The free radical theory of aging suggests reactive oxygen species as a main reason for accumulation of damage events eventually leading to aging. Nox4, a member of the family of NADPH oxidases ...constitutively produces ROS and therefore has the potential to be a main driver of aging. Herein we analyzed the life span of Nox4 deficient mice and found no difference when compared to their wildtype littermates. Accordingly neither Tert expression nor telomere length was different in cells isolated from those animals. In fact, Nox4 mRNA expression in lungs of wildtype mice dropped with age. We conclude that Nox4 has no influence on lifespan of healthy mice.
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•Nox4 is downregulated in murine lungs with increasing age.•Nox4 knock out does not influence total life span in mice.•Nox4 neither affects telomere length nor Tert expression.
Exercise training induces muscular adaptations that are highly specific to the type of exercise. For a systematic study of the differentiated exercise adaptations on a molecular level mouse models ...have been used successfully. The aim of the current study was to develop a suitable mouse model of isometric strength exercise training characterized by specific adaptations known from strength training. C57BL/6 mice performed an isometric strength training (ST) for 10 weeks 5 days/week. Additionally, either a sedentary control group (CT) or a regular endurance training group (ET) groups were used as controls. Performance capacity was determined by maximum holding time (MHT) and treadmill spirometry, respectively. Furthermore, muscle fiber types and diameter, muscular concentration of phosphofructokinase 1 (PFK), succinate dehydrogenase (SDHa), and glucose transporter type 4 (GLUT4) were determined. In a further approach, the effect of ST on glucose intolerance was tested in diabetic mice. In mice of the ST group we observed an increase of MHT in isometric strength tests, a type II fiber hypertrophy, and an increased GLUT4 protein content in the membrane fraction. In contrast, in mice of the ET group an increase of VO(2max), a shift to oxidative muscle fiber type and an increase of oxidative enzyme content was measured. Furthermore strength training was effective in reducing glucose intolerance in mice fed a high fat diet. An effective murine strength training model was developed and evaluated, which revealed marked differences in adaptations known from endurance training. This approach seems also suitable to test for therapeutical effects of strength training.
Tracking of single particles accelerated by synchrotrons is a subject that crosses several physics fields. The high clinical intensities used in particle therapy that can exceed 109 p/s make this ...task very challenging. The tracking of the arrival time of single particles in the ion beam is fundamental for the verification of the particle range and dose delivered to the patient. We present a prototype made of scintillating fibers which has been used to provide time-of-flight (TOF) information for three beam species currently accelerated at the Heidelberg Ion-Beam Therapy Center (HIT). We have demonstrated a time-tracker for a prompt-gamma spectroscopy system that allows for a background TOF rejection with a sub-nanosecond time resolution.
The study aimed to investigate the effects of differentiated exercise regimes on high fat-induced metabolic and inflammatory pathways. Mice were fed a standard diet (ST) or a high fat diet (HFD) and ...subjected to regular endurance training (ET) or resistance training (RT). After 10 weeks body weight, glucose tolerance, fatty acids (FAs), circulating ceramides, cytokines, and immunological mediators were determined. The HFD induced a significant increase in body weight and a disturbed glucose tolerance (p<0.05). An increase of plasma FA, ceramides, and inflammatory mediators in adipose tissue and serum was found (p<0.05). Both endurance and resistance training decreased body weight (p<0.05) and reduced serum ceramides (p<0.005). While RT attenuated the increase of NLRP-3 (RT) expression in adipose tissue, ET was effective in reducing TNF-α and IL-18 expression. Furthermore, ET reduced levels of MIP-1γ, while RT decreased levels of IL-18, MIP-1γ, Timp-1, and CD40 in serum (p<0.001), respectively. Although both exercise regimes improved glucose tolerance (p<0.001), ET was more effective than RT. These results suggest that exercise improves HFD-induced complications possibly through a reduction of ceramides, the reduction of inflammasome activation in adipose tissues, and a systemic downregulation of inflammatory cytokines.
