ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy Jose Manuel Rodriguez-Vargas Maria Jose Ruiz-Magana Carmen Ruiz-Ruiz Jara Majuelos-Melguizo Andreina Peralta-Lea Maria Isabel Rodriguez Jose Antonio Munoz-Gaimez Mariano Ruiz de Almodovar Eva Siles Abelardo Lopez Rivas Marja Jaattela F Javier Oliver
Cell research,
07/2012, Letnik:
22, Številka:
7
Journal Article
Recenzirano
Odprti dostop
In response to nutrient stress, cells start an autophagy program that can lead to adaptation or death. The mechanisms underlying the signaling from starvation to the initiation of autophagy are not ...fully understood. In the current study we show that the absence or inactivation of PARP-1 strongly delays starvation-induced autophagy. We have found that DNA damage is an early event of starvation-induced autophagy as measured by y-H2AX accumulation and comet assay, with PARP-1 knockout cells displaying a reduction in both parameters. During starvation, ROS- induced DNA damage activates PARP-1, leading to ATP depletion （an early event after nutrient deprivation）. The absence of PARP-1 blunted AMPK activation and prevented the complete loss of mTOR activity, leading to a delay in autophagy. PARP-1 depletion favors apoptosis in starved cells, suggesting a pro-survival role of autophagy and PARP-1 activation after nutrient deprivation. In vivo results show that neonates of PARP-1 mutant mice subjected to acute starvation, also display deficient liver autophagy, implying a physiological role for PARP-1 in starvation-in- duced autophagy. Thus, the PARP signaling pathway is a key regulator of the initial steps of autophagy commitment following starvation.
Background
Several lines of evidence indicate that decompensated cirrhosis is characterized by the presence of systemic inflammation. Hepatorenal syndrome (HRS‐AKI) is a unique type of renal failure ...that occurs at late stages of cirrhosis. However, confirmation of the presence and significance of such inflammatory response in HRS‐AKI is lacking.
Aim and Methods
To characterize the systemic inflammatory response, as estimated by measuring a large number of cytokines, in 161 patients hospitalized for an acute decompensation of cirrhosis: 44 patients without acute kidney injury (AKI), 63 patients with hypovolaemia‐induced AKI and 58 patients with HRS‐AKI.
Results
HRS‐AKI was characterized by an altered cytokine profile compared to the other two groups, particularly IL‐6, IL‐8, TNF‐α, VCAM‐1, fractalkine and MIP‐1α. The inflammatory response was not related to presence of bacterial infection, concomitant acute‐on‐chronic liver failure or severity of renal dysfunction. Patients who responded to terlipressin and albumin had only a decrease in TNF‐α and RANTES after treatment without changes in other cytokines. Interestingly, patients with persistent HRS‐AKI had higher levels of IP‐10 and VCAM‐1 compared to those with resolution of HRS‐AKI. VCAM‐1 was also an independent predictor of 3‐month mortality. A systems biology analysis approach showed that the inflammatory status of HRS‐AKI was similar to that of chronic nonhepatic inflammatory conditions, such as lupus erythematosus or inflammatory bowel disease.
Conclusion
Hepatorenal syndrome is characterized by a marked systemic inflammatory state, reminiscent of that of nonhepatic inflammatory diseases, that correlates with patient outcomes.
See Editorial on Page 1199
The settlement of cold and arid environments by Pleistocene hunter-gatherers has been a heated topic in Paleolithic Archaeology and the Quaternary Sciences for years. In the Iberian Peninsula, a key ...area for studying human adaptations to such environments is composed by the large interior and upland regions of the northern and southern plateaus (Mesetas) and bordering areas. As, traditionally, these regions have been relatively under-investigated compared to the ecologically more favored coastal areas of the peninsula, our knowledge of the human settlement of the whole Iberian hinterland remains scarce for the Last Glacial. In this paper we present the discovery and first geoarcheological, paleoenvironmental and chronometric evidence obtained at Charco Verde II, a new site close to the southwestern foothills of the Iberian system range (Guadalajara province, Spain), bearing a sequence of Magdalenian human occupations starting at least at 20.8-21.4 ka cal BP during the Last Glacial Maximum, and covering Greenland Stadial 2 until ~15.1-16.6 ka cal BP, including Heinrich stadial 1. As this site is located in an upland region which today faces one of the harshest climates in Iberia, such occupation sequence, occurred during some of the coldest and most arid phases of the Last Glacial, has relevant implications for our understanding of human-environment-climate interactions and population dynamics in Iberia and Western Europe. These findings support the hypothesis that the Iberian hinterland was not avoided by Upper Paleolithic hunter-gatherers due to ecological constraints, but it hosted a complex and relatively dense settlement at least in some areas, even during cold periods. This suggest, one more time, that the historical scarcity of Upper Paleolithic sites in inland Iberia is, to a significant extent, an artifact of research bias.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
The objective of this study is to describe and understand the experiences of sexuality amongst heterosexual women with morbid obesity (MO) who are in a bariatric surgery program.
