Salivary gland epithelial cell in Sjögren's syndrome: Metabolic shift and altered mitochondrial morphology toward an innate immune cell function.

Salivary gland epithelial cells (SGEC) are the main targets of the autoimmune reactivity in Sjögren's syndrome (SS). This study aimed to investigate the core proteomic differences between SS and Control- (Ct) -derived SGEC. Proteome analysis of cultured SGEC from five SS patients and four Ct was performed in a label-free quantitation format (LFQ). Electron microscopy was applied for analysis of the mitochondrial ultrastructure of SGEC in minor salivary gland sections from six SS patients and four Ct. Four hundred seventy-four proteins were identified differentially abundant in SS- compared to Ct-SGEC. After proteomic analysis, two distinct protein expression patterns were revealed. Gene ontology (GO) pathway analysis of each protein block revealed that the cluster with highly abundant proteins in SS-SGEC showed enrichment in pathways associated with membrane trafficking, exosome-mediated transport and exocytosis as well as innate immunity related mainly to neutrophil degranulation. In contrast, the low abundance protein cluster in SS-SGEC was enriched for proteins regulating the translational process of proteins related to metabolic pathways associated to mitochondria. Electron microscopy showed decreased total number of mitochondria in SS-SGEC, which appeared elongated and swollen with less and abnormal cristae compared to Ct-SGEC mitochondria. This study defines, for the first time, the core proteomic differences of SGEC between SS and Ct, substantiates the metamorphosis of SGEC into an innate immune cell and reveals that these cells are translationally shifted towards metabolism rewiring. These metabolic alterations are related mainly to mitochondria and are mirrored in situ with heavy morphological changes.

The relation of diet with PAF and its metabolic enzymes in healthy volunteers.

PURPOSE: Platelet-activating factor (PAF), a potent inflammatory mediator, is implicated in atherosclerosis. Its key biosynthetic enzymes are lyso-PAF acetyltransferases (lyso-PAF-AT), responsible for PAF synthesis through the remodeling route and a specific CDP-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT), responsible for its de novo biosynthesis. PAF acetylhydrolase (PAF-AH) and its extracellular isoform lipoprotein-associated phospholipase A2 catabolize PAF. The impact of diet on PAF metabolism is ill-defined. The aim was to investigate associations between PAF, its enzymes and dietary factors. METHODS: One-hundred and six (n = 106) healthy volunteers were recruited. Food-frequency questionnaires, dietary recalls, lifestyle and biochemical variables were collected. Food groups, macronutrient intake, a priori (MedDietScore) and a posteriori defined food patterns with PCA analysis, dietary antioxidant capacity (DAC), glycemic index (GI) and glycemic load were assessed. RESULTS: PAF was inversely correlated with antioxidant-rich foods (herbal drinks and coffee), the DAC as well as a dietary pattern characterized by legumes, vegetables, poultry and fish (all Ps < 0.05). PAF was positively correlated to % fat intake. Lyso-PAF-AT was also negatively associated with healthy patterns (fruits, nuts and herbal drinks, and a pattern rich in olive oil and whole-wheat products), as well as the DAC and % monounsaturated fatty acids. PAF-CPT was negatively associated with GI and coffee intake and positively with dietary cholesterol. PAF-AH was negatively associated with coffee and positively associated with alcohol consumption (all Ps < 0.05). CONCLUSIONS: In conclusion, the DAC and healthy dietary patterns were inversely associated with PAF or its biosynthetic enzymes, suggesting potential new mechanisms of the diet-disease associations.

Plasma free amino acid profiles and nutrition proteins in chronic renal failure; effect of dialysis treatment.

A well preserved nutritional status is beneficial in chronically uremic patients for slowing the pace of deterioration of renal function, and delaying the need for dialysis therapy. The purpose of this study was to assess the nutritional profile of 10 patients in a steady state of advanced CRF, and of 15 patients with terminal renal failure immediately prior to their first hemodialysis session (J0), and 7, 14, 45, 60, days post start of dialysis. Patients were 18 to 65 years old with total plasma proteins ≥ 60g/1. Plasma concentrations of amino acids, nutrition proteins, apolipoproteins A1, and B were evaluated. Non inflammatory reaction was evaluated by determination of alpha-1-acid glycoprotein, and C reactive protein. The data (mean ± 1 SD) were compared with mean values of 15 healthy individuals.

Induction of tumour necrosis factor-alpha during haemodialysis. Influence of the membrane type.

Some of the secondary clinical effects induced by long-term haemodialysis in patients with end-stage renal failure have been related to an increased production of interleukin-1 (IL-1). We investigated the role of another cytokine which shares a number of biological properties with IL-1, tumour necrosis factor-alpha (TNF-alpha). In long-term haemodialysed patients, we found at the beginning of the dialysis increased plasma TNF-alpha levels and enhanced monocyte capacity to produce TNF-alpha spontaneously ex vivo. Non-haemodialysed uraemic patients also presented increased plasma TNF-alpha levels. During dialysis with cellulose acetate (CA) or polysulphone (PS) membranes, plasma TNF-alpha levels and the spontaneous and lipopolysaccharide-induced production of TNF-alpha by monocytes remained at predialysis levels. In contrast, when cuprophane membranes were used, there was a significant increase in plasma TNF-alpha levels and in both spontaneous (10-fold) and lipopolysaccharide-induced (seven-fold) ex vivo TNF-alpha production by monocytes. These results suggest that monocytes are stimulated during haemodialysis with the poorly biocompatible cuprophane membrane.

Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure.

Pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, were assessed in 10 chronic uremic patients treated by maintenance hemodialysis in comparison with 10 normal subjects. All subjects ingested a single dose of 1 g of pyrazinamide, the patients receiving the drug immediately after the end of a dialysis session. Bioavailability of pyrazinamide was only slightly increased in patients, its dialysis extraction coefficient being 55.3%. In contrast, pyrazinoic acid has an elimination rate-dependent metabolism with a bioavailability markedly increased in patients and a dialysis extraction coefficient of 59.8%. These data may lead to recommendations of a reduction in the dosage of pyrazinamide in dialysis patients. However, administering the usual dosage of the drug at the end of each dialysis session seems preferable to the daily administration of a reduced dosage.

Changes in erythromycin pharmacokinetics induced by renal failure.

As erythromycin ototoxicity appears to be favored by renal insufficiency, its pharmacokinetics were assessed in chronic uremic patients treated by maintenance hemodialysis in comparison with normal subjects. Two groups of 8 patients each were studied, the first one on an interdialytic day, the second immediately after the end of an hemodialysis session. All subjects ingested a single dose of 1 gram of erythromycin ethylsuccinate. Times of peak serum concentration and biological half-lifes were similar in patients and in controls. Maximum serum concentrations and areas under the serum concentration time-curve were higher in patients than in controls whereas apparent oral clearances were lower in the former. The differences between the two groups of patients were not significant. These pharmacokinetic changes are suggestive of an enhanced bioavailability of erythromycin in chronic renal failure which might predispose uremics to the ototoxicity of the drug.

Penetration of albendazole sulphoxide into hydatid cysts.

The penetration of albendazole sulphoxide, the principal metabolite of albendazole into hydatid cysts (E granulosus) was measured by means of in vitro animal and clinical studies. The drug freely diffuses across the parasitic membranes. Cyst/serum concentrations of 22% were achieved in patients, longer pre-operative therapy produced higher concentrations.