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1.
Cells ; 13(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38994967

RESUMO

This review summarizes the results of a series of studies performed by our group with the aim to define the expression levels of thymosin ß4 and thymosin ß10 over time, starting from fetal development to different ages after birth, in different human organs and tissues. The first section describes the proteomics investigations performed on whole saliva from preterm newborns and gingival crevicular fluid, which revealed to us the importance of these acidic peptides and their multiple functions. These findings inspired us to start an in-depth investigation mainly based on immunochemistry to establish the distribution of thymosin ß4 and thymosin ß10 in different organs from adults and fetuses at different ages (after autopsy), and therefore to obtain suggestions on the functions of ß-thymosins in health and disease. The functions of ß-thymosins emerging from these studies, for instance, those performed during carcinogenesis, add significant details that could help to resolve the nowadays so-called "ß-thymosin enigma", i.e., the potential molecular role played by these two pleiotropic peptides during human development.


Assuntos
Timosina , Humanos , Timosina/metabolismo , Timosina/genética , Regulação da Expressão Gênica no Desenvolvimento
2.
J Public Health Res ; 12(1): 22799036221150332, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36712902

RESUMO

Background: Breakthrough studies have shown that pluripotent stem cells are present in human breast milk. The expression of pluripotency markers by breast milk cells is heterogeneous, relating to cellular hierarchy, from early-stage multi-lineage stem cells to fully differentiated mammary epithelial cells, as well as weeks of gestation and days of lactation. Design and methods: Here, we qualitatively analyze cell marker expression in freshly isolated human breast milk cells, without any manipulation that could influence protein expression. Moreover, we use electron microscopy to investigate cell-cell networks in breast milk for the first time, providing evidence of active intercellular communication between cells expressing different cellular markers. Results: The immunocytochemistry results of human breast milk cells showed positive staining in all samples for CD44, CD45, CD133, and Ki67 markers. Variable positivity was present with P63, Tß4 and CK14 markers. No immunostaining was detected for Wt1, nestin, Nanog, OCT4, SOX2, CK5, and CD34 markers. Cells isolated from human breast milk form intercellular connections, which together create a cell-to-cell communication network. Conclusions: Cells freshly isolated form human breast milk, without particular manipulations, show heterogeneous expression of stemness markers. The studied milk staminal cells show "pluripotency" at different stages of differentiation, and are present as single cells or grouped cells. The adjacent cell interactions are evidenced by electron microscopy, which showed the formation of intercellular connections, numerous contact regions, and thin pseudopods.

3.
Int Immunopharmacol ; 116: 109743, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36706591

RESUMO

Cell metastasis is the main cause of cancer mortality. Inhibiting early events during cell metastasis and invasion could significantly improve cancer prognosis, but the initial mechanisms of cell transition and migration are barely known. Calcium regulates cell migration, whilst Thymosin ß4 is a G-actin and iron binding peptide associated with tumor metastasis and ferroptosis. Under normal cell growth conditions, intracellular free calcium ions and Thymosin ß4 concentrations are strictly regulated, and are not influenced by extracellular supplementation. However, cell starvation decreases intracellular Thymosin ß4 and increases extracellular peptide uptake above the normal range. Unexpectedly, cell starvation significantly increases internalization of extracellular Ca2+/Thymosin ß4 complexes. Elucidating the role of Ca2+/Thymosin ß4 in the early events of metastasis will likely be important in the future to develop therapies targeting metastasis.


Assuntos
Neoplasias , Timosina , Humanos , Cálcio , Movimento Celular , Timosina/metabolismo
4.
J Public Health Res ; 11(4): 22799036221124076, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36310827

RESUMO

Background: A complex sequence of morphogenetic events leads to the development of the adult mouse kidney. In the present study, we investigated the morphological events that characterize the early stages of the mesenchymal-to-epithelial transition of cap mesenchymal cells, analyzing in depth the relationship between cap mesenchymal induction and ureteric bud (UB) branching. Design and methods: Normal kidneys of newborn non-obese diabetic (NOD) mice were excised and prepared for light and electron microscopic examination. Results: Nephrogenesis was evident in the outer portion of the renal cortex of all examined samples. This process was mainly due to the interaction of two primordial derivatives, the ureteric bud and the metanephric mesenchyme. Early renal developmental stages were initially characterized by the formation of a continuous layer of condensed mesenchymal cells around the tips of the ureteric buds. These caps of mesenchymal cells affected the epithelial cells of the underlying ureteric bud, possibly inducing their growth and branching. Conclusions: The present study provides morphological evidence of the reciprocal induction between the ureteric bud and the metanephric mesenchyme showing that the ureteric buds convert mesenchyme to epithelium that in turn stimulates the growth and the branching of the ureteric bud.

