2,490 research outputs found
TWO TOPICS OF PHYSIOPATHOLOGICAL INTEREST IN MITOCHONDRIAL RESEARCH: INNER MEMBRANE CHANNELS AND MITOCHONDRIOTROPIC REDOX-ACTIVE COMPOUNDS
No full textThe group I have been part of during my doctorate thesis research is interested in various aspects of mitochondrial function. The projects I have been involved in are concerned with two very different topics; both studies have however as long-term objective the discovery and validation of compounds potentially useful for an anti-cancer action at the mitochondrial level.
The first of these projects concerns the potassium-selective channels of the inner mitochondrial membrane. A few have been discovered over the past several years. Besides participating in the regulation of mitochondrial processes and parameters these channels have attracted attention because of their involvement in other aspects of cellular physiology. Two of them seem to be able to afford protection from ischemic damage (preconditioning), while a recent study by our group in collaboration with German researchers has provided evidence that a third, mtKV1.3, plays an important role in Bax-mediated apoptosis in lymphocytes. Hence our interest in this channel.
I have verified whether mtKV1.3 might be present in the mitochondria not only of T lymphocytes, where it has been discovered, but also in those of a few other cancerous cell lines. So far I have succeeded in establishing its presence in two human lines (PC3 and MCF7) (Gulbins et al., 2010 – Chapt. 1). I have then investigated whether inhibition of the channel might cause cell death in these lines, a finding which would have been of considerable interest for the development of new chemotherapeutic drugs. Unfortunately I have not been able to obtain evidence of a death-inducing effect by a specific inhibitor of mtKV1.3 (Chapt. 2).
Within this project we have also discovered another mitochondrial channel: Ca2+-activated mtKCa3.1, which we have observed in the mitochondria of a human colon tumor line (HCT116) both by patch-clamping the inner membrane and by Wester blotting (De Marchi et al., 2009 – Chapt. 3). I have then investigated whether its inhibition might be cytotoxic or at least cytostatic, but in this case also the answer has so far been negative. I have checked for the presence of mtKCa3.1 in two other cell lines of colonic origin (C26 and Caco2) to try and understand whether this channel might be expressed in a cancer-specific manner by subsequently performing a comparison with non-tumoral cells or tissue. However, in both cases the channel has turned out to be present only in the plasma membrane (Sassi et al., 2010 – Chapt. 4).
The other project I have taken part in concerns the pharmacological exploitation of plant polyphenols, contained in many foods and beverages. A vast literature shows that these compounds have interesting biological properties which could be useful in health care endeavours such as protection from cardiovascular damage or neurodegeneration, or to prevent the onset and inhibit the growth of many types of cancer. Practical applications for these potentially useful compounds are made difficult by their low bioavailability. A priori, one way to circumvent this problem may be to cause their accumulation in an opportune site of action. The mitochondrion is an obvious choice, since polyphenols are redox-active molecules (whose activity may be anti- or pro-oxidant depending on conditions such as pH, presence of Fe2+/3+ o Cu+/2+ and concentration of the polyphenol itself) and mitochondria are the main cellular site of production of radicals as well as being mechanistically involved in cell death. Mitochondriotropic compounds might turn out to have biomedical relevance regardless of whether their activity may be anti-oxidant/cytoprotective or pro-oxidant/cytotoxic.
Our group has therefore synthesized a few derivatives of quercetin and resveratrol – two much-studied model polyphenols – capable of accumulating into mitochondria. This property is conferred by the triphenylphosphonium group (TPP), a lipophylic cation which can diffuse through biomembranes and accumulate in regions held at negative electrical potential, such as the mitochondrial matrix and the cytoplasm. We have verified that these derivatives indeed accumulate in mitochondria as expected (Mattarei et al., 2008 – Chapt. 5; Biasutto et al., 2008 – Chapt. 6). A first exploration of the biological properties of these new compounds has been carried out with two quercetin derivatives (Q3BTPI, QTA3BTPI). We have observed that these compounds supplied to isolated mitochondria are potential co-inducers of the mitochondrial permeability transition (MPT), as well as inhibitors of respiration and of the F0F1 ATPase. At the cellular level, both compounds induce an MPT-independent depolarization of mitochondria and a modest increase in the cellular production of ROS at least in the case of QTA3BTPI (Biasutto et al., 2010 – Chapt. 7).
