bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of the New Life(style) study: a randomised controlled trial to optimise maternal weight development during pregnancy. [ISRCTN85313483]
Authors: Althuizen Ellen , van Poppel Mireille NM , Seidell Jacob C , van der Wijden Carla , van Mechelen Willem
Published: June 2006

Background

Preventing excessive weight gain during pregnancy is potentially important in the prevention of overweight and obesity among women of childbearing age. However, few intervention studies aiming at weight management during pregnancy have been performed and most of these interventions were not as successful as expected. In this paper the design of the New Life(style) study is described as well as the content of the individually tailored intervention program, which focuses on controlling weight development during pregnancy.

Methods

The effectiveness of the New Life(style) intervention program versus usual care by midwives is evaluated in a randomised controlled trial. Women who expect their first child and visit one of the participating midwifery practices are included. The intervention is standardised in a protocol and executed by trained counsellors with the women who are randomised in the intervention group. During 5 sessions – at 18, 22, 30 and 36 weeks of pregnancy and at 8 weeks postpartum – individual weight gain is discussed in relation to weight gain guidelines for pregnant women of the American Institute of Medicine. Counsellors coach the women to maintain or optimise a healthy lifestyle, in a period of drastic physical and mental changes. Data is collected at 15, 25, 35 weeks of pregnancy and at 6, 26, and 52 weeks after delivery. Primary outcome measures are body weight, BMI, and skinfold thickness. Secondary outcome measures include physical activity, nutrition and blood levels of factors that are associated with energy homeostasis.

Discussion

Results of the current RCT will improve the knowledge of determinants of weight gain during pregnancy, weight retention after childbirth and of the effectiveness of the intervention program that is described. Caregivers and researchers in the field of health promotion are offered more insight in specific elements of the New Life(style) intervention program.
A general method for the unbiased improvement of solution NMR structures by the use of related X-Ray data, the AUREMOL-ISIC algorithm
Authors: Brunner Konrad , Gronwald Wolfram , Trenner Jochen M , Neidig Klaus-Peter , Kalbitzer Hans Robert
Published: June 2006

Background

Rapid and accurate three-dimensional structure determination of biological macromolecules is mandatory to keep up with the vast progress made in the identification of primary sequence information. During the last few years the amount of data deposited in the protein data bank has substantially increased providing additional information for novel structure determination projects. The key question is how to combine the available database information with the experimental data of the current project ensuring that only relevant information is used and a correct structural bias is produced. For this purpose a novel fully automated algorithm based on Bayesian reasoning has been developed. It allows the combination of structural information from different sources in a consistent way to obtain high quality structures with a limited set of experimental data. The new ISIC (I ntelligent S tructural I nformation C ombination) algorithm is part of the larger AUREMOL software package.

Results

Our new approach was successfully tested on the improvement of the solution NMR structures of the Ras-binding domain of Byr2 from Schizosaccharomyces pombe, the Ras-binding domain of RalGDS from human calculated from a limited set of NMR data, and the immunoglobulin binding domain from protein G from Streptococcus by their corresponding X-ray structures. In all test cases clearly improved structures were obtained. The largest danger in using data from other sources is a possible bias towards the added structure. In the worst case instead of a refined target structure the structure from the additional source is essentially reproduced. We could clearly show that the ISIC algorithm treats these difficulties properly.

Conclusion

In summary, we present a novel fully automated method to combine strongly coupled knowledge from different sources. The combination with validation tools such as the calculation of NMR R-factors strengthens the impact of the method considerably since the improvement of the structures can be assessed quantitatively. The ISIC method can be applied to a large number of similar problems where the quality of the obtained three-dimensional structures is limited by the available experimental data like the improvement of large NMR structures calculated from sparse experimental data or the refinement of low resolution X-ray structures. Also structures may be refined using other available structural information such as homology models.
Prediction of solubility on recombinant expression of Plasmodium falciparum erythrocyte membrane protein 1 domains in Escherichia coli
Authors: Ahuja Sanjay , Ahuja Satpal , Chen Qijun , Wahlgren Mats
Published: June 2006

Background

Cellular interactions elicited by Plasmodium falciparum erythrocyte membrane protein antigen 1 (PfEMP1) are brought about by multiple DBL (Duffy binding like), CIDR (cysteine-rich interdomain region) and C2 domain types. Elucidation of the functional and structural characteristics of these domains is contingent on the abundant availability of recombinant protein in a soluble form. A priori prediction of PfEMP1 domains of the 3D7 genome strain, most likely to be expressed in the soluble form in Escherichia coli was computed and proven experimentally.

Methods

A computational analysis correlating sequence-dependent features to likelihood for expression in soluble form was computed and predictions were validated by the colony filtration blot method for rapid identification of soluble protein expression in E. coli.

Results

Solubility predictions for all constituent PfEMP1 domains in the decreasing order of their probability to be expressed in a soluble form (% mean solubility) are as follows: ATS (56.7%) > CIDR1α (46.8%) > CIDR2β (42.9%) > DBL2-4γ (31.7%) > DBL2β + C2 (30.6%) > DBL1α (24.9%) > DBL2-7ε (23.1%) > DBL2-5δ (14.8%). The length of the domains does not correlate to their probability for successful expression in the soluble form. Immunoblot analysis probing for soluble protein confirmed the differential in solubility predictions.

