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Three-dimensional visualization of cellular and subcellular-structures in histological-tissues is essential for understanding the complexities of biological-phenomena, especially with regards structural and spatial relationships and pathologlical-diagnosis. Recent advancements in tissue-clearing technology, such as Magnified Analysis of Proteome (MAP), have significantly improved our ability to study biological-structures in three-dimensional space; however, their wide applicability to a variety of tissues is limited by long incubation-times and a need for advanced imaging-systems that are not readily available in most-laboratories. Here, we present optimized MAP-based method for paper-thin samples, Paper-MAP, which allow for rapid clearing and subsequent imaging of three-dimensional sections derived from various tissues using conventional confocal-microscopy. Paper-MAP successfully clear tissues within 1-day, compared to the original-MAP, without significant differences in achieved optical-transparency. As a proof-of-concept, we investigated the vasculature and neuronal-networks of a variety of human and rodent tissues processed via Paper-MAP, in both healthy and diseased contexts, including Alzheimer’s disease and glioma.

In this communication, a paper-based 3D cell culture device integrated with electrochemical biosensor was applied to on-line monitoring of dopamine release from PC12 cell damage models induced by amyloid-beta peptide (Aβ25-35) and cell intervene models protected by curcumin (Cur) and marrow mesenchymal stem cells (MSC) supernatant. The adhesion and proliferation of PC12 cells cultured on the paper scaffold was characterized by scanning electron microscopy and laser scanning confocal microscopy, which verify unique biocompatibility and 3D microarchitecture similar to human body microenvironment of paper substrate, so an artificial model simulating 3D microenvironment in vivo was constructed easily. The PC12 cells in paper-based devices consisted of four groups containing control group, Aβ25-35 group, Aβ25-35+Cur group and Aβ25-35+MSC supernatant group. Under optimal conditions, this proposed device displayed a wide linear range from 0.05 to 1 μmol/L with a detection limit of 0.009 μmol/L (S/N = 3) and exhibited high sensitivity, good selectivity and excellent reproducibility. Furtherly, electrochemcial analysis and MTT assay gave a clue that the cell viability of Aβ25-35+MSCs supernatant group was higher than that of Aβ25-35+Cur group. Therefore, the detachable paper-based 3D device paves the way to a direct detection of exocytosis DA from neuron cells for on-line cell viability evaluation of neurodegenerative disease cell damage models.

This study presents the research on the chemical analysis and genotoxicity of 28 virgin/recycled paper products in food-contact use. In the chemical analysis, paper products were extracted by reflux with ethanol, and analyzed by gas chromatography/mass spectrometry. 4,4'-bis(dimethylamino)benzophenone (Michler's ketone: MK), 4,4'-bis(diethylamino)benzophenone (DEAB), 4-(dimethylamino)benzophenone (DMAB) and bisphenol A (BPA) were found characteristically in recycled products. Seventy-five percent of the recycled paper products contained MK (1.7-12 microg/g), 67% contained DEAB (0.64-10 micro g/g), 33% contained DMAB (0.68-0.9 microg/g) and 67% contained BPA (0.19-26 microg/g). Although, BPA was also detected in virgin paper products, the detection levels in the recycled products were ten or more times higher than those in the virgin products. The genotoxicity of paper and paperboard extracts and compounds found in them were investigated by Rec-assay and comet assay. Of the 28 products tested by Rec-assay using Bacillus subtilis, 13 possessed DNA-damaging activity. More recycled than virgin products (75% against 25%) exhibited such activity, which, of the compounds, was observed in BPA, 1,2-benzisothiazoline-3-one (BIT), 2-(thiocyanomethylthio)benzothiazole, 2,4,5,6-tetrachloro-isophthalonitrile, 2,4,6-trichlorophenol (TCP), and pentachlorophenol. The critical toxicant in one virgin paper product was concluded to be BIT. Eight samples with DNA-damaging activity were also tested by comet assay using HL-60 cells; six induced comet cells significantly (five times or higher than the control) without a decrease of viable cells. TCP, BZ, DEAB, and BIT also caused a slight increase in comet cells. In conclusion, we showed that most recycled paper products contain chemicals such as MK, DEAB, DMAB, and BPA, and possess genotoxicity. However, the levels of the chemicals in the recycled products could not explain their genotoxic effects.