I have extended the study to evaluate the possible cytostatic/cytotoxic action of the various mitochondriotropic compounds on tumoral (C26) and non-tumoral (MEF) cell lines. I have furthermore investigated what impact these compounds have on the mitochondria of another tumoral cell line (Jurkat lymphocytes). The results of cell vitality determinations showed that the various mitochondriotropic derivatives, administered at concentrations in the μM range, can have a cytotoxic/cytostatic activity vs. rapidly growing cells, while their effect on slowly dividing non-tumoral ones is much more modest. The initial findings of a mechanistic study have revealed that relatively high (10-5 M range) concentrations can elicit structural alterations, mitochondrial depolarization and generation of radical oxygen species (Chapt. 8).Il gruppo presso cui ho svolto il mio corso di dottorato si interessa di vari aspetti della funzionalità mitocondriale. I progetti che ho seguito riguardano due ambiti molto diversi tra loro; tuttavia in entrambi i casi si tratta di studi il cui obiettivo a lungo termine è l’individuazione di composti potenzialmente utili per un’azione antitumorale a livello mitocondriale.
Uno di questi progetti riguarda i canali del potassio presenti nella membrana mitocondriale interna. Negli ultimi anni ne sono stati individuati diversi. Oltre ad aver un ruolo nella regolazione di processi e parametri mitocondriali questi canali son risultati interessanti per il loro coinvolgimento in altri aspetti della fisiologia cellulare. Due di questi sembrano aver un ruolo nella protezione dal danno ischemico (precondizionamento), mentre un recente studio svolto dal nostro gruppo in collaborazione con un gruppo tedesco ha messo in evidenza come un terzo, il mtKV1.3, svolga un ruolo importante nell’apoptosi mediata da Bax in linfociti. Da qui l’interesse da parte nostra verso quest’ultimo canale.
Ho verificato se il mtKV1.3 fosse presente nei mitocondri non solo dei linfociti T, dove è stato individuato inizialmente, ma anche in alcune altre linee tumorali. Sono riuscito finora ad individuarlo in due linee umane (PC3 e MCF7) (Gulbins et al., 2010 - Cap. 1). Ho successivamente indagato se l’inibizione del canale potesse indurre morte cellulare in tali linee. Ciò sarebbe di notevole interesse nello sviluppo di nuovi chemioterapici. Tuttavia dai risultati ottenuti l’utilizzo di inibitori specifici del canale nelle differenti linee non ha mostrato effetti rilevanti di induzione di morte cellulare (Cap. 2).
Sempre nell’ambito di questo progetto abbiamo individuato un altro canale mitocondriale: il mtKCa3.1 che abbiamo osservato nei mitocondri di una linea tumorale del colon umana (HCT116) sia mediante patch-clamp che Western blot. (De Marchi et al., 2009 - Cap. 3). Ho poi verificato se la sua inibizione potesse essere citotossica o almeno citostatica, tuttavia anche in questo caso non abbiamo ottenuto una risposta positiva. Ho verificato la presenza o meno del canale anche in due altre linee tumorali del colon (C26 e Caco2) per comprendere se fosse un canale espresso in modo tumore-specifico procedendo successivamente a confronti con cellule non tumorali, tuttavia in ambedue i casi il canale è risultato presente solo nella plasma membrana (Sassi et al., 2009 - Cap 4).
