B-cell-activating factor (BAFF) and platelet-activating factor (PAF) in pregnancies complicated by maternal obesity and diabetes: a preliminary study.

OBJECTIVE: In pregnancies complicated by maternal obesity and diabetes, a disruption in inflammatory mediators occurs, resulting in endothelial microvascular dysfunction, oxidative stress, tissue damage, and maternal and feto-neonatal complications. To outline this proinflammatory status, an innovative approach is represented by the measurement of proinflammatory cytokines. Among these biomarkers, B-cell-activating factor (BAFF) and platelet-activating factor (PAF) play a key role in metabolic regulation, immune response to infections, tissue homeostasis, and "food-related inflammation." The aim of the present study is to investigate the blood expression of BAFF and PAF in a cohort of pregnant women affected by obesity and diabetes compared with a control group of healthy pregnant women. METHODS: A prospective longitudinal cohort study has been conducted on pregnant women referred to Fondazione Policlinico Universitario Gemelli IRCCS in Rome. For each pregnant woman, a capillary sample was collected with a swab in three different consecutive evaluations carried out in the three trimesters of pregnancy. RESULTS: A total of 77 pregnant women have been enrolled. No significant differences in BAFF and PAF levels were longitudinally observed between groups. Focusing on the exposed group, in the third trimester of pregnancy, both PAF and BAFF levels were lower than the basal time. Among the selected group of patients who developed Gestational Diabetes, only PAF values were longitudinally lower when compared to other groups. The multivariate analysis showed that BAFF levels were positively correlated with thyroid-stimulating hormone levels. No macrosomia, no shoulder dystocia, no major perineal lacerations at birth, and no intrauterine growth restriction were observed in the whole population. CONCLUSIONS: This study supports the involvement of metabolic and proinflammatory biomarkers in the mechanisms related to pregnancy complications. Improving a good metabolic environment for obese and diabetic pregnant women could break the vicious cycle connecting inflammation, oxidative stress, and metabolic disorders.

Glycation-Driven Inflammation: COVID-19 Severity in Pregnant Women and Perinatal Outcomes.

The link between being pregnant and overweight or obese and the infectivity and virulence of the SARS CoV-2 virus is likely to be caused by SARS-CoV-2 spike protein glycosylation, which may work as a glycan shield. Methylglyoxal (MGO), an important advanced glycation end-product (AGE), and glycated albumin (GA) are the results of poor subclinical glucose metabolism and are indices of oxidative stress. Forty-one consecutive cases of SARS-CoV-2-positive pregnant patients comprising 25% pre-pregnancy overweight women and 25% obese women were recruited. The aim of our study was to compare the blood levels of MGO and GA in pregnant women with asymptomatic and symptomatic SARS-CoV-2 infection with pregnant women without SARS-CoV-2 infection with low risk and uneventful pregnancies and to evaluate the relative perinatal outcomes. The MGO and GA values of the SARS-CoV-2 cases were statistically significantly higher than those of the negative control subjects. In addition, the SARS-CoV-2-positive pregnant patients who suffered of moderate to severe COVID-19 syndrome had higher values of GA than those infected and presenting with mild symptoms or those with asymptomatic infection. Premature delivery and infants of a small size for their gestational age were overrepresented in this cohort, even in mild-asymptomatic patients for whom delivery was not indicated by the COVID-19 syndrome. Moreover, ethnic minorities were overrepresented among the severe cases. The AGE-RAGE oxidative stress axis on the placenta and multiple organs caused by MGO and GA levels, associated with the biological mechanisms of the glycation of the SARS-CoV-2 spike protein, could help to explain the infectivity and virulence of this virus in pregnant patients affected by being overweight or obese or having gestational diabetes, and the increased risk of premature delivery and/or low newborn weight.

Food-specific serum IgG and symptom reduction with a personalized, unrestricted-calorie diet of six weeks in Irritable Bowel Syndrome (IBS).

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.

A New Pathway Promotes Adaptation of Human Glioblastoma Cells to Glucose Starvation.

