[Show abstract][Hide abstract] ABSTRACT: State-of the-science (SOS)
(SOS-1) ADIPOBIOLOGY: A RESEARCH FIELD MARKED BY FIVE PARADIGM SHIFTS
George N. Chaldakov1, Luigi Aloe2, Anton B. Tonchev1, Marco Fiore2, Plamen Panayotov3 , Gorana Ranćić4, Neşe Tunçel5, Jerzy Beltowski6, Stoyan Stoev7, Marin Zhelezov1, Peter I. Ghenev8, Alexander Hinev9, Nikolay Evtimov10, Stanislav Yanev11
1Laboratory of Cell Biology, Department of Anatomy and Histology, Medical University, Varna, Bulgaria, 2Institute of Cell Biology and Neurobiology, CNR, Rome, Italy, 3Department of Cardiac Surgery, St Marina University Hospital, Varna, Bulgaria, 4Department of Histology, Medical Faculty, Niš, Serbia, 5Department of Physiology, Medical Faculty, Osmangazi University, Eskişehir, Turkey, 6Department of Pathophysiology, Medical University, Lublin, Poland, 7Department of Forensic Medicine, Medical University, Sofia, Bulgaria, 8Department of Pathology, Medical University, Varna, Bulgaria, 9Urology Clinic, St Marina University Hospital, Varna, Bulgaria, 10Urology Clinic, St Anna University Hospital, Varna, Bulgaria, 11Laboratory of Drug Toxicology, Institute of Neurobiology, BAS, Sofia, Bulgaria
In this candlelight lecture we will start with a brief historical survey. Admittedly, the accumulation of adipose tissue (AT) was linked to obesity. This was known to Hippocrates, who stated that “sudden death is more common in those who are naturally fat than in the lean”. Thomas Short’s book, A Discourse Concerning the Causes and Effects of Corpulency (1727), was the first English language monograph on obesity. The adipocyte, firstly dubbed “fat vesicle”, was recognized as a specific cell type of AT by Hassall (1849). Recently, AT has taken a center stage in many diverse diseases beyond obesity. Based on this intellectual growth process a new field of research, adipobiology, was conceptualized (1). Since the discovery of leptin (1994), AT has undergone five major paradigm shifts (in sense of Thomas Kuhn). The first paradigm shift: from merely a fat storage, AT is now known as a major endocrine and paracrine organ of the human body, producing more than 200 signaling proteins (adipokines) (2). The second paradigm shift: external versus internal adipose depot that spotlights our knowledge about TOFI (thin outside, fat inside) and related phenotypes (3). The third paradigm shift: white versus brown adipocytes, recovering the significance of brown adipobiology (4). The fourth paradigm shift: a link between AT and the human exposome, that is, adipotoxicology (5). The fifth paradigm shift: the involvement of adipokines in the pathogenesis of psychiatric (6) and neurodegenerative diseases, including adipose-Alzheimer (7).
1. Chaldakov GN, Stankulov IS, Hristova MG, Ghenev PI. Adipobiology of disease: adipokines and adipokine-targeted pharmacology. Curr Pharm Des 2003; 9: 1023-1031.
2. Renes J, Mariman E. Application of proteomics technology in adipocyte biology. Mol Biosyst 2013; 9: 1076-1091.
3. Ranćić G, Petrovic A, Sekulovic-Stefanovic L, Bojamic V, Ghenev PI. Adipotopogrpahy: TOFI versus TOTI, or a hidden Homo obesus [Abstract]. In: 1st ISAA, Varna, Bulgaria, 20 October 2007. pp 13-14.
4. Sacks H, Symonds ME. Anatomical locations of human brown adipose tissue: functional relevance and implications in obesity and type 2 diabetes. Diabetes 2013; 62: 1783-1790.
5. Chaldakov GN, Yanev S, Georgiev V. Toxicology of adipose tissue (adipotoxicology) or adipose tissue as a “toxicrine” organ. In: G.N. Pierce et al, editors. Advanced Bioactive Compounds Countering the Effects of Radiological, Chemical and Biological Agents. Chapter 22. pp 253-260. NATO Science for Peace and Security Series A: Chemistry and Biology, Springer Science+Business Media Dordrecht 2013.
6. Wędrychowicz A, Zając A, Pilecki M, Kościelniak B, Tomasik PJ. Peptides from adipose tissue in mental disorders. World J Psychiatr 2014; 4: 103-111.
