Potent-selective peptidomimetic inhibitors of tissue transglutaminase (TG2) were developed through a combination of protein-ligand docking and molecular dynamic techniques. Derivatives of these inhibitors were made with the aim of specific TG2 targeting to the intra- and extracellular space. A cell-permeable fluorescently labeled derivative enabled detection of in situ cellular TG2 activity in human umbilical cord endothelial cells and TG2-transduced NIH3T3 cells, which could be enhanced by treatment of cells with ionomycin. Reaction of TG2 with this fluorescent inhibitor in NIH3T3 cells resulted in loss of binding of TG2 to cell surface syndecan-4 and inhibition of translocation of the enzyme into the extracellular matrix, with a parallel reduction in fibronectin deposition. In human umbilical cord endothelial cells, this same fluorescent inhibitor also demonstrated a reduction in fibronectin deposition, cell motility, and cord formation in Matrigel. Use of the same inhibitor in a mouse model of hypertensive nephrosclerosis showed over a 40% reduction in collagen deposition.

Background: In gestational diabetes mellitus (GDM), pancreatic β-cell breakdown can result from a proinflammatory imbalance created by a sustained level of cytokines. In this study, we investigated the role of specific cytokines, such as B-cell activating factor (BAFF), tumor necrosis factor α (TNF-α), and platelet-activating factor (PAF), together with methylglyoxal (MGO) and glycated albumin (GA) in pregnant women affected by GDM. Methods: We enrolled 30 women whose inflammation and metabolic markers were measured at recruitment and after 12 weeks of strict dietetic therapy. We compared these data to the data obtained from 53 randomly selected healthy nonpregnant subjects without diabetes, hyperglycemia, or any condition that can affect glycemic metabolism. Results: In pregnant women affected by GDM, PAF levels increased from 26.3 (17.4–47.5) ng/mL to 40.1 (30.5–80.5) ng/mL (p < 0.001). Their TNF-α levels increased from 3.0 (2.8–3.5) pg/mL to 3.4 (3.1–5.8) pg/mL (p < 0.001). The levels of methylglyoxal were significantly higher in the women with GDM (p < 0.001), both at diagnosis and after 12 weeks (0.64 (0.46–0.90) μg/mL; 0.71 (0.47–0.93) μg/mL, respectively) compared to general population (0.25 (0.19–0.28) μg/mL). Levels of glycated albumin were significantly higher in women with GDM (p < 0.001) only after 12 weeks from diagnosis (1.51 (0.88–2.03) nmol/mL) compared to general population (0.95 (0.63–1.4) nmol/mL). Conclusion: These findings support the involvement of new inflammatory and metabolic biomarkers in the mechanisms related to GDM complications and prompt deeper exploration into the vicious cycle connecting inflammation, oxidative stress, and metabolic results.

Endoplasmic reticulum (ER) is the primary site for the synthesis and folding of secreted and membrane-bound proteins. Accumulation of unfolded and misfolded proteins in ER underlies a wide range of human neurodegenerative disorders. Hence, molecules regulating the ER stress response represent potential candidates as drug targets for tackling these diseases. Protein disulphide isomerase (PDI) is a chaperone involved in ER stress pathway, its activity being an important cellular defense against protein misfolding. Here, we demonstrate that human neuroblastoma SH-SY5Y cells overexpressing the reticulon protein 1-C (RTN1-C) reticulon family member show a PDI punctuate subcellular distribution identified as ER vesicles. This represents an event associated with a significant increase of PDI enzymatic activity. We provide evidence that the modulation of PDI localization and activity does not only rely upon ER stress induction or upregulation of its synthesis, but tightly correlates to an alteration in its nitrosylation status. By using different RTN1-C mutants, we demonstrate that the observed effects depend on RTN1-C N-terminal region and on the integrity of the microtubule network. Overall, our results indicate that RTN1-C induces PDI redistribution in ER vesicles, and concomitantly modulates its activity by decreasing the levels of its S-nitrosylated form. Thus RTN1-C represents a promising candidate to modulate PDI function.

Background Irritable Bowel Syndrome (IBS) is a widespread disease with variable symptoms that have an important impact on the quality of life. Despite the prevalence of IBS, its etiology and pathophysiology are still to be fully understood, but immune response is known to be involved. In this study, we investigated the variation of two specific cytokines, B-cell activating factor (BAFF) and platelet-activating factor (PAF), the levels of food-specific IgG and the symptom severity, using Irritable Bowel Syndrome—Symptom Severity Score (IBS-SSS), following a personalized and unrestricted-calorie diet. Methods We enrolled 30 subjects with diagnosis of IBS, according to Rome-IV criteria, whose inflammatory markers were measured at baseline and after 6 weeks of dietary intervention. The subjects were monitored in a general practice outpatient setting and nutritional advice was offered remotely via two telephone sessions with a nutritionist. Results BAFF and PAF values did not differ between baseline and end of study, both in compliant (C) and non-compliant (NC) subjects. IgG levels significantly decreased only in compliant subjects: 37.32 (23.24–93.67) IU/mL; 27.9 (7.56–93.96) IU/mL (p = 0.02) and in non-compliant went from 51.83 (13.17–113.1) IU/mL to 44.06 (4.96–255.4) IU/mL (p = 0.97, ns). IBS-SSS significantly decreased in both compliant subjects, from 245 (110–480) to 110 (0–140) (p < 0.0001), and non compliant subjects, from 250 (155–370) to 100 (7–220) (p < 0.0001). Comparing IBS-SSS between week 3 and week 6, only compliant subjects had a significant reduction, from 155 (50–355) to 110 (0–140) (p = 0.005), versus non-compliant, from 115 (35–315) to 100 (7–220) (p = 0.33, ns). Conclusion These findings support the rapid efficacy and suitability of a personalized dietetic intervention with outside consultation in IBS. Trial registration: ClinicalTrials.gov ID NCT04348760 Registered April 15, 2020 (retrospectively registered) https://clinicaltrials.gov/show/NCT04348760

These findings provide evidence of a possible contribution of BAFF to both maternal inflammation and arterial dysfunction associated with PE. Though no relationship was found with another disorder of placentation: normotensive FGR, this condition is not thought to be associated with maternal inflammation.