1,720,996 research outputs found
HIPK2 as a Novel Regulator of Fibrosis
Full text linkFibrosis is an unmet medical problem due to a lack of evident biomarkers to help develop efficient targeted therapies. Fibrosis can affect almost every organ and eventually induce organ failure. Homeodomain-interacting protein kinase 2 (HIPK2) is a protein kinase that controls several molecular pathways involved in cell death and development and it has been extensively studied, mainly in the cancer biology field. Recently, a role for HIPK2 has been highlighted in tissue fibrosis. Thus, HIPK2 regulates several pro-fibrotic pathways such as Wnt/β-catenin, TGF-β and Notch involved in renal, pulmonary, liver and cardiac fibrosis. These findings suggest a wider role for HIPK2 in tissue physiopathology and highlight HIPK2 as a promising target for therapeutic purposes in fibrosis. Here, we will summarize the recent studies showing the involvement of HIPK2 as a novel regulator of fibrosis
HIPK2 in Angiogenesis: A Promising Biomarker in Cancer Progression and in Angiogenic Diseases
Full text linkAngiogenesis is the formation of new blood capillaries taking place from preexisting functional vessels, a process that allows cells to cope with shortage of nutrients and low oxygen availability. Angiogenesis may be activated in several pathological diseases, from tumor growth and metastases formation to ischemic and inflammatory diseases. New insights into the mechanisms that regulate angiogenesis have been discovered in the last years, leading to the discovery of new therapeutic opportunities. However, in the case of cancer, their success may be limited by the occurrence of drug resistance, meaning that the road to optimize such treatments is still long. Homeodomain-interacting protein kinase 2 (HIPK2), a multifaceted protein that regulates different molecular pathways, is involved in the negative regulation of cancer growth, and may be considered a “bona fide” oncosuppressor molecule. In this review, we will discuss the emerging link between HIPK2 and angiogenesis and how the control of angiogenesis by HIPK2 impinges in the pathogenesis of several diseases, including cancer
Reactivation of mutant p53 by capsaicin, the major constituent of peppers
Full text linkBACKGROUND:
Mutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. Mutant p53 proteins are usually more stable than wild-type p53 and may not only impair wild-type p53 activity but also acquire pro-oncogenic functions. Therefore, targeting mutant p53 to clear the hyperstable proteins or change p53 conformation to reactivate wild-type p53 protein functions is a powerful anticancer strategy. Several small molecules have been tested for p53 reactivation in mutant p53-carrying cells while studies exploiting the effect of natural compounds are limited. Capsaicin (CPS) is the major constituent of peppers and show antitumor activity by targeting several molecular pathway, however, its effect on mutant p53 reactivation has not been assessed yet. In this study we aimed at investigating whether mutant p53 could be a new target of capsaicin-induced cell death and the underlying mechanisms.
METHODS:
p53 levels were analysed by western blot upon capsaicin treatment in the presence of the autophagy inhibitor chloroquine. The mutant p53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) assay and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The specific wild-type p53 activation was determined by using the inhibitor of p53 transactivation function, pifithrin-α and siRNA for p53.
RESULTS:
Here, we show that capsaicin induced autophagy that was, at least in part, responsible of mutant p53 protein degradation. Abrogation of mutant p53 by capsaicin restored wild-type p53 activities over mutant p53 functions, contributing to cancer cell death. Similar effects were confirmed in cancer cells bearing tumor-associated p53 mutations and in H1299 (p53 null) with overexpressed p53R175H and p53R273H mutant proteins.
CONCLUSION:
These findings demonstrate for the first time that capsaicin may reduce mutant p53 levels and reactivate wild-type p53 protein in mutant p53-carrying cells and the p53 reactivation contributes to capsaicin-induced cell death
P53-Dependent PUMA to DRAM antagonistic interplay as a key molecular switch in cell-fate decision in normal/high glucose conditions
Full text linkBACKGROUND:
As an important cellular stress sensor phosphoprotein p53 can trigger cell cycle arrest and apoptosis and regulate autophagy. The p53 activity mainly depends on its transactivating function, however, how p53 can select one or another biological outcome is still a matter of profound studies. Our previous findings indicate that switching cancer cells in high glucose (HG) impairs p53 apoptotic function and the transcription of target gene PUMA.
