RESUMEN
Metal ions have unique electrochemical and spectroscopical properties that cannot be attained by purely organic compounds. Most of the metal ions are toxic to humans, but paradoxically, metallodrugs are used in medicine as therapeutics and theranostics. Metallodrugs are eliminated in urine and faeces, and therefore release toxic metals and ligands into aquatic ecosystems, thereby raising concerns regarding environmental risks. The use of metallodrugs based on essential metal ions (i.e., iron, copper and zinc), instead of toxic ions, is a new alternative with minor hazards. Kojic acid is an Asperigillus oryzae metabolite of low toxicity used in the food and cosmetics industries. Its derivatives form stable complexes with iron(III) ions, which bind effectively to DNA and inhibit DNA polymerization. The iron(III)/S2 ligand complexes reduce in vitro colon carcinoma (Caco2) cell viability and significantly decrease the cell number. The kojic acid derivative complexes with iron(III) presented here are an alternative to the currently used platinum complexes in cancer therapy.
Asunto(s)
Complejos de Coordinación , Neoplasias , Aluminio/química , Complejos de Coordinación/farmacología , Cobre/química , ADN , Ecosistema , Humanos , Iones , Hierro/química , Ligandos , PironasRESUMEN
Biomarkers of cell stress are important for proper diagnosis, and in studies of how cells respond to drug treatment. Biomarkers that respond early to pharmacological treatment could improve therapy by tailoring the treatment to the needs of the patient. Thymosin beta-4 (Tß4) plays a significant role in many aspects of cellular metabolism because of its actin-sequestering properties. Other physiological functions of Tß4 have been also reported. Among these, Tß4 may play a crucial role during cellular stress. We addressed the relevance of Tß4 in cellular stress conditions by using different treatments (serum starvation, DMSO, and butyrate administration) in a colon adenocarcinoma cell line (CaCo2), a cell line frequently used for in vitro experimental studies of Tß4. In this study, different stress stimuli were analyzed and the obtained results were compared using immunocytochemistry, and molecular and biochemical methods. Taken together, the data clearly indicate that the Tß4 peptide is involved in adaptive and defensive cellular mechanisms, and that different stress inducers lead to a similar Tß4 cytoplasmic/nuclear translocation. The translocation of Tß4 between the cytoplasm and the nucleus of the cell seems characteristic of a possible molecular response to cellular stress exerted by this peptide.
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Lipodistrofia/epidemiología , Lipodistrofia/genética , Distrofias Musculares/epidemiología , Distrofias Musculares/genética , Distribución de la Grasa Corporal , Comorbilidad , Femenino , Humanos , Cariotipo , Lipodistrofia/diagnóstico , Masculino , Persona de Mediana Edad , Distrofias Musculares/diagnóstico , HermanosRESUMEN
Mutations on the LMNA gene are responsible for an heterogeneous group of diseases. Overlapping syndromes related to LMNA gene alterations have been extensively reported. Study scope is to perform a systematic analysis of the overlapping syndromes so far described and to try to correlate the clinical features to the associated genetic alterations. We evaluated all the dominant overlapping syndromes reported by means of a PubMed search and by the analysis of the main databases containing the pathogenic LMNA gene variations and the associated diseases. Metabolic alterations in association to skeletal and/or cardiac alterations proved to be the most frequent overlap syndrome. Overlapping syndromes are mostly associated to inframe mutations in exons 1, 2, 8 and 9. These data further improve the understanding of the pathogenesis of laminopathies.
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ADN/genética , Genes Sobrepuestos , Lamina Tipo A/genética , Lipodistrofia/genética , Mutación , Análisis Mutacional de ADN , Humanos , Lamina Tipo A/metabolismo , Lipodistrofia/metabolismo , SíndromeRESUMEN
Alterations of the lamin A/C (LMNA) gene are associated with different clinical entities, including disorders that affect skeletal and cardiac muscle, peripheral nerves, metabolism, bones, and disorders that cause premature aging. In this article we review the clinical and genetic characteristics of cardiac and skeletal muscle diseases related to alterations in the LMNA gene. There is no single explanation of how LMNA gene alterations may cause these disorders; however, important goals have been achieved in understanding the pathogenic effects of LMNA gene mutations on cardiac and skeletal muscle.