Adaptation of glioblastoma to caloric restriction induces compensatory changes in tumor metabolism that are incompletely known. Here we show that in human glioblastoma cells maintained in exhausted medium, SHC adaptor protein 3 (SHC3) increases due to down-regulation of SHC3 protein degradation. This effect is reversed by glucose addition and is not present in normal astrocytes. Increased SHC3 levels are associated to increased glucose uptake mediated by changes in membrane trafficking of glucose transporters of the solute carrier 2A superfamily (GLUT/SLC2A). We found that the effects on vesicle trafficking are mediated by SHC3 interactions with adaptor protein complex 1 and 2 (AP), BMP-2-inducible protein kinase and a fraction of poly ADP-ribose polymerase 1 (PARP1) associated to vesicles containing GLUT/SLC2As. In glioblastoma cells, PARP1 inhibitor veliparib mimics glucose starvation in enhancing glucose uptake. Furthermore, cytosol extracted from glioblastoma cells inhibits PARP1 enzymatic activity in vitro while immunodepletion of SHC3 from the cytosol significantly relieves this inhibition. The identification of a new pathway controlling glucose uptake in high grade gliomas represents an opportunity for repositioning existing drugs and designing new ones.

Methylglyoxal, Glycated Albumin, PAF, and TNF-α: Possible Inflammatory and Metabolic Biomarkers for Management of Gestational Diabetes.

BACKGROUND: In gestational diabetes mellitus (GDM), pancreatic ß-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.

Serum- and Glucocorticoid-Inducible Kinase 1 Delay the Onset of Endothelial Senescence by Directly Interacting with Human Telomerase Reverse Transcriptase.

Endothelial senescence is characteristic of vascular aging. Serum- and glucocorticoid-inducible kinase (SGK)1 belongs to a family of serine/threonine kinases regulated by various external stimuli. SGK1 has been shown to be protective against reactive oxygen species (ROS) production and to be involved in processes regulating aging. However, data on the direct relationship between SGK1 and senescence are sparse. In the present study, we sought to investigate the role of SGK1 in cellular aging by using human umbilical vein endothelial cells (HUVECs) infected with different constructs. Senescence was measured at different cellular stages by senescence-associated ß-galactosidase (SA-ß-gal) activity, human telomerase reverse transcriptase (hTERT) activity, p21 protein levels, and ROS production. HUVECs over-expressing full-length SGK1 (wild-type SGK1 [SGK1WT]) showed a decrease in SA-ß-gal and p21 expression and a corresponding increase in hTERT activity in the early stages of aging. Moreover, SGK1WT presented lower levels of ROS production. A direct interaction between SGK1WT and hTERT was also shown by co-immunoprecipitation. The SGK1Δ60 isoform, lacking the amino-terminal 60 amino acids, did not show interaction with hTERT, suggesting a pivotal role of this protein site for the SGK1 anti-aging function. The results from this study may be of particular importance, because SGK1WT over-expression by activating telomerase and reducing ROS levels may delay the processes of endothelial senescence.

Serum glucocorticoid inducible kinase (SGK)-1 protects endothelial cells against oxidative stress and apoptosis induced by hyperglycaemia.

Diabetic hyperglycaemia causes endothelial dysfunction mainly by impairing endothelial nitric oxide (NO) production. Moreover, hyperglycaemia activates several noxious cellular pathways including apoptosis, increase in reactive oxygen species (ROS) levels and diminishing Na(+)-K(+) ATPase activity which exacerbate vascular damage. Serum glucocorticoid kinase (SGK)-1, a member of the serine/threonine kinases, plays a pivotal role in regulating NO production through inducible NO synthase activation and other cellular mechanisms. Therefore, in this study, we aimed to investigate the protective role of SGK-1 against hyperglycaemia in human umbilical endothelial cells (HUVECs). We used retrovirus to infect HUVECs with either SGK-1, SGK-1Δ60 (lacking of the N-60 amino acids-increase SGK-1 activity) or SGK-1Δ60KD (kinase-dead constructs). We tested our hypothesis in vitro after high glucose and glucosamine incubation. Increase in SGK-1 expression and activity (SGK-1Δ60) resulted in higher production of NO, inhibition of ROS synthesis and lower apoptosis in endothelial cell after either hyperglycaemia or glucosamine treatments. Moreover, in this study, we showed increased GLUT-1 membrane translocation and Na(+)-K(+) ATPase activity in cell infected with SGK-1Δ60 construct. These results suggest that as in endothelial cells, an increased SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated NO production after different noxae stimuli. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against diabetic vascular disease.