Alterazione della proteostasi a livello del reticolo endoplasmatico: un potenziale target terapeutico nel carcinoma prostatico

Nel sesso maschile il carcinoma della prostata (CaP) è la neoplasia più frequente ed è tra le prime cause di morte per tumore. Ad oggi, sono disponibili diverse strategie terapeutiche per il trattamento del CaP, ma, come comprovato dall’ancora alta mortalità, spesso queste sono inefficaci, a causa soprattutto dello sviluppo di fenomeni di resistenza da parte delle cellule tumorali. La ricerca si sta quindi focalizzando sulla caratterizzazione di tali meccanismi di resistenza e, allo stesso tempo, sull’individuazione di combinazioni terapeutiche che siano più efficaci e capaci di superare queste resistenze. Le cellule tumorali sono fortemente dipendenti dai meccanismi connessi con l’omeostasi proteica (proteostasi), in quanto sono sottoposte a numerosi stress ambientali (ipossia, carenza di nutrienti, esposizione a chemioterapici, ecc.) e ad un’aumentata attività trascrizionale, entrambi fattori che causano un accumulo intracellulare di proteine anomale e/o mal ripiegate, le quali possono risultare dannose per la cellula e vanno quindi riparate o eliminate efficientemente. La cellula ha sviluppato diversi sistemi di controllo di qualità delle proteine, tra cui gli chaperon molecolari, il sistema di degradazione associato al reticolo endoplasmatico (ERAD), il sistema di risposta alle proteine non ripiegate (UPR) e i sistemi di degradazione come il proteasoma e l’autofagia. Uno dei possibili bersagli in cellule tumorali secretorie, come quelle del CaP, è rappresentato dal reticolo endoplasmatico (RE), organello intracellulare deputato alla sintesi, al ripiegamento e alle modificazioni post-traduzionali delle proteine di membrana e secrete. Alterazioni della protestasi a livello del RE inducono l’UPR, che svolge una duplice funzione nella cellula: primariamente funge da meccanismo omeostatico e di sopravvivenza, ma, quando l’omeostasi non è più ripristinabile e lo stimolo di attivazione dell’UPR cronicizza, può attivare vie di segnalazione che conducono alla morte cellulare programmata. La bivalenza, tipica dell’UPR, lo rende un bersaglio particolarmente interessante per promuovere la morte delle cellule tumorali: si può, infatti, sfruttare da una parte l’inibizione di componenti dell’UPR per abrogare i meccanismi adattativi e di sopravvivenza e dall’altra si può favorire il sovraccarico dell’UPR con conseguente induzione della via pro-apoptotica. Le catechine del tè verde sono composti polifenolici estratti dalle foglie di Camellia sinesis che possiedono comprovati effetti antitumorali: inibiscono la proliferazione, inducono la morte di cellule neoplastiche e riducono l’angiogenesi, l’invasione e la metastatizzazione di diversi tipi tumorali, tra cui il CaP. Diversi studi hanno osservato come il RE sia uno dei bersagli molecolari delle catechine del tè verde. In particolare, recenti studi del nostro gruppo di ricerca hanno messo in evidenza come il Polyphenon E (estratto standardizzato di catechine del tè verde) sia in grado, in modelli animali di CaP, di causare un’alterazione strutturale del RE e del Golgi, un deficit del processamento delle proteine secretorie e la conseguente induzione di uno stato di stress del RE, il quale causa a sua volta l’attivazione delle vie di segnalazione dell’UPR. Nel presente studio su due diverse linee cellulari di CaP (LNCaP e DU145) e in un nostro precedente studio su altre due linee cellulari (PNT1a e PC3) è stato confermato che il Polyphenon E è capace di indurre lo stress del RE e di determinare l’attivazione delle vie di segnalazione dell’UPR, le quali possono fungere da meccanismo di sopravvivenza, ma anche contribuire a favorire la morte cellulare indotta dalle catechine del tè verde (come nel caso delle PC3). Considerati questi effetti delle catechine del tè verde in qualità di induttori dell’UPR, abbiamo ipotizzato che la combinazione di questi polifenoli bioattivi e degli inibitori del proteasoma, anch’essi noti attivatori dell’UPR, potesse comportare un aggravamento dell’UPR stesso tale da innescare meccanismi molecolari di morte cellulare programmata. Abbiamo quindi studiato l’effetto di tale combinazione in cellule PC3 trattate con epigallocatechina-3-gallato (EGCG, la principale tra le catechine del tè verde) e due diversi inibitori del proteasoma, il bortezomib (BZM) e l’MG132. I risultati hanno dimostrato, diversamente da quanto ipotizzato, che l’EGCG quando associato agli inibitori del proteasoma non produce effetti sinergici, ma che anzi, quando viene addizionato al BZM, causa una risposta simil-antagonistica: si osserva infatti una riduzione della citotossicità e dell’effetto inibitorio sul proteasoma (accumulo di proteine poliubiquitinate) indotti dal BZM, inoltre anche l’induzione dell’UPR (aumento di GRP78, p-eIF2α, CHOP) risulta ridotta nelle cellule trattate con la combinazione di EGCG e BZM rispetto alle cellule trattate col solo BZM. Gli stessi effetti non si osservano invece nelle cellule PC3 trattate con l’EGCG in associazione con l’MG132, dove non si registra alcuna variazione dei parametri di vitalità cellulare e dei marcatori di inibizione del proteasoma e di UPR (rispetto a quelli osservati nel singolo trattamento con MG132). Essendo l’autofagia un meccanismo compensativo che si attiva in seguito all’inibizione del proteasoma o allo stress del RE, abbiamo valutato che ruolo potesse avere tale meccanismo nella risposta simil-antagonistica osservata in seguito al co-trattamento con EGCG e BZM. I nostri risultati hanno evidenziato, in cellule trattate con BZM, l’attivazione di un flusso autofagico che si intensifica quando viene addizionato l’EGCG. Tramite l’inibizione dell’autofagia mediante co-somministrazione di clorochina, è stato possibile stabilire che l’autofagia indotta dall’EGCG favorisce la sopravvivenza delle cellule sottoposte al trattamento combinato tramite la riduzione dell’UPR. Queste evidenze ci portano a concludere che per il trattamento del CaP è sconsigliabile associare le catechine del tè verde con il BZM e che in futuri studi di combinazione di questi polifenoli con composti antitumorali sarà importante valutare il ruolo dell’autofagia come possibile meccanismo di resistenza.

