present, the hotspots of metabolic reprogramming of immune cells in pancreatic cancer progression mainly focuses on glucose metabolism, lipid metabolism, tricarboxylic acid cycle and amino acid metabolism, which affect the function of anti-tumor immune cells and immunosuppressive cells in the microenvironment, such as macrophages, dendritic cells, T cells, myeloid-derived suppressor cells, neutrophils and B cells by a series of key metabolic signaling pathways, such as PI3K/AKT, mTOR, AMPK, HIF-1α, c-Myc and p53. Drugs that target the tumor metabolism pathways for clinical treatment of pancreatic cancer are also systematically elaborated, which may constitute food for others' projects involved in clinical anti-cancer research.

Relationship between metabolic reprogramming and drug resistance in breast cancer.

Breast cancer is the leading cause of cancer death in women. At present, chemotherapy is the main method to treat breast cancer in addition to surgery and radiotherapy, but the process of chemotherapy is often accompanied by the development of drug resistance, which leads to a reduction in drug efficacy. Furthermore, mounting evidence indicates that drug resistance is caused by dysregulated cellular metabolism, and metabolic reprogramming, including enhanced glucose metabolism, fatty acid synthesis and glutamine metabolic rates, is one of the hallmarks of cancer. Changes in metabolism have been considered one of the most important causes of resistance to treatment, and knowledge of the mechanisms involved will help in identifying potential treatment deficiencies. To improve women's survival outcomes, it is vital to elucidate the relationship between metabolic reprogramming and drug resistance in breast cancer. This review analyzes and investigates the reprogramming of metabolism and resistance to breast cancer therapy, and the results offer promise for novel targeted and cell-based therapies.

Iron Supplementation Is Associated with Improvement of Motor Development, Hemoglobin Level, and Weight in Preterm Infants during the First Year of Life in China.

Iron supplementation is recommended for preterm infants due to impaired iron endowment. However, the health outcomes of this recommendation remain controversial. Thus, this study aimed to determine the association of iron supplementation with neurobehavioral development, hemoglobin (Hb), and anthropometric characteristics in preterm infants. A retrospective cohort design was applied to collect data from 1568 preterm infants at 0-3 months of corrected age (mo CA) from a hospital in South China. Infants were categorized into a 3-month iron supplementation group (IG, n = 697) or a control group (CG, n = 871) according to medical records, and then followed through to 12 mo CA. Data on neurobehavioral development, anthropometry, Hb level, history of diseases, and nutrition were collected at 3, 6, and 12 mo CA. The results showed that, compared with the CG, iron supplementation was positively related to improved gross motor skills and weight at 6 mo CA (ß = 1.894, ß = 5.322) and 12 mo CA (ß = 4.019, ß = 6.830) and fine motor skills at 12 mo CA (ß = 1.980), after adjustment for confounding factors including illness, nutritional supplements, and diet. Iron supplementation was also related to elevated Hb levels and its increase at 3 mo CA (ß = 2.196, ß = 3.920) and 6 mo CA (ß = 3.011, ß = 7.259). In conclusion, iron supplementation for 3 months in Chinese preterm infants is positively associated with improved motor development, elevated Hb levels, and higher body weight during the first year of life.

Protective effect of Rhein against vancomycin-induced nephrotoxicity through regulating renal transporters and Nrf2 pathway.

Vancomycin (VCM)'s nephrotoxicity limits its application and therapeutic efficiency. The aim of this study was to determine the protective effect of rhein against VCM-induced nephrotoxicity (VIN). VIN models were established in rats and NRK-52E cells. Rhein up-regulated the expressions of renal organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2), mammal multidrug and toxin extrusion proteins 1 (Mate 1) and P-glycoprotein (P-gp) to facilitate the efflux of plasma creatinine, blood urea nitrogen (BUN), and plasma indoxyl sulfate. Rhein increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) to regulate the expression of Mrp2, P-gp, and Mate 1. The increased level of superoxide dismutase (SOD), decreased level of malondialdehyde (MDA) and reduced number of apoptosis cells were observed after treatment of rhein. Rhein decreased the number of apoptosis cells as well as increased the expression of B-cell lymphoma-2 (Bcl-2) and decreased expressions of Bcl-2-like protein 4 (Bax). ML385, as a typical inhibitor of Nrf2, reversed the protective effects of rhein in cells. Rhein oriented itself in the site of Keap1, inhibiting the Keap1-Nrf2 interaction. Rhein ameliorated VIN mainly through regulating the expressions of renal transporters and acting on Nrf2 pathway.

