Acute kidney injury induced by protein-overload nephropathy down-regulates gene expression of hepatic cerebroside sulfotransferase in mice, resulting in reduction of liver and serum sulfatides

Sulfatides, possible antithrombotic factors belonging to sphingoglycolipids, are widely distributed in mammalian tissues and serum. We recently found that the level of serum sulfatides was significantly lower in hemodialysis patients than that in normal subjects, and that the m serum level closely correlated to the incidence of cardiovascular disease. These findings suggest a relationship between the level of serum sulfatides and kidney function; however, the molecular mechanism underlying this relationship remains unclear. In the present study, the influence of kidney dysfunction on the metabolism of sulfatides was examined using an established murine model of acute kidney injury, protein-overload nephropathy in mice. Protein-overload treatment caused severe proximal tubular injuries within 4 days, and this treatment obviously decreased both serum and hepatic sulfatide levels. The sphingoid composition of serum sulfatides was very similar to that of hepatic ones at each time point, suggesting that the serum sulfatide level is dependent on the hepatic secretory ability of sulfatides. The treatment also decreased hepatic expression of cerebroside sulfotransferase (CST), a key enzyme in sulfatide metabolism, while it scarcely influenced the expression of the other sulfatide-metabolizing enzymes, including arylsulfatase A, ceramide galactosyltransferase, and galactosylceramidase. Pro-inflammatory responses were not detected in the liver of these mice: however, potential oxidative stress was increased. These results suggest that down-regulation of hepatic CST expression, probably affected by oxidative stress from kidney injury, causes reduction in liver and serum sulfatide levels. This novel mechanism, indicating the crosstalk between kidney injury and specific liver function, may prove useful for helping to understand the situation where human hemodialysis patients have low levels of serum sulfatides.ArticleBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. 390(4):1382-1388 (2009)journal articl

Kidney dysfunction induced by protein overload nephropathy reduces serum sulfatide levels in mice

We recently proposed serum sulfatides as a novel biomarker for cardiovascular disease in patients with end-stage renal failure (ESRF), based on the possible antithrombotic properties of this molecule. In this earlier study, the level of serum sulfatides was gradually decreased in parallel with kidney dysfunction; however the precise mechanism underlying this decrease was unknown. The aim of the present study was to investigate the mechanism underlying the decrease in serum sulfatide levels caused by kidney dysfunction in an experimental animal model. To produce a kidney dysfunction animal model, we prepared a mouse model of protein overload nephropathy. Using high-throughput analysis combined with matrix-assisted laser desorption ionisation time-of-flight mass spectrometry, we measured the levels of sulfatides in the sera, livers, small intestines and kidneys of protein overload nephropathy mice. As the disease progressed, the levels of sulfatides in sera decreased. Also, the levels in livers and small intestines decreased in a similar manner to those in sera, to approximately 60% of the original levels. On the contrary, those in kidneys increased by approximately 1.4-fold. Our results indicate that kidney dysfunction affects the levels of sulfatides in lipoprotein-producing organs, such as livers and small intestines, and lowers the levels of sulfatides in sera.ArticleNEPHROLOGY. 14(7):658-662 (2009)journal articl

Multiple roles of PPAR alpha in brown adipose tissue under constitutive and cold conditions

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a member of the nuclear receptor family, regulating fatty acid degradation in many organs. Two-dimensional SDS-PAGE of brown adipose tissue (BAT) from PPAR alpha-null mice produced a higher-density spot. Proteomic analysis indicated that the protein was pyruvate dehydrogenase beta (PDH beta). To observe PDH beta regulation in BAT, the organ was stimulated by long-term cold exposure, and the activities of associated enzymes were investigated. Histological and biochemical analyses of BAT showed a significant decrease in the triglyceride content in wild-type mice and some degree of decrease in PPAR alpha-null mice on cold exposure. Analyses of molecules related to glucose metabolism showed that the expression of PDH beta is under PPAR alpha-specific regulation, and that glucose degradation ability may decrease on cold exposure. In contrast, analyses of molecules related to fatty acid metabolism showed that numerous PPAR alpha/gamma target molecules are induced on cold exposure, and that fatty acid degradation ability in wild-type mice is markedly enhanced and also increases to same degree in PPAR alpha-null mice on cold exposure. Thus, this study proposes novel and multiple roles of PPAR alpha in BAT.ArticleGENES TO CELLS. 15(2):91-100 (2010)journal articl