Background
...Morbid obesity is a chronic, metabolic disease that affects women's physical, psychological and sexual health. MO is associated with anxiety, depression and body image disorders. Bariatric surgery is a reliable method for weight loss in people with MO.
Design
A qualitative descriptive study research design was adopted.
Methods
Twenty‐one heterosexual women with MO in a bariatric surgery program were recruited through purposive sampling. Data collection included individual semi‐structured interviews conducted between November 2018 and May 2019. Interviews were audio recorded, transcribed verbatim and analysed using a computer‐assisted qualitative data.
Findings
Three main themes emerged from the analysis: (1) trapped in a body that limits my sexuality; (2) between neglect and hope and (3) the partner as a source of support for sexuality in women with MO.
Conclusion
Women hide a body that they do not accept and ignore their own sexuality, focusing on that of their partner. Although the women have doubts about their partners’ desire for them, they share the decision‐making process with them whilst waiting for bariatric surgery, on which they place all of their hopes for improved sexuality and quality of life.
Impact
The findings highlight the importance of exploring the experiences and sexual issues faced by heterosexual women with MO in a bariatric surgery program. Bariatric nurses have a privileged position to assess these women's sexuality, recommend alternatives to sexual intercourse or refer them to sexologists. As part of the multidisciplinary team, nurses can contribute to managing the expectations of women with MO and their partners in relation to the improvement of their sex lives following bariatric surgery.
The present study aimed to assess energy intake, nutrient profile and food sources in Spanish children participating in the EsNuPI ("Estudio Nutricional en Población Infantil Española") study. ...Plausibility of energy intake and adequacy of nutrient intakes to international recommendations were analyzed in a final sample of 1448 subjects (728 boys and 720 girls) and one group representative of the 1 to <10 years old urban Spanish children (reference sample (
= 707)) who consumed milk and one of the same age who consumed adapted milk over the last year (adapted milk consumers sample (
= 741)) were compared. Both groups completed data of a face-to-face and a telephone 24-h dietary recalls. Both the reference and the adapted milk consumers samples reported an adequate daily energy intake (1503 kcal/day and 1404 kcal/day); and a high contribution to total energy from protein (16.5% and 15.6%) and fat (36.5% and 35.9%). Also, a high percentage of children from both samples were below the lower limit of the recommendations for carbohydrates (47.8% and 39.3%). As the percentage of plausible energy reporters was high for both groups (84.7% and 83.5%, respectively), data for the whole sample were analyzed. Milk and dairy, cereals, meat and derived products, fats and oils, bakery and pastry, fruits and vegetables contributed to about 80% of the total energy intake in both groups. However, the reference sample reported significantly more contribution to energy from cereals, meat and meat products, bakery and pastry and ready to cook/eat foods; meanwhile, the adapted milk consumers sample reported significantly more energy from milk and dairy products, fruits and eggs. Those results suggest that adapted milk consumers have better adherence to the food-based dietary guidelines. Further analyses are warranted to characterize food patterns and the quality of the diet in the EsNuPI study population.
In recent years the emergence and resurgence of arboviruses have generated a global health alert. Among arboviruses, Dengue (DENV), Zika (ZIKV), Yellow Fever (YFV), and West Nile (WNV) virus, belong ...to the genus
, cause high viremia and occasionally fatal clinical disease in humans. Given the genetic austerity of the virus, they depend on cellular factors and organelles to complete its replication. One of the cellular components required for flavivirus infection is cholesterol. Cholesterol is an abundant lipid in biomembranes of eukaryotes cells and is necessary to maintain the cellular homeostasis. Recently, it has been reported, that cholesterol is fundamental during flavivirus infection in both mammal and insect vector models. During infection with DENV, ZIKV, YFV, and WNV the modulation of levels of host-cholesterol facilitates viral entry, replicative complexes formation, assembly, egress, and control of the interferon type I response. This modulation involves changes in cholesterol uptake with the concomitant regulation of cholesterol receptors as well as changes in cholesterol synthesis related to important modifications in cellular metabolism pathways. In view of the flavivirus dependence of cholesterol and the lack of an effective anti-flaviviral treatment, this cellular lipid has been proposed as a therapeutic target to treat infection using FDA-approved cholesterol-lowering drugs. This review aims to address the dependence of cholesterol by flaviviruses as well as the basis for anti flaviviral therapy using drugs which target is cholesterol synthesis or uptake.