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Lamina Tipo A/genética , Músculo Esquelético/patología , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Mutación/genética , Miocardio/patología , Animales , Humanos , Enfermedades Musculares/clasificaciónRESUMEN
We describe a 3-year-old boy who, at age of 8 months, during investigations for upper respiratory tract infection was found to have an incidental grossly elevated CK of 20,000 UI/l. Investigations showed only mild calf hypertrophy and absent Gower's sign, normal cognitive function. Electromyography (EMG) showed myopathic features. Electrocardiography and echocardiography were normal. His muscle biopsy revealed myopathic features indicating Duchenne-type dystrophy. Immunohistochemistry for dystrophin N-terminal, C-terminal and mid-rod antibodies analysis showed the complete absence of dystrophin in the muscle fibers. Genetic studies showed a 141.1 Kb deletion removing muscle promoter, muscle exon 1, Purkinje promoter, Purkinje exon 1, dystrophin muscle enhancers similar to one previously reported in a DMD patient who exhibited some residual expression of dystrophin. The difference in dystrophin expression between these two patients might be due to the extension of deletions. The precise delimitation of the macrodeletion here described provides a better understanding of functional organization of the 5' end of the DMD gene.
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Distrofina/genética , Elementos de Facilitación Genéticos , Eliminación de Gen , Músculo Esquelético/metabolismo , Regiones Promotoras Genéticas , Biopsia , Preescolar , Electromiografía , Humanos , Inmunohistoquímica , Masculino , Músculo Esquelético/patología , Músculo Esquelético/fisiopatologíaRESUMEN
INTRODUCTION: LMNA gene mutations are associated with cardiac and skeletal muscle alterations. METHODS: A cohort of 21 mutated individuals was assessed with clinical and instrumental investigations over the years. RESULTS: The median observation period was 6 years. Cardiac compromise was detected in 16 patients. Bradyarrhythmias were the most frequent manifestations, followed by supraventricular arrhythmias. Two individuals suffered from nonsustained and 1 from sustained ventricular tachyarrhythmias. Dilated cardiomyopathy was detected in 3 patients. Evaluation of the frequencies of the clinical expressions showed a high probability of suffering from analogue heart compromise in study subjects bearing the same LMNA gene mutation. CONCLUSIONS: Cardiac involvement represents a very common phenotypic expression of LMNA gene mutation. Subjects sharing common genetic background seem to suffer from analogue pattern of cardiac manifestation.
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Arritmias Cardíacas/genética , Cardiomiopatía Dilatada/genética , Lamina Tipo A/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The following is a report on a large family with 5 males affected by the X-linked recessive form of Emery-Dreifuss muscular dystrophy with mutation in the STA gene. A detailed longitudinal cardiological evaluation and muscle imaging studies allowed for the assessment of intrafamilial variability of cardiac and muscle involvement. Long term cardiological follow up in the 5 affected males and in 7 female carriers revealed different degrees of severity, ranging from tachycardia-bradycardia syndrome and variable biatrial and left ventricle dilatation, to an episode of isolated symptomatic sustained ventricular tachycardia requiring a device implantation. Muscle imaging in the affected males showed involvement of the soleus and medial head of gastrocnemius on leg muscles and variable involvement on thigh muscles that have not been previously reported. In some cases, imaging showed clear signs of muscle involvement even when no overt signs of weakness could be detected during clinical examination.
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Corazón/fisiopatología , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Linaje , Adulto JovenRESUMEN
Patients with a partial reduction of merosin due to mutations in the laminin-α2 chain gene usually present with a mild form of congenital muscular dystrophy or a limb-girdle-like muscular dystrophy. To our knowledge, cardiac impairment has never been reported in such patients. A longitudinal study of a patient with partial laminin-α2 deficiency secondary to mutations in the LAMA2 gene revealed dilated cardiomyopathy with ventricular arrhythmias. Is this a chance association or a novel phenotype?
