PPARs in Regulation of Paraoxonases: Control of Oxidative Stress and Inflammation Pathways

The paraoxonase (PON) group of enzymes, composed of PON1, PON2, and PON3, play an important role in decreasing oxidative stress by degrading lipid peroxides. PON1 synthesis is upregulated by PPAR. Several pharmacological compounds (acting as antioxidants and, hence, atheroprotective) stimulate both PPAR activity and PON1 expression. Recent evidence suggests that PON1 and the monocyte chemoattractant protein-1 (MCP-1) are involved in coordinating the inflammatory response in damaged tissues; PPAR may be central in the regulation of these biochemical pathways. This article reviews the state of knowledge on PON1 biochemistry and function, the influence of genetic variation, and the regulation of PON1 expression by pharmaceutical compounds that increase PPAR activity. We also describe recent lines of evidence suggesting links between PON1 and MCP-1 and how their production may be regulated by PPAR

The Level of DING Proteins Is Increased in HIV-Infected Patients: In Vitro and In Vivo Studies

DING proteins constitute an interesting family, owing to their intriguing and important activities. However, after a decade of research, little is known about these proteins. In humans, at least five different DING proteins have been identified, which were implicated in important biological processes and diseases, including HIV. Indeed, recent data from different research groups have highlighted the anti-HIV activity of some DING representatives. These proteins share the ability to inhibit the transcriptional step of HIV-1, a key step of the viral cycle that is not yet targeted by the current therapies. Since such proteins have been isolated from humans, we undertook a comprehensive study that focuses on the relationship between these proteins and HIV-infection in an infectious context. Hence, we developed a home-made ELISA for the quantification of the concentration of DING proteins in human serum. Using this method, we were able to determine the concentration of DING proteins in healthy and HIV-infected patients. Interestingly, we observed a significant increase of the concentration of DING proteins in non treated and treated HIV-infected patients compared to controls. In addition, cell cultures infected with HIV also show an increased expression of DING proteins, ruling out the possible role of antiretroviral treatment in the increase of the expression of DING proteins. In conclusion, results from this study show that the organism reacts to HIV-infection by an overexpression of DING proteins

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

The Effects of Aging on Male Mouse Pancreatic β-Cell Function Involve Multiple Events in the Regulation of Secretion: Influence of Insulin Sensitivity

Aging is associated with a decline in peripheral insulin sensitivity and an increased risk of impaired glucose tolerance and type 2 diabetes. During conditions of reduced insulin sensitivity, pancreatic β-cells undergo adaptive responses to increase insulin secretion and maintain euglycemia. However, the existence and nature of β-cell adaptations and/or alterations during aging are still a matter of debate. In this study, we investigated the effects of aging on β-cell function from control (3-month-old) and aged (20-month-old) mice. Aged animals were further categorized in two groups: high insulin sensitive (aged-HIS) and low insulin sensitive (aged-LIS). Aged-LIS mice were hyperinsulinemic, glucose intolerant and displayed impaired glucose-stimulated insulin and C-peptide secretion, whereas aged-HIS animals showed characteristics in glucose homeostasis similar to controls. In isolated β-cells, we observed that glucose-induced inhibition of KATP channel activity was reduced with aging, particularly in the aged-LIS group. Glucose-induced islet NAD(P)H production was decreased in aged mice, suggesting impaired mitochondrial function. In contrast, voltage-gated Ca 2+ currents were higher in aged-LIS β-cells, and pancreatic islets of both aged groups displayed increased glucose-induced Ca 2+ signaling and augmented insulin secretion compared with controls. Morphological analysis of pancreas sections also revealed augmented β-cell mass with aging, especially in the aged-LIS group, as well as ultrastructural β-cell changes. Altogether, these findings indicate that aged mouse β-cells compensate for the aging-induced alterations in the stimulus-secretion coupling, particularly by adjusting their Ca 2+ influx to ensure insulin secretion. These results also suggest that decreased peripheral insulin sensitivity exacerbates the effects of aging on β-cells.This research was supported by grants from the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación, Fondo Europeo de Desarrollo Regional (FEDER) and Generalitat Valenciana (BFU2017-86579-R and PROMETEO/2020/006 to AN and BFU2016-77125-R to IQ) and from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant No. 304388/2020-3 to AR) and the Programa Institucional de Internacionalização from the Coordenação de Aperfeiçoamento de pessoal de Nível Superior (CAPES). CIBERDEM is an initiative of the Instituto de Salud Carlos III

Lynch-like Syndrome: Potential Mechanisms and Management

Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. It is the most common hereditary colorectal cancer syndrome. Screening is regularly performed by using microsatellite instability (MSI) or immunohistochemistry for the MMR proteins in tumor samples. However, in a proportion of cases, MSI is found or MMR immunohistochemistry is impaired in the absence of a germline mutation in MMR genes, BRAF mutation, or MLH1 hypermethylation. These cases are defined as Lynch-like syndrome. Patients with Lynch-like syndrome represent a mixture of truly hereditary and sporadic cases, with a risk of colorectal cancer in first-degree relatives that is between the risk of Lynch syndrome in families and relatives of sporadic colon cancer cases. Although multiple approaches have been suggested to distinguish between hereditary and sporadic cases, a homogeneous testing protocol and consensus on the adequate classification of these patients is still lacking. For this reason, management of Lynch-like syndrome and prevention of cancer in these families is clinically challenging. This review explains the concept of Lynch-like syndrome, potential mechanisms for its development, and methods for adequately distinguishing between sporadic and hereditary cases of this entity

