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Letteratura scientifica selezionata sul tema "Alkaptonuria"

Autore: Grafiati

Pubblicato: 14 marzo 2023

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Articoli di riviste sul tema "Alkaptonuria"

Tharini, GK, Vidhya Ravindran, N. Hema, D. Prabhavathy e B. Parveen. "Alkaptonuria". Indian Journal of Dermatology 56, n. 2 (2011): 186. http://dx.doi.org/10.4103/0019-5154.80415.

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Bassily, Emmanuel, M. Cody O'Dell, Brad Homan e Christopher Wasyliw. "Alkaptonuria". Orthopedics 39, n. 4 (9 maggio 2016): e810-e813. http://dx.doi.org/10.3928/01477447-20160503-03.

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Islam, Md Nazrul, SM Kamal, Sk Amir Hossain e Sirajul Islam. "Alkaptonuria". Bangladesh Medical Journal Khulna 49, n. 1-2 (7 marzo 2017): 37–39. http://dx.doi.org/10.3329/bmjk.v49i1-2.31825.

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Alkaptonuria is a rare metabolic autosomal recessive disorder. It occurs due to lack of an enzyme that results in deposition of homogentisic acid in various tissues. A male patient of 45 years presented with back pain for 20 years and multiple joint pain for 10 years. Patient has multiple nodules in both pinnae and pigmentation in both sclerae. His urine turns black upon standing. These findings are compatible with the diagnosis of Alkaptonuria.Bang Med J (Khulna) 2016; 49 : 37-39

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Indiran, Venkatraman, Dillibabu Ethiraj, Kanakaraj Kannan e ThirumalasettyRamachandra Prasad. "Alkaptonuria". Indian Journal of Rheumatology 13, n. 3 (2018): 209. http://dx.doi.org/10.4103/injr.injr_67_18.

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Brenton, D. P., e S. Krywawych. "Alkaptonuria". Clinics in Rheumatic Diseases 12, n. 3 (dicembre 1986): 755–69. http://dx.doi.org/10.1016/s0307-742x(21)00578-6.

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Mistry, Jemma B., Marwan Bukhari e Adam M. Taylor. "Alkaptonuria". Rare Diseases 1, n. 1 (gennaio 2013): e27475. http://dx.doi.org/10.4161/rdis.27475.

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Harper, P. S. "Alkaptonuria". Journal of Medical Genetics 22, n. 2 (1 aprile 1985): 159. http://dx.doi.org/10.1136/jmg.22.2.159.

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Thapa, Manish, M. Bhatia e V. K. Maurya. "Alkaptonuria". Medical Journal Armed Forces India 74, n. 4 (ottobre 2018): 394–96. http://dx.doi.org/10.1016/j.mjafi.2017.06.006.

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Carlesimo, M., P. Bonaccorsi, G. Tamburrano, I. Carboni, A. Parisi e S. Calvier. "Alkaptonuria". Dermatology 199, n. 1 (1999): 70–71. http://dx.doi.org/10.1159/000018186.

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El-Sayed Ahmed, Magdy M., Omar Hussain, David A. Ott e Muhammad Aftab. "Severe Aortic Valve Stenosis Due to Alkaptonuric Ochronosis". Seminars in Cardiothoracic and Vascular Anesthesia 21, n. 4 (14 luglio 2017): 364–66. http://dx.doi.org/10.1177/1089253217720284.

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Alkaptonuric ochronosis is a rare cause of aortic valve stenosis. We report the case of a 61-year-old female patient with alkaptonuria who presented to our institute with the clinical picture of severe aortic valve stenosis, which was confirmed by transthoracic echocardiography. On aortotomy, she was noted to have an impressive black discoloration of ascending aorta and the aortic root complex involving the aortic valve leaflets. She underwent an uneventful aortic valve replacement. She was discharged home 10 days postoperatively.

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Più fonti

Tesi sul tema "Alkaptonuria"

GAMBASSI, SILVIA. "Novel insights into alkaptonuria physiopathology". Doctoral thesis, Università di Siena, 2016. http://hdl.handle.net/11365/1004463.

