nicola perrotti
Magna Graecia Catanzaro, Human Health, Faculty Member
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Bacterial lipopolysaccharides (LPS) are important triggers of the widespread inflammatory response, which contributes to the development of multiple organ failure during sepsis. The helical 37-amino-acid-long human antimicrobial peptide... more
Bacterial lipopolysaccharides (LPS) are important triggers of the widespread inflammatory response, which contributes to the development of multiple organ failure during sepsis. The helical 37-amino-acid-long human antimicrobial peptide LL-37 not only possesses a broad-spectrum antimicrobial activity but also binds and neutralizes LPS. However, the use of LL-37 in sepsis treatment is hampered by the fact that it is also cytotoxic. To find a less toxic analog of LL-37, we used in silico analysis to identify amphipathic helical regions of LL-37. A 21-amino-acid fragment (GKE) was synthesized, the biological actions of which were compared to those of two equally long peptides derived from the N and C termini of LL-37 as well as native LL-37. GKE displayed antimicrobial activity against Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , Candida albicans , and Candida parapsilosis that was similar to or even stronger than LL-37. GKE, as well as the equally long control p...
Research Interests: Microbiology, Medical Microbiology, Biology, Evaluation, Medicine, and 15 moreCathelicidin, Identification, Humans, Escherichia coli, Animals, Liposomes, Antimicrobial, Antimicrobial Peptide, Lipopolysaccharides, Antimicrobial Cationic Peptides, Amino Acid Sequence, In Silico, Blood Proteins, DNA fragmentation, and Antimicrobial agent
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Research Interests: Biology, Cell Biology, Clinical Biochemistry, Autophagy, Endoplasmic Reticulum Stress, and 15 moreCancer Research, Apoptosis, Medicine, Endometrial Cancer, Humans, Female, Endoplasmic Reticulum, Cellular Physiology, Medical Physiology, Caspase, Heat Shock Proteins, Cell Survival, Antineoplastic Agents, Case Control Studies, and Endometrial neoplasms
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Research Interests: Kinetics, Biology, Membrane Proteins, Medicine, Cell line, and 15 moreHumans, Insulin, Beta decay, Hepatocellular Carcinoma, IRS, Enzyme, Amino Acids, Epidermal Growth Factor, Digestive System, Chemical Reaction, Insulin Receptor, Membrane Protein, Focal Adhesion Kinase, Insulin Receptor Substrate, and Liver neoplasms
Research Interests: Cell Biology and SGK
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The present work describes the distribution of HCV genotypes in Calabria. The data presented suggest that, in the sample of population investigated, genotype 1b is the most prevalent followed by the 2b and the 2a.. In addition it is... more
The present work describes the distribution of HCV genotypes in Calabria. The data presented suggest that, in the sample of population investigated, genotype 1b is the most prevalent followed by the 2b and the 2a.. In addition it is important to note that in Calabria the prevalence of genotype 1b is strikingly high in respect to the other Italian pullulation. An Association between HCV type 1b and the more severe clinical course of the liver disease has been reported. Although the data presented indicate that in Calabria most of the subjects enrolled in the study are infected by a virulent HCV strain, no association has been found with more severe clinical manifestations.