5.
Dalton Trans ; 51(16): 6254-6263, 2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35373808

RESUMO

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.


Assuntos
Complexos de Coordenação , Neoplasias , Alumínio/química , Complexos de Coordenação/farmacologia , Cobre/química , DNA , Ecossistema , Humanos , Íons , Ferro/química , Ligantes , Pironas
6.
Molecules ; 26(21)2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34771023

RESUMO

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.


Assuntos
Fígado/efeitos dos fármacos , Fígado/lesões , Zinco/farmacologia , COVID-19/complicações , Quelantes/metabolismo , Cobre/metabolismo , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/metabolismo , Humanos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , SARS-CoV-2/patogenicidade , Zinco/deficiência , Zinco/metabolismo , Tratamento Farmacológico da COVID-19
7.
Pharmaceutics ; 13(6)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204936

RESUMO

In recent decades, type 2 diabetes complications have been correlated with amylin aggregation, copper homeostasis and metformin side effects. However, each factor was analyzed separately, and only in some rare cases copper/amylin or copper/metformin complexes were considered. We demonstrate for the first time that binary metformin/amylin and tertiary copper (II)/amylin/metformin complexes of high cellular toxicity are formed and lead to the formation of aggregated multi-level lamellar structures on the cell membrane. Considering the increased concentration of amylin, copper (II) and metformin in kidneys of T2DM patients, our findings on the toxicity of amylin and its adducts may be correlated with diabetic nephropathy development.

8.
Ageing Res Rev ; 70: 101391, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34119687

RESUMO

Conformational diseases are caused by the aggregation of misfolded proteins. The risk for such pathologies develops years before clinical symptoms appear, and is higher in people with alpha-1 antitrypsin (AAT) polymorphisms. Thousands of people with alpha-1 antitrypsin deficiency (AATD) are underdiagnosed. Enemy-aggregating proteins may reside in these underdiagnosed AATD patients for many years before a pathology for AATD fully develops. In this perspective review, we hypothesize that the AAT protein could exert a new and previously unconsidered biological effect as an endogenous metal ion chelator that plays a significant role in essential metal ion homeostasis. In this respect, AAT polymorphism may cause an imbalance of metal ions, which could be correlated with the aggregation of amylin, tau, amyloid beta, and alpha synuclein proteins in type 2 diabetes mellitus (T2DM), Alzheimer's and Parkinson's diseases, respectively.


Assuntos
Diabetes Mellitus Tipo 2 , Doença de Parkinson , Deficiência de alfa 1-Antitripsina , Peptídeos beta-Amiloides , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas
9.
RSC Adv ; 10(21): 12680-12688, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35497634

RESUMO

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.

10.
Front Microbiol ; 8: 2067, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29114245

RESUMO

Pistacia lentiscus berry oil (LBO) represents a typical vegetal product of the Mediterranean basin that has been formally used in traditional cuisine for 100s of years. In addition to its interesting alimentary properties, this product could represent an interesting candidate in the field of research on the study of new anti-infective agents. In fact, in Mediterranean countries, lentisk oil still continues to be widely used in folk medicine for oral and skin affections, in particular, acute gingivitis, pediatric skin infections such as impetigo and foot plaques, and biofilm related infections often associated with Streptococcus spp. Following these observations, we have hypothesized a "lentisk oil-bacteria" interaction, placing particular emphasis on the different Streptococcal species involved in these oral and skin diseases. In accordance with this hypothesis, the use of standard antimicrobial-antibiofilm methods (MIC, MBC, MBIC) allowed the interesting behavior of these bacteria to be observed and, in this context, the response to lentisk oil appears to be correlated with the pathogenic profile of the considered microorganism. Two probiotic strains of S. salivarius K12/M18 appeared to be non-sensitive to this product, while a set of five different pathogenic strains (S. agalactiae, S. intermedius, S. mitis, S. mutans, S. pyogenes) showed a response that was correlated to the fatty acid metabolic pathway of the considered species. In fact, at different times of bacteria development, selective High Performance Liquid Chromatography analysis of the growth medium containing LBO detected a significant increase in free unsaturated fatty acids (UFAs) in particular oleic, palmitic and linoleic acids, which are already known for their antibacterial activity. In this context, we have hypothesized that LBO could be able to modulate the pathogen/probiotic rate in a Streptococcal population using the fatty acid metabolic pathway to help the probiotic strain. This hypothesis was strengthened by performing antibacterial testing with oleic acid and an in silico evaluation of the Streptococcal MCRA protein, an enzyme involved in the production of saturated fatty acids from UFA. These results show that LBO may have been used in ancient times as a "natural microbial modulating extract" in the prevention of biofilm- associated diseases.