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Alkaptonuria (AKU) is an ultra-rare genetic disease resulting from a deficient activity of the enzyme homogentisate 1,2- dioxygenase (HGD), responsible for the catabolism of the aromatic amino acids Phenylalanine and Tyrosine. This condition leads to the accumulation of a toxic metabolite, HGA and of its product of oxidation BQA, whose polymerization generates melanin-like aggregates, with amyloidogenic properties, leading to the phenomenon of “Ochronosis”. The most affected structures by the deposition of these ochronotic aggregates are joints, which undergo severe arthropathy; therefore, articular cartilage is the main investigated tissue for the comprehension of AKU physiopathology. Articular cartilage homeostasis is maintained by articular chondrocytes, which have an important role in the synthesis and release of extracellular matrix (ECM) components, essential to properly respond to mechanical compression processes the tissue is constantly subjected to. This mechanism is mediated by chondrocyte cytoskeleton, including the microtubule-based organelle primary cilium, which exerts its function through the activation of the Hedgehog (Hh) signaling pathway. On the basis of the previous considerations, for the aims of this thesis, the set-up of in vitro AKU cellular and tissue models, was fundamental to counteract problems related to the collection of AKU samples, due to the rarity of the disease. Both experimental models were properly characterized, by highlighting the role of HGA in mediating pigment deposition and cartilage degradation processes, through histological and cytological analyses and immunofluorescence assays. Results showed that the ochronotic pigment deposits following HGA treatment lead to an oxidative stress status and to the accumulation of serum amyloid A (SAA) protein in the cartilaginous tissue. Another in vitro model was used to analyse the ability of AKU chondrocytes to respond to mechanical loading in terms of production of ECM components, by applying a 10% strain on adherent cell cultures. AKU chondrocytes resulted unable to respond properly to mechanical strain and HGA seemed to be involved in this altered responsiveness. Afterwards, a deep investigation of the cytoskeleton characteristics of AKU chondrocytes was performed, mainly by focusing on the interaction of each cytoskeletal marker with the amyloidogenic protein serum amyloid A (SAA). An in situ proximity ligation assay confirmed the co-localization of cytoskeletal marker with SAA, thus explaining the severe alterations observed in AKU cytoskeleton. Furthermore, another cytoskeletal component was characterized, the primary cilium, both investigating on its structural features and on its function in terms of Hedgehog (Hh) signaling activation. Primary cilia of AKU chondrocytes resulted shorter than normal chondrocytes and HGA treatment led to the same ciliary phenotype. In order to investigate the activation of the Hh pathway, the expression of the constitutive activator of the pathway (Gli-1) was evaluated both at the gene and at the protein level. This protein was found overexpressed in AKU/HGA-treated chondrocytes. Finally, given the role of Hh activation in mediating processes of cartilage degradation in osteoarthritis-like diseases, a therapeutic approach based on the inhibition of the Hh signaling was adopted, by using treatment with lithium chloride and with small molecule antagonists of the Hh receptor Smoothened (Smo). All the testing compounds resulted efficient in inhibiting Hh signal and in restoring cilia lengths, suggesting the use of these compounds as a potential therapeutic approach for the treatment of AKU.

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Galderisi, Silvia. "Recent discoveries on the ultra-rare disease Alkaptonuria". Doctoral thesis, Università di Siena, 2020. http://hdl.handle.net/11365/1096275.

