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91.
In addition to genetic events, a variety of epigenetic events have been widely reported to contribute to the onset of many diseases including cancer. DNA methylation and histone modifications (such as acetylation, methylation, sumoylation, and phosphorylation) involving chromatin remodelling are among the most studied epigenetic mechanisms for regulation of gene expression leading, when altered, to some diseases. Epigenetic therapy tries to reverse the aberrations followed to the disruption of the balance of the epigenetic signalling ways through the use of both natural compounds and synthetic molecules, active on specific epi-targets. Such epi-drugs are, for example, inhibitors of DNA methyltransferases, histone deacetylases, histone acetyltransferases, histone methyltransferases, and histone demethylases. In this review we will focus on the chemical aspects of such molecules, joined to their effective (or potential) application in cancer therapy. 相似文献
92.
Andrea Savarino Antonello Mai Sandro Norelli Sary El Daker Sergio Valente Dante Rotili Lucia Altucci Anna Teresa Palamara Enrico Garaci 《Retrovirology》2009,6(1):1-10
Background
Bovine Leukemia virus (BLV) is a deltaretrovirus that induces lymphoproliferation and leukemia in ruminants. In ex vivo cultures of B lymphocytes isolated from BLV-infected sheep show that spontaneous apoptosis is reduced. Here, we investigated the involvement of reactive oxygen species (ROS) in this process.Results
We demonstrate that (i) the levels of ROS and a major product of oxidative stress (8-OHdG) are reduced, while the thioredoxin antioxidant protein is highly expressed in BLV-infected B lymphocytes, (ii) induction of ROS by valproate (VPA) is pro-apoptotic, (iii) inversely, the scavenging of ROS with N-acetylcysteine inhibits apoptosis, and finally (iv) the levels of ROS inversely correlate with the proviral loads.Conclusion
Together, these observations underline the importance of ROS in the mechanisms of inhibition of apoptosis linked to BLV infection. 相似文献93.
94.
Alessandro Bartolomucci Elena Bresciani Ilaria Bulgarelli Antonello E. Rigamonti Tiziana Pascucci Andrea Levi Roberta Possenti Antonio Torsello Vittorio Locatelli Eugenio E. Muller Anna Moles 《Genes & nutrition》2009,4(1):49-57
The vgf gene regulates energy homeostasis and the VGF-derived peptide TLQP-21 centrally exerts catabolic effects in mice and hamsters. Here, we investigate the effect of chronic intracerebroventricular (icv) injection of TLQP-21 in mice fed high fat diet (HFD). Fast weight-gaining mice injected with the peptide or cerebrospinal fluid were selected for physiological, endocrine, and molecular analysis. TLQP-21 selectively inhibited the increase in body weight and epididymal white adipose tissue (eWAT) weight induced by HFD in control animals despite both groups having a similar degree of hyperphagia. TLQP-21 normalized the increase in leptin and decrease in ghrelin while increasing epinephrine and epinephrine/norepinephrine ratio when compared to values in controls. Finally, HFD-TLQP-21 mice showed a selective increase of eWAT β3-adrenergic receptor mRNA. Peroxisome-proliferator-activated-receptor-δ and hormone-sensing-lipase mRNA were also upregulated. In conclusion, chronic icv infusion of TLQP-21 prevented the early phase of diet-induced obesity despite overfeeding. These effects were paralleled by activation of catabolic pathways within the eWAT. Our results further support a role for TLQP-21 as a catabolic neuropeptide. 相似文献
95.
Elton Zeqiraj Beatrice Maria Filippi Simon Goldie Iva Navratilova Jér?me Boudeau Maria Deak Dario R. Alessi Daan M. F. van Aalten 《PLoS biology》2009,7(6)
Pseudokinases lack essential residues for kinase activity, yet are emerging as important regulators of signal transduction networks. The pseudokinase STRAD activates the LKB1 tumour suppressor by forming a heterotrimeric complex with LKB1 and the scaffolding protein MO25. Here, we describe the structure of STRADα in complex with MO25α. The structure reveals an intricate web of interactions between STRADα and MO25α involving the αC-helix of STRADα, reminiscent of the mechanism by which CDK2 interacts with cyclin A. Surprisingly, STRADα binds ATP and displays a closed conformation and an ordered activation loop, typical of active protein kinases. Inactivity is accounted for by nonconservative substitution of almost all essential catalytic residues. We demonstrate that binding of ATP enhances the affinity of STRADα for MO25α, and conversely, binding of MO25α promotes interaction of STRADα with ATP. Mutagenesis studies reveal that association of STRADα with either ATP or MO25α is essential for LKB1 activation. We conclude that ATP and MO25α cooperate to maintain STRADα in an “active” closed conformation required for LKB1 activation. It has recently been demonstrated that a mutation in human STRADα that truncates a C-terminal region of the pseudokinase domain leads to the polyhydramnios, megalencephaly, symptomatic epilepsy (PMSE) syndrome. We demonstrate this mutation destabilizes STRADα and prevents association with LKB1. In summary, our findings describe one of the first structures of a genuinely inactive pseudokinase. The ability of STRADα to activate LKB1 is dependent on a closed “active” conformation, aided by ATP and MO25α binding. Thus, the function of STRADα is mediated through an active kinase conformation rather than kinase activity. It is possible that other pseudokinases exert their function through nucleotide binding and active conformations. 相似文献
96.