Patrimonio Arqueológico del Área de Influencia del Corredor Bioceánico (Ejes Quebrada de Agua Negra y Rodeo/Las Flores/Tocota)

Teniendo en consideración el eventual desarrollo de los espacios directamente vinculados con el Corredor Bioceánico en el noroeste de la provincia de San Juan y el consecuente impacto que tal avance podría tener sobre los recursos arqueológicos del área, urge identificar los núcleos de recursos patrimoniales más expuestos o susceptibles de un aprovechamiento organizado e intensivo. Por un lado, este requerimiento enfrenta al problema de saber qué espacios cercanos al Corredor son de libre disponibilidad y en qué otros existen limitaciones emanadas de la presencia de recursos arqueológicos. Por otra parte, es imprescindible prever el futuro manejo de determinados espacios y recursos en el marco de ofertas de turismo cultural, lo que conlleva la necesidad de organizar los pasos que lleven a posibilitar el uso eficiente de los mismos (generación de información, elaboración de planes de manejo en condiciones controladas, participación de las comunidades locales, etc.). Los recursos arqueológicos constituyen uno de los principales componentes del patrimonio cultural de la región. Por su gran abundancia representan también uno de los elementos más vulnerables ante el avance del accionar del hombre. En vista de lo anterior, se realizó un relevamiento no exhaustivo de los recursos arqueológicos regionales destinado a identificar y registrar aquellos sitios que tienen mayores posibilidades de ser afectados directa o indirectamente, a corto o largo plazo, por las obras vinculadas con el Corredor o por el desarrollo de infraestructura de servicio ligada al camino, o de ser incorporados en una futura oferta de prestaciones turísticas relacionadas con los recursos culturales...Fil: García, Eduardo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Nacional de San Juan; Argentina. Universidad Nacional de Cuyo; ArgentinaFil: Damiani, Oscar Antonio. Universidad Nacional de San Juan; ArgentinaFil: Rodriguez, Nadia. Universidad Nacional de San Juan; ArgentinaFil: Rodriguez, Anabel. Universidad Nacional de San Juan; ArgentinaFil: Eguaburo, Ana. Universidad Nacional de San Juan; ArgentinaFil: López, Carlota. Universidad Nacional de San Juan; ArgentinaFil: Riveros, Oscar. Universidad Nacional de San Juan; ArgentinaFil: Heredia, Diego Einar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Nacional de San Juan; ArgentinaFil: Giaconi, Ruben. Universidad Nacional de San Juan; Argentin

Paraoxonase-1 Inhibits Oxidized Low-Density Lipoprotein-Induced Metabolic Alterations and Apoptosis in Endothelial Cells: A Nondirected Metabolomic Study

We studied the influence of PON1 on metabolic alterations induced by oxidized LDL when incubated with endothelial cells. HUVEC cells were incubated with native LDL, oxidized LDL, oxidized LDL plus HDL from wild type mice, and oxidized LDL plus HDL from PON1-deficient mice. Results showed alterations in carbohydrate and phospholipid metabolism and increased apoptosis in cells incubated with oxidized LDL. These changes were partially prevented by wild type mouse HDL, but the effects were less effective with HDL from PON1-deficient mice. Our results suggest that PON1 may play a significant role in endothelial cell survival by protecting cells from alterations in the respiratory chain induced by oxidized LDL. These results extend current knowledge on the protective role of HDL and PON1 against oxidation and apoptosis in endothelial cells

Paraoxonase-1 Inhibits Oxidized Low-Density Lipoprotein-Induced Metabolic Alterations and Apoptosis in Endothelial Cells: A Nondirected Metabolomic Study

We studied the influence of PON1 on metabolic alterations induced by oxidized LDL when incubated with endothelial cells. HUVEC cells were incubated with native LDL, oxidized LDL, oxidized LDL plus HDL from wild type mice, and oxidized LDL plus HDL from PON1-deficient mice. Results showed alterations in carbohydrate and phospholipid metabolism and increased apoptosis in cells incubated with oxidized LDL. These changes were partially prevented by wild type mouse HDL, but the effects were less effective with HDL from PON1-deficient mice. Our results suggest that PON1 may play a significant role in endothelial cell survival by protecting cells from alterations in the respiratory chain induced by oxidized LDL. These results extend current knowledge on the protective role of HDL and PON1 against oxidation and apoptosis in endothelial cells

Galectin-3 in Peripheral Artery Disease. Relationships with Markers of Oxidative Stress and Inflammation

Galectin-3 is a modulator of oxidative stress, inflammation, and fibrogenesis involved in the pathogenesis of vascular diseases. The present study sought to characterize, in patients with peripheral artery disease (PAD), the localization of galectin-3 in arterial tissue, and to analyze the relationships between the circulating levels of galectin-3 and oxidative stress and inflammation. It also sought to compare the diagnostic accuracy of galectin-3 with that of other biochemical markers of this disease. We analyzed femoral or popliteal arteries from 50 PAD patients, and four control arteries. Plasma from 86 patients was compared with that from 72 control subjects. We observed differences in the expression of galectin-3 in normal arteries, and arteries from patients with PAD, with a displacement of the expression from the adventitia to the media, and the intima. In addition, plasma galectin-3 concentration was increased in PAD patients, and correlated with serologic markers of oxidative stress (F2-isoprostanes), and inflammation [chemokine (C−C motif) ligand 2, C-reactive protein, β-2-microglobulin]. We conclude that the determination of galectin-3 has good diagnostic accuracy in the assessment of PAD and compares well with other analytical parameters currently in use