Publications by authors named "Francesco Potì"

43 Publications

HDL and reverse cholesterol transport in humans and animals: Lessons from pre-clinical models and clinical studies.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Oct 9;1867(1):159065. Epub 2021 Oct 9.

Division of Translational Medicine & Human Genetics, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA 19104, USA.

The ability to accept cholesterol from cells and to promote reverse cholesterol transport (RCT) represents the best characterized antiatherogenic function of HDL. Studies carried out in animal models have unraveled the multiple mechanisms by which these lipoproteins drive cholesterol efflux from macrophages and cholesterol uptake to the liver. Moreover, the influence of HDL composition and the role of lipid transporters have been clarified by using suitable transgenic models or through experimental design employing pharmacological or nutritional interventions. Cholesterol efflux capacity (CEC), an in vitro assay developed to offer a measure of the first step of RCT, has been shown to associate with cardiovascular risk in several human cohorts, supporting the atheroprotective role of RCT in humans as well. However, negative data in other cohorts have raised concerns on the validity of this biomarker. In this review we will present the most relevant data documenting the role of HDL in RCT, as assessed in classical or innovative methodological approaches.
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http://dx.doi.org/10.1016/j.bbalip.2021.159065DOI Listing
October 2021

Impact of Dietary Lipids on the Reverse Cholesterol Transport: What We Learned from Animal Studies.

Nutrients 2021 Jul 30;13(8). Epub 2021 Jul 30.

Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.

Reverse cholesterol transport (RCT) is a physiological mechanism protecting cells from an excessive accumulation of cholesterol. When this process begins in vascular macrophages, it acquires antiatherogenic properties, as has been widely demonstrated in animal models. Dietary lipids, despite representing a fundamental source of energy and exerting multiple biological functions, may induce detrimental effects on cardiovascular health. In the present review we summarize the current knowledge on the mechanisms of action of the most relevant classes of dietary lipids, such as fatty acids, sterols and liposoluble vitamins, with effects on different steps of RCT. We also provide a critical analysis of data obtained from experimental models which can serve as a valuable tool to clarify the effects of dietary lipids on cardiovascular disease.
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http://dx.doi.org/10.3390/nu13082643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401548PMC
July 2021

COVID-19 … What are drugs and strategies now?

Acta Biomed 2021 05 12;92(2):e2021096. Epub 2021 May 12.

Anesthesiology, Critical Care and Pain Medicine Division, Department of Medicine and Surgery, University of Parma, Viale Gramsci 14, 43126 Parma, Italy.

From February 2019 the World faces the Covid19 pandemic. The data in our possession are still insufficient to effectively combat this pathology. The gold standard for diagnosis remains molecular testing, while clinical and instrumental and serological diagnostics are highly nonspecific leading to a slowdown in the battle against covid19.[3] Can Artificial Intelligence (AI) and Machine Learning (ML) help us? The use of large databases to cross-reference data to stratify the diagnostic scores, to quickly differentiate a critical Covid-19 patient from a non-critical one is the challenge of the future. All to achieve better management of resources in the field and a more effective therapeutic approach.[2].
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http://dx.doi.org/10.23750/abm.v92i2.11165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182577PMC
May 2021

The "Hitchhiker's Guide to the Galaxy" of Endothelial Dysfunction Markers in Human Fertility.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 42121 Modena, Italy.

Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and represents the first step in the pathogenesis of cardiovascular diseases. The evaluation of endothelial health is fundamental in clinical practice and several direct and indirect markers have been suggested so far to identify any alterations in endothelial homeostasis. Alongside the known endothelial role on vascular health, several pieces of evidence have demonstrated that proper endothelial functioning plays a key role in human fertility and reproduction. Therefore, this state-of-the-art review updates the endothelial health markers discriminating between those available for clinical practice or for research purposes and their application in human fertility. Moreover, new molecules potentially helpful to clarify the link between endothelial and reproductive health are evaluated herein.
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http://dx.doi.org/10.3390/ijms22052584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961823PMC
March 2021

Identification of Sclerostin as a Putative New Myokine Involved in the Muscle-to-Bone Crosstalk.

Biomedicines 2021 Jan 12;9(1). Epub 2021 Jan 12.

Department of Biomedical, Metabolic and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, 41124 Modena, Italy.

Bone and muscle have been recognized as endocrine organs since they produce and secrete "hormone-like factors" that can mutually influence each other and other tissues, giving rise to a "bone-muscle crosstalk". In our study, we made use of myogenic (C2C12 cells) and osteogenic (2T3 cells) cell lines to investigate the effects of muscle cell-produced factors on the maturation process of osteoblasts. We found that the myogenic medium has inhibitory effects on bone cell differentiation and we identified sclerostin as one of the myokines produced by muscle cells. Sclerostin is a secreted glycoprotein reportedly expressed by bone/cartilage cells and is considered a negative regulator of bone growth due to its role as an antagonist of the Wnt/β-catenin pathway. Given the inhibitory role of sclerostin in bone, we analyzed its expression by muscle cells and how it affects bone formation and homeostasis. Firstly, we characterized and quantified sclerostin synthesis by a myoblast cell line (C2C12) and by murine primary muscle cells by Western blotting, real-time PCR, immunofluorescence, and ELISA assay. Next, we investigated in vivo production of sclerostin in distinct muscle groups with different metabolic and mechanical loading characteristics. This analysis was done in mice of different ages (6 weeks, 5 and 18 months after birth) and revealed that sclerostin expression is dynamically modulated in a muscle-specific way during the lifespan. Finally, we transiently expressed sclerostin in the hind limb muscles of young mice (2 weeks of age) via in vivo electro-transfer of a plasmid containing the gene in order to investigate the effects of muscle-specific overproduction of the protein. Our data disclosed an inhibitory role of the muscular sclerostin on the bones adjacent to the electroporated muscles. This observation suggests that sclerostin released by skeletal muscle might synergistically interact with osseous sclerostin and potentiate negative regulation of osteogenesis possibly by acting in a paracrine/local fashion. Our data point out a role for muscle as a new source of sclerostin.
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http://dx.doi.org/10.3390/biomedicines9010071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828203PMC
January 2021

Aortic Gene Expression Profiles Show How ApoA-I Levels Modulate Inflammation, Lysosomal Activity, and Sphingolipid Metabolism in Murine Atherosclerosis.

