Sorafenib is the unique accepted molecular targeted drug for the treatment of patients in advanced stage of hepatocellular carcinoma. The current study evaluated cell signaling regulation of ...endoplasmic reticulum (ER) stress, c‐Jun‐N‐terminal kinase (JNK), Akt, and 5′AMP‐activated protein kinase (AMPK) leading to autophagy and apoptosis induced by sorafenib. Sorafenib induced early (3–12 hr) ER stress characterized by an increase of Ser51P‐eIF2α/eIF2α, C/EBP homologous protein (CHOP), IRE1α, and sXBP1, but a decrease of activating transcription factor 6 expression, overall temporally associated with the increase of Thr183,Tyr185P‐JNK1/2/JNK1/2, Thr172P‐AMPKα, Ser413P‐Foxo3a, Thr308P‐AKt/AKt and Thr32P‐Foxo3a/Foxo3a ratios, and reduction of Ser2481P‐mammalian target of rapamycin (mTOR)/mTOR and protein translation. This pattern was related to a transient increase of tBid, Bim
EL, Beclin‐1, Bcl‐xL, Bcl‐2, autophagy markers, and reduction of myeloid cell leukemia‐1 (Mcl‐1) expression. The progressive increase of CHOP expression, and reduction of Thr308P‐AKt/AKt and Ser473P‐AKt/AKt ratios were associated with the reduction of autophagic flux and an additional upregulation of Bim
EL expression and caspase‐3 activity (24 hr). Small interfering‐RNA (si‐RNA) assays showed that Bim, but not Bak and Bax, was involved in the induction of caspase‐3 in sorafenib‐treated HepG2 cells. Sorafenib increased autophagic and apoptotic markers in tumor‐derived xenograft model. In conclusion, the early sorafenib‐induced ER stress and regulation of JNK and AMPK‐dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK‐CHOP‐dependent rise of Bim
EL, which was associated with the shift from autophagy to apoptosis. The kinetic of Bim
EL expression profile might also be related to the tight balance between AKt‐ and AMPK‐related signaling leading to Foxo3a‐dependent BIM
EL upregulation.
The early sorafenib‐induced endoplasmic reticulum (ER) stress and regulation of JNK and AMPK‐dependent signaling were related to the induction of survival autophagic process. The sustained drug treatment induced a progressive increase of ER stress and PERK‐CHOP‐dependent rise of BimEL, which was associated with the shift from autophagy to apoptosis.
The determination of background pollution levels is fundamental for the interpretation of the results obtained from environmental biomonitoring. In this paper we propose a new probabilistic method, ...based on a Gaussian mixture model, for determining the distribution of regional background levels of different pollutants. The distribution of the reference level is used to categorize the observations as “background” or “above-background” and spatial statistical techniques are then applied to determine the probability of the background level being exceeded. To exemplify its use, we applied the method to concentrations of five potentially toxic elements (Cd, Cu, Hg, Pb and Zn) measured in the moss Pseudoscleropodium purum. The proposed method was applied to data resulting from sampling at ca. 150 sampling stations in a regular grid (15 × 15 km) in Galicia (NW Spain). Sampling was carried out in June in 2000 and 2002, and in March and September in 2004, 2006, 2008 and 2014. The proposed method yielded consistent results for all of the different sampling surveys, and the pollution levels were found to be closely related to the sources of pollution identified in the study region. In short, although not an optimal solution, the proposed method seems to be suitable and realistic for the qualitative assessment of regional pollution.
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•New method for modeling background level distribution based on Gaussian mixtures.•Assignment of sampling stations (SS) to background or above-background distribution.•Qualitative treatment of moss SSs to obtain above-background probability maps.