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The ACE gene has recently been shown to be associated with myocardial infarction, especially in subjects considered at low risk for coronary heart disease (CHD) according to common classification criteria. The possible relationship... more
The ACE gene has recently been shown to be associated with myocardial infarction, especially in subjects considered at low risk for coronary heart disease (CHD) according to common classification criteria. The possible relationship between deletion polymorphism in this gene and CHD risk factors, as well as asymptomatic extracoronary atherosclerosis, has been investigated in the present study. One hundred and seventy-four subjects, enrolled in a cardiovascular disease prevention study, underwent clinical and biochemical examination and ACE-I/D polymorphism determination. Subjects > 45 years of age (n = 107) also received echo-Doppler examination of the carotid arteries. Based on the results of ACE-I/D polymorphism, subjects were divided into three groups: homozygous for deletion (D/D), homozygous for insertion (I/I) and heterozygous (I/D). The prevalence of CHD risk factors as well as of extracoronary atherosclerosis was similar in the three genotype groups. Similarly, there was no association between the presence of atherosclerotic lesions and genotype in subjects at low and high CHD risk. Ten subjects with diabetes mellitus had ACE-D/D genotype. Among these subjects seven had hypertension. Eight subjects with diabetes mellitus had ACE-I/D genotype and only one of these was hypertensive. None of the ACE-I/I subjects was diabetic. ACE-I/D polymorphism seems to play a role in the development of hypertension, at least in diabetic subjects. Its determination may help to identify and monitor diabetic subjects prone to hypertension.
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Research Interests: Physiology, Biology, Medicine, Cercopithecus aethiops, Insulin, and 14 moreAnimals, P-glycoprotein, American, Medical Physiology, Immunoprecipitation, Glycosylation, Oral Hypoglycemic Agents, Transfection, Yeasts, Glucocorticoids, Blood Proteins, Biochemistry and cell biology, Colocalization, and SGK
Research Interests: Engineering, Endocrinology, Medicine, Phosphorus, Humans, and 15 moreInternal Medicine, Blood Glucose, Diabetes mellitus, Cholesterol, Nitrogen, American, Adult, Dietary fiber, Feces, Dietary Carbohydrates, Chronic Kidney Failure, Carbohydrate, Creatinine, Medical and Health Sciences, and Diabetic nephropathies
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Colorectal carcinoma is among the most common malignancies. The tumour cells may arise from mutations in genes encoding proteins involved in the regulation of cell survival and proliferation. Recent evidence disclosed the sensitivity of... more
Colorectal carcinoma is among the most common malignancies. The tumour cells may arise from mutations in genes encoding proteins involved in the regulation of cell survival and proliferation. Recent evidence disclosed the sensitivity of colon carcinoma to the expression of ubiquitous serum and glucocorticoid inducible kinase-1 (SGK1). The kinase is activated by insulin and growth factors via the phosphatidylinositide-3-kinase (PI3K) and the 3-phosphoinositide dependent kinase (PDK1). SGK1 regulates channels, carriers and Na(+)/K(+)-ATPase, enzymes such as glycogen-synthase-kinase-3 (GSK3) and ubiquitin-ligase Nedd4-2, as well as several transcription factors. SGK1 regulates transport, hormone release, neuroexcitability, inflammation, cell proliferation and apoptosis. SGK1 contributes to metabolic syndrome and the pathophysiology of neurodegeneration, allergy, peptic ulcer, fibrosing disease and response to ischemia. SGK1 is upregulated in some tumours but downregulated in others. SGK1-sensitive mechanisms fostering tumour growth include activation of K(+) channels and Ca(2+) channels, Na(+)/H(+) exchanger, amino acid transporters and glucose transporters, upregulation of the nuclear factor NFkappaB and beta-catenin as well as downregulation of the transcription factors Foxo3a/FKHRL1 and p53. SGK1 enhances survival, invasiveness, motility, epithelial to mesenchymal transition and adhesiveness of tumour cells. Following deficiency of APC (adenoma polyposis coli) or chemical cancerogenesis, SGK1 knockout mice develop less intestinal tumours than their wild-type littermates and pharmacological SGK1 inhibition counteracts growth of prostate cancer cells.