Laser–plasma proton sources and their applications to preclinical research has become a very active field of research in recent years. In addition to their small dimensions as compared to classical ...ion accelerators, they offer the possibility to study the biological effects of ultra-short particle bunches and the correspondingly high dose rates. We report on the design of an experimental setup for the irradiation of cell cultures at the L2A2 laboratory at the University of Santiago de Compostela, making use of a 1.2 J Ti: Sapphire laser with a 10 Hz repetition rate. Our setup comprises a proton energy separator consisting of two antiparallel magnetic fields realized by a set of permanent magnets. It allows for selecting a narrow energy window around an adaptable design value of 5 MeV out of the initially broad spectrum typical for Target Normal Sheath Acceleration (TNSA). At the same time, unwanted electrons and X-rays are segregated from the protons. This part of the setup is located inside the target vessel of the L2A2 laser. A subsequent vacuum flange sealed with a thin kapton window allows for particle passage to external sample irradiation. A combination of passive detector materials and real-time monitors is applied for measurement of the deposited radiation dose. A critical point of this interdisciplinary project is the manipulation of biological samples under well-controlled, sterile conditions. Cell cultures are prepared in sealed flasks with an ultra-thin entrance window and analysed at the nearby Fundación Pública Galega Medicina Xenómica and IDIS. The first trials will be centred at the quantification of DNA double-strand breaks as a function of radiation dose.
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that ...are believed to induce reactive oxygen species (ROS) that gradually disrupt signalling pathways responsible for maintaining lung integrity. Here we identify the antioxidant protein sestrin-2 (SESN2) as a repressor of PDGFRβ signalling, and PDGFRβ signalling as an upstream regulator of alveolar maintenance programmes. In mice, the mutational inactivation of Sesn2 prevents the development of cigarette-smoke-induced pulmonary emphysema by upregulating PDGFRβ expression via a selective accumulation of intracellular superoxide anions (O2(-)). We also show that SESN2 is overexpressed and PDGFRβ downregulated in the emphysematous lungs of individuals with COPD and to a lesser extent in human lungs of habitual smokers without COPD, implicating a negative SESN2-PDGFRβ interrelationship in the pathogenesis of COPD. Taken together, our results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD.
Abstract With effective antiretroviral therapy (ART), many HIV-infected people die of diseases other than acquired immune deficiency syndrome (AIDS). In particular, coronary artery disease has ...emerged as one of most critical complications of HIV infection and a major cause of morbidity and mortality. Although reportedly antiretroviral combination therapy itself may accelerate atherosclerosis by enhancing dyslipidemia, most recent epidemiological studies support the notion that HIV infection itself contributes to cardiovascular disease. However, it is still a mystery how the virus can contribute to cardiovascular disease development even while suppressed by ARTs. This review discusses the current understanding of interactions between HIV infection and cardiovascular diseases in both clinical and experimental studies with special focus on those viral proteins that are still produced by HIV. This will help infectious disease/vascular biology experts to gain insights into the pathophysiological mechanisms of HIV-associated cardiovascular disease and new trends to treat and prevent cardiovascular disease in the HIV-infected population.
Long-term cigarette smoking induces inflammatory processes in the pulmonary system that are suggested to "spill over" into systemic inflammation. Regular exercise has been shown to have ...anti-inflammatory properties. The aim of the study was to investigate the effects of therapeutic exercise on inflammation and muscle wasting in smoke-exposed mice. C57BL/6J mice ( n = 30) were separated into three groups to receive either 1) no specific treatment (control group), 2) 8-mo exposure to cigarette smoke smoke-exposed (SE) group, or 3) 8 mo of cigarette smoke combined with exercise training during the last 2 mo (SEex group). The inflammatory status was analyzed by quantifying levels of various plasma proteins using multiplex ELISA and detection of lymphocyte surface markers by flow cytometry. Muscle tissue was analyzed by histological techniques and measurements of RNA/protein expression. SE led to decreased maximal O
uptake (V̇o
) and maximal running speed ( V
), which was reversed by exercise ( P < 0.05). Expression of ICAM-1, VCAM-1, and CD62L on T cells increased and was reversed by exercise ( P < 0.05). Similarly, SE induced an increase of various inflammatory cytokines, which were downregulated by exercise. In muscle, exercise improved the structure, oxidative capacity, and metabolism by reducing ubiquitin proteasome system activation, stimulating insulin-like growth factor 1 expression, and the SE-induced inhibition of mammalian target of rapamycin signaling pathway ( P < 0.05). Exercise training reverses smoke-induced decline in exercise capacity, systemic inflammation, and muscle wasting by addressing immune-regulating, anabolic, and metabolic pathways.
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