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Rare diseases by definition are pathologies that affect small numbers of people in the worldwide. The rarity of some diseases creates important challenges, more for patients and their family but also for researchers and clinicians that attempt to achieve the best care for affected people. Indeed researchers have to face with heterogeneity of rare diseases and their dispersed nature all over the word complicating even more the way that leads to the best knowledge of these pathologies. The aim of this work is to give a contribution to a better knowledge on Alkaptonuria rare disease, the first inborn error of metabolism recognized but still little studied. Alkaptonuria (AKU) is an ultra-rare genetic disease caused by mutations on homogentisate 1,2-dioxygenase (HGD) enzyme responsible for the catabolism of phenylalanine and tyrosine amino acids. The deficient activity of HGD enzyme leads to the failed metabolization of the homogentisic acid (HGA), which accumulates in connective tissues in form of a black pigment called “ochronotic” melanin-like pigment. The system most affected by pigmentations is the osteoarticular one, especially cartilage, which is the main investigated tissue for the study of the AKU disease. In the present project, AKU pathology was studied in different field of the disease (see graphical abstract). The first step of the analysis was an in silico study the HGD structure in order to identify the oxygen pathways that allow O2 molecule to reach the active site and help the enzyme to perform the enzymatic function. A specific route was identified as the principal passage for the oxygen, thanks also to the correspondence of this pathway with a transient pocket, which assumes an important role in the oxygen transition. An AKU cellular model was set up, in order to evaluate the role of HGA in the alteration of the autophagic processes. The application of an AKU in vitro model was important to overcome the rarity of AKU samples to collect. For the first time it was demonstrated that the accumulation of HGA can alter the autophagic processes in human chondrocytic cell line, inducing oxidative stress, mitochondrial damage and activation of chondroptotic processes. Afterwards, an investigation on the role HGA in the alteration of cytoskeleton structure of AKU chondrocytic model was performed, analysing the principal components of the cytoskeletal network, actin, vimentin and tubulin. These alterations have an impact on the extracellular matrix (ECM) organization of alkaptonuric cartilage leading to a pathological tissue. Another aspect analysed in this project is the alteration of the number and disposition of 2 lysosomes in chondrocytic AKU model. After HGA treatment in chondrocytes, lysosomes appeared located in the periphery of cells and, in the perinuclear region of cell, they resulted more acidic in comparison with control. Moreover black spots were found in lysosomes of AKU chondrocytes model, hypothesizing that lysosomes try to eliminate the black pigment contrasting its accumulation, toxic for cells. The toxicity of the ochronotic pigment accumulation was already in depth studied, but less is known about its structure and how HGA polymerizes, creating the ochronotic dark pigment, the main cause of tissue destruction. Through an EPR analysis conducted on AKU dark pigmented cartilage, the formation of two stable radicals on carbon and oxygen were identified. The peak that results only from the EPR analysis of the pigmented black cartilage is due to a signal of melanin-like radicals, probably of a semiquinon structure. It is possible to confirm that the polymerization of HGA takes place by radical reaction. The formation of radical species was also demonstrated after alkalization of AKU urine samples. The addiction of an alkaline solution to AKU urine, in which the concentration of HGA is high, leads to the immediate darkening of the urine colour, activating the instantaneous formation of HGA polymer. Through NMR spectroscopy, this reaction was monitored during the time. Peaks reconnected to the HGA molecule started to decrease in intensity when alkaline solution was added, but no new species were registered with NMR, hypothesising the formation of radical species non visible with NMR. A metabolic analysis was then performed on AKU urine in comparison with control samples. The alteration of the amount of some metabolites, glycine, tyrosine and creatinine, was observed in AKU urine samples, suggesting an increase in the degeneration of articular cartilage and a renal damage of AKU patients, of which glycine and creatinine are markers. Through this metabolic analysis, the measurement of metabolites in AKU urine can be an important method for monitoring kidney and joint damage status by analysing creatinine and glycine concentrations.

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Taylor, Adam Michael. "An investigation of the pathogenesis of ochronosis in alkaptonuria (AKU)". Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539527.

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Lewis, R. "Consequences and prevention of elevated circulating tyrosine during nitisinone therapy in alkaptonuria". Thesis, Liverpool John Moores University, 2018. http://researchonline.ljmu.ac.uk/8867/.

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Abstract (sommario):

Alkaptonuria (AKU) is an ultra-rare, autosomal recessive disorder of tyrosine catabolism due to mutations within the homogentisate 1,2-dioxygenase (HGD) gene. The resulting enzyme deficiency leads to accumulation of homogentisic acid (HGA) and deposition of melanin-like pigment polymers in the connective tissues of the body in a process called ochronosis. This leads to debilitating early onset osteoarthropathy, renal damage and aortic valve disease. As a multisystem disorder, AKU results in progressive and chronic pain and severe morbidity. Most management approaches for AKU are palliative and rely largely on analgesia and arthroplasty. Several therapeutic approaches have been tested with low degrees of clinical effectiveness. Nitisinone is a promising drug that blocks the enzyme catalysing the formation of HGA and thus lowers its plasma concentration. HGA lowering therapy has been widely used in another rare inborn error of metabolism, Hereditary Tyrosinemia type 1 (HT-1) for over 20 years. Nitisinone is highly efficacious in terms of its metabolic effect as it decreases HGA to very low levels, but there is limited toxicology data available for its use in AKU. There are also concerns relating to the adverse side effects of elevated tyrosine and potential neurotoxicity if treatment was implemented in children. The work presented within this thesis presents novel findings to inform the future licensing process for the use of nitisinone in AKU and investigates the safety of implementing treatment in younger patients. Nitisinone treatment had no detrimental effect on learning, memory or motor function in young AKU or wild type mice. The thesis also includes new data from mouse dosing studies concerning the correlation between plasma HGA and ochronotic pigmentation and reveals that plasma HGA must be lowered to a critical level before pigmentation is beneficially reduced. Finally, this thesis reports on the lability of the arteriovenous metabolome relating to AKU and initiates a discussion relating to the HPPA to HPLA excretory conversion pathway along with important considerations for collection, analysis and comparison of blood samples in future studies.

