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Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1–5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD.

BackgroundThe prevalence of early childhood caries (ECC) varies with geographical region and population. The Uygur people, one of 55 officially recognized ethnic minorities in China, have a population of 10,069,346. We performed a preschool-based cross-sectional study of 670 Uygur children from the southern region of Xinjiang, China, to investigate the prevalence and severity of ECC and to identify factors related to the dental health condition of this population.MethodsThe study population of children ranging in age from 3 to 5 years was invited using a three-stage stratified sampling in Kashgar, the westernmost city in China. The “dmft” index was used to assess dental caries. The diagnosis of ECC or severe ECC was based on the oral health diagnostic criteria defined by the American Academy of Pediatric Dentistry. A questionnaire was completed by the children’s caregivers. The survey included questions concerning the children’s sociodemographic background; feeding and eating habits, particularly frequency of sweet beverage and food consumption; dental hygiene-related behaviors; the general oral health knowledge of caregivers; and the dental healthcare experience of caregivers and their children.ResultsA total of 670 Uygur children underwent complete dental caries examination. Most of the children (74.2%) had ECC, with a mean dmft ± SD of 3.95 ± 3.84. The prevalence of severe ECC was 40.1% (N =269), with a mean dmft of 7.72 ± 3.14. More than 99% of caries were untreated. Statistically significant correlations were found between higher ECC prevalence and increased age and lower socioeconomic background, while greater dental health knowledge of the caregiver and positive oral hygiene behaviors were found to be protective. Our findings confirm the multi-factorial etiology of ECC.ConclusionsThe prevalence of ECC among preschool-aged Uygur children in Kashgar was high, particularly among those from lower socioeconomic backgrounds. Caries prevalence was associated with oral hygiene behaviors of children and the general oral health knowledge of caregivers. These factors could be modified through public health strategies, including effective publicity concerning general dental health and practical health advice.Electronic supplementary materialThe online version of this article (doi:10.1186/1472-6831-14-136) contains supplementary material, which is available to authorized users.

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BackgroundThis study assessed the prevalence and severity of early childhood caries (ECC) and identified socioeconomic and behavioral correlates of the disease in preschool children living in Xinjiang.MethodsFor this cross-sectional survey, 1727 children aged 3–5 years in Xinjiang were randomly recruited using a three-stage cluster sampling procedure. The “dmft” index according to the WHO 1997 criteria was used to assess ECC and severe ECC (S-ECC). A questionnaire was completed by caregivers. Variables included sociodemographic characteristics, dietary and oral hygiene behaviors, and access to dental services. The statistical associations of variables with ECC, S-ECC, and dmft were evaluated by univariate and multiple logistic regression analyses.ResultsThe prevalence of ECC was 78.2% and that of S-ECC was 41.2%; mean dmft scores were 5.61 ± 3.56 and 8.17 ± 2.94, respectively. The prevalence of ECC was significantly higher in children from Ining (OR 2.747; 95% CI 2.033–3.713), those whose caregivers had caries (OR 1.78; 95% CI 1.245–2.547), those with a dental visit in the past (OR 2.023; 95% CI 1.429–2.865), and those whose parents had received instructions on oral health care (OR 2.171; 95% CI 1.44–3.272), and increased significantly at age 4 years (OR 2.09; 95% CI 1.506–2.901) and 5 years (OR 2.666; 95% CI 1.855–3.833) and in children who starting tooth brushing at a young age (OR 1.363; 95% CI 1.171–1.587), and decreased significantly in children with a more educated mother (OR 0.817; 95% CI 0.688–1), those from high-income families (OR 0.667; 95% CI 0.582–0.765), those with low consumption of sweets (OR 0.66; 95% CI 0.57–0.763), and those who seldom ate before sleep (OR 0.557; 95% CI 0.437–0.712).ConclusionsECC and S-ECC remain a serious problem among preschool children in Xinjiang. Caries rates were associated with sociodemographic and behavioral factors, which could be modified by public health strategies, including protection of primary dentition, extension of insurance to cover oral preventive services, improvement of the oral health care system, and public health education.Electronic supplementary materialThe online version of this article (10.1186/s12903-017-0432-z) contains supplementary material, which is available to authorized users.

ScopeObesity is closely related to the imbalance of white adipose tissue storing excess calories, and brown adipose tissue dissipating energy to produce heat in mammals. Recent studies revealed that acquisition of brown characteristics by white adipocytes, termed “browning,” may positively contribute to cellular bioenergetics and metabolism homeostasis. The goal was to investigate the putative effects of natural antioxidant sulforaphane (1‐isothiocyanate‐4‐methyl‐sulfonyl butane; SFN) on browning of white adipocytes.Methods and results3T3‐L1 mature white adipocytes were treated with SFN for 48 h, and then the mitochondrial content, function, and energy utilization were assessed. SFN was found to induce 3T3‐L1 adipocytes browning based on the increased mitochondrial content and activity of respiratory chain enzymes, whereas the mechanism involved the upregulation of nuclear factor E2‐related factor 2/sirtuin1/peroxisome proliferator activated receptor gamma coactivator 1 alpha signaling. SFN enhanced uncoupling protein 1 expression, a marker for brown adipocyte, leading to the decrease in cellular ATP. SFN also enhanced glucose uptake and oxidative utilization, lipolysis, and fatty acid oxidation in 3T3‐L1 adipocytes.ConclusionSFN‐induced browning of white adipocytes enhanced the utilization of cellular fuel, and application of SFN is a promising strategy to combat obesity and obesity‐related metabolic disorder.

The recent emergence of the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) 9 system has attracted significant attention for its potential to improve traits of agricultural importance. However, most applications in livestock species to date have depended on aberrant DNA repair to generate frameshifting indels. Whether this genomic engineering technique involving homology-dependent repair (HDR) can be used to introduce defined point mutations has been less explored. Previously, we reported a G→A point mutation (g.231A>G, p.Val397Ile) in the growth differentiation factor 9 (GDF9) gene that has a large effect on the litter size of cashmere goats. In the present study we report that by co-injecting synthesised RNAs and single-stranded oligo deoxynucleotide (ssODN) donor sequences into goat zygotes, we successfully introduced defined point mutations resulting in single amino acid substitutions in the proteins as expected. The efficiency of this precise single-nucleotide substitution in newborn kids was as high as 24% (4/17), indicating that ssODN-directed HDR via zygote injection is efficient at introducing point mutations in the goat genome. The findings of the present study further highlight the complex genome modifications facilitated by the CRISPR/Cas9 system, which is able to introduce defined point mutations. This represents a significant development for the improvement of reproduction traits in goats, as well as for validating the roles of specific nucleotides in functional genetic elements in large animals.

In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1-hydroxypyrene in mediating renal fibrosis.Experimental Approach: We analysed 5406 urine and serum samples from patients with Stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. Key Results:We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated GFR in patients with CKD onset and progression.Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up-regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up-regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up-regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. Conclusion and Implications:Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.