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51.
Gregory M. Fahy Robert T. Brooke James P. Watson Zinaida Good Shreyas S. Vasanawala Holden Maecker Michael D. Leipold David T. S. Lin Michael S. Kobor Steve Horvath 《Aging cell》2019,18(6)
Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (?2.5‐year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from ?1.6 year/year from 0–9 month to ?6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention. 相似文献
52.
Zinaida Dubeykovskaya Alexander Dubeykovskiy Joel Solal-Cohen Timothy C. Wang 《The Journal of biological chemistry》2009,284(6):3650-3662
The secreted trefoil factor family 2 (TFF2) protein contributes to the
protection of the gastrointestinal mucosa from injury by strengthening and
stabilizing mucin gels, stimulating epithelial restitution, and restraining
the associated inflammation. Although trefoil factors have been shown to
activate signaling pathways, no cell surface receptor has been directly linked
to trefoil peptide signaling. Here we demonstrate the ability of TFF2 peptide
to activate signaling via the CXCR4 chemokine receptor in cancer cell lines.
We found that both mouse and human TFF2 proteins (at ∼0.5
μm) activate Ca2+ signaling in lymphoblastic Jurkat
cells that could be abrogated by receptor desensitization (with SDF-1α)
or pretreatment with the specific antagonist AMD3100 or an anti-CXCR4
antibody. TFF2 pretreatment of Jurkat cells decreased Ca2+ rise and
chemotactic response to SDF-1α. In addition, the CXCR4-negative gastric
epithelial cell line AGS became highly responsive to TFF2 treatment upon
expression of the CXCR4 receptor. TFF2-induced activation of mitogen-activated
protein kinases in gastric and pancreatic cancer cells, KATO III and AsPC-1,
respectively, was also dependent on the presence of the CXCR4 receptor.
Finally we demonstrate a distinct proliferative effect of TFF2 protein on an
AGS gastric cancer cell line that expresses CXCR4. Overall these data identify
CXCR4 as a bona fide signaling receptor for TFF2 and suggest a
mechanism through which TFF2 may modulate immune and tumorigenic responses
in vivo.Trefoil factor 2
(TFF2),2 previously
known as spasmolytic polypeptide, is a unique member of the trefoil family
that is expressed primarily in gastric mucous neck cells and is up-regulated
in the setting of chronic inflammation. Experimental induction of ulceration
in the rat stomach leads to rapid up-regulation of TFF2 expression with high
levels observed 30 min after ulceration with persistence for up to 10 days
(1). TFF2 is secreted into the
mucus layer of the gastrointestinal tract of mammals where it stabilizes the
mucin gel layer and stimulates migration of epithelial cells
(2–4),
suggesting an important role in restitution and in maintenance of the
integrity of the gut. Exogenous administration of recombinant TFF2, either
orally or intravenously, provides mucosal protection in several rodent models
of acute gastric or intestinal injury
(5,
6). A TFF2-/-
knock-out mouse model has confirmed the importance of TFF2 in the protection
of gastrointestinal mucosa against chronic injury
(7).It is widely accepted that trefoil factors exert their biological action
through a cell surface receptor. This suggestion comes from studies on binding
of 125I-labeled TFF2 that demonstrated specific binding sites in
the gastric glands, intestine, and colon that could be displaced by
non-radioactive TFF2 (6,
8–10).