7. Ranćić G, Fiore M, Pancheva R, Tunçel N, Beltowski J, Zhelezov M, et al. Adipose tissue: the Renaissance marked by four paradigm shifts. Adipobiology 2014; 6: 49-53.
[Show abstract][Hide abstract] ABSTRACT: Alcohol dependence is a major public health problem worldwide. Brain and behavioral disruptions including changes in cognitive abilities are common features of alcohol addiction. Thus, the present study was aimed to investigate spatial learning and memory in 29 alcoholic men undergoing alcohol detoxification by using a virtual Morris maze task. As age-matched controls we recruited 29 men among occasional drinkers without history of alcohol dependence and/or alcohol related diseases and with a negative blood alcohol level at the time of testing. We found that the responses to the virtual Morris maze are impaired in men undergoing alcohol detoxification. Notably they showed increased latencies in the first movement during the trials, increased latencies in retrieving the hidden platform and increased latencies in reaching the visible platform. These findings were associated with reduced swimming time in the target quadrant of the pool where the platform had been during the 4 hidden platform trials of the learning phase compared to controls. Such increasing latency responses may suggest motor control, attentional and motivational deficits due to alcohol detoxification.
[Show abstract][Hide abstract] ABSTRACT: Nerve growth factor (NGF) is the firstly discovered and best characterized neurotrophic factor, known to play a critical protective role in the development and survival of sympathetic, sensory and forebrain cholinergic neurons. NGF promotes neuritis outgrowth both in vivo and in vitro and nerve cell recovery after ischemic, surgical or chemical injuries. Recently, the therapeutic property of NGF has been demonstrated on human cutaneous and corneal ulcers, pressure ulcer, glaucoma, maculopathy and retinitis pigmentosa. NGF eye drops administration is well tolerated, with no detectable clinical evidence of systemic or local adverse effects. The aim of this review is to summarize these biological properties and the potential clinical development of NGF.
Current Neuropharmacology 05/2015; 13(3). DOI:10.2174/1570159X13666150403231920 · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A number of different studies have shown that neurotrophins, including nerve growth factor (NGF) support the survival of retinal ganglion neurons during a variety if insults. Recently, we have reported that that eye NGF administration can protect also photoreceptor degener-ation in a mice and rat with inherited retinitis pigmentosa. However, the evidence that NGF acts directly on photoreceptors and that other retinal cells mediate the NGF effect could not be excluded. In the present study we have isolated retinal cells from rats with inherited reti-nitis pigmentosa (RP) during the post-natal stage of photoreceptor degenerative. In presence of NGF, these cells are characterized by enhanced expression of NGF-receptors and rhodopsin, the specific marker of photoreceptor and better cell survival, as well as neuritis outgrowth. Together these observations support the hypothesis that NGF that NGF acts directly on photoreceptors survival and prevents photoreceptor degeneration as previously suggested by in vivo studies.
PLoS ONE 04/2015; PLoS ONE 10(4): e0124810.(4). DOI:10.1371/journal.pone.0124810 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been shown that topical nerve growth factor (NGF) administration induces healing action on human cutaneous, corneal and pressure ulcers, glaucoma, maculopathy and retinitis pigmentosa suggesting a therapeutic potential of NGF in human ophthalmology and cutaneous ulcers. A similar therapeutic suggestion has emerged for the NGF gene therapy of Alzheimer's disease and ischemic heart injury. Moreover, over the last few years, the role and biological properties of NGF have also been investigated with transgenic mice over-expressing and down-expressing NGF. However, the results obtained with these transgenic mice seem suitable to confirm and/or support the evidence obtained with exogenous administration of NGF regarding the suggested clinical potentiality of NGF. The aim of the present brief review is to report and comment on these two different findings of NGF's healing properties.
[Show abstract][Hide abstract] ABSTRACT: Nerve growth factor (NGF) is a neurotrophin which promote and regulate the survival of neurons in the peripheral nervous system. We aimed to evaluate the nasal NGF expressions of mast cells in healthy patients after stimulation with sterilized isotonic solution delivered at high pressure.
The first part of the study was made with 21 voluntary individuals. The middle third of the inferior turbinate epithelial cells on the right nostril was scraped using a sterile curette and indicated as (pre), than a spray of sterilized isotonic solution at high pressure on the left nostril was delivered and 25 minutes later a similar stimulation was delivered on the same nostril. The stimulation was made with a specific spray. The middle third of the inferior turbinate epithelial cells on the left nostril was scraped using a sterile curette and indicated as (post).
