Growth hormone nadir during oral glucose load depends on waist circumference, gender and age: normative data in 231 healthy subjects.

Objective  (i) To analyse the predictors of GH suppression after standard glucose load (oGTT) in the healthy population and (ii) to establish the 97th percentile of GH nadir post-oGTT according to these variables. Design  Analytical, retrospective. Measurements  GH nadir after oGTT. Subjects  Two hundred and thirty-one healthy subjects (113 women, 118 men 15-80 years) were studied. Results  The GH nadir after glucose load ranged from 0·01 (<assay detection limit) to 0·65 μg/l was higher in women and was inversely correlated with age, BMI, waist circumference, waist/hip, total cholesterol, triglycerides, basal and maximal glucose and basal insulin levels and directly correlated with basal GH levels, IGF-I SDS and HDL-cholesterol (P values ranging 0·004-<0·0001). On multistep regression analysis, the best predictors of nadir GH levels were waist circumference (t = -9·64, P < 0·0001), gender (t = -3·86, P = 0·0001) and age (t = -3·63, P = 0·0003). The results of comparative analysis among subjects grouped according to these variable showed different results in GH nadir in premenopausal women with waist circumference ≤88 cm (97th percentile 0·65 μg/l), in premenopausal women with waist circumference ≤88 cm and in men of any age with waist circumference ≤102 cm (97th percentile 0·33 μg/l) and in subjects of either gender and any age with waist circumference >88 cm in women and 102 cm in men (97th percentile 0·16 μg/l). Conclusions  The results of this study show that GH nadir after oGTT should be analysed according to gender, menopausal status and waist circumference. The GH cut-off should be limited to the assay used

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC

Sex disparities in COVID-19 severity and outcome : are men weaker or women stronger?

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health issue which has profound effects on most aspects of societal well-being, including physical and mental health. A plethora of studies globally have suggested the existence of a sex disparity in the severity and outcome of COVID-19 patients, mainly due to mechanisms of virus infection, immune response to the virus, development of systemic inflammation, and consequent systemic complications, particularly thromboembolism. Epidemiological data report a sex difference in the severity of COVID-19, with a more favorable course of the disease in women compared to men regardless of age, although the rate of SARS-CoV-2 infection seems to be similar in both sexes. Sex hormones, including androgens and estrogens, may not only impact virus entry and load, but also shape the clinical manifestations, complications, and ultimately the outcome of the disease. The current review comprehensively summarizes the current literature on sex disparities in susceptibility and outcome of COVID-19 as well as the literature underpinning the pathophysiological and molecular mechanisms, which may provide a rationale to a sex disparity. These mechanisms include sex hormone influence on factors that facilitate virus entry and priming, immune and inflammatory response, as well as coagulation and thrombosis diathesis. Based on present evidence, women appear to be relatively protected from COVID-19 because of a more effective immune response and a less pronounced systemic inflammation, with consequent moderate clinical manifestations of the disease, together with a lesser predisposition to thromboembolism. Conversely, men appear to be particularly susceptible to COVID-19 because of a less effective immune response with consequent severe clinical manifestations of the disease, together with a greater predisposition to thromboembolism. In the elderly, generally characterized by the phenomenon of inflammaging, sex disparities in overall mortality following SARS-CoV-2 infection are even more palpable as elderly men appear to be more prone to severe COVID-19 because of a greater predisposition to infections, a weaker immune defense, and an enhanced thrombotic state compared to women. The information revealed from the review highlights potential novel therapeutic approaches employing the administration of hormonal or antihormonal therapy in combination with antiviral drugs in COVID-19 patients.https://www.karger.com/Journal/Home/223855hj2022Immunolog

Polycystic Ovary Syndrome and Hepatic Steatosis: Could Low-Grade Chronic Inflammation Be Mediated by the Spleen?:

Polycystic Ovary Syndrome (PCOS) is characterized by an extreme variety of phenotypes and controversial metabolic implications. Hepatic Steatosis (HS) and low-grade chronic inflammation (LGCI) might be common findings in PCOS. We conducted a cross-sectional study to evaluate the LGCI and HS in young women with PCOS according to their Body Mass index (BMI), Insulin Resistance (IR), and PCOS phenotypes. Sixty young premenopausal PCOS women and 20 age-matched controls participated. Primary outcome measures were the presence/severity of HS; LGCI index evaluated as spleen longitudinal diameter (SLD) by UltraSound, C-Reactive Protein (CRP) and Interleukin (IL)-6 levels; BMI and the Homeostasis Model Assessment (HoMA) of IR. The second outcome measures were testosterone, Sex Hormone-Binding Globulin (SHBG) levels, and Free Androgen Index (FAI). The presence of HS and LGCI was not significantly different between NW and O/O patients, while there were significant differences particularly when the PCOS-women were grouped according to IR or to PCOS phenotypes. At multiple regression adjusted for BMI, HoMA-IR and the spleen size were the major determinants of the severity of HS (β= 0.36, p=0.007, and β= 0.28, p=0.034, respectively). At multiple regression SLD represented the unique predictor of FAI (β=0.32; p=0.018). In young women with PCOS, HS was detected independently from obesity and was well predicted not only by IR but also by spleen size, with variable expression of the liver-spleen axis across the different PCOS subtypes. A possible role of the spleen in determining LGCI also in women with PCOS is emphasized