Introduction: Apoptosis dysregulation plays a substantial role in the pathophysiology of chronic inflammation and its related symptoms such as edema. Regulation of NF-ĸB activation is involved in apoptosis pattern change. The current study aimed at verifying the effects of local inflammation on edema and changes in apoptotic markers, and investigating the possible role of NF-ĸB in apoptosis pattern change during different stages of complete Freund’s adjuvant (CFA)-induced knee arthritis in rats. Methods: A total of 96 male Wistar rats were divided into different experimental groups. Arthritis was evoked into the right knee articular joint. Changes made in knee edema were assessed by caliper on the days 0, 7, 14, and 21 of the study. Synovial NF-ĸB and levels of apoptotic markers were evaluated during different stages of the study using Western blot technique. Results: CFA injection caused intense edema during the whole study period. Synovial NF-ĸB level increased during the whole study period. The level of apoptotic markers increased during the acute phase of study. But during chronic phase, the apoptosis level decreased. Inh-NF-ĸB administration increased synovial apoptosis during the whole study period. Conclusion: It seems that apoptosis pattern change plays an important role in the progression and modulation of CFA-induced inflammation and its related symptoms. Also, it can be concluded that synovial NF-ĸB had a crucial role in synovial apoptosis change during the study period.

Introduction. Alopecia areata (AA) is an autoimmune condition characterized by T-cell-mediated attack on hair follicles. Objective. Evaluation of efficacy of 308 nm excimer light in the treatment of alopecia areata. Material and methods. Patches of AA were treated twice weekly, but not on 2 consecutive days, with UVB excimer 308 nm light. In all patients, half of the AA patch was irradiated and the other half was spared, covered with a black rubber shield and taken as a control. Therapy was started with an initial dose of 300 mJ/cm 2 , with an incremental dose of 100 mJ/cm 2 at every sitting until fine erythema appeared. Results. At the end of the treatment, one patient (3.33%) at the test site showed > 50% hair regrowth vs. none at the control site. After a 2-month post-treatment period, successful hair regrowth (grades 3 and 4) was seen in 12 patients at test sites and in 2 patients at control sites. The differences were statistically significant (p < 0.05). After 4 months successful hair regrowth (grades 3 and 4) was seen in 16 patients at test sites and in 5 patients at control sites. The differences were statistically significant (p 0.05). Conclusions. Excimer light has the potential to stimulate hair regrowth in patches of alopecia areata.

Our previous study reported that galaxamide, which is a cyclo-pentapeptide containing five leucines that was extracted from Galaxaura filamentosa, displayed remarkable anticancer cytotoxicity. This novel cyclo-peptide provided a new skeleton for the structural modifications used in finding new drugs with better anticancer properties. In this study, five analogues were synthesized based on changing the number of d/l amino acids by adding a new amino acid, phenylalanine. Galaxamide and five of its analogues were evaluated through MTT assays to examine their cytotoxic activities. We found that modified analogue 5, which is referred to as A5, displayed broad spectrum cytotoxic activity toward every cell line tested; in addition, the IC50 of A5 was lower than that of galaxamide and the other analogues. Furthermore, we used flow cytometry and western blot assays to investigate whether galaxamide and A5 could induce cancer cell apoptosis. The flow cytometric studies showed that HepG2 cells treated with different concentrations of galaxamide or A5 over 72 h displayed significant and dose-dependent increases in the percentages of early-stage apoptotic cells. Western blotting revealed that both compounds induce caspase-dependent apoptosis in HepG2 cells through a mitochondria-mediated pathway. The results demonstrate that galaxamide and its analogues have potential applications as clinical anticancer drugs.

Hypoxia inducible factor (HIF) is a product of tumor cells that plays an important role in protecting tumor cells and adjusting to low oxygen tension through driving the progression and aggressiveness of tumors and changing the growth, angiogenesis, differentiation and metastasis of tumors. Prolyl hydroxylase 3 (PHD3) is a member of PHDs that are induced in hypoxia. Many studies have shown that PHD3 not only can hydroxylate HIF-1α, but also has various other biological functions. Thus PHD3 plays significant roles in suppressing the growth, angiogenesis, differentiation and metastasis of tumors and promoting apoptosis of tumors under hypoxic conditions. It may become a new tumor suppressor gene and also may become a new approach to investigate tumors.