11.
Genet Mol Biol ; 38(4): 513-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26692159

RESUMO

Two clones, Bt1 from Bos taurus and Om1 from Ovis orientalis musimon, were used as probes for hybridization on genomic DNA and on metaphase chromosomes in members of Bovini and Caprini tribes. Bt1 and Om1 are sequences respectively belonging to the 1.715 and 1.714 DNA satellite I families. Southern blots and fluorescence in situ hybridization experiments showed completely coherent results: the Bovini probe Bt1 hybridized only to members of the Bovini tribe and not to members of Caprini. Likewise, the Caprini probe Om1 hybridized only to members of the Caprini tribe and not to members of Bovini. Hybridization signals were detected in the heterochromatic regions of every acrocentric autosome, except for two pairs of autosomes from Capra hircus that did not show hybridization to probe Om1. No signal was detected on X and Y chromosomes or on bi-armed autosomes. Remarkably, probe Om1 showed almost 100% homology with a bacterial sequence reported in Helicobacter pylori.

12.
PLoS One ; 10(3): e0119642, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25835495

RESUMO

Due to its actin-sequestering properties, thymosin beta-4 (Tß4) is considered to play a significant role in the cellular metabolism. Several physiological properties of Tß4 have been reported;, however, many questions concerning its cellular function remain to be ascertained. To better understand the role of this small peptide we have analyzed by means of transmission immunoelectron microscopy techniques the ultrastructural localization of Tß4 in HepG2 cells. Samples of HepG2 cells were fixed in a mixture of 3% formaldehyde and 0.1% glutaraldehyde in 0.1 M cacodylate buffer and processed for standard electron microscopic techniques. The samples were dehydrated in a cold graded methanol series and embedded in LR gold resin. Ultrathin sections were labeled with rabbit antibodies to Tß4, followed by gold-labeled goat anti-rabbit, stained with uranyl acetate and bismuth subnitrate, observed and photographed in a JEOL 100S transmission electron microscope. High-resolution electron microscopy showed that Tß4 was mainly restricted to the cytoplasm of HepG2 growing in complete medium. A strong Tß4 reactivity was detected in the perinuclear region of the cytoplasmic compartment where gold particles appeared strictly associated to the nuclear membrane. In the nucleus specific Tß4 labeling was observed in the nucleolus. The above electron microscopic results confirm and extend previous observations at light microscopic level, highlighting the subcellular distribution of Tß4 in both cytoplasmic and nuclear compartments of HepG2 cells. The meaning of Tß4 presence in the nucleolus is not on the best of our knowledge clarified yet. It could account for the interaction of Tß4 with nucleolar actin and according with this hypothesis, Tß4 could contribute together with the other nucleolar acting binding proteins to modulate the transcription activity of the RNA polymerases.


Assuntos
Timosina/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Citoplasma/metabolismo , Citoplasma/ultraestrutura , Expressão Gênica , Células Hep G2 , Humanos , Transporte Proteico , Timosina/genética
13.
J Inorg Biochem ; 141: 132-143, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25260149

RESUMO

This work reports the synthesis, characterization and study of complex formation equilibria of the new ligand 6,6'-(2-(diethylamino)ethylazanediyl)bis(methylene)bis(5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) with Fe(III), Al(III), Cu(II) and Zn(II). On the basis of previous encouraging results with tetradentate bis-kojic acid chelators, this ligand was designed to improve the pharmacokinetic properties: increase the solubility, neutral at physiological pH7.4, and enhancement of membrane crossing ability. Fe(III) and Al(III) complexation gave evidence of high metal-sequestering capacity of L9. Cellular assays showed that the ligand is capable of crossing cellular membranes and it does not present toxic effects. Complex formation equilibria with the essential metal ions Cu(II) and Zn(II) have been furthermore studied to evaluate disturbances of this chelator on the homeostatic equilibria of these essential metal ions. A variety of techniques (potentiometry, UV-visible spectrophotometry, 1D and 2D NMR spectroscopy, ESI-MS (electrospray ionization-mass spectrometry), quantum mechanical calculations and X-ray diffraction) have facilitated the characterization of the ligand, and the corresponding iron and zinc complexes, together with an exhaustive analysis of the protonation and complex equilibria.