Proton spectra from Non-Mesonic Weak Decay of p-shell Lambda-Hypernuclei and evidence for the two-nucleon induced process

New spectra from the FINUDA experiment of the Non Mesonic Weak Decay (NMWD) proton kinetic energy for 9(Lambda)Be, 11(Lambda)B, 12(Lambda)C, 13(Lambda)C, 15 (Lambda)N and 16(Lambda)O are presented and discussed along with the published data on 5(Lambda)He and 7(Lambda)Li. Exploiting the large mass number range and the low energy threshold (15 MeV) for the proton detection of FINUDA, an evaluation of both Final State Interactions (FSI) and the two nucleon induced NMWD contributions to the decay process has been done. Based on this evaluation, a linear dependence of FSI on the hypernuclear mass number A is found and for the two nucleon stimulated decay rate the experimental value of Gamma2/Gammap=0.43+-0.25 is determined for the first time. A value for the two nucleon stimulated decay rate to the total decay rate Gamma2/GammaNMWD=0.24+-0.10 is also extracted.Comment: 11 pages and 2 figure

SPELLing out energy leaks: Aiding developers locate energy inefficient code

Although hardware is generally seen as the main culprit for a computer's energy usage, software too has a tremendous impact on the energy spent. Unfortunately, there is still not enough support for software developers so they can make their code more energy-aware.This paper proposes a technique to detect energy inefficient fragments in the source code of a software system. Test cases are executed to obtain energy consumption measurements, and a statistical method, based on spectrum-based fault localization, is introduced to relate energy consumption to the source code. The result of our technique is an energy ranking of source code fragments pointing developers to possible energy leaks in their code. This technique was implemented in the SPELL toolkit.Finally, in order to evaluate our technique, we conducted an empirical study where we asked participants to optimize the energy efficiency of a software system using our tool, while also having two other groups using no tool assistance and a profiler, respectively. We showed statistical evidence that developers using our technique were able to improve the energy efficiency by 43% on average, and even out performing a profiler for energy optimization. (C) 2019 Elsevier Inc. All rights reserved.This work is funded by the ERDF -European Regional Development Fund through the Operational Programme for Competitiveness and Internationalization -COMPETE 2020 Programme within project POCI-01-0145-FEDER-006961, and by National Funds through the Portuguese funding agency, FCT -Fundacao para a Ciencia e a Tecnologia within project POCI010145FEDER016718, UID/EEA/50014/2013, and by FCT grant SFRH/BD/132485/2017. This work is also supported by operation Centro010145FEDER000019 -C4 -Centro de Competencias em Cloud Computing, cofinanced by the European Regional Development Fund (ERDF) through the Programa Operacional Regional do Centro (Centro 2020), in the scope of the Sistema de Apoio a Investigacao Cientifica e Tecnologica -Programas Integrados de IC&DT, and the first author was financed by post-doc grant referencia C4_SMDS_L1-1_D

Down-Regulation of Telomerase Activity and Activation of Caspase-3 Are Responsible for Tanshinone I-Induced Apoptosis in Monocyte Leukemia Cells in Vitro