A rhodium(III) complex, [Rh(MQ)(DMSO)2Cl2] (1), with 8-hydroxy-2-methylquinoline as the ligand was synthesized and characterized. Complex 1 exhibited cytotoxicity against BEL-7404, Hep-G2, NCI-H460, T-24, and A549 cell lines with IC50 values in the micromolar range (6.52–17.86 μM). Various experiments on the Hep-G2 cells showed that complex 1 caused cell cycle arrest at the S phase, downregulation of cdc25 A, cyclin A, cyclin B and CDK2, and upregulation of p21, p27 and p53. Furthermore, cytotoxicity mechanism studies suggested that complex 1-induced apoptosis was achieved via disruption of the mitochondrial function, which led to a significant loss of the mitochondrial membrane potential, an increase in the cellular levels of reactive oxygen species, cytochrome c, and apaf-1, and a fluctuation of the intracellular Ca2+ concentration. Taken altogether, complex 1 can trigger cancer cell death by inducing apoptosis through a mitochondrial dysfunction pathway.

This study evaluates the effects of previously synthesized hydrazinyldiene-chroman-2,4-diones on cell proliferation and apoptosis, cell cycle distribution and migration capacity of MCF-7 breast cancer cells in synergy with doxorubicin. Physicochemical properties of the synthesized compounds were correlated with their structure and activity. Significant cell viability decrease in comparison with the effect of doxorubicin alone and the reference 4-hydroxycoumarin was observed when combination treatment comprising doxorubicin and the title compounds was applied. Synergistic effect with doxorubicin was also observed in down-regulation of phospho-Thr308Akt levels, confirming reduced proliferation and increased apoptosis. Combined treatment increased the percentage of cells arrested at the G2/M stage. Additive inhibition of cell migration was also observed, pointing to the possibility of reducing the risk of metastases. With their solubility profile and log D7.4, all the synthesized compounds follow Lipinski's rule of five for good permeability (absorption) potential.

Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this we will define the key mitochondrial processes that play a role in cardiovascular disease, which are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This Statement will define the key roles that mitochondria play in cardiovascular physiology and disease, and provide insight into how mitochondrial defects can contribute to cardiovascular disease and it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.

Introduction: The ASPP family (apoptosis – stimulating proteins of p53) comprises three proteins, ASPP1, ASPP2 and iASPP, that interact with and modulate the behavior of p53. ASPP1 and ASPP2 enhance the ability of p53 to induce apoptosis by causing p53 to up regulate the expression of proapoptotic genes specifically rather than genes involved in cell cycle arrest. Inhibitory member of the ASPP family (iASPP) acts as inhibitor for the p53, it was originally identified as a nuclear protein that interacts with and inhibits NFkb p56 RelA and inhibits p53-mediated cell death as well. Material and methods: To examine the role of iASPP in acute leukemic patients, we analyzed iASPP mRNA expression in acute leukemia by semi quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Results: The results showed that the median level of iASPP in acute lymphoblastic leukemia and acute myeloid leukemia patients was significantly higher than those in cells from normal donors (p=0.04). The expression of iASPP in ALL and AML patients was not associated with age, gender, hemoglobin, platelets; blasts count in bone marrow, treatment outcome but was associated with blasts count in peripheral blood and total leucocytic count in AL patients. Conclusions: The results of the present study suggest that iASPP may play a role in leukemogenesis and/or disease progression of acute leukemia.