Conclusion

The acidic terminal segment (ATS) and CIDR α/β domain types are suitable for recombinant expression in E. coli while all DBL subtypes (α, β, γ, δ, ε) are a poor choice for obtaining soluble protein on recombinant expression in E. coli. This study has relevance for researchers pursuing functional and structural studies on PfEMP1 domains.
Cytokine response to lipoprotein lipid loading in human monocyte-derived macrophages
Authors: Persson Jenny , Nilsson Jan , Lindholm Marie W
Published: June 2006

Background

Macrophage foam cell formation is a prominent feature of human atherosclerotic plaques, usually considered to be correlated to uptake of and inflammatory response to oxidized low density lipoproteins (OxLDL). However, there are alternative pathways for formation of macrophage foam cells and the effect of such lipid loading on macrophage function remains to be fully characterized. In the present study we investigated basal and inducible cytokine expression in primary human macrophages either loaded with triglycerides through incubation with very low density lipoproteins (VLDL) or with cholesterol through incubation with aggregated LDL (AgLDL). We then analyzed how foam cell lipid content affected secretion of three pro-inflammatory cytokines: interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and of one chemokine: interleukin-8 (IL-8), all of which are considered pro-inflammatory, pro-atherosclerotic, and are expressed by cells in atherosclerotic tissue.

Results

Formation of triglyceride-loaded foam cells resulted in a four-fold increase in basal IL-1β secretion, whereas cholesterol loading lacked significant effect on IL-1β secretion. In contrast, secretion of TNF-α and IL-6 decreased significantly following both cholesterol and triglyceride loading, with a similar trend for secretion of IL-8. Lipid loading did not affect cell viability or expression of caspase-3, and did not significantly affect macrophage ability to respond to stimulation with exogenous TNF-α.

Conclusion

Lipid loading of primary human macrophages resulted in altered cytokine secretion from cells, where effects were similar regardless of neutral lipid composition of cells. The exception was IL-1β, where triglyceride, but not cholesterol, lipid loading resulted in a stimulation of basal secretion of the cytokine. It is apparent that macrophage cytokine secretion is affected by lipid loading by lipoproteins other than OxLDL. As both VLDL and AgLDL have been found in the vessel wall, macrophage cytokine response to uptake of these lipoproteins may have a direct effect on atherosclerotic development in vivo. However, macrophage neutral lipid amount and composition did not affect cellular activation by exogenous TNF-α, making it likely that lipoprotein lipid loading can affect foam cell cytokine secretion during basal conditions but that the effects can be overruled by TNF-α during acute inflammation.
Liver metastases of neuroendocrine tumours; early reduction of tumour load to improve life expectancy
Authors: Veenendaal Liesbeth M , Rinkes Inne HM Borel , Lips Cornelis JM , van Hillegersberg Richard
Published: June 2006

Background

Neuroendocrine tumours frequently metastasize to the liver. Although generally slowly progressing, hepatic metastases are the major cause of carcinoid syndrome and ultimately lead to liver dysfunction, cardiac insufficiency and finally death.

Methods

A literature review was performed to define the optimal treatment strategy and work-up in patients with neuroendocrine hepatic metastases. Based on this, an algorithm for the management of these patients was established.

Results

Platelet serotonin and chromogranin A are useful biomarkers for detection and follow-up of neuroendocrine tumour. Helical computed tomography and somatostatin receptor scintigraphy are the most sensitive diagnostic modalities. Surgical debulking is an accepted approach for reducing hormonal symptoms and to establish better conditions for medical treatment, but is frequently impossible due to the extent of disease. A novel approach is the local ablation of tumour by thermal coagulation using therapies such as radiofrequency ablation (RFA) or laser induced thermotherapy (LITT). These techniques preserve normal liver tissue. There is a tendency to destroy metastases early in the course of disease, thereby postponing or eliminating the surgically untreatable stage. This can be combined with postoperative radioactive octreotide to eliminate small multiple metastases. In patients with extensive metastases who are not suitable for local destruction, systemic therapy by octreotide, 131I-MIBG treatment or targeted chemo- and radiotherapy should be attempted. A final option for selective patients is orthotopic liver transplantation.

Conclusion

Treatment for patients with neuroendocrine hepatic metastases must be tailored for each individual patient. When local ablative therapies are used early in the course of the disease, the occurrence of carcinoid syndrome with end stage hepatic disease can be postponed or prevented.
Distinct expression profiles of TGF-β1 signaling mediators in pathogenic SIVmac and non-pathogenic SIVagm infections
Authors: Ploquin Mickaël J-Y , Desoutter Jean-François , Santos Patricia R , Pandrea Ivona , Diop Ousmane M , Hosmalin Anne , Butor Cécile , Barre-Sinoussi Françoise , Müller-Trutwin Michaela C
Published: June 2006

Background

The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-β1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-β1 induction persists during primary infection [1]. We raised the hypothesis that MACs are unable to respond to TGF-β1 and thus cannot resorb virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory markers as well as of factors involved in the TGF-β1 signaling pathway in SIV-infected AGMs and MACs.

Methods

Levels of transcripts encoding for pro- and anti-inflammatory markers (tnf-α, ifn-γ, il-10, t-bet, gata-3) as well as for TGF-β1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs.

Results

During primary SIVmac infection, up-regulations of tnf-α, ifn-γ and t-bet responses (days 1–16 p.i.) were stronger whereas il-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 3–8 p.i.), a cellular mediator inhibiting the TGF-β1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of gata-3 but not t-bet, a longer lasting up-regulation of smad4 (days 1–21 p.i), a mediator enhancing TGF-β1 signaling, and no smad7 up-regulations.

