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Chronic kidney disease (CKD) induces modifications in lipid and lipoprotein metabolism and homeostasis. These modifications can promote, modulate and/or accelerate CKD and secondary cardiovascular disease (CVD). Lipid and lipoprotein abnormalities — involving triglyceride-rich lipoproteins, LDL and/or HDL — not only involve changes in concentration but also changes in molecular structure, including protein composition, incorporation of small molecules and post-translational modifications. These alterations modify the function of lipoproteins and can trigger pro-inflammatory and pro-atherogenic processes, as well as oxidative stress. Serum fatty acid levels are also often altered in patients with CKD and lead to changes in fatty acid metabolism — a key process in intracellular energy production — that induce mitochondrial dysfunction and cellular damage. These fatty acid changes might not only have a negative impact on the heart, but also contribute to the progression of kidney damage. The presence of these lipoprotein alterations within a biological environment characterized by increased inflammation and oxidative stress, as well as the competing risk of non-atherosclerotic cardiovascular death as kidney function declines, has important therapeutic implications. Additional research is needed to clarify the pathophysiological link between lipid and lipoprotein modifications, and kidney dysfunction, as well as the genesis and/or progression of CVD in patients with kidney disease.Chronic kidney disease (CKD) is associated with alterations in serum lipid profiles that contribute to kidney and cardiovascular disease. Here, the authors examine these changes in serum levels, metabolism and post-translational modifications of lipoproteins and fatty acids that characterize CKD-associated dyslipidaemia.

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MALDI MSI) has become a powerful tool with a high potential relevance for the analysis of biomolecules in tissue samples in the context of diseases like cancer and cardiovascular or cardiorenal diseases. In recent years, significant progress has been made in the technology of MALDI MSI. However, a more systematic optimization of sample preparation would likely achieve an increase in the molecular information derived from MALDI MSI. Therefore, we have employed a systematic approach to develop, establish and validate an optimized “standard operating protocol” (SOP) for sample preparation in MALDI MSI of formalin-fixed paraffin-embedded (FFPE) tissue sample analyses within this study. The optimized parameters regarding the impact on the resulting signal-to-noise (S/N) ratio were as follows: (i) trypsin concentration, solvents, deposition method, and incubation time; (ii) tissue washing procedures and drying processes; and (iii) spray flow rate, number of layers of trypsin deposition, and grid size. The protocol was evaluated on interday variability and its applicability for analyzing the mouse kidney, aorta, and heart FFPE tissue samples. In conclusion, an optimized SOP for MALDI MSI of FFPE tissue sections was developed to generate high sensitivity, to enhance spatial resolution and reproducibility, and to increase its applicability for various tissue types. This optimized SOP will further increase the molecular information content and intensify the use of MSI in future basic research and diagnostic applications.

In recent years, capillary electrophoresis coupled to mass spectrometry (CE-MS) has been increasingly applied in clinical research especially in the context of chronic and age-associated diseases, such as chronic kidney disease, heart failure and cancer. Biomarkers identified using this technique are already used for diagnosis, prognosis and monitoring of these complex diseases, as well as patient stratification in clinical trials. CE-MS allows for a comprehensive assessment of small molecular weight proteins and peptides (<20 kDa) through the combination of the high resolution and reproducibility of CE and the distinct sensitivity of MS, in a high-throughput system. In this study we assessed CE-MS analytical performance with regards to its inter- and intra-day reproducibility, variability and efficiency in peptide detection, along with a characterization of the urinary peptidome content. To this end, CE-MS performance was evaluated based on 72 measurements of a standard urine sample (60 for inter- and 12 for intra-day assessment) analyzed during the second quarter of 2021. Analysis was performed per run, per peptide, as well as at the level of biomarker panels. The obtained datasets showed high correlation between the different runs, low variation of the ten highest average individual log2 signal intensities (coefficient of variation, CV < 10%) and very low variation of biomarker panels applied (CV close to 1%). The findings of the study support the analytical performance of CE-MS, underlining its value for clinical application.