Arterioscler Thromb Vasc Biol 2021 02 17;41(2):651-667. Epub 2020 Dec 17.

Department of Pharmacological and Biomolecular Sciences (M.B., S.M., A.C., F.F., R.O., S.B., G.C.), Università degli Studi di Milano, Italy.

Objective: HDL (high-density lipoprotein) particles are known to possess several antiatherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant, and anti-inflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments. Approach and Results: Eight-week-old EKO mice, EKO mice overexpressing human apoA-I, and wild-type mice as controls were fed either normal laboratory or Western diet for 6 or 22 weeks. Cholesterol distribution among lipoproteins was evaluated, and atherosclerosis of the aorta was quantified. High-throughput sequencing technologies were used to analyze the transcriptome of the aorta of the 3 genotypes in each experimental condition. In addition to the well-known activation of inflammation and immune response, the impairment of sphingolipid metabolism, phagosome-lysosome system, and osteoclast differentiation emerged as relevant players in atherosclerosis development. The reduced atherosclerotic burden in the aorta of EKO mice expressing high levels of apoA-I was accompanied by a reduced activation of immune system markers, as well as reduced perturbation of lysosomal activity and a better regulation of the sphingolipid synthesis pathway.

Conclusions: ApoA-I modulates atherosclerosis development in the aorta of EKO mice affecting the expression of pathways additional to those associated with inflammation and immune response.
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http://dx.doi.org/10.1161/ATVBAHA.120.315669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837693PMC
February 2021

Membrane Estrogen Receptor (GPER) and Follicle-Stimulating Hormone Receptor (FSHR) Heteromeric Complexes Promote Human Ovarian Follicle Survival.

iScience 2020 Dec 18;23(12):101812. Epub 2020 Nov 18.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Ospedale Civile Sant'Agostino-Estense, Via P. Giardini 1355, 41126 Modena, Italy.

Classically, follicle-stimulating hormone receptor (FSHR)-driven cAMP-mediated signaling boosts human ovarian follicle growth and oocyte maturation. However, contradicting data suggest a different view on physiological significance of FSHR-mediated cAMP signaling. We found that the G-protein-coupled estrogen receptor (GPER) heteromerizes with FSHR, reprogramming cAMP/death signals into proliferative stimuli fundamental for sustaining oocyte survival. In human granulosa cells, survival signals are missing at high FSHR:GPER ratio, which negatively impacts follicle maturation and strongly correlates with preferential Gαs protein/cAMP-pathway coupling and FSH responsiveness of patients undergoing controlled ovarian stimulation. In contrast, FSHR/GPER heteromers triggered anti-apoptotic/proliferative FSH signaling delivered via the Gβγ dimer, whereas impairment of heteromer formation or GPER knockdown enhanced the FSH-dependent cell death and steroidogenesis. Therefore, our findings indicate how oocyte maturation depends on the capability of GPER to shape FSHR selective signals, indicating hormone receptor heteromers may be a marker of cell proliferation.
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http://dx.doi.org/10.1016/j.isci.2020.101812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702187PMC
December 2020

Sphingosine-1 phosphate induces cAMP/PKA-independent phosphorylation of the cAMP response element-binding protein (CREB) in granulosa cells.

Mol Cell Endocrinol 2021 01 12;520:111082. Epub 2020 Nov 12.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Background And Aims: Sphingosine-1 phosphate (S1P) is a lysosphingolipid present in the ovarian follicular fluid. The role of the lysosphingolipid in gonads of the female is widely unclear. At nanomolar concentrations, S1P binds and activates five specific G protein-coupled receptors (GPCRs), known as S1P, modulating different signaling pathways. S1P and S1P are highly expressed in human primary granulosa lutein cells (hGLC), as well as in the immortalized human primary granulosa cell line hGL5. In this study, we evaluated the signaling cascade activated by S1P and its synthetic analogues in hGLC and hGL5 cells, exploring the biological relevance of S1PR-stimulation in this context.

Methods And Results: hGLC and hGL5 cells were treated with a fixed dose (0.1 μM) of S1P, or by S1P- and S1P-specific agonists SEW2871 and CYM5541. In granulosa cells, S1P and, at a lesser extent, SEW2871 and CYM5541, potently induced CREB phosphorylation. No cAMP production was detected and pCREB activation occurred even in the presence of the PKA inhibitor H-89. Moreover, S1P-dependent CREB phosphorylation was dampened by the mitogen-activate protein kinase (MEK) inhibitor U0126 and by the L-type Ca channel blocker verapamil. The complete inhibition of CREB phosphorylation occurred by blocking either S1P or S1P with the specific receptor antagonists JTE-013 and TY52156, or under PLC/PI3K depletion. S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulin-encoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. However, S1P or agonists did not modulate granulosa cell viability and proliferation in our conditions.

Conclusions: This study demonstrates for the first time that S1P may induce a cAMP-independent activation of pCREB in granulosa cells, although this is not sufficient to induce intracellular steroidogenic signals and progesterone synthesis. S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P-S1PR axis may cooperate with gonadotropins in modulating follicle development.
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http://dx.doi.org/10.1016/j.mce.2020.111082DOI Listing
January 2021

Impact of S1P Mimetics on Mesenteric Ischemia/Reperfusion Injury.