Conclusion

Our data suggest that the inability to resorb virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is associated with an unresponsiveness to TGF-β1.
A comparative evaluation of pharmacy services in single and no pharmacy towns
Authors: Sunderland V Bruce , Burrows Suzanne D , Joyce Andrew W
Published: June 2006

Background

Recent attention has focused on access of communities to pharmacy services in rural areas. To increase access to pharmacy services in rural Western Australia some doctors have been granted a licence to dispense medication on the rationale that a pharmacy would not be economically viable in that community. However, there have been no studies conducted on whether a doctor dispensing service adequately provides a pharmacy service with respect to access and quality.

Method

Residents of seven single pharmacy towns and seven non-pharmacy rural towns were surveyed to evaluate pharmacy services delivered by a pharmacist and doctor. The towns were chosen to match closely on key demographic features, with an average population of 1,246 and 1,263 respectively. A random sample of 150 households from each town was sent the questionnaire on pharmacy services (1050 in each group). Data was also collected from the Health Insurance Commission (HIC) on dispensing locations for the residents of the two groups of towns.

Results

There was a significant difference in access to pharmacy services with 82.4% of participants from pharmacy towns accessing medications within their town compared to 51.3% of non-pharmacy town participants. The HIC data supported these trends with pharmacy town residents having relatively higher prescription rates within their town compared to non-pharmacy town residents where they were more likely to access prescriptions out of their town.

Conclusion

Pharmacy town participants were more satisfied with access to health and pharmacy services within their town. Continuation of the doctor dispensing policy requires a greater consideration of the pharmacy needs of rural residents.
The Free Radical Fantasy
Authors: HOWES RANDOLPH M.
Published: June 2006

Abstract:  Overly exuberant and exaggerated past expectations and claims of the free radical theory have been quieted by extensive randomized, double‐blind, controlled human studies. A half century of data demonstrates its lack of predictability and it has not been validated by the scientific method. Widespread use of antioxidants has failed to quell the current pandemic of cancer, diabetes, and cardiovascular disease or to stop or reverse the aging process. Electronically modified oxygen derivatives contribute to the modulation of cellular redox status, which is of primary importance in disease prevention and homeostasis.
Cellular Redox Regulation and Prooxidant Signaling Systems
Authors: LINNANE ANTHONY W. , EASTWOOD HAYDEN
Published: June 2006

Abstract:  The overarching role of coenzyme Q10 in gene regulation, bioenergy formation, cellular redox poise regulation, and hydrogen peroxide formation is presented. Coenzyme Q10 has a central role acting as a prooxidant in the generation of H2O2. Contrary to the dogma that superoxide and H2O2 formation are highly deleterious to cell survival this premise is rejected. Data are discussed that continuous superoxide and hydrogen peroxide formation are essential for normal cell function and that they play a major role in subcellular redox state modulation. It is the prooxidant activity of the so‐called antioxidants that may be responsible for previously claimed benefits for high doses of oxido‐reduction nutritional supplements such as alpha lipoic acid and coenzyme Q10. Oxygen‐free radical formation is essential for the biological function and is not a direct causation of the mammalian aging process; aging is a multisystem stochastic process.
Aging in Mouse and Human Systems
Authors: DEMETRIUS LLOYD
Published: June 2006

Abstract:  This article discusses the significance of mouse models as a basis for elucidating the aging process in humans. We identify certain parallels between mouse and human systems and review the theoretical and empirical support for the claim that the large divergence in the rate of aging between the two species resides in differences in the stability of their metabolic networks. We will show that these differences in metabolic stability have their origin in the different ecological constraints the species experience during their evolutionary history. We exploit these ideas to compare the effect of caloric restriction on murine and human systems. The studies predict that the large increases in mean life span and maximum life‐span potential observed in laboratory rodents subject to caloric restriction will not obtain in human populations. We predict that, in view of the different metabolic stability of the two systems, caloric restriction will have no effect on the maximum life‐span potential of humans, and a relatively minor effect on the mean life span of nonobese populations. This article thus points to certain intrinsic limitations in the use of mouse models in elucidating the aging process in humans. We furthermore contend the view that these limitations can be mitigated by considering the metabolic stability of the two species.
Unraveling Age‐Dependent Variation of the Mitochondrial Proteome
Authors: DENCHER NORBERT A. , GOTO SATARO , REIFSCHNEIDER NICOLE H. , SUGAWA MICHIRU , KRAUSE FRANK
Published: June 2006

Abstract:  Blue‐native and colorless‐native gel electrophoresis combined with subsequent 2D‐SDS‐PAGE and MALDI mass spectrometry are successfully applied for understanding the role of mitochondria in cellular dysfunction, aging, and cellular death. The partial mitochondrial proteome maps of various tissues (liver, brain, kidney, heart, and skeletal muscle) obtained from rat serve now as a database for the elucidation of age‐dependent changes, including alterations in protein–protein interactions as well as in posttranslational modifications.
Brain Lipopigment Accumulation in Normal and Pathological Aging
Authors: RIGA DAN , RIGA SORIN , HALALAU FLORIN , SCHNEIDER FRANCISC
Published: June 2006