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Taylor, Leah Frances. "Assessment of disease progression in the rare disease alkaptonuria by quantitative image analysis". Thesis, University of Liverpool, 2018. http://livrepository.liverpool.ac.uk/3022580/.

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Abstract (sommario):

Alkaptonuria (AKU) arises from a genetic deficiency of homogentisate 1,2 dioxygenase (HGD) an enzyme involved in tyrosine metabolism. AKU is characterised by high circulating homogentisic acid (HGA) some of which is deposited as ochronotic pigment in connective tissues, mainly cartilage, leading to multisystemic damage dominated by premature severe osteoarthropathy. Pathological changes in the spine as a result of ochronosis can be imaged using fluorine-18 labelled sodium fluoride positron emission tomography (18F-NaF PET). This imaging modality allows quantitative assessment of focal bone remodelling by measuring the uptake of 18F into the hydroxyapatite crystal of bone and calcified cartilage. The mean standardised uptake value (SUVm), a mathematically derived ratio of tissue radioactivity in a region of interest (ROI) and the decay corrected injected dose per kilogram of the patient's body weight has common place in oncology. The functional changes that 18F-NaF PET detects have led to this modality being re-evaluated for its advantages in skeletal diseases such as osteoarthritis and AKU. AKU patients underwent a variety of clinical testing and imaging including 18F-NaF PET scanning at the Royal Liverpool University Hospital. Semi-quantitative analysis of the PET scans was utilised to investigate the anatomical distribution of increased 18F uptake. Quantitative SUVms were also obtained as a measure of Fluoride uptake in the bony vertebrae and cartilaginous intervertebral discs (IVD). Other clinical data were taken from the case notes for correlation. The anatomical distribution of increased 18F uptake was confirmed to primarily affect the weight bearing joints. The quantitative SUVm methodology revealed a striking variation between AKU and control SUVms in the IVDs thought to represent calcification of the IVDs in AKU. The mechanism proposed is that calcium hydroxyapatite or calcium pyrophosphate dihydrate are deposited in the fibrocartilaginous IVDs in AKU due to biochemical alterations of the disease. 18F binds to the calcium deposits resulting in high SUVms compared to the control. The SUVms obtained from the vertebrae in both AKU and control patients are similar across the lumbar and thoracic spine suggesting that generalised rates of bone turnover in AKU and control patients are comparable. With age the AKU SUVms of the IVDs followed an interesting trend (the inverted 'U' shaped trend) that was strikingly different to that of the control group that appears to remain stable with age. It is proposed that the AKU trend demonstrates the process of disc degeneration. In the bony vertebrae, an age-related decline in SUVm was observed in both AKU and control groups, thought to represent reduced bone turnover with age. Correlations were made with the IVD SUVms and other clinical data. Reduced vertebrae SUVm and increased IVD SUVm were found to be associated with higher clinical scores, pain scores, excessive spinal curvature angles, lower BMD T-scores and spinal flexibility measurements. The proposed reason for this is primarily due to reduced BMD with age and spinal arthropathy associated with calcified IVDs. All in all, this thesis has provided new insights into spinal arthropathy in AKU. The utilisation of novel quantitative techniques demonstrated in this thesis can be used to aid in clinical interpretation of PET scans as well as providing a measure of disease severity and to analyse disease progression and response to therapy.

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Schiavone, Maria Lucia. "The investigation of molecular mechanisms of Alkaptonuria through novel cellular and tissue models". Doctoral thesis, Università di Siena, 2020. http://hdl.handle.net/11365/1096846.