Pharmaceuticals (Basel) 2020 Oct 9;13(10). Epub 2020 Oct 9.

Food and Drug Department, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy.

Mesenteric ischemia/reperfusion (I/R), following the transient deprivation of blood flow to the gut, triggers an acute flogistic process involving the disruption of endothelial and epithelial barriers integrity, the activation of immune cells, and the abundant release of inflammatory mediators. Among them, the lipid mediator sphingosine-1-phosphate (S1P) is involved in maintaining epithelial and endothelial barrier integrity and in governing the migration of immune cells through the interaction with S1P receptors. Therefore, the present work aims to investigate the involvement of S1P signaling in intestinal I/R-induced injury by studying the effects of FTY720, the non-selective S1P agonist, and comparing them with the responses to ozanimod, selective S1P agonist, in a murine model of gut I/R. Intestinal edema, gut and lung neutrophil infiltration, and oxidative stress were evaluated through biochemical and morphological assays. The collected results highlight the protective action of FTY720 against the inflammatory cascade elicited by mesenteric I/R injury, mainly through the control of vascular barrier integrity. While these beneficial effects were mimicked by ozanimod and can be therefore attributed largely to the effects exerted by FTY720 on S1P, the recruitment of myeloid cells to the injured areas, limited by FTY720 but not by ozanimod, rather suggests the involvement of other receptor subtypes.
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http://dx.doi.org/10.3390/ph13100298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601119PMC
October 2020

Treatments for COVID-19: emerging drugs against the coronavirus - reply.

Authors:
Francesco Potì

Acta Biomed 2020 06 30;91(3):ahead of print. Epub 2020 Jun 30.

Dipartimento di Medicina e Chirurgia - Unità di Neuroscienze dell'Università di Parma.

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http://dx.doi.org/10.23750/abm.v91i3.10108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716991PMC
June 2020

WISP-2 expression induced by Teriparatide treatment affects in vitro osteoblast differentiation and improves in vivo osteogenesis.

Mol Cell Endocrinol 2020 08 18;513:110817. Epub 2020 May 18.

Department of Biomedical, Metabolic and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, Modena, Italy.

The Osteocyte, recognized as a major orchestrator of osteoblast and osteoclast activity, is the most important key player during bone remodeling processes. Imbalances occurring during bone remodeling, caused by hormone perturbations or by mechanical loading alterations, can induce bone pathologies such as osteoporosis. Recently, the active fraction of parathormone, PTH (1-34) or Teriparatide (TPTD), was chosen as election treatment for osteoporosis. The effect of such therapy is dependent on the temporal manner of administration. The molecular reasons why the type of administration regimen is so critical for the fate of bone remodeling are numerous and not yet well known. Our study attempts to analyze diverse signaling pathways directly activated in osteocytes upon TPTD treatment. By means of gene array analysis, we found many molecules upregulated or downregulated in osteocytes. Later, we paid attention to Wisp-2, a protein involved in the Wnt pathway, that is secreted by MLO-Y4 cells and increases upon TPTD treatment and that is able to positively influence the early phases of osteogenic differentiation. We also confirmed the pro osteogenic property of Wisp-2 during mesenchymal stem cell differentiation into the preliminary osteoblast phenotype. The same results were confirmed with an in vivo approach confirming a remarkable Wisp-2 expression in metaphyseal trabecular bone. These results highlighted the anabolic roles unrolled by osteocytes in controlling the action of neighboring cells, suggesting that the perturbation of certain signaling cascades, such as the Wnt pathway, is crucial for the positive regulation of bone formation.
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http://dx.doi.org/10.1016/j.mce.2020.110817DOI Listing
August 2020

Treatments for COVID-19: emerging drugs against the coronavirus.

Acta Biomed 2020 May 11;91(2):118-136. Epub 2020 May 11.

Department of Medicine and Surgery - Unit of Neurosciences, University of Parma, Parma, Italy.

The Coronavirus disease 19 (COVID-19) outbreak has been recognized as a global threat to public health. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and no effective therapies currently exist against this novel viral agent. Along with extensive public health measures, an unprecedented global effort in identifying effective drugs for the treatment is being implemented. Potential drug targets are emerging as the result of a fast-evolving understanding of SARS-CoV-2 virology, host response to the infection, and clinical course of the disease. This brief review focuses on the latest and most promising pharmacological treatments against COVID-19 currently under investigation and discuss their potential use based on either documented efficacy in similar viral infections, or their activity against inflammatory syndromes. Ongoing clinical trials are also emphasized.
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http://dx.doi.org/10.23750/abm.v91i2.9639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569629PMC
May 2020

Critical and emerging topics in dietary carbohydrates and health.

Int J Food Sci Nutr 2020 May 5;71(3):286-295. Epub 2019 Sep 5.

Department of Food and Drug, University of Parma, Parma, Italy.

Multiple factors may affect the metabolic fate of carbohydrates. Today, well-standardised and accepted methods may allow for the definitions of the changes in the glucose and insulin curves following the ingestion of either carbohydrate-based and other foods. More debate is still raised on the clinical meaning of these classifications when used at a population level, while emphasis is raised on the approach to carbohydrate metabolism on an individual basis. Within these ranges of applications, other compounds, such as plant polyphenols, may favourably add synergic effects through the modulation of carbohydrate digestion and glucose metabolic steps, resulting in lowering postprandial glucose and insulin levels. Finally, a growing knowledge suggests that the balance of dietary fructose and individual physical activity represent the key point to address the compound towards either positive, energy sparing effects, or a degenerative metabolic burden. The carbohydrate quality within a whole dietary and lifestyle pattern may therefore challenge the individual balance towards health or disease.
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http://dx.doi.org/10.1080/09637486.2019.1661979DOI Listing
May 2020

GnRH Antagonists Produce Differential Modulation of the Signaling Pathways Mediated by GnRH Receptors.

