Aromatic L-Amino Acid Decarboxylase Deficiency: A Genetic Screening in Sicilian Patients with Neurological Disorders.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare autosomal recessive neurometabolic disorder caused by AADC deficiency, an enzyme encoded by the DDC gene. Since the enzyme is involved in the biosynthesis of serotonin and dopamine, its deficiency determines the lack of these neurotransmitters, but also of norepinephrine and epinephrine. Onset is early and the key signs are hypotonia, movement disorders (oculogyric crises, dystonia and hypokinesia), developmental delay and autonomic dysfunction. Taiwan is the site of a potential founder variant (IVS6+4A>T) with a predicted incidence of 1/32,000 births, while only 261 patients with this deficit have been described worldwide. Actually, the number of affected persons could be greater, given that the spectrum of clinical manifestations is broad and still little known. In our study we selected 350 unrelated patients presenting with different neurological disorders including heterogeneous neuromuscular disorders, cognitive deficit, behavioral disorders and autism spectrum disorder, for which the underlying etiology had not yet been identified. Molecular investigation of the DDC gene was carried out with the aim of identifying affected patients and/or carriers. Our study shows a high frequency of carriers (2.57%) in Sicilian subjects with neurological deficits, with a higher concentration in northern and eastern Sicily. Assuming these data as representative of the general Sicilian population, the risk may be comparable to some rare diseases included in the newborn screening programs such as spinal muscular atrophy, cystic fibrosis and phenylketonuria.

A Next-Generation Sequencing Study in a Cohort of Sicilian Patients with Parkinson's Disease.

Parkinson's disease (PD) is a multisystem and multifactorial disorder and, therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. We conducted a clinical-demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. DNA was extracted from the peripheral blood for each patient, followed by sequencing using a Next-Generation Sequencing system. This system was based on a custom gene panel comprising 162 genes. The sample underwent further filtering, taking into account the allele frequencies of genetic variants, their presence in the Human Gene Mutation Database, and their association in the literature with PD or other movement/neurodegenerative disorders. The largest number of variants was identified in the leucine-rich repeat kinase 2 (LRRK2) gene. However, variants in other genes, such as acid beta-glucosidase (GBA), DNA polymerase gamma catalytic subunit (POLG), and parkin RBR E3 ubiquitin protein ligase (PRKN), were also discovered. Interestingly, some of these variants had not been previously associated with PD. Enhancing our understanding of the genetic basis of PD and identifying new variants possibly linked to the disease will contribute to improved diagnostic accuracy, therapeutic developments, and prognostic insights for affected individuals.

Specific Learning Disorders: Variation Analysis of 15 Candidate Genes in 9 Multiplex Families.

Background and Objectives: Specific Learning Disorder (SLD) is a complex neurobiological disorder characterized by a persistent difficult in reading (dyslexia), written expression (dysgraphia), and mathematics (dyscalculia). The hereditary and genetic component is one of the underlying causes of SLD, but the relationship between genes and the environment should be considered. Several genetic studies were performed in different populations to identify causative genes. Materials and Methods: Here, we show the analysis of 9 multiplex families with at least 2 individuals diagnosed with SLD per family, with a total of 37 persons, 21 of whom are young subjects with SLD, by means of Next-Generation Sequencing (NGS) to identify possible causative mutations in a panel of 15 candidate genes: CCPG1, CYP19A1, DCDC2, DGKI, DIP2A, DYM, GCFC2, KIAA0319, MC5R, MRPL19, NEDD4L, PCNT, PRMT2, ROBO1, and S100B. Results: We detected, in eight families out nine, SNP variants in the DGKI, DIP2A, KIAA0319, and PCNT genes, even if in silico analysis did not show any causative effect on this behavioral condition. In all cases, the mutation was transmitted by one of the two parents, thus excluding the case of de novo mutation. Moreover, the parent carrying the allelic variant transmitted to the children, in six out of seven families, reports language difficulties. Conclusions: Although the present results cannot be considered conclusive due to the limited sample size, the identification of genetic variants in the above genes can provide input for further research on the same, as well as on other genes/mutations, to better understand the genetic basis of this disorder, and from this perspective, to better understand also the neuropsychological and social aspects connected to this disorder, which affects an increasing number of young people.

Halloysite Nanotubes and Sepiolite for Health Applications.