Abstract:  A principal marker of brain vulnerability, stress, aging, and related pathology is represented by lipopigments (LPs)—lipofuscin, and ceroid. During ontogenesis, neuronal LP accumulations are significantly correlated with important changes in nerve cell morphology and biochemistry. In the aged neurons, LPs are present in all cellular compartments. Moreover, neuronal LP accumulations coexist with glial LP storage, especially in microglia. Owing to their transporting properties, and the migration capacity of microglia, glial cells deposit LP clusters in pericapillary areas. Thus, LP conglomerates appear in the whole nervous tissue, creating specific patterns of LP architectonics. Direct interrelations, critical LP concentrations, which generate cascades of negative subcellular events, and indirect impairment correlations determine characteristic neuropathologic aging profiles. These specific and associated negative neuropathologic consequences of LP accumulation have multiple and detrimental impacts on neuron and glia homeostasis, ranging from neuronal function to central nervous system physiology.
Aging and Orchidectomy Modulate Expression of VEGF Receptors (Flt‐1 and Flk‐1) on Corpus Cavernosum of the Rat
Authors: NEVES DELMINDA , SANTOS JANETE , TOMADA NUNO , ALMEIDA HENRIQUE , VENDEIRA PEDRO
Published: June 2006

Abstract: Aging and hypogonadic states are known risk factors for erectile dysfunction (ED), contributing together to vascular damage of penile tissue. In the present study, VEGF‐specific membrane receptor (VEGFR‐1/Flt‐1 and VEGFR‐2/Flk‐1) expression was studied by confocal immunofluorescence in the corpus cavernosum of control rats, rats aged 12 and 18 months, and orchidectomized Wistar rats (90 days of bilateral orchidectomy). Immunocytochemical results demonstrated VEGFR‐2 expression restricted to the endothelium in both control and orchidectomized rats. Aged animals (12 and 18 months) presented enlarged vessels with intense VEGFR‐2 endothelial staining. On the other hand, VEGFR‐1 was demonstrated in smooth muscle fibers, particularly in those that surround vessel endothelium, the endothelial expression being very low in control and orchidectomized rats. However, in the aged rats, a shift resulting in a VEGFR‐1 and VEGFR‐2 co‐localization in the endothelial cell was observed. The findings suggest an upregulation of VEGFR‐1 in the corpora cavernosa during aging in the rat, which is evident from an increased expression by endothelial cells.
Role of Angiotensin II and Endothelin‐1 Receptors in Aging‐Related Functional Changes in Rat Cardiovascular System
Authors: ISHIHATA AKIRA , KATANO YUMI
Published: June 2006

Abstract:  Angiotensin II (AII) and endothelin‐1 (ET‐1) are regarded as key players in the age‐related changes in cardiovascular function. They are known to be involved in the pathogenesis of cardiac fibrosis and coronary vascular atherosclerosis. AII‐ and ET‐induced vasoconstriction was augmented in coronary arteries of Langendorff‐perfused heart from aged rats. In papillary muscles, ET‐1‐induced positive inotropic effect (PIE) was diminished by aging. On the other hand, both ET‐1 and AII caused greater vasoconstriction in aged rat coronary arteries compared to those in the young rat. To further elucidate the mechanism of these age‐dependent changes in cardiovascular effects of ET‐1 and AII, we examined the expression of AII and ET‐1 receptors in young (2‐month‐old) and aged (24‐month‐old) rats. Total RNA was isolated from left ventricles. For determination of the gene expression of AT1 receptor and ETA/ETB receptor mRNA, competitive RT‐PCR and Northern blot analysis were performed, respectively. [125I]ET‐1 receptor assay was carried out in left ventricular membrane fraction. AT1‐receptor, ETA‐, and ETB‐receptor mRNA were upregulated in the left ventricles of senescent rats compared with young ones. The affinity of ET‐1‐receptor was not changed, but receptor density was significantly increased in aged rats. Although the precise mechanism for the upregulation of AT1 receptor and ET‐1 receptor in the aged rat heart has not been clarified yet, these findings suggest that the activation of the renin–angiotensin system as well as ET receptor may be important for the physiological changes in aged hearts.
DNA Damage by Free Radical Production by Aminoguanidine
Authors: SUJI GEORGE , SIVAKAMI SUBRAMANIUM
Published: June 2006

Abstract:  Aminoguanidine (AG), a prototype therapeutic dicarbonyl scavenger, is the most potent drug available today to inhibit the formation of advanced glycation endproducts (AGEs) and to reverse glycation‐mediated damage in normal aging. This paper examines the ability of AG to cause damage to supercoiled plasmid DNA in the presence of the transition metal, Fe+3. Damage to DNA was dependent on the concentrations of both the transition metal and AG. We could detect hydroxyl radical as well as hydrogen peroxide during the incubation of AG with Fe+3. Thus this finding further cautions against the indiscriminate use of AG in clinical prophylaxis in diabetes and questions its use as a therapeutic agent.
CARF Regulates p19ARF‐p53‐p21WAF1 Senescence Pathway by Multiple Checkpoints
Authors: KAUL SUNIL C. , HASAN KAMRUL , WADHWA RENU
Published: June 2006

Abstract:  CARF was first cloned as a novel binding partner of ARF from a yeast‐interactive screen. CARF and ARF colocalize in the perinucleolar region and have a collaborative function. In the nucleoplasm, CARF interacts with p53 and enhances its function. We demonstrate that p53 downregulates CARF in a negative feedback regulatory loop and may also involve p53 antagonist HDM2.
Aging of Murine Mesenchymal Stem Cells
Authors: FEHRER CHRISTINE , LASCHOBER GERHARD , LEPPERDINGER GÜNTER
Published: June 2006

