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5 recordsLinked to original sources
PubMed2025

iTRAQ-based quantitative proteomics reveals reduced expression of KRT19, KRT7, and PSTDG in cutaneous specimens after kidney transplantation.

Clinical improvement in pigmentation is frequently observed after kidney transplantation. However, the underlying molecular and histological mechanisms remain unclear. We conducted a study to quantify the skin color change using a handheld reflected light colorimeter and to investigate protein expression changes in the skin before and after kidney transplantation. Paired skin biopsies were obtained from three patients who underwent kidney transplantation before and one month after transplantation. Protein expression was analyzed using iTRAQ-based quantitative proteomics. Differentially expressed proteins were identified and visualized using hierarchical clustering and volcano plots. Histopathological evaluation included hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemical (IHC) staining for keratin (KRT) 7, KRT19, and MelanA. Skin pigmentation of the arms, ankles, and abdomen had significant L-value improvement after kidney transplantation. Proteomic profiling identified 2148 proteins, with six proteins showing significant differential expression after transplantation. Among them, KRT7, KRT19, and prostaglandin D2 synthase (PTGDS) were significantly downregulated, potentially reflecting reduced epithelial stress and systemic inflammation. H&E and Masson's trichrome staining revealed a post-transplantation reduction in dermal pigmentation and collagen content. IHC showed decreased KRT7, KRT19, and MelanA expression after transplantation. Our results suggest that targeting KRT or prostaglandin pathways may offer new treatments for ESRD-related skin symptoms.

Humans↗
PubMed2026

Beyond NAD Depletion: SARM1-Induced ATP Collapse Involves Direct ATP Degradation and Mitochondrial Dysfunction and Is Pharmacologically Reversible.

Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is an inducible NAD-consuming enzyme and execution factor in axon degeneration. Rapid ATP collapse after SARM1 activation, however, is not fully explained by NAD depletion alone. We used SARM1-overexpressing HEK293 cells and the cell-permeant activator CZ-48 to examine SARM1-induced non-apoptotic cell death, termed sarmoptosis. CZ-48 induced cell death that was suppressed by HSP90/70-annotated ATP-competitive compounds, especially geldanamycin and VER-155008 (VER), without reducing SARM1 abundance. VER preserved NAD and ATP during SARM1 activation but failed to rescue FK866-mediated NAD starvation, thereby distinguishing CZ-48/SARM1-driven cytotoxicity from generic NAD depletion. In cell-free assays, purified SARM1 reduced ATP levels; this effect was enhanced by SARM1's activator NMN and attenuated by its pharmacological inhibitors, although the in vitro activity was modest and the reaction products remain to be identified. ATPase-related perturbations, including thapsigargin and bafilomycin A1, also protected cells from CZ-48-induced death, further supporting a central role for ATP collapse in sarmoptosis. iTRAQ proteomics, MitoSOX Red staining, and DiOC6(3) staining revealed that CZ-48 treatment was associated with mitochondrial and metabolic remodeling, mitochondrial ROS accumulation, and mitochondrial depolarization, all of which were mitigated by VER. Collectively, these findings support a convergent ATP-collapse model in which SARM1 activation promotes NAD depletion, directly consumes ATP, and is associated with mitochondrial dysfunction that may amplify ATP-production failure.

ATP collapse↗
PubMed2026

Integration of metabolomics and proteomics reveals the toxicological mechanisms of environmentally relevant concentrations of cadmium on juvenile rockfish (Sebastes schlegelii).