Assuntos
Quelantes/síntese química , Complexos de Coordenação/síntese química , Etilenodiaminas/síntese química , Ferro/química , Prótons , Pironas/síntese química , Zinco/química , Alumínio/química , Transporte Biológico , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Etilenodiaminas/farmacologia , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Cinética , Ligantes , Pironas/farmacologia , Relação Estrutura-Atividade
14.
PLoS One ; 8(8): e67999, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23967050

RESUMO

Thymosin beta-4 (Tß4) is an ubiquitous multi-functional regenerative peptide, related to many critical biological processes, with a dynamic and flexible conformation which may influence its functions and its subcellular distribution. For these reasons, the intracellular localization and trafficking of Tß4 is still not completely defined and is still under investigation in in vivo as well as in vitro studies. In the current study we used HepG2 cells, a human hepatoma cell line; cells growing in normal conditions with fetal bovine serum expressed high levels of Tß4, restricted to the cytoplasm until 72 h. At 84 h, a diffuse Tß4 cytoplasmic immunostaining shifted to a focal perinuclear and nuclear reactivity. In the absence of serum, nuclear reactivity was localized in small granules, evenly dispersed throughout the entire nuclear envelop, and was observed as earlier as at 48 h. Cytoplasmic immunostaining for Tß4 in HepG2 cells under starvation appeared significantly lower at 48 h and decreased progressively at 72 and at 84 h. At these time points, the decrease in cytoplasmic staining was associated with a progressive increase in nuclear reactivity, suggesting a possible translocation of the peptide from the cytoplasm to the nuclear membrane. The normal immunocytochemical pattern was restored when culture cells submitted to starvation for 84 h received a new complete medium for 48 h. Mass spectrometry analysis, performed on the nuclear and cytosolic fractions of HepG2 growing with and without serum, showed that Tß4 was detectable only in the cytosolic and not in the intranuclear fraction. These data suggest that Tß4 is able to translocate from different cytoplasmic domains to the nuclear membrane and back, based on different stress conditions within the cell. The punctuate pattern of nuclear Tß4 immunostaining associated with Tß4 absence in the nucleoplasm suggest that this peptide might be localized in the nuclear pores, where it could regulate the pore permeability.


Assuntos
Meios de Cultura/metabolismo , Soro , Timosina/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Bovinos , Núcleo Celular/metabolismo , Regulação da Expressão Gênica , Células Hep G2 , Humanos
15.
J Matern Fetal Neonatal Med ; 25 Suppl 3: 41-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23016617

RESUMO

An emerging hypothesis from the recent literature explain how specific adverse factors related with growth retardation as well as of low birth weight (LBW) might influence renal development during fetal life and then the insurgence of hypertension and renal disease in adulthood. In this article, after introducing a brief overview of human nephrogenesis, the most important factors influencing nephron number at birth will be reviewed, focusing on the "in utero" experiences that lead to an increased risk of developing hypertension and/or kidney disease in adult. Since nephrogenesis in preterm human newborns does not stop at birth, but it continues for 4-6 weeks postnatally, a better knowledge of the mechanisms able to accelerate nephrogenesis in the perinatal period, could represent a powerful tool in the hands of neonatologists. We suggest to define this approach to a possible therapy of a deficient nephrogenesis at birth "physiological renal regenerating medicine". Our goal in preterm infants, especially VLBW, could be to prolong the nephrogenesis not only for 6 weeks after birth but until 36 weeks of post conceptual age, allowing newborn kidneys to restore their nephron endowment, escaping susceptibility to hypertension and to renal disease later in life.


