El carboni, l'esquelet de la vida

El carboni va esdevenir, fa més de tres mil cinc-cents milions d'anys, l'element bàsic sobre el qual es va generar la vida a la Terra. Per què? Quines característiques el van fer tan especial? D'on va sortir el carboni necessari perquè es desenvolupés la vida? On i com el trobem? En aquest article donarem respostes a aquestes preguntes, tot estudiant l'àtom de carboni, la seva reactivitat, les formes en què es presenta a la naturalesa i els intercanvis que es produeixen entre els diversos compartiments terrestres: atmosfera, hidrosfera, litosfera i biosfera. Però l'objectiu principal serà repassar els diversos tipus de biomolècules que han permès establir, consolidar i evolucionar totes les formes de vida conegudes al nostre planeta. Els glúcids o sucres són molècules força oxidades i entre ells trobem combustibles essencials per a les nostres cèl·lules com la glucosa o la fructosa, però també molècules estructurals, com la cel·lulosa o la quitina. Els àcids grassos permeten la síntesi de diversos lípids derivats, com els triacilglicerols (greixos i olis) i els fosfolípids de les nostres membranes cel·lulars. Els lípids esteroides tenen funcions tant estructurals, en el cas del colesterol, com hormonals (com ara les hormones sexuals o la progesterona). Els aminoàcids, caracteritzats per la presència d'un grup àcid i un altre nitrogenat, són els elements bàsics per fabricar les proteïnes, responsables en darrer terme de totes les nostres funcions. Els nucleòtids, per la seva part, constitueixen els àcids nucleics, portadors i gestors de la informació necessària per fabricar les proteïnes

El sistema A: un transportador d'aminoàcids ubic i altament modulable

El transport de bona part d'aminoàcids neutres des de la sang, on són majoritaris, cap a 1'interior de la pràctica totalitat de cèl·lules de mamífer, depèn essencialment d'un sistema de transport conegut com a sistema A. Com la majoria de sistemes de captació de soluts orgànics i inorgànics, l'A ha estat caracteritzat com una entitat cinètica, és a dir, es defineix segons la seva funcionalitat biològica, la qual implica tot un seguit de característiques pròpies pel que fa al tipus de substrat que pot captar, 1'afinitat envers aquests substrats, 1'existència o no d'inhibidors específics, la dependència de fluxos acoblats (dependència de Na+, per exemple), la susceptibilitat a ser regulat bé sigui per mecanismes a curt o a llarg termini i moltes altres 'qualitats' funcionals que permeten assumir que una determinada activitat biològica probablement es correspongui amb un producte gènic determinat

Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs

Background: Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite 50-deoxy-5-fluorouridine (50-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA in cancer cells treated with 50-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3 participates in the activity of genotoxic agents. Methods: The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. Results: 50-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. Conclusions: Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest

Breast mammographic Density: stromal implications on breast cancer detection and therapy

Current evidences state clear that both normal development of breast tissue as well as its malignant progression need many-sided local and systemic communications between epithelial cells and stromal components. During development, the stroma, through remarkably regulated contextual signals, affects the fate of the different mammary cells regarding their specification and differentiation. Likewise, the stroma can generate tumour environments that facilitate the neoplastic growth of the breast carcinoma. Mammographic density has been described as a risk factor in the development of breast cancer and is ascribed to modifications in the composition of breast tissue, including both stromal and glandular compartments. Thus, stroma composition can dramatically affect the progression of breast cancer but also its early detection since it is mainly responsible for the differences in mammographic density among individuals. This review highlights both the pathological and biological evidences for a pivotal role of the breast stroma in mammographic density, with particular emphasis on dense and malignant stromas, their clinical meaning and potential therapeutic implications for breast cancer patients

Lipopolysaccharide-induced apoptosis of macrophages determines the up-regulation of concentrative nucleoside transporters Cnt1 and Cnt2 through tumor necrosis factor-alpha-dependent and -independent mechanisms