Both immediate medical treatment and rapid reperfusion to limit myocardial damage are strongly recommended for the treatment of acute myocardial infarction (AMI) [1,2]. However, beside obvious beneficial effects, reperfusion initiates additional lethal injury, known as ‘ischaemia-reperfusion (IR) injury’ and results in increased cardiac cells death through both necrosis and apoptosis [3] (see Fig. 1 for schematic presentation). Genetic perturbation in animal models of critical proapoptotic pathways involved in IR injury has been demonstrated to be beneficial [4,5] and underline the involvement of apoptosis in IR lesions. To reduce this phenomenon, various cardioprotective strategies including post-, remote or pharmacological conditioning target specifically IR injury. The ‘noble cell’ to rescue appears often to be the cardiomyocyte. However, other cellular populations are of importance. Nearly 75% of the cells in the healthy heart are not cardiomyocytes [6], representing one-third of the mass or 10% of the volume. Most of these cells are fibroblasts [7], and endothelial cells could represent 10–15% of the volume of the heart [7]. The noncardiomyocytes cells play also critical roles, especially regulating fibrosis and extracellularmatrix as regards fibroblasts (see recent review [8]). Inflammatory cells play a major role in local inflammation during IR injury. The importance of endothelial cells (EC) should not be underestimated: they are not only deeply involved in ischaemic disease but also could participate in paracrine regulation, proinflammatory and profibrotic pathways. The pathophysiology of IR injury could then be considered as a cross-talk between various cellular populations and different biological pathways could be logically intricate (see Fig. 1 for a schematic presentation). ECs should be an interesting therapeutic target as they are easy to identify, especially after acute coronary syndromes [9] and linked with treatments [10]. Here, Forteza et al. explore in vitro the dynamics of EC viability, apoptosis and necrosis when treated with sera drawn in patients with acute STEMI after primary angioplasty. This study although small and in vitro provides important data on the subject. First, the authors establish that both EC viability nadir and EC apoptosis peak occur relatively late after the onset of reperfusion, that is at 96 h, which challenges the usually admitted narrow window for cardioprotection after AMI [11,12]. Indeed, cardioprotective therapies could be of interest even after the early minute following reperfusion because the development of biological events triggered by reperfusion occurs during a wider time window. This consideration is reinforced by the fact that EC apoptosis assessed in vitro remains active even at day 30, whereas EC necrosis appears as a rare event. Secondly, the kinetics of this phenomenon and the important role played by EC deserve to be underlined: these data illustrate that apoptotic phenomena triggered by IR are involved not only in myocytes, but likely in all cell types present or migrating on site (see for schematic presentation the Fig. 1). Among them, EC represent a promising target for immediate and delayed therapeutic intervention. Clinical translation in the field of cardioprotection is deeply mutating as recently reviewed [13]. Presently, due to new tools such asmagnetic resonance imaging, infarct size is not the single point of interest in AMI, but myocardial oedema or microvascular obstruction could be accurately evaluated [14]. In a near future, among the numerous trials on cardioprotection in patients with AMI, new parameters and endpoints could be proposed such as distinguishing various pathophysiologies. For instance, beyond infarct size, apoptotic events, activation of progenitor cells, specific proinflammatory or profibrotic pathways need to be explored, to better understand the impact of specific drugs and perhaps to better tailor individual treatments. Consistently, EC appear as an important target both in basic [15,16] and clinical approaches [17], especially to correct myocardial oedema [18] and because they can be easily and promptly targeted by a drug. The further step could even be to modulate the cross-talks between various players.

