[show abstract][hide abstract] ABSTRACT: Understanding how the precise interactions of nerves, immune cells, and adipose tissue account for cardiovascular and metabolic biology is a central aim of biomedical research at present. A long standing paradigm holds that the vascular wall is composed of three con-centric tissue coats (tunicae): intima, media, and adventitia. However, large-and medium-sized arteries, where usually atherosclerotic lesions develop, are consistently surrounded by periadventitial adipose tissue (PAAT), we recently designated tunica adiposa (in brief, adiposa like intima, media, and adventitia).Today, atherosclerosis is considered an immune-mediated inflammatory disease featured by endothelial dysfunction/intimal thickening, medial atrophy, and adventitial lesions associated with adipose dysfunction, whereas hyper-tension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltra-tion of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. How-ever, the role of vascular nerves and their interactions with immune cells and paracrine adipose tissue is not yet evaluated in such an integrated way. The present review attempts to briefly highlight the findings in basic and translational sciences in this area focusing on neuro–immune–adipose interactions, herein referred to as triactome. Triactome-targeted pharmacology may provide a novel therapeutic approach in cardiovascular disease.
Frontiers in Immunology 01/2014; Front. Immunol. 5:130..
[show abstract][hide abstract] ABSTRACT: One of biggest recent achievements of neurobiology is the study on neurotrophic factors. The neurotrophins are exciting examples of these factors. They belong to a family of proteins consisting of nerve growth fac-tor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, NT-6, and NT-7. Today, NGF and BDNF are well recognized to mediate a diz-zying number of trophobiological effects, ranging from neurotrophic through immunotrophic and epitheliotro-phic to metabotrophic effects. These are implicated in the pathogenesis of various diseases. In the same vein, recent studies in adipobiology reveal that this tissue is the body's largest endocrine and paracrine organ producing multiple signaling proteins collectively termed adipokines, with NGF and BDNF being also produced from adipose tissue. Altogether, neurobio-logy and adipobiology contribute to the improvement of our knowledge on diseases beyond obesity such
The World Journal of Pharmacology. 12/2013; 2(4):92.
[show abstract][hide abstract] ABSTRACT: Purpose: To investigate if the survival effects of nerve growth factor (NGF) eyedrops on retinal ganglion cell (RGCs) are related to vascular endothelial growth factor (VEGF) in a rat model of diabetic retinopathy.
Methods: Diabetes was induced in adult rats by streptozotocin injection and changes in the NGF/TrkA and VEGF retina levels were related to the progression of RGC loss. Diabetic rats were subjected to administration of NGF eyedrops or intraocular injection of anti-NGF antibody. All morphologic, immunohistochemical, and biochemical analyses were performed on whole retinas dissected after 7 or 11 weeks after diabetes induction.
Results: Diabetes was successfully induced in rats as shown by glycemic levels >250 mg/dL. The NGF levels increased in diabetic retinas at 7 weeks and decreased at 11 weeks, while VEGF levels increased at all time points. The RGC loss in diabetic retinopathy worsened with anti-NGF administration, which did not alter retina VEGF levels significantly. Administration of NGF eyedrops restored TrkA levels in the retina, and protected RGCs from degeneration without influencing VEGF levels.
Conclusions: The early increase of NGF in diabetic retina might be an endogenous response for protecting RGCs from degeneration. This protective mechanism is impaired at 11 weeks following diabetes induction, and results in a marked RGC degeneration that is improved by exogenous NGF administration and worsened by anti-NGF. The observed NGF-induced neuroprotection on damaged RGCs was not associated with changes in VEGF retina levels, which were constantly high in diabetic rats and were not altered by anti-NGF administration.
European journal of ophthalmology 09/2013; · 0.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Abstract The nerve growth factor (NGF) belongs to a family of neurotrophic factors called neurotrophins. It was discovered as a molecule that stimulates the survival and maturation of developing neurons in the peripheral nervous system and has later been shown to protect adult neurons in the degenerating mammalian brain. Basic and clinical studies have been undertaken to use NGF as a therapeutic agent aimed at restoring and maintaining neuronal function in the central nervous system and to determine the mechanisms to safely deliver the molecule into the brain. Recent studies have also recognized that the role of NGF extends far beyond the horizon of nerve cells and even beyond the peripheral and central nervous system. Studies published from our laboratory have shown that topical application of NGF possesses a protective action on human pressure ulcer, corneal ulcer and glaucoma. Here, we will review these studies, supporting the therapeutic potential of NGF.