The need for safe, therapeutically effective, and patient-compliant drug delivery systems continuously leads researchers to design novel tools and strategies. Clay minerals are widely used in drug products both as excipients and active agents but, in recent years, there has been a growing interest in research aimed at the development of new organic or inorganic nanocomposites. The attention of the scientific community has been drawn by nanoclays, thanks to their natural origin, worldwide abundance, availability, sustainability, and biocompatibility. In this review, we focused our attention on the studies inherent to the pharmaceutical and biomedical applications of halloysite and sepiolite, and their semi-synthetic or synthetic derivatives, as drug delivery systems. After having described the structure of both materials and their biocompatibility, we delineate the use of the nanoclays to enhance the stability, the controlled release, the bioavailability, and the adsorption properties of drugs. Several types of surface functionalization have been discussed, showing that these materials could be used for the development of an innovative therapeutic approach.

The Mitochondrial tRNASer(UCN) Gene: A Novel m.7484A>G Mutation Associated with Mitochondrial Encephalomyopathy and Literature Review.

Mitochondrial tRNASer(UCN) is considered a hot-spot for non-syndromic and aminoglycoside-induced hearing loss. However, many patients have been described with more extensive neurological diseases, mainly including epilepsy, myoclonus, ataxia, and myopathy. We describe a novel homoplasmic m.7484A>G mutation in the tRNASer(UCN) gene affecting the third base of the anticodon triplet in a girl with profound intellectual disability, spastic tetraplegia, sensorineural hearing loss, a clinical history of epilepsia partialis continua and vomiting, typical of MELAS syndrome, leading to a myoclonic epilepticus status, and myopathy with severe COX deficiency at muscle biopsy. The mutation was also found in the homoplasmic condition in the mother who presented with mild cognitive deficit, cerebellar ataxia, myoclonic epilepsy, sensorineural hearing loss and myopathy with COX deficient ragged-red fibers consistent with MERRF syndrome. This is the first anticodon mutation in the tRNASer(UCN) and the second homoplasmic mutation in the anticodon triplet reported to date.

Dyslexia and Attention Deficit Hyperactivity Disorder Associated to a De Novo 1p34.3 Microdeletion.

The authors report on a boy with dyslexia and attention deficit hyperactivity disorder. A protocol of standardized tests assessed the neuroadaptive profile, allowing deep neuropsychiatric phenotyping. In addition to the diagnosis of dyslexia and attention deficit hyperactivity disorder, such methodology led to endeavor cognitive, adaptive, and academic skills. Chromosomal microarray analysis detected a 452.4 Kb de novo heterozygous microdeletion in chromosomal region 1p34.3, including seven OMIM genes. The authors took a thorough evaluation of the association to the phenotype of the deleted genes. Further reports could strengthen such association.

Nanomaterials: A Review about Halloysite Nanotubes, Properties, and Application in the Biological Field.

The use of synthetic materials and the attention towards environmental hazards and toxicity impose the development of green composites with natural origins. Clay is one of the candidates for this approach. Halloysite is a natural clay mineral, a member of the Kaolin group, with characteristic tubular morphology, usually named halloysite nanotubes (HNTs). The different surface chemistry of halloysite allows the selective modification of both the external surface and the inner lumen by supramolecular or covalent interactions. An interesting aspect of HNTs is related to the possibility of introducing different species that can be released more slowly compared to the pristine compound. Due to their unique hollow morphology and large cavity, HNTs can be employed as an optimal natural nanocarrier. This review discusses the structure, properties, and application of HNTs in the biological field, highlighting their high biocompatibility, and analyse the opportunity to use new HNT hybrids as drug carriers and delivery systems.

Spelling deficits in children with intellectual disabilities: Evidence from a regular orthography.