La proteïna secretada Apoptosis inhibitor expressed by macrophages (AIM) és expressada per macròfags tissulars en condicions d’inflamació. És una glicoproteïna que pertany a la família dels Receptors Scavenger Rics en Cisteïnes (SRCR-SF). Mitjançant models murins in vitro i in vivo s’ha observat com l’expressió d’AIM depèn de l’activació de l’heterodímer LXR/RXR i diversos estudis han demostrat com la forma murina AIM (mAIM) evita l’apoptosi de macròfags i altres tipus cel•lulars. En aquest context, estudis amb models murins d’aterosclerosi, deficients en el LDLr, han suggerit que mAIM actua com a factor aterogènic. En aquest sentit s’ha demostrat que AIM juga un paper rellevant en el procés ateroscleròtic murí incrementant l’apoptosi del macròfag, però es desconeix la seva implicació en l’aterosclerosi humana. A més, resultats recents la descriuen com un possible marcador de sèrum de condicions d’inflamació. La present tesi té com a objectiu principal aprofundir en el coneixement del paper de la proteïna humana AIM en els processos moleculars implicats en l’aterosclerosi. En la tesi presentada s’observa com pacients afectats per PAD tenen menors nivells de hAIM en sèrum que pacients sans. Tot i que aquestes diferències són estadísticament significatives, no són suficients per utilitzar els nivells de hAIM en sèrum com a biomarcador de la patologia, a no ser que es combini amb altres factors analítics. Aquests resultats es correlacionen amb els resultats obtinguts amb els macròfags cultivats in vitro, on la presència de la proteïna hAIM disminueix en el sobrenedat dels macròfags incubats amb d‘OxLDL mentre que augmenta en els llisats cel•lulars, suggerint el possible segrest de hAIM pel macròfag en presència d‘OxLDL. Per contra, en sèrum de models murins d’aterosclerosi els nivells de mAIM són majors que en el ratolins control, la qual cosa suggereix diferències en la regulació de la forma murina d’AIM en sèrum respecte la seva homòloga humana (hAIM). A més s’observa que la regulació del RNAm de hAIM augmenta amb l’activació dels receptors nuclears LXR/RXR, al igual que la seva homologa murina, mAIM. Mitjançant estudis funcionals es mostra que hAIM manté les característiques antiapoptòtiques de mAIM en front de les LDL modificades. I per primer cop, es suggereix que hAIM augmenta la formació dels macròfags escumosos, com s’observa per tincions amb Oil Red O o Nile Red O i dels resultats de colesterol total o èsters de colesterol. Aquest augment no és degut a la disminució del transport de colesterol cap a l’espai extracel•lular, ja que hAIM no modifica significativament l’eflux dels macròfags cap als acceptors lipídics plasmàtics. De fet, mitjançant estudis de citometria s’observa que hAIM incrementa la captació de les lipoproteïnes OxLDL i AcLDL marcades amb fluorescència, resultats correlacionats amb l’augment de l’expressió dels principals Receptors Scavenger implicats en la captació de LDL modificades (CD36 i SR-A1). En concordança amb aquests resultats, mitjançant assajos d’ELISA es suggereix que hAIM s’uneix a OxLDL i a AcLDL, i a més a més, mitjançant estudis de microscòpia de fluorescència s’observa que hAIM augmenta la capacitat de les cèl•lules HEK-293 transfectades amb CD36 en captar OxLDL i d’aquesta manera es suggereix que hAIM podria facilitar la captació d’OxLDL via CD36. Per altra banda, durant els estudis de participació de hAIM en l’adhesió del macròfag, s’observa que hAIM augmenta l’expressió de LFA-1 i la conseqüent adhesió a la molècula d’adhesió ICAM-1. Els resultats de la tesi doctoral presentada suggereixen que hAIM està involucrada en la supervivència del macròfag, la formació del macròfag escumós i l’adhesió del macròfag, així doncs hAIM podria contribuir significativament en els mecanismes relacionats en l’evolució de l’aterosclerosi., Apoptosis inhibitor expressed by macrophages (AIM) is expressed by tissue macrophages under inflammatory conditions. In mice, it acts as an atherogenic factor by protecting macrophages from the apoptotic effects of oxidized lipids. In humans, it is detected in atherosclerotic lesions, but no role related to atherosclerosis has been reported to date. This study aimed to investigate the contribution of human AIM (hAIM) to the macrophage events that lead to atherosclerosis. Our data show that serum levels of hAIM in patients with peripheral arterial disease (n=16) decreased with respect to controls (n=35) (median [interquartile range]): 98 [61] vs. 116 [72] ng/ml (p= 0.017). These findings are consistent with reduced hAIM secretion by monocytic THP1 cells and macrophages differentiated from peripheral blood monocytes upon OxLDL treatment. Functional studies with these cell types indicated that hAIM retains the anti-apoptotic effects against modified LDL (mLDL), and increased macrophage adhesion to endothelial ICAM-1 by enhancing LFA-1 expression. Furthermore, hAIM increased foam cell formation, as shown by Oil Red O and Nile Red staining as well as quantification of total and esterified cholesterol content. This was not due to decreased reverse cholesterol transport, because hAIM did not significantly affect the efflux from 3H-cholesterol-laden macrophages driven by plasma, apoA-I or HDL2 acceptors. Rather, flow cytometry studies indicated that hAIM increased macrophage endocytosis of fluorescent OxLDL, which correlated with an increase in the expression of the OxLDL receptor CD36. Moreover, hAIM bound to OxLDL in ELISA assays and enhanced the capacity of HEK-293 cells expressing CD36 to endocytose OxLDL as studied using immunofluorescence microscopy, suggesting that hAIM serves to facilitate CD36-mediated uptake of OxLDL. In conclusion, our data represent the first evidence that macrophage hAIM is involved in in atherosclerosis: macrophage survival, adhesion and foam cell formation, and suggest a significant contribution to atherosclerosis-related mechanisms in the macrophage.