[show abstract][hide abstract] ABSTRACT: The first cell growth factor, nerve growth factor (NGF), was discovered by Rita Levi-Montalcini (RLM) in the early 1950's. Originally identified as neurite outgrowth-stimulating factor, later studies revealed that non-neuronal cells, including immune cells, endothelial cells, cardiomyocytes, pancreatic beta cells, prostate epithelial and adipose tissue cells, were also targets for and/or sources of NGF. Nerve growth factor is well recognized as mediating multiple biological phenomena, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. Consequently, NGF and other members of the neurotrophin family are implicated in the pathogenesis of a large spectrum of neuronal and non-neuronal diseases, ranging from Alzheimer's and other neurodegenerative diseases to atherosclerosis and cardiometabolic disorders. Recent studies have demonstrated the therapeutic potentials of NGF in these conditions, including ocular and cutaneous diseases. NGF TrkA receptor antagonists emerged as novel drugs for pain, prostate and breast cancer, melanoma, and urinary bladder syndromes. Here we briefly describe the "unpredictable" ideogenesis of the discovery of NGF, a eureka in the neuroscience.
Cell Biology International 03/2013; · 1.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Diabesity is a new term which refers to type 2 diabetes mellitus and obesity found in one individual, hence Homo diabesus. Previously we presented our hypothesis of metabo-trophic factors (MTF), also termed metabotrophins. Onward we described Homo obesus (man obese) as a metabotrophin-deficient species. Now -as a phenotypic variety of this species -we introduce H. diabesus. Endogenous MTF are in general signaling proteins able to improve cardiovascular and metabolic homeostasis including that of lipids, glu-cose, energy, inflammation, angiogenesis, and cognition. Hence pharmacological ma-nipulations of the secretion and/or signaling of MTF might bring a therapeutic benefit for H. diabesus. Here we Dance Round the hypothesis that deficit and/or dysfunction of MTF may lead to diabesity. Arguably, an updated list of MTF including nerve growth factor, brain-derived neurotrophic factor, adiponectin, humanin, irisin and other adi-pose-and nonadipose-derived bioactive molecules is presented. Overall this may culti-vate a novel pathogenic and therapeutic thinking for cardiometabolic disease.
[show abstract][hide abstract] ABSTRACT: Diabetic polyneuropathy (DPN), characterized by early hyperalgesia and increased nerve growth factor (NGF), evolves in late irreversible neuropathic symptoms with reduced NGF support to sensory neurons. Electroacupuncture (EA) modulates NGF in the peripheral nervous system, being effective for the treatment of DPN symptoms. We hypothesize that NGF plays an important pathogenic role in DPN development, while EA could be useful in the therapy of DPN by modulating NGF expression/activity. Diabetes was induced in rats by streptozotocin (STZ) injection. One week after STZ, EA was started and continued for three weeks. NGF system and hyperalgesia-related mediators were analyzed in the dorsal root ganglia (DRG) and in their spinal cord and skin innervation territories. Our results show that four weeks long diabetes increased NGF and NGF receptors and deregulated intracellular signaling mediators of DRG neurons hypersensitization; EA in diabetic rats decreased NGF and NGF receptors, normalized c-Jun N-terminal and p38 kinases activation, decreased transient receptor potential vanilloid-1 ion channel, and possibly activated the nuclear factor kappa-light-chain-enhancer of activated B cells (Nf- κ B). In conclusion, NGF signaling deregulation might play an important role in the development of DPN. EA represents a supportive tool to control DPN development by modulating NGF signaling in diabetes-targeted neurons.
Evidence-based Complementary and Alternative Medicine 01/2013; 2013:652735. · 1.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: At the end of the nineteenth century, it was envisaged by Santiago Ramon y Cajal but has not been proven that life at the neuronal level requires trophic support. The proof was obtained in the early 1950’s by work initiated by Rita Levi-Montalcini (RLM) discovering the nerve growth factor (NGF). Today, NGF and its relatives collectively designated neurotrophins are well recognized as mediators of multiple biological phenomena in health and disease, ranging from the neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. Consequently, NGF and other neurotrophins are implicated in the pathogenesis of a large spectrum of neuronal and non-neuronal diseases, ranging from Alzheimer’s and other neurodegenerative diseases to atherosclerosis and other cardiometabolic diseases. Recent studies demonstrated the therapeutic potentials of NGF in these diseases including ocular and cutaneous diseases. Whereas NGF TrkA receptor antagonists emerged as novel drugs for pain, prostate and breast cancer, melanoma, and urinary bladder syndromes. Altogether, NGF’s multiple potential in health and disease is briefly described here.
