Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria.

Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.

[Infection of the pacific saury Cololabis saira by acanthocephalans in the Kuril Islands area].

The Pacific saury Cololabis saira (Brevoort, 1856) is one of the important target species of commercial fisheries. Food manufacturers and consumers encounter problems due to the infection of the saury by acanthocephalans, which are quite difficult to clean out completely during on-board catch processing. Infection of C. saira was not studied on a regular basis, therefore, our knowledge about the parasites of saury is fragmentary. This paper contains infection indices (only acanthocephalans) of the Pacific saury caught in the Kuril Islands area (Russian Exclusive Economic Zone) in 2015.

[Ruptured sinus of Valsalva aneurysm and pregnancy: what anesthetic technique should be preferred for a scheduled cesarean section?]. / Aneurisma del seno de Valsalva roto y gestación. Qué técnica anestésica es preferible para una cesárea electiva?

Sinus of Valsalva aneurysm is a rare cardiac abnormality rupture the right sinus and if ruptured open into the right ventricle or atrium. Usually silent, may cause significant hemodynamic changes. Few cases of ruptured Valsalva sinus aneurysm have been reported in the literature, and the course of this condition during pregnancy and anesthetic management have scarcely been mentioned. We report the case of a primipara with a Valsalva sinus aneurysm that ruptured into the right ventricle. Cardiac function worsened as pregnancy progressed. A cesarean section under spinal anesthesia was scheduled.

Aneurisma del seno de Valsalva roto y gestación. ¿Qué técnica anestésica es preferible para una cesárea electiva? / Ruptured sinus of valsalva aneurysm and pregnancy: what anesthetic technique should be preferred for a scheduled cesarean section?

El aneurisma de seno de Valsalva es una anomalíacardiaca infrecuente. En la mayoría de los casos dependedel seno derecho y si se rompe lo hace al ventrículo oaurícula derechos. Este evento suele ser silente aunqueen algunos casos puede provocar alteraciones hemodinámicasrelevantes. Hay pocos casos documentados derotura de seno de Valsalva. La evolución durante la gestacióny el manejo anestésico apenas aparecen en la literatura.Presentamos el caso de una primípara con unaneurisma de seno de Valsalva roto al ventrículo derechocon empeoramiento clínico de su cardiopatía con elavance de la gestación. Se decidió finalizar el embarazomediante cesárea electiva con anestesia intradural(AU)

Sinus of Valsalva aneurysm is a rare cardiacabnormality rupture the right sinus and if rupturedopen into the right ventricle or atrium. Usually silent,may cause significant hemodynamic changes. Few casesof ruptured Valsalva sinus aneurysm have been reportedin the literature, and the course of this condition duringpregnancy and anesthetic management have scarcelybeen mentioned. We report the case of a primipara witha Valsalva sinus aneurysm that ruptured into the rightventricle. Cardiac function worsened as pregnancyprogressed. A cesarean section under spinal anesthesiawas scheduled(AU)

Differences between molecular mechanisms involved in the regulation of haptoglobin gene expression during the acute phase response and dietary restriction.

Haptoglobin is a glycoprotein involved in the acute phase response. Previously we reported that haptoglobin gene expression was up-regulated during dietary restriction in young female rats. The present study aimed at determining whether chronic dietary restriction affects haptoglobin blood levels through changing levels and/or activities of IL-6-related transcription factors STAT and C/EBP in the liver as is the case during the acute phase response. To this end, we compared a female Wistar rat model of 50% 6-week-long dietary restriction with the standard laboratory model for the acute phase response induced by turpentine administration. During the turpentine-induced acute phase response, the transitory 5.4-fold increase of rat haptoglobin expression was accompanied by a prominent rise of serum IL-6 concentration and the increased binding of STAT3 and 35kD C/EBPbeta/LAP transcription factors to the haptoglobin gene hormone-responsive element. Results obtained after immunoblotting and DNA affinity chromatography (using hormone-responsive element) suggest that the stable 1.7-fold increase of serum haptoglobin level during dietary restriction was the result of increased amounts and activities of constitutive transcription factors C/EBPalpha and STAT5b, and to a smaller extent of STAT3. When dietary restriction rats were administered turpentine, a 8.7-fold increase in haptoglobin expression was followed by a considerable increase in the amount and hormone-responsive element binding activity of STAT3 but not 35kD C/EBPbeta/LAP. We concluded that haptoglobin gene up-regulation during chronic dietary restriction was regulated by different mechanisms than during the acute phase response, and that it depended on the amount(s) and activit(ies) of transcription factor(s) that characterize low-grade inflammatory conditions.

