The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture.

BACKGROUND AND AIMS: Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. METHODS: Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a ß-aminopropionitrile monofumarate-induced AD model. RESULTS: The transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88% (58.3%-83.3% for coenzyme Q10 treatment), 150.15% (33.3%-83.3% for 2-week T-5224), and 175.38% (33.3%-91.7% for 3-week T-5224) in the ß-aminopropionitrile monofumarate-induced AD model. CONCLUSIONS: This cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor-OXPHOS-AP-1 axis.

Self-Assembled Nanocarrier Delivery Systems for Bioactive Compounds.

Although bioactive compounds (BCs) have many important functions, their applications are greatly limited due to their own defects. The development of nanocarriers (NCs) technology has gradually overcome the defects of BCs. NCs are equally important as BCs to some extent. Self-assembly (SA) methods to build NCs have many advantages than chemical methods, and SA has significant impact on the structure and function of NCs. However, the relationship among SA mechanism, structure, and function has not been given enough attention. Therefore, from the perspective of bottom-up building mechanism, the concept of SA-structure-function of NCs is emphasized to promote the development of SA-based NCs. First, the conditions and forces for occurring SA are introduced, and then the SA basis and molecular mechanism of protein, polysaccharide, and lipid are summarized. Then, varieties of the structures formed based on SA are introduced in detail. Finally, facing the defects of BCs and how to be well solved by NCs are also elaborated. This review attempts to describe the great significance of constructing artificial NCs to deliver BCs from the aspects of SA-structure-function, so as to promote the development of SA-based NCs and the wide application of BCs.

The non-covalent and covalent interactions of whey proteins and saccharides: influencing factor and utilization in food.

During the application of Whey proteins (WPs), they often have complex interactions with saccharides (Ss), another important biopolymer in food substrate. The texture and sensory qualities of foods containing WPs and Ss are largely influenced by the interactions of WPs-Ss. Moreover, the combination of WPs and Ss is possible to produce many excellent functional properties including emulsifying properties and thermal stability. However, the interactions between WPs-Ss are complex and susceptible to some processing conditions. In addition, with different interaction ways, they can be applied in different fields. Therefore, the non-covalent interaction mechanisms between WPs-Ss are firstly summarized in detail, including electrostatic interaction, hydrogen bond, hydrophobic interaction, van der Waals force. Furthermore, the existence modes of WPs-Ss are introduced, including complex coacervates, soluble complexes, segregation, and co-solubility. The covalent interactions of WPs-Ss in food applications are often formed by Maillard reaction (dry or wet heat reaction) and occasionally through enzyme induction. Then, two common influencing factors, pH and temperature, on non-covalent/covalent bonds are introduced. Finally, the applications of WPs-Ss complexes and conjugations in improving WP stability, delivery system, and emulsification are described. This review can improve our understanding of the interactions between WPs-Ss and further promote their wider application.

Confocal Surface-Enhanced Raman Imaging of the Intestinal Barrier Crossing Behavior of Model Nanoplastics in Daphnia Magna.

Nanoplastics (nP) pose hazards to aquatic animals once they are ingested. Significant knowledge gaps exist regarding the nP translocation across the animal intestine, which is the first barrier between the ingested nP and the animal body. We examined the intestinal barrier crossing behavior of nP in an aquatic animal model (Daphnia magna) and determined the translocation mechanism with the help of model "core-shell" polystyrene nanoplastics (nPS) and confocal surface-enhanced Raman spectroscopy (SERS). The Raman reporter (4-mercaptobenzoic acid)-tagged gold "core" of the model nPS enables sensitive and reliable particle imaging by confocal SERS. This method detected SERS signals of model nPS concentration as low as 4.1 × 109 particles/L (equivalent to 0.27 µg/L PS "shell" concentration). The translocation was observed with the help of multilayer stacked Raman maps of SERS signals of the model nPS. With a higher concentration or longer exposure time of the model nPS, uptake and translocation of the plastic particles increased. In addition, we demonstrated that clathrin-dependent endocytosis and macropinocytosis were two major mechanisms underlying the translocation. This study contributes to a mechanistic understanding of nP translocation by using the pioneering model nPS and an analytical toolkit, which undergird further investigations into nP behavior and health effects in aquatic species.