[show abstract][hide abstract] ABSTRACT: the 1986 Nobel Prize win-ner in Physiology or Medicine for the discovery of nerve growth factor (NGF), died Sunday, 30 December 2012, at her home in Rome, Italy. She was 103 years old. Her amazing journey in Eureka-land started from her "pri-vate laboratory" in Turin which she named Robinson Crusoe, later on through Viktor Hamburger's Department of Zool-ogy of Washington University in St Louis, MO and in Herta Mayer's Tissue Culture Laboratory in Rio de Janeiro to Rome, Italy where in 1962, Levi-Montalcini became Director of the Institute of Cell Biology, splitting her time between St Louis and Rome until 1977. Levi-Montalcini's NGF provided a conceptual framework for the formulation of the neurotrophic hypothesis: particu-lar neuronal types require trophic ("nutritional") factor(s) for neurite growth and neurotransmitter production for proper function and survival. Her data on the prototype neurotrophic factor, NGF, triggered an unprecedented search for a family of related proteins now commonly called neurotrophins. More importantly, Levi-Montalcini's NGF determined a new concept of biology, that cells require specific protein signals for differentiation and survival, that is, the general theory of cell growth factors. All this resulted in the discovery of hundreds of growth factors that affect almost all facets of cell biology. In analogy with Mendelevium (Md), Einsteinium (Es) and Fermium (Fm) in Dimitri Mendeleev's Periodic Table of chemical elements, we may now introduce NGF as Mon-talcinium (Mt) in the Periodic Table of biomolecules. Her centennial life created the scientific bridge between two millenia, a path followed by many generations. This is the guarantee of her "presence in the absence".
[show abstract][hide abstract] ABSTRACT: The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher's attention, in view of possible clinical use in Alzheimer's disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases.
Journal of Translational Medicine 11/2012; 10(1):239. · 3.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Purpose We aimed to evaluate the NGF pathway and its influence on corneal healing mechanisms in normal conditions and in an animal model of corneal denervation induced by capsaicin. Methods Peripheral sensory damage was induced in rat pups by subcutaneous injection of capsaicin and the effects evaluated by hot-plate test, corneal nerve count, and tear secretion. Corneal damage was induced in capsaicin-treated and untreated rats by epithelial scraping. Healing rate, NGF pathway (NGF, TrkA, p75), and the stem cell marker p63 were evaluated by RT-PCR, ELISA, Western Blot and immunohistochemistry. The effects of exogenous NGF administration as eye drop formulation were also tested. Results Capsaicin treatment induced a significant reduction of peripheral sensitivity, corneal innervation, tear secretion and corneal healing rate. The ocular effects of capsaicin treatment were associated with a NGF pathway alteration. NGF eye drop treatment aided corneal healing mechanisms through a significant increase in the NGF receptors TrkA and p75, and in the stem cell marker p63. Conclusions In this study we show that an alteration in NGF pathway is responsible for a delay in corneal healing in an animal model of sensory denervation. Moreover, we show that NGF eye drop administration modulates corneal innervation, epithelial cell healing, and corneal stem cells. These findings may trigger further research on the role of the NGF pathway in limbal stem cell deficiency.
[show abstract][hide abstract] ABSTRACT: VEGF and NGF are known to modulate corneal healing, neovascularisation and tear secretion. While a VEGF-NGF cross talk has been recently shown to modulate corneal healing in rats, it is not known whether it also plays a role in the regulation of lacrimal function. In this study we aim to investigate the effects of anti-VEGF eye drop treatment on lacrimal gland function and on the local expression of VEGF and NGF in rats. Tear function was measured in 3 months old rats by modified Schirmer test at baseline and after 3 weeks of topical anti-VEGF eye drop treatment. Whole lacrimal glands from rats were removed after treatment and analysed by ELISA for VEGF and NGF levels. To investigate if the effects of anti-VEGF were mediated by changes in the NGF-pathway, we repeated the experiments in RCS rats, a strain with NGF-pathway impairment associated with decreased tear flow. After topical treatment with anti-VEGF eye drops, an increase in tear secretion was observed in both wild-type and RCS rats. A significant decrease of VEGF levels was also observed in lacrimal glands of both RCS and SD rats, accompanied by a significant increase in NGF levels. Inhibition of VEGF at the ocular surface in rats results in changes of tear function and lacrimal gland levels of VEGF and NGF. Further studies on the VEGF/NGF cross-talk at the ocular surface may expand our knowledge on the pathogenesis of several diseases characterized by tear dysfunction.