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Abstract (sommario):

Alkaptonuria (AKU) is an ultra-rare genetic disease resulting from a lack in activity of the enzyme Homogentisate 1,2- dioxygenase (HGD) and responsible for one of the steps in the catabolism of the aromatic amino acids Phenylalanine and Tyrosine. This condition leads to the accumulation of Homogentisic Acid (HGA) and of its products caused by oxidation and polymerization which can generate melanin-like aggregates, with amyloidogenic properties related to the phenomenon “Ochronosis”. The most affected parts of the body are the joints with a consequent arthropathy. This work is focused on the investigation of molecular mechanisms of Alkaptonuria through different novel models. The first part is a set up of an osteoblast model and the consequent investigation on the mechanisms which link HGA with the high bone reabsorption and osteoporosis that often occurs in alkaptonuric patients. The results suggest an impairment in the RANK-L/Osteoprotegerin system related to Wnt-Beta catenin signaling inhibition. In the same model an altered redox status rate was found and further investigated in the second part of this work. The further advance of the study evidenced a strong involvement of NADPH and mitochondria in oxidative stress generation and propagation. Ulterior analysis revealed an impairment in the antioxidant system related to Nrf2 which seems to be affected by 4-HNE derived from HGA induced lipid peroxidation. The last part of the work is the set -up of a skin tissue model of alkaptonuria which revealed the activation of NLRP1 related inflammasome. The data was further confirmed using a novel cellular model which includes endothelial cells, fibroblast and keratinocytes.

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Keenan, Craig. "Identification of ochronosis, its inhibition by nitisinone, and the use of surgical and chemical interventions in murine models of alkaptonuria". Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/2006679/.

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Abstract (sommario):

Alkaptonuria (AKU) is an ultra rare autosomal recessive disorder resulting from a deficiency of the homogentisate 1,2-dioxygenase (Hgd) enzyme and is characterized by accumulation of homogentisic acid (HGA) in plasma. The disorder has three distinct stages of disease beginning with the excretion of large quantities of HGA in the urine, followed by deposition of HGA as a polymerized pigment in collagenous tissues principally in the cartilages of loaded joints (termed ochronosis), and finally the early onset of severe and devastating osteoarthropathy. There is currently no effective treatment available to AKU patients. Studying the extreme osteoarthritis (OA) phenotype seen in AKU is helping to increase understanding of more common OA, and may help elucidate the mechanisms behind the initiation and progression of OA. Although a murine model of AKU has previously been reported, published studies reported that Hgd-/- mice did not develop ochronosis. The aim of this thesis was to make a comprehensive survey of Hgd-/- mice to identify if ochronosis was present, determine the pathogenesis of the disorder, and to establish whether a potential treatment could prevent pigment deposition in tissues. Through studying a large number of Hgd-/- mice, of a wide variety of ages, this thesis has provided novel findings in relation to the presence of ochronosis in these mice. Using a modified version of Schmorl’s stain, which can specifically identify ochronotic pigment, ochronosis was observed in Hgd-/- mice for the first time. The identification of the earliest stages of ochronosis in Hgd-/- mice provided an opportunity to follow the pathogenesis of the disease throughout their lifespan. Pigmentation was initially identified in the pericellular matrix (PCM) of chondrons in the articular calcified cartilage (ACC), before progressing intracellularly. Examination of aged mice revealed widespread pigmentation throughout all areas of the tibio-femoral joint. Quantification of the pigmented chondrons demonstrated a progressive, linear increase in pigmentation with increasing age. Similar to ochronosis observed in AKU patients, Hgd-/- mice exhibited signs of ochronotic osteoarthropathy which became progressively worse with age. The early identification of ochronosis and its associated osteoarthropathy in Hgd-/- mice is helping to investigate the biochemical and pathological changes associated with AKU in humans. Following the identification of ochronosis Hgd-/- mice were treated with nitisinone, which had been identified as a possible therapeutic for AKU. Administration of nitisinone throughout the lifespan completely prevented deposition of ochronotic pigment. When given mid-life, nitisinone stopped any further pigment deposition but was unable to reverse the effects of ochronosis which had already taken place. The results showed nitisinone to be an effective treatment against the initiation and progression of AKU. During the course of investigation to identify ochronotic pigment at the ultrastructural level, high resolution transmission electron microscopy revealed the presence of previously undescribed microanatomical concentric lamellae in the ACC of Hgd-/- and wild type mice. Although the pathogenesis of these structures is still undetermined they may play a role in OA development as they appear to be associated with tidemark advancement and increased cartilage mineralization. In summary the studies reported in this thesis present novel findings on the identification of pigmentation, and on the initiation, progression and mechanism of ochronosis which leads to ochronotic osteoarthropathy in Hgd-/- mice. The prevention of ochronotic pigmentation, using the drug nitisinone, was also reported for the first time.