Serum total folate, 5-methyltetrahydrofolate and vitamin B12 concentrations on incident risk of lung cancer.

Tobacco smoking is a major known risk factor for lung cancer. While micronutrients, especially those involved in maintaining DNA integrity and regulating gene expression, may be protective, research on this association is limited. This report aimed to investigate associations of total folate, 5-methyltetrahydrofolate (5-mTHF) and vitamin B12 with incident risk of lung cancer, and whether the associations vary by smoking status. A nested case-control study with 490 incident lung cancer cases and 490 controls matched by age (±1 year), sex, residence, and center, drawn from a community-based prospective study in China, was conducted from 2016 to 2019. 5-mTHF accounted for the majority of total folate. Only 4.4% had detectable unmetabolized folic acid. Lung cancer cases had lower levels of 5-mTHF compared to controls. There was an inverse, nonlinear association between 5-mTHF and lung cancer, which persisted after adjustment for covariables (P for trend = .001). Compared to the lowest 5-mTHF quartile, those in higher quartiles had lower risks of lung cancer: second quartile OR = 0.65; 95% CI: 0.45-0.93; third quartile OR = 0.50; 95% CI: 0.34-0.74; fourth quartile OR = 0.56; 95% CI: 0.38-0.83. This inverse association was more pronounced among ever smokers; consistently, the highest risk of lung cancer (OR = 3.21, 95% CI: 1.97-5.24) was observed among ever smokers with low 5-mTHF levels compared to participants who never smoked and had higher 5-mTHF levels. Vitamin B12 was not associated with lung cancer risk. In this sample of Chinese adults without confounding by unmetabolized folic acid, higher levels of 5-mTHF were associated with lower risk of incident lung cancer.

Milk-derived small extracellular vesicles: a new perspective on dairy nutrition.

Milk contains bioactive compounds that have multiple essential benefits. Milk-derived small extracellular vesicles (M-sEVs) have emerged as novel bioactive milk components with various beneficial biological functions and broad applications. The M-sEVs from different mammalian sources have similar composition and bioactive functions. The digestive stability and biocompatibility of the M-sEVs provide a good foundation for their physiological functions. Evidence suggests that M-sEVs promote intestinal, immune, bone, neural, liver, and heart health and show therapeutic effects against cancer, indicating their potential for use in functional foods. In addition, M-sEVs can be developed as natural delivery carriers owing to their superior structural characteristics. Further studies are needed to elucidate the relationship between the specific components and functions of M-sEVs, standardize their extraction processes, and refine relevant clinical trials to advance the future applications of M-sEVs. This review summarizes the structure and composition of M-sEVs isolated from different milk sources and discusses several common extraction methods. Since the introduction of M-sEVs for digestion and absorption, studies have been conducted on their biological functions. Furthermore, we outline the theoretical industrial production route, potential application scenarios of M-sEVs, and the future perspectives of M-sEV research.

Prevalence, antimicrobial susceptibility, and antibiotic resistance gene transfer of Bacillus strains isolated from pasteurized milk.