Acute-phase related binding ability of p53 for the hormone response element of the haptoglobin gene in adult rats.

Interaction between transcription factor p53 and the hormone response element (HRE) of the haptoglobin (Hp) gene in adult rat liver was studied. We detected a sequence homologous to the p53 consensus DNA-binding site in the regulatory promoter element of the Hp gene. DNA-affinity chromatography, followed by Western immunoblot analysis with an antibody to p53 indicated that components of the nuclear extract possessed the same antigen determinants as p53. While p53 was identified in both control and acute-phase (AP) samples, DNA-binding affinity for the Hp gene HRE was detected only in the nuclear extract prepared from rats undergoing the AP response. Whether either as an inducible or as a constitutive transcription factor, p53 could be involved in the transcriptional regulation of the Hp gene in adult rat liver.

The effect of O-glcnac glycosylation of rat liver nucleoproteins on their acute phase-dependent binding ability to the hormone responsive element of the haptoglobin gene.

We examined whether the transcriptional activation of the rat haptoglobin (Hp) gene during the acute phase (AP) response reflects the O-linked N-acetylglucosamine (O-GlcNAc) status of liver nucleoproteins (NPs) and their binding for the hormone responsive element (HRE). After deglycosylation with N-acetylglucosaminidase of the O-GlcNAc glycoproteins obtained by WGA, affinity chromatography and South-Western analysis, it was observed that only increased HRE binding ability of p64/p70 in control and p51 obtained from turpentine-treated rats can be directly attributed to the presence of O-GlcNAc residues. Therefore, expression of the rat Hp gene could be controlled by this modification of certain trans-acting NPs.

Expression of the rat liver haptoglobin gene is mediated by isoforms of C/EBPalpha, -beta and -delta proteins.

CCAAT/enhancer binding proteins (C/EBP) alpha, -beta and -delta play an important role in mediating I interleukin-6 (IL-6) dependent expression of acute-phase protein (APP) genes in liver during acute-phase (AP) response. Based on the presence of type IL-6 responsive element (IL-6 RE) in the rat haptoglobin (Hp) gene promoter we assumed that some C/EBPalpha, -beta and/or -delta isoforms could mediate the expression of this gene during turpentine-induced AP response. By Western immunoblot and Northern blot assays, we found that turpentine treatment of rats led to a coordinate induction of C/EBPbeta and -delta as well as repression of C/EBPalpha isoforms pool levels in rat liver nuclear extracts (NEs) which was preceded by an adequate alteration of their mRNAs expression in liver. Consequently, results of DNA affinity chromatography revealed that affinity of certain C/EBPalpha isoforms to bind the type I IL-6 RE within the rat Hp gene promoter decreased whereas affinities of certain C/EBPbeta isoforms and C/EBPdelta were increased and induced, respectively. Our data suggest that turpentine-induced alterations of C/EBPalpha, -beta and -delta pool levels and DNA-binding activities can be regarded as an integral part of activation of the Hp gene expression in the course of AP response.

Autonomic neuropathy in end-stage cirrhotic patients and evolution after liver transplantation.

Autonomic neuropathy (AN), which is frequently observed in cirrhosis patients, has been associated with a higher mortality. We have prospectively evaluated the prevalence of AN, its relationship with the degree of liver dysfunction and circulatory disturbances, and the evolution of AN after liver transplantation (LT) in 62 end-stage liver cirrhosis patients. AN was evaluated by seven cardiovascular tests assessing sympathetic or parasympathetic function before and 6 months after LT. Patients were classified as showing absent (A), early (E), or definite dysfunction (D). AN appeared in 67.7% of cases (E: 24.2%, D: 43.5%) without relation to liver disease etiology. Parasympathetic dysfunction was more prevalent than sympathetic dysfunction (59.7% vs. 20.9%). AN was significantly related to Child-Pugh score. Hyperdynamic circulation was more marked in the D than the A group as shown by a greater cardiac output (CO)(9 vs. 7.3 L/min) and a lower peripheral resistance (SVR)(666 vs. 866 dyn.s.cm(-5)). Moreover, AN scores significantly correlated with CO and SVR. Overall the prevalence of AN decreased 6 months after LT (67.7% vs 48%) due to a significant reduction in definite AN (43.5 vs. 14.8%; P<.05). AN improved in 70% of cases after LT. Sympathetic dysfunction remained in only one patient. We conclude that AN is frequent in liver transplant candidates; its severity is associated with the degree of liver failure. Systemic circulatory disturbances seem to correlate with the severity of AN. AN is clearly improved by LT. The evaluation of AN may contribute to a better selection of LT recipients.