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Milella, Maria Serena. "Study of molecular mechanisms and pharmacological approaches of Alkaptonuria's disease". Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1204563.

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Abstract (sommario):

Alkaptonuria (AKU) is an autosomal recessive disorder, called also Black Bone Disease, for the characteristic dark coloration that some tissues and parts of the body assumed. The pathology is caused by the failure of the enzyme homogentisate 1,2- dioxygenase (HGD), that leads the accumulation of the metabolic intermediate homogentisic acid (HGA), derived by tyrosine. HGA highly reactivity triggers the formation of HGA-derived oxidized products, that react with cellular macromolecules, causing a significant generation of ROS and occurrence of oxidative stress. The ongoing oxidative stress status induces the expression of pro-inflammatory cytokines and the activation of immune cell system, with the consequently occurrence in patients of chronic inflammation and secondary AA amyloidosis. Moreover, HGA molecules bonds generate a dark polymer, called ochronotic pigment, that sticks on several organs, particularly on articular joints. Ochronosis triggers detrimental effects on tissues, as cellular death, extracellular matrix destruction, collagen fibrils rupture, since organs lose their function. Tyrosine and phenylalanine are daily taken by the body with diet, and catabolized by the HGD pathway. Thus, in AKU patients, HGA production is constant, since HGA levels in blood and urine are always elevated. Differently, the ochronotic pigment formation and deposit require more time, indeed symptoms in patients generally appear after the fourth decade of life. The rarity of AKU implies important challenges for its study. Actually, some aspects of the disease are still unexplored, despite it represents the first genetic disorder discovered that follows the principles of Mendelian recessive inheritance. In particular, one of the principal obstacles is the retrieval of AKU samples, that are scarce and generally in bad condition, for the nature of the disease. For this reason, the first step of this thesis project, described in Chapter 3, focused on the set up of in vitro model that allowed to reproduce, in a simple and cheap manner, all the characteristics of pathology. Specifically, it was set up an AKU model based on human primary chondrocytes, that allowed to study the most affected compartment in the disorder. Moreover, it was showed a preliminary study on the development of an in vivo Zebrafish model, with the objective of overcome the numerous limitations related to AKU mouse model. The aim of the present thesis work was dual: explore the molecular characteristics still unknown in AKU, and propose an innovative therapeutic approach, that could be extended to all the chronic inflammatory pathologies (Fig.1). In our lab, it was already showed that HGA administration to cells led the activation of autophagic process. Following this observation, it was explored in Chapter 4 the role of lysosomes in AKU. Indeed, is known that a dysregulation of these organelles frequently occurs in different kind of pathologies, as autoimmune or neurodegenerative disorders. Actually, an increase in lysosomes’ number had been detected in both AKU samples and model. Moreover, AKU lysosomes were localized in the periphery of cells, that represent a not physiologic conformation suggesting a decrease in their activity. Despite the ochronotic pigment deposition on cartilage and collagen fibrils was deeply studied, its formation and intracellular localization was never explicated. Thus, considering lysosomes’ role in the storage and degradation of toxic compounds, it was demonstrated in this work, for the first time, that, when cells were exposed to HGA, the ochronotic pigment was developed intracellularly and concentrated in lysosomes. Obviously, this observation could have enormous impact for the treatment of the disease and the counteraction of ochronotic pigment accumulation. Oxidative detrimental effects of HGA had been already described. Cellular macromolecules, as proteins and lipids, but also organelles, as mitochondria, undergo oxidative reactions, with the occurrence of damages often irreversible. Is known that oxidative stress and ROS target also DNA, with possible deleterious effects for cells and for all the body, considering the potential development of mutations that lead tumors onset. Thus, this aspect needs to be monitored in the progression of disorders. Therefore, the effect of HGA on the genome integrity was studied for the first time, as shown in Chapter 5. It was highlighted that HGA indirectly affected DNA, causing strand breaks and nucleolar stress. This induced the activation of repair mechanisms, on which depended cells destiny. In addition, Chapter 8 was dedicated to the study of inflammatory signal activated in AKU, a crucial characteristic of the disease. For the first time, the disorder was modeled on immune cells, in order to analyze the pattern of cytokines stimulated by HGA. It was demonstrated that the molecule was able to directly induce pro-inflammatory cytokines expression in different immune cell types. This preliminary study provides the basis for deeply understand the key issue of inflammation and immune cells activation in AKU patients. In scientific research, the molecular understanding of biological mechanisms and pathways involved in disorders results fundamental to improve their knowledge. This, beside its crucial significance, provides also the theoretical starting point for the research of possible therapeutic cure. Therefore, frequently these approaches are developed together and strictly connected. Until few years ago, AKU patients were treated only with palliative cure. Recently, EMA (European Medicines Agency) extended the application of the drug nitisinone for the treatment of AKU in adult patients. Despite this represents an important progress for the patients’ care, the drug carries some collateral effects, due to the induction of tyrosinemia, and its inability to counteract inflammation. Hence, in the present project it was studied a new therapeutic approach, described in Chapters 6 and 7, based on the combination of low-doses methotrexate (MTX), a widely used anti-inflammatory drug, with antioxidant molecules. In this way, it was obtained a formulation that combined anti-inflammatory and antioxidants properties, with a stronger effect in the counteraction of these conditions, compared to the effect of single treatments. Moreover, it was proved that the co-administration of drugs allowed to use a low concentration of MTX, with the consequent decrease of its adverse effects, and beneficial impact on patients’ health. The effectiveness of the proposed treatment was tested against typical markers of inflammation, oxidative stress and amyloidosis, proving that its application could be extended to different kind of inflammatory disorders (Chapter 6). It was also studied specifically its effect on AKU model, and demonstrated that the combination of MTX and antioxidants successfully reduced ochronotic pigment and amyloid fibrils (Chapter 7). In summary, the present thesis work gives new insight into molecular mechanisms of AKU and presented a new potential formulate for its treatment.