Pasteurization is carried out in dairy industries to kill harmful bacteria present in raw milk. However, endospore-forming bacteria, such as Bacillus, cannot be completely eliminated by pasteurization. In this study, a total of 114 Bacillus strains were isolated from 133 pasteurized milk samples. Antibiotic susceptibility tests showed that the percentage of Bacillus with intrinsic resistance to ampicillin and penicillin were 80 and 86%, respectively. Meanwhile, some Bacillus isolates had acquired resistance, including trimethoprim-sulfamethoxazole resistance (10 isolates), clindamycin resistance (8 isolates), erythromycin resistance (2 isolates), and tetracycline resistance (1 isolate). To further locate these acquired resistance genes, the plasmids were investigated in these 16 Bacillus strains. The plasmid profile indicated that Bacillus cereus BA008, BA117, and BA119 harbored plasmids, respectively. Subsequently, the Illumina Novaseq PE150 was applied for the genomic and plasmid DNA sequencing. Notably, the gene tetL encoding tetracycline efflux protein was found to be located on plasmid pBC46-TL of B. cereus BA117. In vitro conjugative transfer indicated that pBC46-TL can be transferred into Bacillus invictae BA142, Bacillus safensis BA143, and Bacillus licheniformis BA130. The frequencies were of 1.5 × 10-7 to 1.7 × 10-5 transconjugants per donor cells. Therefore, Bacillus strains with acquired antibiotic resistance may represent a potential risk for the spread of antibiotic resistance between Bacillus and other clinical pathogens via horizontal gene transfer.

Salt stress altered anaerobic microbial community and carbon metabolism characteristics: The trade-off between methanogenesis and chain elongation.

Discharge of saline organic wastewater is increasing worldwide, yet how salt stress disrupts the microbial community's structure and metabolism in bioreactors has not been systematically investigated. The non-adapted anaerobic granular sludge was inoculated into wastewater with varying salt concentration (ranging from 0% to 5%) to examine the effects of salt stress on the structure and function of the anaerobic microbial community. Result indicated that salt stress had a significant impact on the metabolic function and community structure of the anaerobic granular sludge. Specifically, we observed a notable reduction in methane production in response to all salt stress treatments (r = -0.97, p < 0.01), while an unexpected increase in butyrate production (r = 0.91, p < 0.01) under moderate salt stress (1-3%) with ethanol and acetate as carbon sources. In addition, analysis of microbiome structures and networks demonstrated that as the degree of salt stress increased, the networks exhibited lower connectance and increased compartmentalization. The abundance of interaction partners (methanogenic archaea and syntrophic bacteria) decreased under salt stress. In contrast, the abundance of chain elongation bacteria, specifically Clostridium kluyveri, increased under moderate salt stress (1-3%). As a consequence, the microbial carbon metabolism patterns shifted from cooperative mode (methanogenesis) to independent mode (carbon chain elongation) under moderate salt stress. This study provides evidence that salt stress altered the anaerobic microbial community and carbon metabolism characteristics, and suggests potential guidance for steering the microbiota to promote resource conversion in saline organic wastewater treatment.

Bioremediation system consisted with Leclercia adecarboxylata and nZVI@Carbon/Phosphate for lead immobilization: The passivation mechanisms of chemical reaction and biological metabolism in soil.

Bioremediation is one of the most promising strategies for heavy metal immobilization. A new remediation system was demonstrated in this research, which combined phosphate solubilizing bacteria (PSB) with nZVI@Carbon/Phosphate (nZVI@C/P) composite to remediate lead contaminated soil. Experimental results indicated that the new system (nZVI@C/P + PSB) could effectively convert the labile Pb into the stable fraction after 30 days of incubation, which increased the maximum residual fraction percentage of Pb by 70.58%. The characterization results showed that lead may exist in the forms of Pb5(PO4)3Cl, PbSO4 and 3PbCO3·2Pb(OH)2·H2O in the soil treated with nZVI@C/P + PSB. Meanwhile, soil enzyme activities and Leclercia abundance were enhanced in the treated soil compared with CK during the incubation time. In addition, the specialized functions (e.g. ABC transporters, siderophore metabolism, sulfur metabolism and phosphorus metabolism) in PSB and nZVI@C/P + PSB group were also enhanced. These phenomena proved that the key soil metabolic functions may be maintained and enhanced through the synergistic effect of incubated PSB and nZVI@C/P. The study demonstrated that this new bioremediation system provided feasible way to improve the efficacy for lead contaminated soil remediation.

