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

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

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

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 [...

A cheap and effective method for virtual ergonomic analysis and comfort driven redesign: An application to lunch-boxes' distribution station at university of salerno

The application of ergonomic principles to the design of processes, workplace and organization, is not only a way to respond to legal requirements, but also an indispensable premise for any company that wants to pursue a business logic. This paper shows a cheap and effective method to acquire workplaces, work-cycles and workers-postures, in a work-environment, in order to analyze how workers move themselves into the work environment around the workstations, with their own tools and devices, and do their jobs. The aim of the analysis is to determine the best way to plan the movement of the workers and their work-cycle in order to optimize the productivity and to obtain the best ergonomic rating for the workers. For those purposes, authors used Virtual Prototyping techniques and OCRA Analysis for making the biomechanical risk assessment; time acquisition and video acquisition has been made to analyze the work cycle. DELMIA® software was used to model the workstation and for modelling activities and postures associated with various repetitive actions; pictures taken by cameras have been processed through the KINOVEA® software and simulations have been made for the own worker percentile. If needed, an ergonomic/comfort driven redesign of the work-environment has been suggested in order to optimize the work cycle in terms of risk minimization. The application has been made on the lunch-boxes’ distribution station’s workers at University of Salerno (Italy)

Influence of Bisphenol A on Type 2 Diabetes Mellitus

Bisphenol A (BPA) is an organic synthetic compound employed to produce plastics and epoxy resins. It is used as a structural component in polycarbonate beverage bottles and as coating for metal surface in food containers and packaging. The adverse effects of BPA on human health are widely disputed. BPA has been recently associated with a wide variety of medical disorders and, in particular, it was identified as potential endocrine-disrupting compound with diabetogenic action. Most of the clinical observational studies in humans reveal a positive link between BPA exposure, evaluated by the measurement of urinary BPA levels, and the risk of developing type 2 diabetes mellitus. Clinical studies on humans and preclinical studies on in vivo, ex vivo, and in vitro models indicate that BPA, mostly at low doses, may have a role in increasing type 2 diabetes mellitus developmental risk, directly acting on pancreatic cells, in which BPA induces the impairment of insulin and glucagon secretion, triggers inhibition of cell growth and apoptosis, and acts on muscle, hepatic, and adipose cell function, triggering an insulin-resistant state. The current review summarizes the available evidences regarding the association between BPA and type 2 diabetes mellitus, focusing on both clinical and preclinical studies

Reduced bone mineral density in glycogen storage disease type III: Evidence for a possible connection between metabolic imbalance and bone homeostasis

Introduction: Glycogen storage disease type III (GSDIII) is an inborn error of carbohydrate metabolism caused by deficient activity of glycogen debranching enzyme (GDE). It is characterized by liver, cardiac muscle and skeletal muscle involvement. The presence of systemic complications such as growth retardation, ovarian polycystosis, diabetes mellitus and osteopenia/osteoporosis has been reported. The pathogenesis of osteopenia/osteoporosis is still unclear. Objectives: The aim of the current study was to evaluate the bone mineral density (BMD) in GSDIII patients and the role of metabolic and endocrine factors and physical activity on bone status. Methods: Nine GSDIII patients were enrolled (age 2-20years) and compared to eighteen age and sex matched controls. BMD was evaluated by Dual-emission-X-ray absorptiometry (DXA) and Quantitative ultrasound (QUS). Clinical and biochemical parameters of endocrine system function and bone metabolism were analyzed. Serum levels of the metabolic control markers were evaluated. Physical activity was evaluated by administering the International Physical Activity Questionnaire (IPAQ). Results: GSDIII patients showed reduced BMD detected at both DXA and QUS, decreased serum levels of IGF-1, free IGF-1, insulin, calcitonin, osteocalcin (OC) and increased serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX). IGF-1 serum levels inversely correlated with AST and ALT serum levels. DXA Z-score inversely correlated with cholesterol and triglycerides serum levels and directly correlated with IGF-1/IGFBP3 molar ratio. No difference in physical activity was observed between GSDIII patients and controls. Discussion: Our data confirm the presence of reduced BMD in GSDIII. On the basis of the results, we hypothesized that metabolic imbalance could be the key factor leading to osteopenia, acting through different mechanisms: chronic hyperlipidemia, reduced IGF-1, Insulin and OC serum levels. Thus, the mechanism of osteopenia/osteoporosis in GSDIII is probably multifactorial and we speculate on the factors involved in its pathogenesis