Structural studies have revealed potential binding sites for receptors for all
members of the trefoil factor family
(11,
12). In concordance with this
hypothesis, several membrane proteins were found to interact with TFF2. First
it was shown that recombinant human TFF2 (and TFF3) could bind to a 28-kDa
peptide from membrane fractions of rat jejunum and two human adenocarcinoma
cell lines, MCF-7 and Colony-29
(13). Later it was found that
recombinant TFF3 fused with biotin selectively bound with a 50-kDa protein
from the membrane of rat small intestinal cells
(14). However, these 28- and
50-kDa proteins were characterized only by their molecular size without
further identification. Two TFF2-binding proteins that have been characterized
include a 140-kDa protein, the β subunit of the fibronectin receptor, and
a 224-kDa protein called muclin
(15). Another TFF2-binding
protein was isolated by probing two-dimensional blots of mouse stomach with a
murine TFF2 fusion protein, leading to the identification of the gastric
foveolar protein blottin, a murine homolog of the human peptide
TFIZ1(16). Although these
three proteins have now been well characterized, none of them has been shown
to mediate responses to TFF2, and no activated signaling cascades have been
shown.Despite the absence of an identified cell surface receptor for TFF2, there
is nevertheless clear evidence that TFF2 and TFF3 rapidly activate signal
transduction pathways (17,
18). TFF3 prevents cell death
via activation of the serine/threonine kinase AKT in colon cancer cell lines
(19). The TFF3 protein also
activates STAT3 signaling in human colorectal cancer cells, thus providing
cells with invasion potential
(20). TFF3 treatment leads to
EGF receptor activation and β-catenin phosphorylation in HT-29 cells
(21) and to transient
phosphorylation of ERK1/2 in oral keratinocytes
(22). With respect to TFF2,
recombinant peptide enhances the migration of human bronchial epithelial cell
line BEAS-2B (4). TFF2 has been
shown to induce phosphorylation of c-Jun NH2-terminal kinase (JNK)
and ERK1/2. Consistent with this observation, the motogenic effect of TFF2 is
significantly inhibited by antagonists of ERK kinases and protein kinase C but
not by inhibitors of p38 mitogen-activated protein kinase (MAPK). It is
believed that the motogenic effect of trefoil factors and of TFF2 in
particular, could contribute to in vivo restitution of gastric
epithelium by enhancing cell migration.Although previous studies have suggested that TFF2 functions primarily in
cytoprotection, accumulating evidence now suggests that TFF2 may also play a
role in the regulation of host immunity. For example, recombinant TFF2 reduces
inflammation in rat and mouse models of colitis
(23,
24). In addition, TFF2 was
detected in rat lymphoid tissues (spleen, lymph nodes, and bone marrow)
(25). Recently we and others
found TFF2 mRNA expression in primary and secondary lymphopoietic organs
(26,
27). These data suggest that
TFF2 may play some function in the immune system. In concordance with these
findings, we detected an exacerbated inflammatory response to acute injury in
TFF2 knock-out animals (27,
28). These observations
prompted us to look at the possible function of TFF2 in immune cells.
Unexpectedly we found that TFF2 modulates Ca2+ and AKT signaling in
lymphoblastic Jurkat cells and that these effects appear to be mediated
through the CXCR4 receptor. 相似文献
53.
Wacław L. Kretovich Zinaida G. Evstigneeva Alexander V. Pushkin Tina Z. Dzhokharidze 《Phytochemistry》1981,20(4):625-629
It has been shown that the leaves of pumpkin (Cucurbita pepo) contain two molecular forms of glutamine synthetase (GS), one occurring in the cytosol (GS1)and the other in the chloroplasts (GS2). The activities of both forms were greater when ammonium ion was infiltrated into the leaves and this was shown to be due to de novo synthesis. The two synthetases were purified by ammonium sulphate fractionation, ion exchange chromatography on DEAE-cellulose, selective adsorption on calcium phosphate gel, and preparative polyacrylamide gel electrophoresis. The MWs of GS1 and GS2, estimated by gel filtration on Sephacryl S-200, were 480 000 and 370 000 respectively. During polyacrylamide gel electrophoresis in the presence of SDS both GS1 and GS2 were dissociated into polypeptide chains with MWs of 58 000 and 50 000 respectively, suggesting that GS, 1 and GS2 are octamers consisting of identical monomers. The synthetases showed noticeable differences in their amino acid composition. In GS1 and GS2 the proportions of α- helical segments were 34 and 17 % respectively. In the presence of Mg2+, the pH optima for GS1 and GS2 were 7.25 and 7.75 respectively, and Km values toward l-glutamate were 13 and 46 mM respectively. From the experimental data it is inferred that GS1 and GS2 are isoenzymes. 相似文献
54.