Serum L-Carnitine Levels Are Associated With First Stroke in Chinese Adults With Hypertension.

BACKGROUND: This study aimed to evaluate the association of serum L-carnitine with first stroke and explore potential effect modifiers. METHODS: This is a nested, case-control study drawn from the China Stroke Primary Prevention Trial among rural Chinese adults with hypertension, including 557 first stroke cases and 557 age-matched, sex-matched, treatment group-matched, and residence-matched controls. Serum L-carnitine was measured by liquid chromatography with tandem quadrupole mass spectrometry. Multiple conditional logistic regression models were used to evaluate the association between L-carnitine and first stroke. RESULTS: The mean level of serum L-carnitine in the stroke population was 4.7 µg/mL, which was significantly lower than that of the control group (5.7 µg/mL). When L-carnitine was assessed as quintiles, compared with the reference group (quintile 1, <3.3 µg/mL), the odds of stroke were 0.62 (95% CI, 0.39-1.00) in quintile 2, 0.66 (95% CI, 0.40-1.10) in quintile 3, 0.47 (95% CI, 0.28-0.81) in quintile 4, and 0.50 (95% CI, 0.30-0.84) in quintile 5. The trend test was significant (P=0.01). When quintiles 2 to 5 were combined, the adjusted odds ratio of first stroke was 0.58 (95% CI, 0.38-0.87) compared with quintile 1. Similar associations were found for ischemic stroke and hemorrhagic stroke. In subgroup analysis, a significant L-carnitine-stroke association was only observed in the normal folate group (P interaction, 0.039) and in the MTHFR CC genotype group (P interaction, 0.047). CONCLUSIONS: In this study of rural Chinese adults with hypertension, serum L-carnitine had an inverse but nonlinear association with first stroke. Folate status and the MTHFR C677T variant were significant effect modifiers of the association.

Inverse Association between Plasma Phylloquinone and Risk of Ischemic Stroke in Chinese Adults with Hypertension and High BMI: A Nested Case-Control Study.

BACKGROUND: Evidence on the association between phylloquinone status and cardiovascular diseases is scarce and conflicting. These inconsistencies may be due to differences in individual characteristics of the study populations, which may modify the association. OBJECTIVE: This study aimed to evaluate the association between plasma phylloquinone and the risk of first total stroke and its subtypes, and to examine potential effect modifications by BMI in patients with hypertension. METHODS: We performed a nested case-control study including 604 first stroke cases and 604 matched controls. The mean age was 62.2 y (range, 45 to 75). Lower BMI was defined as <25 kg/m2  and higher BMI was defined as ≥25 kg/m2. The risks of the first stroke were estimated by ORs and 95% CIs using conditional logistic regression. The primary outcome was total stroke or ischemic stroke. RESULTS: The relation between log-transformed phylloquinone concentration and stroke or ischemic stroke was modified by BMI. Higher phylloquinone concentrations were associated with lower stroke risk in those with a higher BMI. When plasma phylloquinone was assessed as tertiles, the adjusted ORs of first stroke and ischemic stroke for participants with a high BMI in tertile 2-3 were 0.70 (95% CI: 0.46, 1.08) and 0.57 (95% CI: 0.35, 0.92) compared with those in tertile 1, respectively. However, there was no significant association between plasma phylloquinone and risk of first total stroke or ischemic stroke for those with a lower BMI. Patients with a higher BMI and lower phylloquinone concentrations had the highest risk of ischemic stroke and showed a statistically significant difference compared with the reference group with a lower BMI and higher phylloquinone (OR = 1.80, 95% CI: 1.06, 3.10; P-interaction: 0.017). CONCLUSIONS: In Chinese patients with hypertension, there was an inverse association between baseline plasma phylloquinone and risk of first ischemic stroke among those with a higher BMI. This trial was registered at clinicaltrials.gov as NCT00794885.