Background: Exocrine (acinar) destruction and endocrine (islet) preservation in chronic pancreatitis (CP) is related to differential apoptotic indices within these cellular compartments. Aim: To define the role of cell cycle regulatory proteins in the control of pancreatic epithelial cell apoptosis. Methods: Formalin-fixed, paraffin-embedded tissue from six cases of CP and eight normal controls (N) were studied using immunohistochemistry for BCl-2, Bax, retinoblastoma protein (Rb) and Fas ligand (Fas-L). Labelling patterns were assessed using semi-quantitative (intensity-proportion [I-P]) or fully quantitative (labelling index [LI]) analysis. Results: Rb protein was expressed at a higher level by acinar cells in CP than N (mean acinar cell Rb LI 1.45% in CP and 0.437% in N; p

DE LA TESI:L´apoptosi és un dels principals tipus de mort cel.lular programada i es caracteritza per ser un procés actiu encaminat a produir la mort cel.lular de manera controlada. Aquest procés juga un paper important en el correcte desenvolupament del sistema nerviós central, ja que permet l'eliminació de les cèl.lules innecessàries. En canvi, l´activació anòmala d´aquest mecanisme en el cervell adult contribueix de manera significativa en el desencadenament de moltes malalties neurodegeneratives, com són la malaltia d´Alzheimer o la de Parkinson entre d´altres. Així doncs, la determinació i comprensió de les diferents rutes senyalitzadores pro-apoptòtiques involucrades en aquestes malalties permetrà identificar noves dianes terapèutiques.L´objectiu d´aquesta tesi doctoral ha estat estudiar el paper anti-apoptòtic en neurones granulars de cerebel (CGNs) dels inhibidors de dos proteïnes cinases: la Glycogen Sinthase Kinase-3beta (GSK-3beta) i la c-Jun NH2-terminal Kinase (JNK), i determinar per quines rutes senyalitzadores protegeixen a les neurones de la mort apoptòtica provocada per la deprivació de sèrum i potassi (DV S/K). El model escollit per realitzar aquests estudis ha estat la DV S/K en cultius primaris de CGNs, ja que permet reproduir in vitro la mort neuronal programada provocada per la deprivació de factors tròfics.En quant a la GSK-3beta s´ha demostrat que la seva inhibició protegeix de la mort induïda per la DV S/K i que aquesta protecció ve donada, com a mínim, per dos mecanismes no descrits prèviament. En primer lloc s´ha determinat que la GSK-3beta intervé en l'activació anòmala del cicle cel.lular, fet que en CGNs condueix a l'activació de l'apoptosi, i en segon lloc que la GSK-3beta intervé en l'alliberament desde els mitocondris de la proteína pro-apoptòtica AIF. En quant a la JNK també s'ha detectat que la seva inhibició protegeix d'aquest estímul apoptòtic i que una de les raons subjacents a aquest fet, és que la inhibició de la JNK manté activa la via de supervivència de l'AKT.La conclusió final d'aquesta tesi doctoral és que tant la GSK-3beta com la JNK tenen un paper clau en l'activació de l'apoptosi en neurones i que per aquest motiu podrien ser considerades potencials dianes farmacològiques per tractar malalties neurodegeneratives.

Human apolipoprotein L1 (ApoL1) possesses both extra- and intra-cellular functions crucial in host defense and cellular homeostatic mechanisms. Alterations in ApoL1 function due to genetic, environmental, and lifestyle factors have been associated with African sleeping sickness, atherosclerosis, lipid disorders, obesity, schizophrenia, cancer, and chronic kidney disease (CKD). Importantly, two alleles of APOL1 carrying three coding-sequence variants have been linked to CKD, particularly in Sub-Saharan Africans and African Americans. Intracellularly, elevated ApoL1 can induce autophagy and autophagy-associated cell death, which may be critical in the maintenance of cellular homeostasis in the kidney. Similarly, ApoL1 may protect kidney cells against renal cell carcinoma (RCC). We summarize the role of ApoL1 in RCC and CKD, highlighting the critical function of ApoL1 in autophagy.