East Asia, ca. 1749 (Image 1 of 2) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Tartariae Sinensis mappa geographica : ex Tabulis specialibus RRPP Iesuitarum nec non Relationibus R.P. Gerbillon, per Dom d'Anville, ... primum A° 1732 nunc se ; nunc secundum LL. projectionis stereographicae in usum translationis Germanicae Historiae Sinens. Haldianae descripta per Tobiam Mayer. It was published by Curis Homannianorum Heredum ca. 1749. Scale [ca 1:5,250,000]. This layer is image 1 of 2 total images of the two sheet source map, representing the western portion of the map. Covers a portion of East Asia including North Korea, South Korea, Mongolia, and portions of China, Russia, and Japan. Map in Latin and French. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Asia North Lambert Conformal Conic coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as drainage, cities and other human settlements, territorial boundaries, roads, shoreline features, the Great Wall of China, and more. Relief shown pictorially. Includes notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

East Asia, ca. 1749 (Image 2 of 2) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Tartariae Sinensis mappa geographica : ex Tabulis specialibus RRPP Iesuitarum nec non Relationibus R.P. Gerbillon, per Dom d'Anville, ... primum A° 1732 nunc se ; nunc secundum LL. projectionis stereographicae in usum translationis Germanicae Historiae Sinens. Haldianae descripta per Tobiam Mayer. It was published by Curis Homannianorum Heredum ca. 1749. Scale [ca 1:5,250,000]. This layer is image 2 of 2 total images of the two sheet source map, representing the eastern portion of the map. Covers a portion of East Asia including North Korea, South Korea, Mongolia, and portions of China, Russia, and Japan. Map in Latin and French. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Asia North Lambert Conformal Conic coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as drainage, cities and other human settlements, territorial boundaries, roads, shoreline features, the Great Wall of China, and more. Relief shown pictorially. Includes notes.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Medicinal plants - prophylactic and therapeutic options for gastrointestinal and respiratory diseases in calves and piglets? A systematic review.

BACKGROUND Gastrointestinal and respiratory diseases in calves and piglets lead to significant economic losses in livestock husbandry. A high morbidity has been reported for diarrhea (calves ≤ 35 %; piglets ≤ 50 %) and for respiratory diseases (calves ≤ 80 %; piglets ≤ 40 %). Despite a highly diverse etiology and pathophysiology of these diseases, treatment with antimicrobials is often the first-line therapy. Multi-antimicrobial resistance in pathogens results in international accordance to strengthen the research in novel treatment options. Medicinal plants bear a potential as alternative or additional treatment. Based on the versatile effects of their plant specific multi-component-compositions, medicinal plants can potentially act as 'multi-target drugs'. Regarding the plurality of medicinal plants, the aim of this systematic review was to identify potential medicinal plant species for prevention and treatment of gastrointestinal and respiratory diseases and for modulation of the immune system and inflammation in calves and piglets. RESULTS Based on nine initial sources including standard textbooks and European ethnoveterinary studies, a total of 223 medicinal plant species related to the treatment of gastrointestinal and respiratory diseases was identified. A defined search strategy was established using the PRISMA statement to evaluate 30 medicinal plant species starting from 20'000 peer-reviewed articles published in the last 20 years (1994-2014). This strategy led to 418 references (257 in vitro, 84 in vivo and 77 clinical trials, thereof 48 clinical trials in veterinary medicine) to evaluate effects of medicinal plants and their efficacy in detail. The findings indicate that the most promising candidates for gastrointestinal diseases are Allium sativum L., Mentha x piperita L. and Salvia officinalis L.; for diseases of the respiratory tract Echinacea purpurea (L.) MOENCH, Thymus vulgaris L. and Althea officinalis L. were found most promising, and Echinacea purpurea (L.) MOENCH, Camellia sinensis (L.) KUNTZE, Glycyrrhiza glabra L. and Origanum vulgare L. were identified as best candidates for modulation of the immune system and inflammation. CONCLUSIONS Several medicinal plants bear a potential for novel treatment strategies for young livestock. There is a need for further research focused on gastrointestinal and respiratory diseases in calves and piglets, and the findings of this review provide a basis on plant selection for future studies.