The pharmacological activity of organotin(IV) complexes in cancer therapy is well recognized but their large applicability is hampered by their poor water solubility. Hence, carbon dots, in ...particular nitrogen-doped graphene quantum dots (NGQDs), may be a promising alternative for the efficient delivery of organotin(IV) compounds as they have a substantial aqueous solubility, a good chemical stability, and non-toxicity as well as a bright photoluminescence that make them ideal for theranostic applications against cancer. Two different multifunctional nanosystems have been synthesized and fully characterized based on two fragments of organotin-based cytotoxic compounds and 4-formylbenzoic acid (FBA), covalently grafted onto the NGQDs surface. Subsequently, an in vitro determination of the therapeutic and theranostic potential of the achieved multifunctional systems was carried out. The results showed a high cytotoxic potential of the NGQDs-FBA-Sn materials against breast cancer cell line (MDA-MB-231) and a lower effect on a non-cancer cell line (kidney cells, HEK293T). Besides, thanks to their optical properties, the dots enabled their fluorescence molecular imaging in the cytoplasmatic region of the cells pointing towards a successful cellular uptake and a release of the metallodrug inside cancer cells (NGQDs-FBA-Sn).
The design of the mode of operation of heating, ventilation and air-conditioning systems in office buildings has become increasingly important in recent years. This is due mainly to their ...relationship, both with the comfort of their occupants and with energy efficiency. The adaptive thermal comfort theory addresses this problem by linking the indoor comfort temperature with the outside temperature. This idea represents a relaxation in the presence of strict set-point temperatures. This results in a greater tolerance of the indoor environment and thus, in a wider range of acceptability on the part of the occupants of the buildings. Nonetheless, and although previous studies have been carried out on naturally ventilated buildings, there are no standards or application guides for hybrid buildings. This study shows the applicability of the adaptive model to hybrid buildings. An adaptive model for hybrid buildings is proposed, valid for both the free-running and air-conditioned modes, based on a field study carried out in the southwestern region of Spain. A total of 4.243 responses in mixed mode buildings and a total of 891 in air-conditioned building were collected over the period of a year. The comfort temperature in hybrid buildings was observed at an average operative temperature of 23.6 °C. The results show the energy-saving potential of hybrid buildings, without foregoing the comfort of their occupants, and show that it would be possible to implement a law that optimizes the operation of conditioning systems and which would undoubtedly lead to greater energy efficiency in such buildings.
•An automatized field study has been carried out in MM and AC buildings in Spain.•Spanish occupants of MM offices are more adaptive than those in AC offices.•A single adaptive model is proposed, both for NV and AC modes of operation.•Comfort temperatures in mild climate were lower than international guidelines.
Coronavirus disease 2019 (COVID‐19) can lead to a massive cytokine release. The use of the anti‐interleukin‐6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this ...hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID‐19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6‐point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6‐point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon‐β (adjusted odds ratio aOR: 0.23; 95% confidence interval CI: 0.06‐0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06‐0.99; P = .048) were negatively associated with clinical improvement by day 7. All‐cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C‐reactive protein levels dropped by day 2. There were no TCZ‐attributable adverse events. In this observational single‐center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID‐19 pneumonia.
Highlights
COVID‐19 can lead to a hyperinflammatory state that mirrors the cytokine release syndrome.
The off‐labeluse of the anti‐interleukin‐6 receptor monoclonal antibody tocilizumab has been proposed to abrogate this deleterious inflammatory response, although the supporting evidence is scarce.
In the present single‐centre study comprising 88 consecutive patients with COVID‐19 pneumonia that received at least one dose of intravenous tocilizumab between March 16 and 27, 2020, the rates of clinical improvement (defined by discharge to home and/or a decrease of = 2 points on a six‐point ordinal scale) were 44.3% (39/88) and 73.9% (65/88) by days 7 and 14, respectively.
The previous or concomitant use of interferon‐β and baseline serum lactate dehydrogenase levels >450 U/L were negatively associated with clinical improvement by day 7. All‐cause mortality was 6.8%, with no tocilizumab‐attributable adverse events.
This novel neurocognitive intervention significantly improved occupational and interpersonal functioning in patients with bipolar I and II disorder
ObjectiveThe authors sought to assess the efficacy ...of functional remediation, a novel intervention program, on functional improvement in a sample of euthymic patients with bipolar disorder.MethodIn a multicenter, randomized, rater-blind clinical trial involving 239 outpatients with DSM-IV bipolar disorder, functional remediation (N=77) was compared with psychoeducation (N=82) and treatment as usual (N=80) over 21 weeks. Pharmacological treatment was kept stable in all three groups. The primary outcome measure was improvement in global psychosocial functioning, measured blindly as the mean change in score on the Functioning Assessment Short Test from baseline to endpoint.ResultsAt the end of the study, 183 patients completed the treatment phase. Repeated-measures analysis revealed significant functional improvement from baseline to endpoint over the 21 weeks of treatment (last observation carried forward), suggesting an interaction between treatment assignment and time. Tukey’s post hoc tests revealed that functional remediation differed significantly from treatment as usual, but not from psychoeducation.ConclusionsFunctional remediation, a novel group intervention, showed efficacy in improving the functional outcome of a sample of euthymic bipolar patients as compared with treatment as usual.
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