Abstract:  Mesenchymal stem cells (MSCs) are able to differentiate into distinct lineages such as adipo‐, osteo‐, and chondrocytes. MSCs were isolated from three mouse strains, which are short‐ (SAMP6, 9.7 months), medium‐ (SAMR1, 16.3 months), or long‐lived (C57BL/6, 28 months). We investigated primary colony‐forming units with regard to bone marrow stroma and found differences that correlate with mean life expectancies of the particular genetic backgrounds. However, MSC derived from the various mouse strains behaved equivalently in vitro with respect to growth rate. By genomic means, we analyzed the cellular milieu in vivo and found considerable differences among the various mouse strains. This implies that, although individual MSCs show an equivalent differentiation potential in vitro, the primary stem cells are greatly influenced by their molecular environment.
Prevention of Accelerated Cell Aging in the Werner Syndrome
Authors: DAVIS TERENCE , HAUGHTON MICHÈLE F. , JONES CHRISTOPHER J. , KIPLING DAVID
Published: June 2006

Abstract:  In the Werner syndrome (WS) fibroblasts have an increased life span and growth rate when treated with the p38 inhibitor SB203580. Additionally, the cellular morphology reverts to that seen in young normal fibroblasts. The p38 pathway is activated in young WS cells, associated with high levels of p21WAF1 leading to cell cycle arrest, and is suppressed by SB203580. As these changes are also seen in telomerized WS cells, these data show that the growth problems seen in WS cells, and perhaps the accelerated in vivo aging, are due to a telomere‐independent premature senescence mechanism. The suppression of this mechanism by SB203580 treatment suggests a route whereby WS may be amenable to therapeutic intervention.
Oxidative Stress Induces Intralysosomal Accumulation of Alzheimer Amyloid β‐Protein in Cultured Neuroblastoma Cells
Authors: ZHENG LIN , ROBERG KARIN , JERHAMMAR FREDRIK , MARCUSSON JAN , TERMAN ALEXEI
Published: June 2006

Abstract:  Oxidative stress is considered important for the pathogenesis of Alzheimer's disease (AD), which is characterized by the formation of extracellular senile plaques, mainly composed of amyloid β‐protein (Aβ). Aβ also accumulates within AD neurons and is believed to exert cellular toxicity through lysosomal labilization. We report that the exposure of human neuroblastoma cells to hyperoxia (40% vs. 8% ambient oxygen) induced the accumulation of large (over 1 μM) Aβ‐containing lysosomes, which were not typical of control cells, showing a distinct localization of Aβ and lysosomal markers. An inhibitor of autophagy, 3‐methyladenine, suppressed the effect of hyperoxia. The results suggest a link between the involvement of oxidative stress and lysosomes in AD.
The Genetics of Human Longevity
Authors: CAPRI MIRIAM , SALVIOLI STEFANO , SEVINI FEDERICA , VALENSIN SILVANA , CELANI LAURA , MONTI DANIELA , PAWELEC GRAHAM , DE BENEDICTIS GIOVANNA , GONOS EFSTATHIOS S. , FRANCESCHI CLAUDIO
Published: June 2006

Abstract:  Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify “longevity genes” in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of “candidate” polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes‐positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL‐1 cluster, IL‐6, IL‐10, TNF‐α, TGF‐β, TLR‐4, PPARγ), insulin/IGF‐1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66shc) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.
Association between +1059G/C CRP Polymorphism and Acute Myocardial Infarction in a Cohort of Patients from Sicily
Authors: BALISTRERI CARMELA RITA , VASTO SONYA , LISTÌ FLORINDA , GRIMALDI MARIA PAOLA , LIO DOMENICO , COLONNA‐ROMANO GIUSEPPINA , CARUSO MARCO , CAIMI GREGORIO , HOFFMANN ENRICO , CARUSO CALOGERO , CANDORE GIUSEPPINA
Published: June 2006

Abstract:  Inflammation plays a role in all the phases of atherosclerosis, and increased production of the acute‐phase reactant, C‐reactive protein (CRP), predicts future cardiovascular events. Furthermore, CRP has been claimed to play a role in the pathogenesis of atherosclerosis; therefore, CRP polymorphisms might be associated with acute myocardial infarction (AMI). We have analyzed male patients affected by AMI and healthy age‐related male controls from Sicily for +1059G/C CRP single‐nucleotide polymorphism (SNP). There was a significantly higher frequency of +1059C SNP (P= 0.0008; OR 3.86) in patients compared to controls. CRP serum levels were significantly higher in C+ healthy subjects rather than in C− subjects (P= 0.0075). The results of the present pilot case–control study performed in a homogeneous caucasoid population suggest that +1059C CRP gene SNP is associated with AMI. In any case, the results of the present study should add to the growing body of evidence on the role of pro‐inflammatory genotypes in unsuccessful aging, determining susceptibility to immune‐inflammatory diseases such as coronary heart disease.
Frequency of Polymorphisms of Signal Peptide of TGF‐β1 and −1082G/A SNP at the Promoter Region of Il‐10 Gene in Patients with Carotid Stenosis
Authors: CRIVELLO ANTONIO , GIACALONE ANTONIO , SCOLA LETIZIA , FORTE GIUSI IRMA , NUZZO DOMENICO , GIACCONI ROBERTINA , CIPRIANO CATIA , CANDORE GIUSEPPINA , MOCCHEGIANI EUGENIO , ROMANO GIUSEPPINA COLONNA , LIO DOMENICO , CARUSO CALOGERO
Published: June 2006