Introduction: In individuals with intellectual disabilities (ID), efficient reading and writing skills promote social integration, self-autonomy, and independence. However, research has mainly focused on reading skills, while evidence on spelling skills is scarce and mostly on English-speaking subjects. In the present research project, we compared the spelling skills of children with intellectual disabilities (ID) learning in Italian, a regular orthography, to those of typically developing children matched for school level. Methods: In the first study, the performance on a Passage Dictation Test of forty-four children with ID attending regular classrooms from 4th to 8th grades (mean age = 12.16 years; SD = 1.57) were compared with controls matched for sex and grade. In the second study, a Words and Nonwords Dictation Test was administered (with stimuli varying for lexicality, orthographic complexity, regularity of transcription, and the presence of different types of phonetic-phonological difficulties) to twenty-two children with ID attending regular classrooms from 4th to 8th grades (mean age = 12.2 years; SD = 1.37) and 22 controls matched for sex and grade. In both studies, an error analysis was performed to characterize types of misspellings. Separate ANOVAs were performed on z scores. Results: Children with ID generally had a lower performance than controls. In the Passage Dictation Test, they showed a higher number of phonological (and phonetic-phonological) errors than phonologically plausible ones, indicating, as a group, predominant phonological difficulties as compared to lexical-orthographic ones. In the Words and Nonwords Dictation Test, they performed poorly on regular stimuli presenting specific types of phonetic-to-phonological difficulties (geminates, non-continuant consonants) and committed more minimal distance, context-sensitive and simple conversion misspellings. However, deficits in the orthographic-lexical procedure, as indicated by a low performance in words with unpredictable spelling, were present in a high percentage of children. Discussion: It is concluded that children with ID have significant spelling difficulties not confined to the orthographic process but also in phoneme-to-grapheme mapping that, in a regular orthography like Italian, should be acquired early and easily.

A new p65 isoform that bind the glucocorticoid hormone and is expressed in inflammation liver diseases and COVID-19.

Inflammation is a physiological process whose deregulation causes some diseases including cancer. Nuclear Factor kB (NF-kB) is a family of ubiquitous and inducible transcription factors, in which the p65/p50 heterodimer is the most abundant complex, that play critical roles mainly in inflammation. Glucocorticoid Receptor (GR) is a ligand-activated transcription factor and acts as an anti-inflammatory agent and immunosuppressant. Thus, NF-kB and GR are physiological antagonists in the inflammation process. Here we show that in mice and humans there is a spliced variant of p65, named p65 iso5, which binds the corticosteroid hormone dexamethasone amplifying the effect of the glucocorticoid receptor and is expressed in the liver of patients with hepatic cirrhosis and hepatocellular carcinoma (HCC). Furthermore, we have quantified the gene expression level of p65 and p65 iso5 in the PBMC of patients affected by SARS-CoV-2 disease. The results showed that in these patients the p65 and p65 iso5 mRNA levels are higher than in healthy subjects. The ability of p65 iso5 to bind dexamethasone and the regulation of the glucocorticoid (GC) response in the opposite way of the wild type improves our knowledge and understanding of the anti-inflammatory response and identifies it as a new therapeutic target to control inflammation and related diseases.

Reading and spelling disorders in a school-based population screening in Sicily (Italy).

This research was carried out according to the Italian Consensus Conference on Specific Learning Disability guidelines for screening initiatives. It describes a three-year screening project involving 2.469 students, aged 8-15 years, from various classes of primary, lower and upper secondary schools of Sicily. Students were assessed for reading and spelling skills. Overall, 4.9% met the risk criteria for suspected reading disorder, 6.1% for spelling disorder, while 8.5% for both conditions. Results showed that out of 932 pupils in the primary school, 4.6% met the risk criteria for reading disorder and 6.5% for spelling disorder; out of 855 pupils of the lower secondary school, 5.3% for reading disorder and 5.5% for spelling disorder; out of 652 pupils of the upper secondary school, 4.9% for reading disorder and 6.1% for spelling disorder. No significant difference in the prevalence of students at risk of reading disorder or spelling disorder, within the three grade-levels over 3 years, was found. At project conclusion further clinical investigation to verify the screening results on student sub-sample (57%) was carried out. The percentage of students with SLD was equal to 3.15%, in the primary school, 3.76% in the lower secondary school and 2.51%, in the upper secondary school.

Study of Uptake Mechanisms of Halloysite Nanotubes in Different Cell Lines.