High-resolution Fourier transform infrared (FTIR) solar observations are particularly relevant for climate studies, as they allow atmospheric gaseous composition and multiple climate processes to be ...monitored in detail. In this context, the present paper provides an overview of 20 years of FTIR measurements taken in the framework of the NDACC (Network for the Detection of Atmospheric Composition Change) from 1999 to 2018 at the subtropical Izaña Observatory (IZO, Spain). Firstly, long-term instrumental performance is comprehensively assessed, corroborating the temporal stability and reliable instrumental characterization of the two FTIR spectrometers installed at IZO since 1999. Then, the time series of all trace gases contributing to NDACC at IZO are presented (i.e. C2H6, CH4, ClONO2, CO, HCl, HCN, H2CO, HF, HNO3, N2O, NO2, NO, O3, carbonyl sulfide (OCS), and water vapour isotopologues H216O, H218O, and HD16O), reviewing the major accomplishments drawn from these observations. In order to examine the quality and long-term consistency of the IZO FTIR observations, a comparison of those NDACC products for which other high-quality measurement techniques are available at IZO has been performed (i.e. CH4, CO, H2O, NO2, N2O, and O3). This quality assessment was carried out on different timescales to examine what temporal signals are captured by the FTIR records, and to what extent. After 20 years of operation, the IZO NDACC FTIR observations have been found to be very consistent and reliable over time, demonstrating great potential for climate research. Long-term NDACC FTIR data sets, such as IZO, are indispensable tools for the investigation of atmospheric composition trends, multi-year phenomena, and complex climate feedback processes, as well as for the validation of past and present space-based missions and chemistry climate models.
Patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT) have a variable 5-year survival rate limited mostly by tumor recurrence. The etiology, age, sex, ...alcohol, Child-Pugh, and the immunesuppressor have been associated with tumour recurrence. The expression of ΔNp73 is related to the reduced survival of patients with HCC. The study evaluated the expression of p63 and p73 isoforms and cell death receptors, and their relation to tumour recurrence and survival. The results were in vitro validated in HCC cell lines.
HCC sections from patients submitted to OLT were used. The in vitro study was done in differentiated hepatitis B virus (HBV)-expressing Hep3B and control HepG2 cells. The expression of cell death receptors and cFLIPS/L, caspase-8 and -3 activities, and cell proliferation were determined in control and p63 and p73 overexpressing HCC cells.
The reduced tumor expression of cell death receptors and TAp63 and TAp73, and increased ΔNp63 and ΔNp73 expression were associated with tumor recurrence and reduced survival. The in vitro study demonstrated that HBV-expressing Hep3B vs HepG2 cells showed reduced expression of p63 and p73, cell death receptors and caspase activation, and increased cFLIPL/cFLIPS ratio. The overexpression of TAp63 and TAp73 exerted a more potent pro-apoptotic and anti-proliferative effects in Hep3B than HepG2-transfected cells which was related to cFLIPL upregulation.
The reduction of TAp63 and TAp73 isoforms, rather than alteration of ΔN isoform expression, exerted a significant functional repercussion on cell death and proliferation in HBV-expressing HepB cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tea polyphenols, especially the catechins, are potent antimicrobial and antioxidant agents, with positive effects on human health. White tea is one of the less studied teas but the flavour is more ...accepted than that of green tea in Europe. The concentrations of various catechins in 13 different kinds of infusion were determined by capillary electrophoresis. The total polyphenol content (Folin–Ciocalteu method), the trolox equivalent antioxidant capacity (TEAC value determined with the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation) and the inhibitory effects of infusions on the growth of some microorganisms were determined. Five different infusions (black, white, green and red teas and rooibos infusion) were added to a model food system, comprising a sunflower oil-in-water emulsion containing 0% or 0.2% bovine serum albumin (BSA), and the oxidative stability was studied during storage at 37
°C. Oxidation of the oil was monitored by determination of the peroxide value.
The highest radical-scavenging activity observed was for the green and white teas. Emulsions containing these extracts from these teas were much more stable during storage when BSA was present than when it was not present, even though BSA itself did not provide an antioxidant effect (at 0.2% concentration). Rooibos infusion did not show the same synergy with BSA. Green tea and white tea showed similar inhibitions of several microorganisms and the magnitude of this was comparable to that of the commercial infusion 2 (C.I.2), “té de la belleza”. This tea also had an antioxidant activity comparable to green tea.