Abstract:  The role of inflammation in atherosclerosis is well recognized. We have evaluated the allele frequencies of the +869T/C and +915G/C polymorphisms (SNPs) at the TGF‐β1 gene and −1082G/A SNP at IL‐10 promoter sequence, two well‐known immunosuppressive and anti‐inflammatory cytokines, in patients with carotid stenosis. Our data suggest a lack of association between these SNPs and the susceptibility to atherosclerosis although other reports have demonstrated this association. These results may be due to the pleiotropic effects of the cytokines and/or differences in haplotype combination that should be investigated to elucidate the role of TGF‐β1 and IL‐10 polymorphisms in atherosclerosis.
Heat‐Shock Protein 70 Genes and Human Longevity
Authors: SINGH RIPUDAMAN , KØLVRAA STEEN , BROSS PETER , CHRISTENSEN KAARE , GREGERSEN NIELS , TAN QIHUA , JENSEN UFFE BIRK , EIBERG HANS , RATTAN SURESH I. S.
Published: June 2006

Abstract:  We have studied the association of three single nucleotide polymorphisms (SNPs) present in the three HSP70 (heat‐shock protein) genes on 6p21 with human longevity. The availability of biological samples from various population cohorts in Denmark has given us the opportunity to try novel methods of gene association with human longevity. A significant association of one haplotype with male longevity was observed. Furthermore, a significant difference in the survival of the carriers of the different genotypes in females was observed. We also found an age‐dependant decline in the ability of peripheral blood mononuclear cells to respond to heat stress in terms of Hsp70 induction.
Prevention and Treatment of Skin Aging
Authors: McCULLOUGH JERRY L. , KELLY KRISTEN M.
Published: June 2006

Abstract:  Skin aging is a complex biological process that is a consequence of both intrinsic or genetically programmed aging that occurs with time, and extrinsic aging caused by environmental factors. The dramatic increase in the aging population and the psychosocial impact of skin aging has created a demand for effective interventions. The advances that have been made in the past 25 years in our understanding of the clinical, biochemical, and molecular changes associated with aging have led to the development of many different approaches to reduce, postpone, and in some cases, repair the untoward effects of intrinsic programmed aging and extrinsic environmental injury.
Epidermal and Dermal Characteristics in Skin Equivalent after Systemic and Topical Application of Skin Care Ingredients
Authors: VICANOVA JANA , BOUEZ CHARBEL , LACROIX SOPHIE , LINDMARK LARS , DAMOUR ODILE
Published: June 2006

Abstract:  Effects of active ingredients from topical and systemic skincare products on structure and organization of epidermis, dermal–epidermal junction (DEJ), and dermis were examined using an in vitro reconstructed skin equivalent (SE). Imedeen Time Perfection (ITP) ingredients (a mixture of BioMarine Complex, grape seed extract, tomato extract, vitamin C) were supplemented systemically into culture medium. Kinetin, an active ingredient from Imedeen Expression Line Control Serum, was applied topically. Both treatments were tested separately or combined. In epidermis, all treatments stimulated keratinocyte proliferation, showing a significant increase of Ki67‐positive keratinocytes (P < 0.05). Kinetin showed a twofold increase of Ki67‐positive cells, ITP resulted in a fivefold, and ITP+kinetin showed a nine‐fold increase. Differentiation of keratinocytes was influenced only by kinetin since filaggrin was found only in kinetin and kinetin+ITP samples. At the DEJ, laminin 5 was slightly increased by all treatments. In dermis, only ITP increased the amount of collagen type I. Both kinetin and ITP stimulated formation of fibrillin‐1 and elastin deposition. The effect of kinetin was seen in upper dermis. It stimulated not only the amount of deposited fibrillin‐1 and elastin fibers but also their organization perpendicularly to the DEJ. ITP stimulated formation of fibrillin‐1 in deeper dermis. In summary, the combination of topical treatment with kinetin and systemic treatment with ITP had complementary beneficial effects in the formation and development of epidermis and dermis.
Does Chronic Glycolysis Accelerate Aging? Could This Explain How Dietary Restriction Works?
Authors: HIPKISS ALAN R.
Published: June 2006

Abstract:  The mechanisms by which dietary restriction (DR) suppresses aging are not understood. Suppression of glycolysis by DR could contribute to controlling senescence. Many glycolytic intermediates can glycate proteins and other macromolecules. Methyglyoxal (MG), formed from dihydroxyacetone‐ and glyceraldehyde‐3‐phosphates, rapidly glycates proteins, damages mitochondria, and induces a prooxidant state to create a senescent‐like condition. Ad libitum‐fed and DR animals differ in mitochondrial activity and glycolytic flux rates. Persistent glycolysis in the unrestricted condition would increase the intracellular load of glycating agents (e.g., MG) and increase ROS generation by inactive mitochondria. Occasional glycolysis during DR would decrease MG and reactive oxygen species (ROS) production and could be hormetic, inducing synthesis of glyoxalase‐1 and anti‐glycating agents (carnosine and polyamines).
The Necessity of Having a Proper Dose of (−)Deprenyl (D) to Prolong the Life Spans of Rats Explains Discrepancies among Different Studies in the Past
Authors: KITANI KENICHI , KANAI SETSUKO , MIYASAKA KYOKO , CARRILLO MARIA CRISTINA , IVY GWEN O.
Published: June 2006

