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.
Background and Purpose
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.
Ischemia/reperfusion (I/R) injury is a life-threatening vascular emergency following myocardial infarction. Our previous study showed cardioprotective effects of metformin against myocardial I/R ...injury. In this study, we further examined the involvement of AMPK mediated activation of NLRP3 inflammasome in this cardioprotective effect of metformin. Myocardial I/R injury was simulated in a rat heart Langendorff model and neonatal rat ventricle myocytes (NRVMs) were subjected to hypoxi/reoxygenation (H/R) to establish an in vitro model. Outcome measures included myocardial infarct size, hemodynamic monitoring, myocardial tissue injury, myocardial apoptotic index and the inflammatory response. myocardial infarct size and cardiac enzyme activities. First, we found that metformin postconditioning can not only significantly alleviated myocardial infarct size, attenuated cell apoptosis, and inhibited myocardial fibrosis. Furthermore, metformin activated phosphorylated AMPK, decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and decreased NLRP3 inflammasome activation. In isolated NRVMs metformin increased cellular viability, decreased LDH activity and inhibited cellular apoptosis and inflammation. Importantly, inhibition of AMPK phosphorylation by Compound C (CC) resulted in decreased survival of cardiomyocytes mainly by inducing the release of inflammatory cytokines and increasing NLRP3 inflammasome activation. Finally, in vitro studies revealed that the NLRP3 activator nigericin abolished the anti-inflammatory effects of metformin in NRVMs, but it had little effect on AMPK phosphorylation. Collectively, our study confirmed that metformin exerts cardioprotective effects by regulating myocardial I/R injury-induced inflammatory response, which was largely dependent on the enhancement of the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.
Chronic kidney disease (CKD), characterized as renal dysfunction, is recognized as a major public health problem with high morbidity and mortality worldwide. Unfortunately, there are no obvious ...clinical symptoms in early stage disease until severe damage has occurred. Further complicating early diagnosis and treatment is the lack of sensitive and specific biomarkers. As such, novel biomarkers are urgently needed. Metabolomics has shown an increasing potential for identifying underlying disease mechanisms, facilitating clinical diagnosis and developing pharmaceutical treatments for CKD. Recent advances in metabolomics revealed that CKD was closely associated with the dysregulation of numerous metabolites, such as amino acids, lipids, nucleotides and glycoses, that might be exploited as potential biomarkers. In this review, we summarize recent metabolomic applications based on animal model studies and in patients with CKD and highlight several biomarkers that may play important roles in diagnosis, intervention and development of new therapeutic strategies.
•Chronic kidney disease is a major public problem with high morbidity and mortality.•Potential biomarkers are useful for the diagnosis of chronic kidney disease.•Metabolomics shows the potential for biomarker discovery and clinical diagnosis.•Biomarkers provide new therapeutic strategy for patient with chronic kidney disease.
Chronic kidney disease (CKD) results in high morbidity and mortality worldwide causing a huge socioeconomic burden. MicroRNA (miRNA) exert critical regulatory functions by targeting downstream genes ...and have been associated with many pathophysiologic processes including CKD. In fact, many studies have shown that the expression of various miRNAs was significantly changed in CKD. Current investigations have focused on revealing the relationship between miRNAs and CKD states including diabetic nephropathy, lupus nephritis, focal segmental glomerulosclerosis and IgA nephropathy. In this review, we summarize the latest advances elucidating miRNA involvement in the progression of CKD and demonstrate that miRNAs have the potential to be effective biomarkers and therapeutic targets for subsequent treatment.
•microRNAs (miRNAs) have the critical regulatory function in CKD.•microRNAs affect the pathogenesis of CKD by targeting downstream genes.•microRNAs have the potential to be biomarkers and therapeutic targets for CKD.