Echinocactus platyacanthus is a Mexican cactus highly tolerant to stressful conditions. In recent years it has been increased evidence that plant microbiome is closely linked to plant physiology. We ...hypothesize that E. platyacanthus responds to environmental changes by altering its physiology, which modifies the bacterial communities in its rhizosphere, especially the abundance of plant growth-promoting bacteria. Physiological changes associated with adult individuals of E. platyacanthus during the rainy and dry seasons were analyzed chlorophyll fluorescence, photosynthetic pigments, nocturnal acidity, water potential, reactive oxygen species, and root exudates (amino acids). Rhizosphere samples were taken to determine the soil's physicochemical properties and bacterial communities. During the dry season, E. platyacanthus makes significant physiological adjustments to respond to the decrease in soil water and nutrient availability, mainly increasing chlorophyll b and carotenoids. The physiological regulation cascade modifies the profile of amino acids exuded by its roots. In turn, the rhizosphere bacterial community changed. Beneficial bacteria to the plant from the phylum Armatimonadota, classes Actinobacteria and Dehalococcoidia, and families Gemmataceae and Nitrosococcaceae, were more abundant in the dry season. Based on a regularized generalized canonical correlation analysis, we showed a model to explain how E. platyacanthus tolerance to the dry season could be conferred by an interaction between its physiological regulatory mechanisms and the symbiotic relationships with soil bacteria mediated through root exudation. Furthermore, this work is the first description of the amino acids exuded by cacti that stimulate the increase in the populations of beneficial bacteria in the rhizosphere.
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•E. platyacanthus makes major physiological adjustments during the dry season.•The physiological regulation modifies the amino acids profile exuded by roots.•Amino acids from cactus promote the rise in the rhizosphere microbial populations.•First description of cactus exudates recruiting beneficial microorganisms.
Despite its legislative regulation and control, the quality and safety of aquatic products is somewhat questioned due to the potential bioaccumulation of pollutants. The elements (Al, B, Ba, Ca, Cd, ...Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, Pb, Sr, V and Zn) were determined in the liver and muscle of wild and captive-reared Seriola dumerili with the aim of studying possible differences between origins, and sex-related variations. Additionally, the dietary intake of these elements derived from its consumption was also evaluated. Most of the elements and metals analyzed were accumulated to a higher extent in the liver of wild specimens whereas lower differences were observed in the muscle. Overall, the elements and metal composition of wild females strongly differed from that of captive-reared specimens probably related to the mobilization of nutrients for the spawning season in wild mature females, which were greater than their captive-reared counterparts.
•Metals were determined in tissues of wild and captive-reared Seriola dumerili.•Most of the metals were accumulated in the liver of wild specimens.•RDI of metals, the nutritional value of this species seems not to be very relevant.
Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO) synthase type III (NOS-3) overexpression induces cell death in hepatoma cells. The study developed gene therapy designed to ...specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. Hepa 1-6 cells were used for in vitro and in vivo experiments. The first generation adenovirus was designed to overexpress NOS-3 (or GFP) and luciferase cDNA under the regulation of murine alpha-fetoprotein (AFP) and Rous Sarcoma Virus (RSV) promoters, respectively. Both adenoviruses were administered through the tail vein two weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-Luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8 activity in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by l-NAME or p53 siRNA. The tail vein infusion of AFP-NOS- 3/RSV-Luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.
The recent discoveries of genomic and molecular markers in hepatocellular carcinoma (HCC) have improved the understanding about the complexity of the signal transduction pathways as well as their ...relevance in normal and liver cancer cells. The identification of the functional repercussions of punctual mutations and crosstalk among cell signaling will promote the identification of specific combinatorial targeted molecular therapies to specific subsets of patients which will allow the development of personalized-based therapy and increase the survival of patients. Numerous molecular targets are in the cross-road between oncogenic and anti-apoptotic programs, genetic or epigenetic alterations, which overall may have a similar cellular phenotype. The standard antineoplastic chemotherapeutic regimes based on cytotoxic agents leads to significant side effect and modest response rates, marginal changes in natural history, and toxicities that may impact the quality of life of patients. Different strategies involving gene therapy, targeted antibodies or small molecules have been used to regulate cell death/proliferation signals, as well as angiogenesis in liver tumors. In this sense, Sorafenib recently approved for renal cell carcinoma, represents the first tyrosine kinase inhibitor (TKI) licensed for the treatment of patients with advanced HCC. This review summarizes the current status of molecular receptor TKI-based targeted therapy in HCC driving different pathways involved in cell survival, proliferation, migration, angiogenesis and metastasis, which include the regulation of Raf/MEK/ERK, PI3K/Akt/mTOR, and Jak/STAT cell signaling. The study also provides information about cell signaling crosstalk relevant in tyrosine kinase receptors (TKR)-based systemic therapy in HCC.
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