Forced nasal stress induced by local delivery of high pressure physiological solution causes an increase in the number of mast cells and enhances level of NGF in the nasal fluid compared to the control subjects. So based on the first part of our study, since NGF is universally known as effective in protection and repairing of neural cells damage, we started the second part and gave a treatment on the same patients, to increase NGF levels with a six months daily therapy and observed the variations in Sensorineural Hearing Loss (SNHL) and tinnitus intensity from the beginning to the end of the therapy. All patients received sterilized isotonic solution at high pressure (pression emission level: PEL): 7 g/sec for 0.5 sec (emission time: ET) in both nostrils. 25 minutes later a similar stimulation was delivered twice a day. The control group (21 pts) received normal therapy with betahistine dihydrochloride 16 mg twice a day.
Upon acuphenometry, there was a lower intensity of tinnitus and the improvement was signaled by the patients. Patients with SNHL treated with conventional therapy had a slight worsening, while the patients treated with our new therapy which increased NGF levels, showed improvement of hearing. This new therapy represents a new therapy of SNHL, tinnitus and hearing disorders.
[Show abstract][Hide abstract] ABSTRACT: Today’s achievements in systems biology and -omics sciences have facilitated a shift from studying individual molecules and tissues to characterising molecules and cells holistically. In this article, we attempt to discuss the status of a much-needed coherent view that integrates studies on neurobiology and adipobiology, as well as those on diabetes and obesity. Globally, cardiometabolic diseases (atherosclerosis, hypertension, type 2 diabetes mellitus, obesity, diabesity, and metabolic syndrome) are the most prevalent pathologies. In 2000, Astrup and Finer (Obes Rev 1: 57-59) wrote the following: “Since type 2 diabetes is obesity dependent, and obesity is the main aetiogical cause of type 2 diabetes, we propose the term ‘diabesity’ should be adopted.” Arguably, the research field of adipobiology has witnessed three major paradigm shifts since the discovery of leptin, an adipose-derived hormone, in 1994. Various neuroendocrine and neurotrophic factors are included in the growing list of endocrine and paracrine adipose-secreted signaling proteins collectively designated adipokines. These findings open a novel field of research known as neuroadipocrinology, a component of neuroendocrinology. Adipokines, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), mediate multiple biological processes, such as food intake, immunity, inflammation, memory, mood, and metabolism. The effects on metabolism involve the maintenance of glucose, lipid and energy homeostasis as well as cardioprotection, neuroprotection, and aging. In this article, we highlight the role of metabotrophic factors (MTF) and the adipose- and nonadipose-derived biomolecules that mediate these effects. Recent results demonstrate that circulating and tissue levels of certain MTFs, e.g., adiponectin, NGF, BDNF, glucagon-like protein-1, sirtuin-1, interleukin- 10, and aquaporin-7, are altered in cardiometabolic diseases, including diabesity. Overall, this may cultivate a novel thinking for diabesity, herein also referred to as Homo diabesus.
Serbian Journal of Experimental and Clinical Research 06/2014; 15(2):61-69. DOI:10.2478/sjecr-2014-0008,
[Show abstract][Hide abstract] ABSTRACT: The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an increased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deficits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.
Neural Regeneration Research 05/2014; 9(10):1025-30. DOI:10.4103/1673-5374.133161 · 0.22 Impact Factor
[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 concentric 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 hypertension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltration of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. However, 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 04/2014; 5:130. DOI:10.3389/fimmu.2014.00130
[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
[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; 24(2). DOI:10.5301/ejo.5000359 · 1.07 Impact Factor
[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 08/2013; 37(8). DOI:10.1002/cbin.10098 · 1.93 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: 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 04/2013; 2013(12):652735. DOI:10.1155/2013/652735 · 1.88 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: At the end of the 19(th) century, it was envisaged by Santiago Ramon y Cajal, but not, 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, 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. Furthermore, 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.
Balkan Journal of Medical Genetics 03/2013; 30(1):4-7. DOI:10.5152/balkanmedj.2013.003 · 0.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diabetes often correlates with tau phosphorylation and the development of Alzheimer's disease. Both are associated with brain cholinergic dysfunction that could benefit from nerve growth factor (NGF)-based therapies. Electroacupuncture (EA) improves brain NGF availability and action. Here we assessed the variations of NGF and tau phosphorylation in the cortex and hippocampus, as well as the expression of choline acetyltransferase in the basal forebrain following diabetes induction and EA in adult rats. We found that EA counteracts diabetes-associated tau hyperphosphorylation and decreases in NGF and choline acetyltransferase, suggesting a possible beneficial effect of EA on brain cholinergic system in diabetes.