METHODS AND RESULTS:
Here we report that, in response to drug adriamycin (ADR) in HG, p53 efficiently induced the expression of DRAM (damage-regulated autophagy modulator), a p53 target gene and a stress-induced regulator of autophagy. We found that ADR treatment of cancer cells in HG increased autophagy, as displayed by greater LC3II accumulation and p62 degradation compared to ADR-treated cells in low glucose. The increased autophagy in HG was in part dependent on p53-induced DRAM; indeed DRAM knockdown with specific siRNA reversed the expression of the autophagic markers in HG. A similar outcome was achieved by inhibiting p53 transcriptional activity with pifithrin-α. DRAM knockdown restored the ADR-induced cell death in HG to the levels obtained in low glucose. A similar outcome was achieved by inhibition of autophagy with cloroquine (CQ) or with silencing of autophagy gene ATG5. DRAM knockdown or inhibition of autophagy were both able to re-induce PUMA transcription in response to ADR, underlining a reciprocal interplay between PUMA to DRAM to unbalance p53 apoptotic activity in HG. Xenograft tumors transplanted in normoglycemic mice displayed growth delay after ADR treatment compared to those transplanted in diabetics mice and such different in vivo response correlated with PUMA to DRAM gene expression.
CONCLUSIONS:
Altogether, these findings suggest that in normal/high glucose condition a mutual unbalance between p53-dependent apoptosis (PUMA) and autophagy (DRAM) gene occurred, modifying the ADR-induced cancer cell death in HG both in vitro and in vivo
p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex
Full text linkThe hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according to tumor stage. The present study aimed at investigating whether the zinc–curcumin Zn(II)–curc compound, which we previously showed to display anticancer effects through multiple mechanisms, could induce NRF2 activation and to explore the underlying molecular mechanisms. Biochemical studies showed that Zn(II)–curc treatment increased the NRF2 protein levels along with its targets, heme oxygenase-1 (HO-1) and p62/SQSTM1, while markedly reduced the levels of Keap1 (Kelch-like ECH-associated protein 1), the NRF2 inhibitor, in the cancer cell lines analyzed. The silencing of either NRF2 or p62/SQSTM1 with specific siRNA demonstrated the crosstalk between the two molecules and that the knockdown of either molecule increased the cancer cell sensitivity to Zn(II)–curc-induced cell death. This suggests that the crosstalk between p62/SQSTM1 and NRF2 could be therapeutically exploited to increase cancer patient response to therapies
Signaling pathways involved in lipopolysaccharide stimulation of prostaglandin production by rat hypothalamic astroglial cells
No full textThe aim of this study was to investigate the mechanisms through which bacterial lipopolysaccharide (LPS) stimulates prostaglandin (PG) production in rat hypothalamic astroglial cells in vitro. The latter were treated with LPS alone or LPS plus antagonists of the interleukin-1 (IL-1) and nitric oxide (NO) pathways, and the subsequent changes in cyclooxygenase (COX) activity were monitored by measuring a COX end-product, prostaglandin E2 (PGE2), released into the incubation medium. LPS produced a concentration-dependent increase in PGE2 release from astroglia after 24 h incubation; experiments with selective antagonists showed that the increase in PGE2 release induced by LPS may be, at least in part, mediated by IL-1 and NO
TERAPIE AVANZATE: LE SPERANZE DEL DOMANI