Int J Mol Sci 2019 Nov 7;20(22). Epub 2019 Nov 7.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini 1355, 41126 Modena, Italy.

Commercial gonadotropin-releasing hormone (GnRH) antagonists differ by 1-2 amino acids and are used to inhibit gonadotropin production during assisted reproduction technologies (ART). In this study, potencies of three GnRH antagonists, Cetrorelix, Ganirelix and Teverelix, in inhibiting GnRH-mediated intracellular signaling, were compared in vitro. GnRH receptor (GnRHR)-transfected HEK293 and neuroblastoma-derived SH-SY5Y cell lines, as well as mouse pituitary LβT2 cells endogenously expressing the murine GnRHR, were treated with GnRH in the presence or absence of the antagonist. We evaluated intracellular calcium (Ca) and cAMP increases, cAMP-responsive element binding-protein (CREB) and extracellular-regulated kinase 1 and 2 (ERK1/2) phosphorylation, β-catenin activation and mouse luteinizing-hormone β-encoding gene () transcription by bioluminescence resonance energy transfer (BRET), Western blotting, immunostaining and real-time PCR as appropriate. The kinetics of GnRH-induced Ca rapid increase revealed dose-response accumulation with potency (EC50) of 23 nM in transfected HEK293 cells, transfected SH-SY5Y and LβT2 cells. Cetrorelix inhibited the 3 × EC GnRH-activated calcium signaling at concentrations of 1 nM-1 µM, demonstrating higher potency than Ganirelix and Teverelix, whose inhibitory doses fell within the 100 nM-1 µM range in both transfected HEK293 and SH-SY5Y cells in vitro. In transfected SH-SY5Y, Cetrorelix was also significantly more potent than other antagonists in reducing GnRH-mediated cAMP accumulation. All antagonists inhibited pERK1/2 and pCREB activation at similar doses, in LβT2 and transfected HEK293 cells treated with 100 nM GnRH. Although immunostainings suggested that Teverelix could be less effective than Cetrorelix and Ganirelix in inhibiting 1 µM GnRH-induced β-catenin activation, gene expression increase occurring upon LβT2 cell treatment by 1 µM GnRH was similarly inhibited by all antagonists. To conclude, this study has demonstrated Cetrorelix-, Ganirelix- and Teverelix-specific biased effects at the intracellular level, not affecting the efficacy of antagonists in inhibiting gene transcription.
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http://dx.doi.org/10.3390/ijms20225548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888270PMC
November 2019

Biglycan and atherosclerosis: Lessons from high cardiovascular risk conditions.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 02 28;1865(2):158545. Epub 2019 Oct 28.

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. Electronic address:

Atherosclerosis (ATH) is a chronic, dynamic, evolutive process involving morphological and structural subversion of artery walls, leading to the formation of atherosclerotic plaques. ATH generally initiates during the childhood, occurring as a result of a number of changes in the intima tunica and in the media of arteries. A key event occurring during the pathobiology of ATH is the accumulation of lipoproteins in the sub-intimal spaces mediated by extracellular matrix (ECM) molecules, especially by the chondroitin sulfate/dermatan sulfate (CS/DS) -containing proteoglycans (CS/DSPGs). Among them, the proteoglycan biglycan (BGN) is critically involved in the onset and progression of ATH and evidences show that BGN represents the missing link between the pro-atherogenic status induced by both traditional and non-traditional cardiovascular risk factors and the development and progression of vascular damage. In the light of these findings, the role of BGN in dyslipidemia, hypertension, cigarette smoking, diabetes, chronic kidney disease and inflammatory status is briefly analyzed and discussed in order to shed new light on the underlying mechanisms governing the association between BGN and ATH.
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http://dx.doi.org/10.1016/j.bbalip.2019.158545DOI Listing
February 2020

Enhanced expression of the sphingosine-1-phosphate-receptor-3 causes acute myelogenous leukemia in mice.

Leukemia 2020 03 21;34(3):721-734. Epub 2019 Oct 21.

Dept. of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Giardini 1355, Modena, Italy.

Acute myeloid leukemia (AML) carries a 10-100 fold lower mutational burden than other neoplastic entities. Mechanistic explanations for why a low number of mutations suffice to induce leukemogenesis are therefore required. Here we demonstrate that transgenic overexpression of the wild type sphingosine-1-phosphate receptor 3 (S1P) in murine hematopoietic stem cells is sufficient to induce a transplantable myeloid leukemia. In contrast, S1P expression in more mature compartments does not cause malignant transformation. Treatment with the sphingosine phosphate receptor modulator Fingolimod, which prevents receptor signaling, normalized peripheral blood cell counts and reduced spleen sizes in S1P expressing mice. Gene expression analyses in AML patients revealed elevated S1P expression specifically in two molecular subclasses. Our data suggest a previously unrecognized contribution of wild type S1P signaling to leukemogenesis that warrants the exploration of S1P antagonists in preclinical AML models.
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http://dx.doi.org/10.1038/s41375-019-0577-7DOI Listing
March 2020

Seizures of illicit substances for personal use in two Italian provinces: analysis of trends by type and purity from 2008 to 2017.

Subst Abuse Treat Prev Policy 2019 09 18;14(1):41. Epub 2019 Sep 18.

Forensic Toxicology Laboratory; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via del Pozzo, 71, 41124, Modena, Italy.