PURPOSE: Halloysite nanotubes (HNTs) are a natural aluminosilicate clay with a chemical formula of Al2Si2O5(OH)4×nH2O and a hollow tubular structure. Due to their peculiar structure, HNTs can play an important role as a drug carrier system. Currently, the mechanism by which HNTs are internalized into living cells, and what is the transport pathway, is still unclear. Therefore, this study aimed at establishing the in vitro mechanism by which halloysite nanotubes could be internalized, using phagocytic and non-phagocytic cell lines as models. METHODS: The HNT/CURBO hybrid system, where a fluorescent probe (CURBO) is confined in the HNT lumen, has been used as a model to study the transport pathway mechanisms of HNTs. The cytocompatibility of HNT/CURBO on cell lines model was investigated by MTS assay. In order to identify the internalization pathway involved in the cellular uptake, we performed various endocytosis-inhibiting studies, and we used fluorescence microscopy to verify the nanomaterial internalization by cells. We evaluated the haemolytic effect of HNT/CURBO placed in contact with human red blood cells (HRBCs), by reading the absorbance value of the supernatant at 570 nm. RESULTS: The HNT/CURBO is highly biocompatible and does not have an appreciable haemolytic effect. The results of the inhibition tests have shown that the internalization process of nanotubes occurs in an energy-dependent manner in both the investigated cell lines, although they have different characteristics. In particular, in non-phagocytic cells, clathrin-dependent and independent endocytosis are involved. In phagocytic cells, in addition to phagocytosis and clathrin-dependent endocytosis, microtubules also participate in the halloysite cellular trafficking. Upon internalization by cells, HNT/CURBO is localized in the cytoplasmic area, particularly in the perinuclear region. CONCLUSION: Understanding the cellular transport pathways of HNTs can help in the rational design of novel drug delivery systems and can be of great value for their applications in biotechnology.

Halloysite nanotubes-carbon dots hybrids multifunctional nanocarrier with positive cell target ability as a potential non-viral vector for oral gene therapy.

HYPOTHESIS: The use of non-viral vectors for gene therapy is hindered by their lower transfection efficiency and their lacking of self-track ability. EXPERIMENTS: This study aims to investigate the biological properties of halloysite nanotubes-carbon dots hybrid and its potential use as non-viral vector for oral gene therapy. The morphology and the chemical composition of the halloysite hybrid were investigated by means of high angle annular dark field scanning TEM and electron energy loss spectroscopy techniques, respectively. The cytotoxicity and the antioxidant activity were investigated by standard methods (MTS, DPPH and H2O2, respectively) using human cervical cancer HeLa cells as model. Studies of cellular uptake were carried out by fluorescence microscopy. Finally, we investigated the loading and release ability of the hybrid versus calf thymus DNA by fluorescence microscopy, circular dichroism, dynamic light scattering and ζ-potential measurements. FINDINGS: All investigations performed confirmed the existence of strong electrostatic interactions between the DNA and the halloysite hybrid, so it shows promise as a multi-functional cationic non-viral vector that has also possesses intracellular tracking capability and promising in vitro antioxidant potential.

Multifunctional Carrier Based on Halloysite/Laponite Hybrid Hydrogel for Kartogenin Delivery.

A novel carrier system based on halloysite nanotubes (HNT), for the potential intraarticular delivery of kartogenin (KGN) by means laponite (Lap) hydrogel (HNT/KGN/Lap), is developed. The drug was first loaded into HNT, and the hybrid composite obtained was used as filler for laponite hydrogel. Both the filler and the hydrogel were thoroughly investigated by several techniques and the hydrogel morphology was imaged by transmission electron microscopy. Furthermore, the gelating ability of laponite in the presence of the filler and the rheological properties of the hybrid hydrogel were also investigated. The kinetic release of kartogenin from HNT and HNT/Lap hybrid hydrogel was studied both in physiological conditions and in ex vivo synovial fluid. In the last case, the kinetic results highlighted that HNT carrier can effectively release KGN in a sustained manner for at least 38 days. Finally, a preliminary biological assays showed that the HNT/KGN/Lap hybrid hydrogel did not exhibit any cytotoxic effect.

Reading Deficits in Intellectual Disability Are still an Open Question: A Narrative Review.

BACKGROUND: In children with intellectual disability (ID), the acquisition of reading skills constitutes a basic step towards the possibility of independent living, social inclusion and participation. METHODS: We carried out a narrative review of the literature on reading fluency and accuracy of individuals with ID resulting from different genetic syndromes (Fragile X, Williams, Velocardiofacial, Prader-Willi, and Down syndrome). Our aim was to define their reading profiles in light of the dual-route reading model. For this purpose, studies that examined both word and non-word reading in children with ID were included in the analysis. RESULTS: Seventeen studies emerged based on the selection criteria. The results were different depending on the control group used. A deficit in reading non-words emerged in studies that used the reading-level match design but not when standardized scores were used, when controls were age-matched or when a mental age matching was used. Thus, a deficit in reading non-words emerged only in studies that used the reading-level match design. However, severe methodological criticisms were recently raised about the use of this matching design. CONCLUSIONS: In view of the methodological problems in using grade equivalents, it is premature to draw definite conclusions about the reading profile of children with ID resulting from different genetic syndromes. In any case, the reviewed evidence provides little support for the idea that children with ID have selective difficulty in phonological reading. Thus, the reading profile of children with ID remains an open question that needs to be investigated by means of methodologically sound research.