Chronic kidney disease (CKD) is characterized by the loss of kidney function. The molecular mechanisms underlying the development and progression of CKD are still not fully understood. Among others, the urinary peptidome has been extensively studied, with several urinary peptides effectively detecting disease progression. However, their link to proteolytic events has not been made yet. This study aimed to predict the proteases involved in the generation of CKD-associated urinary excreted peptides in a well-matched (for age, sex, lack of heart disease) case-control study. The urinary peptide profiles from CKD (n = 241) and controls (n = 240) were compared and statistically analyzed. The in-silico analysis of the involved proteases was performed using Proteasix and proteases activity was predicted based on the abundance changes of the associated peptides. Predictions were cross-correlated to transcriptomics datasets by using the Nephroseq database. Information on the respective protease inhibitors was also retrieved from the MEROPS database. Totally, 303 urinary peptides were significantly associated with CKD. Among the most frequently observed were fragments of collagen types I, II and III, uromodulin, albumin and beta-2-microglobulin. Proteasix predicted 16 proteases involved in their generation. Through investigating CKD-associated transcriptomics datasets, several proteases are highlighted including members of matrix metalloproteinases ( MMP7 , MMP14 ) and serine proteases ( PCSK5 ); laying the foundation for further studies towards elucidating their role in CKD pathophysiology.

The gut microbiota consists of trillions of microorganisms, fulfilling important roles in metabolism, nutritional intake, physiology and maturation of the immune system, but also aiding and abetting the progression of chronic kidney disease (CKD). The human gut microbiome consists of bacterial species from five major bacterial phyla, namely Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia. Alterations in the members of these phyla alter the total gut microbiota, with a decline in the number of symbiotic flora and an increase in the pathogenic bacteria, causing or aggravating CKD. In addition, CKD-associated alteration of this intestinal microbiome results in metabolic changes and the accumulation of amines, indoles and phenols, among other uremic metabolites, which have a feedforward adverse effect on CKD patients, inhibiting renal functions and increasing comorbidities such as atherosclerosis and cardiovascular diseases (CVD). A classification of uremic toxins according to the degree of known toxicity based on the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence was selected to identify the representative uremic toxins from small water-soluble compounds, protein-bound compounds and middle molecules and their relation to the gut microbiota was summarized. Gut-derived uremic metabolites accumulating in CKD patients further exhibit cell-damaging properties, damage the intestinal epithelial cell wall, increase gut permeability and lead to the translocation of bacteria and endotoxins from the gut into the circulatory system. Elevated levels of endotoxins lead to endotoxemia and inflammation, further accelerating CKD progression. In recent years, the role of the gut microbiome in CKD pathophysiology has emerged as an important aspect of corrective treatment; however, the mechanisms by which the gut microbiota contributes to CKD progression are still not completely understood. Therefore, this review summarizes the current state of research regarding CKD and the gut microbiota, alterations in the microbiome, uremic toxin production, and gut epithelial barrier degradation.

Collagen is a major component of the extracellular matrix (ECM) and has an imminent role in fibrosis, in, among others, chronic kidney disease (CKD). Collagen alpha-1(I) (col1a1) is the most abundant collagen type and has previously been underlined for its contribution to the disease phenotype. Here, we examined 5000 urinary peptidomic datasets randomly selected from healthy participants or patients with CKD to identify urinary col1a1 fragments and study their abundance, position in the main protein, as well as their correlation with renal function. We identified 707 col1a1 peptides that differed in their amino acid sequence and/or post-translational modifications (hydroxyprolines). Well-correlated peptides with the same amino acid sequence, but a different number of hydroxyprolines, were combined into a final list of 503 peptides. These 503 col1a1 peptides covered 69% of the full col1a1 sequence. Sixty-three col1a1 peptides were significantly and highly positively associated (rho > +0.3) with the estimated glomerular filtration rate (eGFR), while only six peptides showed a significant and strong, negative association (rho < −0.3). A similar tendency was observed for col1a1 peptides associated with ageing, where the abundance of most col1a1 peptides decreased with increasing age. Collectively the results show a strong association between collagen peptides and loss of kidney function and suggest that fibrosis, potentially also of other organs, may be the main consequence of an attenuation of collagen degradation, and not increased synthesis.