DNA binding activity of C/EBPbeta and C/EBPdelta for the rat alpha2-macroglobulin gene promoter is regulated in an acute-phase dependent manner.

Turpentine-induced acute-phase (AP) response in rats is followed by transcriptional activation of the alpha2-macroglobulin (MG) gene mediated by cytokine interleukin-6 (IL-6) and glucocorticoids. Based on nucleotide sequence analysis of the alpha2-MG gene promoter regions responsive to IL-6, we postulated that binding of members of the liver-enriched CCAAT-enhancer-binding proteins (C/EBP) family of transcription factors to the type I IL-6 responsive element (IL-6RE) may participate in the transcriptional activation of this gene during AP response. Results of Western immunoblot and Northern-blot assays revealed coordinate changes in the pool levels of C/EBPalpha, -beta. and -delta protein isoforms and their genes expression in liver in response to turpentine. By means of an in vitro phosphorylation assay, South-Western blot, and selective proteolysis we have also found that only abilities of 35-kD C/EBPbeta and 27-kD C/EBPdelta to bind to the alpha2-MG gene promoter were affected by phosphorylation. Based on these data we concluded that transcriptional induction of the rat alpha2-MG gene during AP response correlates with both increased synthesis and phosphorylation-induced binding of 35-kD C/EBPbeta and 27-kD C/EBPdelta.

Opposite nuclear level and binding activity of STAT5B and STAT3 proteins with rat haptoglobin gene under normal and turpentine induced acute phase conditions.

Transcription of the rat gene encoding haptoglobin (Hp) is highly induced during acute phase (AP) response which has been previously shown to be mediated by inducible STAT3 member of the Signal Transducer and Activators of Transcription (STATs) family proteins. In this study, we observed that under normal but not in the turpentine induced AP conditions, another member of the STAT family proteins, STAT5b is expressed and binds to the hormone regulatory element (HRE) of the rat Hp gene. We found that the nuclear amounts of constitutively active STAT5b in rat liver decreased significantly with time of turpentine treatment as opposed to that of cytosol STAT5b, suggesting possible export of constitutive STAT5b from the nucleus. Nuclear accumulation and binding of inducible STAT3 proteins to the rat Hp gene HRE following turpentine treatment implicated that STAT5b negatively regulates Hp gene expression during normal conditions.

HMG-1 as regulatory trans-acting protein in the acute phase-induced expression of the rat liver haptoglobin gene.

Expression of the haptoglobin (Hp) gene is liver specific and acute phase (AP) responsive. It was previously shown that transcriptional induction process of the rat Hp gene during turpentine induced AP response has been mediated by the liver nucleoprotein p29 which was shown to be homologous to the HMG-1 chromatin-associated protein. The results presented in this report offered further evidence for the existence of structural and functional similarities between these two proteins implicating an involvement of HMG-1 in the regulation of the rat Hp gene transcription. By DNA binding assays we found the HMG-1 binding sites in the rat Hp gene cis-regulatory subelements A and C and revealed an increase in its DNA-binding after induction of AP response. In view of our previous and here shown data we assume that this increase could be a consequence of AP-induced release of HMG-1 from the chromatin and subsequent increase in its nuclear amount.

STAT3 involvement in the acute phase-related expression of the rat haptoglobin gene.

Turpentine-induced acute-phase (AP) response in rats is followed by transcriptional activation of the haptoglobin (Hp) gene in liver. Analysing the promoter sequence of the rat Hp gene we postulated an involvement of Signal Transducer and Activator of Transcription 3 (STAT3) in the regulation of this process. Results obtained by using a combination of Western immunoblot and DNA-binding assays revealed AP-induced binding of constitutive 86kD-and inducible 91kD-STAT3 isoforms to the rat Hp gene inducible promoter element. On the basis of these data we assumed that AP-related interactions of these two STAT3 isoforms correlates with an activated transcriptional status of the rat Hp gene.

Acute-phase induced phosphorylation of rat liver nucleoprotein p70 modulates its binding affinity for the haptoglobin gene.

An increase in the binding affinity of rat liver trans-acting nucleoprotein p70 for the hormone responsive element of the rat haptoglobin gene in acute-phase reactions has implicated a posttranslational modification. This investigation examines the proposed acute-phase related structural alterations of p70 using an in vitro phosphorylation/dephosphorylation assay and selective digestion of p70 with Staphylococcal aureus V8 protease. The results show that p70 requires phosphorylation to express its DNA-binding ability. Selective proteolysis of p70 provided evidence that acute-phase induced phosphorylation of this protein alters its conformation in such a way that its DNA-binding ability is increased.

