New benzophenone and quercetin galloyl glycosides from Psidium guajava L.

New benzophenone and flavonol galloyl glycosides were isolated from an 80% MeOH extract of Psidium guajava L. (Myrtaceae) together with five known quercetin glycosides. The structures of the novel glycosides were elucidated to be 2,4,6-trihydroxybenzophenone 4-O-(6″-O-galloyl)-β-d-glucopyranoside (1, guavinoside A), 2,4,6-trihydroxy-3,5-dimethylbenzophenone 4-O-(6″-O-galloyl)-β-d-glucopyranoside (2, guavinoside B), and quercetin 3-O-(5″-O-galloyl)-α-l-arabinofuranoside (3, guavinoside C) by NMR, MS, UV, and IR spectroscopies. Isolated phenolic glycosides showed significant inhibitory activities against histamine release from rat peritoneal mast cells, and nitric oxide production from a murine macrophage-like cell line, RAW 264.7

Scaling of cardiac morphology is interrupted by birth in the developing sheep Ovis aries.

Scaling of the heart across development can reveal the degree to which variation in cardiac morphology depends on body mass. In this study, we assessed the scaling of heart mass, left and right ventricular masses, and ventricular mass ratio, as a function of eviscerated body mass across fetal and postnatal development in Horro sheep Ovis aries (~50-fold body mass range; N = 21). Whole hearts were extracted from carcasses, cleaned, dissected into chambers and weighed. We found a biphasic relationship when heart mass was scaled against body mass, with a conspicuous 'breakpoint' around the time of birth, manifest not by a change in the scaling exponent (slope), but rather a jump in the elevation. Fetal heart mass (g) increased with eviscerated body mass (Mb , kg) according to the power equation 4.90 Mb0.88 ± 0.26 (± 95%CI) , whereas postnatal heart mass increased according to 10.0 Mb0.88 ± 0.10 . While the fetal and postnatal scaling exponents are identical (0.88) and reveal a clear dependence of heart mass on body mass, only the postnatal exponent is significantly less than 1.0, indicating the postnatal heart becomes a smaller component of body mass as the body grows, which is a pattern found frequently with postnatal cardiac development among mammals. The rapid doubling in heart mass around the time of birth is independent of any increase in body mass and is consistent with the normalization of wall stress in response to abrupt changes in volume loading and pressure loading at parturition. We discuss variation in scaling patterns of heart mass across development among mammals, and suggest that the variation results from a complex interplay between hard-wired genetics and epigenetic influences

Pulmonary intravascular lymphoma diagnosed by 18-fluorodeoxyglucose positron emission tomography-guided transbronchial lung biopsy in a man with long-term survival: a case report

<p>Abstract</p> <p>Introduction</p> <p>18-Fluorodeoxyglucose positron emission tomography can detect the pulmonary involvement of intravascular lymphoma that presents no abnormality in a computed tomography scan.</p> <p>Case presentation</p> <p>We report the case of a 61-year-old Japanese man who had pulmonary intravascular lymphoma and no computed tomography abnormality. We were able to make an antemortem diagnosis of pulmonary intravascular lymphoma by transbronchial lung biopsy according to 18-fluorodeoxyglucose positron emission tomography findings. He is free of recurrent disease 24 months after chemotherapy.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the first reported case of a long-term survivor of pulmonary intravascular lymphoma diagnosed by transbronchial lung biopsy under the guide of 18-fluorodeoxyglucose positron emission tomography.</p

Different ways to die: cell death modes of the unicellular chlorophyte Dunaliella viridis exposed to various environmental stresses are mediated by the caspase-like activity DEVDase

Programmed cell death is necessary for homeostasis in multicellular organisms and it is also widely recognized to occur in unicellular organisms. However, the mechanisms through which it occurs in unicells, and the enzymes involved within the final response is still the subject of heated debate. It is shown here that exposure of the unicellular microalga Dunaliella viridis to several environmental stresses, induced different cell death morphotypes, depending on the stimulus received. Senescent cells demonstrated classical and unambiguous apoptotic-like characteristics such as chromatin condensation, DNA fragmentation, intact organelles, and blebbing of the cell membrane. Acute heat shock caused general swelling and altered plasma membrane, but the presence of chromatin clusters and DNA strand breaks suggested a necrotic-like event. UV irradiated cells presented changes typical for necrosis, together with apoptotic characteristics resembling an intermediate cell-death phenotype termed aponecrosis-like. Cells subjected to hyperosmotic shock revealed chromatin spotting without DNA fragmentation, and extensive cytoplasmic swelling and vacuolization, comparable to a paraptotic-like cell death phenotype. Nitrogen-starved cells showed pyknosis, blebbing, and cytoplasmic consumption, indicating a similarity to autophagic/vacuolar-like cell death. The caspase-like activity DEVDase was measured by using the fluorescent substrate Ac-DEVD-AMC and antibodies against the human caspase-3 active enzyme cross-reacted with bands, the intensity of which paralleled the activity. All the environmental stresses tested produced a substantial increase in both DEVDase activity and protein levels. The irreversible caspase-3 inhibitor Z-DEVD-FMK completely inhibited the enzymatic activity whereas serine and aspartyl proteases inhibitors did not. These results show that cell death in D. viridis does not conform to a single pattern and that environmental stimuli may produce different types of cell death depending on the type and intensity of the stimulus, all of which help to understand the cell death-dependent and cell death-independent functions of caspase-like proteins. Hence, these data support the theory that alternative, non-apoptotic programmed cell death (PCDs), exist either in parallel or in an independent manner with apoptosis and were already present in single-celled organisms that evolved some 1.2-1.6 billion years ago