Reliability and validity of the FFQ and feeding index for 7-to 24-month-old children after congenital heart disease surgery.

BACKGROUND: Congenital heart disease (CHD) is the most common congenital defect in neonates. Infants with CHD often have more nutritional difficulties, but currently, there is no unified Food Frequency Questionnaire (FFQ) for infants and young children aged 7-24 months in China. Therefore, we designed this study to assess the reliability and validity of the FFQ and feeding index for 7-to 24-month-old children after congenital heart disease surgery. METHODS: From July to October 2018, infants and young children aged 7-24 months after congenital heart disease surgery in Guangzhou were selected. Participants were categorized into two groups, in the first group (n = 95), the FFQ was completed twice at intervals of 7-10 days to assess reproducibility. In the second group (n = 98), participants accomplished both the FFQ and the 24-h diet records from 3 consecutive days to assess validity. The score of the Infant and Child Feeding Index (ICFI) and its qualified rate were caculated. Intraclass correlation coefficients (ICC) and Spearman correlation coefficient (SCC) were calculated for reliability and validity, respectively. RESULTS: The average intraclass correlation coefficients and spearman correlation coefficient of the FFQ were 0.536 and 0.318, all with statistical significance except the frequency of meat added. The ICFI of the first group was 8.61 (± 3.20), the qualified rate was 0.06% (6/95). The intraclass correlation coefficients of the ICFI ranged from 0.374 to 0.958; and the spearman correlation of the ICFI was -0.066 to -0.834. CONCLUSIONS: The FFQ possesses satisfactory reliability and moderate validity. The reliability of the ICFI is acceptable, but the validity results are quite different, indicating that the questionnaire is limited in the evaluation of the ICFI.

Adiposity measures in screening for metabolic syndrome among Chinese children and adolescents.

BACKGROUND: Existing various and complicated metabolic syndrome (MetS) definitions have contributed to the difficulty in assessing MetS in children and adolescents, and therefore it is urgently needed to develop a convenient and effective screening tool for pediatric MetS. This study aimed to identify the optimal adiposity measure to screen for pediatric MetS. METHODS: The cross-sectional data was collected from 8,150 children and adolescents aged 7-17 y living in southern China. Anthropometric indices, blood lipids, and serum glucose were determined. Results of two commonly used MetS definitions were compared: International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel Ⅲ (NCEP-ATP) modified by Cook. Receiver operating characteristic curve analyses were performed and areas under the curve (AUCs) were calculated to determine the optimal index for MetS screening. RESULTS: MetS prevalence assessed by NCEP-ATP was significantly higher than that by IDF (6.2% vs. 1.5%, p<0.001). Waist-to-height ratio (WHtR) showed the highest screening power for MetS defined by both IDF and NCEP-ATP (AUC 0.932 and 0.900, respectively), and its optimal cut-off point was 0.48 by both IDF and NCEP-ATP definition (sensitivity 0.944 and 0.847, specificity 0.800 and 0.830, respectively), regardless of age or sex. When taking sex diversity into account, the optimal WHtR cut-off point was 0.49 (IDF) or 0.50 (NCEP-ATP) in boys, and 0.46 (both definitions) in girls. CONCLUSIONS: Among children and adolescents aged 7-17 y in southern China, a WHtR greater than 0.48 can be a simple but effective screening tool for MetS.

Antenatal Iron-Rich Food Intervention Prevents Iron-Deficiency Anemia but Does Not Affect Serum Hepcidin in Pregnant Women.