Diatom abundance in sediments of ODP Holes 186-1150A and 186-1151C

The diatom flora from two sediment cores recovered from the upper 27 meters below seafloor (mbsf) in the oceanic frontal area off Sanriku, northeast Japan, during Ocean Drilling Program Leg 186 were analyzed. Diatom abundance seems to be in interglacial stages and suggests a south-north shifting of the frontal area. Diatom temperature values are less reliable because frequency of the warm-water species is smaller. Site 1151 was in a warm climate at ~50 ka, as were Deep Sea Drilling Project Sites 579 and 580 in the western North Pacific Ocean. A mixed diatom assemblage in the upper 3 mbsf at Site 1150 is evidence that the Tsugaru Warm Current flowed into the studied area through the Tsugaru Strait.

Elsinoe australis; Myriangiaceae

Elsinoe australis Bitanc. & Jenkins

A voyage to China and the East Indies /

Goldsmiths'-Kress no. 10715.

Epidemiology of Opisthorchis viverrini

Opisthorchis viverrini is a food home trematode, important because of the sheer numbers of people infected and its serious morbidities such as hepatobiliary diseases and cholangiocarcinoma (CHCA). Although infections are identified throughout Southeast Asia, the epi-center is northeast Thailand, where high prevalence coexists with a high incidence of CHCA. In this review, we present the basic population features and the factors influencing transmission between the different hosts. (C) 2003 Elsevier B.V. All rights reserved.

Herbs or natural substances as complementary therapies for chronic kidney disease: ideas for future studies

Chronic kidney disease (CKD) is an increasingly common condition with limited treatment options that is placing a major financial and emotional burden on the community. The use of complementary and alternative medicines (CAMS) has increased many-fold over the past decade. Although several compelling studies show renal toxicities and an adverse outcome from use of some CAMS, there is also emerging evidence in the literature that some may be renoprotective. Many nephrologists are unaware of these potential therapeutic benefits in treating CKD, or they are reluctant to consider them in research trials for fear of adverse effects (including nephrotoxicity) or deleterious interaction with co-prescribed, conventional medicines. The increased use of self-prescribed CAMS by their patients suggests that practitioners and researchers should keep abreast of the current information on these agents. A primary goal of this article was to review the available scientific evidence for the use of herbs or natural substances as a complementary treatment for patients with CKD. A further goal was to report the literature on herbs that have been reported to cause kidney failure.

Compositional analysis of teas from Australian supermarkets

Caffeine, total amino acids, water extract and moisture content are considered to be quality indicators for leaf teas and teabags. These analyses were examined in 20 leaf teas and 36 teabags sampled from Australian supermarkets. About 70% of the analysed samples showed a moisture content higher than Vie maximum accepted level, 6.5%, for tea storage and marketing by the tea industries and traders. Water appropriate extract of 15 samples out of 36 teabags was lower than that of the teas without teabags, which indicates that the quality of the paper used for teabags needs to be evaluated. Moreover, one of the black leaf tea samples was found to have a water extract below the lower limit of international standards. Four green and black teas of the same brand, claimed to contain less than 3% caffeine, were found to have 3-4%, the same as the other samples analysed in this study. The mean total contents of amino acids were 2.50% and 1.76% in black leaf teas and the teabags, respectively, whereas they were 3.44% and 2.28% in green leaf teas and the teabags, respectively. Furthermore, the weights of 28 teabags out of 36 samples were found to lie outside of the proposed +/- 2% variation accepted by the tea industries and traders, and 4 samples showed even larger variation, 10% being out of the proposed weights. This investigation also showed that the solubility of caffeine and water extract was affected by the permeability of teabags, whereas total amino acids were very variable. These results suggest that an efficient and practical quality control system for both imported and Australian-made teas in the Australian supermarkets should be developed, implemented and enforced. Chemical analysis should be a part of the system for establishing an objective assessment for the quality control. (c) 2004 Elsevier Ltd. All rights reserved.