[cat] La isquèmia/reperfusió (IR) intestinal és una patologia clínica amb una elevada mortalitat del 70% que no ha disminuït durant dècades. La IR intestinal succeeix quan hi ha una disminució o una reducció total del flux sanguini cap a l’intestí, seguida pel restabliment d’aquest flux o reperfusió. Aquesta situació pot succeir per diferents causes, entre elles per trombosi, aneurismes o diverses intervencions quirúrgiques, essent la més característica el transplantament intestinal. El procés d’isquèmia/reperfusió provoca alteracions en el metabolisme cel•lular, entre elles el pas de metabolisme aeròbic a anaeròbic i la conseqüent formació de radicals lliures de l’oxigen (ROS). A més, en els neutròfils, s’ha descrit que una IR provoca un retard en la seva mort cel•lular programada o apoptosi, tot i que en el cas concret de la IR intestinal aquesta situació no ha estat descrita. Una correcta apoptosi dels neutròfisl permet que el seu contingut tòxic intracel•lular no provoqui danys en els teixits circumdants, doncs aquestes restes són fagocitades pels macròfags, comportant una millora de la inflamació. Un retard en l’apoptosi condueix a un augment dels ROS y a la incorrecta resolució de la inflamació degut a l’alteració dels mecanismes fagocítics. L’objectiu del nostre estudi és aconseguir una millora o reducció de la inflamació associada a la IR intestinal mitjançant la modulació del retard de l’apoptosi del neutròfil. Per a aquest fi s’han realitzat experiments en models animals de rata (soques Sprague Dowley i Brown Norway) a les que se’ls hi ha realitzat una IR intestinal mitjançant el clampatge de l’artèria mesentèrica. Per a la modulació de l’apoptosi dels neutròfils es va administrar intravenosament Escherichia coli morta i opsonitzada. El mecanisme apoptòtic dels neutròfils s’ha estudiat amb un model anòxic in vitro amb la línia cel•lular MPRO clon 2.1. Aquesta línia cel•lular és capaç de diferenciar-se a neutròfils madurs en presència de factor de creixement (GM-CSF) i àcid retinòic. Els resultats obtinguts en aquest treball demostren que l’apoptosi dels neutròfils es troba retardada després d’una IR intestinal, i que la modulació d’aquesta apoptosi és capaç de millorar el dany associat. La disminució de l’oxigen provoca l’estabilització del Factor Induïble per la Hipòxia (HIF) en els neutròfils, el que porta a una disminució de la via de senyalització WNT i del seu gen diana 24p3, provocant el retard en l’apoptosi d’aquestes cèl•lules., [eng] Intestinal ischemia/reperfusion (IR) injury is a clinical pathology with a high mortality rate that has not diminished through decades. Intestinal IR occurs when there is a blood flow diminution or total reduction through the intestine, followed by the restoration of this flow or reperfusion. This situation can happen because of many causes, between them, thrombosis, aneurisms or different surgical interventions, being the most characteristic of them intestinal transplantation. Ischemia/reperfusion process provokes alterations in the cellular metabolism, between them, the transition from aerobic metabolism to anaerobic and the consequent formation of Reactive Oxygen Species (ROS). Furthermore, in neutrophils, it has been described that IR provokes a delay in their apoptosis, although it has not been described in the intestine yet. A delay in neutrophil apoptosis drives to an increase of ROS and the incorrect resolution of the inflammation because the phagocytic mechanisms are altered. On the contrary, correct neutrophil apoptosis avoids the possibility of damaging the surrounding tissue because their citotoxic content is phagocytosed by macrophages, driving to an amelioration of the inflammation The aim of our work is to obtain an improvement or a reduction of the intestinal IR associated inflammation through the modulation of the neutrophil apoptosis delay. For this end, experiments were conducted in rats (Sprague Dowley and Brown Norway), and the intestinal IR was provoked through the obstruction of the mesenteric artery with ac clamp. For the neutrophil apoptosis modulation, death and opsonized Escherichia coli were intravenously administered. Neutrophil apoptotic mechanism was studied in an in vitro anoxic model (MPRO clon 2.1 cellular line). This cellular line is able to differentiate into mature neutrophils in presence of growth factor (GM-CSF) and retinoic acid. The results obtained in this work demonstrate that neutrophil apoptosis is delayed after an intestinal IR, and that the modulation of this apoptosis is able to ameliorate the associated injury. The decrease of oxygen provokes the stabilization of the Hypoxia Inducible Factor (HIF) in neutrophils, what drives to a decrease in the WNT signaling pathway and its target gene 24p3, provoking a delay in the apoptosis of these cells.