Michael S Kramer Lidia Matush Irina Vanilovich Robert Platt Natalia Bogdanovich Zinaida Sevkovskaya Irina Dzikovich Gyorgy Shishko Bruce Mazer 《BMJ (Clinical research ed.)》2007,335(7624):815
Objective To assess whether exclusive and prolonged breast feeding reduces the risk of childhood asthma and allergy by age 6.5 years.Design Cluster randomised trial.Setting 31 Belarussian maternity hospitals and their affiliated polyclinics.Participants A total of 17 046 mother-infant pairs were enrolled, of whom 13 889 (81.5%) were followed up at age 6.5 years.Intervention Breastfeeding promotion intervention modelled on the WHO/UNICEF baby friendly hospital initiative.Main outcome measures International study of asthma and allergies in childhood (ISAAC) questionnaire and skin prick tests of five inhalant antigens.Results The experimental intervention led to a large increase in exclusive breast feeding at 3 months (44.3% v 6.4%; P<0.001) and a significantly higher prevalence of any breast feeding at all ages up to and including 12 months. The experimental group had no reduction in risks of allergic symptoms and diagnoses or positive skin prick tests. In fact, after exclusion of six sites (three experimental and three control) with suspiciously high rates of positive skin prick tests, risks were significantly increased in the experimental group for four of the five antigens.Conclusions These results do not support a protective effect of prolonged and exclusive breast feeding on asthma or allergy.Trial registration Current Controlled Trials ISRCTN37687716. 相似文献
55.
If we understand the structural rules governing antibody (Ab)-antigen (Ag) interactions in a given virus, then we have the molecular basis to attempt to design and synthesize new epitopes to be used as vaccines or optimize the antibodies themselves for passive immunization. Comparing the binding of several different antibodies to related Ags should also further our understanding of general principles of recognition.To obtain and compare the three-dimensional structure of a large number of different complexes, however, we need a faster method than traditional experimental techniques. While biocomputational docking is fast, its results might not be accurate. Combining experimental validation with computational prediction may be a solution.As a proof of concept, here we isolated a monoclonal Ab from the blood of a human donor recovered from dengue virus infection, characterized its immunological properties, and identified its epitope on domain III of dengue virus E protein through simple and rapid NMR chemical shift mapping experiments. We then obtained the three-dimensional structure of the Ab/Ag complex by computational docking, using the NMR data to drive and validate the results. In an attempt to represent the multiple conformations available to flexible Ab loops, we docked several different starting models and present the result as an ensemble of models equally agreeing with the experimental data. The Ab was shown to bind a region accessible only in part on the viral surface, explaining why it cannot effectively neutralize the virus. 相似文献
56.
Andrei I. Granovitch Alexei N. Maximovich Alina V. Avanesyan Zinaida I. Starunova Natalia A. Mikhailova 《Genetica》2013,141(7-9):293-301
Populations of periwinkles Littorina saxatilis (Olivi 1792) and L. arcana Hannaford Ellis, 1978 are well suited for microevolutionary studies, being at the same time closely related and intraspecifically diverse. The divergence between these two sibling species, sympatric over large parts of their distribution areas, is small, the only morphological difference being the pallial gland complex structure in females. Molecular identification is possible with the use of a RAPD nuclear marker (cloned A2.8 DNA fragment) typical for L. arcana. However, in some individuals from sympatric populations molecular and morphological criteria suggest conflicting species affiliation, which may be explained either by hybridization or by shared ancestral polymorphism. We tested the hybridization hypotheses examining the micro-spatial distribution of these two species across the intertidal zone in two distant sites at the Barents Sea. We found that (a) the frequency of putative hybrids in sympatric populations was proportional to the frequency of L. arcana; (b) L. saxatilis bearing A2.8 DNA fragment were almost absent in the lower part of the intertidal zone, where L. arcana was absent too; (c) there was a close positive correlation between the distribution of potential parent molluscs and putative hybrids. Moreover, logistic regression models showed a good agreement between the distribution of putative hybrid frequencies and that of parental species frequencies. All our observations taken together support the hypothesis of hybridization between L. saxatilis and L. arcana. Elucidating the mechanisms that support the species status of these sympatric populations is necessary. 相似文献