Participation of two isoforms of C/EBPbeta transcription factor in the acute-phase regulation of the rat haptoglobin gene.

Previous analyses of the mechanism of the transcriptional induction of the rat haptoglobin (Hp) gene during acute-phase (AP)-reaction have revealed the involvement of several trans-acting nucleoproteins (NPs) in controlling this process. In this study, by using antibodies against C/EBPbeta factor in Western immunoblot assay, we found that rat liver trans-acting NPs p35 and p20 are two characteristic C/EBPbeta isoforms whose expression is induced under AP-conditions. DNA-binding assays identified the binding sites for these two C/EBPbeta proteins in the functionally defined elements A and C of the rat Hp gene and also revealed that they have specific binding affinity towards these elements. Under non-induced conditions, p35 was the only C/EBPbeta binding factor; however, upon AP-conditions both, 35 kDa- and 20 kDa-C/EBPbeta binding activities were significantly induced suggesting that these interactions are necessary for the activation of the Hp gene. By in vitro phosphorylation assay and selective proteolysis, we also present evidence that p35 requires phosphorylation for its DNA binding ability. Thus, we conclude that increase in binding of C/EBPbeta isoforms during AP-reaction occurs through their upregulation and structural modification.

Structural and functional homology between the 29 kD rat liver nucleoprotein and the high mobility group 1 protein.

A 29 kD soluble rat liver nucleoprotein (p29) has increased binding affinity for the hormone responsive element (RE) of the rat haptoglobin (Hp) gene during the acute-phase reaction. In this work the possibility of its structural and functional homology to the high mobility group 1 (HMG1) nonhistone protein constituent of chromatin was examined. The results of two-dimensional gel electrophoresis, Southwestern and Western immunoblot analyses, showed that p29 and HMG1 are homologous protein species. On the basis of in vitro and in vivo phosphorylation/dephosphorylation experiments, we discuss the modulatory role of phosphate groups in view of the structure and function of p29.

The DNA binding affinity of rat liver nucleoproteins to the regulatory elements of the haptoglobin and alpha 2-macroglobulin genes.

Transcriptional regulation and binding interactions between soluble nucleoproteins and the hormone response elements (REs) of the rat haptoglobin (Hp) and alpha 2-macroglobulin (alpha 2MG) genes was examined in the livers of rats during the acute-phase reaction. Our results demonstrate that the elevation of the Hp and alpha 2MG genes' transcription rates in acute-phase liver relies essentially on an increase in the binding-affinity of pre-existing soluble nucleoproteins, enhancing their capability to bind the examined cis-regulatory elements. The 35kD nucleoprotein that displayed an acute-phase inducible affinity to bind hormone REs of rat Hp and alpha 2MG genes, was identified as a C/EBP beta isoform.

Acute phase-dependent changes in the binding of rat liver nucleoproteins to the cytokine response element of the rat haptoglobin gene.

Hormones released during the acute phase reaction promote the transcriptional activation of the haptoglobin (Hp) gene and a consequent increase of Hp protein synthesis in the liver. The mechanisms underlying the alterations of basal transcription rates of eukaryotic genes are assumed to result from modulations of the binding affinities between nucleoproteins and specific DNA sequences in the enhancer and promoter elements. In order to characterize the changes in the interaction of nucleoproteins with the promoter that accompany the induction of the Hp gene, nuclear extracts from normal and inflamed livers were probed with hormone responsive element (HRE) of the rat Hp gene by gel mobility shift and Southwestern assays. Each of the three cis-acting sequences of the HRE, elements A, B, and C, recognized a distinct set of proteins. Together they conferred an additional level of specificity to the protein binding sites of the entire ABC-element. These sites were recognized by proteins in liver nuclear extracts isolated from both control and treated rats. The differences in the gel shift and Southwestern patterns of the corresponding DNA-protein complexes suggested that transcriptional activation of the Hp gene relied on changes in the concentrations and/or functional modifications of preexisting proteins rather than on the induction of new trans-acting factors.

Lidar measurement of atmospheric aerosol extinction profiles: a comparison between two techniques-Klett inversion and pure rotational Raman scattering methods.

Two lidar methods of determining an atmospheric extinction coefficient profile are compared. The methods are the Klett inversion method for elastic lidar return and the log-derivative method for rotational Raman backscattered signal processing. The comparison includes numerical modeling and processing of lidar measurements when both the elastic and the rotational Raman backscattered signals are measured simultaneously. The suggested idea is that such a comparison can be used as a criterion for the reliability of the results of lidar measurements, similar to the comparison between the results of lidar and contact measurements.