p21WAF1/Cip1 belongs to the Cip/Kip family of cyclin kinase inhibitors (CKI) (p21Waf1/Cip1, p27Kip1, p57Kip1). p21Waf1/Cip1 was first described as a potent and universal inhibitor of cyclin-dependent kinases (Cdks). Two forms of functionally active p21 has been localized and described: a nuclear and a cytoplasmic forms. In this paper the structures of p21 has been described and as well as it functional biology in terms of differentiation, proliferation and apoptotic activities. The upregulation of p21 by p53-dependent and p53-independent mechanisms is also described., peer-reviewed

Many people are studying how autophagy intersects with cell death. While most of those studies relate to autophagy acting as a protective mechanism (e.g., to block apoptosis), many papers conclude that autophagy is a death mechanism, and there is a widespread belief that autophagy (in most, but not all cases, we are talking about macroautophagy) can both kill and protect cells depending on the circumstances. Not surprisingly therefore, many of the papers submitted to Autophagy study the relationship between autophagy and cell death.

L´apoptosi, o mort cel.lular programada, és un procés actiu que mobilitza els recursos cel.lulars amb l´objectiu de mantenir l´homeostasi de l´organisme a expenses del suïcidi de cèl.lules individuals. Diferents estudis han mostrat un increment de l´activiat d´algunes cdk, especialment Cdk1 i Cdk2, en correlació amb la progressió dels primers estadis apoptòtics. En el nostre laboratori l´estudi de l´apoptosi en timòcits, els quals no tenen una activitat cdk significativa degut a l´aturada del cicle cel.lular en G1, demostren que la inducció de l´activitat de Cdk2 després del tractament amb radiació gamma o amb glucocorticoides és necessària per l´inici de l´apoptosi. Mentre cap de les ciclines conegudes sembla ser la proteïna activadora de Cdk2 en apoptosi, en el nostre laboratori hem identificat un nou membre de la família de les ciclines, denominada Ciclina O, capaç d´activar aquesta kinasa in vivo en línies cel.lulars. L´expressió d´aquesta nova ciclina en el timus, i altres teixits, s´indueix ràpidament després del tractament amb radiació gamma i coincideix amb l´aparició de l´apoptosi. Aquests resultats posicionen la Ciclina O com a millor candidat a ser l´activador de Cdk2 necessari per induïr la mort cel.lular programada en el timus, i probablement també en altres òrgans., The apoptosis, also called programmed cell death, is an active process able to use the cellular mechanisms to kill individual cells in order to keep the functional homeostasis of the whole organism. Different studies had shown a correlation between the first apoptotic events and the induction of some cdk proteins, particularly Cdk1 and Cdk2. The studies of thymocytes in our laboratory, wich lacks the most amount of cdk activity related to the cell cycle because of its arrest in G1, had shown that the induction of Cdk2 activity after the treatment with gamma radiation or glucocorticoids is a necessary step for the apoptosis induction. While any of the cyclins described at the moment seems to be the Cdk2 activator for apoptosis a new member of the cyclin family able to activate the kinase Cdk2 in vivo in cell lines has been identified in our laboratory. The expresion of this cyclin, known as Cyclin O, is quickly induced in the thymus after the treatment with gamma radiation and correlates with the induction of apoptosis. These results position Cyclin O as the best candidate to activate Cdk2 and inuce the programmed cell death in the thymus, and probably other tissues.

Cardiac remodeling is generally accepted as a determinant of the clinical course of heart failure (HF). Defined as genome expression resulting in molecular, cellular and interstitial changes and manifested clinically as changes in size, shape and function of the heart resulting from cardiac load or injury, cardiac remodeling is influenced by hemodynamic load, neurohormonal activation and other factors still under investigation. Although patients with major remodeling demonstrate progressive worsening of cardiac function, slowing or reversing remodeling has only recently become a goal of HF therapy. Mechanisms other than remodeling can also influence the course of heart disease, and disease progression may occur in other ways in the absence of cardiac remodeling. Left ventricular end-diastolic and end-systolic volume and ejection fraction data provide support for the beneficial effects of therapeutic agents such as angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents on the remodeling process. These agents also provide benefits in terms of morbidity and mortality. Although measurement of ejection fraction can reliably guide initiation of treatment in HF, opinions differ regarding the value of ejection fraction data in guiding ongoing therapy. The role of echocardiography or radionuclide imaging in the management and monitoring of HF is as yet unclear. To fully appreciate the potential benefits of HF therapies, clinicians should understand the relationship between remodeling and HF progression. Their patients may then, in turn, acquire an improved understanding of their disease and the treatments they are given.