Asunto(s)
Arritmias Cardíacas/genética , Cardiomiopatía Dilatada/genética , Laminina/deficiencia , Mutación/genética , Fenotipo , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/metabolismo , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/metabolismo , Sistema de Conducción Cardíaco/metabolismo , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Laminina/genética , Estudios Longitudinales , MasculinoRESUMEN
INTRODUCTION: Familial dilated cardiomyopathy with conduction system defects variably associated with skeletal muscle abnormalities is frequently caused by LMNA gene mutations. METHODS: A family affected by cardiac abnormalities, either isolated or variably associated with skeletal muscle compromise, was identified. LMNA gene analysis was applied to all family members. RESULTS: A novel intron 5 (c.937-11 C > G) mutation was identified. mRNA transcription analysis was subsequently performed, and cDNA was obtained from mutated patients. It displayed an aberrant splice product featuring the insertion of 40 nucleotides from intron 5, leading to a frameshift. Computational predictions identified a cryptic splice site 40 bp upstream from the canonical site; this alternative splicing event was elicited by intronic mutation, which seems to interfere with the polypyrimidine tract of the canonical site. CONCLUSIONS: We have described the first mutation on the LMNA gene interfering with the polypyrimidine tract. Our findings underline the importance of including introns in the search for mutations.
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Empalme Alternativo/genética , Intrones/genética , Lamina Tipo A/genética , Mutación/genética , Proteína de Unión al Tracto de Polipirimidina/genética , Adulto , Anciano , Secuencia de Bases , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , LinajeRESUMEN
Laminopathies are a heterogeneous group of LMNA-gene-mutation-related clinical disorders associated with alterations of cardiac and skeletal muscle and peripheral nerves, metabolic defects, and premature aging. Leg muscle imaging investigations were performed in a cohort of patients with LMNA gene alterations who were suffering from Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B, isolated cardiac disorders or a phenotype of cardiac disorders, and lipodystrophy, including one individual with peripheral neuropathy. Leg muscle imaging revealed varying degrees of alteration in the soleus and medial head of gastrocnemius in each subject. This study demonstrates that LMNA-gene-mutated patients devoid of any clinically detectable skeletal muscle involvement have the same pattern of leg muscle involvement as patients with overt skeletal muscle compromise. This finding suggests the presence of a continuum of skeletal muscle involvement among phenotypes of LMNA-gene-mutation-related skeletalmyopathy and cardiomyopathy.
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Lamina Tipo A/genética , Lipodistrofia/genética , Imagen por Resonancia Magnética , Músculo Esquelético/patología , Mutación/genética , Fenotipo , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Lipodistrofia/diagnóstico , Masculino , Persona de Mediana Edad , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Distrofia Muscular de Emery-Dreifuss/genética , Adulto JovenRESUMEN
The case of a family in which several members displayed conduction defects inherited as a dominant trait is reported. The proband was a young woman with a 1st degree atrio-ventricular block and high serum creatine kinase. Several members of the family featured cardiologic symptoms. All adult family members were clinically evaluated and blood tests including serum creatine-kinase levels, standard and Holter ECG, echocardiogram and muscle MRI were performed. LMNA gene analysis was carried out and a novel missense mutation consisting in substitution of exon 4 c.799 T/C, p.Tyr267His was revealed. The mutation was present in seven family members, five of whom displayed cardiac defects alone with no involvement of the skeletal muscle. In all mutated individuals muscle MRI featured a pattern of skeletal muscle involvement similar to that observed in autosomal dominant Emery Dreifuss muscular dystrophy, suggesting that even patients bearing a LMNA gene mutation associated to an apparently selective cardiac phenotype may present subclinical skeletal muscle involvement.
Asunto(s)
Cardiopatías/genética , Cardiopatías/patología , Lamina Tipo A/genética , Imagen por Resonancia Magnética , Mutación , Miocardio/patología , Adulto , Creatina Quinasa/sangre , Análisis Mutacional de ADN , Ecocardiografía/métodos , Electrocardiografía/métodos , Salud de la Familia , Femenino , Cardiopatías/sangre , Cardiopatías/complicaciones , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/complicaciones , Distrofia Muscular de Emery-Dreifuss/genética , FenotipoRESUMEN
Lamins are the principal components of the nuclear lamina, a network constituting the major structural framework of the nuclear envelope. Alterations in lamin A/C have been associated with a heterogeneous series of human disorders known as laminopathies. We report the finding of a novel deletion in the central rod domain of lamin A/C exon 3 gene in four members of the same family. This genetic alteration was likely responsible for the relatively homogeneous clinical phenotype observed in our three patients, represented by a prominent cardiac conduction-system disease necessitating permanent pacemaker implantation, and limited skeletal involvement manifested by spinal rigidity and contractures. The findings from these cases further expand the clinical spectrum associated with mutations in the LMNA gene.