Background: The use of illicit substances represents one of the most difficult problems to confront in the health system. Drug use is a global problem but is not uniform throughout the world, within the same country and changes over time. Therefore, knowing the illicit substances that are used in a territory is essential to better organize health services in that specific geographical area. To this aim, we analysed 4200 samples confiscated from individuals who held them for personal use by police forces in the Italian provinces of Modena and Reggio Emilia from 2008 to 2017.

Methods: The suspected samples were screened by gas-chromatography-mass spectrometry (GC-MS) and by liquid chromatography-tandem mass spectrometry (LC-MS/MS); all samples were subsequently analysed by gas chromatography-flame ionization detector (GC-FID) for quantitative analyses.

Results: Cannabis was the most seized illicit substance (70.7%). Over the study period, the number of seizures of herb with a high content of Δ-THC increased. The number of cocaine seizures remained stable (total 16.1%), but the median purity of seized cocaine increased to 75% in 2017. Heroin seizures decreased over time, but the median purity of seized heroin reached 16.8% in 2017. In almost all the years, heroin samples with a purity exceeding the 97.5 percentile were found. Especially from 2014, the range of seized substances increased and started to include synthetic cathinones, phenylethylamines, UR-144, LSD, psilocybe, prescription opioid and hypnotics. In two cases, tramadol together with tropicamide was seized. Most of the seizures involved male subjects and 82% of the seizures were from individuals younger than 35 years of age.

Conclusions: The persistence of old illicit drugs and the rapid emergence of new psychoactive substances represented a serious challenge for public health in the studied Italian area. Some useful interventions might be: informing mainly young people about the possible complications of cannabis use; implementing standardized procedures to diagnose and treat cocaine-related emergencies in hospitals; increasing the distribution of naloxone to antagonize possible heroin overdoses; equipping laboratories to be able to identify the new psychoactive substances.
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http://dx.doi.org/10.1186/s13011-019-0229-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751801PMC
September 2019

Glycosylation Pattern and Bioactivity of Reference Follitropin alfa and Biosimilars.

Front Endocrinol (Lausanne) 2019 24;10:503. Epub 2019 Jul 24.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Recombinant follicle-stimulating hormone (FSH) (follitropin alfa) and biosimilar preparations are available for clinical use. They have specific FSH activity and a unique glycosylation profile dependent on source cells. The aim of the study is to compare the originator (reference) follitropin alfa (Gonal-f®)- with biosimilar preparations (Bemfola® and Ovaleap®)-induced cellular responses . Gonadotropin N-glycosylation profiles were analyzed by ELISA lectin assay, revealing preparation specific-patterns of glycan species (Kruskal-Wallis test; < 0.05, = 6) and by glycotope mapping. Increasing concentrations of Gonal-f® or biosimilar (1 × 10-1 × 10 ng/ml) were used for treating human primary granulosa lutein cells (hGLC) and FSH receptor (FSHR)-transfected HEK293 cells . Intracellular cAMP production, Ca increase and β-arrestin 2 recruitment were evaluated by BRET, CREB, and ERK1/2 phosphorylation by Western blotting. 12-h gene expression, and 8- and 24-h progesterone and estradiol synthesis were measured by real-time PCR and immunoassay, respectively. We found preparation-specific glycosylation patterns by lectin assay (Kruskal-Wallis test; < 0.001; = 6), and similar cAMP production and β-arrestin 2 recruitment in FSHR-transfected HEK293 cells (cAMP EC range = 12 ± 0.9-24 ± 1.7 ng/ml; β-arrestin 2 EC range = 140 ± 14.1-313 ± 18.7 ng/ml; Kruskal-Wallis test; ≥ 0.05; = 4). Kinetics analysis revealed that intracellular Ca increased upon cell treatment by 4 μg/ml Gonal-f®, while equal concentrations of biosimilars failed to induced a response (Kruskal-Wallis test; < 0.05; = 3). All preparations induced both 8 and 24 h-progesterone and estradiol synthesis in hGLC, while no different ECs were demonstrated (Kruskal-Wallis test; > 0.05; = 5). Apart from preparation-specific intracellular Ca increases achieved at supra-physiological hormone doses, all compounds induced similar intracellular responses and steroidogenesis, reflecting similar bioactivity, and overall structural homogeneity.
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http://dx.doi.org/10.3389/fendo.2019.00503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667556PMC
July 2019

Targeted invalidation of SR-B1 in macrophages reduces macrophage apoptosis and accelerates atherosclerosis.

Cardiovasc Res 2020 03;116(3):554-565

Sorbonne Université, INSERM, UMR_S 1166 ICAN, F-75013, Paris, France.

Aims: SR-B1 is a cholesterol transporter that exerts anti-atherogenic properties in liver and peripheral tissues in mice. Bone marrow (BM) transfer studies suggested an atheroprotective role in cells of haematopoietic origin. Here, we addressed the specific contribution of SR-B1 in the monocyte/macrophage.

Methods And Results: We generated mice deficient for SR-B1 in monocytes/macrophages (Lysm-Cre × SR-B1f/f) and transplanted their BM into Ldlr-/- mice. Fed a cholesterol-rich diet, these mice displayed accelerated aortic atherosclerosis characterized by larger macrophage-rich areas and decreased macrophage apoptosis compared with SR-B1f/f transplanted controls. These findings were reproduced in BM transfer studies using another atherogenic mouse recipient (SR-B1 KOliver × Cholesteryl Ester Transfer Protein). Haematopoietic reconstitution with SR-B1-/- BM conducted in parallel generated similar results to those obtained with Lysm-Cre × SR-B1f/f BM; thus suggesting that among haematopoietic-derived cells, SR-B1 exerts its atheroprotective role primarily in monocytes/macrophages. Consistent with our in vivo data, free cholesterol (FC)-induced apoptosis of macrophages was diminished in the absence of SR-B1. This effect could not be attributed to differential cellular cholesterol loading. However, we observed that expression of apoptosis inhibitor of macrophage (AIM) was induced in SR-B1-deficient macrophages, and notably upon FC-loading. Furthermore, we demonstrated that macrophages were protected from FC-induced apoptosis by AIM. Finally, AIM protein was found more present within the macrophage-rich area of the atherosclerotic lesions of SR-B1-deficient macrophages than controls.