The in cis T251I and P587L POLG1 base changes: description of a new family and literature review.

Mutations in the polymerase gamma-1 (POLG1) gene, encoding the catalytic subunit of the mtDNA-specific polymerase-γ, compromise the stability of mitochondrial DNA (mtDNA) and are responsible for numerous clinical presentations as autosomal dominant or recessive progressive external ophthalmoplegia (PEO), sensory ataxia, neuropathy, dysarthria and ophthalmoparesis (SANDO), spinocerebellar ataxia with epilepsy (SCAE) and Alpers syndrome. POLG1 mutations result in extremely heterogeneous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes, and genotype-phenotype correlations are still unclear. We describe a new family with a particular spectrum of clinical signs, that carried the c.752C>T mutation in exon 3 (T251I) and the c.1760C>T in exon 10 (P587L) in cis. These mutations were associated in the proband and in her brother with the new probably pathogenic mutation c.347C>A in exon 2 (P116Q). The proband presented a progressive cognitive impairment, mild myopathy, dilated cardiac right atrium and posterior white matter mild signal alteration, while her brother had migraine, mild myopathy, palpebral ptosis and posterior white matter mild signal alteration. Their mother and their sister carried the in cis T251I and the P587L mutations. The first presented neurosensorial hypoacusia, fatigue, heart block and a cerebral arteriovenous malformation nidus, while the latter had borderline intellectual functioning and signs of muscular involvement. Their father, with the P116Q mutation, had diabetes and myopathy. The complexity of the genotype-phenotype correlations associated with POLG1 mutations is reinforced in this work as evidenced by the presence of different clinic features in patients carrying the same mutations.

An Albanian open source telemedicine platform.

INTRODUCTION: The use of open source technologies to create collaboration platforms can produce huge advantages with small investment. MATERIALS AND METHODS: We set up a telemedicine network for a healthcare district with typical centralization issues of developing countries. Our network was built using broadband Internet connection, and the digital divide in rural areas was reduced by means of wireless Internet connection. A software infrastructure was deployed on the network to implement the collaboration platform among different healthcare facilities. RESULTS: We obtained an integrated platform with modest investment in hardware and operating systems and no costs for application software. Messaging, content management, information sharing, and videoconferencing are among the available services of the infrastructure. Furthermore, open source software is managed and continuously updated by active communities, making it possible to obtain systems similar to commercial ones in terms of quality and reliability. CONCLUSIONS: As the use of free software in public administration is being widely promoted across the European Union, our experience may provide an example to implement similar infrastructures in the field of healthcare and welfare.

Exploring the anticancer potential of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives: the effect on apoptosis induction, cell cycle and proliferation.

In order to investigate their anticancer potential, four new pyrazolo[1,2-a]benzo[1,2,3,4]tetrazinone derivatives, designed through the chemometric protocol VLAK, and three of the most active compounds of the previous series have been evaluated on some cellular events including proliferation, apoptosis induction, and cell cycle. The NCI one dose (10 µM) screening revealed that the 8,9-di-methyl derivative showed activity against Leukemia (CCRF-CEM) and Colon cancer cell line (COLO 205), reaching 81% and 45% of growth inhibition (GI), respectively. Replacement of the two methyl groups with two chlorine atoms maintained the activity toward Leukemia cell (CCRF-CEM, GI 77%) and selectively enhanced the activity against COLO 205 attaining a LD50 in the µM range and against SW-620 a GI of 77%. Interestingly, an appreciable growth inhibition of 47% against therapeutically "refractory" Non-Small Cell Lung Cancer (NCI-H522) was observed. Moreover, the apoptosis induction, based on mitochondrial membrane depolarization, was found in the range EC50 3-5 µM on HeLa cell, evidencing a well defined relationship with the related in vitro cell growth inhibitory assays (MTT) performed against other selected tumor cell lines not included in the NCI tumor panel (HeLa, cervix; H292, lung; LAN-5, CNS; CaCo-2, colon; 16HBE, normal human cell lung) and against MCF-7 tumor cell line (breast). Only for the most active compounds, further cell cycle tests on HeLa displayed a cell arrest on S phase. Thus, a promising new class of anticancer candidates, acting as valuable apoptotic inductors, is proposed.