BACKGROUND: Limited evidence supports the efficacy of iron-rich foods (IRFs) in improving iron status during pregnancy. OBJECTIVES: The study aims to evaluate the effect of IRFs on iron status and biomarkers of iron metabolism in the third trimester of pregnancy. METHODS: A total of 240 pregnant women at 11-13 wk of gestation without iron-deficiency anemia (IDA) in South China were recruited to this single-blind clinical trial [non-IDA referred to both hemoglobin (Hb) ≥110g/L and serum ferritin (SF) ≥15ng/mL],  randomly assigned to 1) control, 2) IRFs containing 20 mg iron/d (IRF-20), or 3) IRFs containing 40 mg iron/d (IRF-40). The IRFs were consumed 3 days a week, including pork liver, chicken/duck blood, soybean, and agaric. The IRFs started at recruitment and ended in the predelivery room. Primary outcome included anemia (Hb <110 g/L), iron deficiency (ID, definition 1: SF <15 ng/mL; definition 2: SF <12 ng/mL), and IDA (ID and Hb <110 g/L). Secondary outcome was plasma Hb and iron indices, including SF, serum hepcidin, and iron. RESULTS: All participants who completed the trial with full data (n = 170) were included in the analysis. At the endline, both intervention groups showed lower ID and IDA rates than control. Specifically, IRF-40 showed a lower ID (SF <12 ng/mL) rate than control (9.0% compared with 22.8%, P = 0.022). For IDA by definition 1, the incidence in IRF-40 was lower than that in control (1.9% compared with 8.9%, P = 0.045). For IDA by definition 2, the incidence in IRF-20 was lower than that in control (3.9% compared with 17.9%, P = 0.049). Moreover, IRF-20 showed higher SF concentrations than control (P = 0.039). No effects of IRFs on anemia (P = 0.856), plasma Hb (P = 0.697), serum hepcidin (P = 0.311), and iron (P = 0.253) concentrations were observed. The assessed iron intakes were 22.2 mg/d in IRF-20 and 25.0 mg/d in IRF-40, respectively. CONCLUSIONS: Antenatal IRFs reduce the risk of ID and IDA in late pregnancy, although the present results are inadequate to confirm an ideal dosage (No. ChiCTR1800017574).

Effects of Caloric Restriction and Rope-Skipping Exercise on Cardiometabolic Health: A Pilot Randomized Controlled Trial in Young Adults.

The aim of this study is to investigate the effects of calorie restriction (CR), rope-skipping (RS) exercise, and their joint effects on cardiometabolic health in young adults. An 8-week randomized trial was conducted on 46 undergraduates aged 19-21 y from South China. The participants were randomized into the following three groups: Calorie restriction (CR) group (n = 14), Rope-skipping (RS) group (n = 14), and CR plus RS (CR-RS) group (n = 12). At both allocation and the end of the intervention, data on anthropometry, serum metabolic, and inflammatory markers were collected. A total of 40 participants completed the intervention and were included in the analysis. After the 8-week intervention, the participants from the CR group and the CR-RS group reduced in body weight (-1.1 ± 1.7 kg, -1.3 ± 2.0 kg), body mass index (-0.4 ± 0.6 kg/m2, -0.5 ± 0.7 kg/m2), body fat percentage (-1.2 ± 1.6%, -1.7 ± 1.8%), and body fat mass (-1.1 kg (-2.2, -0.3), -1.1 kg (-2.5, -0.4)) compared to the baseline (p < 0.05 or p = 0.051). For metabolic and inflammatory factors, the participants in the CR-RS group showed significant decreases in low density lipoprotein cholesterol (-0.40 mmol/L) and interleukin-8 (-0.73 mmol/L). While all the above markers showed no significant difference among the groups after intervention, in the subgroup of overweight/obese participants (n = 23), the CR-RS group had significantly lower blood pressure, fasting insulin, homeostatic model assessment of insulin resistance, tumor necrosis factor-α, and interleukin-8 levels than the CR or RS groups (p < 0.05). In conclusion, both CR and CR-RS could reduce weight and improve body composition in young adults. More importantly, in those with overweight or obesity, CR-RS intervention might be superior to either CR or RS in improving cardiometabolic health.