Conclusion: Our findings suggest that macrophage SR-B1 plays a role in plaque growth by controlling macrophage apoptosis in an AIM-dependent manner.
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http://dx.doi.org/10.1093/cvr/cvz138DOI Listing
March 2020

Inferring biallelism of two FSH receptor mutations associated with spontaneous ovarian hyperstimulation syndrome by evaluating FSH, LH and HCG cross-activity.

Reprod Biomed Online 2019 May 23;38(5):816-824. Epub 2018 Dec 23.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Centre for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy. Electronic address:

Research Question: What is the cumulative effect of two follicle-stimulating hormone receptor (FSHR) mutations in spontaneous ovarian hyperstimulation syndrome (sOHSS) pathogenesis? Are these mutations in the mono- or biallelic state?

Design: Two FSHR mutations were found in a pregnant patient affected by sOHSS with no predisposing conditions. While the p.Asn106His mutation is novel, the p.Ser128Tyr mutation has been associated with sOHSS previously. The patient's FSHR gene was analysed by Sanger sequencing, and FSHR cDNAs carrying a single or both point mutations were created by mutagenesis in vitro. cAMP activation by recombinant FSH, luteinizing hormone (LH), human chorionic gonadotropin (HCG) and thyroid-stimulating hormone (TSH) was evaluated in transfected HEK293 cells by bioluminescence resonance energy transfer.

Results: All mutations decreased the 50% effective concentration of FSH calculated for cAMP (P < 0.05, n = 6), resulting in two- to 10-fold lower ligand potency. TSH failed to induce an FSHR-mediated increase in intracellular cAMP, while LH was approximately four-fold more potent than HCG in p.Ser128Tyr FSHR-expressing HEK293 cells despite lower cAMP plateau levels (P < 0.05, n = 5). The p.Ser128Tyr FSHR mutation was found to be responsible for an LH-/HCG-induced increase in cAMP when it was in the biallelic heterozygous state with p.Asn106His, but no increase in cAMP was induced in the monoallelic state.

Conclusion: In-vitro data support that, in pregnant patients with sOHSS, the two FSHR mutations have an opposing effect on the pathogenesis of sOHSS and are in the biallelic heterozygous form, allowing HCG to induce a p.Ser128Tyr FSHR-mediated increase in cAMP.
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http://dx.doi.org/10.1016/j.rbmo.2018.12.021DOI Listing
May 2019

Polyphenol Health Effects on Cardiovascular and Neurodegenerative Disorders: A Review and Meta-Analysis.

Int J Mol Sci 2019 Jan 16;20(2). Epub 2019 Jan 16.

Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.

Several studies have demonstrated that polyphenol-enriched diets may have beneficial effects against the development of degenerative diseases, including atherosclerosis and disorders affecting the central nervous system. This activity has been associated not only with antioxidant and anti-inflammatory properties, but also with additional mechanisms, such as the modulation of lipid metabolism and gut microbiota function. However, long-term studies on humans provided controversial results, making the prediction of polyphenol impact on health uncertain. The aim of this review is to provide an overview and critical analysis of the literature related to the effects of the principal dietary polyphenols on cardiovascular and neurodegenerative disorders. We critically considered and meta-analyzed randomized controlled clinical trials involving subjects taking polyphenol-based supplements. Although some polyphenols might improve specific markers of cardiovascular risk and cognitive status, many inconsistent data are present in literature. Therefore, definitive recommendations for the use of these compounds in the prevention of cardiovascular disease and cognitive decline are currently not applicable. Once pivotal aspects for the definition of polyphenol bioactivity, such as the characterization of pharmacokinetics and safety, are addressed, it will be possible to have a clear picture of the realistic potential of polyphenols for disease prevention.
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http://dx.doi.org/10.3390/ijms20020351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359281PMC
January 2019

Clusterin enhances AKT2-mediated motility of normal and cancer prostate cells through a PTEN and PHLPP1 circuit.

J Cell Physiol 2019 07 22;234(7):11188-11199. Epub 2018 Nov 22.

Department of Biomedical, Metabolic, and Neural Sciences, Section of Morphology, Signal Transduction Unit, University of Modena and Reggio Emilia, Modena, Italy.

Clusterin (CLU) is a chaperone-like protein with multiple functions. sCLU is frequently upregulated in prostate tumor cells after chemo- or radiotherapy and after surgical or pharmacological castration. Moreover, CLU has been documented to modulate the cellular homolog of murine thymoma virus akt8 oncogene (AKT) activity. Here, we investigated how CLU overexpression influences phosphatidylinositol 3'-kinase (PI3K)/AKT signaling in human normal and cancer epithelial prostate cells. Human prostate cells stably transfected with CLU were broadly profiled by reverse phase protein array (RPPA), with particular emphasis on the PI3K/AKT pathway. The effect of CLU overexpression on normal and cancer cell motility was also tested. Our results clearly indicate that CLU overexpression enhances phosphorylation of AKT restricted to isoform 2. Mechanistically, this can be explained by the finding that the phosphatase PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1), known to dephosphorylate AKT2 at S474, is markedly downregulated by CLU, whereas miR-190, a negative regulator of PHLPP1, is upregulated. Moreover, we found that phosphatase and tensin homolog (PTEN) was heavily phosphorylated at the inhibitory site S380, contributing to the hyperactivation of AKT signaling. By keeping AKT2 phosphorylation high, CLU dramatically enhances the migratory behavior of prostate epithelial cell lines with different migratory and invasive phenotypes, namely prostate normal epithelial 1A (PNT1A) and prostatic carcinoma 3 (PC3) cells. Altogether, our results unravel for the first time a circuit by which CLU can switch a low migration phenotype toward a high migration phenotype, through miR-190-dependent downmodulation of PHLPP1 expression and, in turn, stabilization of AKT2 phosphorylation.
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http://dx.doi.org/10.1002/jcp.27768DOI Listing
July 2019