Identifying the key toxic players within an in-vivo toxic syndrome is crucial to develop targeted therapies. Here, we established a novel method that characterizes the effect of single substances by means of an ex-vivo incubation set-up. We found that primary human spermatozoa elicit a distinct motile response on a (uremic) toxic milieu. Specifically, this approach describes the influence of a bulk toxic environment (uremia) as well as single substances (uremic toxins) by real-time analyzing motile cellular behavior. We established the human spermatozoa-based toxicity testing (HSTT) for detecting single substance-induced toxicity to be used as a screening tool to identify in-vivo toxins. Further, we propose an application of the HSTT as a method of clinical use to evaluate toxin-removing interventions (hemodialysis).

The cardiorenal syndrome (CRS) is defined as the confluence of heart-kidney dysfunction. This study investigates the molecular differences at the level of the urinary peptidome between CRS patients and controls and their association to disease pathophysiology. The urinary peptidome of CRS patients (n = 353) was matched for age and sex with controls (n = 356) at a 1:1 ratio. Changes in the CRS peptidome versus controls were identified after applying the Mann–Whitney test, followed by correction for multiple testing. Proteasix tool was applied to investigate predicted proteases involved in CRS-associated peptide generation. Overall, 559 differentially excreted urinary peptides were associated with CRS patients. Of these, 193 peptides were specifically found in CRS when comparing with heart failure and chronic kidney disease urinary peptide profiles. Proteasix predicted 18 proteases involved in > 1% of proteolytic cleavage events including multiple forms of MMPs, proprotein convertases, cathepsins and kallikrein 4. Forty-four percent of the cleavage events were produced by 3 proteases including MMP13, MMP9 and MMP2. Pathway enrichment analysis supported that ECM-related pathways, fibrosis and inflammation were represented. Collectively, our study describes the changes in urinary peptides of CRS patients and potential proteases involved in their generation, laying the basis for further validation.

Xanthohumol (XN) is a prenylated plant polyphenol that naturally occurs in hops and its products, e.g. beer. It has shown to have anti-inflammatory and angiogenesis inhibiting effects and it prevents the proliferation of cancer cells. These effects could be in particular interesting for processes within the periodontal ligament, as previous studies have shown that orthodontic tooth movement is associated with a sterile inflammatory reaction. Based on this, the study evaluates the anti-inflammatory effect of XN in cementoblasts in an in vitro model of the early phase of orthodontic tooth movement by compressive stimulation. XN shows a concentration-dependent influence on cell viability. Low concentrations between 0.2 and 0.8 µM increase viability, while high concentrations between 4 and 8 µM cause a significant decrease in viability. Compressive force induces an upregulation of pro-inflammatory gene ( Il-6, Cox2, Vegfa ) and protein (IL-6) expression. XN significantly reduces compression related IL-6 protein and gene expression. Furthermore, the expression of phosphorylated ERK and AKT under compression was upregulated while XN re-established the expression to a level similar to control. Accordingly, we demonstrated a selective anti-inflammatory effect of XN in cementoblasts. Our findings provide the base for further examination of XN in modulation of inflammation during orthodontic therapy and treatment of periodontitis.

[...]CKD has been identified as an independent risk factor for CVD [5], but therapeutic options are highly inadequate. Inflammation and fibrosis are increased in CKD patients [11,12,13], and the Chronic Renal Insufficiency Cohort (CRIC) study recently revealed that inflammation biomarkers are independently associated with atherosclerotic cardiovascular events and death in CKD patients [14]. [...]vascular calcification is highly prevalent in CKD patients, increases with declining kidney function [15] and is associated with increased risk of cardiovascular events and death in CKD [16,17,18,19]. [...]an overview of current mouse models to study cardiac remodeling in CKD is provided and potential therapeutic targets are being discussed in the context of current knowledge. [...]the concept of chronodisruption as a chronic disturbance of circadian rhythms with a negative impact on health is being discussed in the context of CKD.