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Lamas, Joana Pereira da Silva. "Alkaptonuria - An obscure disease". Master's thesis, 2016. https://repositorio-aberto.up.pt/handle/10216/90269.

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Lamas, Joana Pereira da Silva. "Alkaptonuria - An obscure disease". Dissertação, 2016. https://repositorio-aberto.up.pt/handle/10216/90269.

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Libri sul tema "Alkaptonuria"

Rovenský, Jozef, Tibor Urbánek, Boldišová Oľga e James A. Gallagher, a cura di. Alkaptonuria and Ochronosis. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3.

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Parker, James N., e Philip M. Parker. Alkaptonuria: A bibliography and dictionary for physicians, patients, and genome researchers [to internet references]. San Diego, CA: ICON Health Publications, 2007.

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Introne, Wendy J. Alkaptonuria. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0015.

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Abstract (sommario):

Alkaptonuria is an autosomal recessive disorder with an incidence of 1:250,000 to 1:500,000. Aside from urine that darkens, the disease is relatively asymptomatic in childhood. As a result, the diagnosis is often overlooked early in life and not considered in many patients until they begin to manifest symptoms as adults. Features include pigment deposition (ochronosis) on the eyes, ears, and hands; early-onset, progressive arthritis, particularly of the spine and large joints; valvular heart disease; and renal and prostate stones. Management continues to be symptomatic, but specific treatment with nitisinone appears promising with additional clinical trials being planned.

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Rovenský, Jozef, Tibor Urbánek, Boldišová Oľga e James A. Gallagher. Alkaptonuria and Ochronosis. Springer, 2016.

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Rovenský, Jozef, Tibor Urbánek, Boldišová Oľga e James A. Gallagher. Alkaptonuria and Ochronosis. Springer, 2015.

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Oľga, Boldisová, Jozef Rovenský, Tibor Urbánek e James A. Gallagher. Alkaptonuria and Ochronosis. Springer, 2015.

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Sybert, Virginia P. Metabolic Disease. Oxford University Press, 2012. http://dx.doi.org/10.1093/med/9780195397666.003.0011.

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Abstract (sommario):

Porphyrias – Congenital Erythropoietic Porphyria – Erythropoietic Protoporphyria – Hereditary Coproporphyria – Porphyria Cutanea Tarda – Variegate Porphyria – Mucopolysaccharidoses – Hunter Syndrome – Other Metabolic Disorders – Acrodermatitis Enteropathica – Alkaptonuria – Biotinidase Deficiency – Familial Cutaneous Amyloidosis – Prolidase Deficiency

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Sybert, Virginia P. Metabolic Disease. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190276478.003.0011.