Archives italiennes de biologie 03/2012; 150(1):15-21. · 1.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recently, the secretory -endocrine, paracrine and autocrine -phenotype of adipose tissue, consisting of adipo-cytes, stromovascular cells and immune cells, has increasingly been recognized. In humans, adipose tissue is partitioned into two large depots (subcutaneous and visceral) and many small depots associated with heart, blood vessels, major lymph nodes, pancreas, prostate gland, ovaries. Accordingly, two major subfields of adipobiology have emerged, adi-poendocrinology (studying the endocrine activity of adipose tissue) and adipoparacrinology (studying the paracrine activ-ity of adipose tissue). Traditional concept of the pathogenesis of atherosclerosis focuses on intimal surface, where endo-thelial dysfunction expressed by an "inside-out" inflammatory process triggers the formation of atherosclerotic plaque. The present short review highlights evidence for the possible role of dysfunctional paracrine activity of epicardial adipose tissue and of periadventitial adipose tissue in an "outside-in" pathway in the development of coronary and peripheral athe-rosclerosis, respectively. Such a paradigm may have various therapeutic applications including in coronary artery bypass surgery.
[show abstract][hide abstract] ABSTRACT: White adipose tissue (WAT) is a dynamic multicellular assembly composed of adipocytes and stromovascular cells, including fibroblasts, endothelial and immune cells, nerve fibers, and stem cells. In humans, WAT is a responsive and secretory (endocrine and paracrine) tissue partitioned into two large
depots (subcutaneous and visceral) and many small depots associated with the heart, blood vessels, major lymph nodes, prostate gland, ovaries and mammary glands. This short review conceptualizes evidence for the paracrine activity of adipose tissue in founding a new research field, designated adipoparacrinology. Here we focus on (i) epicardial and periadventitial adipose tissue in atherogenesis, (ii) mammary gland-associated adipose tissue in breast cancer, and (iii) periprostatic adipose tissue in prostate cancer. Other examples include: (i) mesenteric adipose tissue in Crohn’s disease, (ii) lymph node-associated (perinodal) adipose tissue in Crohn’s disease and HIV-associated adipose redistribution syndrome, (iii) infrapatellar fat pad (Hoffa’s fat pad) in knee osteoarthritis, (iv) orbital adipose tissue in thyroid-associated (Graves’) ophthalmopathy, and (v) parasellar region-associated adipose tissue in brain disorders. The therapy aspect of adipoparacrinology is also discussed.
Key Words: Adipokines, atherosclerosis, breast cancer, epicardial adipose tissue, NGF, periadventitial adipose tissue, periprostatic adipose tissue, prostate cancer
[show abstract][hide abstract] ABSTRACT: Effects of 3-month exposure to microgravity environment on the expression of genes and proteins in mouse brain were studied. Moreover, responses of neurobiological parameters, nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), were also evaluated in the cerebellum, hippocampus, cortex, and adrenal glands. Spaceflight-related changes in gene and protein expression were observed. Biological processes of the up-regulated genes were related to the immune response, metabolic process, and/or inflammatory response. Changes of cellular components involving in microsome and vesicular fraction were also noted. Molecular function categories were related to various enzyme activities. The biological processes in the down-regulated genes were related to various metabolic and catabolic processes. Cellular components were related to cytoplasm and mitochondrion. The down-regulated molecular functions were related to catalytic and oxidoreductase activities. Up-regulation of 28 proteins was seen following spaceflight vs. those in ground control. These proteins were related to mitochondrial metabolism, synthesis and hydrolysis of ATP, calcium/calmodulin metabolism, nervous system, and transport of proteins and/or amino acids. Down-regulated proteins were related to mitochondrial metabolism. Expression of NGF in hippocampus, cortex, and adrenal gland of wild type animal tended to decrease following spaceflight. As for pleiotrophin transgenic mice, spaceflight-related reduction of NGF occurred only in adrenal gland. Consistent trends between various portions of brain and adrenal gland were not observed in the responses of BDNF to spaceflight. Although exposure to real microgravity influenced the expression of a number of genes and proteins in the brain that have been shown to be involved in a wide spectrum of biological function, it is still unclear how the functional properties of brain were influenced by 3-month exposure to microgravity.