In murine bone marrow macrophages, lipopolysaccharide (LPS) induces apoptosis through the autocrine production of tumor necrosis factor-alpha (TNF-alpha), as demonstrated by the fact that macrophages from TNF-alpha receptor I knock-out mice did not undergo early apoptosis. In these conditions LPS up-regulated the two concentrative high affinity nucleoside transporters here shown to be expressed in murine bone marrow macrophages, concentrative nucleoside transporter (CNT) 1 and 2, in a rapid manner that is nevertheless consistent with the de novo synthesis of carrier proteins. This effect was not dependent on the presence of macrophage colony-stimulating factor, although LPS blocked the macrophage colony-stimulating factor-mediated up-regulation of the equilibrative nucleoside transport system es. TNF-alpha mimicked the regulatory response of nucleoside transporters triggered by LPS, but macrophages isolated from TNF-alpha receptor I knock-out mice similarly up-regulated nucleoside transport after LPS treatment. Although NO is produced by macrophages after LPS treatment, NO is not involved in these regulatory responses because LPS up-regulated CNT1 and CNT2 transport activity and expression in macrophages from inducible nitric oxide synthase and cationic amino acid transporter (CAT) 2 knock-out mice, both of which lack inducible nitric oxide synthesis. These data indicate that the early proapoptotic responses of macrophages, involving the up-regulation of CNT transporters, follow redundant regulatory pathways in which TNF-alpha-dependent- and -independent mechanisms are involved. These observations also support a role for CNT transporters in determining extracellular nucleoside availability and modulating macrophage apoptosis

El sistema A: un transportador d'aminoàcids ubic i altament modulable

El transport de bona part d'aminoàcids neutres des de la sang, on són majoritaris, cap a 1'interior de la pràctica totalitat de cèl·lules de mamífer, depèn essencialment d'un sistema de transport conegut com a sistema A. Com la majoria de sistemes de captació de soluts orgànics i inorgànics, l'A ha estat caracteritzat com una entitat cinètica, és a dir, es defineix segons la seva funcionalitat biològica, la qual implica tot un seguit de característiques pròpies pel que fa al tipus de substrat que pot captar, 1'afinitat envers aquests substrats, 1'existència o no d'inhibidors específics, la dependència de fluxos acoblats (dependència de Na+, per exemple), la susceptibilitat a ser regulat bé sigui per mecanismes a curt o a llarg termini i moltes altres 'qualitats' funcionals que permeten assumir que una determinada activitat biològica probablement es correspongui amb un producte gènic determinat

Regulation of nucleoside transport regulation by lipopolysaccharide, phorbol esters and TNF in human B lymphocytes

Nucleoside transport systems and their regulation in human B-lymphocytes have been characterized using the cell lines Raji and Bare lymphoma syndrome-1 (BLS-1) as experimental models. These cells express at least three different nucleoside transport systems as follows: a nitrobenzylthioinosine-sensitive equilibrative transport system of the es-type, which appears to be associated with hENT1 expression, and two Na+-dependent transport systems that may correspond to N1 and to the recently characterized N5-type, which is nitrobenzylthioinosine-sensitive and guanosine-preferring. B cell activators such as phorbol 12-myristate 13-acetate and lipopolysaccharide (LPS) up-regulate both concentrative transport systems but down-regulate the equilibrative es-type transporter, which correlates with lower hENT1 mRNA levels. These effects are dependent on protein kinase C activity. Phorbol 12-myristate 13-acetate and LPS also induce an increase in tumor necrosis factor-alpha (TNF-alpha) mRNA levels, which suggest that this cytokine may mediate some of the effects triggered by these agents, since addition of TNF-alpha alone can increase N1 and N5 transport activities by a mechanism that also depends on protein kinase C activation. Interestingly, TNF-alpha down-regulates es activity, but this effect cannot be abolished by inhibiting protein kinase C. This study reveals differential regulation of nucleoside transport systems following activation of human B-lymphocyte cell lines by agents of physiological relevance such as TNF-alpha and LPS. Moreover, it indicates that the recently characterized N5 transport system can also be regulated following B cell activation, which may be relevant to lymphocyte physiology and to the treatment of lymphocyte malignancies

Intestinal and hepatic nitrogen balance in the rat after the administration of an oral protein load

The fate of a small oral dose of protein given to overnight-starved rats was studied. After 3 h, 62 per cent of the protein amino acids had been absorbed. Most of the absorbed N went into the bloodstream through the portal in the form of amino acids, but urea and ammonia were also present. About one-quarter of all absorbed N was carried as lymph amino acids. The liver was able to take all portal free ammonia and a large proportion of portal amino acids, releasing urea. The hepatic N balance was negative, indicating active proteolysis and net loss of liver protein