Abstract:  (−)Deprenyl (D) has been shown to be effective in prolonging life span in experimental animals, although, there are some discrepancies in its effect on the life span the even within the same species (rats). The present study aims to clarify the reason for these discrepancies. Male F344/DuCrj rats began receiving subcutaneous (s.c.) injections of D at the age of 18 months. Doses used were 0.25, 0.50, and 1.0 mg/kg/injection (inj.), three times a week. Average life spans of animals were significantly longer in male rats given 0.25 and 0.5 mg/kg/inj.; however, rats given a 1.0 mg/kg dose began dying earlier than control rats, leading to an inverse U‐shaped dose–efficacy relationship, a hormesis. Old (27‐month‐old) rats given different doses of D for 1 month showed a typical hormetic response for antioxidant enzyme activities, indicating a significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in brain dopaminergic regions with four lower doses (0.25 to 2 mg/kg/inj., 3 times a week), but a significantly negative response with the highest dose (4 mg/kg/inj.). Our results clearly indicate that a proper dose of D within a certain dose range can significantly increase the life span of rats, but that a greater dose becomes less effective and may actually adversely affect the life span of rats. A similar hormetic response for its effect on antioxidant enzyme activities and the parallel between the two different effects of D suggest a possible causal relationship between these two effects of D. The presence of this effective dose range of D may explain previously reported discrepancies in the effect of D on the life span of animals.
Processing, Lysis, and Elimination of Brain Lipopigments in Rejuvenation Therapies
Authors: RIGA SORIN , RIGA DAN , SCHNEIDER FRANCISC , HALALAU FLORIN
Published: June 2006

Abstract:  Cerebral lipopigments (LPs)—lipofuscin and ceroid—represent a significant marker in postmitotic normal and pathologic aging, connected with causal and associated neuropathologic damage. Therefore, LP processing, lysis, and elimination may be the main targets in anti‐aging and rejuvenation therapies. The regenerative neuroactive factors improve neuron supply with specific nutrients from plasma. They enhance the antioxidative defense, have anti‐LP‐poietic actions, stimulate brain anabolism, support energetic metabolism, and elevate the reduced lysosomal enzymes. In the second stage, by cytoplasm rehydration, they initiate the breaking up of the neuronal aggregated LP conglomerates, by consecutive disintegration. Then, possibly by the localized exo‐endocytosis process between neurons and adjacent glia (especially microglia), intercellular LP transfer can be realized. So, therapeutically activated glia turn into brain garbage collectors and transporters. Therapeutic processing of glial LPs increases in the capillary neighborhood. Highly processed LPs, by glio‐endothelial transfer, reach capillary walls before being eliminated. Consequently, neuroactive therapies having these synergistic rejuvenative actions represent new prospects in deceleration of normal and pathological cerebral aging.
Effect of Dietary Restriction on Learning and Memory Impairment and Histologic Alterations of Brain Stem in Senescence‐Accelerated Mouse (SAM) P8 Strain
Authors: TAKAHASHI RYOYA , KOMIYA YUKARI , GOTO SATARO
Published: June 2006

Abstract:  The age‐associated spontaneous spongy degeneration in the brain stem of senescence‐accelerated mouse (SAM) P8 strain has been suggested to be closely associated with the ability to learn and memorize. In this study, we investigated the effects of dietary restriction (DR) initiated from weaning on learning and memory and histologic changes of the brain stem in P8 and control R1 mice. Although no effect of DR was observed in the retention of the passive‐avoidance response in both the P8 and R1 mice, the acquisition of the task was significantly improved by DR in P8 mice. On the other hand, the total area and number of vacuoles in the brain stem was significantly higher in ad libitum‐fed (AD)‐P8 mice than in AD‐R1 mice. However, no significant effect was observed on the vacuole formation in the brain stem of P8 mice by DR. These observations suggest that the improvement of the acquisition of the task by DR in P8 mice is possibly due to changes in neuronal function rather than histologic alteration in brain stem.
Curcumin's Biphasic Hormetic Response on Proteasome Activity and Heat‐Shock Protein Synthesis in Human Keratinocytes
Authors: ALI REHAB E. , RATTAN SURESH I. S.
Published: June 2006

Abstract:  Curcumin (diferuloylmethane), is a component of the yellow powder prepared from the roots of Curcuma longa (Zingiberaceae), also known as tumeric or turmeric. It is widely cultivated and used as a food ingredient in tropical areas of Asia and Central America. Treatment of mid‐passage human epidermal keratinocytes with curcumin resulted in a biphasic hormetic dose–response with respect to proteasome activity. Curcumin treatment (up to 1 μM for 24 h) increased chymotrypsin‐like activity by 46% compared to that in untreated keratinocytes. However, higher concentrations of curcumin were inhibitory, and at 10 μM the proteasome activity decreased to 46% of its initial value. Furthermore, the preincubation of human keratinocytes at 43°C for 1 h, followed by 24‐h treatment with 3 μM curcumin, led to an increase in heat‐shock protein (hsp70 and hsp90) levels by 24% and 19%, respectively, and the effect was sustained at concentrations up to 10 μM. On the other hand, the level of the small hsp27 was unaffected by curcumin concentrations of 0.3–1 μM, while it decreased by 34% at 10 μM.
Preincubation with the Proteasome Inhibitor MG‐132 Enhances Proteasome Activity via the Nrf2 Transcription Factor in Aging Human Skin Fibroblasts
Authors: KRAFT DAVID CHRISTIAN , DEOCARIS CUSTER C. , WADHWA RENU , RATTAN SURESH I. S.
Published: June 2006

