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1.
Alessandro Fraldi Fabio Annunziata Alessia Lombardi Hermann-Josef Kaiser Diego Luis Medina Carmine Spampanato Anthony Olind Fedele Roman Polishchuk Nicolina Cristina Sorrentino Kai Simons Andrea Ballabio 《The EMBO journal》2010,29(21):3607-3620
The function of lysosomes relies on the ability of the lysosomal membrane to fuse with several target membranes in the cell. It is known that in lysosomal storage disorders (LSDs), lysosomal accumulation of several types of substrates is associated with lysosomal dysfunction and impairment of endocytic membrane traffic. By analysing cells from two severe neurodegenerative LSDs, we observed that cholesterol abnormally accumulates in the endolysosomal membrane of LSD cells, thereby reducing the ability of lysosomes to efficiently fuse with endocytic and autophagic vesicles. Furthermore, we discovered that soluble N‐ethylmaleimide‐sensitive factor attachment protein (SNAP) receptors (SNAREs), which are key components of the cellular membrane fusion machinery are aberrantly sequestered in cholesterol‐enriched regions of LSD endolysosomal membranes. This abnormal spatial organization locks SNAREs in complexes and impairs their sorting and recycling. Importantly, reducing membrane cholesterol levels in LSD cells restores normal SNARE function and efficient lysosomal fusion. Our results support a model by which cholesterol abnormalities determine lysosomal dysfunction and endocytic traffic jam in LSDs by impairing the membrane fusion machinery, thus suggesting new therapeutic targets for the treatment of these disorders. 相似文献
2.
The liver peptide hepcidin regulates body iron, is upregulated in iron overload and inflammation, and is downregulated in iron deficiency/hypoxia. The transmembrane serine protease matriptase-2 (TMPRSS6) inhibits the hepcidin response and its mutational inactivation causes iron-deficient anemia in mice and humans. Here we confirm the inhibitory effect of matriptase-2 on hepcidin promoter; we show that matriptase-2 lacking the serine protease domain, identified in the anemic Mask mouse (matriptase-2(MASK)), is fully inactive and that mutant R774C found in patients with genetic iron deficiency has decreased inhibitory activity. Matriptase-2 cleaves hemojuvelin (HJV), a regulator of hepcidin, on plasma membrane; matriptase-2(MASK) shows no cleavage activity and the human mutant only partial cleavage capacity. Matriptase-2 interacts with HJV through the ectodomain since the interaction is conserved in matriptase-2(MASK). The expression of matriptase-2 mutants in zebrafish results in anemia, confirming the matriptase-2 role in iron metabolism and its interaction with HJV. 相似文献
3.
Yan G. Ni Jon H. Condra Laura Orsatti Xun Shen Stefania Di Marco Shilpa Pandit Matthew J. Bottomley Lionello Ruggeri Richard T. Cummings Rose M. Cubbon Joseph C. Santoro Anka Ehrhardt Dale Lewis Timothy S. Fisher Sookhee Ha Leila Njimoluh Dana D. Wood Holly A. Hammond Douglas Wisniewski Cinzia Volpari Alessia Noto Paola Lo Surdo Brian Hubbard Andrea Carf�� Ayesha Sitlani 《The Journal of biological chemistry》2010,285(17):12882-12891
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Alessia Visconti Simone Ribero Marianna Sanna Tim D. Spector Veronique Bataille Mario Falchi 《Pigment cell & melanoma research》2020,33(2):326-333
Body site is highly relevant for melanoma: it affects prognosis and varies according to the patient's sex. The distribution of naevi, a major risk factor for melanoma, at different body sites also varies according to sex in childhood. Using naevus counts at different body sites in 492 unrelated adults from both sexes, we observed that women have an increased number of naevi on the lower limbs compared to men (p = 8.5 × 10?5), showing that a high naevus count on this site persists from childhood throughout life. Then, using data from 3,232 twins, we observed, in women, the lowest naevus count heritability on the trunk (26%), and the highest on the lower limbs (69%). Finally, we showed that, in 2,864 women, six genomic loci previously associated with both naevus count and melanoma risk (IRF4, DOCK8, MTAP, 9q31.2, KITLG and PLA2G6) have an effect on naevus count that is body site‐specific, but whose effect sizes are predominantly stronger on the lower limbs. Sex‐specific genetic influence on naevus count at different sites may explain differences in site‐specific melanoma incidence as well as prognosis between sexes. 相似文献
6.
Integrated requirement of non‐specific and sequence‐specific DNA binding in Myc‐driven transcription
7.
Nicola Bizzaro Elena Bartoloni Gabriella Morozzi Stefania Manganelli Valeria Riccieri Paola Sabatini Matteo Filippini Marilina Tampoia Antonella Afeltra Giandomenico Sebastiani Claudia Alpini Vittorio Bini Onelia Bistoni Alessia Alunno Roberto Gerli 《Arthritis research & therapy》2013,15(1):R16
Introduction
The diagnostic, predictive and prognostic role of anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis (RA) patients is widely accepted. Moreover, detection of these antibodies in subjects presenting with undifferentiated arthritis (UA) is associated with a significant risk to develop the disease. On the other hand, clinical and prognostic significance of evaluating anti-CCP levels in subjects with inflammatory arthritis at disease onset has not been fully clarified. The goal of this prospective study is to analyze the value and prognostic significance of anti-CCP titer quantification in UA subjects.Methods
Serial anti-CCP assays were measured in 192 consecutive patients presenting with UA lasting less than 12 weeks. Clinical and serological data and arthritis outcome were evaluated every 6 months until two years of follow-up.Results
Anti-CCP positivity, at both low and high titer, and arthritis of hand joints significantly predicted RA at two years, risk increasing in subjects with high anti-CCP titers at baseline. Moreover, time to RA diagnosis was shorter in patients with high anti-CCP2 titers at enrollment with respect to those with low antibody concentration.Conclusions
Presence of anti-CCP antibodies, at both low and high concentration, is significantly associated with RA development in subjects with recent onset UA. However, time interval from the onset of the first symptoms to the fulfilment of the classification criteria appears to be directly related to the initial anti-CCP level. 相似文献8.
9.
10.
Cecilia Marini Barbara Salani Michela Massollo Adriana Amaro Alessia Isabella Esposito Anna Maria Orengo Selene Capitanio Laura Emionite Mattia Riondato Gianluca Bottoni Cinzia Massara Simona Boccardo Marina Fabbi Cristina Campi Silvia Ravera Giovanna Angelini Silvia Morbelli Michele Cilli Renzo Cordera Mauro Truini Davide Maggi Ulrich Pfeffer Gianmario Sambuceti 《Cell cycle (Georgetown, Tex.)》2013,12(22):3490-3499
Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of 18F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer. 相似文献