Joint Associations between Plasma 25-Hydroxyvitamin D, Glycemic Status, and First Stroke in General Hypertensive Adults: Results from the China Stroke Primary Prevention Trial (CSPPT).

BACKGROUND: Associations between vitamin D and stroke remain inconsistent. One major risk factor for stroke is high blood glucose, but the role it plays in this association is not well studied. OBJECTIVES: We aimed to evaluate the individual association between plasma 25-hydroxyvitamin D [25(OH)D] and risk of first stroke stratified by fasting blood glucose (FBG), and the joint associations between plasma 25(OH)D, glycemic status, and first stroke in hypertensive adults. METHODS: This study was a nested, case-control design utilizing data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 591 first stroke cases (of which 475 were ischemic stroke, 114 were hemorrhagic stroke, and 2 were uncertain type) and 591 matched controls. The age range of the study population was 45-75 y. The normal FBG (NFG) group had FBG <5.6 mmol/L,  and the impaired FBG (IFG) group had FBG ≥5.6 mmol/L and <7.0 mmol/L. Diabetes was defined as participants with FBG ≥7 mmol/L or who were receiving treatment with hypoglycemic agents. ORs (95% CIs) were calculated using unconditional logistic regression models. RESULTS: Multivariable adjusted models revealed an inverse association between quartiles of 25(OH)D and risk of first stroke among participants with NFG, but the opposite trend was observed for those with IFG or diabetes. The largest ORs (>2) were observed among patients with diabetes, compared with the reference group of NFG and high 25(OH)D. Those with NFG and low 25(OH)D (OR = 1.73, 95% CI: 1.22 to 2.44) or those with IFG and high 25(OH)D (OR = 1.74, 95% CI: 1.14 to 2.67) both had a higher risk of total stroke. There was a significant interaction between 25(OH)D and a combined group of IFG and diabetes (P = 0.001). Similar results were observed for ischemic stroke. CONCLUSIONS: In a hypertensive population, the relation between plasma 25(OH)D and risk of first stroke was significantly modified by FBG. This trial was registered at https://www.clinicaltrials.gov as NCT00794885.

The application of lactoferrin in infant formula: The past, present and future.

Human milk is universally regarded as the gold standard to fulfill nutrition needs of infants. Lactoferrin (LF) is a major multiple bioactive glycoprotein in human milk but little is presented in infant formula. LF can resist digestion in the infant gastrointestinal tract and is absorbed into the bloodstream in an intact form to perform physiological functions. Evidence suggest that LF prevents pathogen infection, promotes immune system development, intestinal development, brain development and bone health, as well as ameliorates iron deficiency anemia. However, more clinical studies of LF need to be further elucidated to determine an appropriate dosage for application in infant formula. LF is sensitive to denaturation induced by processing of infant formula such as heat treatments and spay drying. Thus, further studies should be focus on maximizing the retention of LF activity in the infant formula process. This review summarizes the structural features of LF. Then the digestion, absorption and metabolism of LF in infants are discussed, followed by the function of LF for infants. Further, we summarize LF in infant formula and effects of processing of infant formula on bioactivities of LF, as well as future perspectives of LF research.

Association between plasma copper levels and first stroke: a community-based nested case-control study.