Targeting renal OATs to develop renal protective agent from traditional Chinese medicines: Protective effect of Apigenin against Imipenem-induced nephrotoxicity.

Imipenem (Imp) is a widely used broad-spectrum antibiotic. However, renal adverse effects limit its clinical application. We previously reported that organic anion transporters (OATs) facilitated the renal transport of Imp and contributed its nephrotoxicity. Natural flavonoids exhibited renal protective effect. Here, we aimed to develop potent OAT inhibitors from traditional Chinese medicines (TCMs) and to evaluate its protective effect against Imp-induced nephrotoxicity. Among 50 TCMs, Tribuli Fructus, Platycladi Cacumen, and Lycopi Herba exhibited potent inhibition on OAT1/3. After screening their main components, Apigenin strongly inhibited Imp uptake by OAT1/3-HEK293 cells with IC50 values of 1.98 ± 0.36 µM (OAT1) and 2.29 ± 0.88 µM (OAT3). Moreover, Imp exhibited OAT1/3-dependent cytotoxicity, which was alleviated by Apigenin. Furthermore, Apigenin ameliorated Imp-induced nephrotoxicity in rabbits, and reduced the renal secretion of Imp. Apigenin inhibited intracellular accumulation of Imp and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells (rPTCs). Apigenin, a flavone widely distributed in TCMs, was a potent OAT1/3 inhibitor. Through OAT inhibition, at least in part, Apigenin decreased the renal exposure of Imp and consequently protected against the nephrotoxicity of Imp. Apigenin can be used as a promising agent to reduce the renal adverse reaction of Imp in clinic.

Anaemia, iron deficiency, iron-deficiency anaemia and their associations with obesity among schoolchildren in Guangzhou, China.

OBJECTIVE: The association of Fe metabolism with obesity in children remains unclear. The present study aimed to assess the status of Fe metabolism parameters, the prevalence of anaemia, Fe deficiency (ID) and Fe-deficiency anaemia (IDA), and the associations of these variables with obesity in Chinese schoolchildren. DESIGN: A cross-sectional study conducted in 5295 schoolchildren aged 7-11 years in Guangzhou, China, 2014-2015. Full data of anthropometric and Fe metabolic parameters were collected to assess obesity, anaemia, ID and IDA. Logistic regression models were established to determine the possible associations of anaemia, ID and IDA with obesity. Two-tailed P values of <0·05 was considered statistically significant. SETTING: Guangzhou City, China. PARTICIPANTS: Schoolchildren aged 7-11 years (n 5295). RESULTS: In this sample, mean Hb concentration was 128·1 g/l and the prevalence of anaemia, ID and IDA was 6·6, 6·2 and 0·6 %, respectively. Of the participants, 14·0 % were overweight and 8·8 % were obese. Importantly, obesity was associated with lower anaemia risk (adjusted OR = 0·553; 95 % CI 0·316, 0·968) but higher ID risk (adjusted OR = 1·808; 95 % CI 1·146, 2·853) after adjustment for confounders. No significant relationship was found between obesity and IDA. CONCLUSIONS: Our results confirmed that anaemia and ID remain public health concerns among schoolchildren in Guangzhou, while IDA is remarkably less prevalent. Furthermore, obesity was associated with lower anaemia risk, but higher ID risk. More efforts should be made to prevent the onset of ID and obesity in the same individual, thus improving the health and fitness of children.

Protective effect of cilastatin against diclofenac-induced nephrotoxicity through interaction with diclofenac acyl glucuronide via organic anion transporters.