PLoS ONE 01/2012; 7(7):e40112. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Human adipose tissue is partitioned into two large depots (subcutaneous and visceral), and many small depots associated with internal organs, e.g. heart, blood vessels, major lymph nodes, pancreas, prostate gland and ovaries. Since the adipose 'Big Bang' led to the discovery of leptin (Zhang, Proenca, Maffei, Barone, Leopold and Friedman, Nature 1994;372:425-32), adipose tissue has been seen not merely as a lipid store, but as a secretory - endocrine and paracrine - organ, particularly in the pathogenesis of a number of diseases. Accordingly, two major sub-fields of adipobiology have emerged, viz. adipoendocrinology and adipoparacrinology, the latter herein being illustrated by PAAT (periadventitial adipose tissue) in vascular walls. A long-standing paradigm holds that the vascular wall consists of three coats, tunica intima, tunica media and tunica adventitia. It is now imperative that 'to further elucidate vascular function, we should no longer, as hitherto, separate adventitia and PAAT from the vascular wall, but keep them attached and in place, and subject to thorough examination' (Chaldakov, Fiore, Ghenev, Stankulov and Aloe, Int Med J 2000;7:43-9; Chaldakov, Stankulov and Aloe, Atherosclerosis 2001;154:237-8; Chaldakov GN, Stankulov IS, Fiore M, Ghenev PI and Aloe L, Atherosclerosis 2001;159:57-66). From the available data, we propose that it is time to rethink about vascular wall composition, and suggest that the PAAT may be considered the fourth and outermost vascular coat, hence, tunica adiposa (regarding the proximal segment of coronary artery, it is the innermost part of the EAT (epicardial adipose tissue) situated around the coronary adventitia). Its significance in the pathogenesis and therapy of CMDs (cardiometabolic diseases), particularly atherosclerosis and hypertension, requires further basic, translational and clinical studies.
Cell Biology International 12/2011; 36(3):327-30. · 1.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: The nerve growth factor (NGF) is a signaling protein, discovered by Rita Levi-Montalcini in the early 1950's for its effect on growth and differentiation of specific populations of neurons of the peripheral nervous system. Originally identified as neurite outgrowth-stimulating factor, later studies revealed that the purified molecule has a number of target cells in the central nervous system and on nonneuronal cells. Moreover, recent studies showed the potential therapeutic properties of NGF in neuropathies of the central and peripheral nervous system and diseases of the eye and skin. Here I briefly describe the discovery of NGF, the early studies of Rita LeviMontalcini, a pioneer in modern neuroscience, and my scientific and human experience working in her laboratory for over 40 years.
Archives italiennes de biologie 06/2011; 149(2):175-81. · 1.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypoxic-ischemic injuries (HII) of the brain, optic pathways, and skin are frequently associated with poor neurological and clinical outcome. Unfortunately, no new therapeutic approaches have been proposed for these conditions. Recently, experimental and clinical studies showed that nerve growth factor (NGF) can improve neurological deficits, visual loss and skin damage after HII. Based on these studies, we report the effects of NGF administration in different lesions of the brain, optic pathways and skin. 2.5S NGF purified and lyophilized from male mouse submaxillary glands was utilized for the treatment. NGF administration was started in absence of recovery after conventional and standardized treatment. One mg NGF was administered via the external catheter into the brain, by drop administration in the eye, and by subcutaneous administration in the skin. We treated 4 patients: 2 children with hypoxic-ischemic brain damage, an adult patient with an optic glioma-induced visual loss and a child with a severe crush syndrome of the lower left limb. After NGF treatment, we observed an amelioration of both neurological and electrophysiological function of the brain, a subjective and objective improvement of visual function, and a gradual improvement of ischemic skin lesion. No side effects were related to NGF treatment in all patients studied. Our observation shows that NGF administration may be an effective and safe adjunct therapy in patients with severe HII. The beneficial and prolonged effect on nerve function suggests a neuroprotective mechanism exerted by NGF on the residual viable neurological pathways of these patients.
Archives italiennes de biologie 06/2011; 149(2):275-82. · 1.43 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nerve Growth Factor (NGF) and its receptors TrkA and p75 are expressed in physiological states in the anterior and posterior segments of the human eye, where they exert several tissue-specific functions. The roles played by NGF in the homeostasis of the eye and in vision are, therefore, crucial and have been widely investigated both in vitro and in vivo, with growing evidence of an NGF-pathway alteration in several ocular diseases. In this review we describe the functions of NGF in health and diseases states of the eye, and discuss the potential therapeutic effectiveness of NGF in preliminary clinical reports performed in severe ocular diseases unresponsive to any standard treatment. In fact, pharmacodynamic studies showing that NGF administered topically on the ocular surface affects not only the ocular surface but is also able to reach the retina, optic nerve and brain, recently opened new perspectives for the treatment of challenging ocular surface diseases, optic nerve diseases, and degenerative diseases of the retina currently lacking an effective therapy.
Archives italiennes de biologie 06/2011; 149(2):283-92. · 1.43 Impact Factor