BACKGROUND AND AIMS: Uncertainty remains regarding the association between the risk of stroke and plasma copper levels in population with copper mostly in normal range due to limited data. We examined the association between baseline plasma copper and risk of first stroke in Chinese community-dwelling population. METHODS: We conducted a nested case control study from 'H-type Hypertension and Stroke Prevention and Control Project'. A total of 1255 first stroke cases and 1255 controls matched for age, sex and study site were included in the analysis. Conditional logistic regression analyses were performed to evaluate the association between plasma copper and first stroke. RESULTS: The overall mean of copper was 15.90 (2.66) µmol/L. In total, 94.26% participants' copper concentration was in the normal range by Mayo Clinic laboratory reference values. Smoothing curve showed that the associations of plasma copper with first stroke and its subtypes were linear. Each standard deviation (SD) increment of plasma copper was independently and positively associated with risk of first stroke [odds ratio (OR): 1.17, 95% confidence interval (CI): 1.07-1.28]. The multivariable ORs with 95% CIs for total stroke, ischemic stroke and hemorrhagic stroke in the highest versus the lowest quartile of plasma copper were 1.49 (1.16-1.90; P-trend = 0.001), 1.46 (1.12-1.92; P-trend = 0.004) and 2.05 (0.95-4.38; P-trend = 0.050), respectively. CONCLUSIONS: Baseline plasma copper was positively associated with risk of first ischemic stroke in an approximately linear fashion among Chinese community population (80.32% hypertensives), although their copper levels were mostly within the normal range according to current reference values. Our findings warrant additional investigation.

Lactoferrin Is a Potential Activator of the Vitamin D Receptor in Its Regulation of Osteogenic Activities in C57BL/6J Mice and MC3T3-E1 Cells.

BACKGROUND: Lactoferrin (LF) has been shown to promote bone anabolism, and the vitamin D receptor (VDR) mediates the effects of vitamin D on bone. We hypothesized that LF improves bone health by increasing VDR expression. OBJECTIVES: We sought to determine the role of VDR activation in LF-induced osteogenic activity in vivo and in vitro and the underlying molecular mechanisms. METHODS: Sixty male C57BL/6J mice (aged 4 wk) were randomly assigned into 6 groups and fed vitamin D-deficient (VDD; 0 IU/kg) or vitamin D-normal diet (VDN; 1000 IU cholecalciferol/kg) and administered placebo or LF (100 or 1000 mg/kg body weight) by gavage for 24 wk. Trabecular bone structure was analyzed using micro-CT, and VDR expression was assessed by immunohistochemistry. In vitro, MC3T3-E1 cells were treated with 100 µg LF/mL to evaluate its effect on VDR expression. Finally, the direct recruitment of LF to the Vdr promoter was confirmed by chromatin immunoprecipitation assay. In addition, cells were transfected with pGL3-basic Vdr vector for monitoring Vdr promoter activation using luciferase assays. RESULTS: LF supplementation at 100 and 1000 mg/kg revealed an ∼6.5% (P < 0.05) increase in bone mineral density in mice on VDD diet and exhibited an enhanced expression of VDR in bone compared with control. This increased expression of VDR was also observed in the bone of mice on the VDN diet, but the effect was more pronounced in VDD diet. In vitro, compared with the control group, Vdr mRNA expression was 18 times greater (P < 0.05) and peaked at 2 h posttreatment of LF. By cotransfection of the pGL3-basic Vdr vector, LF induced luciferase activity by 30% (P < 0.05) in MC3T3-E1 cells. CONCLUSIONS: In vivo and in vitro, LF, a potential activator of VDR, promotes osteogenesis. This suggests that dairy products, which are rich in LF, may serve as a functional food to improve bone health.

Egg consumption associated with all-cause mortality in rural China: a 14-year follow-up study.

BACKGROUND: Dietary recommendations regarding egg intake remain controversial topic for public health. We hypothesized that there was a positive association between egg consumption and all-cause mortality. METHODS: To test this hypothesis, we enrolled 9885 adults from a community-based cohort in Anhui Province, China during 2003-05. Egg consumption was assessed by food questionnaire. Stratified analyses were performed for age, sex, body mass index (BMI), blood pressure, smoking, drinking and laboratory tests. RESULTS: After an average follow-up of 14.1 years, 9444 participants were included for analysis. A total of 814 deaths were recorded. Participants' BMI and lipid profile had no significantly difference between three egg consumption groups. BMI was 21.6±2.7 of the whole population, especially BMI>24 was only 17.3%. A bivariate association of egg consumption >6/week with increased all-cause mortality was observed compared with ≤6/week (RR: 1.35, 95% CI: 1.05, 1.73, P = 0.018). A significant interaction was observed for BMI ≥ 21.2 kg/m2 vs. BMI<21.2 kg/m2 (P for interaction: 0.001). No other significant interactions were found. CONCLUSIONS: In this study, consuming >6 eggs/week increased risk of all-cause mortality, even among lean participants, especially who with BMI ≥ 21.2 kg/m2. Eggs are an easily accessible and constitute an affordable food source in underdeveloped regions. Consuming <6 eggs/week may be the most suitable intake mode.