Margherita Conchedda Antonello Antonelli Aldo Caddori Flavio Gabriele 《Parasitology international》2010,59(3):454-459
To assess the current impact of human CE in Sardinia (Italy) and to monitor the changes over time, a survey has been carried out for the period 2001–2005 using hospital inpatient discharge reports (HDR) as information source, supplementing data wherever possible with additional information retrieved directly from medical records. The total of 726 admissions with “Echinococcosis” as primary diagnosis (annual rate of 8.9 per 100,000 inhabitants) concerned 540 CE cases with an annual mean incidence rate of 6.62 per 100,000 inhabitants. Male-to-female ratio was 1.36, suggesting a marked risk associated with traditional male occupations. Age-specific incidence showed increasing rates of clinical CE with age for both genders. The liver was found to be the most common localization, affecting 72% of patients, while pulmonary CE was more frequent in males than in females. CE risk was unevenly distributed in the island. The more pastoral areas had the highest probability of humans becoming infected, with an incidence rate of clinical cases of ~ 14.0 per 100,000 for areas with sheep/inhabitants index of > 6. Compared to the past, incidence rates appear to be decreasing both for pulmonary and hepatic localizations, while there is a reversal of the CE “urbanization” trend resulting in “ruralization”, accompanied by a greater degree of parasite ecological “isolation” and focus-points of infection risk. In spite of this decrease, the cost of hospital care alone (~4 million euros) suggests that the monetary plus non-monetary costs of CE are still very high but not fully recognised. 相似文献
97.
Palacios D Mozzetta C Consalvi S Caretti G Saccone V Proserpio V Marquez VE Valente S Mai A Forcales SV Sartorelli V Puri PL 《Cell Stem Cell》2010,7(4):455-469
How regeneration cues are converted into the epigenetic information that controls gene expression in adult stem cells is currently unknown. We identified an inflammation-activated signaling in muscle stem (satellite) cells, by which the polycomb repressive complex 2 (PRC2) represses Pax7 expression during muscle regeneration. TNF-activated p38α kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzymatic subunit of the complex, leading to the formation of repressive chromatin on Pax7 promoter. TNF-α antibodies stimulate satellite cell proliferation in regenerating muscles of dystrophic or normal mice. Genetic knockdown or pharmacological inhibition of the enzymatic components of the p38/PRC2 signaling--p38α and EZH2--invariably promote Pax7 expression and expansion of satellite cells that retain their differentiation potential upon signaling resumption. Genetic knockdown of Pax7 impaired satellite cell proliferation in response to p38 inhibition, thereby establishing the biological link between p38/PRC2 signaling to Pax7 and satellite cell decision to proliferate or differentiate. 相似文献
98.
Eduardo J. FernandezPerez Braulio Muoz Denisse A. Bascuan Christian Peters Nicolas O. RiffoLepe Maria P. Espinoza Peter J. Morgan Caroline Filippi Romain Bourboulou Urmi Sengupta Rakez Kayed Jrme Epsztein Luis G. Aguayo 《Aging cell》2021,20(9)
Intracellular amyloid beta oligomer (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer''s disease (AD). However, to date, no mechanism linking iAβo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain‐derived (h‐iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor‐mediated current. Both effects were PKC‐dependent. Parallel recordings of synaptic currents and nitric oxide (NO)‐associated fluorescence showed that the increased frequency, related to pre‐synaptic release, was dependent on a NO‐mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current‐clamp recordings suggested that iAβo increased neuronal excitability via AMPA‐driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic‐driven mechanism and offers an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures. 相似文献
99.
Brockschmidt A Filippi A Charbel Issa P Nelles M Urbach H Eter N Driever W Weber RG 《Human genetics》2011,130(5):645-655
In this study, we performed an in-depth analysis of the neurologic and ophthalmologic phenotype in a patient with Pitt–Hopkins
syndrome (PTHS), a disorder characterized by severe mental and motor retardation, carrying a uniallelic TCF4 deletion, and studied a zebrafish model. The PTHS-patient was characterized by high-resolution magnetic resonance imaging
(MRI) with diffusion tensor imaging to analyze the brain structurally, spectral-domain optical coherence tomography to visualize
the retinal layers, and electroretinography to evaluate retinal function. A zebrafish model was generated by knockdown of
tcf4-function by injection of morpholino antisense oligos into zebrafish embryos and the morphant phenotype was characterized
for expression of neural differentiation genes neurog1, ascl1b, pax6a, zic1, atoh1a, atoh2b. Data from PTHS-patient and zebrafish morphants were compared. While a cerebral MRI-scan showed markedly delayed myelination
and ventriculomegaly in the 1-year-old PTHS-patient, no structural cerebral anomalies including no white matter tract alterations
were detected at 9 years of age. Structural ocular examinations showed highly myopic eyes and an increase in ocular length,
while retinal layers were normal. Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes,
small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. In summary, tcf4-knockdown in zebrafish embryos does not seem to affect early neural patterning and regionalization of the forebrain, but
may be involved in later aspects of neurogenesis and differentiation. We provide evidence for a role of TCF4/E2-2 in ocular
growth control in PTHS-patients and the zebrafish model. 相似文献
100.
Uric Acid Amplifies Aβ Amyloid Effects Involved in the Cognitive Dysfunction/Dementia: Evidences From an Experimental Model In Vitro 下载免费PDF全文