L’altro progetto da me intrapreso riguarda lo sfruttamento farmacologico dei polifenoli vegetali presenti in molti cibi e bevande. Una notevole letteratura mostra come tali composti possiedano interessanti proprietà biologiche che potrebbero esser utili in diversi ambiti, come la protezione cardiovascolare o dalla neurodegenerazione, oppure nel prevenire l’insorgere e nell’inibire la crescita di molti tipi di cancro. Questi composti dalle interessanti potenzialità trovano una notevole difficoltà d’utilizzo a causa della loro scarsa biodisponibilità. A priori, un modo per ovviare a questo problema è accumulare tali composti in un’opportuna sede d’azione. Una scelta ovvia è il mitocondrio, dato che i polifenoli sono molecole redox-attive (la cui attività può essere anti- o pro-ossidante in base a differenti condizioni come pH, presenza di Fe2+/3+ o Cu+/2+ e concentrazione del composto) e che i mitocondri son il principale sito di produzione dei radicali, oltre ad esser coinvolti nei processi di morte cellulare. Questi composti mitocondriotropici potrebbero aver una rilevanza biomedica sia che dimostrino un’attività anti-ossidante/citoprotettiva sia invece che si comportino da pro-ossidanti citotossici.
Il nostro gruppo ha quindi sintetizzato alcuni derivati di quercitina e resveratrolo - due polifenoli particolarmente studiati presi a modello - in grado di accumularsi nei mitocondri. Questo grazie alla funzionalizzazione con un gruppo trifenilfosfonio (TPP+), un catione lipofilico che può diffondere attraverso le membrane biologiche e accumularsi in regioni a potenziale negativo, quali la matrice mitocondriale e il citoplasma. Abbiamo verificato che questi derivati si accumulassero effettivamente nei mitocondri (Mattarei et al, 2008 - Cap. 5; Biasutto et al, 2008 – Cap. 6). Una prima indagine sugli effetti biologici di questi nuovi composti è stata condotta con due derivati della quercetina (Q3BTPI, QTA3BTPI). Abbiamo osservato come questi composti con mitocondri isolati siano potenziali co-induttori della transizione di permeabilità mitocondriale (MPT), nonché inibitori della respirazione e dell’ATP sintasi mitocondriale. Osservazioni a livello cellulare mostrano una depolarizzazione mitocondriale indipendente dalla MPT indotta da entrambi i composti e un modesto aumento della produzione cellulare di ROS da parte della QTA3BTPI (Biasutto et al., 2010 – Cap. 7).
Ho ampliato lo studio per valutare la possibile azione citotossica/citostatica su linee cellulari tumorali (C26) e non (MEF) dei vari composti mitocondriotropici. Ho anche indagato come tali composti influiscano sull’attività mitocondriale di un’altra linea cellulare tumorale (Jurkat). I risultati di esperimenti di vitalità cellulare mostrano come diversi composti mitocondriotropici, somministrati a concentrazioni in ambito micromolare, possano aver un’ attività citotossica/citostatica su cellule a crescita veloce, mentre il loro effetto su cellule non tumorali è molto modesto se esse hanno crescita lenta. I risultati iniziali di uno studio meccanicistico hanno evidenziato come concentrazioni relativamente elevate (nell’ambito di 10-5 M) di questi composti possano causare alterazioni morfologiche, depolarizzazione mitocondriale e generazione di specie radicaliche (Cap. 8)
Italian Guidelines for Energy Performance of Cultural Heritage and Historical Buildings: The Case Study of the Sassi of Matera
No full textThe Sassi of Matera are a unique example in the world of rock settlements, developed from natural caves carved into the rock and molded into increasingly complex structures inside two large natural amphitheaters. Research focuses on the compatibility of the energy efficiency measures applied in Sassi buildings with the recent MiBACT guidelines on "Energy efficiency improvements in cultural heritage" and AiCARR guidelines on "Energy efficiency of historical buildings". The paper aims to analyze energy and environmental performance of different building typologies and monuments of the Sassi site
A Hidden Water-Harvesting System: The Sassi de Matera
No full textThe water-harvesting system of the ancient Sassi di Matera, in the Basilicata region of southern Italy, represents a clever way of living with water in an arid climate. The terrain, with its soft rocks (Calcarenite di Gravina), provided the foundation for the water-harvesting system that shaped the cave dwellings of Sassi physically, socially and culturally. People caught, guided and stored water in private and public spaces, mostly underground, ensuring its availability for all. In 1993 UNESCO declared the cave village a World Heritage Site. Unfortunately, the water-harvesting system of Sassi di Matera is no longer functioning. Its historic ingenuity is not as visible as the system deserves and its cultural and social values are almost forgotten. Using layered visual analysis – the illustrative method – knowledge can be collected and communicated in drawings to get insight regarding more resilient, circular, and people-related approaches (Bobbink, Chourairi and Di Nicola 2022). This article and the included drawings focus on the water system’s value, from which we can learn today.Landscape Architectur
Recensione ad A. Carbone, Viaggio nei Sassi. Famiglia, infanzia e assistenza a Matera in età moderna. Bari, Cacucci, 2005
No full textRecensione al volume di Angela Carbone, Vita nei Sassi. Famiglia, assistenza e infanzia a Matera in Età Moderna, Bari, Cacucci, 2005, pp. 260.