Research Interests: Biology, Enzyme Inhibitors, Cancer Research, Medicine, Ion Channels, and 15 moreSignal Transduction, Humans, Mice, Animals, Male, Glucose Transport, Cell Proliferation, Cell Survival, Knockout Mice, Epithelial to Mesenchymal Transition, Biochemistry and cell biology, Colorectal Neoplasms, SGK, Prostatic neoplasms, and Glycogen Synthase Kinase
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Research Interests: Biology, Enzyme Inhibitors, Cell Biology, Oxidative Stress, Apoptosis, and 15 moreMedicine, Signal Transduction, Humans, Reactive Oxygen Species, Cytoprotection, Mitogen Activated Protein Kinase, Clinical Sciences, Hydrogen Peroxide, Endothelial cell, Public health systems and services research, Methionine, Circulation, Protein isoforms, Amino Acid Substitution Rates, and Cardiovascular medicine and haematology
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Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback... more
Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Moreover, TP sequence has a high affinity with plasmin, a protease recognized as overexpressed in many solid cancers, including HCC and ovarian carcinoma. The prodrugs were synthesized and fully characterized in terms of in vitro ADME properties, plasma stability and plasmin-induced release of the parent drug. The inhibitory activity against Sgk1 was evaluated and in vitro growth inhibition was evaluated on ovarian carcinoma and HCC cell lines in the presence and absence of human plasmin. In vivo pharmacokinetic properties and preliminary tissue distribution confirmed a better profile highlighting the importance of the prodrug approach. Finally, the prodrug antitumor efficacy was evaluated in an HCC xenografted murine model, where a significant reduction (around 90%) in tumor growth was observed. Treatment with ProSi113-TP in combination with paclitaxel in a paclitaxel-resistant ovarian carcinoma xenografted murine model, resulted in an impressive reduction of tumor volume greater than 95%. Our results revealed a promising activity of Si113 prodrugs and pave the way for their further development against resistant cancer.
Research Interests: Chemistry, Organic Chemistry, Medicine, Humans, Mice, and 15 moreFemale, Animals, Hepatocellular Carcinoma, Paclitaxel, Kinase Inhibitors, Ovarian Carcinoma, ADME, HCC, Drug Stability, Cell Survival, Antineoplastic Agents, Pharmacokinetic, Liver neoplasms, Pharmacology and pharmaceutical sciences, and Ovarian Neoplasms
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The beta-subunit of the insulin receptor possesses a tyrosine-specific protein kinase activity which may play a role in coupling insulin binding to insulin action. Previously, we have identified a substrate for the receptor-associated... more
The beta-subunit of the insulin receptor possesses a tyrosine-specific protein kinase activity which may play a role in coupling insulin binding to insulin action. Previously, we have identified a substrate for the receptor-associated protein kinase in a cell-free system. This endogenous substrate (pp120), which appeared to be a glycoprotein with an apparent mol wt of 120,000, was detected in rat liver microsomes. In the present work, we have demonstrated that pp120 is localized to a highly purified preparation of rat liver plasma membranes (Neville preparation). Moreover, pp120 appears to be specific to liver, having been detected in liver from rat, monkey, and rabbit, but not in rat brain, skeletal muscle, heart, kidney, or adipocytes. As a preliminary to addressing the question of whether insulin stimulates phosphorylation of pp120 in intact cells, we have sought to identify tissue culture cell lines that contain both insulin receptors and pp120. We have succeeded in identifying pp120 in two cell lines derived from rat liver: 1) H35 hepatoma cells (Reuber hepatoma) and 2) rat hepatocytes transformed with a temperature-sensitive mutant form of SV-40 (cultivated at both permissive and nonpermissive temperatures). In conclusion, pp120 appears to be a liver-specific plasma membrane glycoprotein which serves as a substrate for phosphorylation by the insulin receptor-associated protein kinase in a soluble cell-free system. The presence of pp120 in cultured cell lines will facilitate investigation of whether the phosphorylation of pp120 in intact cells is physiologically regulated in response to insulin.