BACKGROUND AND PURPOSE: Diclofenac is a widely used nonsteroidal anti-inflammatory drug. However, adverse effects in the kidney limit its clinical application. The present study was aimed to evaluate the potential effect of cilastatin on diclofenac-induced acute kidney injury and to clarify the potential roles of renal organic anion transporters (OATs) in the drug-drug interaction between cilastatin and diclofenac. EXPERIMENTAL APPROACH: The effect of cilastatin was evaluated in diclofenac-induced acute kidney injury in mice. Human OAT1/3-transfected HEK293 cells and renal primary proximal tubule cells (RPTCs) were used to investigate OAT1/3-mediated transport and the cytotoxicity of diclofenac. KEY RESULTS: Cilastatin treatment decreased the pathological changes, renal dysfunction and elevated renal levels of oxidation products, cytokine production and apoptosis induced by diclofenac in mice. Moreover, cilastatin increased the plasma concentration and decreased the renal distribution of diclofenac and its glucuronide metabolite, diclofenac acyl glucuronide (DLF-AG). Similarly, cilastatin inhibited cytotoxicity and mitochondrial damage in RPTCs but did not change the intracellular accumulation of diclofenac. DLF-AG but not diclofenac exhibited OAT-dependent cytotoxicity and was identified as an OAT1/3 substrate. Cilastatin inhibited the intracellular accumulation and decreased the cytotoxicity of DLF-AG in RPTCs. CONCLUSION AND IMPLICATIONS: Cilastatin alleviated diclofenac-induced acute kidney injury in mice by restoring the redox balance, suppressing inflammation, and reducing apoptosis. Cilastatin inhibited OATs and decreased the renal distribution of diclofenac and DLF-AG, which further ameliorated the diclofenac-induced nephrotoxicity in mice. Cilastatin can be potentially used in the clinic as a therapeutic agent to alleviate the adverse renal reaction to diclofenac.

Identification of risk factors affecting catch-up growth after infant congenital heart disease surgery: rationale and design of a multicentre prospective cohort study in China.

INTRODUCTION: Successful surgical treatment of congenital heart disease improves neonates' long-term survival and leads to catch-up growth, which however does not occur in part of the patient population for largely undetermined reasons. METHODS AND ANALYSIS: A multicentre, prospective cohort study is being conducted in four paediatric medical institutions in China to collect detailed nutritional, anthropometric and clinical data at perioperative phases and during a 1-year period of follow-up after surgery. The study is expected to recruit approximately 5000 patients by the year of 2023 when the cohort is fully established. The primary endpoint of this study is the occurrence of postoperative catch-up growth, which will be determined in both absolute and relative terms (ie, reduced anthropometric deficits from the reference measures and improved z-scores that have passed the -2 SD cut-offs). Multivariable regression analyses will be performed to identify factors that are statistically significantly associated with the absence of postoperative catch-up growth. ETHICS AND DISSEMINATION: The protocol of this study has been approved by the individual ethics committees of the participating centres (Guangzhou Women and Children's Medical Centre (2008071601), the Children's Hospital of Zhejiang University School of Medicine (2018-IRB-094), Gansu Provincial Maternity and Child-Care Hospital (2019-IRB-01) and Zhengzhou Cardiovascular Hospital (2019012001)). Written informed consent from parents will be obtained before study entry. Findings of this study will be disseminated through publications in international peer-reviewed journals and will be presented in academic conferences.

Iron metabolism and its association with dyslipidemia risk in children and adolescents: a cross-sectional study.

BACKGROUND: Information on the association between iron metabolism and dyslipidaemia in children is limited. Thus, this study aims to evaluate the iron metabolic status of children with different body mass index (BMI) and to examine the association between iron metabolism and dyslipidaemia risk. METHOD: In total, 1866 children and adolescents aged 7-18 were enrolled in this study, including 912 boys and 954 girls. In this cross-sectional study, parameters for anthropometry, lipids and iron metabolism including transferrin, soluble transferrin receptor (sTfR), ferritin and serum iron (SF) were evaluated. Data regarding demographic characteristics, diet, and physical activity were collected by self-reported questionnaires. RESULTS: The prevalence of dyslipidaemia and iron deficiency in children and adolescents increased based on BMI categories (both P < 0.05) and were 58.3 and 8.9% in subjects with obesity, respectively. The lowest SF and the highest ferritin levels were observed in subjects who were obese (both P < 0.001). Subjects with dyslipidaemia had lower SF, transferrin and sTfR levels by different BMI categories, and those who were obese had higher ferritin levels (all P < 0.05). Most importantly, higher concentrations of transferrin and sTfR were related to lower dyslipidaemia risk (OR for transferrin: 0.49, 95% CI: 0.33-0.71; OR for sTfR: 0.68, 95% CI: 0.46-0.99). CONCLUSIONS: A downward trend in SF level by BMI categories and the highest ferritin level in subjects with obesity suggested that iron storage was associated with BMI in children and adolescents. Moreover, an inverse relationship was observed between transferrin and sTfR concentrations and dyslipidaemia risk in children with different BMI.