The microbiome in fermentation has direct impacts on the quality of fermented foods and is of great scientific and commercial interest. Despite considerable effort to explain the microbial metabolism ...associated with food fermentation, the role of the microbiome in pu-erh tea fermentation remains unknown. Here, we applied integrated meta-omics approaches to characterize the microbiome in two repeated fermentations of pu-erh tea. Metabarcoding analysis of bacterial 16S rRNA genes showed a decrease in the proportion of Proteobacteria and an increase in the abundance of Firmicutes during fermentation. Metabarcoding analysis of fungal internal transcribed spacer (ITS) sequence demonstrated that Rasamsonia, Thermomyces, and Aspergillus were dominant at the intermediate stage, whereas Aspergillus was dominant at other stages in fermentation. Metaproteomics analysis assigned primary microbial metabolic activity to metabolism and identified microbial carbohydrate-active enzymes involved in the degradation of polysaccharides including cellulose, xylan, xyloglucan, pectin, starch, lignin, galactomannan, and chitin. Metabolomics and high-performance liquid chromatography analysis revealed that levels of phenolic compounds, including gallates, decreased whereas contents of gallic acid and ellagic acid significantly increased after fermentation (P < 0.05). The changes in levels of gallates and gallic acid were associated with the hydrolysis of tannase. Glycoside hydrolases, phenol 2-monooxygenase, salicylaldehyde dehydrogenase, salicylate 1-monooxygenase, catechol O-methyltransferase, catechol dioxygenase, and quercetin 2,3-dioxygenases were hypothesized to be related to oxidation, conversion, or degradation of phenolic compounds. We demonstrated microbiota in fermentation and their function in the production of enzymes related to the degradation of polysaccharides, and metabolism of phenolic compounds, resulting in changes in metabolite contents and the quality of pu-erh tea. IMPORTANCE Fermented foods play important roles in diets worldwide and account for approximately one-third of all foods and beverages consumed. To date, traditional fermentation has used spontaneous fermentation. The microbiome in fermentation has direct impacts on the quality and safety of fermented foods and contributes to the preservation of traditional methods. Here, we used an integrated meta-omics approach to study the microbiome in the fermentation of pu-erh tea, which is a well-known Chinese fermented food with a special flavor and healthful benefits. This study advanced the knowledge of microbiota, metabolites, and enzymes in the fermentation of pu-erh tea. These novel insights shed light onto the complex microbiome in pu-erh fermentation and highlight the power of integrated meta-omics approaches in understanding the microbiome in food fermentation ecosystems.
Difficulties in emotion regulation are commonly reported among individuals with alcohol and drug addictions and contribute to the acquisition and maintenance of addictive behaviors. Alterations in ...neural processing of negative affective stimuli have further been demonstrated among individuals with addictions. However, it is unclear whether these alterations are a general feature of addictions or are a result of prolonged exposure to drugs of abuse. To test the hypothesis of altered negative affect processing independent of drug effects, this study assessed neural function among drug-naïve youth with a behavioral addiction-Internet gaming disorder (IGD). Fifty-six young adults (28 with IGD, 28 matched controls) participated in fMRI scanning during performance of a well-validated emotion regulation task. Between-group differences in neural activity during task performance were assessed using a whole-brain, mixed-effects ANOVA with correction for multiple comparisons at currently recommended thresholds (voxel-level p<0.001, pFWE<0.05). Compared to controls, youth with IGD exhibited significantly blunted neural responses within distributed subcortical and cortical regions including the striatum, insula, lateral prefrontal cortex and anterior cingulate in response to negative affective cues, as well as during emotion regulation. Independent component analysis (ICA) further identified between-group differences in engagement of a fronto-cingulo-parietal network, involving decreased engagement in IGD youth relative to controls. Study findings are largely consistent with those from prior neuroimaging studies in substance-use disorders, thus raising the possibility that neural processing of negative affect may be blunted across drug and behavioral addictions independent of acute or chronic drug effects.