Research Interests: Endocrinology, Biology, Localization, Biological Sciences, Adipose tissue, and 15 moreCell line, Internal Medicine, Kidney, Insulin, Animals, Male, IRS, Digestive System, Insulin Receptor, Brain Chemistry, Biochemistry and cell biology, Focal Adhesion Kinase, Insulin Receptor Substrate, Cell Membrane, and Haplorhini
Research Interests: Cardiology, Polymorphism, Medicine, Internal Medicine, Blood Pressure, and 15 moreRenin Angiotensin Aldosterone System, Polymerase Chain Reaction, Enzyme, Genotype, Public health systems and services research, Cardiovascular Risk Factor, Odds ratio, Left ventricular hypertrophy, Angiotensin Converting Enzyme, Indexation, Confidence Interval, Ambulatory Blood Pressure, Essential Hypertension, Hardy-Weinberg equilibrium, and Cardiovascular medicine and haematology
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Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in... more
Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.
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The family of tyrosine-specific protein kinases includes proteins encoded by retroviral oncogenes as well as receptors for insulin and several growth factors. Antibodies to pp60src, the protein encoded by the src oncogene of Rous sarcoma... more
The family of tyrosine-specific protein kinases includes proteins encoded by retroviral oncogenes as well as receptors for insulin and several growth factors. Antibodies to pp60src, the protein encoded by the src oncogene of Rous sarcoma virus (RSV), can specifically immunoprecipitate affinity-labeled insulin receptors from cultured human lymphocytes (IM-9 cells). This precipitation is specifically inhibited by the src gene product purified from RSV-transformed rat cells. These observations provide evidence that there is structural homology between the insulin receptors and pp60src.
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Research Interests: Biochemistry, Chemistry, Membrane Proteins, Medicine, Insulin, and 15 moreAnimals, Male, IRS, Phosphorylation, Glycoproteins, Epidermal Growth Factor, Rats, GRB, Insulin Receptor, Cell free System, Biochemistry and cell biology, Insulin Receptor Substrate, Rat Liver, Receptor Insulin, and Protein tyrosine kinases
The frequency and distribution of angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism, and its association with other known risk factors for coronary atherosclerosis, has been studied, in a normal south Italian... more
The frequency and distribution of angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism, and its association with other known risk factors for coronary atherosclerosis, has been studied, in a normal south Italian population. Subjects homozygous for deletion showed elevated fasting blood glucose levels when compared with subjects homozygous for insertion. The difference was consistent with an increased number of type 2 diabetics among the former group of subjects.
Research Interests: Endocrinology, Genetics, Human Genetics, Polymorphism, Complementary and Alternative Medicine, and 15 moreBiology, Humans, Internal Medicine, Blood Glucose, Male, Gene, Enzyme, Middle Aged, Genotype, Genetic Polymorphism, Risk Factors, Angiotensin Converting Enzyme, Coronary Artery Disease, Fasting Blood Glucose, and Paediatrics and reproductive medicine
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The impact of molecular genetics in the diagnosis and management of various forms of heritable cardiac or vascular disorders is continuously increasing thanks to the newly available laboratory tools. Familial hypertrophic cardiomyopathy... more
The impact of molecular genetics in the diagnosis and management of various forms of heritable cardiac or vascular disorders is continuously increasing thanks to the newly available laboratory tools. Familial hypertrophic cardiomyopathy (FHC), an autosomal dominant inherited disease characterized by unexplained left ventricular hypertrophy and a wide range of clinical symptoms, is the first cardiac disorder whose genetic bases have been elucidated. Linkage analysis studies have shown a statistically significant association between the disease status and at least seven genetic loci, all coding for sarcomeric proteins, in unrelated kindreds. A major challenge for physicians is to make an accurate and early diagnosis, not only on the basis of the traditional tools (i.e. physical examination and electro-echocardiography) but also to focus on the impact of genotype on clinical manifestations of FHC. In this review we present the more recent findings on the genetic basis of FHC and analyze the genotype-phenotype correlations of this disorder, whose expression may be modulated by additional factors (modifier genes, genetic background, environmental factors) other than mutations in any of the sarcometric proteins.