Abacavir, nevirapine, and ritonavir modulate intracellular calcium levels without affecting GHRH-mediated growth hormone secretion in somatotropic cells in vitro.

Mol Cell Endocrinol 2019 02 11;482:37-44. Epub 2018 Dec 11.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy.

Growth Hormone (GH) deficiency is frequent in HIV-infected patients treated with antiretroviral therapy. We treated GH3 cells with antiretrovirals (nevirapine, ritonavir or abacavir sulfate; 100 pM-1 mM range), after transfection with human growth hormone releasing hormone (GHRH) receptor cDNA. Cells viability, intracellular cAMP, phosphorylation of CREB and calcium increase, GH production and secretion were evaluated both in basal condition and after GHRH, using MTT, bioluminescence resonance energy transfer, western blotting and ELISA. Antiretroviral treatment did not affect GHRH 50% effective dose (EC) calculated for 30-min intracellular cAMP increase (Mann-Whitney's U test; p ≥ 0.05; n = 4) nor 15-min CREB phosphorylation. The kinetics of GHRH-mediated, rapid intracellular calcium increase was perturbed by pre-incubation with drugs, while GHRH failed to induce the ion increase in ritonavir pre-treated cells (ANOVA; p < 0.05; n = 3). Antiretrovirals did not impact 24-h intracellular and extracellular GH levels (ANOVA; p ≥ 0.05; n = 3). We demonstrated the association between antiretrovirals and intracellular calcium increase, without consequences on somatotrope cells viability and GH synthesis. Overall, these results suggest that antiretrovirals may not directly impact on GH axis in HIV-infected patients.
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http://dx.doi.org/10.1016/j.mce.2018.12.005DOI Listing
February 2019

Alcohol Pattern Consumption Differently Affects the Efficiency of Macrophage Reverse Cholesterol Transport in Vivo.

Nutrients 2018 Dec 3;10(12). Epub 2018 Dec 3.

Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.

It has been well established that moderate alcohol consumption inversely correlates with cardiovascular morbidity and mortality, whereas binge alcohol drinking increases cardiovascular disease risk. The aim of this study was to assess in vivo the impact of different drinking patterns on reverse cholesterol transport (RCT); the atheroprotective process leading to the removal of excess cholesterol from the body. RCT was measured with a standardized, radioisotope-based technique in three groups of atherosclerosis-prone apolipoprotein E knock out mice: Placebo group, receiving water, which would mimic the abstainers; moderate group, receiving 0.8 g/kg alcohol/day for 28 days, which would mimic a moderate intake; binge group, receiving 0.8 g/kg alcohol/day for 5 days/week, followed by the administration of 2.8 g/kg alcohol/day for 2 days/week, which would mimic a heavy intake in a short period. Mice in the binge drinking group displayed an increase in total cholesterol, high density lipoprotein cholesterol (HDL-c) and non-HDL-c (all < 0.0001 vs. placebo), and a significantly reduced elimination of fecal cholesterol. The moderate consumption did not lead to any changes in circulating lipids, but slightly improved cholesterol mobilization along the RCT pathway. Overall, our data confirm the importance of considering not only the total amount, but also the different consumption patterns to define the impact of alcohol on cardiovascular risk.
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http://dx.doi.org/10.3390/nu10121885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316025PMC
December 2018

Elevating Endogenous Sphingosine-1-Phosphate (S1P) Levels Improves Endothelial Function and Ameliorates Atherosclerosis in Low Density Lipoprotein Receptor-Deficient (LDL-R-/-) Mice.

Thromb Haemost 2018 Aug 30;118(8):1470-1480. Epub 2018 Jul 30.

Center for Laboratory Medicine, University Hospital Münster, University of Münster, Münster, Germany.

Background:  Sphingosine-1-phosphate (S1P) is a bioactive lysosphingolipid and a constituent of high-density lipoprotein (HDL) exerting several atheroprotective effects in vitro. However, the few studies addressing anti-atherogenic effects of S1P in vivo have led to disparate results. We here examined atherosclerosis development in low-density lipoprotein receptor (LDL-R)-deficient (LDL-R) mice with elevated endogenous S1P levels.

Methods And Results:  Sub-lethally irradiated LDL-R mice were transplanted with bone marrow deficient in sphingosine kinase 2 (SphK2), which led to the elevation of S1P concentrations in erythrocytes, plasma and HDL by approximately 1.5- to 2.0-fold in SphK2/LDL-R mice. Afterwards, mice were fed a Western diet for 14 weeks. Elevation of endogenous S1P significantly reduced atherosclerotic lesion formation by approximately half without affecting the plasma lipid profile. Furthermore, the macrophage content of atherosclerotic lesions and lipopolysaccharide-induced monocyte recruitment to the peritoneal cavity were reduced in SphK2/LDL-R mice. Studies using intra-vital microscopy revealed that endogenous S1P lowered leukocyte adhesion to capillary wall and decreased endothelial permeability to fluorescently labelled LDL. Moreover, SphK2/LDL-R mice displayed decreased levels of vascular cell adhesion molecule 1 in atherosclerotic lesions and in plasma. Studies in vitro demonstrated reduced monocyte adhesion and transport across an endothelial layer exposed to increasing S1P concentrations, murine plasma enriched in S1P or plasma obtained from SphK2-deficient animals. In addition, decreased permeability to fluorescence-labelled dextran beads or LDL was observed in S1P-treated endothelial cells.