Tanshinone I (Tan-I) is a diterpene quinone extracted from the traditional herbal medicine Salvia miltiorrhiza Bunge. Recently, Tan-I has been reported to have anti-tumor effects. In this study, we investigated the growth inhibition and apoptosis inducing effects of Tan-I on three kinds of monocytic leukemia cells (U937, THP-1 and SHI 1). Cell viability was measured by MTT assay. Cell apoptosis was assessed by flow cytometry (FCM) and AnnexinV/PI staining. Reverse transcriptase polymerase chain reaction (RT-PCR) and PCR–enzyme-linked immunosorbent assay (ELISA) were used to detect human telomerase reverse transcriptase (hTERT) expression and telomerase activity before and after apoptosis. The activity of caspase-3 was determined by Caspase colorimetric assay kit and Western blot analysis. Expression of the anti-apoptotic gene Survivin was assayed by Western blot and Real-time RT-PCR using the ABI PRISM 7500 Sequence Detection System. The results revealed that Tan-I could inhibit the growth of these three kinds of leukemia cells and cause apoptosis in a time- and dose-dependent manner. After treatment by Tan-I for 48 h, Western blotting showed cleavage of the caspase-3 zymogen protein with the appearance of its 17-kD subunit, and a 89-kD cleavage product of poly (ADP-ribose) polymerase (PARP), a known substrate of caspase-3, was also found clearly. The expression of hTERT mRNA as well as activity of telomerase were decreased concurrently in a dose-dependent manner. Moreover, Real-time RT-PCR and Western blot revealed a significant down-regulation of Survivin. We therefore conclude that the induction of apoptosis by Tan-I in monocytic leukemia U937 THP-1 and SHI 1 cells is highly correlated with activation of caspase-3 and decreasing of hTERT mRNA expression and telomerase activity as well as down-regulation of Survivin expression. To our knowledge, this is the first report about the effects of Tan-I on monocytic leukemia cells

Resveratrol Inhibits Inflammatory Responses via the Mammalian Target of Rapamycin Signaling Pathway in Cultured LPS-Stimulated Microglial Cells

Resveratrol have been known to possess many pharmacological properties including antioxidant, cardioprotective and anticancer effects. Although current studies indicate that resveratrol produces neuroprotection against neurological disorders, the precise mechanisms for its beneficial effects are still not fully understood. We investigate the effect of anti-inflammatory and mechamisms of resveratrol by using lipopolysaccharide (LPS)-stimulated murine microglial BV-2 cells.BV-2 cells were treated with resveratrol (25, 50, and 100 µM) and/or LPS (1 µg/ml). Nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by Griess reagent and ELISA. The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by RT-PCR and double immunofluorescence labeling, respectively. Phosphorylation levels of PTEN (phosphatase and tensin homolog deleted on chromosome 10), Akt, mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) cascades, inhibitor κB-α (IκB-α) and cyclic AMP-responsive element-binding protein (CREB) were measured by western blot. Resveratrol significantly attenuated the LPS-induced expression of NO, PGE2, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nuclear factor-κB (NF-κB) in BV-2 cells. Resveratrol increased PTEN, Akt and mTOR phosphorylation in a dose-dependent manner or a time-dependent manner. Rapamycin (10 nM), a specific mTOR inhibitor, blocked the effects of resveratrol on LPS-induced microglial activation. In addition, mTOR inhibition partially abolished the inhibitory effect of resveratrol on the phosphorylation of IκB-α, CREB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK).This study indicates that resveratrol inhibited LPS-induced proinflammatory enzymes and proinflammatory cytokines via down-regulation phosphorylation of NF-κB, CREB and MAPKs family in a mTOR-dependent manner. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of resveratrol

New results on mesonic weak decay of p-shell Λ-hypernuclei

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Correlated Λt\Lambda t pairs from the absorption of K−K^- at rest in light nuclei

Novel data from the $K^{-}_{stop}A$ absorption reaction in light nuclei $^{6,7}$Li and $^{9}$Be are presented. The study aimed at finding $\Lambda t$ correlations. Regardless of $A$, the $\Lambda t$ pairs are preferentially emitted in opposite directions. Reaction modeling predominantly assigns to the $K^-_{stop}A\to\Lambda t(N)A'$ direct reactions the emission of the $\Lambda t$ pairs whose yield is found to range from $10^{-3}$ to $10^{-4}$$/K^-_{stop}$. The experiment was performed with the FINUDA spectrometer at DA$\Phi$NE (LNF).Comment: 11 pages, 5 figures, accepted for publication in Phys. Lett.