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Insulin receptors resemble receptors for certain growth factors (epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor I) in that all possess tyrosine-specific protein kinase activity. These cell surface... more
Insulin receptors resemble receptors for certain growth factors (epidermal growth factor, platelet-derived growth factor, and insulin-like growth factor I) in that all possess tyrosine-specific protein kinase activity. These cell surface receptors resemble protein kinases encoded by viral oncogenes in that both groups of enzymes phosphorylate proteins on tyrosine. Recently, we reported that there is immunological similarity between the insulin receptor and pp60src [the protein encoded by the src oncogene of Rous sarcoma virus (RSV)]. This is supported by the observation that anti-pp60src antiserum (TBR serum) immunoprecipitated radiolabeled insulin receptors derived from cultured human cells (IM-9 lymphoblasts and U-937 monocytes) and rabbit liver. Moreover, highly purified preparations of src protein inhibit the immunoprecipitation of insulin receptors by TBR serum, and the inhibition is correlated with the src kinase activity present in the preparation used. However, two observations suggested that there were immunological differences between pp60src and mammalian insulin receptors. 1) Even at a relatively high concentration (dilution, 1:10), TBR serum immunoprecipitated a relatively small percentage (approximately 20%) of the labeled insulin receptors. 2) Some lots of TBR serum with a high titer against pp60src failed to immunoprecipitate the insulin receptor. Viral oncogenes are thought to have been derived from proto-oncogenes in the host cell. Therefore, because the chicken is the natural host for RSV, we inquired whether there might be closer homology between pp60src and avian insulin receptors. Surprisingly, under conditions where TBR serum immunoprecipitates human insulin receptors, we could not detect immunoprecipitation of avian insulin receptors from chicken liver, chicken embryo fibroblasts, or turkey erythrocytes. The immunoprecipitation of human insulin receptor is not dependent on the method used for labeling the cells ([125I]insulin cross-linking), inasmuch as the receptor labeled by autophosphorylation with [gamma-32P]ATP could also be immunoprecipitated by TBR serum. These observations suggest that there is structural homology between pp60src and the insulin receptor (most likely the beta-subunit). Nevertheless, it seems unlikely that the insulin receptor gene is the proto-oncogene for the src gene of RSV.
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Lizard insulin receptors are evolutionarily highly conserved. Wheat germ agglutinin-purified brain membranes demonstrate the presence of an endogenous substrate (pp 105) for both the insulin and insulin-like growth factor-I receptors.... more
Lizard insulin receptors are evolutionarily highly conserved. Wheat germ agglutinin-purified brain membranes demonstrate the presence of an endogenous substrate (pp 105) for both the insulin and insulin-like growth factor-I receptors. Both insulin and I-insulin-like growth factor-I stimulate the phosphorylation of this endogenous substrate in a dose-dependent manner. Following insulin-stimulated autophosphorylation of the beta subunit, there is a lag period of about 5 min prior to observable phosphorylation of the endogenous substrate. Phosphoamino acid analysis of both the beta subunit as well as pp 105 reveal primarily phosphotyrosine in both the basal as well as the stimulated state.
Research Interests: Kinetics, Biology, Biological Chemistry, Medicine, Biological Sciences, and 15 moreBrain, Insulin, Liver, Lizards, Animals, Phosphorylation, Phosphotyrosine, CHEMICAL SCIENCES, Amino Acids, Receptor, Insulin Receptor, Molecular weight, Cell Membrane, Receptor Insulin, and Medical and Health Sciences
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Protein phosphorylation is an important mechanism of regulation in many metabolic pathways.In muscle glycogen metabolism,the enzymes involved in anabolic steps are activated by a dephosphorylation,the enzymes involved in catabolic steps... more
Protein phosphorylation is an important mechanism of regulation in many metabolic pathways.In muscle glycogen metabolism,the enzymes involved in anabolic steps are activated by a dephosphorylation,the enzymes involved in catabolic steps are activated by a phosphorylation.