Eum.21.00
Thermo-hygrometric and comfort analysis of a vernacular multi-room settlement in the Sassi of Matera
No full textThe present work is focused on the thermo-hygrometric and comfort analysis of a vernacular
multi-room settlement in the Sassi of Matera. The vernacular multi-room settlement is
composed of n. 8 rooms divided into two levels, partly built and partly excavated into the
calcareous rocks. The case study hypothesizes a possible low-level environmental system
solution able to respect with the strictest design standards, within a structure located in the
Sassi district of Matera.
Our first goal is to outline a microclimate profile of typical environment of Sassi of Matera.
To do this we carried out a comparative analysis of climatic data from different sources:
Energy Plus weather data, ALSIA-Matera data and ilmeteo.it- Gioia del Colle data. From the
analysis conducted we have found that Enegy Plus weather data series presents temperature
lower than ALSIA-Matera and ilmeteo.it- Gioia del Colle data series with an average of
absolute deviation in winter and summer season respectively of 0.9 °C and 0.45 °C.
Measures conducted have been useful to analyse the energy behavior in spontaneous regime
i.e. without heating or cooling system. In this case thermal comfort is not acceptable.
Assuming to install absorption heat pump in all multi-room settlement comfort is acceptabl
Thermo-hygrometric evaluations in the recovery of rocky buildings of the ‘‘Sassi of Matera’’ (Italy)
No full textThe Sassi of Matera are a very interesting example of a rocky settlement. The limestone walls often present high moisture content which negatively influences the room microclimate. In the first part of this paper, rooms without evident problems of moisture were analyzed for the purpose of carrying out a statistical analysis, to be repeated in analogous situations and to identify the distribution of what we can define as background moisture of the rocky installation. The knowledge of moisture, however, greatly influences the evaluation of heat loss since thermal conductivity of a material increases with an increase in the percentage of water that is contained within it. Consequently, the second part of the paper deals with thermal conductivity and other thermal physical properties related to the moisture of the calcareous sandstone present in the installation of the "Sassi," continuing the analysis initiated in a previous work
Author Meets Reader: Not the Marrying Kind: A Feminist Critique of Same-Sex Marriage
No full textThis is an audio recording of an author meets reader session held at the SLSA Annual Conference, University of York, 27 March 2013. Nicola Barker's book, Not the Marrying Kind: A Feminist Critique of Same-Sex Marriage, was the winner of the 2013 Hart SLSA Book Prize. In the session she introduces the book and then engages in discussion about it with Daniel Monk
South Thompson Valley and Pinantan official settlement plan.
No full textThe recommended policies contained in this plan provide the Thompson-Nicola Regional District with the means to protect and enhance the agricultural economic base, regulate the supply and location of rural residential growth, guide commercial and industrial development and satisfy the historical, recreational, social and environmental concerns of the settlement plan area.Not peer reviewedPlanning documen
Rural Residential Study
No full textThe Thompson-Nicola Regional District has recently been grappling with some of the basic problems and conflicts of trying to provide for rural residential lot demand and, at the same tie, trying to protect the resources, aesthetics and social climate of existing rural area.Not peer reviewedstudydraf
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