Glucocorticoids are the only therapy that has been demonstrated to alter the progress of Duchenne muscular dystrophy (DMD), the most common muscular dystrophy in children. However, glucocorticoids ...disturb skeletal muscle metabolism and hamper myogenesis and muscle regeneration. The mechanisms involved in the glucocorticoid-mediated suppression of myogenic differentiation are not fully understood. Glycogen synthase kinase-3β (GSK-3β) is considered to play a central role as a negative regulator in myogenic differentiation. Here, we showed that glucocorticoid treatment during the first 48 h in differentiation medium decreased the level of phosphorylated Ser9-GSK-3β, an inactive form of GSK-3β, suggesting that glucocorticoids affect GSK-3β activity. We then investigated whether GSK-3β inhibition could regulate glucocorticoid-mediated suppression of myogenic differentiation in vitro. Two methods were employed to inhibit GSK-3β: pharmacological inhibition with LiCl and GSK-3β gene knockdown. We found that both methods resulted in enhanced myotube formation and increased levels of muscle regulatory factors and muscle-specific protein expression. Importantly, GSK-3β inhibition attenuated glucocorticoid-induced suppression of myogenic differentiation. Collectively, these data suggest the involvement of GSK-3β in the glucocorticoid-mediated impairment of myogenic differentiation. Therefore, the inhibition of GSK-3β may be a strategy for preventing glucocorticoid-induced muscle degeneration.
Hydroxyapatite(HA)/5% hydrophilic graphene(HG) composites showed superior cell proliferation rate and excellent cell adhesion.
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•HA/HG composites were synthesized by hydrothermal ...method.•HA/HG composites showed a nest-like layered structure.•Wettability and roughness of HA/HG composites were adjusted by the content of HG.•HA/5%HG composites showed superior cell proliferation rate and cell adhesion.
Cell adhesion was the first step of bone reconstruction. While hydroxyapatite (HA)/graphene composites had been utilized for improving the cell adhesion and bone osteogenesis, the impact of cell adhesion and HA/graphene composites, especially HA/hydrophilic graphene (HG) composites, on internal interaction force and external surface properties remained poorly understood. Here, higher stability HA/HG composites were synthesized without extra ion introduction with in situ self-assembling method. And with XRD, FT-IR, XPS and Raman analyses, the evidences of the formation of HA and the introduction of HG was clear. TEM and SEM images showed the net-like spatial structure due to the internal interaction force between HA and HG, which provided the strain stimulation for cell adhesion. Subsequently, the external surface properties of HA/HG composites demonstrated that the roughness and hydrophilic ability of HA/HG composites could be artificially regulated by increasing the content of HG. Besides, the cell proliferation rate of HA/HG composites had been investigated. Compared to the intrinsic HA, HA/5%HG possessed the higher cell proliferation rate (264.81%) and promoted the spreading and growth of MC3T3-E1 cells. Finally, the regulation mechanism between HA/HG and cell adhesion were illuminated in detail. The excellent regular behavior of HA/HG composites for cell adhesion made them promising candidates for bone reconstruction and repairing. The present work provided the reference for the design of modifiable biomaterials and offered much inspiration for the future research of bone reconstruction engineering.
Anthocyanin is an important parameter for evaluating the quality of wine grapes. However, the effects of different light intensities on anthocyanin synthesis in grape berry skin and its regulation ...mechanisms are still unclear. In this experiment, clusters of wine grape cv. 'Marselan' were bagged using fruit bags with different light transmittance of 50%, 15%, 5%, and 0, designated as treatment A, B, C and D, respectively. Fruits that were not bagged were used as the control, designated as CK. The anthocyanin composition and concentration, as well as gene expression profiles in the berry skin were determined. The results showed that the degree of coloration of the berry skin reduced with the decrease of the light transmittance, and the veraison was postponed for 10 days in D when compared with the CK. Total anthocyanin concentration in the berry skin treated with D decreased by 51.50% compared with CK at the harvest stage. A total of 24 and 21 anthocyanins were detected in CK and D, respectively. Among them, Malvidin-3-
-coumaroylglucoside (trans), which showed a significant positive correlation with the total concentration of anthocyanins at the harvest stage (
= 0.775) and was not detected in D, was presumed to be light-induced anthocyanin. Other anthocyanins which were both synthesized in CK and D were considered to be light-independent anthocyanins. Among them, Malvidin-3-
-coumaroylglucoside (cis) and Malvidin-3-
-acetylglucoside were typical representatives. Remarkably, the synthesis of light-inducible anthocyanins and light-independent anthocyanins were regulated by different candidate structural genes involved in flavonoid biosynthesis pathway and members of MYB and bHLH transcription factors.
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