As a highly toxic heavy metal, cadmium (Cd) is widely distributed in the coastal environments of the Bohai Sea, posing significant ecological and health risks. This is of particular concern for Sebastes schlegelii, a rockfish species commonly found along the Bohai coast and consumed by local populations. In this study, juvenile S. schlegelii were randomly assigned to three groups (control, 5 and 50&#xa0;&#x3bc;g/L Cd) for a 14-day exposure period, followed by analysis of Cd bioaccumulation, as well as metabolomic and proteomic profiling. ICP-MS analysis indicated dose-dependent Cd bioaccumulation in the whole body, with 0.11&#xa0;&#xb1;&#xa0;0.07&#xa0;&#x3bc;g/g dry weight in the 5&#xa0;&#x3bc;g/L group and 0.38&#xa0;&#xb1;&#xa0;0.09&#xa0;&#x3bc;g/g dry weight in the 50&#xa0;&#x3bc;g/L group (9.5-fold higher than the control, p&#xa0;<&#xa0;0.05). An iTRAQ-based proteomic analysis determined 168 differentially expressed proteins, while 1H NMR-based metabolomic profiling identified 34 metabolites with significant alterations. Integrated analysis of the proteomic and metabolomic data provided insights into the molecular responses of juvenile rockfish to Cd exposure. Specifically, metabolomic results indicated significant alterations in key metabolites, including lactate, phosphocholine, adenosine triphosphate, alanine, and inosine in the Cd-treated groups. Proteomic analysis further suggested that Cd exposure was associated with immune and oxidative stress responses, neurotoxicity, cellular damage, and disruptions in critical metabolic pathways, such as glycolysis, the tricarboxylic acid cycle, amino acid and lipid metabolism. Overall, this study demonstrates the utility of integrating proteomics and metabolomics to characterize molecular responses to Cd stress in juvenile S. schlegelii.

Animals↗
PubMed2013

The identification of novel potential injury mechanisms and candidate biomarkers in renal allograft rejection by quantitative proteomics.

Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p < 0.05) with a significant finding that SUMO2 (small ubiquitin-related modifier 2) was identified as a "hub" protein for graft injury irrespective of causation. Sixty-nine urine proteins had differences in abundance (p < 0.01) in AR compared with stable graft, of which 12 proteins were up-regulated in AR with a mean fold increase of 2.8. Nine urine proteins were highly specific for AR because of their significant differences (p < 0.01; fold increase >1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of monitoring these urinary proteins for the specific and sensitive noninvasive diagnosis of acute renal allograft rejection.

Acute Kidney Injury↗
PubMed2025

N-glycan remodeling by &#x3b1;-D-mannosidase and &#x3b2;-D-N-acetylhexosaminidase regulates fruit softening, redox balance, and post-harvest pathogen resistance.

Post-harvest loss of fruits and vegetables poses significant challenges to food security and economic sustainability, primarily due to ripening-associated excessive softening that shortens shelf life and increases susceptibility to pathogens. N-glycans, N-glycoproteins, and their processing enzymes are integral to various plant processes, including fruit ripening. Among these, &#x3b1;-D-mannosidase (&#x3b1;-Man) and &#x3b2;-D-N-acetylhexosaminidase (&#x3b2;-Hex) are key ripening-specific enzymes that modulate fruit softening. Previously, we have shown that RNAi-mediated suppression of &#x3b1;-Man or &#x3b2;-Hex improves fruit shelf life and firmness in both climacteric and non-climacteric fruits. However, the underlying molecular and biochemical basis of fruit softening regulation by &#x3b1;-Man and &#x3b2;-Hex was not well understood. In this study, we developed transgenic tomato (Solanum lycopersicum) plants by silencing &#x3b1;-Man and &#x3b2;-Hex simultaneously using RNAi. Suppression of these enzymes reduces N-glycoprotein degradation, downregulates pectin dissolution, and inhibits ripening-related gene expression. RNAi fruits exhibited enhanced shelf life, greater firmness, reduced reactive oxygen species (ROS) accumulation and increased resistance against post-harvest pathogens without affecting plant growth, fruit development, yield, or nutritional quality. To further explore the molecular mechanism of &#x3b1;-Man and &#x3b2;-Hex function, we purified and quantified N-glycans in RNAi fruits and other ripening-impaired mutants, identifying key N-glycan species. We also carried out iTRAQ-based quantitative proteome profiling to investigate the abundance of proteins in ripened fruit affected by silencing of &#x3b1;-Man and &#x3b2;-Hex. Molecular insights revealed that N-glycan processing and degradation are key events during ripening, influencing cell wall softening, fruit redox state, and post-harvest quality attributes. This study highlights the potential of co-silencing &#x3b1;-Man and &#x3b2;-Hex as a novel approach to extending the shelf life of fruits, regardless of their climacteric behavior, without compromising quality or yield.

Fruit↗