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Chapter 11 covers Porphyrias (Congenital Erythropoietic Porphyria, Erythropoietic Protoporphyria, Hereditary Coproporphyria, Porphyria Cutanea Tarda, and Variegate Porphyria), Mucopolysaccharidoses (Hunter Syndrome), and Other Metabolic Disorders (Acrodermatitis Enteropathica, Alkaptonuria, Biotinidase Deficiency, Familial Cutaneous Amyloidosis, and Prolidase Deficiency). Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.

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Hollak, Carla E. M. Skeletal Abnormalities. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0072.

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The skeleton is frequently involved in inborn error of metabolism as part of a chronic, multisystem disease. Several disorders in adulthood may present with skeletal symptoms as a first sign of an underlying metabolic disease. Examples are Gaucher disease, alkaptonuria, hypofosfatasia or hereditary hypophosphatemic rickets. In addition, secondary skeletal problems, specifically osteoporosis, is a frequent complication of a wide range of inborn errors of metabolism. The presence of additional symptoms, specific radiographical appearance and/or biochemical abnormalities can assist in making the appropriate diagnosis.

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Capitoli di libri sul tema "Alkaptonuria"

Al-Tubaikh, Jarrah Ali. "Ochronosis (Alkaptonuria)". In Internal Medicine, 344–45. Berlin, Heidelberg: Springer Berlin Heidelberg, 2010. http://dx.doi.org/10.1007/978-3-642-03709-2_69.

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Hrnčíř, Zbyněk. "Alkaptonuria and Ochronosis". In Alkaptonuria and Ochronosis, 3. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3_2.

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Rovenský, Jozef, e Tibor Urbánek. "Therapy of Alkaptonuria". In Alkaptonuria and Ochronosis, 127–28. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3_25.

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Bošák, Vladimír. "Genetics of Alkaptonuria". In Alkaptonuria and Ochronosis, 19–27. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3_7.

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Rovenský, Jozef, Richard Imrich, Tibor Urbánek e Vladimir Bošák. "Alkaptonuria and Ochronosis". In Gerontorheumatology, 233–43. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-31169-2_19.

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Rovenský, Jozef. "Introduction". In Alkaptonuria and Ochronosis, 1. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3_1.

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Rovenský, Jozef, e Tibor Urbánek. "Ochronotic Arthropathy". In Alkaptonuria and Ochronosis, 41–43. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3_10.

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Rovenský, Jozef, e Tibor Urbánek. "Clinical Manifestation of Ochronotic Arthropathy in Spine". In Alkaptonuria and Ochronosis, 45–52. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3_11.

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Rovenský, Jozef, Mária Krátka e Tibor Urbánek. "Analysis of X-Ray Symptomatology of Ochronotic Arthropathy in Spine". In Alkaptonuria and Ochronosis, 53–57. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3_12.

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Urbánek, Tibor, Štefan Kopecký e Jozef Rovenský. "Clinical Manifestation of Ochronotic Arthropathy in Peripheral Joints". In Alkaptonuria and Ochronosis, 59–64. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15108-3_13.

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Atti di convegni sul tema "Alkaptonuria"

Frediani, B., L. Millucci, G. Bernardini, D. Braconi, M. Bardelli, B. Marzocchi, O. Spiga et al. "SAT0620 Further evidences of secondary amyloidosis in alkaptonuria". In Annual European Congress of Rheumatology, EULAR 2018, Amsterdam, 13–16 June 2018. BMJ Publishing Group Ltd and European League Against Rheumatism, 2018. http://dx.doi.org/10.1136/annrheumdis-2018-eular.4645.

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Köhler, J., D. Schöler, B. Förner, V. Korpel, L. Wagner, P. May, V. Keitel-Anselmino, T. Luedde e S. vom Dahl. "Therapie der Alkaptonurie mit Nitisinon: eine erste retrospektive Analyse bei 14 Patienten". In Viszeralmedizin 2021 Gemeinsame Jahrestagung Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Sektion Endoskopie der DGVS, Deutsche Gesellschaft für Allgemein und Viszeralchirurgie (DGAV). Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1733765.

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