Assuntos
Nefropatias/embriologia , Néfrons/embriologia , Animais , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Nefropatias/prevenção & controle , Néfrons/crescimento & desenvolvimento , Néfrons/ultraestrutura
16.
Diagn Mol Pathol ; 19(1): 1-8, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20186005

RESUMO

BRAF is an oncogene that is commonly mutated in both melanomas and papillary thyroid carcinomas (PTCs). Usually, mutations in the codons 600 or 601 lead to constitutive activity in the Ras-mitogen-activated protein kinase pathway and, recently, the BRAF deletion was described as a relevant risk factor for loco-regional PTC lymph node metastasis. For these reasons, BRAF mutations may be considered a key genetic factor for the metastatic progression of PTC and also for other tumors such as melanoma and colon cancer and a new BRAF-specific therapeutic strategy was already suggested. In this report we describe the development of a rapid qualitative fluorescent real-time polymerase chain reaction assay designed for the detection of BRAF deletion using 2 specific molecular beacons. The assay is able to detect in a single tube the homozygous as well the heterozygous genotypes. The procedure combines the great sensitivity of the polymerase chain reaction, the specificity provided by allele-specific molecular beacons, and the throughput of a multicolor fluorescence detection procedure. This technique, together with an earlier described real-time test specific for V600E and K601E will be useful for research and molecular diagnostic laboratories involved in the study of BRAF-related neoplasia.


Assuntos
Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Sondas de Oligonucleotídeos/química , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Alelos , Heterozigoto , Homozigoto , Humanos , Sondas de Oligonucleotídeos/genética , Patologia Molecular/métodos
17.
Coll Antropol ; 32 Suppl 1: 51-8, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18405058

RESUMO

Brains affected by Alzheimer's disease (AD) show a large spectrum of mitochondrial alterations at both morphological and genetic level. The causal link between amyloid beta peptides (AP) and mitochondrial dysfunction has been established in cellular models of AD using Abeta concentrations capable of triggering massive neuronal death. However, mitochondrial changes related to sublethal exposure to Abeta are less known. Here we show that subtoxic, 1 microM Abeta(1-42) exposure does not change the mitochondrial shape of living cells, as visualized upon the uptake of the non-potentiometric fluorescent probe Mitotracker Green and enhanced yellow fluorescent protein (EYFP)-tagged cytochrome c oxidase expression. Immunolocalization of oxidative adducts 8-hydroxy-2'-deoxyguanosine, 8-hydroxyguanine and 8-hydroxyguanosine demonstrates that one-micromolar concentration of Abeta(1-42) is also not sufficient to elicit dramatic qualitative changes in the RNA/DNA oxidative products. However, in comparison with controls, semi-quantitative analysis of the overall mitochondrial mass by integrated fluorescence intensity reveals an ongoing down-regulation in mitochondrial biosynthesis or, conversely, an enhanced autophagic demise of Abeta treated cells. Furthermore, a significant increase of the full-length mitochondrial DNA (mtDNA) from Abeta-treated versus control cells is found, as measured by long range polymerase chain reaction (PCR). Such up-regulation is accompanied by extensive fragmentation of the unamplified mtDNA, probably due to the detrimental effect of Abeta. We interpret these results as a sequence of compensatory responses induced by mtDNA damage, which are devoted to repression of oxidative burst. In conclusion, our findings suggest that early therapeutic interventions aimed at prevention of mitochondrial oxidative damage may delay AD progression and help in treating AD patients.


Assuntos
Peptídeos beta-Amiloides/toxicidade , DNA Mitocondrial/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/genética , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Aldeídos , Animais , Linhagem Celular Tumoral , DNA Mitocondrial/genética , Corantes Fluorescentes , Camundongos , Mitocôndrias/metabolismo , Transfecção
18.
Diagn Mol Pathol ; 12(4): 237-9, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14639110

RESUMO

A 73-year-old never-smoker woman with chronic bronchitis, increasing dyspnoea, and airflow limitation with a FEV1 of 49% of predicted value had low serum level of alpha-1-antitrypsin (69 mg/dL, normal range 150-350). Isoelectric focusing showed an Mlike pattern. Direct sequencing showed, in the second exon, a particular DNA alteration localized between codon 41 and codon 51: a region of 30 base pairs (bp) was completely deleted and substituted by a 22-bp sequence. The resulting loss of 8 bp yields, in the second exon, a 70-71 stop codon. This new Mlike variant was denominated MVarallo from the site where it was discovered.


Assuntos
Variação Genética , Doença Pulmonar Obstrutiva Crônica/genética , Inibidores da Tripsina/genética , alfa 1-Antitripsina/genética , Idoso , Alelos , Sequência de Bases , DNA/análise , DNA/genética , Feminino , Volume Expiratório Forçado , Heterozigoto , Humanos , Focalização Isoelétrica , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Inibidores da Tripsina/análise , alfa 1-Antitripsina/análise
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