Abstract:  Strategies that lead to the upregulation of the proteasome are known to elicit beneficial consequences to the organism by countering oxidative stress–associated disorders, such as protein conformational diseases, cancer, and aging. Mild treatment with proteasome inhibitors has been previously demonstrated to stimulate proteasome activity and cellular resistance against oxidative injury. However, the mechanism for this action has not been clearly defined. We examined the role of the nuclear factor‐E2‐related factor 2 (Nrf2) in fibroblasts, a key transactivator of the antioxidant response pathway, in the regulation of the proteasome by its inhibitor MG‐132. Here, we demonstrate that the stimulation of the proteasome by low levels of MG‐132 can be abrogated by small interfering RNAs (siRNAs) targeted against Nrf2. Consistently, cells that constitutively express Nrf2 exhibit elevated levels of proteasome activities. We further investigate how its beneficial effects, that is, proteasome stimulation, are manifested in young and replicative‐senescent cells. Our data underscore that manipulation of Nrf2 by the administration of pharmacologically low levels of proteasome inhibitors may prove to be an alternatively potent strategy for inducing long‐term protective effects against oxidative stress.
Heat Shock–Induced Enhancement of Osteoblastic Differentiation of hTERT‐Immortalized Mesenchymal Stem Cells
Authors: NØRGAARD RUNE , KASSEM MOUSTAPHA , RATTAN SURESH I. S.
Published: June 2006

Abstract:  Heat shock (HS)–induced stress response in human cells results in a variety of biological effects and is known to induce the transcription of heat‐shock proteins, which help the cells to cope with different kinds of stress. We have studied the effects of HS on the differentiation of human mesenchymal stem cells (hMSCs) into osteoblastic cells. As a model for hMSCs we used a telomerase‐immortalized hMSC line designated hMSC‐TERT. Cells were exposed to 1 h HS at 41°C, 42.5°C, or 44°C prior to incubation in a medium containing either 10−8 M 1α,25‐dihydroxy‐vitamin‐D3 (calcitriol) or 10−8 M calcitriol, 50 μg/mL l‐ascorbic acid, and 10 mM β‐glycerophosphate followed by an analysis of induction of osteoblast differentiation and the formation of mineralized matrix, respectively. Our results indicate that the exposure of cells to mild heat stress enhances the extent of differentiation of hMSCs by 12% to 42%. These effects are an expression of the phenomenon of mild stress‐induced hormesis.
Selective PPAR Agonists for the Treatment of Type 2 Diabetes
Authors: NEHLIN JAN O. , MOGENSEN JOHN P. , PETTERSON INGRID , JEPPESEN LONE , FLECKNER JAN , WULFF ERIK M. , SAUERBERG PER
Published: June 2006

Abstract:  Type 2 diabetes is a metabolic disease characterized by increased plasma glucose and insulin as well as dyslipidemia. If left untreated, chronic diseases will develop that are associated with neuropathic damage and higher mortality risk. Using a rational drug design, novel compounds have been developed that selectively activate the human PPAR receptors, leading to lessening of hyperglycemia and hyperinsulinemia as well as reduction of lipid levels in conjunction with an increase of the beneficial HDL‐cholesterol. These PPAR agonists showed increased potency and efficacy compared to previously marketed insulin sensitizers. Lead compounds with desirable pharmacokinetic properties were chosen for further testing in several animal models. The in vivo activity of some synthetic ligands, capable of activating two or all three members of peroxisome proliferator‐activated receptors (PPAR) family of receptors, suggested that they may have improved efficacy in type 2 diabetes therapy. Here, we briefly summarize the development of some novel PPAR agonists identified by our group in recent years.
Alzheimer's Disease Pathogenesis
Authors: HARMAN DENHAM
Published: June 2006

Abstract:  Alzheimer's disease (AD) is the chief cause of dementia, and age is its major risk factor. The majority of cases (90–95%) are sporadic (SAD), and the remainder are familial (FAD). AD is characterized by two brain lesions, intraneuronal fibrillary tangles and extracellular plaques. The lesions are identical in SAD and FAD as well as to those in persons with Down's syndrome (DS). The same lesions are also observed frequently in elderly non‐demented individuals (E‐ND). Both AD lesions may stem from the normal progressive increases in oxidative stress (OxS) throughout the body with age. Onset of dementia due to the accumulating lesions is around 40 years for DS, 40–60 years for FAD, over about 65 years for SAD, while that for E‐ND is unknown. The lesions are made clinically manifest with time by the normal increase with age of OxS, “the dementia of old age,” or by a process specific for each AD category, which enhances the normal OxS so as to lower the unknown onset age of dementia for E‐ND individuals to that associated with the AD category. A plausible process can be advanced for each AD category. The hypothesis suggests convenient, effective measures to prevent and treat, for example, by decreasing brain OxS levels with oral antioxidants such as lipoic or dehydroascorbic acids that are capable of passing the blood–brain barrier.