Hypoglycemia and the Origin of Hypoxia-Induced Reduction in Human Fetal Growth

The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated.The maternal arterial – venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced.Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia

MEK–ERK-dependent multiple caspase activation by mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma cell death

Recently developed heavy ion irradiation therapy using a carbon beam (CB) against systemic malignancy has numerous advantages. However, the clinical results of CB therapy against glioblastoma still have room for improvement. Therefore, we tried to clarify the molecular mechanism of CB-induced glioma cell death. T98G and U251 human glioblastoma cell lines were irradiated by CB, and caspase-dependent apoptosis was induced in both cell lines in a dose-dependent manner. Knockdown of Bax (BCL-2-associated X protein) and Bak (BCL-2-associated killer) and overexpression of Bcl-2 or Bcl-xl (B-cell lymphoma-extra large) showed the involvement of Bcl-2 family proteins upstream of caspase activation, including caspase-8, in CB-induced glioma cell death. We also detected the activation of extracellular signal-regulated kinase (ERK) and the knockdown of ERK regulator mitogen-activated protein kinase kinase (MEK)1/2 or overexpression of a dominant-negative (DN) ERK inhibited CB-induced glioma cell death upstream of the mitochondria. In addition, application of MEK-specific inhibitors for defined periods showed that the recovery of activation of ERK between 2 and 36 h after irradiation is essential for CB-induced glioma cell death. Furthermore, MEK inhibitors or overexpression of a DN ERK failed to significantly inhibit X-ray-induced T98G and U251 cell death. These results suggested that the MEK–ERK cascade has a crucial role in CB-induced glioma cell death, which is known to have a limited contribution to X-ray-induced glioma cell death

High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response

Abstract The elucidation of mechanisms involved in resistance to therapies is essential to improve the survival of patients with malignant gliomas. A major feature possessed by glioma cells that may aid their ability to survive therapy and reconstitute tumors is the capacity for self-renewal. We show here that glioma stem cells (GSCs) express low levels of MKP1, a dual-specificity phosphatase, which acts as a negative inhibitor of JNK, ERK1/2, and p38 MAPK, while induction of high levels of MKP1 expression are associated with differentiation of GSC. Notably, we find that high levels of MKP1 correlate with a subset of glioblastoma patients with better prognosis and overall increased survival. Gain of expression studies demonstrated that elevated MKP1 impairs self-renewal and induces differentiation of GSCs while reducing tumorigenesis in vivo. Moreover, we identified that MKP1 is epigenetically regulated and that it mediates the anti-tumor activity of histone deacetylase inhibitors (HDACIs) alone or in combination with temozolomide. In summary, this study identifies MKP1 as a key modulator of the interplay between GSC self-renewal and differentiation and provides evidence that the activation of MKP1, through epigenetic regulation, might be a novel therapeutic strategy to overcome therapy resistance in glioblastoma

Mathematical Modelling of Cell-Fate Decision in Response to Death Receptor Engagement

Cytokines such as TNF and FASL can trigger death or survival depending on cell lines and cellular conditions. The mechanistic details of how a cell chooses among these cell fates are still unclear. The understanding of these processes is important since they are altered in many diseases, including cancer and AIDS. Using a discrete modelling formalism, we present a mathematical model of cell fate decision recapitulating and integrating the most consistent facts extracted from the literature. This model provides a generic high-level view of the interplays between NFκB pro-survival pathway, RIP1-dependent necrosis, and the apoptosis pathway in response to death receptor-mediated signals. Wild type simulations demonstrate robust segregation of cellular responses to receptor engagement. Model simulations recapitulate documented phenotypes of protein knockdowns and enable the prediction of the effects of novel knockdowns. In silico experiments simulate the outcomes following ligand removal at different stages, and suggest experimental approaches to further validate and specialise the model for particular cell types. We also propose a reduced conceptual model implementing the logic of the decision process. This analysis gives specific predictions regarding cross-talks between the three pathways, as well as the transient role of RIP1 protein in necrosis, and confirms the phenotypes of novel perturbations. Our wild type and mutant simulations provide novel insights to restore apoptosis in defective cells. The model analysis expands our understanding of how cell fate decision is made. Moreover, our current model can be used to assess contradictory or controversial data from the literature. Ultimately, it constitutes a valuable reasoning tool to delineate novel experiments