The environment and male reproductive system: the potential role and underlying mechanisms of cadmium in testis cancer

: Cadmium is a known human carcinogen, and has been shown to profoundly affect male reproductive function, at multiple levels, by exerting both endocrine and non-endocrine actions. Nevertheless, the potential role of cadmium in the etiology of testis cancer has been scantly investigated in humans, and, currently, available epidemiological observational studies are insufficient to draw definitive conclusions in this regard. On the contrary, experimental studies in laboratory animals demonstrated that cadmium is a strong inducer of testis tumors, mostly represented by benign Leydig cell adenoma; moreover, malignant transformation was also reported in few animals, following cadmium treatment. Early experimental studies in animals proposed an endocrine-dependent mechanism of cadmium-induced testis tumorigenesis; however, more recent findings from cell-free assays, in vitro studies, and short-term in vivo studies, highlighted that cadmium might also contribute to testis tumor development by early occurring endocrine-independent mechanisms, which include aberrant gene expression within the testis, and genotoxic effects, and take place well before the timing of testis tumorigenesis. These endocrine-independent mechanisms, however, have not been directly investigated on testis tumor samples retrieved from affected, cadmium-treated animals so far. The present review focuses on the relationship between cadmium exposure and testis cancer, by reporting the few epidemiological observational human studies available, and by providing animal-based experimental evidences of cadmium implication in the pathogenesis and progression of testis tumor. Moreover, the relevance of experimental animal studies to human cadmium exposure and the translational potential of experimental findings will be extensively discussed, by critically addressing strengths and weaknesses of available data

Neuropsychiatric disorders in Cushing's syndrome

Endogenous Cushing's syndrome (CS), a rare endocrine disorder characterized by cortisol hypersecretion, is associated with psychiatric and neurocognitive disorders. Major depression, mania, anxiety, and neurocognitive impairment are the most important clinical abnormalities. Moreover, patients most often complain of impairment in quality of life, interference with family life, social, and work performance. Surprisingly, after hypercortisolism resolution, despite the improvement of the overall prevalence of psychiatric and neurocognitive disorders, the brain volume loss at least partially persists and it should be noted that some patients may still display depression, anxiety, panic disorders, and neurocognitive impairment. This brief review aimed at describing the prevalence of psychiatric and neurocognitive disorders and their characterization both during the active and remission phases of CS. The last section of this review is dedicated to quality of life, impaired during active CS and only partially resolved after resolution of hypercortisolism

Vitamin D Reverts the Exosome-Mediated Transfer of Cancer Resistance to the mTOR Inhibitor Everolimus in Hepatocellular Carcinoma

: Several multi-kinase inhibitors were widely tested as potential first-line or second-line therapy in patients with advanced hepatocellular carcinoma (HCC). However, acquired drug resistance limits their clinical efficacy. Exosomes are microvesicles secreted by tumor and stromal cells that participate in many biological processes, including drug resistance. The current study evaluated the capability of exosomes derived from everolimus (EVE)-resistant HCC cells in inducing drug resistance in parental human HCC cells and the effect of 1,25(OH)2Vitamin D (VitD) treatment in restoring EVE sensitivity. The internalization of exosomes from EVE-resistant (EveR) cells into parental cells conferred the transmission of aggressive phenotype by promoting the transition of epithelial-to-mesenchymal phenotype, as demonstrated by immunofluorescence, and the acquisition of EVE resistance, as demonstrated by cell proliferation and colony formation assays. Moreover, the internalization of exosomes from EveR into parental cells induced deregulation of the mTOR pathway mainly by triggering the activation of the serine/threonine protein kinase Akt, involved in the cellular survival pathway, as demonstrated by Western blot analysis. Interestingly, the treatment with VitD prevented exosome-induced EVE resistance in HCC cells, significantly inhibiting cell proliferation but also partially reducing colony and size number when combined with EVE compared with control. In conclusion, the results of the current study demonstrated that exosomes derived from EveR cells could induce EVE resistance in EVE-sensitive HCC cells and that VitD can revert the exosome-induced EVE resistance by resensitizing to EVE treatment