No full textLa mappatura del genoma umano e lo sviluppo di tecnologie per il sequenziamento dei geni hanno portato rapidamente ad una maggiore comprensione delle basi genetiche di molte malattie. I notevoli progressi tecnologici nel campo delle manipolazioni in vitro di cellule (isolamento, coltivazione, espansione, diffe-renziamento) e del trasferimento di materiale genetico da una cellula ad un’altra hanno consentito di sviluppare tecniche di ingegneria cellulare tramite le quali manipolare sia cellule staminali che cellule ad uno stadio di differenziamento terminale. Queste metodiche, applicate a cellule umane, lasciano presagire nuove opzioni terapeutiche per un’ampia gamma di patologie, trasformando e talora mettendo in discussione la nozione convenzionale di “medicina”. Il termine “terapie avanzate” fa riferimento a nuovi prodotti medicinali (Advanced Therapeutic Medicinal Products/ATMPs) che utilizzano geni (terapia genica), cellule (terapia cellulare) e tessuti (ingegneria tissutale) quali preparazioni farmaceutiche a scopo terapeutico o preventivo (ad esempio, se un difetto genetico evidenziato dall’analisi molecolare viene corretto prima che la patologia si manifesti in modo conclamato). Le distinzioni fra le categorie sono sottili ed occasionalmente alcuni prodotti potrebbero rientrare in più di una categoria. La produzione e sperimentazione di questi prodotti è strettamente regolata a livello internazionale. Tale regolamentazione impone criteri specifici atti a garantire in primo luogo la sicurezza del prodotto finale, poiché destinato alla somministrazione a pazienti, ma non secondariamente anche l’efficacia, poiché non è ritenuto etico sottoporre dei pazienti ad un trattamento che non abbia dato sufficiente prova di efficacia terapeutica
Compliance o aderenza: uno strumento essenziale per l’efficacia terapeutica
No full textDrugs don’t work in patients who don’t take them. — C. Everett Koop
L’efficacia e la tollerabilità di un trattamento farmacologico vengono valutate attraverso studi sperimentali (trial clinici), disegnati per analizzare la relazione tra la somministrazione di un farmaco e gli esiti clinici associati. Questi studi sono anche organizzati in modo che siano attuate le condizioni di trattamento più adeguate perché si possa mettere in evidenza l’effetto terapeutico desiderato. Nel trattamento dell'ipertensione arteriosa, ad esempio, queste condizioni sono rappresentate dal dosaggio, dalla durata e dalla continuità del trattamento considerato.
Stimare il grado di osservanza al trattamento da parte del paziente non è stato sempre considerato di primaria importanza al momento dell’impostazione di un trial clinico. L’accertamento della compliance terapeutica, intesa come aderenza del paziente alla terapia nella durata e nel dosaggio prescritto dal medico curante, rappresenta oggi una condizione necessaria per la verifica del raggiungimento degli esiti previsti. La rilevanza clinica dei risultati di uno studio dovrebbe essere giudicata sulla base dell’effettiva influenza che essi avranno nel modificare la pratica clinica reale. L’efficacia sperimentale attesa (efficacy) è la capacità di un trattamento di modificare in maniera positiva il decorso di una malattia, in condizioni organizzative migliori di quelle della pratica quotidiana. L’efficacia nella pratica (effectiveness) è il beneficio che un trattamento mostra durante la sua applicazione nelle condizioni di pratica clinica corrente, di solito con minore controllo dell’aderenza e peggiori condizioni organizzative di quelle proprie di uno studio sperimentale. Negli ultimi anni, è emerso che il grado di compliance al trattamento rappresenta una variabile molto importante nel determinare differenze tra gli esiti clinici riscontrati durante i trials clinici e la pratica clinica quotidiana.
Ciò ha incentivato lo sviluppo di studi volti ad una valutazione quantitativa dei processi che realmente avvengono nella pratica clinica e dei risultati di efficacia terapeutica che da essi ne derivano. Rilevare e quantificare l’aderenza dei pazienti alla terapia negli studi clinici è di grande valore al fine di ottenere risultati di efficacia altamente generalizzabili, in quanto si riferiscono ai pazienti che hanno effettivamente portato a termine la sperimentazione in rapporto a quanti hanno abbandonato la terapia nel corso dello studio. L’analisi di questo fenomeno ha assunto una rilevante importanza perché può ridimensionare l'efficacia complessiva finale di uno schema terapeutico e, anche, metterne in dubbio l’applicabilità futura
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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