The 9-bp deletion in region V of mtDNA: a risk factor of hearing loss and encephalomyopathy in Caucasian populations?

A deletion of one of the two copies of the 9-bp tandem repeat sequence (CCCCCTCTA), in the small non-coding/untranslated segment located between the cytochrome oxidase II and lysine tRNA genes of mitochondrial DNA (mtDNA), has previously been used as a polymorphic anthropological marker (MIC9D) for people of Africa and Asia, but it has been rarely reported in Europe. 32 Sicilian patients with syndromic hearing loss, negative for mutations in GJB2 and GJB6 genes, were tested for mtDNA known point mutations associated with syndromic or non-syndromic hearing loss by RFLP and/or direct sequencing. We identified the presence of the MIC9D in homoplasmy in lymphocytes and muscle of three subjects with sensorineural hearing loss and encephalomyopathy, two of these also presented moderate mental retardation. This deletion was absent in 300 Caucasian controls. Although further studies are warranted, our results suggest that the MIC9D polymorphism could have a susceptibility role in Caucasus, such as Sicily population.

BRAFV600E mutation, TIMP-1 upregulation, and NF-κB activation: closing the loop on the papillary thyroid cancer trilogy.

BRAF(V600E) is the most common mutation found in papillary thyroid carcinoma (PTC). Tissue inhibitor of metalloproteinases (TIMP-1) and nuclear factor (NF)-κB have been shown to play an important role in thyroid cancer. In particular, TIMP-1 binds its receptor CD63 on cell surface membrane and activates Akt signaling pathway, which is eventually responsible for its anti-apoptotic activity. The aim of our study was to evaluate whether interplay among these three factors exists and exerts a functional role in PTCs. To this purpose, 56 PTC specimens were analyzed for BRAF(V600E) mutation, TIMP-1 expression, and NF-κB activation. We found that BRAF(V600E) mutation occurs selectively in PTC nodules and is associated with hyperactivation of NF-κB and upregulation of both TIMP-1 and its receptor CD63. To assess the functional relationship among these factors, we first silenced BRAF gene in BCPAP cells, harboring BRAF(V600E) mutation. We found that silencing causes a marked decrease in TIMP-1 expression and NF-κB binding activity, as well as decreased invasiveness. After treatment with specific inhibitors of MAPK pathway, we found that only sorafenib was able to increase IκB-α and reduce both TIMP-1 expression and Akt phosphorylation in BCPAP cells, indicating that BRAF(V600E) activates NF-κB and this pathway is MEK-independent. Taken together, our findings demonstrate that BRAF(V600E) causes upregulation of TIMP-1 via NF-κB. TIMP-1 binds then its surface receptor CD63, leading eventually to Akt activation, which in turn confers antiapoptotic behavior and promotion of cell invasion. The recognition of this functional trilogy provides insight on how BRAF(V600E) determines cancer initiation, progression, and invasiveness in PTC, also identifying new therapeutic targets for the treatment of highly aggressive forms.

IKK-beta inhibitors: an analysis of drug-receptor interaction by using molecular docking and pharmacophore 3D-QSAR approaches.

The IKK kinases family represents a thrilling area of research because of its importance in regulating the activity of NF-kB transcription factors. The discovery of the central role played by IKK-beta in the activation of transcription in response to apoptotic or inflammatory stimuli allowed to considerate its modulation as a promising tool for the treatment of chronic inflammation and cancer. To date, several IKK-beta inhibitors have been discovered and tested. In this work, an analysis of the interactions between different classes of inhibitors and their biological target was performed, through the application of Molecular Docking and Pharmacophore/3D-QSAR approaches to a set of 141 inhibitors included in the Binding Database. In order to overcome the difficulty due to the lack of crystallographic data for IKK-beta, a homology model of this protein has been built and validated. The results allowed to study in depth the structural bases for the interaction of each family of inhibitors and provided clues for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting this enzyme.