Plasma 25-Hydroxyvitamin D3 Concentrations and Risk of New-Onset Proteinuria in Patients With Hypertension.

OBJECTIVE: We aimed to evaluate the relationship of plasma 25-hydroxyvitamin D3 (25[OH]D3) with the risk of new-onset proteinuria and examine the possible effect modifiers in patients with hypertension and without chronic kidney disease at baseline. METHODS: This is a post hoc analysis of the renal substudy of the China Stroke Primary Prevention Trial. A total of 1655 patients with hypertension, who had plasma 25(OH)D3 measurements, as well as without proteinuria and with an estimated glomerular filtration rate of ≥60 mL/min/1.73 m2 at baseline, were included in the present study. The main outcome was new-onset proteinuria, defined as a urine dipstick reading of ≥1+ at the exit visit. RESULTS: The mean (standard deviation) 25(OH)D3 level at baseline was 18.6 (7.5) ng/mL. The median follow-up duration was 4.4 years. Overall, there was a significant inverse association between plasma 25(OH)D3 and the risk of new-onset proteinuria (per standard deviation increment; [odds ratio] OR: 0.70; 95% confidence interval [CI]: 0.50, 0.97). Accordingly, when 25(OH)D3 was assessed as quartiles, a significantly lower risk of new-onset proteinuria was found in participants in quartiles 3-4 (≥17.8 ng/mL; OR: 0.45; 95% CI: 0.23, 0.87), compared with those in quartile 1 (<13.1 ng/mL). Furthermore, a stronger inverse relationship of plasma 25(OH)D3 and new-onset proteinuria was observed in nondiabetic participants (per standard deviation increment; OR: 0.57; 95% CI: 0.39, 0.83; vs. diabetics: OR: 1.48; 95% CI: 0.67, 3.28; P for interaction = 0.028). CONCLUSION: There was a significant inverse association between plasma 25(OH)D3 and the risk of proteinuria in patients with hypertension, especially in those without diabetes.

Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents.

OBJECTIVE: Patients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD). DESIGN: Characterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls. Multidimensional data integration to reveal links between these datasets and the use of chronic kidney disease (CKD) rodent models to test the effects of intestinal microbiome on toxin accumulation and disease severity. RESULTS: A group of microbial species enriched in ESRD correlates tightly to patient clinical variables and encode functions involved in toxin and secondary bile acids synthesis; the relative abundance of the microbial functions correlates with the serum or faecal concentrations of these metabolites. Microbiota from patients transplanted to renal injured germ-free mice or antibiotic-treated rats induce higher production of serum uraemic toxins and aggravated renal fibrosis and oxidative stress more than microbiota from controls. Two of the species, Eggerthella lenta and Fusobacterium nucleatum, increase uraemic toxins production and promote renal disease development in a CKD rat model. A probiotic Bifidobacterium animalis decreases abundance of these species, reduces levels of toxins and the severity of the disease in rats. CONCLUSION: Aberrant gut microbiota in patients with ESRD sculpts a detrimental metabolome aggravating clinical outcomes, suggesting that the gut microbiota will be a promising target for diminishing uraemic toxicity in those patients. TRIAL REGISTRATION NUMBER: This study was registered at ClinicalTrials.gov (NCT03010696).