JBP485 attenuates vancomycin-induced nephrotoxicity by regulating the expressions of organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) in rats.

The present study aimed to investigate the regulation of JBP485 on the expressions of renal organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp), which can accelerate the renal excretion of accumulated endogenous toxins to attenuate vancomycin-induced nephrotoxicity (VIN) in rats. Vancomycin suppressed the mRNA and protein expressions of Oat1, Oat3, Oct2, Mrp2 and P-gp to reduce the renal excretion of endogenous toxins (e.g. indoxyl sulfate). However, JBP485 could reverse these effects and improved the pathological condition and morphology of rat kidney with a decrease in wet weight. Moreover, JBP485 decreased the number of apoptosis cells in TUNEL staining as well as reversed the decreased expression of B-cell lymphoma-2 (Bcl-2) and the increased expressions of Bcl-2-like protein 4 (Bax) and Caspase-3 in rat kidney. In addition, JBP485 also increased the level of superoxide dismutase (SOD) and decreased the level of malondialdehyde (MDA) in rat kidney. But JBP485 did not affect the plasma concentrations of vancomycin. In conclusion, the mechanism of VIN might be involved in, at least in part, suppressing the expressions of Oat1, Oat3, Oct2, Mrp2 and P-gp, and JBP485 could attenuate VIN in rats.

Effects of purified anthocyanin supplementation on platelet chemokines in hypocholesterolemic individuals: a randomized controlled trial.

BACKGROUND: It is becoming increasingly evident that platelet chemokines are involved in distinct aspects of atherosclerosis. The aim of this study was to examine the effects of long-term supplementation with purified anthocyanins on platelet chemokines in hypercholesterolemic individuals and to identify correlations of decreased platelet chemokine levels with serum lipid and inflammatory marker levels. METHODS: A total of 146 hypercholesterolemic individuals were recruited and treated with 320 mg of purified anthocyanins (n = 73) or a placebo (n = 73) daily for 24 weeks in this randomized, double-blind, placebo-controlled trial. RESULTS: Anthocyanin supplementation for 24 weeks significantly decreased the plasma CXCL7 (-12.32% vs. 4.22%, P = 0.001), CXCL5 (-9.95% vs. 1.93%, P = 0.011), CXCL8 (-6.07% vs. 0.66%, P = 0.004), CXCL12 (-8.11% vs. 5.43%, P = 0.023) and CCL2 levels (-11.63% vs. 12.84%, P = 0.001) compared with the placebo. Interestingly, the decreases in the CXCL7 and CCL2 levels were both positively correlated with the decreases in the serum low-density lipoprotein-cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP) and interleukin-1ß (IL-1ß) levels after anthocyanin supplementation for 24 weeks. The decrease in the CXCL8 level was negatively correlated with the increase in the how-density lipoprotein-cholesterol (HDL-C) level and was positively correlated with the decrease in the soluble P-selectin (sP-selectin) level in the anthocyanin group. In addition, a positive correlation was observed between the decreases in the CXCL12 and tumornecrosis factor-α (TNF-α) levels after anthocyanin supplementation. However, the plasma CXCL4L1, CXCL1, macrophage migration inhibitory factor (MIF) and human plasminogen activator inhibitor 1 (PAI-1) levels did not significantly change following anthocyanin supplementation. CONCLUSIONS: The present study supports the notion that platelet chemokines are promising targets of anthocyanins in the prevention of atherosclerosis. TRIAL REGISTRATION: ChiCTR-TRC-08000240. Registered: 10 December 2008.