Serum 25-Hydroxyvitamin D Levels, phosphoprotein enriched in diabetes gene product (PED/PEA-15) and leptin-to-adiponectin ratio in women with PCOS

<p>Abstract</p> <p>Background</p> <p>Polycystic ovary syndrome (PCOS) is frequently associated with hypovitaminosis D. Vitamin D is endowed with pleiotropic effects, including insulin resistance (IR) and apoptotic pathway. Disruption of the complex mechanism that regulated ovarian apoptosis has been reported in PCOS. Phosphoprotein enriched in diabetes gene product (PED/PEA-15), an anti-apoptotic protein involved in type 2 diabetes mellitus (T2DM), is overexpressed in PCOS women, independently of obesity. Leptin-to-adiponectin ratio (L/A) is a biomarker of IR and low-grade inflammation in PCOS. The aim of the study was to investigate the levels of 25-hydroxy vitamin D (25(OH)D), and L/A, in association with PED/PEA-15 protein abundance, in both lean and overweight/obese (o/o) women with PCOS.</p> <p>Patients and Methods</p> <p>PED/PEA-15 protein abundance and circulating levels of 25(OH)D, L/A, sex hormone-binding globulin, and testosterone were evaluated in 90 untreated PCOS patients (25 ± 4 yrs; range 18-34) and 40 healthy controls age and BMI comparable, from the same geographical area. FAI (free androgen index) and the homeostasis model assessment of insulin resistance (HoMA-IR) index were calculated.</p> <p>Results</p> <p>In o/o PCOS, 25(OH)D levels were significantly lower, and L/A values were significantly higher than in lean PCOS (p < 0.001), while there were no differences in PED/PEA-15 protein abundance. An inverse correlation was observed between 25(OH)D and BMI, PED/PEA-15 protein abundance, insulin, HoMA-IR, FAI (p < 0.001), and L/A (p < 0.05). At the multivariate analysis, in o/o PCOS L/A, insulin and 25(OH)D were the major determinant of PED/PEA-15 protein abundance (β = 0.45, β = 0.41, and β = -0.25, respectively).</p> <p>Conclusions</p> <p>Lower 25(OH)D and higher L/A were associated to PED/PEA-15 protein abundance in PCOS, suggesting their involvement in the ovarian imbalance between pro-and anti-apoptotic mechanisms, with high L/A and insulin and low 25(OH)D levels as the main determinants of PED/PEA-15 protein variability. Further studies, involving also different apoptotic pathways or inflammatory cytokines and granulosa cells are mandatory to better define the possible bidirectional relationships between 25(OH)D, PED/PEA-15 protein abundance, leptin and adiponectin in PCOS pathogenesis.</p

The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms

Role of mTOR system and its relation with somatostatin and dopamine receptors on cell proliferation, hormone secretion and intracellular signalling in hepatocellular and cholangiocellular carcinomas.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are among the most lethal of human malignancies with s a very poor prognosis, with a <3% 5-years survival rate for untreated cancer. The actual therapies are limited to a little percentage of patients they are often diagnosed in advanced stages or even in metastatic conditions. In the last years, the idea of an “omics revolution” has given the basis to a new kind of therapies cancer, a molecular approach. In this work, we have focused our attention on mTOR pathway, its inhibitors and on their antiproliferative effects evaluating not only cell lines viability decrease after treatment with them, but also the molecular mechanism at basis of this phenomenon. In addition, our research project has investigated also somatostatin and dopamine receptor expression with the purpose to identify a molecular profile of this cancer, using four different cell lines and 23 Caucasian patients. So, stimulation of these receptors with the correspondent ligands has demostrated that their best therapeutical effect is observed with use of drugs with affinity for two different receptors, probably due to heterodimerization of somatostatin receptors. These data have been confirmed by different kinds of experiments (evaluating proliferation, hormone secretion and intracellular signalling) revealing an emergent aspect of HCC, its neuroendocrine fenotype. Our future purpose is to clarify better some molecular aspects that regulate heterodimerization and to define the intracellular pathways activated by these analogues. We, also are going to evaluate the effects of a potential combination between mTOR inhibitors and somatostatin analogues underlining a possible signalling interaction

How May Obesity-Induced Oxidative Stress Affect the Outcome of COVID-19 Vaccines? Lesson Learned from the Infection

The coronavirus disease 2019 (COVID-19) outbreak, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has induced a global emergency [...

How May Obesity-Induced Oxidative Stress Affect the Outcome of {COVID}-19 Vaccines? Lesson Learned from the Infection

The coronavirus disease 2019 (COVID-19) outbreak, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has induced a global emergency [...