Conclusion:  We conclude that raising endogenous S1P levels exerts anti-atherogenic effects in LDL-R mice that are mediated by favourable modulation of endothelial function.
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http://dx.doi.org/10.1055/s-0038-1666870DOI Listing
August 2018

Osteocytes Specific GSK3 Inhibition Affects In Vitro Osteogenic Differentiation.

Biomedicines 2018 May 21;6(2). Epub 2018 May 21.

Department of Biomedical, Metabolic Science and Neuroscience, University of Modena and Reggio Emilia, Via Largo del Pozzo 71, 41124 Modena, Italy.

Osteocytes, the most important regulators of bone processes, are producers of molecules (usually proteins) that act as signals in order to communicate with nearby cells. These factors control cell division (proliferation), differentiation, and survival. Substantial evidence showed different signaling pathways activated by osteocytes and involved in osteoblast differentiation, in particular in the last decade, when the Wingless-related integration site (WNT) pathway assumed a critical large importance. WNT activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism, making GSK3 a potential therapeutic target for bone diseases. In our study, we hypothesized an important role of the osteocyte MLO-Y4 conditioned medium in controlling the differentiation process of osteoblast cell line 2T3. We found an effect of diminished differentiation capability of 2T3 upon conditioning with medium from murine long bone osteocyte-Y4 cells (MLO-Y4) pre-treated with GSK3 inhibitor CHIR2201. The novel observations of this study provide knowledge about the inhibition of GSK3 in MLO-Y4 cells. This strategy could be used as a plausible target in osteocytes in order to regulate bone resorption mediated by a loss of osteoblasts activity through a paracrine loop.
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http://dx.doi.org/10.3390/biomedicines6020061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027076PMC
May 2018

Pharmacogenetics of G-protein-coupled receptors variants: FSH receptor and infertility treatment.

Best Pract Res Clin Endocrinol Metab 2018 04 31;32(2):189-200. Epub 2018 Jan 31.

Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy; Department of Medicine, Endocrinology, Metabolism and Geriatrics, Azienda Ospedaliero-Universitaria of Modena, Italy.

Infertility treatment may represent a paradigmatic example of precision medicine. Follicle-stimulating hormone (FSH) has been proposed as a valuable therapeutic option both in males and in females, even if a standardized approach is far to be established. To date, several genetic mutations as well as polymorphisms have been demonstrated to significantly affect the pathophysiology of FSH-FSH receptor (FSHR) interaction, although the underlying molecular mechanisms remain unclear. This review aims to highlight possible aspects of FSH therapy that could benefit from a pharmacogenetic approach, providing an up-to-date overview of the variability of the response to FSH treatment in both sexes. Specific sections are dedicated to the clinical use of FSH in infertility and how FSHR polymorphisms may affect the therapeutic endpoints.
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http://dx.doi.org/10.1016/j.beem.2018.01.001DOI Listing
April 2018

'Spare' Luteinizing Hormone Receptors: Facts and Fiction.

Trends Endocrinol Metab 2018 04 9;29(4):208-217. Epub 2018 Feb 9.

Department of Medicine and Surgery - Unit of Neurosciences, University of Parma, via Volturno 39/F, 43125 Parma, Italy. Electronic address:

It is common opinion that maximal activation of luteinizing hormone (LH)-dependent steroidogenic signal occurs at <1% of human LH/choriogonadotropin (hCG) receptor (LHCGR) occupancy. This effect would be a consequence of an excess of receptors expressed on the surface of theca cells, resulting in a pool of LHCGRs remaining unbound (spare). This concept was borrowed from historical pharmacological studies, when discrepancies between ligand-receptor binding and dose-response curves of cAMP were evaluated by treating mouse or rat Leydig cells with hCG in vitro. Recent findings demonstrated the specificity of LH- and hCG-dependent effects, receptor heterodimerization, and differing behaviors of rodent versus human gonadotropin-responsive cells, which may help to revise the 'spare' LHCGRs concept applied to human ovarian physiology and assisted reproduction.
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http://dx.doi.org/10.1016/j.tem.2018.01.007DOI Listing
April 2018

'Spare' Luteinizing Hormone Receptors: Facts and Fiction.

Trends Endocrinol Metab 2018 04 9;29(4):208-217. Epub 2018 Feb 9.

Department of Medicine and Surgery - Unit of Neurosciences, University of Parma, via Volturno 39/F, 43125 Parma, Italy. Electronic address:

It is common opinion that maximal activation of luteinizing hormone (LH)-dependent steroidogenic signal occurs at <1% of human LH/choriogonadotropin (hCG) receptor (LHCGR) occupancy. This effect would be a consequence of an excess of receptors expressed on the surface of theca cells, resulting in a pool of LHCGRs remaining unbound (spare). This concept was borrowed from historical pharmacological studies, when discrepancies between ligand-receptor binding and dose-response curves of cAMP were evaluated by treating mouse or rat Leydig cells with hCG in vitro. Recent findings demonstrated the specificity of LH- and hCG-dependent effects, receptor heterodimerization, and differing behaviors of rodent versus human gonadotropin-responsive cells, which may help to revise the 'spare' LHCGRs concept applied to human ovarian physiology and assisted reproduction.
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http://dx.doi.org/10.1016/j.tem.2018.01.007DOI Listing
April 2018
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