Human Milk Oligosaccharides Activate Epidermal Growth Factor Receptor and Protect Against Hypoxia-Induced Injuries in the Mouse Intestinal Epithelium and Caco2 Cells.

BACKGROUND: Hypoxia-induced intestinal barrier injuries lead to necrotizing enterocolitis (NEC). Although NEC in preterm neonates is preventable by human milk oligosaccharides (HMOs), the underlying mechanism remains unknown. OBJECTIVE: To reveal the role and mechanism of HMOs in protecting against hypoxia-induced injuries in intestinal epithelium of neonatal mice and cultured Caco2 cells. METHODS: NEC was induced by hypoxia and cold stress. Seventy C57BL/C pups (7-d-old) were divided into 5 groups and fed maternal breast milk (BM), formula alone (FF), or the formula added with HMOs at 5 (LHMO), 10 (MHMO), or 20 mg/mL (HHMO) for 3 d. Ileal hypoxia inducible factor 1α (HIF1α) and cleaved Caspase 3 were determined, along with staining for Ki-67 protein to labeled proliferative cells. In vitro, adherent Caco2 cells (undifferentiated, passage 14) were treated with HMOs, galacto-oligosaccharides, fructo-oligosaccharides, or mixed oligosaccharides at 10 mg/mL for 1 d exposed to 1% O2. Cell proliferation and apoptosis, along with phosphorylated epidermal growth factor receptor (P-EGFR) and 38KD MAPK (P-P38), were assayed in differentiated or undifferentiated Caco2 cells. RESULTS: Compared with the FF-fed mice, those fed MHMO and HHMO had 52% lower (P < 0.05) NEC scores, 60-80% greater (P < 0.05) KI67-positive cell numbers, and 56-71% decreases (P < 0.05) in ileal HIF1α and cleaved Caspase 3 (56-71%). Compared with those untreated, the HMO-treated Caco2 cells displayed 60% greater (P < 0.05) proliferative activity and 19% lower (P < 0.05) apoptotic cells after the hypoxia exposure. The HMO treatment led to 58% or 10-fold increases (P < 0.05) of P-EGFR and 48-89% decreases (P < 0.05) of P-P38 in either differentiated or undifferentiated Caco2 cells compared with the controls. CONCLUSION: Supplementing HMOs at 10-20 mg/mL into the formula for neonatal mice or media for Caco2 cells conferred protection against the hypoxia-induced injuries. The protection in the Caco2 cells was associated with an activation of EGFR.

Plasma Magnesium Concentrations and Risk of Incident Cancer in Adults with Hypertension: A Nested Case-Control Study.

OBJECTIVE: The association between plasma magnesium and risk of incident cancer remains inconclusive in previous studies. We aimed to investigate the prospective relationship of baseline plasma magnesium concentrations with the risk of incident cancer and to examine possible effect modifiers. METHODS: A nested case-control study with 228 incident cancer cases and 228 matched controls was conducted using data from the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013. Study outcomes included incident cancer and its subtypes. RESULTS: When plasma magnesium concentrations were assessed as quartiles, a significantly higher incident risk of total cancer was found in participants in quartile 1 (<0.76 mmol/L; odds ratio [OR] = 2.70; 95% CI: 1.33-5.49) and quartile 4 (≥0.89 mmol/L; OR = 2.05; 95% CI: 1.12-3.76), compared with those in quartile 3 (0.83 to <0.89 mmol/L). In cancer site-specific analyses, similar trends were found for gastrointestinal cancer, esophageal cancer, gastric cancer, breast cancer, lung cancer, and other cancers. Furthermore, none of the variables, including age, sex, current smoking status, current alcohol intake, BMI, systolic blood pressure, and total cholesterol levels at baseline significantly modified the association between plasma magnesium and cancer risk. CONCLUSIONS: Both low and high plasma magnesium concentrations were significantly associated with an increased incident risk of cancer, compared with the reference concentrations of 0.83 to <0.89 mmol/L among hypertensive adults.